2014 - ir - thematic seminar on new medicines
DESCRIPTION
2014 - IR - Thematic Seminar on New MedicinesTRANSCRIPT
IR THEMATIC SEMINAR ON NEW MEDICINES
November 20, 2014
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Forward Looking Statements
This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words "expects", "anticipates", "believes", "intends", "estimates", "plans" and similar expressions. Although Sanofi's management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labeling and other matters that could affect the availability or commercial potential of such product candidates, the absence of guarantee that the product candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives, the Group's ability to benefit from external growth opportunities, trends in exchange rates and prevailing interest rates, the impact of cost containment policies and subsequent changes thereto, the average number of shares outstanding as well as those discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under "Risk Factors" and "Cautionary Statement Regarding Forward-Looking Statements" in Sanofi's annual report on Form 20-F for the year ended December 31, 2013. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements.
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Agenda
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Introductory Comments ● Serge Weinberg, Chairman of the Board of Directors - CEO
Advancing Late Stage R&D Portfolio ● Elias Zerhouni, MD, President, Global R&D
Cerdelga™ / Lemtrada® ● David Meeker, MD, CEO, Genzyme
Praluent™ (alirocumab) ● Jay Edelberg, MD, PhD, Vice President, Head of the PCSK9 Development & Launch Unit ● Harold Bays, MD, Medical Director, President of Louisville Metabolic & Atherosclerosis Research Center
● Victoria Carey, Vice President, Head of U.S. Alirocumab Commercial
Q&A Session Break
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Agenda (cont’d)
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Toujeo® / Afrezza® / LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine, University of Western Ontario ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session Dengue vaccine
● Duane Gubler, ScD, MS, Professor, Emerging Infectious Diseases Program, Duke NUS, Singapore ● Nicholas Jackson, Associate Vice President R&D, Dengue Vaccine Company, Sanofi Pasteur ● Guillaume Leroy, Vice President, Dengue Vaccine Company, Sanofi Pasteur
Sarilumab / dupilumab ● Elias Zerhouni, MD, President, Global R&D
Conclusion ● Elias Zerhouni, MD, President, Global R&D
Q&A Session
IR Thematic Seminar Focus on Selected New Medicines and Vaccines
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Our main objectives for today are:
● Highlight the unmet medical needs addressed
by Sanofi’s key late stage assets
● Provide a high-level clinical profile of those products
● Share information on our strategy to seize their commercial potential
IR Thematic Seminar on New
Medicines
Help the Street to better evaluate near-term contribution from R&D
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Introductory Comments
Serge Weinberg
Chairman of the Board of Directors CEO
Introductory Comments ● Serge Weinberg, Chairman of the Board of Directors - CEO
Advancing Late Stage R&D Portfolio ● Elias Zerhouni, MD, President, Global R&D
Cerdelga™ / Lemtrada® ● David Meeker, MD, CEO, Genzyme
Praluent™ (alirocumab) ● Jay Edelberg, MD, PhD, Vice President, Head of the PCSK9 Development & Launch Unit ● Harold Bays, MD, Medical Director, President of Louisville Metabolic & Atherosclerosis Research Center
● Victoria Carey, Vice President, Head of U.S. Alirocumab Commercial
Q&A Session Break
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Agenda
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Sanofi – Opportunity for Sustainable Growth Driven by Platforms and Pipeline
Sanofi has transformed into a company positioned for sustainable growth through its growth platforms(1) and late-stage pipeline of new biologics
Growth platforms now account for 76% of sales(1)
47% of sales derived from biologics(2)
72% of R&D projects are biologics(3)
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(1) Growth Platforms include Emerging Markets, Diabetes Solutions, Vaccines, Consumer Healthcare, Animal Health, Genzyme & Other Innovative Products. In 9M 2014, sales from Growth Platforms accounted for 76.1% of Group sales or €18,801m
(2) Biologic sales in 9M 2014 were €11,625m and included insulins (Lantus®, Apidra®, Insuman®), Genzyme rare disease products, Lovenox®, Sanofi Pasteur vaccines, Merial vaccines, selected oncology products (Thymoglobulin®, Mozobil®, Zaltrap®), Lemtrada® and half of SPMSD sales (non-consolidated)
(3) R&D projects in clinical development: 33 NMEs and vaccines out of a total of 46 in Nov 2014
R&D Plays a Major Role in the Successful Execution of Sanofi’s Strategy
Deliver sustainable long-term growth
by improving patients' lives Seize value-enhancing growth
opportunities 3
Bring innovative products to market 2
Grow a global healthcare leader with synergistic platforms 1
9
Adapt structure for future challenges and opportunities 4
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10 10
R&D Is Entering a New Era by Increasing its Expected Contribution to the Sustainable Growth of Sanofi
2007 - 2009 2010 - 2013 2014+
Low R&D Productivity
R&D Transformation
Strong R&D Pipeline Emerging
• Advanced high-value development projects
• Created efficient global R&D organization
• Shifted portfolio from small molecules to biologics
• Grew value of external R&D collaborations
• Launch new products • Maintain discipline in
portfolio prioritization • Accelerate early-stage
development • Expand open innovation
model
• Confronted multiple R&D setbacks
• Faced low returns despite growing R&D spend
• Cleaned up R&D pipeline
Over the Last 7 Years, Sanofi Launched Several New Drugs but Only One with Peak Sales Potential >$1bn
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®
(ex-U.S.)
(U.S.)
(ex-U.S.)
®
(U.S.)
10 Launches 2007-2013
Sanofi Expects to Launch High Potential New Medicines and Vaccines at an Accelerated Pace Beginning in 2014
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Up to 18 Launches 2014 - 2020
sarilumab
(U.S.)
Dengue Vaccine
patisiran Anti-CD38 mAb
PR5i Vaccine
Vaccine
Shan5
(U.S.)
insulin lispro
Praluent™ alirocumab
Rotavirus Vaccine
Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions.
ILLUSTRATIVE
13 (1) At CER, 5 years for each product from and including the first full year of launch (2) Non-risk adjusted sales projections
Significantly Improving Returns from R&D
Up to 18 launches expected
10 launches achieved Potential cumulative
first 5 years sales
~€7.5bn(1,2)
2007 - 2013
2014 - 2020 Potential cumulative first 5 years sales
>€30bn(1,2)
10 Early Assets to Watch
1
2
3
4
5
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Vatelizumab(1) Multiple Sclerosis
IL4/IL13 bi-specific mAb Idiopathic Pulmonary Fibrosis
Anti-CD38 mAb Multiple Myeloma
Anti-GDF8 mAb Sarcopenia
Revusiran (TTRsc) Familial Amyloid Cardiomyopathy
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7
8
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rhASM Niemann-Pick type B
Neo GAA Pompe Disease
C-MET kinase inhibitor Solid Tumors
Anti-CXCR5 mAb Systemic Lupus Erythematosus
GLP-1/GIP co-agonist Diabetes
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(1) Anti-VLA2 mAb
Sanofi Has Additional Potentially Transformative Drugs at Earlier Stages of Development
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Sanofi Has Established a Model of Productive R&D Collaborations
● Global strategic collaboration
● Secured access to highly productive therapeutic human antibody platform
● A platform to regularly bring new mAbs into clinical development
Example 1 Example 2
● World-class RNAi technology
● Focus on genetically defined diseases with a clear translational model for RNA interference
● A platform for sustained drug development for rare diseases for Genzyme
Strengthening the R&D Leadership Team with New Talent
Philip Just Larsen Diabetes - Head of Research & Early Development
Jay Edelberg VP, Head of Alirocumab Unit
Gary Nabel SVP, CSO Andrew Plump
SVP, Research and Translational Medicine
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Christian Antoni VP, Head Development Immunology & Inflammation
Victoria Richon Oncology - Head of Research & Early Development
Eckhard Leifke Diabetes - Head of Development
Mike Panzara VP, Multiple Sclerosis and Neurology, Genzyme
Fabian Kausche Head of Merial R&D
Anthony Muslin VP, Cardiovascular & Fibrosis Unit
Hilary Malone VP, Global Regulatory Affairs John Shiver
SVP, R&D, Sanofi Pasteur
Jorge Insuasty SVP, Development Maya Said
VP, Strategy External Innovation & Science Policy
Dominique Carouge VP, Administration & Management
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Agenda
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Genzyme ● David Meeker, MD, CEO, Genzyme
Cerdelga™ (eliglustat)
Lemtrada® (alemtuzumab)
Genzyme Understands Unmet Needs of Gaucher Patients
61% of Gaucher patients would like their treatment to be an oral formulation(1)
(1) PeopleMetrics survey in Gaucher patients (n= 238) What improvements would you like to see in treatments for Gaucher Disease? 18
GD-1: Gaucher Disease type 1 ERT: Enzyme Replacement Therapy (1) Cerdelga™ is a highly specific ceramide analogue inhibitor of GL-1 synthesis with broad tissue distribution (2) AEs generally mild to moderate, most common related to treatment being diarrhea (6%), headache (4%), arthralgia (3%),
flatulence (3%), abdominal pain (3%), fatigue (3%), nausea (3%). Less than 2% of people treated with Cerdelga™ discontinued treatment because of a side effect.
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● Novel substrate inhibitor(1)
● Largest ever development program in Gaucher
● Almost 400 adults in 29 countries
● Efficacy demonstrated in untreated patients (ENGAGE) and in patients switching from ERT (ENCORE)
● Majority of adverse reactions are mild and transient(2)
● Genotyping required before starting therapy to determine CYP2D6 phenotype
● U.S. FDA approval granted in Aug 2014
● EU CHMP opinion expected in Q4 2014
The Only First-Line Oral Therapy for Adults with Gaucher Disease Type 1
ENGAGE - Change in Primary and Secondary Endpoints at 9 Months(1)
Efficacy Demonstrated in Untreated Patients (ENGAGE)
Parameter Eliglustat Placebo Difference P Value
Spleen Volume -28% +2% 30% <0.0001
Hemoglobin Level +0.7 g/dL -0.5 g/dL 1.2 g/dL 0.0006
Liver Volume -5.2% +1.4% 6.6% 0.0072
Platelet Count +32% -9% 41% <0.0001
(1) Pastores et al. ACMG 2013 (poster) 20
Efficacy Demonstrated in Patients Switching From ERT (ENCORE)
(1) Baris Feldman EWGGD 2014 (presentation) (2) Non-Inferiority with respect to primary composite endpoint (i.e. lower bound of 95% CI of difference > -25% non-inferiority margin)
95% 93% 96% 96%
85%
100% 100% 100%94% 94%
0%
20%
40%
60%
80%
100%
StableHemoglobin
StablePlatelets
Stable SpleenVolume
Stable LiverVolume
Composite
Eliglustat Imiglucerase
ENCORE - % of Patients Who Met Stability at 12 Months(1,2)
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Potential to grow Gaucher market
and expand Genzyme Gaucher
franchise to
>€1bn(2)
Genzyme Leading Innovation in Treating Gaucher Disease with Cerezyme® and Now Cerdelga™
~38% ~42%
(1) 2013 Gaucher Treatment Tracker Survey, n = 241 physicians from15 countries - Q4 2013 / Q1 2014 (2) Genzyme Gaucher franchise includes Cerezyme® (imiglucerase) and Cerdelga™ (eliglustat)
% of Gaucher Patients in Whom Physicians Would Use Cerdelga™(1)
Existing patients Newly diagnosed patients
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Agenda
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Genzyme ● David Meeker, MD, CEO, Genzyme
Cerdelga™ (eliglustat)
Lemtrada® (alemtuzumab)
New MS Treatment Goals - Focus on Patient Outcomes
Symptom Alleviation Decrease MS activity and improve quality of life
Halt or reverse damage and disability
Promote repair, remyelination, durable disability improvement
Improve disease control Freedom from disease activity
Convenient treatment regimens to improve compliance
Dosing options, new routes of administration, less frequent dosing
Maximize patient outcomes Superior effectiveness and favorable benefit/risk vs. existing treatment
24 MS: Multiple Sclerosis
Unmet Needs in MS New Goals
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A Large and Growing Global MS Market
(1) National Multiple Sclerosis Society (2) http://msj.sagepub.com/content/18/5/628.full.pdf (3) Adapted from Evaluate Pharma July 2014; Reported sales of Copaxone®, Avonex®, Rebif®, Betaseron/Betaferon®, Extavia®,
Tysabri® and Gilenya® for 2013; 2007 sales converted using €/$ of 1.37, 2013 sales and 2020e sales converted using €/$ of 1.33
Multiple Sclerosis Market Global Sales(3)
2013
2020e
U.S. ROW
~€12bn
~€17bn
2007
~€5bn
~43% ~57%
~50% ~50%
Multiple Sclerosis
● Serious disease with significant unmet medical needs
● Symptoms include fatigue, weakness, walking and balance difficulties, vision problems
● A major impact on family, social and professional life
● ~2.1m patients worldwide(1)
● ~410,000 patients in the U.S.(1)
● ~630,000 patients in EU(2)
2013-20 growth driven by new therapies, satisfying the unmet needs of convenient administration and more efficacious therapy
DMT: Disease Modifying Treatment SAD: sustained accumulation of disability (1) Eva Havrdova, ACTRIMS-ECTRIMS 2014 (2) ln CARE-MS l, Lemtrada® was significantly more effective than interferon beta-1a at reducing annualized relapse rates;
the difference observed in slowing disability progression did not reach statistical significance. ln CARE-MS ll, Lemtrada® was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in patients given Lemtrada® vs. interferon beta-1a.
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Sustained Reduction in Disability Through Year 4
Disease-Free Outcomes: 3-Year Follow-up of the CARE-MS Studies(1)
Parameter CARE-MS I CARE-MS II
% of Lemtrada® patients relapse-free 87% 82%
% of Lemtrada® patients 6-month SAD-free(2) 99% 96%
% of patients who did not receive alternative DMTs 99% 97%
% of Lemtrada® patients who did not receive retreatment in Year 3 82% 80%
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FDA Approval Is a Major Step Forward for People with Relapsing Forms of MS
(1) EU, Canada, Australia and other countries (2) The most common side effects of Lemtrada® are rash, headache, thyroid disorder, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia,
upper respiratory tract infection, herpes viral infection, urticaria, pruritus, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. Other serious side effects associated with Lemtrada® include autoimmune thyroid disease, autoimmune cytopenias, infections and pneumonitis.
(3) Label includes a boxed warning noting a risk of serious, sometimes fatal autoimmune conditions, serious and lifethreatening infusion reactions and noting Lemtrada® may cause an increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders. Lemtrada® is contraindicated in patients with HlV infection.
(4) Genzyme holds the worldwide rights to alemtuzumab and has responsibility for its development and commercialízation in MS. Bayer Healthcare receives contingent payments based on global sales revenue.
● Regulatory approvals granted in >40 countries(1)
● FDA approval received on Nov 14, 2014 ● Because of its safety profile, the use of Lemtrada® should generally be reserved
for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS(2,3)
● Only available in the U.S. through a restricted distribution program: the Lemtrada® Risk Evaluation and Mitigation Strategy (REMS)
● New dedicated salesforce recruited for the U.S.(4) ● Targeted U.S. launch approach for the first 3 months
● Ensuring appropriate education and confidence to prescribe
● Full launch expected throughout 2015
With Aubagio® and Lemtrada®, Genzyme is well positioned to grow its MS franchise
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Agenda
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Praluent™ (alirocumab)
CV Disease Burden & ODYSSEY Program
● Jay Edelberg, MD, PhD Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective ● Harold Bays, MD, Medical Director and President of Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9 Opportunity
● Victoria Carey Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions. (1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II clinical study
CV Disease Remains an Area of High Unmet Need
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(1) WHO. http://who.int/mediacentre/factsheets/fs317/en/ (EU, East. Mediterranean, The Americas, SE Asia, West Pacific, Africa) (2) NHLBI. http://www.nhlbi.nih.gov/about/documents/factbook/2012/chapter4.htm (3) WHO. http://www.who.int/whr/2002/en/whr02_en.pdf?ua=1 (4) U.S. NHANES, Market Scan, IMS and Sanofi estimates
LDL-C contributes to 60% of coronary heart disease and 40% of all ischemic stroke(3)
Cardiovascular disease causes 17.3m deaths per year(1)
Despite available treatment options, including statins, 24m high-risk patients fail to reach LDL-C goals(4)
The estimated economic cost of CVD is huge in the U.S.(2) ● $193bn in direct health expenditures ● $122bn in indirect cost of mortality
60%
17.3m
24m
$315bn
(1) Adapted from O’Keefe et al. J Am Coll Cardiol 2004;43:2142-6; LaRosa JC et al. N Engl J Med 2005;352:1425-35
LDL-C
25
20
15
10
5
0
CARE
TNT-80A TNT-10A
50 1.3
70 1.8
110 2.8
130 3.4
150 3.9
170 4.4
190 4.9
90 2.3
210 5.4
(mg/dL) (mmol/L)
CHD Events (%) Primary prevention trials
AFCAPS
WOSCOPS
ASCOT
AFCAPS
WOSCOPS
ASCOT
4S
CARE
LIPID
LIPID
Secondary prevention trials
Placebo
Placebo
4S
Active treatment
Active treatment
Lowering LDL-C with Statins Is Effective in Decreasing CV Risk
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Despite high efficacy of statin therapy, unmet needs persist in familial hypercholesterolemia, high CV risk and statin intolerance
LDL-C Prevention Trials(1)
Despite Current Therapy, a Significant Proportion of Hypercholesterolemic Patients Are at High CV Risk
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Diabetes(2)
10.1m
Secondary Prevention without Diabetes
10.3m
Statin Intolerant 2.9m
Heterozygous Familial Hypercholesterolemia
24m Patients With High CV Risk
(1) U.S. NHANES, Market Scan, IMS and Sanofi estimates (2) Diabetes with 2 Risk Factors with or w/o CV Event
Secondary Prevention
5.3m
Primary Prevention
4.8m
2016 Estimates for U.S., EU Top 5 and Japan (in million patients)(1)
1.2m
Sense of Urgency to Lower LDL-C to Reduce CV Risk Varies According to Patient Types
● Well defined but underdiagnosed population
● High engagement of patients
● Large proportion of uncontrolled patients with current therapies
HeFH
● High LDL-C levels comparable to HeFH
● Pragmatic approach used by physicians but no objective definition
● Low satisfaction level with existing treatment options
Statin Intolerant
● Large and diverse population with associated CV risks
● Large proportion of patients with previous CV event
● Strong awareness of risk, especially for recent events
● Significant overlap with diabetes population
High CV Risk
HeFH: heterozygous familial hypercholesterolemia 32
The Development of Alirocumab, an Anti-PCSK9 mAb, Is a Prime Example of Modern Translational Medicine
(1) Seidah NG. Proc Natl Acad Sci USA 003;100:928-33 (2) Abifadel M. Nat Genet 2003;34:154-6 (3) Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100-5 (4) Rashid S. Proc Natl Acad Sci USA 2005;102:5374-79 (5) Cohen JC. N Engl J Med 2006;354:1264-72
The PCSK9 Discovery Decade
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PCSK9 discovery(1,2) PCSK9-targeted
mAb preclinical(8)
Gain-of-function mutations observed
2003 2004 2005 2006 2007 2008 2009 2010 2012 2013
Proof of principle in animals(3,4)
Human target validation(5,6,7)
2011
First subject treated with PCSK9 mAb
Phase II study results(9)
First Phase III study results
Loss-of-function mutations observed
(6) Zhao Z. Am J Hum Genet 2006;79:514-23 (7) Hooper AJ. Atherosclerosis 2007;193:445-8 (8) Chan JC. Proc Natl Acad Sci USA 2009;106:9820-5 (9) Lambert G et al. J Lipid Res 2012; 53(12): 2515-24
2014
U.S./EU regulatory submissions
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● Largest Phase III program
● 14 trials with >23,500 patients
● Primary endpoint evaluated at 24 weeks
● Double-blind design (6, 12, 18 and 24 months)
A Differentiated Clinical Development Program
● Evaluation of q2w and q4w dosing regimens and 75mg and 150mg doses
● Interim data on lower rate of adjudicated major CV events in LONG TERM trial
● ≥4,500 patient years exposure(4)
All studies: every two weeks (q2w) regimens (75/150mg with potential dose ↑ from 75 to 150 mg) except CHOICE I (300mg q4w) and II (150mg q4w) (1) Open-Label Extension open to HeFH patients included in other studies (2) ODYSSEY MONO included patients at moderate CV risk (3) ODYSSEY CHOICE II includes some patients on additional non-statin lipid-lowering therapy (4) ≥4,500 double-blind patient years at completion of pivotal studies in initial submission
HeFH High CV Risk
On top of max tolerated statin
On top of max tolerated statin
FH I (n=486)
COMBO II (n=720) FH II (n= 249)
HIGH FH (n=107)
OLE(1) (n≥1,000)
COMBO I (n=316) OPTIONS I (n=355)
OPTIONS II (n=305)
CHOICE I (n=700)
MONO(2) (n=103)
ALTERNATIVE (n=314)
CHOICE II(3) (n=200)
On top of regular statin doses
OUTCOMES (n=18,000)
LONG TERM (n=2,341)
Not receiving statin
Statin Intolerant
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Next Regulatory Milestones and Development Steps
(1) Rationale and design in Schwartz GG et al. Am Heart J 2014;0:1-8.e1.
Regulatory submissions in the U.S. and EU on track ● U.S. submission expected before year end 2014
6-month FDA priority review from filing date expected ● EU submission also targeted before year end 2014
ODYSSEY CHOICE I & II and Open Label Extension (OLE) ongoing ● CHOICE I & II explore monthly dosing of alirocumab ● Expect to report primary endpoints in 2015 and beyond
ODYSSEY OUTCOMES ongoing (n=18,000)(1)
● Assess the potential of alirocumab to demonstrate CV benefit
1
2
3
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Agenda
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Praluent™ (alirocumab)
CV Disease Burden & ODYSSEY Program
● Jay Edelberg, MD, PhD Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective ● Harold Bays, MD, Medical Director and President of Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9 Opportunity
● Victoria Carey Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
(1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II clinical study
Study Dosing q2w
Baseline LDL-C (mg/dL)
LDL-C Change from Baseline at 24 Weeks
Alirocumab Comparator
HeFH
HIGH FH 150 mg 198 ↓ 46% ↓ 7% placebo
On top of max statin doses
FH I 75/150 mg(1) 145 ↓ 49% ↑ 9% placebo
FH II 75/150 mg(1) 134 ↓ 49% ↑ 3% placebo
High CV Risk
LONG TERM 150 mg 122 ↓ 61% ↑ 1% placebo
COMBO I 75/150 mg(1) 102 ↓ 48% ↓ 2% placebo
COMBO II 75/150 mg(1) 108 ↓ 51% ↓ 21% ezetimibe
OPTION I 75/150 mg(1) 105 ↓ 44-54% ↓ 21-23% ezetimibe ↓ 5% statin x2 ↓ 21% statin switch
On top of regular statin
doses OPTION II 75/150 mg(1) 111 ↓ 36-51% ↓ 11-14% ezetimibe
↓ 16% statin switch
Statin Intolerant ALTERNATIVE 75/150 mg(1) 191 ↓ 45% ↓ 15% ezetimibe
Not receiving statins Moderate
CV Risk MONO 75/150 mg(1) 140 ↓ 48% ↓ 16% ezetimibe
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Significant and Consistent LDL-C Reduction across All 10 Reported Trials
Primary efficacy endpoint met in all 10 reported trials
(1) Per protocol dose increase to 150 mg possible based on pre-specified LDL-C levels
Achieved LDL-C Over Time(1) All Patients on Background of Maximally Tolerated Statin ± other LLT
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LONG TERM
Robust and Durable LDL-C Reduction Maintained over 52 Weeks
Mean (SE) LDL-C in mg/dL
0
20
40
60
80
100
120
140
Week
118.9 mg/dL (+0.8%)
48.3 mg/dL (−61.0%)
123.0 mg/dL (+4.4%)
53.1 mg/dL (−56.8%)
Difference −61.9%
0 4 8 12 16 24 36 52
Difference −61.3%
Placebo Alirocumab 150 mg q2w
LLT: Lipid lowering therapy Intent-to-treat analysis (1) LDL-C: Calculated LDL-C, least-squares (LS) means (SE standard error)
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Consistent LDL-C Reduction across a Range of Baseline LDL-C Values
Mean % Change in LDL-C from Baseline to Week 24 Placebo Alirocumab
-61.3% -62.0% -59.8% -59.5%
13.6% 0.5%
-5.2% -18.2%
-70-60-50-40-30-20-10
01020
100 to <130 mg/dL <100 mg/dL
130 to <160 mg/dL ≥160 mg/dL
Interaction p-value <0.0001
n=470 n=241 n=562 n=285 n=271 n=143 n=227 n=111
LDL-C Change from Baseline(1) All Patients on Background of Maximally Tolerated Statin ± Other LLT
LLT: Lipid lowering therapy Intent-to-treat analysis (1) LDL-C: Least-squares (LS) means
LONG TERM
40
All patients on background of maximally tolerated statin ± other lipid-lowering therapy Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients overall who completed W78 visit) (1) Confirmed by adjudication. Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD
death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization, ischemia driven coronary revascularization procedure [PCI, CABG]
(2) Company MedDRA Queries (CMQ)
Alirocumab (n=1550)
Placebo (n=788)
General allergic reaction events 9.0 9.0
Treatment-emergent local injection site reactions 5.8 4.3
Myalgia 4.9 3.0
Neurological events(2) 4.2 3.9
All cardiovascular events(1) 4.0 4.4
Ophthalmological events(2) 2.5 1.9
Neurocognitive disorders(2) 1.2 0.5
ALT increase 1.1 0.5 CPK increase 0.5 0.5 AST increase 0.2 0
Safety Profile from Long Term Study LONG TERM
% of Patients with Treatment Emergent Adverse Events of Interest
41
Post-hoc Adjudicated Major Adverse Cardiovascular Events(1)
TEAEs: Treatment emergent adverse events (1) Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring
hospitalization. LLT, lipid-lowering therapy (2) ≥ 52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit
Safety Analysis(2)
Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT 150 mg q2w
788 1550
776 1534
731 1446
703 1393
682 1352
667 1335
321 642
127 252
84 72 60 48 36 24 12 0
0.06
0.05
0.03
0.02
0.01
0.00
0.04
Cum
ulat
ive
prob
abili
ty o
f eve
nt Cox model analysis:
HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01
Weeks No. at Risk Placebo Alirocumab
Mean treatment duration: 65 weeks
LONG TERM
Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event
Patient at LDL-C Goal
42
ALTERNATIVE
Safety and Efficacy in Statin Intolerant Patients with Very High LDL-C (~190mg/dL)
Baseline LDL-C levels (ITT): 191.1 and 194.2 mg/dL in alirocumab and ezetimibe arms (1) Intent-to Treat analysis (2) Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue (3) Cox model analysis (95% CI for alirocumab vs atorvastatin: 0.38 to 0.99 ; for alirocumab vs ezetimibe: 0.47 to 1.06) (4) 89.5% of randomized patients entered the Open-label Treatment Period (including 94% of those randomized to atorvastatin) and received alirocumab
Skeletal Muscle Adverse Events
Goals alirocumab ezetimibe
LDL-C <70 mg/dL or <100 mg/dL (depending on risk)
42% 4%
LDL-C <100 mg/dL 61% 10%
alirocumab vs.
atorvastatin
alirocumab vs.
ezetimibe
Hazard Ratio 0.61 0.71
Nominal P(3) 0.042 0.096
Only 0.7% myalgia leading to discontinuation with alirocumab in open-label treatment period(4)
∆: P<0.0001(1)
Significantly More SI Patients Achieved LDL-C Goals
with Alirocumab
Fewer Skeletal Muscle Adverse Events(2) with Alirocumab
than with Atorvastatin
Significant and sustained reductions in LDL-C over 1 year on top of existing therapies across different patient populations
Balanced safety and tolerability profile across patient groups with preliminary data on CV safety from long-term treatment trial
Flexible dosing providing options for physicians and patients
1mL dosage forms for subcutaneous self-injection at home
Alirocumab Has the Potential to Transform LDL-C Management
43
44 44
Agenda
44
Praluent™ (alirocumab)
CV Disease Burden & ODYSSEY Program
● Jay Edelberg, MD, PhD Vice President, Head of the PCSK9 Development & Launch Unit
Clinical Perspective ● Harold Bays, MD, Medical Director and President of Louisville Metabolic and Atherosclerosis Research Center(1)
Evaluating the PCSK9 Opportunity
● Victoria Carey Vice President, Head of U.S. Alirocumab Commercial
Q&A Session
(1) Harold Bays is an investigator of the ODYSSEY OPTIONS I and II clinical study
Key Factors Impacting Uptake of PCSK9 mAbs in High CV Risk Patients
45
Physician awareness
Likelihood to prescribe
Efficacy attributes
Patient acceptance
Payor dynamics
1
2
3
4
5
1
62%
49%
36%
73%
54% 52%
Very High and Growing Awareness
46
(1) Aided and Unaided Awareness. Questions: ”Please name and describe all the potential treatments in development for hypercholesterolemia of which you are aware” and “Please indicate your familiarity with the following classes of therapy in development for hypercholesterolemia”
Source: Proprietary survey conducted in U.S., UK and Germany
~13,000 ~1,100 ~3,500
Percent of Specialists Aware of PCSK9 Inhibitor Class(1)
Q4 2013 Q2 2014
Estimated Number of Specialists Aware
High Likelihood to Prescribe
64%
49%
63% 71%
64% 71%
47
(1) Question: “Based on your experiences and anything you might have heard, how likely would you be to prescribe a PCSK9 Inhibitor for the treatment of hypercholesterolemia, if available in the future? (Answers based on own physician’s knowledge without being exposed to any product profile)
Source: Proprietary survey conducted in U.S., UK and Germany
2
Percent of Specialists Likely/Very Likely to Prescribe a PCSK9 Inhibitor(1)
Q4 2013 Q2 2014
Efficacy Attributes Are Most Important for Specialists
48
Substantial data in high CV risk patients like diabetes, CHD, stroke
Achieves significant reduction of LDL-C, particularly high CV risk patients
Achieves significant reduction of LDL-C for majority of patients
Good treatment option for statin intolerant patients
Demonstrates good tolerability profile resulting in minimal monitoring of AEs
Demonstrates significant decrease in CV morbidity / mortality
OOP: Out of pocket Source: Proprietary survey conducted in the U.S.
3
Covered, affordable for patients (reasonable level of OOP cost to patients)
Acts on atheroma plaque
Achieves significant increase of HDL-C
U.S. Specialists
67
78
95
116
146
163
211
232
247
Average score of importance = 100
High Patient Acceptance and Perception of Benefit
49
DM: Diabetes Mellitus CKD: Chronic Kidney Disease Source: Proprietary surveys conducted in the U.S/EU (2012/2013) The HeFH patient population was not part of the survey conducted in Europe
4
Share of Patients Likely / Very Likely to Accept and Fill PCSK9 Treatment Share of Patients Likely/Very Likely to Accept and Fill PCSK9 Treatment Prescription
70%
52% 52% 53%
HeFH Statin Intolerants
Primary Prevention (DM/CKD)
Secondary Prevention
70% Managed by Endos
Statin Intolerants
Primary Prevention (DM/CKD)
Secondary Prevention
65% 65% 65%
50
Satisfaction Rating ODYSSEY MONO(2)
(1) Some patients have been titrated up to 150mg; >70% of patients remained on 75 mg (2) 53 respondents out of 105 patients who completed the ODYSSEY MONO study Question: “How do you rate your overall experience in performing an injection on yourself with the study drug auto-injector pen?”; 98% respondents satisfied
Flexibility in Dose & Delivery Options Available Auto-Injector
75 mg(1)
150 mg
q2w
98%
Broad Experience of Home Self-Injection with Alirocumab 4
Payor Dynamics
51
5
Important Factors for the Alirocumab Payor Value Proposition
Payor price pressure on innovations
Large unmet medical need in a generic market
Importance of LDL-C as a primary risk factor for CV disease and of LDL-C lowering to reduce the risk
Sense of urgency to treat a condition with significant adverse outcomes and system costs
Recognition of PCSK9 inhibitors as effective tool in the treatment algorithm for appropriate patients
Definition of appropriate patients that can be targeted to ensure maximum allowable access to target populations
Engaging Significant Resources to Ensure Alirocumab Launch Success in the U.S.
52 Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions.
Praluent™ alirocumab
Q&A
53
BREAK
54
Return in 15 Minutes
55 55
Agenda
55
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
(1) Motivation and characterization of insulin patients, patient interviews (2) Highs = Hyperglycemia / Lows = Hypoglycemia
Frustration Imprisonment
Embarrassment
56
“I hate this so much. It’s like a constant thorn in my side that I can’t rip
out”
“When I experience a high(2), I go into a state of
euphoria and worry others notice”
At start, a challenge ● Frustration of poor
control
● Fear of hypoglycemia
At stay, a variable experience
● Satisfaction?
● Motivation?
There Is Need for an Improved Basal Insulin Experience to Get More Patients to Control(1)
Diabetes Patients in the U.S. (Random Sample)
Despite Treatment, Many Patients with Diabetes Are Still not at A1c Goal(1)
57
47% 47%
53% 53%
2013(437)
2013(2215)
Uncontrolled (>7%)
Controlled (<=7%)
T1D Patients T2D Patients
A1c: glycated haemoglobin (1) Adelphi Real World Diabetes Disease Specific Programme (DSP) X, 2013 Base: U.S. diabetic patients where doctor has stated most recent A1c (random sample) All patients are treated patients and must be on an OAD, GLP-1 or insulin
(1) Idea Exchange Report Toujeo® Titration Exploration (9.4.2014); Sanofi market research
>1 month
37%
<1 month
63%
58
Timing of Dose Increase after First Week on Basal Insulin
Patients wish for a quick titration
experience to achieve immediate control
but fear hypos
Most Patients Delay Increasing their Dose After Initiation of Therapy Despite Not Being at Goal(1)
(1) Data on file – Real-World Data on Hypos Following Basal Insulin Initiation (2) Peyrot M et al. Diabet Med 2012;29:682–689. (3) Leiter LA et al. Can J Diabetes 2005;29:186–192
modify their insulin dose after experiencing a severe hypoglycemia event(2) 6 in10
patients
59
4 in10 people experienced hypoglycemia within the first month(1)
of people who experienced hypoglycemia within 6 months of initiation had discontinued within 1 year(3) 77%
Patients Respond to Hypoglycemia by Modifying their Dose or Discontinuing Therapy
Inappropriate Diabetes Management Leads to Costly Consequences
60
Microvascular Complications
● Diabetic Retinopathy
● Diabetic Nephropathy
● Diabetic Neuropathy
(1) Endocrinol Metab Clin 1996;25:243 - 254 (DCC Trial) (2) Diabetes Care Publish Ahead of Print, published online March 6, 2013
Risk of Complications and A1c(1)
25% to 45% of diabetes-attributed medical expenditures spent treating complications of diabetes(2)
A1c (%)
Relative Risk in %
1
3
5
7
9
11
13
15
6 7 8 9 10 11 12
Retinopathy Nephropathy
Microalbuminuria Neuropathy
Macrovascular Complications
● Stroke
● Heart Disease
● Peripheral Vascular Disease
50% of basal insulin patients are
not at A1c goal
30% to 60% experience hypoglycemia
59% of new to Lantus® patients in the U.S. have
significant compliance gaps
(1) IMS Lifelink; U300 segmentation; Sanofi market research; expert interviews; Sanofi analysis 61
The launch of Toujeo® will offer opportunities to address unmet needs
Hypoglycemia Contributes to Poor Compliance and Affects Treatment Efficacy(1)
62 62
Agenda
62
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
Patients Hate Hypoglycemia
Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212.
● Very unpleasant and disruptive symptoms (e.g. blurry vision, rapid heartbeat, sudden mood changes, headache, trouble concentrating)
● A medical emergency that can result in fainting, seizures, unconsciousness, coma and death
Mild to moderate
hypoglycemia
Severe hypoglycemia
Nocturnal hypoglycemia
● Imagine going to sleep each night needing to protect yourself against hypoglycemia while you sleep
● Imagine sleeping next to someone and worrying about whether their blood sugar is high enough
63
Toujeo®
A Smoother and Prolonged PK/PD Profile vs. Lantus®
Lantus®
Toujeo® Lantus®
64
Median insulin concentration, µU/mL
Glucose infusion rate, mg/kg/min
3
0
2
1
Lantus®
0 6 30 36 24 18 12
Toujeo®
Time, h
160
100
140
120
Lantus®
0 6 30 36 24 18 12
Toujeo®
Lantus® 10
20
0 6 30 36 24 18 12
Toujeo®
0
Blood glucose, mg/dL
64
Reduction of Volume by 2/3
Reduction of Depot Surface Area by 1/2
More Constant PK/PD Profile(1)
PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile (1) Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22.pii:DC_140006
Type 1 Diabetes - Continuous Glucose Monitoring Study(1)
Offering Greater Consistency Over the Course of the Day
Average 24-hour glucose profiles showed a more
constant glucose level with Toujeo®
vs Lantus®
65 (1) Bergenstal RM et al. Poster presentation at EASD 2014; data combining morning and evening injections
Time, h
Lantus®
Toujeo®
11
10
9
8
7 0 2 4 6 8 10 12 14 16 18 20 22 24
All Studies of EDITION Phase III Program Met their Primary Endpoint(1,2)
66
(1) Non inferiority on A1c (2) Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990; Bolli GB et al. Poster
presentation at EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014; Abstract 148; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975
vs.
EDITION 1 EDITION 2
EDITION 3
EDITION JP1
EDITION 4
EDITION JP2
Primary Endpoint Non inferiority (Change in A1c) Population
T2DM on basal and mealtime insulin + OADs
T2DM on basal insulin + OADs
T2DM insulin-naïve + OADs
T1DM on basal and mealtime insulin
T1DM on basal and mealtime insulin
T2DM on basal insulin + OAD
0
10
20
30
40
50
-20%
-31%
% Participants with ≥1 Confirmed and/or Severe Hypoglycemia(2)
Baseline to week 8
Baseline to month 6
Week 9 to month 6
67
Nocturnal Hypoglycemia(1,3)
Pooled analysis of EDITION 1-2-3 Lantus®
Toujeo®
-25%
Benefit on Nocturnal Hypoglycemia
(1) Defined as 00:00–05:59h (2) ≤70 mg/dL (≤3.9 mmol/L) (3) Ritzel R et al. Poster presentation at EASD 2014; Abstract 963
RR 0.75 (0.68 to 0.83)
RR 0.69 (0.58 to 0.81)
RR 0.80 (0.71 to 0.91)
68
0
10
8
4
2
4 8 12 16 20 24 28
6
Time, weeks 0
0
3
Lantus®
Toujeo®
2
1
4 8 12 16 20 24 28 Time, weeks
0
Nocturnal(2) At any time(3)
(1) Confirmed events based on plasma glucose ≤3.9 mmol/L (≤70 mg/dL); Ritzel RA, et al. Poster presented at EASD 2014; Abstract 963. (2) 00:00–05:59h (3) 24 h
-31%
-14%
Confirmed or Severe Hypoglycemia per Patient per Year Significantly Lower
Cumulative Mean Number of Confirmed or Severe Hypoglycemia per Participant(1,3)
Pooled analysis of EDITION 1-2-3
p=0.0002
p=0.0116
Hypoglycemia Benefit Consistently Demonstrated
69
(1) Pooled analysis of Edition 1,2,& 3 - Type 2 Diabetic patients; Ritzel R et al. Poster presentation at EASD 2014; Abstract 963 (2) % Participants with ≥1 Confirmed (≤70 mg/dL [3.9 mmol/L]) and/or Severe Hypoglycemia baseline to month 6: -9% at any time and -25% nocturnal
(00:00–05:59h) / % Participants with ≥1 Confirmed (<54 mg/dL [3.0 mmol/L]) and/or Severe Hypoglycemia:-19% at any time and -27% nocturnal (00:00–05:59h)
(3) Lower rate of confirmed or severe hypoglycemia with Toujeo® during the night until 10 am (4) EDITION 1-1 year; Riddle MC et al. Poster presentation at EASD 2014; Abstract 980: % of participants reporting ≥1 event from baseline to month
12: -22% and annualized event rates from baseline to month 12: -26%
Benefit maintained regardless of hypoglycemia definition(1,2)
● ≤70 mg/dL [3.9 mmol/L] OR <54 mg/dL [3.0 mmol/L]
Consistent benefit on hypoglycemia independent of definition of night duration(1,3)
● Standard definition: 00:00–05:59h
● Lower rate up to 10:00h
Benefit in nocturnal hypoglycemia maintained over time either as % of Patients or Event Rate(4)
7,0
7,5
8,0
8,5
BL W12 M6 M12 M9
7,0
7,5
8,0
8,5
LS: Least Squares (1) Type 2 Diabetic patients uncontrolled with basal bolus (2) Type 2 Diabetic patients uncontrolled with Basal + OAD 70
EDITION 1(1)
EDITION 2(2)
Toujeo®
Lantus®
Toujeo®
Lantus®
LS Mean (95% CI) Difference in A1c Between Groups at Month 12
A1c (%) mean ± SE
Sustained Glycemic Control at 1 Year
8.5
8.0
7.5
7.0
8.5
8.0
7.5
7.0
−0.17% p=0.0074
0.06% p=0.4932
(1) Type 2 Diabetic patients; Ritzel R et al. Poster presentation at EASD 2014; Abstract 963
Weight Change Difference Maintained Over Time
71
LS mean difference: –0.28 kg p=0.039
1.5
1.0
0.5
0.0
-0.5 BAS Week
2 Week
4 Week
8 Week
12 Month
4 Month
6
Lantus®
Toujeo®
Mean Weight Change (kg ± SE)(1)
Pooled analysis of EDITION 1-2-3
0
10
20
30
40
50
60
70
Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal (≤70 mg/dL [3.9 mmol/L])
Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal (≤70 mg/dL [3.9 mmol/L])
Flexible dosing
Fixed dosing
(1) Riddle MC et al. Poster presentation at ADA 2014; Abstract 919-P 72
T2D Patients who Occasionally Adapted the Timing of their Once-Daily Injections of Toujeo® (24 ± 3 h) Did Not Impact Glycemic Control or Affect Frequency of Hypoglycemia(1)
72
EDITION 1 EDITION 2 Percentage of patients experiencing ≥1 event, %
Flexibility in Injection Time (24 hours ± 3 hours)
A Unique Clinical Profile
● Easy insulin initiation
Smoother glucose lowering and prolonged PK/PD profile
Less hypoglycemia during the initiation period when titration occurs
Less weight gain
● Long lasting benefit
Sustained glucose control at 1 year
Benefit in reduction of hypoglycemia maintained at 1 year
Flexibility in injection time, when occasionally patients need it
73 PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile
74 74
Agenda
74
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
The Next Generation of Basal Insulin with a Smoother PK/PD Profile than Lantus®
TOUJEO • Smoother PK/PD
profile than Lantus®
• Full 24h coverage • Less hypos than
Lantus • Improved patient
experience
LANTUS
• Once daily • Less hypos
than NPH • Treat to target NPH
75 PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile
Total Addressable U.S. Basal Insulin Market for Toujeo® Is ~6m Patients(1)
(1) Sanofi market research, expert interviews
Million patients
● 14.3m insulin naïve drug-treated patients
● 1m new basal insulin starts every year
76
+ Levemir®
Existing Patients
5m
Million patients
Estimated Annual New Basal Insulin
Naïve Patients
1m/year
Total Addressable Market
~6m
A Compelling Value Proposition
(1) Jax T et al. Poster presented at EASD 2013; Abstract 1029. Available at http://www.easdvirtualmeeting.org/resources/6226 Accessed May 2014 (2) Ritzel R, et al. Diabetes 2014;63 (suppl 1A) (3) Riddle MC et al. Poster presentation at EASD 2014; Abstract 980 (4) ORIGIN Trial Investigators. N Engl J Med. 2012 Jul 26;367(4):319-28 77
77%
US EU Top 5
52%
US EU Top 5
Aided Awareness of Toujeo®(1)
Scientific Data Communication Created Strong Pre-launch Awareness and Willingness to Prescribe
78 (1) Sanofi Market Research – Awareness and Trial Tracking (August 2014)
50%
75%
% of Endocrinologist Willing to Prescribe
Willingness to Prescribe Toujeo®(1)
40%
60%
% of Endocrinologist Aware
Target Switch Segments Represent Almost 60% of Existing Basal Insulin Patients Pre-Launch(1)
(1) Toujeo® segmentation survey: Segmentation solutions and expert interviews (2) Target Patient Profile
Engaged and satisfied (Type 1 / Type 2 controlled)
Motivated but are falling short (Type 2 basal bolus, controlled w/ hypos)
Frustrated and challenged: Type 1 (Uncontrolled)
Frustrated and challenged: Type 2 (Uncontrolled)
More limited drivers for engaged and satisfied patients to switch from current treatment 43%
22%
6%
29%
Segment size % basal insulin pop
Receptive to Toujeo® TPP(2)
Concerned about hypos
Looking for better options
Natural switchers
Require convincing
79
May become unsatisfied over time
An Enhanced SoloStar® Device: Accurate, Precise and Easier to Use
80
● Smaller injection volume(1)
● Ergonomic design improvements
● No additional training needed(1)
● 50% more units per pen (450 IU)(1)
Toujeo® SoloStar®: Adapted for the Next-Generation Basal Insulin
(1) Compared to Lantus® SoloStar®
Regular touch points
Mix of face to face/ phone/ webinar
interactions
Adapted locally
Toujeo® and Customized Patient Support Program Intended to Ensure a Smoother Start and Better Stay
81
A Customized Patient Support Program to achieve personalized glycemic goals
● Support successful initiation of Toujeo® following prescription
● 31% of diabetes patients do not initiate prescription(1)
● Support patients to up-titrate quickly to target A1c
● 15% to 20% of patients discontinue insulin in first 3 months(2)
● Motivate patients to stay on therapy
(1) M Fischer et al., J Gen Intern. Med, 25(4):284-90, 2010 (2) Lantus® satisfaction study, Impact Rx, Dec 2012 (US/EU5 & JP)
Improved clarity and impact of Lantus® promotion messages Raised PCP preference for Lantus®
Increased sales force call productivity From 35% to 90% ≥ 8 calls/day
Increased sales force call targeting Significant improvement in % calls to priority customers
Raised perception of Sanofi on “best in meeting physician needs”
+4 pts over baseline
82
Ensuring U.S. Sales Force Readiness for Launch
Enhancement of U.S. commercial effectiveness to improve Lantus® performance and prepare for the Toujeo® launch
Toujeo® is a better insulin vs. Lantus® based
on the EDITION program
Achieving Payor Access is Necessary for Franchise Conversion
83 83
● Current Lantus® access and volume provides foundation for Toujeo®
● Price expected not to be a barrier to access
● Maintain top quality access over time with a strong documented value proposition
Preparing for Launch
July 2014: FDA acceptance of NDA review
● Expected regulatory decision: Q1 2015
May 2014: EMA acceptance of the marketing authorization application
● Expected regulatory decision: Q2 2015 July 2014: NDA submission to Japanese Health Authorities
● Expected regulatory decision: Q2 2015
84
Regulatory Timelines:
Ensure Toujeo® patients have an improved insulin experience
Convert basal insulin users, especially Lantus®, to Toujeo®
Become the preferred basal insulin
Our Diabetes Team is Focused on Improving Patient Outcomes
85
3
2
1 Ambition for
to generate a substantial
proportion of Sanofi’s glargine
volume in the U.S. within 3 years after launch
86 86
Agenda
86
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
Patients on 2+ OADs Are Resistant to Starting Insulin Therapy
The Majority of Patients on 2+ OADs Resist Starting Insulin Therapy(1,2)
Resistant because of injections Resistant not because of injections Not Resistant to taking insulin
66%
% of Patients
39%
27%
66% Resistant to starting insulin
87
(1) Nielsen DD Quantitative Market Research (T2D patients on 2+OADs, n=77. Note that these data are patient reported captured in a market research setting and do not necessarily reflect actual future behavior.
(2) When physician recommends initiating insulin therapy
Indication
A New and Innovative Treatment Option for Diabetes
● Afrezza® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes
● Not recommended for patients who smoke
Large 5-year safety study to assess potential risk of pulmonary malignancy to be conducted
● Acute bronchospasm has been observed in patients with asthma and COPD using Afrezza®
● Contraindicated in patients with chronic lung disease such as asthma or COPD
Afrezza® (insulin human) Product Label
Black Box Warnings & Precautions
88
● Most common adverse event is cough ● Should not be used in patients with
active lung cancer
Dosage & Administration
● Administered at the beginning of a meal ● Before initiating, perform a detailed
medical history, physical exam, and spirometry (FEV1) in all patients to identify lung disease
COPD: Chronic Obstructive Pulmonary Disease
Focus of Initial Commercial Strategy for Afrezza®(1,2,3)
~2.0m ~1.1m
Insulin Initiation Insulin Intensification
Uncontrolled patients(1) (A1c > 7%) Controlled patients (A1c < 7%)
Many Diabetes Patients Are Not at A1c Goals Due to Delayed Insulin Initiation and Intensification
(1) Adelphi Real World: Diabetes DSP 9 (2012), Data on File. US Data. (2) NHANES Data (2009-201), CDC, US Data, 16% of PWD are smokers; 19% are non-smokers w/ COPD (Chronic Obstructive Pulmonary Disease)
and/or Asthma; (3) Sanofi market research (4) Patients for whom Afrezza® is contraindicated
Patients on 2+ OADs or GLP1 ± OADs Patients on Basal Insulin or Basal ± GLP1 ± OAD
Smokers, patients with asthma & COPD(2,4)
89
~3.1m Diabetes Patients
Device is Unique and Innovative
90
● Small, discreet, easy-to-use inhaler
● No cleaning required
● No parts need to be replaced
● Breath powered
● Efficient delivery to the deep lung
● Minimal training needed
● Disposed after 15 days of use
91
Afrezza®
Higher bioavailability and faster clearance
Small device
Easy to use
Doses equivalent to insulin units
Less training required
No cleaning requirement
Exubera®
Lower bioavailability and slower clearance
Large device
Complicated titration system
Doses were in milligrams
Time consuming in-office training
Device required weekly cleaning
Afrezza® Delivers a Distinctly Different Patient Experience than the Previous Inhaled Insulin
Insulin Initiation Insulin Intensification
Majority of Patients Surveyed Prefer Afrezza® over Insulin Pen Device or Injectable Mealtime Insulins(1)
Preference for Afrezza®
No preference Preference for insulin pen device
Preference for Adding Afrezza® vs. Injectable Mealtime Insulins
(% of basal patients)
57%
32%
11%
Preference for Afrezza® vs. Insulin Pen Device
(% of patients on 2+ OADs)
66%
60%
17% 23%
92
Preference for Afrezza®
No preference Preference for injectable mealtime insulin
(1) Nielsen DD Quantitative Market Research (T2D patients on 2+OADs, n=77; T2D patients taking basal insulin +/- OADs, n=79 ). Based on exposure to an Afrezza® product profile and a video demonstration (blinded as Product X). Note that these data are patient reported captured in a market research setting and do not necessarily reflect future behavior.
Insulin Initiation Insulin Intensification
Physician Survey Indicates Afrezza® Would Be an Appealing Option for Insulin Initiation and Intensification(1)
56%
25% 19%
“The product will make it significantly easier to initiate insulin among my
uncontrolled oral patients” (% of physicians)
66%
62%
23% 15%
93
Agree
Neither agree nor disagree Disagree
“I would be comfortable using the product instead of injectable rapid acting insulin
for my basal bolus patients” (% of physicians)
(1) Nielsen DD Quantitative Market Research (n=583 physicians – PCPs, n=391; ENDOs, n=192. Based on exposure to a clinical Afrezza® product profile and a video demonstration (blinded as Product X). Note that these data are physician reported captured in a market research setting and do not necessarily reflect future behavior.
Agree
Neither agree nor disagree Disagree
Expansion Drivers
● Novel product delivery ● Early adopters ● Current label
94
2015 U.S. Launch
● Label enhancement studies
● Safety study completed
● Potential ex-U.S. launches
● Supply of Sanofi insulin
The Launch Will Occur in Two Phases
95 95
Agenda
95
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
96
A Strong Drug Profile Emerging from PoC Study in Type 2 Diabetes
(1) Mean A1c change of 1.8% at Week 24 (n=161) (2) Mean change in body weight from baseline to Week 24 (n=161) (3) Documented symptomatic hypoglycemic events ≤70 mg/dL occured in 21.7% of patients (n=161)
Proof-of-Concept Study of Fixed-Ratio Once-Daily LixiLan in Type 2 DM on Metformin
84% of patients reached A1c goal <7%
68% reached this target with no documented hypoglycemia
56% reached it with no weight gain
46% with no weight gain and no documented hypoglycemia
● Robust A1c reduction from 8.1% to 6.3%
● Reduced body weight (-1 kg)
● Less frequent nausea and vomiting compared to what has been reported for the GLP-1 Rapid Acting class
● Low incidence of symptomatic hypoglycemia
(1) Proof of concept study (323 patients) - a 24-week randomized, open-label, trial comparing the efficacy and safety of insulin glargine/ lixisenatide fixed ratio combination versus insulin glargine, in type 2 diabetes inadequately controlled with metformin
(2) DUAL™ I Phase III study (around 1,600 people) – a 26-week, randomized, open-label trial comparing the efficacy and safety of IDegLira, insulin degludec and liraglutide, in people with type 2 diabetes inadequately controlled with metformin with or without pioglitazone
LixiLan(1) Data IDegLira(2) Liraglutide
8.06 Baseline A1c (%) 8.3 8.3
6.3 End point A1c (%) 6.4 7.0
-1.8 Change in A1c (Abs. %) -1.9 -1.3
-60 Change in FPG (mg/dL) -65 -32
84% % Achieving A1c <7% 81% 60%
7.5% Nausea (%) 8.8% 19.7%
2.5% Vomiting (%) 3.9% 8.5%
-1.0 Change in Body Weight (kg) -0.5 -3.0
High Proportion of Type 2 Diabetes Patients Reached A1c Target in PoC Study
97
Combining Insulin Glargine with Lixisenatide in a Single Daily Injection
98
● Phase III program initiated in Q1 2014 ● LixiLan-O study in patients insufficiently
controlled on OADs (1,125 patients)
● LixiLan-L study in patients not at goal on basal insulin (700 patients)
● Completion of both studies expected by Q3 2015
● Results of ELIXA CV outcome trial with lixisenatide expected in Q2 2015
● Targeted FDA submission of LixiLan as early as end of 2015
Patients Uncontrolled
with basal therapy
~4m patients
Patients Not at Target
on OAD ~5.5m
patients
Number of patients estimated for the U.S. (2017 projections based on internal model adapted from Adelphi)
1st injectable drug
Basal Intensification
U.S. Target Populations of T2D Patients for
99 99
Agenda
99
Toujeo® / Afrezza® / LixiLan
Unmet Needs of Basal Insulin Management ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Clinical Evidence on Toujeo® ● Stewart B. Harris, MD, Professor of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Toujeo® - the Next Generation of Basal Insulin
● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
Afrezza® ● Andrew Purcell, Vice President, Commercial Business Unit Head U.S. Diabetes
LixiLan ● Riccardo Perfetti, MD, Senior Medical Officer, Diabetes
Conclusion ● Pierre Chancel, Senior Vice President, Diabetes
Q&A Session
Broadening our Portfolio to Sustain a Leadership Position in Diabetes
100
1 Establish next generation of basal insulins
2 Capture untapped patient needs by addressing their reluctance to start insulin
3 Innovate with a new combination of basal insulin and GLP-1
5 Drive better outcomes through integrated care solutions
4 Expand access to Lantus® in developing countries
Q&A
101
102 102 102
Dengue Vaccine
Dengue – A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases Program, Duke NUS, Singapore
Dengue Vaccine – Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D, Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company, Sanofi Pasteur
Agenda
Aedes mosquito
Humans
Dengue: A Mosquito-Borne Disease
● Family Flaviviridae: Four serotypes ● Mosquito-borne virus
● Primary vector is Aedes aegypti ● Secondary vector is Aedes albopictus
● Female Aedes aegypti mosquito acquires virus while feeding on the blood of an infected person ● Highly domesticated ● Strongly anthropophilic
● Once infected, the virus is transmitted from the mosquito to other humans(2,3)
● The mosquito remains infective for the rest of its life(2)
103
Dengue Is the Most Important Vector-Borne Viral Disease of Humans(1)
(1) Gubler, 2010, Dengue, Trop Med Health (2) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control (3) Whitehead, 2007, Nat Rev Microbiol.
● Urbanization ● Travel and globalization ● Vector control effectiveness and
sustainability ● Factors adding to the proliferation of
dengue(2,3)
● Seasonal trends
Spread of Dengue Follows Growing Trend of Urbanization
104
Important Determinants of the Dengue Disease Epidemiology(1)
(1) Kyle, 2008, Ann Rev Microbiol. (2) Higa, 2011, Trop Med Health (3) Descloux, 2012, PLoS Negl Trop Dis.
105
2.5 billion people(2)
live in dengue-endemic countries (over 40% of the world’s population)
50 to 100 million dengue infections(2)
occur worldwide each year
500,000 people with severe dengue(2)
require hospitalization each year
12,500(2,3)
people with severe dengue die
Estimates Based on 2013 Modeling(5)
WHO objective: estimate true
disease burden by 2015(4)
(1) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control (2) World Health Organization, 2014, Dengue factsheet (3) ~12,500 people or 2.5% people with severe dengue die each year (4) WHO, 2012, Global Strategy for Dengue Prevention and Control (5) Bhatt, 2013, Nature
Four distinct serotypes with unpredictable distribution(5)
Dramatic Expansion of Dengue with a 30-Fold Increase in Dengue Incidence over the Last 50 Years(1)
WHO Estimates
96 million symptomatic infections per year
390 million infections per year
Contributes to a large reservoir
of infection that influences disease burden
Every Year, an Estimated 2 Million People with Dengue Require Hospitalization(1)
~2.5% of severe
dengue cases result in
death
106
Characteristics of Severe Dengue(2)
(1) Beatty 2009 (2) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control
● Plasma leakage
● Severe gastrointestinal involvement
● Severe organ impairment
● Significant bleeding
● Altered level of consciousness
Dengue Has an Adverse Economic and Societal Impact in Endemic Regions
107
Dengue can affect anyone, regardless of age and socioeconomic status(4,8)
(5) Mavalankar, 2009, IIMA (6) Shepard, 2013, PLoS Negl Trop Dis. (7) Shepard, 2011, Am J Trop Med Hyg. (8) OK DoH website, 2013, Oklahoma Department of Health
(1) Shepard et al. 2014, poster ASTMH 2014 (2) Infectious Disease Cost Calculator, Accessed Nov 2014 (3) Gubler, 2002, Trends Microbiol. (4) Douglas, 2013, PLoS Negl Trop Dis.
Dengue Disease Is Estimated to Cost Between US$6.3bn(1) and US$12bn Each Year in Endemic Countries(2)
Lost productivity(3)
Fear of infection(4)
Dengue “phobia”(4)
Community disruption(4)
Economic cost(3,4,6,7)
Perceived government
failure(4) Decrease in
tourism(5)
Overcrowded healthcare facilities(3)
Sanofi Pasteur Dengue Vaccine Can Make the 2020 Objectives of WHO Achievable
108
WHO Objectives(1)
Technical elements
Diagnosis & case management
Future vaccine
implementation
*2010 is baseline year. Vaccination is a crucial element in achieving the WHO objectives
Sustainable vector control
Integrated surveillance &
outbreak preparedness
Basic operational & implementation
research
(1) WHO, 2012, Global Strategy for Dengue Prevention and Control
Reduce dengue
morbidity by ≥25% by 2020*
Reduce dengue
mortality by ≥50% by 2020*
Estimate true
burden of disease by 2015
Dengue Vaccine
Dengue – A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases Program, Duke NUS, Singapore
Dengue Vaccine – Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D, Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company, Sanofi Pasteur
109 109
Agenda
109
A Significant Technological Advance(1,2)
● 4 genetic constructs, 1 for each serotype
● Envelope and precursor membrane genes from each serotype combined with the genes encoding the capsid and non-structural proteins from the yellow fever (YFV 17D) vaccine strain
● 4 recombinant, live, attenuated dengue viruses combined into a single vaccine that is freeze-dried and contains no adjuvant or preservatives(3)
110
17D Yellow fever Dengue
Chimeric Virus
17D yellow fever Dengue
Recombinant virus
YFV 17D VIRUS DENV-1 DENV-2 DENV-3 DENV-4 RECOMBINANT DENV-1, -2, -3, and -4
C NS PrM E PrM E PrM E PrM E
(1) Vaccine referred to in the literature as Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV) (2) Guirakhoo, 2001, J Virol. (3) Guy, 2011, Vaccine
111
CYD14 Phase III Efficacy Study Asia Countries: Thailand, Indonesia, Malaysia, Viet Nam, Philippines
Sites : 11
Age group: 2–14 years
Sample size: 10,278
Phase III Evaluation Provides Complementary and Pivotal Data for Efficacy, Safety, and Immunogenicity of the Dengue Vaccine(2,3)
(1) Nearly 30,000 individuals across age groups have received the vaccine and approximately 12,000 individuals have received placebo or control vaccine Status as of October 25, 2013
(2) ClinicalTrials.gov, 2013, NCT01374516 (3) ClinicalTrials.gov, 2013, NCT01373281
CYD15 Phase III Efficacy Study in LatAm(2)
● Countries: Colombia, Mexico, Honduras, Puerto Rico and Brazil
● Sites: 22 ● Age group: 9 to 16 years ● Sample size: 20,875
CYD14 Phase III Efficacy Study in Asia(3) ● Countries: Thailand, Indonesia, Malaysia,
Vietnam and Philippines ● Sites: 11 ● Age group: 2 to 14 years ● Sample size: 10,278
More than 41,000 Individuals Included in Sanofi’s Dengue Vaccine Clinical Trial Program(1)
Inclusion Criteria
• Children 2–14 years (Asia) • Children 9–16 years (LatAm) • Good health • No plans to leave study area
Exclusion Criteria
• Febrile illness (until resolution)
• Receiving other vaccines (until 4 weeks after vaccination)
• Congenital or acquired immunodeficiency
RANDOMIZATION
0 6 12 13 18 25 Year 6 Months
Vaccination with Dengue Vaccine
Active Phase Active Surveillance/Detection of Dengue Cases
Hospital Phase Additional follow-up for safety of
hospitalized dengue cases for 4 years after the end of the active
phase
112
Vaccination with Placebo*
2:1
Phase III Studies Design: Randomized 2:1, Observer-Blind, Placebo-Controlled, Multicenter(1,2)
The vaccination follows a 3-dose schedule
*Participants who received placebo were designated as the control group (1) Capeding, 2014, Lancet (2) Villar, 2014, N Engl J Med.
● Per-protocol analysis: follow-up from month 13–25.
● Intent-to-treat analysis: follow-up from month 0–25.
Meta-Analysis Demonstrates Significant Reduction in Dengue across All Serotypes after 3 Doses Schedule(1,2)
113
STUDY (n cases) EFFICACY and 95% CI
DENV-1
ASIA / CYD14 (n=250)
DENV-2
DENV-3
DENV-4
LATAM / CYD15 (n=397) Any
Serotype
ASIA / CYD14 (n=101)
LATAM / CYD15 (n=132)
ASIA / CYD14 (n=67)
LATAM / CYD15 (n=108)
ASIA / CYD14 (n=33)
LATAM / CYD15 (n=125)
ASIA / CYD14 (n=51)
LATAM / CYD15 (n=58)
43.8 56.5 66.4
52.0 60.8 68.0
52.3 59.2 65.0
24.6 50.0 66.8
29.1 50.3 65.2
35.6 50.2 61.5
-9.2 35.0 61.0
14.0 42.3 61.1
18.7 39.6 55.2
52.9 78.4 90.8
61.9 74.0 82.4
65.1 74.9 82.0
54.5 87.0
60.2 77.7 88.0
65.0 76.6 84.4
-20 0 20 40 60 80 100
Pooled (n=647)
Pooled (n=233)
Pooled (n=175)
Pooled (n=158)
Pooled (n=109)
75.3
(1) Capeding, 2014, Lancet (2) Villar, 2014, N Engl J Med.
Overview of Efficacy Results Against Virologically Confirmed Dengue (Severe and Hospitalized)(1,2,3)
52.7 80.0 92.4
64.9 95.0 99.9
50.3 67.2 78.6
64.7 80.3 89.5
0 20 40 60 80 100
EFFICACY and 95% CI
ASIA / CYD14 (n=28)
LATAM / CYD15 (n=11)
Vaccine Efficacy on Dengue Hemorrhagic
Fever (DHF) cases (WHO 1997 definition)
ASIA / CYD14 (n=101)
LATAM / CYD15 (n=60)
Vaccine Efficacy(4) on hospitalized dengue cases
STUDY (n episodes)
(1) Capeding, 2014, Lancet (2) Villar and al., 2014, NEJM (3) Intent to Treat analysis (25m follow-up from months 0–25) (4) The relative risk (RR) of hospital admissions for virologically confirmed dengue was calculated as the ratio of annual incidence in the vaccine group
and control groups, and presented here as vaccine efficacy (i.e., 1−RR)
Higher Efficacy Demonstrated Against Severe Dengue, Including Reduction in Hospitalized Cases(1,2)
Results relevant in public health context (ie, vaccine could help reduce disease burden)(1,2)
114
Efficacy According to Dengue Serostatus at Baseline(2) in Asia & Latam(1,2)
EFFICACY and 95% CI
DENV + (n=52)
DENV – (n=41)
ASIA / CYD14
DENV + (n=31)
DENV – (n=18)
LATAM / CYD15
STUDY (n episodes)
Higher Efficacy Observed in Those Previously Exposed to Dengue, During the Active Phase
115
Age can be used as a surrogate of prior exposure to dengue
(1) Comparison made on ITT. RR=relative risk: incidence of VC dengue cases in CYD group vs control group. (2) Dengue +: baseline titer for at least 1 DENV serotype is ≥10 1/dil.
74.3
35.5
83.7
43.2
-80 -60 -40 -20 0 20 40 60 80 100
Favorable Safety Profile in Vaccinated Subjects during the Active Phase of Phase III Efficacy Studies
116
Safety analyses* showed similar reporting rates between the vaccine and control groups during the studies
(1) Capeding, 2014, Lancet (2) Villar and al., 2014, NEJM
CYD14 & CYD15 Safety Results (Active Phase)(1,2)
* solicited reactions, unsolicited events and Serious Adverse Events (SAEs)
SAEs were consistent with medical disorders in the age group: mainly infections, injuries and accidents
No safety issue and no evidence of sensitization over the 25-month follow-up period
Long term safety results analysis on-going for 60 months post-dose 3
Safety profile over the 25-month is favorable and
consistent with the favorable safety profile documented in
previous studies (Phase I, II, III)
Both Efficacy Studies in Asia and LatAm Consistently Demonstrate a Reduction in Dengue Disease
117
CYD 14, Asia(2) Key Study Results
CYD 15, LatAm(3)
*95% CI: 52.7-92.4 †95% CI: 64.9-99.9 ‡95% CI: 50.3-78.6 §95% CI: 64.7-89.5
56.5% Reduction in
symptomatic dengue(4)
60.8% Reduction in
symptomatic dengue(4)
Both Studies Met their Primary Efficacy Endpoints and Showed Consistent Safety Profile for the Observed Active Phase(2,3)
67.2%‡ Reduction in
hospitalized cases(6)
80%* Reduction in severe
disease(5)
80.3%§ Reduction in
hospitalized cases(6)
95%† Reduction in severe
disease(5)
(1) World Health Organization, 2014, Dengue factsheet (2) Capeding, 2014, Lancet (3) Villar and al., 2014, NEJM
2.5 billion people(1)
live in dengue-endemic countries (over 40% of the world’s population)
50-100 million dengue infections(1)
occur worldwide each year
500,000 people with severe dengue(1)
require hospitalization each year
2.5%(1) of people
with severe dengue die
(4) Post Dose 3 (5) DHF, WHO 1997 criteria, intent to treat (6) Intent To Treat
Dengue Vaccine
Dengue – A Major Public Health Concern
● Duane Gubler, MS, ScD, Professor, Emerging Infectious Diseases Program, Duke NUS, Singapore
Dengue Vaccine – Clinical Development Program
● Nicholas Jackson, Associate Vice President R&D, Dengue Vaccine Company, Sanofi Pasteur
From Vaccine Development to Vaccination Programs
● Guillaume Leroy, Vice President, Dengue Vaccine Company, Sanofi Pasteur
118 118
Agenda
118
119
No vaccination
Routine vaccination
at 10 y
Routine plus
catch-up 10–14 y
Routine plus
catch-up 10–18 y
Routine plus
catch-up 10–22 y
Routine plus
catch-up 10–26 y
40
35
30
25
20
15
10
5
0
19% 34%
53% 73%
81% Prevented
hospitalized cases (%)
Number of hospitalized
cases (per 10,000
dengue cases)
Hospitalized cases
A Broad Vaccination Program Has the Potential to Lead to a Significant Reduction in Hospitalizations
ILLUSTRATIVE
Modeling the Prevention of Hospitalized Dengue Cases by Adding Multiple Catch-up Cohorts to a Routine Vaccination Program in a Given Population(1)
(1) Sanofi internal analysis, based on Coudeville & Garnett [2010]; prevented cases in the first 10 years of vaccine introduction
From Vaccine Efficacy to Vaccination Impact(1-7)
120
(1) Chao, 2012, PLoS Negl Trop Dis. (2) Coudeville, 2012, PLoS One (3) Durham, 2013, Vaccine (4) Rodriguez-Barraquer, 2013, Vaccine
(5) Dasbach, 2006, Epidemiol Rev. (6) Farrington, 2003, Math Biosci. (7) McLean, 1998, Dev Biol Stand.
Vaccination Impact
Vaccination Coverage
# cohorts x coverage in each cohort
Vaccine Efficacy
Direct protection & indirect protection
% Population Protected by Vaccination
x
Disease Endemicity =
ƒ
A Successful Vaccination Program Defined by Several Factors
121
121
1
2
3
4
Age for routine vaccination
Define the optimal age range for routine vaccination population in an endemic country
Catch-up cohort size
Determine the optimal catch-up cohort size to maximize impact of vaccination (range of age)
Geographic breadth
Agree on the geographic breadth of the vaccination program with local government
Compliance Ensure highest impact through compliance with 3-dose schedule
Outbreaks Incorporate the outbreak nature of the disease into an integrated strategy 5
122 122
An Unprecedented Industrial Commitment to Ensure the Success of Large Scale Vaccination Programs
Manufacturing Site, Neuville-sur-Saone, France
122
● State-of-the-art facilities dedicated to the production of the dengue vaccine ● €300m investment
● Manufacturing capacity for 100m doses annually ● Initial inventory build-up underway
● Investment in additional manufacturing capacity in the U.S.
● Large scale filling and packing to start from 2015
● 1-dose and 5-dose vial presentations
Ready to Produce >1bn Doses over the Next 10 Years
The Global Roll-out of Sanofi’s Dengue Vaccine
123
Steady Uptake at Launch Due to Broad Coverage in Endemic Countries
● First launches in dengue most endemic countries
● Initial sales evolution expected to be driven by public markets
● Private markets to complement public programs and adding strong growth momentum
ILLUSTRATIVE 2015 2020
124 124 124
Dengue Vaccine Launch Expected to Start by End of 2015
Make Dengue
the Next Vaccine-Preventable
Disease
125 125
Agenda
125
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
Immunology & Inflammation Set to Become a New Growth Platform for Sanofi
126
Immuno-Modulation is at the core of
Sanofi’s R&D strategy
Rheumatoid Arthritis
Asthma Atopic Dermatitis
Multiple Sclerosis
Inflammatory Bowel Disease
Systemic Lupus
Erythematosus
Rheumatoid Arthritis Is a Chronic, Debilitating Autoimmune Disease and a Major Cause of Disability
Rheumatoid Arthritis (RA)
● Up to 70m people worldwide(1) estimated to be affected by RA
Joints become chronically inflamed, painful and swollen
Patients can become increasingly disabled as cartilage and bone is damaged(2)
127 (1) World Health Organisation. Chronic rheumatic conditions (2) Patient UK. Rheumatoid arthritis
128
MTX/DMARDS 1st line treatment
Add Anti-TNF 1st line biologic
Switch to Other MOA’s (Add on to MTX)
RA Combination
Tx Market
~70%
RA Mono Tx Market
~30%
Current guidelines make no distinction between which biologic to start on
MTX/DMARDS 1st line treatment
T cell
IL-6R
JAK
CD 20
IL-6R
JAK
TNF
Current guidelines recommend using IL-6R
as a 1st choice monotherapy(1)
Incomplete Response or Intolerance Leads Patients to Cycle through Multiple Biologics
MTX: Methotrexate DMARD: Disease-Modifying Anti-Rheumatic Drugs Actemra® (tocilizumab) is marketed by Roche Humira® (adalimumab) is marketed by AbbVie Enbrel® (etanercept) is marketed by Amgen Remicade® (infliximab) is marketed by J&J Simponi® (golimumab) is marketed by J&J Cimzia® (certolizumab) is marketed by UCB Orencia® (abatacept) is marketed by BMS Xeljanz® (tofacitinib) is marketed by Pfizer Rituxan® (rituximab) is marketed by Roche (1) EULAR guidelines
129
Sarilumab: An Investigational IL-6R mAb for RA
● Fully human, high affinity, IL-6R mAb ● 2 effective doses: 150mg or 200mg ● Delivered subcutaneously every other week ● Evaluated for use with ergonomic pre-filled syringe or autoinjector
● Efficacy demonstrated across three co-primary endpoints in first Phase III trial(1)
● Additional Phase III data expected in 2015
● Regulatory submission expected in late 2015 in the U.S. and late 2016 in EU and Japan
IL-6R – Interleukin-6 receptor Sarilumab is developed in collaboration with Regeneron (1) SARIL-RA-MOBILITY in MTX IR moderate-to-severe RA - Clinically relevant and statistically significant improvements in
both sarilumab groups compared to placebo in all three co-primary endpoints: ACR 20 at 24 weeks, improvement of physical function at 16 weeks and inhibition of progression of structural damage at 52 weeks
sarilumab
A Broad Clinical Development Program Aiming for a Robust Label at Launch
130
~2,500 RA patients targeted in SARIL-RA program
Study Design n Objectives Status sarilumab + MTX MTX IR patients 1,197
● Evaluation of use as 1st & 2nd line biologic therapy
● Assessment of long term safety up to 5 years
● Safety calibration
● Duration of inhibition of structural damage
Completed
sarilumab + DMARD Anti-TNFα IR patients 546 2015
sarilumab + MTX Anti-TNFα IR patients Safety calibrator vs. Actemra®
200 2015
sarilumab + DMARD Long-term extension study 2,000 Ongoing
sarilumab monotherapy (open-label) DMARD-IR patients 120
● Evaluation of use with or without DMARD (MTX)
2015
sarilumab monotherapy vs. Humira® MTX-IR, intolerant and inappropriate patients 340 2016
sarilumab + MTX Auto-injector real-life use 200 ● Assessment of pre-filled
syringe vs. autoinjector 2015
MOBILITY
EASY
MONARCH
ONE
EXTEND
ASCERTAIN
TARGET
MTX: Methotrexate DMARD-IR: Disease-Modifying Anti-Rheumatic Drugs Inadequate Responders Actemra® (tocilizumab) is marketed by Roche Humira® (adalimumab) is marketed by AbbVie
Significant Improvements in Signs and Symptoms of RA with Sarilumab(1)
SARIL-RA-MOBILITY - ACR Scores (% of Patients)
33
17 7
32
18*
9
58*
37*
20*
54*
40*
25*
66*
46*
25*
59* 53*
28*
ACR 20 ACR 50 ACR 70 ACR 20 ACR 50 ACR 70
Placebo + MTX Sarilumab 150mg + MTX Sarilumab 200mg + MTX
ACR Response at Week 24 ACR Response at Week 52
* p<0.0001 vs. placebo ** Co-primary endpoint (n=398) (n=400) (n=399)
**
ACR – American College Of Rheumatology (ACR) Scoring System (1) Clinically relevant and statistically significant improvements in both sarilumab groups compared to placebo in all three
co-primary endpoints: ACR 20, improvement of physical function and inhibition of progression of structural damage 131
SARIL-RA-MOBILITY - Change from Baseline in mTSS
* p<0.0001 vs Placebo Week
*
*
mTSS: modified
Total Sharp Score
Sarilumab: van der Heijde
modified Total Sharp Score
(0-448)
Inhibiting Progression of Structural Damage in RA with Sarilumab
70% 90%
132
3
2.5
2
1.5
1
0.5
0
0 13 26 36 52
Placebo + MTX
Sarilumab 150 mg + MTX
Sarilumab 200 mg + MTX
SARIL-RA-MOBILITY - Safety Data
Safety Findings Consistent with Prior Investigational Studies with Sarilumab
133
● Higher incidence of TEAEs leading to withdrawal
● Higher incidence of infections, the most frequently reported adverse events(1) ● Dose-dependent decrease in mean
neutrophil counts
● Serious infections not associated with grades 3 and 4 neutropenia in this study
● Increases in mean LDL-C and transaminases observed
TEAEs – Treatment Emergent Adverse Events (1) Sarilumab and placebo, both in combination with MTX
Placebo +MTX
2.3%
31.1%
Sarilumab 200mg +MTX
39.6%
2.6% 4.0%
Sarilumab 150mg +MTX
40.1%
Infections of which serious infections
Placebo +MTX
4.7%
Sarilumab 200mg +MTX
13.9%
Sarilumab 150mg + MTX
12.5% TEAEs leading to withdrawal
Rheumatoid Arthritis - Worldwide Sales of Biologics(1)
~$18bn
● Share of IL-6R inhibitors projected to increase four-fold to nearly 20% of the RA market by 2021 driven by expanded use and new entrants
● Blockbuster status reached with ~5% share
IL-6R 5%
IL-6R 19%
Further Establish the IL-6R Class in an $18bn Rheumatoid Arthritis Biologic Market
134
~$21bn
2013 2021
Anti-TNFα
Other(2)
IL-6R
(1) Decision Resources - Internal estimates (2) Other includes: JAK inhibitors, B Cell, Co-stimulation, IL-17, IL-1
Develop sarilumab to become the preferred IL-6R mAb
135 135
Agenda
135
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
PULMONOLOGY
Moderate-to-Severe Asthma
DERMATOLOGY
Moderate-to-Severe Atopic Dermatitis
OTOLARYNGOLOGY
Chronic Sinusitis with Nasal Polyps
Dupilumab is a fully human monoclonal antibody targeting IL-4Rα blocking intracellular signaling of both IL-4 and IL-13
Dupilumab Offers Potential to Change Management of Multiple Th2-Mediated Allergic Inflammatory Diseases
Dupilumab is developed in collaboration with Regeneron Th2: T-helper 2 cells, involved in “humoral-mediated” immunity 136
IL-4
IL-4Rα γc
Type I Receptor
Type II Receptor
IL-13
IL-4Rα IL-13Rα1
or
1
2
3
IL-4/IL-13 pathway may be a fundamental driver in allergic diseases
● >5m people in the U.S. and EU(1)
estimated to be affected by moderate-to-severe atopic dermatitis
● Characterized by eczematous dermatitis with intractable pruritus
● Current therapies often inadequate and associated with unwanted side effects ● 40% of moderate-to-severe patients
uncontrolled with topicals
137
Atopic Dermatitis (AD)
Atopic Dermatitis Is a Serious, Chronic, Inflammatory Skin Condition
137 (1) Adapted from White Book on Allergy published in 2011, http://www.worldallergy.org/UserFiles/file/WAO-White-Book-on-Allergy_web.pdf
Negative impact on QoL Similar or higher than
in psoriasis Determined by degree
of skin involvement, severity and localization
3
2
1
The Negative Impact of Atopic Dermatitis on Quality of Life Is Largely Underestimated
(1) Journal of Psychomatic Research 57 (2004) 195-200 (2) Acta Derm Venereol 2004;84(3):205-12 (3) Suicide Life Threat Behav 2006 2006 Feb;36(1):120-4 (4) J Allergy Clin Immunol 2006 Jul;118(1):226-32 138
Sleep disturbance and fatigue(4)
Greater risk for psychological distress • Mood disorders, such as anxiety and depression(1)
• Suicidal ideation(2,3)
Low self-esteem • Impact on social life
Dose-Dependent Efficacy in Adults with Moderate-to-Severe Atopic Dermatitis Uncontrolled by Topicals
139
Phase IIb Study in AD - Mean Percent Change in EASI
At Week 16 Over 16 Weeks
EASI=Eczema Area Severity Index IL-4Rα – Interleukin-4 receptor sub-unit α
-90
-80
-70
-60
-50
-40
-30
-20
-10
0Placebo
100 mgq4w
300 mgq4w
200 mgq2w
300 mgq2w
300 mgqw
p < 0.0001 vs placebo -90
-80
-70
-60
-50
-40
-30
-20
-10
00 2 4 6 8 10 12 14 16
Placebo
100mg q4w
300mg q4w 200mg q2w 300mg q2w 300mg qw p<0.0001 vs placebo at Week 16
All other time points p<0.05 vs placebo
Phase IIb Study in AD - Change in Efficacy Endpoints at 16 Weeks(1-5)
Parameter Placebo 300mg q2w 300mg qw
EASI Score 18% 68.2% 73.7% 50/75/90 EASI Improvement 29.5%/11.5%/3.3% 78.1%/53.1%/29.7% 82.5%/60.3%/36.5%
IGA Response 1.6% 29.7% 33.3%
Pruritus NRS 11.4% 52.9% 59.7% 5-D Pruritus
Score 8.2% 35.4% 43.6%
(1) Mean percent change in EASI (Eczema Area Severity Index) (2) Proportion of patients achieving EASI-50/70/90 (3) Proportion of patients achieving IGA ≤ 1 (Investigator’s Global Assessment score of 0 “clear” or 1 “almost clear”) (4) Mean percent change in pruritus NRS (Numeric Rating Scale) weekly averaged (5) Mean percent change 5-D Pruritus Score
Dupilumab Significantly Improved Signs and Symptoms in Moderate-to-Severe AD Patients Uncontrolled by Topicals
300mg qw and 300mg q2w dose regimens selected for Phase III program
140
p<0.0001 vs placebo for all parameters
Phase IIb Study in Moderate-to-Severe Atopic Dermatitis - Safety Data
Safety Findings in Moderate-to-Severe Atopic Dermatitis
141
21%
Placebo Dupilumab
23%
18.5%
Nasopharyngitis
8%
Placebo Dupilumab
15%
12%
Headache
3%
Dupilumab Placebo
9.5%
5%
Injection site reactions
● Nasopharyngitis, the most common adverse event, balanced across dupilumab treatment groups vs. placebo
● Headache and injection site reactions more frequent with dupilumab
Ongoing follow-up period of 16 weeks after treatment
LIBERTY - Phase III Clinical Program of Dupilumab in Moderate-to-Severe AD
Dupilumab Leads Development of Biologics in AD with Recent Start of Phase III Program
CHRONOS Combination with
topical corticosteroids in adults(1)
142
(1) CHRONOS study will assess efficacy of dupilumab in combination with topical corticosteroids through 16 weeks and long-term safety and efficacy of dupilumab up to 52 weeks, using 2 dosing regimens of dupilumab or placebo in 700 adult patients
(2) SOLO 1 and 2 studies will assess efficacy and safety of dupilumab as monotherapy in adults through 16 weeks using 2 dosing regimens of dupilumab and matching placebo in 600 adult patients each
(3) The Open-Label Extension (OLE) study will assess long-term safety and efficacy of repeat doses of dupilumab in adults who have previously participated in controlled studies of dupilumab
SOLO 1 SOLO 2 Monotherapy
in adults(2)
OLE Open-label
extension study in adults(3)
● 235-300m people worldwide estimated to be affected by asthma(1)
● ~25m people in the U.S. alone ● 10 to 20% of patients uncontrolled despite
existing therapies
● Chronic inflammatory disease leading to acute and chronic narrowing of the airway and increased mucus production
● Patients with asthma experience wheezing, shortness of breath, cough and chest tightness
143
Moderate-to-Severe Asthma
Moderate-to-Severe Asthma Negatively Impacts the Lives of Patients and Is Associated with High Burden to Society
143 (1) WHO, http://www.who.int/mediacentre/factsheets/fs307/en/
Dupilumab Shows Improvement in Lung Function in Phase IIb in Moderate-to-Severe Asthma
144
Phase IIb - Mean Improvement in FEV1 (mL and % Change from Baseline)
FEV1=forced expiratory volume over one second During the treatment period, patients continue their stable medium- or high-dose inhaled corticosteroid and long-acting beta agonist (ICS/LABA) combination product This result was based on a pre-specified interim analysis, which occurred when all patients had reached Week 12 of the 24-week treatment period
0
100
200
300
400
500
High Eosinophils Population Overall population
Placebo200mg Q2W300mg Q2W
10.4%
25.9%(1)
25.8%(2)
mL
18.0%(1) 17.7%(1)
6.2%
(1) p<0.001 vs placebo
(2) p<0.01 vs placebo
Phase IIb: Annualized Rate of Severe Exacerbation Events
145
Dupilumab Shows a 64-75% Reduction in Exacerbations in Phase IIb in Moderate-to-Severe Asthma
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
High Eosinophils Population Overall population
Placebo200mg Q2W300mg Q2W
During the treatment period, patients continue their stable medium- or high-dose inhaled corticosteroid and long-acting beta agonist (ICS/LABA) combination product This result was based on a pre-specified interim analysis, which occurred when all patients had reached Week 12 of the 24-week treatment period
-75%(1)
-64%(1) -67%(2)
-67%(3)
(1) p<0.05 vs placebo
(2) p<0.01 vs placebo
(3) p<0.001 vs placebo
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
146
Safety Profile in Moderate-to-Severe Asthma
Phase III start in moderate-to-severe uncontrolled asthma expected in 2015
Phase IIb Study in Moderate-to-Severe Asthma - Safety Data
46%
Placebo Dupilumab
45% 42%
Infections
5%
Placebo Dupilumab
7%
3%
Severe AEs
12%
Dupilumab Placebo
25%
13%
Injection site reactions
● Injection site reaction was the most common adverse event and was more frequent with dupilumab ● Other common adverse events in the study included upper respiratory tract infection, headache,
nasopharyngitis and bronchitis ● Incidence of infections of serious adverse events was balanced across treatment groups
● CSwNP causes mucosal inflammation and polyps in the nasal cavity and sinuses ● Long-term symptoms of nasal obstruction and congestion
● Reduction in or loss of sense of smell
● Facial pain
● Many patients do not respond to intranasal corticosteroids
● In the U.S. alone, approximately 200,000 CSwNP patients have sinus surgery(2)
147
Chronic Sinusitis with Nasal Polyps (CSwNP)
Prevalence of Chronic Sinusitis with Nasal Polyps Is Estimated at 3% to 5% in EU and the U.S.(1)
147 (1) Adapted from White Book on Allergy published in 2011: http://www.worldallergy.org/definingthespecialty/white_book.php (2) Bhattacharyya 2010 otolaryngology head and neck surgery (2010) 143,147-151
Dupilumab Delivers Positive Results in PoC Study in Patients with Nasal Polyposis and Chronic Symptoms of Sinusitis
148
Chronic Sinusitis
with Nasal Polyps(3)
(1) From baseline to week 16 / p<0.0001 (2) Sense of smell, congestion, postnasal drip, runny nose and sleep disturbance (3) Who do not respond to intra-nasal corticosteroids
● Strong efficacy of dupilumab 300mg qw vs. placebo, on top of Nasonex®
● Rapid, clinically and significant reduction size of nasal polyposis(1)
● Consistent improvement in measures of sinusitis by CT scan, nasal air flow and patient-reported symptoms(2)
● Most common AEs were injection site reactions, nasopharyngitis, oropharyngeal pain, epistaxis, headache and dizziness
Nasal Polyp Score (NPS)
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Week Baseline 4 8 12 16
Placebo
Dupilumab
Mean change +/- SE
149
Dupilumab Has the Potential to Change Management of Patients Severely Affected by Various Allergic Diseases(1)
● Execute Phase III program in Atopic Dermatitis as first-in-class biologic
● Design Phase III program in Asthma to potentially position as best-in-class biologic
● Accelerate development in Chronic Sinusitis with Nasal Polyps
● Expand development program with new indications
1
2
3
4
(1) Atopic Dermatitis, Asthma, Nasal Polyposis
150 150
Agenda
150
● Elias Zerhouni, MD, President, Global R&D
Sarilumab
Dupilumab
Wrap-up and Q&A Session
New R&D Strategy Expected to Continue to Lead to Innovative New Medicines and Vaccines Reaching Market
151
Multiple new product launches underway or imminent
High potential late stage projects
Promising early stage development pipeline
Q&A
152
APPENDICES R&D Pipeline
153
154
Late Stage Pipeline – Pharma & Vaccines
LixiLan lixisenatide + insulin glargine Fixed-Ratio / Type 2 diabetes
alirocumab Anti-PCSK-9 mAb
Hypercholesterolemia
Dengue Mild-to-severe
dengue fever vaccine
Toujeo® (U300) Insulin glargine
Type 1+2 diabetes, U.S., EU
Lyxumia® (lixisenatide) GLP-1 agonist
Type 2 diabetes, U.S.
Kynamro® (mipomersen) Apolipoprotein B-100 antisense
Severe HeFH, U.S.
Clostridium difficile Toxoid vaccine
Lemtrada® (alemtuzumab) Anti-CD52 mAb
Multiple sclerosis, U.S.
sarilumab Anti-IL-6R mAb
Rheumatoid arthritis
Jevtana® (cabazitaxel) Metastatic prostate cancer (1L)
Rotavirus Live attenuated tetravalent
Rotavirus oral vaccine
Cerdelga™ (eliglustat tartrate) Glucosylceramide synthetase inhibitor
Gaucher disease, EU
dupilumab Anti-IL4Rα mAb Atopic dermatitis
SYNVISC-ONE®
Medical device Pain in hip OA
VaxiGrip® QIV IM Quadrivalent inactivated
influenza vaccine
PR5i DTP-HepB-Polio-Hib
Pediatric hexavalent vaccine, U.S.
patisiran mRNA inhibitor
Familial amyloid polyneuropathy
Fluzone® QIV ID Quadrivalent inactivated
influenza vaccine intradermal
Quadracel® Diphtheria, tetanus, pertussis & polio vaccine; 4-6 y of age
N
154
N
N
N
N New Molecular Entity Immune Mediated Diseases
Rare Diseases
Oncology Diabetes Solutions
Vaccines Infectious Diseases Cardiovascular / Renal Diseases
Age Related Degenerative Diseases
Ophthalmology
Biosurgery
N
Phase III Registration
N
N
Early Stage Pipeline – Pharma & Vaccines
dupilumab Anti-IL4Rα mAb
Asthma; Nasal polyposis
SAR391786 Anti-GDF8 mAb
Sarcopenia
Rabies VRVg Purified vero rabies vaccine
vatelizumab Anti-VLA 2 mAb Multiple sclerosis
SAR650984 Anti-CD38 naked mAb
Multiple myeloma
Meningitis ACYW conj. 2nd generation meningococcal
conjugate infant vaccine
SAR156597 IL4/IL13 Bi-specific mAb
Idiopathic pulmonary fibrosis
SAR3419 Maytansin-loaded anti-CD19 mAb
B-cell refractory/relapsed malignancies
Tuberculosis Recombinant subunit vaccine
SAR438714 (ALN-TTRsc) RNAi
Familial amyloid cardiomyopathy
Combination SAR245409 (XL765) / MSC1936369B Oral dual inhibitor of PI3K & mTOR / pimasertib
Ovarian cancer
sarilumab Anti-IL-6R mAb
Uveitis
Combination ferroquine / OZ439
Antimalarial Malaria
fresolimumab TGFβ antagonist
Focal segmental glomerulosclerosis
Phase II
N
N
N
N
N
155
N
155
N
N New Molecular Entity Immune Mediated Diseases
Rare Diseases
Oncology Diabetes Solutions
Vaccines Infectious Diseases Cardiovascular / Renal Diseases
Age Related Degenerative Diseases
Ophthalmology
Biosurgery
N
N
Early Stage Pipeline – Pharma & Vaccines
SAR405838 (MI-773) HDM2 / p53 antagonist
Solid tumors
SAR408701 Anti-CEACAM5 ADC
Solid tumors
GZ402663 (sFLT-01) Gene therapy
Age-related macular degeneration (AMD)
Streptococcus pneumonia Meningitis & pneumonia vaccine
SAR566658 Maytansin-loaded anti-CA6 mAb
Solid tumors
SAR113244 Anti-CXCR5 mAb
Systemic lupus erythematosus
StarGen® Gene therapy
Stargardt disease
Herpes Simplex Virus Type 2 HSV-2 vaccine
SAR125844 C-MET kinase inhibitor
Solid tumors
SAR252067 Anti-LIGHT mAb Crohn’s disease
UshStat® Gene therapy
Usher syndrome 1B
SAR260301 PI3K β selective inhibitor PTEN – Deficient tumors
SAR228810 Anti-protofibrillar AB mAb
Alzheimer’s disease
GZ402665 (rhASM)
Niemann-Pick type B
SAR307746 Anti-ANG2 mAb
Solid tumors
SAR425899 GLP-1 / GCGR agonist
Diabetes
GZ402671 Oral GCS Inhibitor
Fabry Disease
SAR245408 (XL147) Oral PI3K inhibitor
Solid tumors
SAR342434 Insulin Lispro
Diabetes
GZ402666 neo GAA
Pompe Disease
Combination SAR405838 / MSC1936369B
Solid tumors
SAR438584 (REGN2222) anti-RSV-F protein mAb
Respiratory syncytial virus
Phase I N
N
N
N
N
N
N
N
N N
N N
156 156
N
N
N New Molecular Entity Immune Mediated Diseases
Rare Diseases
Oncology Diabetes Solutions
Vaccines Infectious Diseases Cardiovascular / Renal Diseases
Age Related Degenerative Diseases
Ophthalmology
Biosurgery
N
N
N
N
157
Phase I Phase II Phase III Registration TOTAL
Oncology 7 3 0 0 10
Diabetes Solutions 1 0 1 1 3
Cardiovascular / Renal Diseases 0 1 1 0 2
Immune Mediated Diseases 2 2 2 0 6
Infectious Diseases 1 1 0 0 2
Ophthalmology 3 0 0 0 3
Rare Diseases 3 1 1 1 6
Age Related Degenerative Diseases 1 1 0 0 2
Vaccines 2 3 4 3 12
TOTAL 20 12 9 5
R&D Pipeline Summary Table(1)
32 14 NMEs & Vaccines
46
157
34
(1) Excluding life cycle management programs
158
Expected R&D Milestones
158
Product Event Timing New Insulin Lispro (SAR342434) Expected start of Phase III trial in Diabetes Q4 2014
Praluent™ (alirocumab) Expected U.S. and EU regulatory submissions in Hypercholesterolemia Q4 2014
Fluzone® QIV ID Expected U.S. regulatory decision Q4 2014
Fluzone® High Dose Expected U.S. label upgrade Q4 2014
Cerdelga™ (eliglustat tartrate) Expected EU regulatory decision in Gaucher disease Q1 2015
PR5i (DTP-HepB-Polio-Hib) Expected EU regulatory submission Q1 2015
Quadracel® Expected U.S. regulatory decision Q1 2015
Toujeo® (U300) Expected U.S. regulatory decision in Diabetes Q1 2015
Dengue vaccine Expected regulatory submission in endemic countries H1 2015
Toujeo® (U300) Expected EU regulatory decision in Diabetes Q2 2015
Lyxumia® (lixisenatide) Expected ELIXA CV outcome trial top-line results Q2 2015
Dupilumab Expected start of Phase III trial in Asthma Q2 2015
159
Expected R&D Milestones (cont’d)
159
Product Event Timing Praluent™ (alirocumab) Expected U.S. regulatory decision in Hypercholesterolemia Q3 2015
PR5i (DTP-HepB-Polio-Hib) Expected U.S. regulatory decision Q3 2015
LixiLan Expected Phase III top line results in Diabetes Q3 2015
Lyxumia® (lixisenatide) Expected U.S. regulatory submission in Diabetes Q3 2015
Sarilumab Expected Phase III top line results in Rheumatoid Arthritis H2 2015
Dengue vaccine Expected regulatory decision in endemic countries Q4 2015
LixiLan Expected U.S. and EU regulatory submissions in Diabetes Q4 2015
Sarilumab Expected U.S. regulatory submission in Rheumatoid Arthritis Q4 2015
APPENDICES Regeneron Agreement Financial Terms
160
Antibodies Collaboration Agreement with Regeneron
● In November 2007, Sanofi and Regeneron entered into a global collaboration to discover, develop and commercialize fully human monoclonal antibodies.
● The collaboration is governed by a Discovery and Preclinical Development Agreement and a License and Collaboration Agreement (each as amended in November 2009).
● In January 2014, Sanofi and Regeneron agreed to amend and restate the original investor agreement. The Amended Investor Agreement was amended to, among other things, provide Sanofi with the right to nominate a single independent director to the Regeneron Board of Directors upon reaching 20% ownership of Regeneron's outstanding Share Capital and to extend the term of the lock-up obligations.
161
Discovery and Development Activities with Regeneron
● Regeneron leads the antibody discovery activities to identify and validate potential drug discovery targets and develop fully human monoclonal antibodies against these targets.
● In return, Sanofi funded $120 million per year for 2007 through 2009 and will fund up to $160 million per year of Regeneron’s antibody discovery activities from 2010 through 2017
● Sanofi has an option to extend certain antibody development and preclinical activities for up to an additional three years after 2017.
162
Discovery activities
Development activities
● For each drug candidate identified through discovery research under the discovery agreement which advances to an IND filing, Sanofi has the option to license rights to the candidate under the license agreement. If Sanofi elects to do so, Sanofi co-develops the drug candidate with Regeneron through product approval.
● Development costs for the drug candidate are generally funded up front by Sanofi, except that following receipt of the first positive Phase III trial results for a co-developed drug candidate, subsequent Phase III trial-related costs for that drug candidate are funded 80% by Sanofi and 20% by Regeneron.
● Regeneron is responsible for reimbursing Sanofi for half of the total development costs for all collaboration antibody products from their share of profits from commercialization of collaboration products; limited to 10% of their share of profits from commercialization of collaboration products in any calendar quarter.
● The discovery fees as well as the total development costs for all collaboration antibody products are booked under the “Research and development expenses” P&L line.
● The reimbursement to be received from Regeneron for half of the total development costs for all collaboration antibody products will be booked under the “Research and development expenses” P&L line.
Accounting treatment in Sanofi’s income statements
Commercial Activities with Regeneron
163
● Sanofi leads commercialization activities for products developed under the license agreement, subject to Regeneron’s right to copromote such products.
● In the event that Regeneron desires to copromote in a particular country, Regeneron’s copromotion effort shall be between 25% and 50% of the anticipated total effort.
● Sanofi and Regeneron share profits and losses from sales. ● Within the United States, Sanofi and Regeneron share equally profits and
losses. ● Outside the United States, Sanofi and Regeneron share profits on a sliding
scale based on sales starting at 65% (Sanofi) / 35% (Regeneron) and ending at 55% (Sanofi) / 45% (Regeneron), and share losses at 55% (Sanofi) / 45% (Regeneron).
● In addition to profit sharing, Sanofi is required to pay to Regeneron up to $250 million in sales milestone payments, with milestone payments commencing after aggregate annual sales outside the United States exceed $1.0 billion on a rolling 12-month basis.
● If Sanofi does not exercise its licensing option for an antibody under development, Sanofi would be entitled to receive a royalty once the antibody begins to be marketed.
Commercial activities
● The sales will be booked by Sanofi solely and the commercial costs incurred by Sanofi are booked under the “Selling and general expenses” P&L line.
● Regeneron share of net profit or loss is recognized under the “Other operating income and expenses” P&L line.
Accounting treatment in Sanofi’s income statements
Record of Sanofi Holding in Regeneron
164
● Pursuant to the Amended and Restated Investor Agreement, Sanofi has purchased additional shares of Common Stock to increase its beneficial ownership to approximately 22% of the Common Stock outstanding.
● Sanofi has recorded under the “Share of profits from associates” P&L line its holding in Regeneron (approximately 22%) accounted for using the equity method since beginning of April as follows ● Segment operating result (BOI) includes the share of Regeneron net profit (IFRS restated) before
• acquisition-related effects (workdown of acquired inventories and intangible assets remeasured at fair value at the acquisition date) and dilution impact due to stock option exercises
● Net income additionally includes:
• Workdown inventory step-up, after tax
• Amortization intangible step-up, after tax
• Dilution impact due to stock option exercises
Accounting treatment in Sanofi’s income statements