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Translational Drug Discovery
Transforming Science into MedicineAndy Plump, MD, PhD
Deputy to the President R&D, Research & Translational Medicine
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tranSMARTChilly-Mazarin/Longjumeau , France
Nov 5th, 2013
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
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Research & Early DevelopmentEvolution of Sanofi Strategy
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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
Two Pillars to Reinvent Biomedical R&D
Translational Medicine
Open Innovation
Based on Outstanding Science
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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
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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
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TRANSLATIONAL APPROACH TO TARGET SELECTION
DiseaseDiseaseTarget
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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
The Most Important Decision We MakeChoice of Target
High Confidence
HumanPharmacological Evidence
Human Genetics
Mechanistic Rationale or Unproven Animal Model
Low Confidence
TargetRationale
TargetRationale
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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
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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
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Driven by human genetics, human biology, bioinformatics and understanding human disease
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
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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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
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Therapeutic PCSK9 Antibody Decreased LDL-C by up to 73% on Top of Statin Treatment
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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
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
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Driven by human genetics, human biology, bioinformatics and understanding human disease
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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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
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Driven by human genetics, human biology, bioinformatics and understanding human disease
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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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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HDM2 Inhibits p53 Function
HDM2 - an enzyme that degrades p53
P53
HDM2
DNA
Damage
DNA Repair & ApoptosisX
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SAR405838, a Potent HDM2 Ligand
(Structure first described by Kussie PH. et al. Science. 1996, 274(5289):948-53)
Shaomeng WangU. Michigan
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HDM2 Inhibitor in Early Development, SAR405838, Mechanism of Action
SAR405838
P53
HDM2
DNA
Damage
DNA Repair & ApoptosisX
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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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Mechanisms of P53 Inactivation in CancerExtension beyond liposarcoma…
Wild Type MutantP53 status:
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
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Driven by human genetics, human biology, bioinformatics and understanding human disease
Gaucher DiseaseA Lysosomal Storage Disorder
Philippe C. E. Gaucher (1854-1918)
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Gaucher Disease Type 1: Pathophysiology
Gaucher Cell
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Gaucher Disease Inappropriate Tissue Accumulation of ‘Fat’
Liver
Bone Marrow
Spleen
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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
We Have Come a Long Way in Gaucher Disease
1983 1991
2001 2011
Used with patient’s permission for NGF 201030
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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Eliglustat is a Phase 3 Program for Gaucher Patients
Ceramide Eliglustat
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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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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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Eliglustat - Transforming Lives
December 2006pre-treatment (18 yrs)
December 20093 years post treatment (21 yrs)
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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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