Remaining Competitive in a Rapidly Evolving Field:...
Transcript of Remaining Competitive in a Rapidly Evolving Field:...
Francis Kern
Senior Director, External Scientific Affairs
Daiichi Sankyo Pharmaceutical Development.
2nd Annual Immune Checkpoint Inhibitor Meeting
March 17, 2016
Remaining Competitive in a Rapidly Evolving Field:
Strategies to Establish and Reinforce Market Share
Passion for Innovation.
Compassion for Patients.TM
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Forward-Looking Statements
Financial forecasts, future projections and R&D information that Daiichi Sankyo discloses may include information that might be classified as “Forward-Looking Statement”. These forward-looking statements represent our current assumptions based on information currently available. Please note that such are subject to a number of known and unknown risks and uncertainties and our future performance may differ from the expectations as expressed in such statements.
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2012 2013 2014 2015 2016 2017 2018 2019 2020
Wo
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wid
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’s)
Blincyto (Amgen) Provenge (Dendreon) Prostvac (Bavarian Nordic) Rintega (Celldex Thera.)
Yervoy (BMS) Opdivo (BMS) Keytruda (MRK) Durvalumab (Celgene)
Atezolizumab (Roche) Avelumab (Pfizer) Durvalumab (AZ)
Projection for the I-O Market Vary Widely; Most Analysts Predict
the Category to Reach ≥$20B Annually in Less than 10 Years
• 45k pts treated with Immunotherapy (2015) could grow to 60% of 2.7MM pts treated each year for cancer
• Analyst predictions for worldwide immuno-oncology market sales vary widely:
Citigroup: Market could reach up to sales of up to $35 billion/year within the next 10 yrs
Leerink Swan: $29 billion by 2025
Sanford C. Bernstein: $16 billion by 2020
Decision Resources: $13.3 billion by 2023
Sources: The Future of Immuno-Oncology: Perspectives from Academia and Industry (Sep. 2014), (Defined Health, Sep. 2014),Priceless Pills (The Economist, Sept. 2014),
EvaluatePharma
PD1/PD-L1
inhibitors
CTLA-4
inhibitors
Therapeutic
vaccines
Worldwide Immunotherapy Sales for Key Products
Majority of the growth in sales anticipated to come from checkpoint inhibitors, particularly PD1/PD-L1 inhibitors
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Daiichi Sankyo has been an innovative pharmaceutical company since its foundation
Daiichi Sankyo
Mr. Joji Nakayama
Edoxaban
Olmesartan Pravastatin
Levofloxacin
Sankyo Daiichi
Pharmaceutical
Dr. Jokichi Takamine Dr. Katsuzaemon Keimatsu
2007
1899 1915
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Japan Pharmaceutical Market 2014
0 1000 2000 3000 4000 5000 6000 7000
Eisai
GSK
Otsuka
Novartis
MSD
Mitsubishi Tanabe
Pfizer
Chugai
Daiichi Sankyo
Astellas
Takeda
(US$ Millions)
$1 = JPY 115 © 2015 IMS Japan KK. All rights reserved. Source: IMS JPM / Reprinted with Permission
2,588
2,608
2,654
3,115
3,187
3,350
3,698
3,823
5,174
5,585
6,040
6 as of March 2015
>16,000 Worldwide Employees
- Germany
- UK
- Ireland
- France
- Spain
- Portugal
- Italy
- Netherlands
- Belgium
- Austria
- Switzerland
- Turkey
- China
- South Korea
- Taiwan
- Hong Kong
- Thailand
- India - Brazil
- Venezuela
EU 2100
Asia 2000
Latin America
500
US 3300
Japan 8600
Our Global Prominence
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Clinical Development Pipeline (Ph2-Ph3) -Oncology
Generic Name / Project code number
Class Target indication Stage Remarks
Denosumab Anti-RANKL antibody Breast cancer adjuvant JP P3 additional indication
Rheumatoid arthritis JP P3 additional indication
Tivantinib MET inhibitor Hepatocellular cancer US/EU P3
Nimotuzumab Anti-EGFR antibody Gastric cancer JP P3
Vemurafenib BRAF inhibitor Melanoma adjuvant US/EU P3
additional indication
Licensee Roche is conducting
the study. Submission in 2016 is
planned.
Quizartinib FLT3-ITD inhibitor Acute myeloid leukemia
US/EU/
Asia P3
JP P1
Pexidartinib
(PLX3397)
CSF-1R/KIT/Flt3-ITD
inhibitor
Tenosynovial Giant Cell
Tumor (TGCT) US/EU P3
including pigmented
villonodular synovitis
Glioblastoma US P2
Melanoma US P2
Melanoma, solid tumor US P1/2
combination with
pembrolizumab in collaboration
with Merck
Patritumab Anti-HER3 antibody
NSCLC US/EU P2
NSCLC JP P1
Breast cancer US P2
Breast cancer JP P1
Head & Neck cancer EU P1
as of January 2016
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Clinical Development Pipeline (Ph1) -Oncology
Generic Name / Project code number
Class Target indication Stage Remarks
DS-3032 MDM2 inhibitor Solid cancer, lymphoma US/JP P1
Leukemia US P1
PLX7486 Fms/Trk inhibitor Solid cancer US P1
DS-8895 Anti-EPHA2 antibody Solid cancer JP P1
DS-8273 Anti-DR5 antibody Solid cancer US P1
PLX8394 BRAF inhibitor Solid cancer, leukemia US P1
DS-6051 NTRK/ROS1 inhibitor Solid cancer US P1
DS-5573 Anti-B7-H3 antibody Solid cancer JP P1
PLX9486 KIT inhibitor Solid cancer US P1
DS-8201 Anti-HER2 antibody drug
conjugate Solid cancer JP P1
U3-1784 Anti-FGFR4 antibody Solid cancer EU P1
DS-1123 Anti-FGFR2 antibody Solid cancer JP P1
as of January 2016
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Causes of Rapid Evolution in Oncology Therapeutic Area Strategy Development
1) Realization that Resistance to Targeted Therapies Is a Fait Accompli
Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling Nikhil Wagle, Caroline Emery, Michael F. Berger, Matthew J. Davis, Allison Sawyer, Panisa Pochanard, Sarah M. Kehoe, Cory M. Johannessen, Laura E. MacConaill, William C. Hahn, Matthew Meyerson, and Levi A. Garraway
JCO August 1, 2011 vol. 29 no. 22 3085-3096
After 15 weeks of vemurafinib Before initiation After 23 weeks of therapy
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Causes of Rapid Evolution in Oncology Therapeutic Area Strategy Development:
2) Tumor Heterogeneity, “Genomic Chaos” and Frequent Mutation of Currently
Undruggable Targets
Gerlinger et al., Intratumor Heterogeneity and
Branched Evolution Revealed by Multiregion
Sequencing, NEJM 366:883, 2012
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Causes of Rapid Evolution in Oncology Therapeutic Area Strategy Development:
Prolonged and Deep Responses to the Combination of Ipilimumab and
Nivolumab in Melanoma
Objective responses occurred in 9 of 17 patients (53%; 95% CI, 28 to 77), including 3 with a complete response.
All 9 patients who had a response had tumor reduction of 80% or more at their first scheduled assessment
J.S. Wolchuk et al., NEJM 369:122 (2013)
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Are Targeted Therapies Obsolete?
2015 FDA New Oncology Drug Approvals
Drug (brand name) Sponsor Properties Indication
Palbociclib (Ibrance) Pfizer CDK4 and CDK6 inhibitor ER-positive, HER2-negative
advanced breast cancer
Lenvatinib (Lenvima) Eisai VEGFR inhibitor Thyroid cancer
Panobinostat (Farydak) Novartis Histone deacetylase inhibitor Multiple myeloma
Dinutuximab (Unituxin) United Therapeutics GD2-binding mAb Neuroblastoma
Sonidegib (Odomzo) Novartis Smoothened inhibitor Basal cell carcinoma
Tipiracil plus trifluridine (Lonsurf) Taiho
Thymidine phosphorylase
inhibitor plus a nucleoside
metabolic inhibitor
Colorectal cancer
Trabectedin (Yondelis) Johnson & Johnson Alkylating drug Liposarcoma or
leiomyosarcoma
Cobimetinib (Cotellic) Genentech MEK inhibitor Melanoma with
BRAFV600E/Kmutations
Osimertinib (Tagrisso) AstraZeneca EGFR inhibitor NSCLC with
EGFRT790Mmutations
Daratumumab (Darzalex) Johnson & Johnson CD38-directed mAb Multiple myeloma
Ixazomib (Ninlaro) Takeda Oral proteasome inhibitor Multiple myeloma
Necitumumab (Portrazza) Eli Lilly EGFR antagonist NSCLC
Elotuzumab (Empliciti) Bristol-Myers Squibb SLAMF7-directed mAb Multiple myeloma
Alectinib (Alecensa) Roche ALK inhibitor NSCLC
Adapted from Asher Mullard, Nature Reviews Drug Discovery 15, 73–76 (2016)
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Nonsynonymous mutation burden associated with clinical
benefit of anti–PD-1 therapy.
Naiyer A. Rizvi et al. Science 2015;348:124-128
How Far Can We Extend the Benefit of Immunotherapy
Combinations: The Elephant in the Room
Le DT et al. N Engl J Med 2015;372:2509-2520.
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Clinical Responses to Pembrolizumab Treatment
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Ton N. Schumacher, and Robert D. Schreiber Science
2015;348:69-74
Estimate of the Neoantigen Repertoire in Human Cancer
LB Alexandrov et al. Nature 500, 415-21 (2013) doi:10.1038/nature12477
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Distribution of HLA-A*0201 epitopes by sample.
Neil H. Segal et al. Cancer Res 2008;68:889-892
Do Neo-Antigens Exist in Tumors with Low Mutational
Burden?
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But It’s Not Just Mutational Burden: Tumor Heterogeneity
Also Influences anti-PD1 Therapy Benefit
N. McGranahan et al., Science 10.1126/science.aaf490 (2016).
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Larkin J et al. N Engl J Med 2015;373:23-
34.
The Prevailing Sentiment: Combinations Will Be Required but with What and in What Situations?
PDL1+
ITT
PDL1-
Phase 3 Study Results of Nivolumab plus
Ipilimumab combination in metastatic
melanoma
• Benefit of ipilumumab addition is
limited to patients with PDL1 negative
tumors
• Biomarkers will be needed to spare
patients unnecessary toxicity (55%
grade 3 or 4 AEs in combination group)
• ~50% of patients are refractory after
one year
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So Many Combination Choices, So Little Guidance
Co-stimulatory
Compugen – Bayer
FivePrime – BMS
Celldex (CD-27 mAb)
GITR Inc (GITR mAb)
Agenus (GITR, OX40 mAbs - Incyte)
Pelican (TNFRSF25 mAb, TL1A Fc
fusion)
Bionovion (CD-27, CD-70 – Aduro )
Apexigen (CD-70)
Pieris (OX40, GITR)
Treg inhibitors Pelican (TNFRSF25 mAb)
Boston Immune Technologies and Therapeutics
(TNFR2 mAb)
IDAC Theranostics (CD4 mAb)
Progenra (USP7 inhibitor)
Xoma (TGF-beta - Novartis)
Macrophage Directed immunotherapy Trillium (SIRPaFc CD47 blocking agent)
Novimmune (CD47/TAA bispecific)
MDSC Inhibitors/Macrophage
polarization Peregrine (Bavituximab)
Active Biotech (S100A9 SMI)
Inflammatorx (S100A9 mAb)
Deciphera (TIE2 inhibitor)
Calithera (Arginase)
Advancer Cancer Therapeutics (PFKFB3)
Cytokine fusion proteins
Philogen (Darleukin L19-IL2)
Cytune (IL-2/IL-15Rbg agonist - RLI-15)
ARMO (PEGylated IL-10)
Pivotal Biosciences (Liver Expressed
Cytokine)
Chemocentryx (CCR2)
Altor (IL-15 sushi Fc)
Vaccines
Immunevaccine (DPX Survivac)
PDS Biotechnology (Versamune)
Aduro (Listeria - Janssen)
Advaxis (Listeria monocytogenes)
Globeimmune (Tamogen yeast
deliveryplatform)
ImmuneDesign (recombinant
lentivirus for selective transduction of
dendritic cells with tumor associated
antigens)
Celldex (ADC directed NY-ESO
antibody fusion and associated
platform)
Immutep (LAG-3 Fc fusion protein)
Oncosec (IL-12 plasmid injection)
Checkpoints
Cytomx (PD-L1 probody – BMS)
Curtech (CT-011 PD1 - Medivation)
Sorrento (STI-A1010 PD-L1 -
NantWorks)
Merck KGa (PD-L1 - Pfizer)
TESARO (PD-1)
Bionovion (PD-1, PD-L1)
CoStim (Tim-3 –Novartis)
MabLife MAT-303 CD160 receptor
(BTLA)
Immunext (VISTA-Janssen)
Agenus (LAG-3, Tim-3)
TESARO (Tim-3, Lag-3)
Simulators of Inate Immunity
Mologen (TLR9 agonist)
ImmuneDesign (TLR agonist)
Aduro (STING agonist – Novartis)
Oncolytic Viruses
Genelux
Viralytics (Coxackie)
Virttu (HSV)
Tocagen (cytosine deaminase retrovirus)
Bispecific T cell engagers
Amgen/Micromet
Macrogenics
Affimed
Bionovion
Xencor
HLA-peptide directed antibodies
or TCRs
Eureka (WT1 and others)
Immunocore (ImTacs - GSK, Lilly,
AZ, Genentech)
BioNTech
Allogenic Cell based Therapy
Cellectis (CART - Pfizer)
Intrexon (UltraCART)
Bispecific or
multi-antibody
platforms
TESARO
F-Star
Bionovion
Symphogen
Macrogenics
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Phase 1b Study Combining the IDO Inhibitor
Epacadostat and Pembrolizumab
Gangadhar et al.: Journal for ImmunoTherapy of Cancer 2015 3(Suppl 2):O7.
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Pembrolizumab Combination Clinical Results Disclosed
Thus Far in Metastatic Melanoma
Source: Evaluate Pharma, Merck press release Nov. 21, 2015
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Galluzi et al.,Oncotarget. 2014 Dec 30;5(24):12472-508.
IL-15
agonist
(Admune)
CART-T
(U Penn)
Tim-3 (Costim)
Lag-3
PD-L1
Anti-
TGFb1,2
(Xoma)
4 preclinical
programs
(Surface
Oncology)
STING
Agonist
(Aduro)
Areas Where other Late-Comers Are Accessing External
Opportunities: Novartis
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Collaboration with Merck:
• Pexidartinib in combination with anti-PD-1
therapy for advanced melanoma and
multiple other solid tumors
Other potential indications:
• Glioblastoma
• Ovarian cancer
• Breast cancer
• Sarcomas
Investigational CSF-1R (FMS) Inhibitor • Tenosynovial Giant Cell Tumor (TGCT)
• Granted Orphan Drug Designation by the FDA and EMA
• Granted Breakthrough Therapy Designation by FDA
Pexidartinib: PLX3397
Further Investigations
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T CELL
CANCER CELL
SIGNAL
PD-1
PD-L1
PD-1 mAb
Pembrolizumab
GENE
Myeloid
Suppressor
Cell
Pexidartinib
CSF1R
CSF1*
T-Cell- Mediated
Killing
* colony stimulating factor 1
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Peering into the Crystal Ball
• Early combination data suggests that intervention at multiple
points in the Cancer Immunity Cycle will confer additional clinical
benefit to PD-1 or PD-L1 antibodies
• Early results suggest that patients deriving benefit from addition of
one agent to an anti-PD1 or PD-L1 regimen may not be the same
as those deriving benefit from a different combination partner
• Results of Randomized Combination Studies with predictive
biomarkers for which patients benefit from specific combinations
are still a ways off.
• For some time it will remain unclear whether different agents
targeting the same point in the Cancer Immunity Cycle will be
interchangeable as part of a combination regimen with PD-1 or
PD-L1 antibodies
• Portfolios of IO agents and IO biomarker discovery capabilities will
be required to be a significant player
• Combination partners that target multiple points in the Cancer
Immunity Cycle may circumvent the need for personalized
combination regimens
• PD-1 or PD-L1 antibodies may need to be included as part of the
portfolio to preserve return on investment in combination partners