tranSMART Community Meeting 5-7 Nov 13 - Session 1: Translational Drug Discovery - Transforming Science into Medicine

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tranSMART Community Meeting 5-7 Nov 13 - Session 1: Translational Drug Discovery - Transforming Science into Medicine Current challenges in translational Drug Discovery at Sanofi R&D Andy Plump, Sanofi

Text of tranSMART Community Meeting 5-7 Nov 13 - Session 1: Translational Drug Discovery - Transforming...

  • 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, 20131|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 experience2 3. Research & Early Development Evolution of Sanofi Strategy Problem Statement Industry research productivity has been poor & Sanofi has laggedSanofi Approach to Improve Productivity Innovation ExecutionKey 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 reverse3 4. Two Pillars to Reinvent Biomedical R&DTranslational MedicineOpen InnovationBased on Outstanding Science 4 5. Translational Medicine is Patient & Disease First Applies to All Stages of Our Pipeline Research Research Target ID and ValEarly Development Early DevelopmentLead Lead Identification Optimization Target selection (Milestone 0)Lead selection (Milestone 1)Target ID & ValidationPreclinicalCandidate selection (Milestone 2)Phase 1 First in human (FIH)Biomarkers Efficacy/Safety/ Pt Segment Clinical Trial DesignLate Development Late Development Phase 2a/2bPhase 3Proof of concept (POC)FilingSubmissionMechanism of Action5 6. Translational Medicine is Patient & Disease First Applies to All Stages of Our Pipeline Research Research Target ID and ValEarly Development Early DevelopmentLead Lead Identification Optimization Target selection (Milestone 0)Lead selection (Milestone 1)Target ID & ValidationPreclinicalCandidate selection (Milestone 2)Phase 1 First in human (FIH)Biomarkers Efficacy/Safety/ Pt Segment Clinical Trial DesignLate Development Late Development Phase 2a/2bPhase 3Proof of concept (POC)FilingSubmissionMechanism of Action6 7. Applying Translational Medicine to Target Selection Reversing the Approach - and the Results TRADITIONAL APPROACH TO TARGET SELECTIONDrugTarget1Disease2TRANSLATIONAL APPROACH TO TARGET SELECTIONDisease1Target2MechanismDrug3|7 8. The Most Important Decision We Make Choice of Target High Confidence Target Target Rationale RationaleHuman Pharmacological Evidence Human Genetics Mechanistic Rationale or Unproven Animal Model Low Confidence8 9. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9TrkA TrkAHeart Disease Heart DiseasePain PainP53 P53Glycolipids GlycolipidsCancer CancerGauchers Disease Gauchers Disease & Beyond & Beyond 10. Four Translational Medicine Stories from Sanofi & Our Collaborators Driven by human genetics, human biology, bioinformatics and understanding human disease PCSK9 PCSK9TrkA TrkAHeart Disease Heart DiseasePain PainP53 P53Glycolipids GlycolipidsCancer CancerGauchers Disease & Gauchers Disease & Beyond Beyond 11. Wild TypePCSK9142X or PCSK9679X (N=85)Mutantmean 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 Events88%PCSK9142X or PCSK9679XCohen 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 GeneticsDrug interventionsMendelian randomisationHumans with Normal PCSK9 LDL 140 mg/dlRandomized Clinical TrialsHumans with Mutant PCSK9 28% ControlLDL 100 mg/dlLDL 140 mg/dlAlirocumab57% ~40% Heart Attack Cohenet al., NEJM 2006LDL 60 mg/dl TBD Odyssey StudyStein et al, NEJM 201212 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 ReductionThree Phase 2 studiesPCSK9-targeted mAb preclinicalPCSK9 discoveryPhase 3200020012002200320042005200620072008200920102012Seidah 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 doseLS Mean % Change in LDL-C Level at Week 8/12 LOCFPooled Studies 11565 + 1003 Placebo N=46150 mg Q2W N=45Koren MJ, et al. Oral presentation at the ESC Congress Munich, Germany; August 26, 2012. Abstract #429. 14Study 11566 150 mg Q2W + A 10 mg N=31150 mg Q2W + A 80 mg N=30Placebo + A 80 mg N=31 Pooled studies (All patients on atorva 10, 20 or 40 mg) *P