Stephen T Holgate, Faculty of Medicine, University of Southampton
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Transcript of Stephen T Holgate, Faculty of Medicine, University of Southampton
Stephen T Holgate,Faculty of Medicine,
University of Southampton
Personalized medicine for the European Citizen
“Medicine became a science by combining clinical observation
with pathology and function and through the application of
chemical, biological and physical sciences”.
William Osler: the Father of modern medicine But we now face very serious problems:
• Reductionist models are failing to account for much of the chronic inflammatory and degenerative disease facing society.
• These non-communicable diseases are increasing as we survive longer and as developing nations adopt aspects of the Western lifestyle.
• After years of improvement in public health, lifestyle influences (sedentary, smoking, diet, “recreational” drugs, stress ), especially on the young are creating a health “time-bomb” in NC diseases (e.g. cancer, obesity, diabetes, hypertension, COPD, asthma).
• Unsustainable drug development industry based on “blockbuster, one size fits all” business model.
R&D for a New Medicine: 10+ years, $1 bn+
Source: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org;
Indefinite
Drug DiscoveryPreclinical Clinical Trials
RegulatoryReview
Scale-Up to Manufacture
Post-MarketingSurveillance
1Approved
NewMedicine
0.5 – 2 Years6 – 7 Years3 – 6 Years
Number Of Patients / Subjects
PhaseI
PhaseII
PhaseIII
5250~ 5,000 – 10,000
Compounds
Pre-
Disc
over
y
20 – 100 100 – 500 1,000 – 5,000
IND
Subm
itted
NDA
Sub
mitt
ed
Drug discovery: a big challenge for addressing both developed and developing world diseases
Set against this is:
• The explosion of new technology to interrogate complex cellular processes – the ‘omics (genomomics, transcriptomics, proteomics, epigenomics, microbiomics, metabolomics) and the exposome.
• New non-hierarchical approaches to phenotyping complex disease (e.g. cluster analyses, machine learning).
• Applications of informatics to interrogate large data-sets from biological collections, clinical trials and linked population-based case records and prescribing practice.
The Changing Focus of Healthcare:
Information and knowledge Health practitioner Patient
Information and knowledge Patient Health practitioner
Massive cultural change to shift focus to pulling patients through whole pathways not just
managing stages of diagnosis and treatment
The emergence and rapid developmental evolution of ‘omics technology platforms
Next “Genomics”The ’omics cascadeWhat can happen
What appears to be happening
What makes itHappen
What has happened
& is happening
The plummeting cost of complete genome sequencing
Towards the $1000 genome
How do these developments impact upon healthcare and drug development?
Days in Active Treatment
Malmstrom et al. Ann Intern Med. 1999; 130: 487-95.
Comparison of inhaled corticosteroid, leukotriene receptor antagonist and placebo in asthmatic patients (15 Years) not controlled on as required inhaled b2-agonists
bronchodilators
-10
0
10
20
30
40
50
1 3 5 7 9 11 13 15 17 19 21
am-PEF(Mean
ChangeFrom
Baseline; L/min ± SE)
Beclomethasone
Montelukast
Placebo
P<0.001
Patients(%)
% Improvement in lung function
30
25
20
15
10
5
0<-30 -30 to
<-20-20 to<-10
-10 to<0
0 to<10
10 to<20
20 to<30
40 to<50
5030 to<40
Beclomethasone (n=246)
Montelukast (n=375)
Distribution of individual asthmatic patient responses to the 2 active treatments
BetterWorse
Stratified Medicine: What are we talking about?
“the tailoring of medical treatment to the individual characteristics of each patient …. involves the use of companion diagnostics to achieve the best outcomes in the management of a patient's disease or disease predisposition. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not”.
Adapted from: “Priorities for Personalized Medicine” by the US President’s Council of Advisors on Science and Technology (PCAST), 2008
• Personalised Medicine has arrived to an extent:– Herceptin®, Gleevec®, SelzentryTM, Ziagen®, Vectibix® , IressaTM
Stratified medicine for cancer therapyShaw EC & Johnson PWM. Drug Discovery Today 2012; 17: 261–26
A summary of the major disrupted cellular pathways in a series of pancreatic cancers, according to data on genetic abnormalities detected by sequencing, microarrays and transcriptomics: (a), with the specific gene alterations discovered in two of the cases mapped in detail (b), case Pa14C (c), case Pa10X).
Abbreviations: JNK: Jun N-terminal kinases; TGF-β: transforming growth factor-beta
(a) (b)
(c)
Similar evolution of lung cancer and chronic inflammatory disease (e.g. asthma – Th2, non-Th2 etc)
Signatures of mutational processes in human cancerAlexandrov LB et al. Nature 2013: 500; 415–421
Genetic map of cancer reveals trails of mutation that lead to disease
The first detailed map of genetic faults that cause cancers, offering profound insights into the disease.
The map describes more than 20 "genetic signatures", or patterns of mutation, that alone or in combination drive 30 different types of cancer, including brain, lung, pancreas and breast tumours.
Research that looked at more than 7,000 cancers to identify "signature" patterns in genetic mutations. These signature patterns suggest how the cancer-causing mutations arise. Almost five million mutations fell into 21 signature patterns. The causes of some of these signatures were identified.
Signatures of mutational processes in human cancerAlexandrov LB et al. Nature 2013: 500; 415-21
Multiple Companies Offer These Services
ESF 2013: Personalised Medicine for the European Citizen: Towards more precise medicine for the diagnosis, treatment
and prevention of disease
Medicine will move from a reactive to a proactive discipline over the next decade;
one that is predictive, personalised, preventive and participatory
ESF Forward Look launch Brussels 28 January 2013
Forward Look on Personalised Medicine
80 recommendations
…
resulting in a
PersonalisedMedicine“Target”
The promise of personalised medicine
• More effective medicines• Safer medicines• Cheaper medicines• Better healthcare• Cheaper healthcare• Less (rather than more) healthcare
disparity
G551D is the third most common mutation, affecting ~4% of patients. For patients homozygous for D508, Vertex has another drug, VX-809, which acts by increasing the transport of CFTR protein to the cell surface. A phase 2 clinical trial of combined VX-809 and VX-770 treatment in D508 patients is in progress.
Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Jih KY. et al. PNAS. 2013; 110: 4404-9
Vx-770; Ivacaftor
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation (most prevalent gating mutation)
Ramsey BW, et al. N Engl J Med. 2011; 3658: 1663-72
Complex disease will be stratified into a series of pathway specific disorders creating opportunities for
both companion diagnostics and targeted prevention and treatments.
But also a new Taxonomy of disease will be created based upon knowledge of causative pathways and
neyworks rather than signs and symptoms.
Creation of a New Taxonomy first requires an “Information Commons” in which data on large populations of patients become broadly available for research
use and a “Knowledge Network” that adds value to these data by highlighting their inter-connectedness and integrating them with evolving knowledge of
fundamental biological processes
Toward Precision Medicine. US Nat Acad Sci 2011
Reclassification of human disease by identifiable causal pathways
The ‘holy trinity of biology’ where biology drives technology - drives
computational/mathematical tools. • This requires a cross-disciplinary environment
where scientists of many different disciplines learn to speak the languages of the other scientists and learn to work together in teams.
• When this is practiced effectively enormous amounts of biological information can be generated rapidly.
Personalised or P4 Medicine: Predictive Preventive
Personalised Participatory
Cross-Disciplinary culture
Team Science
Biological Information
Wellness Quantified Disease Demystified
Liver cancer per 10,000
Chronic infection with hepatitis B and C causes 75-80% of liver cancers diagnosed world-wide.
Prevalence of hepatitis B and C
Prediction of outcome (survival) in acute on chronic liver failure patients
Candidate BiomarkersChange in non-survivors vs survivors
Annotated HR-MAS NMR spectral profiles from centre of tumour(Ct) (A) and healthy appearing mucosa 5 cm from tumour margin (Hm) (B)
Rapid diagnosis and staging of colorectal cancer via High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) Spectroscopy
of intact tissue biopsiesMirnezami R et al. Ann Surg. 2013 Jul 15. [Epub ahead of print]
Rapid diagnosis and staging of colorectal cancer via High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR-MAS NMR) Spectroscopy
of intact tissue biopsiesMirnezami R et al. Ann Surg. 2013; Jul 15. [Epub ahead of print]
Distinct HR-MAS NMR spectroscopy–based metabolic phenotypes according to T-stage.
Patient reported
Clinical
Functional
Cellular
Molecular
Integrating knowledge for Systems MedicineAuffray, Adcock, Chung, Djukanovic, Pison, Sterk. Chest 2010;137:1410-16
The “Grand Challenge” is how to combinethe different data types for interrogation
Metabolomics
DNA and RNA sequencing
Imaging
Functional imaging
Microbiome
Lifestyle database
Family history
Software to Implement Genetic Testing in the Clinic Setting
BRIGHAM AND WOMEN’S HOSPITAL
MASSACHUSETTSGENERAL HOSPITAL
HARVARDMEDICAL SCHOOL
Scott T. Weiss, M.D., M.S.Professor of MedicineHarvard Medical SchoolAssociate Director, Channing LaboratoryBrigham and Women’s HospitalDirector, Partners HealthCare Center for Personalized Genetic MedicineBoston, MA
Where science and unmet need converge
Cystic Fibrosis
OSA
ARDS
Infant RDS IPF
Idiopathic Fibrotic NSIP
Fibrotic ILD Assoc RA
Fibrotic ILD Assoc SLE
Fibrotic ILD Assoc Sys Scl
Sarcoidosis
Idiopathic BOOP
Chronic CoughPAH
AAT Deficiency
Bronchitis - acute
Bronchiectasis
BPD
HPS
HistoplasmosisInfluenza
Legionellosis
LAM
Silicosis
Berylliosis
HP - Farmer's LungPneumonia
PE
RSV
Bronchiolitis
SIDS
Chronic sinusitis
Nasal polyposis
AR
NAR - Pure AR - Pure + Mixed
Peanut Allergy
Atopic dermatitis
COPD
Asthma
0
1
2
3
4
5
100 1,000 10,000 100,000 1,000,000 10,000,000 100,000,000
US Population Prevalence/Incidence (Log Scale)
Unm
et N
eed
Inde
x
Progressive, Fibrotic ILD (inc. IPF, NSIP, ILD Assoc CTDs - RA / SLE / Sys Scl)
Emergent science drives new disease opportunities
Lung repairCOPD, fibrotic lung
diseases (IPF, ILD, CF)
Neuronal mechanisms
Rhinitis, asthma, COPD, cough
Immunomodulation Asthma, allergic rhinitis
Core diseases Opportunities in “new” diseases featured in the business plan Key emergent areas of
science
Not just medical treatments but also applies to adverse and beneficial environmental exposures –
the exposome
Implications of the exposome for exposure scienceRappaport S M. J Expos Sci Env Epid. 2011; 21: 5-9
By embracing the exposome as its operational paradigm, exposure science can play a major role in discovering and mitigating these exposures.
Bottom-up exposomics: chemicals measured in air, water and food would identify potentially important exogenous exposures and their sources, but would miss endogenous exposures.
Environmental exposures to chemicals arise from both external and internal sources. The exposome represents the combined exposures from all sources that reach the internal chemical environment
Top-down exposomics: chemicals measured in blood would identify all potentially important exposures, but would provide no information about their sources.
ESF Position Paper
May 2011
Technology
19-20 Sept 2011London, UK
Disease Summit
18-20 Oct 2011The Hague, NL
1) CV & metabolicdiseases
2) Oncology3) Rare Diseases
“Big picture” Summiton clustered issues
13-14 Feb 2012Dubrovnik, HR
Identify grand challenges and recommendation
Stakeholder conference
18 April 2012Rome, IT
Consensus discussion on Grand Challenges and overall
recommendations
ESF Forward Look - DG Research - Brussels, 11 September 2012
Forward Look on Personalised Medicine
•Final Report•Recommendations•Implementation