transmart community meeting 5-7 nov 13 - session 1: translational drug discovery - transforming...

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| 1 Translational Drug Discovery Transforming Science into Medicine Andy Plump, MD, PhD Deputy to the President R&D, Research & Translational Medicine 1 tranSMART Chilly-Mazarin/Longjumeau , France Nov 5 th , 2013

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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

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

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Translational Drug Discovery

Transforming Science into MedicineAndy Plump, MD, PhD

Deputy to the President R&D, Research & Translational Medicine

1

tranSMARTChilly-Mazarin/Longjumeau , France

Nov 5th, 2013

Page 2: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Research2,425(47%)

EarlyDevelopment

1,667(33%)

LateDevelopment

1,033(20%)

Decreasing ProductivityThe Cost of Failure

Sources: 2011 CMR; 2011 KMR; Paul et. al; DiMassi et al.; BCG analysis and experience

R&D Cost per Approved Drug: €5,125M

2

Page 3: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Research & Early DevelopmentEvolution of Sanofi Strategy

3

Problem StatementIndustry 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

Page 4: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Two Pillars to Reinvent Biomedical R&D

Translational Medicine

Open Innovation

Based on Outstanding Science

4

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

Translational Medicine is Patient & Disease FirstApplies to All Stages of Our Pipeline

Target ID & Validation

Mechanism of Action

BiomarkersEfficacy/Safety/

Pt Segment

Clinical Trial Design

ResearchResearch Early DevelopmentEarly Development Late DevelopmentLate Development

Targetselection(Milestone 0)

Leadselection(Milestone 1)

Candidateselection(Milestone 2)

First in human(FIH)

Proof ofconcept(POC)

Submission

Target ID and Val

Lead Identification

Lead Optimization

PreclinicalPhase

1Phase 2a/2b

Phase3

Filing

5

Page 6: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Target ID & Validation

Mechanism of Action

BiomarkersEfficacy/Safety/

Pt Segment

Clinical Trial Design

ResearchResearch Early DevelopmentEarly Development Late DevelopmentLate Development

Targetselection(Milestone 0)

Leadselection(Milestone 1)

Candidateselection(Milestone 2)

First in human(FIH)

Proof ofconcept(POC)

Submission

Target ID and Val

Lead Identification

Lead Optimization

PreclinicalPhase

1Phase 2a/2b

Phase3

Filing

Translational Medicine is Patient & Disease FirstApplies to All Stages of Our Pipeline

6

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

TRANSLATIONAL APPROACH TO TARGET SELECTION

DiseaseDiseaseTarget

| 7

Applying Translational Medicine to Target SelectionReversing the Approach - and the Results

DrugDrug

1 2

TRADITIONAL APPROACH TO TARGET SELECTION

DiseaseDisease Target DrugDrug1 2 3

Mechanism

Page 8: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

The Most Important Decision We MakeChoice of Target

High Confidence

HumanPharmacological Evidence

Human Genetics

Mechanistic Rationale or Unproven Animal Model

Low Confidence

TargetRationale

TargetRationale

8

Page 9: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Four Translational Medicine Stories from Sanofi & Our Collaborators

Driven by human genetics, human biology, bioinformatics and understanding human disease

PCSK9PCSK9

Heart DiseaseHeart Disease

TrkATrkA

PainPain

P53P53

CancerCancer

GlycolipidsGlycolipids

Gaucher’s Disease & Beyond

Gaucher’s Disease & Beyond

9

Page 10: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Four Translational Medicine Stories from Sanofi & Our Collaborators

PCSK9PCSK9

Heart DiseaseHeart Disease

TrkATrkA

PainPain

P53P53

CancerCancer

GlycolipidsGlycolipids

Gaucher’s Disease & Beyond

Gaucher’s Disease & Beyond

10

Driven by human genetics, human biology, bioinformatics and understanding human disease

Page 11: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

PCSK9 Mutations Are Associated With a Substantial Reduction in LDL-c & CV Events

PCSK9142X or PCSK9679X

Co

ron

ary

Hea

rt D

isea

se (

%)

Plasma LDL Cholesterol in Black Subjects (mg/dl)

PCSK9142X or PCSK9679X

(N=85)

Cohen JC, et al. N Engl J Med 2006;354:1264-72

mean LDL-C28%

88%Wild Type

Mutant

Page 12: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Cohenet al., NEJM 2006 Stein et al, NEJM 2012

Innovative in Human Genetics for New TargetsPCSK9 – A Cardiovascular Regeneron Collaboration Project

Mendelian randomisation

Humans withNormal PCSK9

Humans withMutant PCSK9

LDL 140 mg/dl

~40% Heart Attack

Genetics Drug interventionsRandomized Clinical Trials

Control Alirocumab

LDL 140 mg/dl LDL 60 mg/dl

TBDOdyssey Study

LDL 100 mg/dl28% 57%

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

PCSK9-Targeted TherapiesFrom Bedside to Bench to Bedside in Less than a Decade

First subject treatedwith PCSK9 mAB

(SAR236553)

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.

PCSK9-targeted mAb preclinicalPCSK9 discovery

Proof of principle in animals

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012

Three Phase 2 studies

Human CV Risk Reduction

Phase 3

13

Page 14: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Therapeutic PCSK9 Antibody Decreased LDL-C by up to 73% on Top of Statin Treatment

14

Koren MJ, et al. Oral presentation at the ESC CongressMunich, Germany; August 26, 2012. Abstract #429.

150 mg Q2WN=45

150 mg Q2W

+ A 10 mgN=31

150 mg Q2W

+ A 80 mgN=30

Placebo + A 80 mg

N=31

PlaceboN=46

Pooled Studies†

11565 + 1003 Study 11566

LS

Mea

n %

Ch

ang

e in

LD

L-C

Lev

el

at W

eek

8/12

LO

CF

† Pooled studies (All patients on atorva 10, 20 or 40 mg)*P<0.0001 vs. Placebo/Placebo + A80 mg

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

Page 15: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Four Translational Medicine Stories from Sanofi & Our Collaborators

PCSK9PCSK9

Heart DiseaseHeart Disease

TrkATrkA

PainPain

P53P53

CancerCancer

GlycolipidsGlycolipids

Gaucher’s Disease & Beyond

Gaucher’s Disease & Beyond

15

Driven by human genetics, human biology, bioinformatics and understanding human disease

Page 16: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

TrkA Inhibitor for PainLeveraging Human Genetics to Identify New Targets

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

Human Mutations Human Mutations in TrkA Linked to in TrkA Linked to Congenital Pain Congenital Pain

InsensitivityInsensitivity

Human Mutations Human Mutations in TrkA Linked to in TrkA Linked to Congenital Pain Congenital Pain

InsensitivityInsensitivity

TrkA Antagonist for Injection Directly

into the Painful Joint

Best-in-Class Therapy?

Potential for Efficacy Plus Safety

Potential for Efficacy Plus Safety

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Page 17: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Four Translational Medicine Stories from Sanofi & Our Collaborators

PCSK9PCSK9

Heart DiseaseHeart Disease

TrkATrkA

PainPain

P53P53

CancerCancer

GlycolipidsGlycolipids

Gaucher’s Disease & Beyond

Gaucher’s Disease & Beyond

17

Driven by human genetics, human biology, bioinformatics and understanding human disease

Page 18: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

P53 for CancerTranslational Medicine Focus in CancerSanofi Oncology Highlighted in December 23, 2012

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

“A Single Drug to Kill Cancers in Many Forms” by Gina Kolata

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Page 19: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

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)

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Page 20: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

HDM2 Inhibits p53 Function

HDM2 - an enzyme that degrades p53

P53

HDM2

DNA

Damage

DNA Repair & ApoptosisX

20

Page 21: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

SAR405838, a Potent HDM2 Ligand

(Structure first described by Kussie PH. et al. Science. 1996, 274(5289):948-53)

Shaomeng WangU. Michigan

21

Page 22: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

HDM2 Inhibitor in Early Development, SAR405838, Mechanism of Action

SAR405838

P53

HDM2

DNA

Damage

DNA Repair & ApoptosisX

22

Page 23: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

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

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Page 24: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Mechanisms of P53 Inactivation in CancerExtension beyond liposarcoma…

Wild Type MutantP53 status:

Page 25: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Four Translational Medicine Stories from Sanofi & Our Collaborators

PCSK9PCSK9

Heart DiseaseHeart Disease

TrkATrkA

PainPain

P53P53

CancerCancer

GlycolipidsGlycolipids

Gaucher’s Disease & Beyond

Gaucher’s Disease & Beyond

25

Driven by human genetics, human biology, bioinformatics and understanding human disease

Page 26: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Gaucher DiseaseA Lysosomal Storage Disorder

Philippe C. E. Gaucher (1854-1918)

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Page 27: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Gaucher Disease Type 1: Pathophysiology

Gaucher Cell

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Page 28: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Gaucher Disease Inappropriate Tissue Accumulation of ‘Fat’

Liver

Bone Marrow

Spleen

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Page 29: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Gaucher Disease TreatmentReplace the Enzyme Ceredase, Cerezyme

So makes recombinant version Cerezyme produced in cultured cellsSo makes recombinant version Cerezyme produced in cultured cells

1994 approved by FDA 2004 available in 61 countries

But supply of Ceredase limited by availability of human placentaBut supply of Ceredase limited by availability of human placenta

22,000 placentae/patient/year

1964 Roscoe Brady reports disease caused by enzyme deficiency1964 Roscoe Brady reports disease caused by enzyme deficiency

Makes enzyme from human placenta - Ceredase

Page 30: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

We Have Come a Long Way in Gaucher Disease

1983 1991

2001 2011

Used with patient’s permission for NGF 201030

Page 31: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Enzyme Replacement TherapyCerezyme, Ceredase

NeuraminidaseSialidosis

b-Hexosaminidase ATay-Sachs

b-HexosaminidaseA and B

Sandhoff

b-Galactosidase

b-GalactosidaseKrabbe

Arylsulfatase AMetachromatic

Leukodystrophy

CeramidaseFarber

a-Galactosidase Fabry

glucocerebroside

Substrate ReductionTherapyEliglustat XX

Gaucher

ceramide

But We Have More to Accomplish for Gaucher’s PatientsSubstrate Reduction Therapy

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Page 32: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Eliglustat is a Phase 3 Program for Gaucher Patients

Ceramide Eliglustat

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Page 33: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Platelets +95%

Hemoglobin +2.3 g/dL

Phase 2 Data: Improvements in Hematologic and Organ Volume Parameters Through 4 Years

Mean with 95% CI

P<0.0001 for spleen, liver, and hemoglobin and P=0.0003 for platelets at 4 years.

-4

-2

0

2

4

6

Hb

Ch

ang

e f

rom

Bas

elin

e (g

/dL

)

-100%

-50%

0%

50%

100%

150%

Mean

Pe

rcen

t Ch

ang

e from

Ba

seline

Liver -28%

Spleen -63%

Year 1(n=22)

Year 2(n=20)

Year 3(n=18 to19)

Year 4(n=18 to 19)

Baseline(n=26)

-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.

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Page 34: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Decrease in Dark Marrow Signal with EliglustatPatient 0903, A 30-year Old Male

Baseline Year 3 Baseline Year 3

Proximal and Distal Femur

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Page 35: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Eliglustat - Transforming Lives

December 2006pre-treatment (18 yrs)

December 20093 years post treatment (21 yrs)

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Page 36: tranSMART Community Meeting 5-7 Nov 13 - Session 1:  Translational Drug Discovery - Transforming Science into Medicine

Two Pillars to Reinvent Biomedical R&D

Translational Medicine

Open Innovation

Based on Outstanding Science

Human Disease

Genetics, Informatics, Biology, Experimental

Medicine

Partnerships

Academic, Industry, Government, Patient

Groups

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