Dr. Stefan Müllner - BioTech Pharma Summit...2020/07/06 · Psoriatic Arthritis (MEASE 2004,...
Transcript of Dr. Stefan Müllner - BioTech Pharma Summit...2020/07/06 · Psoriatic Arthritis (MEASE 2004,...
Dr Stefan MuumlllnerPorto October 26 2017
Options for Biomarker based Patient Stratification
in NON-ONCOLOGY Clinical Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Pharma
Dr S Muumlllner Porto 26102017 wwwfundamentade
3
What if the FDA decides tomorrow that all new drug
approvals require Companion Diagnostics (CDx)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Response Rate of Standard TherapiesDisease
Average of
non-
Responders
Author Citation
Rheumatoid Arthritis (ACR20) 28 - 58 Craig Beavers et alOrthopedics
January 2010 - Volume 33 middot Issue 1
Ankylosing spondylitis (ASAS
20)40 C McLeod et al Health Technol Assess 2007111ndash158
Psoriatic Arthritis (MEASE
2004 24weeks PsARC and
ARC50)
30 - 63 M Rodgers et All Health Technology Assessment 2011 Vol 15 No 10 p19
SLE (EULAR 2009) 45 Merrill EULAR 2009 Benlysta BLISS 52 and 76
Lupus Nephritis 44 - 47 G Apple JAm Soc Nephrol 2009 Cellcept vs Cyclophosphamide
Multiple Sclerosis 50Communication of DMSG on
Fingolimod
httpwwwdmsgdemultiple-sklerose-
newsindexphpw3pid=newsampkategorie=therapienampanr=
2310
Crohns Disease - Primary non
responders to anti TNF-alpha30 - 40 Remo Panaccione MD FRCPC
Advanced Therapy of Inflammatory Bowel Disease
Volume 2 IBD and Crohns von Theodore
BaylessStephen B Hanauer
Crohns Disease - Secondary
non responders to anti TNF-
alpha
30 - 40 Remo Panaccione MD FRCPC httpwwwmedscapeorgviewarticle578444_3
Ulcerative Colitis 41 - 50 Walter Reinisch et al Gut 201160780e787 Results of NCT00385736
Epilepsy (Lacosamide) 59 - 67 E Ben-Menachem Epilepsia 2007 48 (7) 1308-17
Epilepsy (Zonisamide) 50 MJ Brodie Epilepsia 2005 46(1)31-41
Parkinsons Disease
(Rotigotine)52 RL Watts et al Neurology 200768(4)272
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Pharmaceutical Industry needs to
change
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Pharma
Dr S Muumlllner Porto 26102017 wwwfundamentade
3
What if the FDA decides tomorrow that all new drug
approvals require Companion Diagnostics (CDx)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Response Rate of Standard TherapiesDisease
Average of
non-
Responders
Author Citation
Rheumatoid Arthritis (ACR20) 28 - 58 Craig Beavers et alOrthopedics
January 2010 - Volume 33 middot Issue 1
Ankylosing spondylitis (ASAS
20)40 C McLeod et al Health Technol Assess 2007111ndash158
Psoriatic Arthritis (MEASE
2004 24weeks PsARC and
ARC50)
30 - 63 M Rodgers et All Health Technology Assessment 2011 Vol 15 No 10 p19
SLE (EULAR 2009) 45 Merrill EULAR 2009 Benlysta BLISS 52 and 76
Lupus Nephritis 44 - 47 G Apple JAm Soc Nephrol 2009 Cellcept vs Cyclophosphamide
Multiple Sclerosis 50Communication of DMSG on
Fingolimod
httpwwwdmsgdemultiple-sklerose-
newsindexphpw3pid=newsampkategorie=therapienampanr=
2310
Crohns Disease - Primary non
responders to anti TNF-alpha30 - 40 Remo Panaccione MD FRCPC
Advanced Therapy of Inflammatory Bowel Disease
Volume 2 IBD and Crohns von Theodore
BaylessStephen B Hanauer
Crohns Disease - Secondary
non responders to anti TNF-
alpha
30 - 40 Remo Panaccione MD FRCPC httpwwwmedscapeorgviewarticle578444_3
Ulcerative Colitis 41 - 50 Walter Reinisch et al Gut 201160780e787 Results of NCT00385736
Epilepsy (Lacosamide) 59 - 67 E Ben-Menachem Epilepsia 2007 48 (7) 1308-17
Epilepsy (Zonisamide) 50 MJ Brodie Epilepsia 2005 46(1)31-41
Parkinsons Disease
(Rotigotine)52 RL Watts et al Neurology 200768(4)272
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Pharmaceutical Industry needs to
change
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
3
What if the FDA decides tomorrow that all new drug
approvals require Companion Diagnostics (CDx)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Response Rate of Standard TherapiesDisease
Average of
non-
Responders
Author Citation
Rheumatoid Arthritis (ACR20) 28 - 58 Craig Beavers et alOrthopedics
January 2010 - Volume 33 middot Issue 1
Ankylosing spondylitis (ASAS
20)40 C McLeod et al Health Technol Assess 2007111ndash158
Psoriatic Arthritis (MEASE
2004 24weeks PsARC and
ARC50)
30 - 63 M Rodgers et All Health Technology Assessment 2011 Vol 15 No 10 p19
SLE (EULAR 2009) 45 Merrill EULAR 2009 Benlysta BLISS 52 and 76
Lupus Nephritis 44 - 47 G Apple JAm Soc Nephrol 2009 Cellcept vs Cyclophosphamide
Multiple Sclerosis 50Communication of DMSG on
Fingolimod
httpwwwdmsgdemultiple-sklerose-
newsindexphpw3pid=newsampkategorie=therapienampanr=
2310
Crohns Disease - Primary non
responders to anti TNF-alpha30 - 40 Remo Panaccione MD FRCPC
Advanced Therapy of Inflammatory Bowel Disease
Volume 2 IBD and Crohns von Theodore
BaylessStephen B Hanauer
Crohns Disease - Secondary
non responders to anti TNF-
alpha
30 - 40 Remo Panaccione MD FRCPC httpwwwmedscapeorgviewarticle578444_3
Ulcerative Colitis 41 - 50 Walter Reinisch et al Gut 201160780e787 Results of NCT00385736
Epilepsy (Lacosamide) 59 - 67 E Ben-Menachem Epilepsia 2007 48 (7) 1308-17
Epilepsy (Zonisamide) 50 MJ Brodie Epilepsia 2005 46(1)31-41
Parkinsons Disease
(Rotigotine)52 RL Watts et al Neurology 200768(4)272
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Pharmaceutical Industry needs to
change
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Response Rate of Standard TherapiesDisease
Average of
non-
Responders
Author Citation
Rheumatoid Arthritis (ACR20) 28 - 58 Craig Beavers et alOrthopedics
January 2010 - Volume 33 middot Issue 1
Ankylosing spondylitis (ASAS
20)40 C McLeod et al Health Technol Assess 2007111ndash158
Psoriatic Arthritis (MEASE
2004 24weeks PsARC and
ARC50)
30 - 63 M Rodgers et All Health Technology Assessment 2011 Vol 15 No 10 p19
SLE (EULAR 2009) 45 Merrill EULAR 2009 Benlysta BLISS 52 and 76
Lupus Nephritis 44 - 47 G Apple JAm Soc Nephrol 2009 Cellcept vs Cyclophosphamide
Multiple Sclerosis 50Communication of DMSG on
Fingolimod
httpwwwdmsgdemultiple-sklerose-
newsindexphpw3pid=newsampkategorie=therapienampanr=
2310
Crohns Disease - Primary non
responders to anti TNF-alpha30 - 40 Remo Panaccione MD FRCPC
Advanced Therapy of Inflammatory Bowel Disease
Volume 2 IBD and Crohns von Theodore
BaylessStephen B Hanauer
Crohns Disease - Secondary
non responders to anti TNF-
alpha
30 - 40 Remo Panaccione MD FRCPC httpwwwmedscapeorgviewarticle578444_3
Ulcerative Colitis 41 - 50 Walter Reinisch et al Gut 201160780e787 Results of NCT00385736
Epilepsy (Lacosamide) 59 - 67 E Ben-Menachem Epilepsia 2007 48 (7) 1308-17
Epilepsy (Zonisamide) 50 MJ Brodie Epilepsia 2005 46(1)31-41
Parkinsons Disease
(Rotigotine)52 RL Watts et al Neurology 200768(4)272
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Pharmaceutical Industry needs to
change
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Pharmaceutical Industry needs to
change
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Anti-Rheumatics Top 10 Pharmaceutical
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Market Size
In 2016 Global anti-rheumatic drugs sale $533 billion in 2016
Abbvie a global pharmaceutical company still dominates the anti-rheumatic
market with the market share of 302 and Humira from Abbvie
with $165 billion in sales
Connective Tissue Diseases
Rheumatic diseases are chronic diseases involving the inflammation and severe
pain in joints tendons ligaments bones and muscles Hence medical
researchers have devoted their time and efforts to develop effective drugs for
the treatment of these diseases
Epidemiology
Clinical research has identified that people with the age between 40 and 50
suffer mostly from rheumatic diseases However elderly patients and children
may also suffer from these conditions According to a study around 30 percent
of people of the world suffer from rheumatic diseases more than 46 million
Americans
7
Market of Anti-Rheumatics
Not yet any CDx on the market or required for approval
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Patient Stratification Benlysta (SLE) Case Study
Quantifiable Benefits for Patient Stratification
Clinical savings already represent a strong driver to use biomarkers
4000 patients
screened for
eligibility in
Phase III based
on AAB
Regulatory Approval
2500 patients
enrolled with
positive
outcome
Phase II Phase III
Phase II failed
but association
between
outcome
and AAB was found Approval
First drug in Lupus
in last 50 years
1500 patients
(not enrolled)
30000 $patient
(fully loaded
costs in Phase III)
Savings
45 M $
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Chance and the Challenge
VALUABLE
MOLECULAR
INSIGHTS
BIOLOGICAL
SAMPLE
MULTI PURPOSE
MULTI MODALITY
NOVEL
DxCDxTXVx
Fingerprinting Blood provides Big Data Opportunities
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Precision Medicine - Current Status
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Following a successful Example
Oncology Dx and CDx
1Source Frontiers in Oncology 16th May 2014 lsquoCompanion Diagnostics for Targeted Cancer Drugs ndash Clinical and Regulatory Aspectsrsquo and Jasen2Pharmgenomics Pers Med 2015 8 99ndash110Published online 2015 Mar 31 rsquoThe current and future state of companion diagnosticsrsquo 1
11
Genomic solutions for Oncology dominate
the molecular Dx amp CDx market
Autoimmune Diseases are 10-20 years behind
Regulatory Requirements and Guidelines will come soon
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Genomics ndash Current Bench Mark in Precision Medicine
Microbiome
analysis
Detection
of disease risks
Personalization
of therapiesIdentification
of drug
targets
Understanding
disease
mechanisms
Monitoring of
disease progression
Prediction of
therapeutic
response
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Companion Diagnostics (CDx) Development
bull More than 46 of all therapies are linked to biomarkers
bull Immuno oncology will generate a 30$B market and guidance
for treatment is required
bull Chronic diseases are at the start for targeted patient
stratification
bull More than 25 companies are actively developing therapies
targeting the microbiome across 13 diseases turning into a
relevant CDx area
bull Liquid biopsy testing is seen as a major growth driver
bull Stratification of patients enables economic clinical trials
smaller in size with faster success and lower attrition rates
bull Next-Gen Sequencing (NGS) is rapidly adopting and will
further expand to clinical genomic testing
bull Transformation from sample prep to bioinformatics analysis
will revolutionize future clinical testing and data reporting
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Scope of Companion Diagnostics
The challenge The demand
Biomarkers confirmed
Diagnostic partner technology identified
Attrition and timelines of clinical program
Complete CDxtoolbox workflow
Cost-effective Efficient to operate
Many barriers hampering CDx development bdquoOne Stop Shop Sellingldquo partner requested
Project
Scope
Workplan
IP Access
Biomarker
Technology
CDx Track
Record
Approval
Commercial
Collaboration
Agreement
Project
Management
Governance
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Key Areas in Precision Medicine
Relevance () ndash Next 5 Years
95Oncology
Disease Areas
21CNS Cardio
45Immunology
18Other GI ID
68
Technologies
45NGS
54
Liquid Biopsy
28Multiplexing
Bioinformatics
Emerging trends
Immuno OncologyCombinatorial Drug Testing
Patient MonitoringFrequent Testing
Human MicrobiomeSurrogate biomarkers
Data ReportingEnabling Bioinformatics
GI Gastro Intestinal ID Infectious Diseases Source Hanson Wade Survey Analysis
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Pharmaceutical companies developing targeted therapies
choose an external diagnostic partner to access
technology and in vitro diagnostic expertise
bull More than 300 company press releases about CDx
relationships Partnership types were
bull 51 Development developing a companion diagnostic
product for a companyrsquos pre-existing drug candidate
bull 21 Licensing exclusive license between 2 companies
on CDx development and commercialization
bull 16 Commercialization agreement on Rx-Dx co-
commercialization in various market regions
bull 15 RampD Collaboration permission to use a
diagnostic test for drug candidates or funding from the
Pharma company for RampD on a CDx
16
Types of Partnerships between
Pharma and Diagnostic Industry
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Biomarkers are Key and fueling the
CDx Program
Full biomarker use
(100 of trials)
Moderate biomarker use
(20-50 of trials)15
Heavy biomarker use(50-99 of trials)
Low biomarker use
(lt20 of trials) 26
21
38
47
Number of biomarkers in clinical Phase III trials
SOURCE ClinicalTrialsgov httpwwwnaturecomnrdjournalv14n12fullnrd4759html
Number of biomarkers by Pharma companies
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Clinical Trial Programs
- Cumulative success rates of oncology trials from Phase I to launch remain le12
- Attrition rate is defined by percentage of likelihood of moving to next clinical phase
- Inconsistently achieving superior reimbursement for use of Companion Dx
A challenge remains the high attrition rate of trials amp superior reimbursement
Majority
of CDx
programsAttrition rate ~60
Attrition rate ~40
AR ~32
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
How to develop a better CDx
Example Gene ndash EGFR) | Variant ndash L858R | Therapy ndash Iressa
bull Test 1 Limit of detection 1261 ndash Qiagen ndash PCR Technology
bull Test 2 Limit of detection 82 ndash ThermoFisher ndash NGS Technology
Both FDA approved Both Technologies have high Sensitivity
Needs for development
1 Specific and sensitive Technology
2 Regulatory Approval with reference material and clinical studies
1 therascreen EGFR RGQ PCR Kit
2 The Oncominetrade Dx Target Test FDA Summary of Safety and Effectiveness Data
Details provided on this slide from wwwsens-idcom
Patient material Engineered Reference Material
Source comparable to human Human or Bacteria (plasmids)
Allelic frequency variable controlled and specific
RNA Expression variable controlled
Protein Expression variable controlled
Certified No YesNo (Depending on provider)
Any Biomarker No Virtually yes
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
The earlier you can treat the better
-Consequences for Test1 and 2-
The more sensitive your CDx the better for the patient
Details provided on this slide are wwwsens-idcom assumptioins
Tu
mo
rsp
ecific
ge
ne
tic a
lte
ratio
n
Time in
years
Surgery Onset of
disease
relapse
Relapse
Identification
Early Late
Early Late
Treatment Possibility
0 41 2 3
LOD (Test 2)
LOD (Test 1)
LOD = Limit of detection
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Current Status in Precision Medicine
Autoimmune
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Autoimmune Diseases and CDx Development
The auto-immune market is forecasted at $75bn (2018) with RA 45 followed by MS
At the edge to enter into clinical testing
- first clinically relevant biomarkers are emerging
- huge diagnostic potential deriving from CDx and monitoring testing
RA Rheumatoid Arthritis MS Multiple Sclerosis
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
DiseaseNon-disease
Arbuckle et al 2003
Autoantibodies are
bull a constitutive and dynamic components of the immune system
bull present in blood of diseased and healthy individuals
bull changing specifically with the development of diseases and treatment
bull useful for diagnostics patient stratificationCDx and precision medicine
bull enable retrospectiveprospective studies
-23-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Arbuckle et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus
N Engl J Med 349(16)1526-33
Retrospective case study in systemic lupus erythematosus (SLE)
bull using US Dept of Defense Serum Repository samples
bull detection of established diagnostic SLE-autoantibodies
bull autoantibodies present many years prior to diagnosis
Autoantibodies
detected
in this study
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Autoantibodies
Brain
Lung
Liver
Colon
Expression Libraries bull High-throughput production
of human proteins
Protein Arraysbull Nitrocellulose or
bead-based arrays
Informationbull Measurement of patientsrsquo
polyclonal antibody pool
High-Throughput technology with human proteins as analytes
Serum based no need for tedious sample preparation
-25-
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Other Indications and Technologies
Proteomics ndash Protein Biomarkers in Serum
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Adapted from Leigh Anderson 2002 Randall Nelson 2008
Protein Analytes in Serum and Plasma
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull Variability exacerbated by disease heterogeneity and
sample complexity
bull Generally little to no routine use of internal standards or
reference materials
bull Candidate qualificationvalidation remains a significant
barrier to adoption of biomarkers
bull Many (including underpowered ill designed) studies
made it into the scientific peer review literature
bull Cited in subsequent (including underpowered and ill-
designed) studies as confirmatory fact (pseudo-validation
by literature)
S The Biomarker Dilemma
Over 1200 proteins are published as biomarker candidates
for cancer
H L21 1a AA5
1000 2000 3000 4000 5000 6000 7000 8000 9000 10000Time0
100
07231-04_b 1 TOF MS ES+
BPI
176e3
6 96 9
5 02 3
50 2 3
6 31 9
6 74 4
6 44 4
5 89 3
9 24 4
13 66 6
76 7 9 7 25 9
61 73
65 74
6 31 8
7 20 459 53
7 99 9
65 5 4
5 36 3
6 93 9
8 83 4
63 64
69 3 9
69 39
79 69
6 29 4
71 44
6 29 4
78 8 0
6 94 4
69 69
6 96 9
67 29
7 44 8
7 25 4
8 62 0
67 3 9
6 64 9
799 4
65 99
6 89 4
77 54
8 66 563 9 4
Proteomics Technologies
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The ldquoBlack Holerdquo Validation of Protein Biomarker Candidates
Adapted from Leigh Anderson PPI
Biomarker Development
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Liquid Biopsy
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Longitudinal testing becomes Reality
Initial diagnosis Monitoring helliphellip Monitoring hellip Monitoring hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Liquid Biopsy is a significant Market Opportunity
Sources JP Morgan estimates
Companion Dx
Companion
Diagnostics
combines targeted
therapeutics with
diagnostics
Prognosis
predicting
recurrence
Monitoring therapy
tracking
drug-
resistant
Liquid biopsy is a potentially disruptive
approach that can guide physicians in
choosing the appropriate course of therapy
We segment the market opportunity into four
distinct applications
Key Focus Area
Dr S Muumlllner Porto 26102017 wwwfundamentade
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Reality or Hype Only few people benefit
from Cancer Immunotherapy
69
bull Immunotherapy a new form of cancer therapy uses
the bodyrsquos own immune system to fight cancer
bull The first checkpoint inhibitor (CPI) was approved in
2011 this class of drugs unleashes the bodyrsquos
immune system against cancer and is the subject of
much enthusiasm
bull The percent of cancer patients who might actually
benefit from immunotherapy is much smaller
surprising given the way these drugs are described
bull The low percentage of people benefiting from cancer
immunotherapy may not change greatly
bull Doctors researchers the pharmaceutical industry
reporters patient advocates mdash all use sensational
language to describe these drugs
bull Navigating the waters of accurate information and
reasonable hope is a big challenge for oncology
Not approved
Checkpoint inhibitors(IO specific compounds)
Cancer Patients
26Drug Benefit
Cancer Patients
IO Immuno Oncology
Dr S Muumlllner Porto 26102017 wwwfundamentade
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
A new Concept introduced by the FDA
bull Companion Diagnostics bull Complementary Diagnostics
bull Provides information that is essential for the safe and effective use of a corresponding therapeutic product
bull Identify biomarkers that can be used to stratify the likely outcomes for individuals exposed to therapy
bull Provide additional information about how a drug might be used or whether someone should receive a class of drugs
bull Potential to be used more broadly with a class of drugs and not confirmed to labeling
bull A new concept introduced by the FDA
Dr S Muumlllner Porto 26102017 wwwfundamentade
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges in CDx Development
Epigenetics
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Epigenetics - Definition
Epigenetics refers to a gene activity state that may be stable over long periods of time persist through many cell divisions or even be inherited through several generations all without any change to the primary DNA sequence
DNA methylationbull cytosine residues in DNA
bull Transcriptional silencing
bull catalyzed by DNA methyltransferases (DNMTs)
Histone Modificationsbull post-translational modifications alter chromatin activity
bull Diverse modifications complex regulatoin little understood
Non coding RNA regulationbull Small interfering RNA (siRNA)
bull Piwi-interacting RNA (piRNA)
bull Mircro RNA(miRNA)
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Development of Autoimmne Diseases
It is currently assumed that epigenetic mechanisms affect the immune system
mechanisms or the target organ of the of autoimmunity
Environmental Influence =gt Epigenetic Dysregulation =gt Autoimmunity
Genetic Predisposition plays a central role
Susceptibility
Initiation
Manifestation
Propagation
Tissue Specific Systemic
autoreactive T Cells
Autoantibodies
Phases
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challenges for CDx Development
Multiplexing and Multimodality
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multiplexing
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Read-out technology or platform with low CV for single marker values
- Logical and synergistic combination of 5-10 single markers measured with the same technology
- Trade off between validation costs and diagnostic improvement
- Special demand in NON-ONCOLOGY indications
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Multimodality
Values of individual readouts for multiple markers feed into an algorithm to calculate the diagnostic result
- Logical and synergistic combination of values created by different technologies and technologybias
- Extremely robust technologies required to guarantee low CVs for single marker values
- Novel biostatistic concepts necessary
- Multimodal Cross-OMICS technologies will revolutionize Precision Medicine
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Refining the Autoimmune Landscape
Kohonen maps create a landscapes of based on biomarkers and
their relationship to each other
with specific disease clusters for novel targeted Tx development
41
Novel proprietary
biomarkers enable
differentiation of
autoimmune diseases
Identification of patient
subsets provide specific
targets for therapeutic
development amp CDx
Increases probability of
success and approvals
for novel drugs amp
therapies
New Biostatistic Models will enable Multimodality
Self organizing map according to Teuvo Kohonen Finnish engineneur
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
The Digital Challenge
Future healthcare will be built on digital multi-modality not just in
oncology
Understanding
disease on the
molecular level
Combining data
repositories for novel
therapy approaches
Defining biological
pathways drug targets
and mode-of-action
Improving the
effectiveness of
healthcare
1990 to 2002
2004 to 2010
2010 to 2020
2020 and beyond
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Challanges in CDx Development
Regulatory Aspects and Consequences
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Timeline for Drug Development starting today
bull Treatment cost per patientindicationyear will be restricted premium
reimbursement only for proven personalized therapies
bull Regulatory bodies worldwide require gt 75 responder rate for approval of any
innovative new drug
bull No approval of novel drugs without companion diagnostics in major markets
bull EMACFDA and other Regulatory Bodies follow with own Guidelines
bull FDA issues General Guidelines for Companion Diagnostics
bull Subgroup definition by molecular diagnostics will segregate syndromes
into distinct diseases
bull Novel concepts integrating novel and trusted biomarkers by multiplexing and
multimodality define disease subgroups on the molecular level
44
2016
2017
2018
2020
2023
2028
2030
The Future starts today Precision Medicine is able to shape it
Details provided on this slide are the fundamenta assumptions
2018
2019
2020
2022
2025
2030
2032
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
bull more biomarkers
bull more standards and standartization
bull more precise discovery platforms
bull more and dedicated Biobanks with exactly described patient samples (serum plasma liquor urine tissue etc) and disease parameters (clinical scores IHC staging etc)
bull more precision driven biomarker research and specific government funding for biomarker validation under industrial standards for SMEs and Academia
bull more sophisticated and technology aligned biostatistics
bull more multiplexing
bull more multimodality approaches
Precision Medicine needs hellip
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Consulting for Innovative Companies in Challenging Markets
Company Strategy ndash Business Development ndashTechnology assessment ndash Financial Transaction
There is no blueprint for a targeted development of a life science company to market and
financial success Identification of the right market segment with the right product idea in life
science is challenging and a high financial risk
Therefore it is our mission to minimize the risks for our clients by employing the synergistic
industrial experience of the fundamenta management partners
About us
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita
Dr S Muumlllner Porto 26102017 wwwfundamentade
Explore Terra Incognita