tranSMART Community Meeting 5-7 Nov 13 - Session 1: Translational Drug Discovery - Transforming Science into Medicine
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This document summarizes Andy Plump's presentation on translational drug discovery at Sanofi. It discusses two pillars of Sanofi's strategy: translational medicine and open innovation. Translational medicine focuses on human genetics, biology and disease to select targets and design clinical trials, moving from patients to research and back. Four success stories are highlighted: PCSK9 for heart disease, TrkA for pain, P53 for cancer, and glycolipids for Gaucher's disease. The presentation emphasizes applying lessons from human genetics and biology throughout the drug development process.
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tranSMART Community Meeting 5-7 Nov 13 - Session 1: Translational Drug Discovery - Transforming Science into Medicine
- 1. Translational Drug Discovery Transforming Science into Medicine Andy Plump, MD, PhD Deputy to the President R&D, Research & Translational Medicine tranSMART Chilly-Mazarin/Longjumeau , France Nov 5th, 2013 1 | 1
- 2. Decreasing Productivity The Cost of Failure R&D Cost per Approved Drug: €5,125M Early Development 1,667 (33%) Late Development 1,033 (20%) Research 2,425 (47%) Sources: 2011 CMR; 2011 KMR; Paul et. al; DiMassi et al.; BCG analysis and experience 2
- 3. Research & Early Development Evolution of Sanofi Strategy Problem Statement Industry research productivity has been poor & Sanofi has lagged Sanofi Approach to Improve Productivity • Innovation • Execution Key Success Elements of Strategy • Deep efforts in a limited number of disease areas; • Intensive focus on human biology, genetics and informatics; • Adapting technology to the disease, not the reverse 3
- 4. Two Pillars to Reinvent Biomedical R&D Translational Medicine Open Innovation Based on Outstanding Science 4
- 5. Translational Medicine is Patient & Disease First Applies to All Stages of Our Pipeline Research Research Target ID and Val Early Development Early Development Lead Lead Identification Optimization Target selection (Milestone 0) Lead selection (Milestone 1) Target ID & Validation Preclinical Candidate selection (Milestone 2) Phase 1 First in human (FIH) Biomarkers Efficacy/Safety/ Pt Segment Clinical Trial Design Late Development Late Development Phase 2a/2b Phase 3 Proof of concept (POC) Filing Submission Mechanism of Action 5
- 6. Translational Medicine is Patient & Disease First Applies to All Stages of Our Pipeline Research Research Target ID and Val Early Development Early Development Lead Lead Identification Optimization Target selection (Milestone 0) Lead selection (Milestone 1) Target ID & Validation Preclinical Candidate selection (Milestone 2) Phase 1 First in human (FIH) Biomarkers Efficacy/Safety/ Pt Segment Clinical Trial Design Late Development Late Development Phase 2a/2b Phase 3 Proof of concept (POC) Filing Submission Mechanism of Action 6
- 7. Applying Translational Medicine to Target Selection Reversing the Approach - and the Results TRADITIONAL APPROACH TO TARGET SELECTION Drug Target 1 Disease 2 TRANSLATIONAL APPROACH TO TARGET SELECTION Disease 1 Target 2 Mechanism Drug 3 | 7
- 8. The Most Important Decision We Make Choice of Target High Confidence Target Target Rationale Rationale Human Pharmacological Evidence Human Genetics Mechanistic Rationale or Unproven Animal Model Low Confidence 8
- 9. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9 TrkA TrkA Heart Disease Heart Disease Pain Pain P53 P53 Glycolipids Glycolipids Cancer Cancer Gaucher’s Disease Gaucher’s Disease & Beyond & Beyond
- 10. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9 TrkA TrkA Heart Disease Heart Disease Pain Pain P53 P53 Glycolipids Glycolipids Cancer Cancer Gaucher’s Disease & Gaucher’s Disease & Beyond Beyond
- 11. Wild Type PCSK9142X or PCSK9679X (N=85) Mutant mean LDL-C 28% Plasma LDL Cholesterol in Black Subjects (mg/dl) Coronary Heart Disease (%) PCSK9 Mutations Are Associated With a Substantial Reduction in LDL-c & CV Events 88% PCSK9142X or PCSK9679X Cohen JC, et al. N Engl J Med 2006;354:1264-72
- 12. Innovative in Human Genetics for New Targets PCSK9 – A Cardiovascular Regeneron Collaboration Project Genetics Drug interventions Mendelian randomisation Humans with Normal PCSK9 LDL 140 mg/dl Randomized Clinical Trials Humans with Mutant PCSK9 28% ↓ Control LDL 100 mg/dl LDL 140 mg/dl Alirocumab 57% ↓ ~40% ↓ Heart Attack Cohenet al., NEJM 2006 LDL 60 mg/dl TBD Odyssey Study Stein et al, NEJM 2012 12
- 13. PCSK9-Targeted Therapies From Bedside to Bench to Bedside in Less than a Decade First subject treated with PCSK9 mAB (SAR236553) Proof of principle in animals Human CV Risk Reduction Three Phase 2 studies PCSK9-targeted mAb preclinical PCSK9 discovery Phase 3 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012 Seidah NG. Proc Natl Acad Sci USA 2003;100:928-33. Abifadel M. Nat Genet 2003;34:154-6. Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100-5. Rashid S. Proc Natl Acad Sci USA 2005;102:5374-79. Cohen JC. N Engl J Med 2006;354:1264-72. Zhao Z. Am J Hum Genet 2006;79:514-23. Hooper AJ. Atherosclerosis 2007;193:445-8. Chan JC. Proc Natl Acad Sci USA 2009;106:9820-5. Stein et al. N Engl J Med 2012;366:1108-18. 13
- 14. Therapeutic PCSK9 Antibody Decreased LDL-C by up to 73% on Top of Statin Treatment Patients with primary hypercholesterolemia FH or non-FH, LDL-C ≥100 mg/dL on background lipid-lowering therapies. Double-blind, randomized, placebo-controlled phase 2 studies of 8- or 12-week. Pool analysis of the 150mg Q2W dose LS Mean % Change in LDL-C Level at Week 8/12 LOCF Pooled Studies† 11565 + 1003 Placebo N=46 150 mg Q2W N=45 Koren MJ, et al. Oral presentation at the ESC Congress Munich, Germany; August 26, 2012. Abstract #429. 14 Study 11566 150 mg Q2W + A 10 mg N=31 150 mg Q2W + A 80 mg N=30 Placebo + A 80 mg N=31 † Pooled studies (All patients on atorva 10, 20 or 40 mg) *P<0.0001 vs. Placebo/Placebo + A80 mg
- 15. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9 TrkA TrkA Heart Disease Heart Disease Pain Pain P53 P53 Glycolipids Glycolipids Cancer Cancer Gaucher’s Disease Gaucher’s Disease & Beyond & Beyond
- 16. TrkA Inhibitor for Pain Leveraging Human Genetics to Identify New Targets Human Mutations in TrkA Linked to Congenital Pain Insensitivity TrkA Antagonist for Injection Directly into the Painful Joint Potential for Efficacy Plus Safety Best-in-Class Therapy? Indo Y, Clin Auton Res 12(Suppl 1) (2002) I20–I32 & Hum Mutat 18 (2001) 462–471; Greco A et al, Am J Hum Genet 64 (1999) 1207–1210. Comparative therapeutic data: Pfizer, ACR 2008, Chris Murray; Dave Parmelee; Chris Leo; www.clinicaltrials.gov 16
- 17. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9 TrkA TrkA Heart Disease Heart Disease Pain Pain P53 P53 Glycolipids Glycolipids Cancer Cancer Gaucher’s Disease Gaucher’s Disease & Beyond & Beyond
- 18. P53 for Cancer Translational Medicine Focus in Cancer Sanofi Oncology Highlighted in December 23, 2012 “A Single Drug to Kill Cancers in Many Forms” by Gina Kolata Caption: Dr. Don Bergstrom, above, is a cancer specialist of Sanofi, one of the three companies working on a drug to restore a tendency of damaged cells to self-destruct
- 19. P53 - The Guardian of the Human Genome p53 acts as a “molecular guardian’ monitoring the integrity of the genome Loss of p53 function is a universal feature of human cancers: p53 is inactivated by multiple mechanisms (e.g., HDM2 or by genetic mutation) 19
- 20. HDM2 Inhibits p53 Function HDM2 Damage P53 DNA X DNA Repair & Apoptosis HDM2 - an enzyme that degrades p53 20
- 21. SAR405838, a Potent HDM2 Ligand Shaomeng Wang U. Michigan (Structure first described by Kussie PH. et al. Science. 1996, 274(5289):948-53)
- 22. HDM2 Inhibitor in Early Development, SAR405838, Mechanism of Action SAR405838 HDM2 Damage P53 DNA X DNA Repair & Apoptosis 22
- 23. From Patient to Bench and Back Dedifferentiated Liposarcoma (DD-LS) HDM2 Amplification in 90% DD-LS HDM2/P53 inhibitor causes regressions in DD-LS with HDM2 amplification in preclinical studies Defined Patient Population and Strategy for Clinical Development Defined Patient Population and Strategy for Clinical Development 23
- 24. Mechanisms of P53 Inactivation in Cancer Extension beyond liposarcoma… P53 status: Wild Type Mutant
- 25. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9 TrkA TrkA Heart Disease Heart Disease Pain Pain P53 P53 Glycolipids Glycolipids Cancer Cancer Gaucher’s Disease Gaucher’s Disease & Beyond & Beyond
- 26. Gaucher Disease A Lysosomal Storage Disorder Philippe C. E. Gaucher (1854-1918) 26
- 27. Gaucher Disease Type 1: Pathophysiology Gaucher Cell 27
- 28. Gaucher Disease Inappropriate Tissue Accumulation of ‘Fat’ Liver Spleen Bone Marrow 28
- 29. Gaucher Disease Treatment Replace the Enzyme Ceredase, Cerezyme 1964 Roscoe Brady reports disease caused by enzyme deficiency 1964 Roscoe Brady reports disease caused by enzyme deficiency Makes enzyme from human placenta - Ceredase But supply of Ceredase limited by availability of human placenta But supply of Ceredase limited by availability of human placenta 22,000 placentae/patient/year So makes recombinant version Cerezyme produced in cultured cells So makes recombinant version Cerezyme produced in cultured cells 1994 approved by FDA 2004 available in 61 countries
- 30. We Have Come a Long Way in Gaucher Disease 1983 2001 1991 2011 Used with patient’s permission for NGF 2010 30
- 31. But We Have More to Accomplish for Gaucher’s Patients Substrate Reduction Therapy b-Hexosaminidase A Tay-Sachs b-Hexosaminidase A and B Sandhoff a-Galactosidase Neuraminidase Fabry Sialidosis b-Galactosidase Gaucher glucocerebroside Substrate ReductionTherapy Eliglustat XX Enzyme Replacement Therapy Cerezyme, Ceredase ceramide Arylsulfatase A Metachromatic Leukodystrophy b-Galactosidase Krabbe Ceramidase Farber 31
- 32. Eliglustat is a Phase 3 Program for Gaucher Patients Ceramide Eliglustat 32
- 33. Phase 2 Data: Improvements in Hematologic and Organ Volume Parameters Through 4 Years 150% Platelets +95% Mean with 95% CI 4 100% 2 50% Hemoglobin +2.3 g/dL 0 0% Liver -28% -2 -50% Spleen -63% -4 Mean Percent Change from Baseline Hb Change from Baseline (g/dL) 6 -100% Baseline (n=26) Year 1 (n=22) Year 2 (n=20) Year 3 (n=18 to19) Year 4 (n=18 to 19) P<0.0001 for spleen, liver, and hemoglobin and P=0.0003 for platelets at 4 years. 33 -Peterschmitt J et al. Eliglustat, an Investigational Oral Therapy for Gaucher Disease Type 1(GD1): Updated Phase 2 Results 4-year Follow-Up [poster]. Presented at Lysosomal Disease Networks 8th Annual Meeting (WORLD Symposium 2012), Feb 8-10 2012, San Diego, CA.
- 34. Decrease in Dark Marrow Signal with Eliglustat Patient 0903, A 30-year Old Male Proximal and Distal Femur Baseline 34 Year 3 Baseline Year 3 34
- 35. Eliglustat - Transforming Lives December 2009 3 years post treatment (21 yrs) December 2006 pre-treatment (18 yrs) 35
- 36. Two Pillars to Reinvent Biomedical R&D Human Disease Genetics, Informatics, Biology, Experimental Medicine Partnerships Academic, Industry, Government, Patient Groups Translational Medicine Open Innovation Based on Outstanding Science 36
Editor's Notes
- Stabilized or Improved Bone Disease at 4 Years, Femur MRI Results (n=19) Dark Marrow*: Present in 95% (18/19) of patients at baseline Improved: 50% (9/18) Stable: 44% (8/18) Enlargement of an existing dark marrow lesion in 1 patient: 6% (1/18) Lytic Lesions: Present in 42% (8/19) of patients at baseline All existing lesions remained stable No new lesions Bone Infarcts: Present in 37% (7/19) of patients at baseline Existing infarcts Remained stable (6 patients) Two lesions improved in 1 patient New Infarcts 1 new asymptomatic lesion in 1 patient 1 possible new infarct (asymptomatic): area previously excluded on previous MRIs in 1 patient who has a stable pre-existing infarct Previously reported: asymptomatic progression of a pre-existing lesion in a patient who was discontinued after Year 1 *Dark marrow: MRI assessment believed to reflect Gaucher cell infiltration of bone marrow; improvement refers to a decrease in dark marrow signal.