IR THEMATIC SEMINAR ON NEW MEDICINES November 20, 2014 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. 2 Agenda 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 3 Agenda (cont’d) 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 4 IR Thematic Seminar Focus on Selected New Medicines and Vaccines Our main objectives for today are: IR Thematic Seminar on New Medicines 1● Highlight the unmet medical needs addressed by Sanofi’s key late stage assets 2● Provide a high-level clinical profile of those products 3● Share information on our strategy to seize their commercial potential Help the Street to better evaluate near-term contribution from R&D 5 Introductory Comments Serge Weinberg Chairman of the Board of Directors CEO 6 Agenda 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 7 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) (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 8 R&D Plays a Major Role in the Successful Execution of Sanofi’s Strategy 1 Grow a global healthcare leader with synergistic platforms 2 Bring innovative products to market 3 Seize value-enhancing growth opportunities 4 Adapt structure for future challenges and opportunities Deliver sustainable long-term growth by improving patients' lives 99 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 • Confronted multiple R&D setbacks • Faced low returns despite growing R&D spend • Cleaned up R&D pipeline • 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 10 Over the Last 7 Years, Sanofi Launched Several New Drugs but Only One with Peak Sales Potential >$1bn ® (ex-U.S.) (ex-U.S.) ® 10 Launches 2007-2013 (U.S.) (U.S.) 11 Sanofi Expects to Launch High Potential New Medicines and Vaccines at an Accelerated Pace Beginning in 2014 ILLUSTRATIVE Up to 18 Launches 2014 - 2020 Praluent™ Shan5 (U.S.) sarilumab (U.S.) alirocumab Dengue PR5i Vaccine Vaccine insulin patisiran Anti-CD38 Rotavirus Vaccine mAb lispro Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions. Vaccine 12 Significantly Improving Returns from R&D 2007 - 2013 10 launches achieved 2014 - 2020 Up to 18 launches expected (1) At CER, 5 years for each product from and including the first full year of launch (2) Non-risk adjusted sales projections Potential cumulative first 5 years sales ~€7.5bn(1,2) Potential cumulative first 5 years sales >€30bn(1,2) 13 Sanofi Has Additional Potentially Transformative Drugs at Earlier Stages of Development 10 Early Assets to Watch 1 Vatelizumab(1) 6 Multiple Sclerosis 2 IL4/IL13 bi-specific mAb Niemann-Pick type B 7 Idiopathic Pulmonary Fibrosis 3 Anti-CD38 mAb Anti-GDF8 mAb 8 Revusiran (TTRsc) Familial Amyloid Cardiomyopathy (1) Anti-VLA2 mAb C-MET kinase inhibitor Solid Tumors 9 Sarcopenia 5 Neo GAA Pompe Disease Multiple Myeloma 4 rhASM Anti-CXCR5 mAb Systemic Lupus Erythematosus 10 GLP-1/GIP co-agonist Diabetes 14 Sanofi Has Established a Model of Productive R&D Collaborations Example 1 Example 2 ● Global strategic collaboration ● World-class RNAi technology ● Secured access to highly productive therapeutic human antibody platform ● Focus on genetically defined diseases with a clear translational model for RNA interference ● A platform to regularly bring new mAbs into clinical development ● A platform for sustained drug development for rare diseases for Genzyme 15 Strengthening the R&D Leadership Team with New Talent Maya Said VP, Strategy External Innovation & Science Policy Jorge Insuasty SVP, Development Gary Nabel SVP, CSO Andrew Plump SVP, Research and Translational Medicine Dominique Carouge VP, Administration & Management Hilary Malone VP, Global Regulatory Affairs John Shiver SVP, R&D, Sanofi Pasteur Jay Edelberg VP, Head of Alirocumab Unit Fabian Kausche Head of Merial R&D Christian Antoni VP, Head Development Immunology & Inflammation Anthony Muslin VP, Cardiovascular & Fibrosis Unit Mike Panzara VP, Multiple Sclerosis and Neurology, Genzyme Eckhard Leifke Diabetes - Head of Development Philip Just Larsen Diabetes - Head of Research & Early Development Victoria Richon Oncology - Head of Research & Early Development 16 Agenda Genzyme ● David Meeker, MD, CEO, Genzyme Cerdelga™ (eliglustat) Lemtrada® (alemtuzumab) 17 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 The Only First-Line Oral Therapy for Adults with Gaucher Disease Type 1 ● 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 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. 19 Efficacy Demonstrated in Untreated Patients (ENGAGE) ENGAGE - Change in Primary and Secondary Endpoints at 9 Months(1) Parameter Eliglustat Placebo Difference P Value -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 Spleen Volume (1) Pastores et al. ACMG 2013 (poster) 20 Efficacy Demonstrated in Patients Switching From ERT (ENCORE) ENCORE - % of Patients Who Met Stability at 12 Months(1,2) 100% 95% 100% 100% 96% 93% 100% 96% 94% 94% 85% 80% 60% 40% 20% 0% Stable Hemoglobin Stable Platelets Stable Spleen Volume Eliglustat Stable Liver Volume Composite Imiglucerase (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) 21 Genzyme Leading Innovation in Treating Gaucher Disease with Cerezyme® and Now Cerdelga™ % of Gaucher Patients in Whom Physicians Would Use Cerdelga™(1) ~38% ~42% Potential to grow Gaucher market and expand Genzyme Gaucher franchise to >€1bn(2) Existing patients Newly diagnosed patients (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) 22 Agenda Genzyme ● David Meeker, MD, CEO, Genzyme Cerdelga™ (eliglustat) Lemtrada® (alemtuzumab) 23 New MS Treatment Goals - Focus on Patient Outcomes Unmet Needs in MS New Goals 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 MS: Multiple Sclerosis 24 A Large and Growing Global MS Market Multiple Sclerosis Market Global Sales(3) Multiple Sclerosis ~€17bn ● 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) ~€12bn ~57% ~€5bn 2020e ~50% ~50% ● ~410,000 patients in the U.S.(1) ● ~630,000 patients in EU(2) ~43% 2013 2007 U.S. ROW 2013-20 growth driven by new therapies, satisfying the unmet needs of convenient administration and more efficacious therapy (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 25 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% 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. 26 FDA Approval Is a Major Step Forward for People with Relapsing Forms of MS ● 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 (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. 27 Agenda 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 28 CV Disease Remains an Area of High Unmet Need Cardiovascular disease causes 17.3m deaths per year(1) The estimated economic cost of CVD is huge in the U.S.(2) ● $193bn in direct health expenditures 17.3m $315bn ● $122bn in indirect cost of mortality LDL-C contributes to 60% of coronary heart disease and 40% of all ischemic stroke(3) 60% Despite available treatment options, including statins, 24m high-risk patients fail to reach LDL-C goals(4) 24m (1) (2) (3) (4) WHO. http://who.int/mediacentre/factsheets/fs317/en/ (EU, East. Mediterranean, The Americas, SE Asia, West Pacific, Africa) NHLBI. http://www.nhlbi.nih.gov/about/documents/factbook/2012/chapter4.htm WHO. http://www.who.int/whr/2002/en/whr02_en.pdf?ua=1 U.S. NHANES, Market Scan, IMS and Sanofi estimates 29 Lowering LDL-C with Statins Is Effective in Decreasing CV Risk LDL-C Prevention Trials(1) 25 Primary prevention trials 4S CHD Events (%) Active treatment Placebo 20 4S 15 2.8 WOSCOPS TNT-10A 5 ASCOT WOSCOPS AFCAPS ASCOT 0 Placebo 110 CARE TNT-80A Active treatment CARE LIPID 10 Secondary prevention trials LIPID AFCAPS 50 70 90 130 150 170 190 1.3 1.8 2.3 3.4 3.9 4.4 4.9 210 (mg/dL) 5.4 (mmol/L) LDL-C Despite high efficacy of statin therapy, unmet needs persist in familial hypercholesterolemia, high CV risk and statin intolerance (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 30 Despite Current Therapy, a Significant Proportion of Hypercholesterolemic Patients Are at High CV Risk 2016 Estimates for U.S., EU Top 5 and Japan (in million patients)(1) Heterozygous Familial Hypercholesterolemia 1.2m Statin Intolerant 2.9m Primary Prevention 4.8m 24m Patients With High CV Risk Diabetes(2) Secondary Prevention 5.3m 10.1m Secondary Prevention without Diabetes 10.3m (1) U.S. NHANES, Market Scan, IMS and Sanofi estimates (2) Diabetes with 2 Risk Factors with or w/o CV Event 31 Sense of Urgency to Lower LDL-C to Reduce CV Risk Varies According to Patient Types HeFH Statin Intolerant High CV Risk ● Well defined but underdiagnosed population ● High LDL-C levels comparable to HeFH ● Large and diverse population with associated CV risks ● High engagement of patients ● Pragmatic approach used by physicians but no objective definition ● Large proportion of patients with previous CV event ● Large proportion of uncontrolled patients with current therapies ● Low satisfaction level with existing treatment options HeFH: heterozygous familial hypercholesterolemia ● Strong awareness of risk, especially for recent events ● Significant overlap with diabetes population 32 The Development of Alirocumab, an Anti-PCSK9 mAb, Is a Prime Example of Modern Translational Medicine The PCSK9 Discovery Decade First Phase III study results Loss-of-function mutations observed Proof of principle in animals(3,4) Gain-of-function mutations observed Phase II study results(9) Human target validation(5,6,7) PCSK9 discovery(1,2) 2003 U.S./EU regulatory submissions First subject treated with PCSK9 mAb PCSK9-targeted mAb preclinical(8) 2004 (1) (2) (3) (4) (5) 2005 2006 2007 2008 Seidah NG. Proc Natl Acad Sci USA 003;100:928-33 Abifadel M. Nat Genet 2003;34:154-6 Maxwell KN. Proc Natl Acad Sci USA 2004;101:7100-5 Rashid S. Proc Natl Acad Sci USA 2005;102:5374-79 Cohen JC. N Engl J Med 2006;354:1264-72 2009 (6) (7) (8) (9) 2010 2011 2012 Zhao Z. Am J Hum Genet 2006;79:514-23 Hooper AJ. Atherosclerosis 2007;193:445-8 Chan JC. Proc Natl Acad Sci USA 2009;106:9820-5 Lambert G et al. J Lipid Res 2012; 53(12): 2515-24 2013 2014 33 A Differentiated Clinical Development Program HeFH High CV Risk On top of max tolerated statin On top of max tolerated statin On top of regular statin doses Not receiving statin FH I (n=486) COMBO I (n=316) OPTIONS I (n=355) MONO(2) (n=103) FH II (n= 249) COMBO II (n=720) OPTIONS II (n=305) CHOICE II(3) (n=200) HIGH FH (n=107) CHOICE I (n=700) Statin Intolerant LONG TERM (n=2,341) OLE(1) (n≥1,000) ALTERNATIVE (n=314) OUTCOMES (n=18,000) ● 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) ● 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 34 Next Regulatory Milestones and Development Steps 1 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 2 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 3 ODYSSEY OUTCOMES ongoing (n=18,000)(1) ● Assess the potential of alirocumab to demonstrate CV benefit (1) Rationale and design in Schwartz GG et al. Am Heart J 2014;0:1-8.e1. 35 Agenda 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 36 Significant and Consistent LDL-C Reduction across All 10 Reported Trials LDL-C Change from Baseline at 24 Weeks Study Dosing q2w Baseline LDL-C (mg/dL) Alirocumab HIGH FH 150 mg 198 ↓ 46% ↓ 7% placebo FH I 75/150 mg(1) 145 ↓ 49% ↑ 9% placebo FH II 75/150 mg(1) 134 ↓ 49% ↑ 3% placebo 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% ↓ 5% ↓ 21% ezetimibe statin x2 statin switch OPTION II 75/150 mg(1) 111 ↓ 36-51% ↓ 11-14% ↓ 16% ezetimibe statin switch Statin Intolerant ALTERNATIVE 75/150 mg(1) 191 ↓ 45% ↓ 15% ezetimibe Moderate CV Risk MONO 75/150 mg(1) 140 ↓ 48% ↓ 16% ezetimibe HeFH High CV Risk Comparator On top of max statin doses On top of regular statin doses Not receiving statins 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 37 Robust and Durable LDL-C Reduction Maintained over 52 Weeks LONG TERM Achieved LDL-C Over Time(1) All Patients on Background of Maximally Tolerated Statin ± other LLT Mean (SE) LDL-C in mg/dL 140 123.0 mg/dL (+4.4%) 118.9 mg/dL (+0.8%) 120 100 Difference −61.9% 80 Placebo Alirocumab 150 mg q2w Difference −61.3% 60 40 53.1 mg/dL (−56.8%) 48.3 mg/dL (−61.0%) 20 0 0 4 8 12 16 24 LLT: Lipid lowering therapy Intent-to-treat analysis (1) LDL-C: Calculated LDL-C, least-squares (LS) means (SE standard error) 36 52 Week 38 Consistent LDL-C Reduction across a Range of Baseline LDL-C Values LONG TERM LDL-C Change from Baseline(1) All Patients on Background of Maximally Tolerated Statin ± Other LLT Mean % Change in LDL-C from Baseline to Week 24 Placebo Alirocumab Interaction p-value <0.0001 20 10 0 -10 -20 -30 -40 -50 -60 -70 n=241 100 to <130 mg/dL n=562 n=285 13.6% 0.5% <100 mg/dL n=470 130 to <160 mg/dL n=271 n=143 ≥160 mg/dL n=227 -18.2% -5.2% -61.3% LLT: Lipid lowering therapy Intent-to-treat analysis (1) LDL-C: Least-squares (LS) means -62.0% -59.8% n=111 -59.5% 39 Safety Profile from Long Term Study LONG TERM % of Patients with Treatment Emergent Adverse Events of Interest Alirocumab Placebo (n=1550) (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 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) 40 Post-hoc Adjudicated Major Adverse Cardiovascular Events(1) LONG TERM Cumulative probability of event Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event 0.06 Safety Analysis(2) 0.05 Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01 0.04 Placebo + max-tolerated statin ± other LLT 0.03 Alirocumab + max-tolerated statin ± other LLT 150 mg q2w 0.02 Mean treatment duration: 65 weeks 0.01 0.00 Weeks No. at Risk Placebo 0 12 24 36 48 60 72 84 788 776 731 703 682 667 321 127 Alirocumab 1550 1534 1446 1393 1352 1335 642 252 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 41 ALTERNATIVE Safety and Efficacy in Statin Intolerant Patients with Very High LDL-C (~190mg/dL) Patient at LDL-C Goal Skeletal Muscle Adverse Events Significantly More SI Patients Achieved LDL-C Goals with Alirocumab Fewer Skeletal Muscle Adverse Events(2) with Alirocumab than with Atorvastatin Goals alirocumab ezetimibe LDL-C <70 mg/dL or <100 mg/dL (depending on risk) 42% 4% LDL-C <100 mg/dL 61% 10% ∆: P<0.0001(1) 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) 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 42 Alirocumab Has the Potential to Transform LDL-C Management 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 43 Agenda 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 44 Key Factors Impacting Uptake of PCSK9 mAbs in High CV Risk Patients 1 Physician awareness 2 Likelihood to prescribe 3 Efficacy attributes 4 Patient acceptance 5 Payor dynamics 45 1 Very High and Growing Awareness Percent of Specialists Aware of PCSK9 Inhibitor Class(1) 73% Q4 2013 Q2 2014 62% 49% 54% 52% 36% Estimated Number of Specialists Aware ~13,000 ~1,100 ~3,500 (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 46 2 High Likelihood to Prescribe Percent of Specialists Likely/Very Likely to Prescribe a PCSK9 Inhibitor(1) Q4 2013 64% 71% Q2 2014 64% 71% 63% 49% (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 47 3 Efficacy Attributes Are Most Important for Specialists U.S. Specialists Demonstrates significant decrease in CV morbidity / mortality 247 232 Substantial data in high CV risk patients like diabetes, CHD, stroke 211 Achieves significant reduction of LDL-C, particularly high CV risk patients 163 Achieves significant reduction of LDL-C for majority of patients 146 Good treatment option for statin intolerant patients 116 Demonstrates good tolerability profile resulting in minimal monitoring of AEs 95 Covered, affordable for patients (reasonable level of OOP cost to patients) Acts on atheroma plaque Achieves significant increase of HDL-C OOP: Out of pocket Source: Proprietary survey conducted in the U.S. 78 Average score of importance = 100 67 48 4 High Patient Acceptance and Perception of Benefit ShareShare of Patients of Patients Likely/Very LikelyLikely / Very to Likely Accept to Accept and Filland PCSK9 Fill PCSK9 Treatment Treatment Prescription 70% Managed by Endos 70% HeFH 52% 52% Statin Intolerants Secondary Prevention 65% 65% Statin Intolerants Secondary Prevention 65% 53% Primary Prevention (DM/CKD) 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 Primary Prevention (DM/CKD) 49 4 Broad Experience of Home Self-Injection with Alirocumab Flexibility in Dose & Delivery Options 75 mg(1) Available Auto-Injector Satisfaction Rating ODYSSEY MONO(2) q2w 150 mg 98% (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 50 5 Payor Dynamics 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 51 Engaging Significant Resources to Ensure Alirocumab Launch Success in the U.S. Praluent™ alirocumab Praluent™ is the intended trade name for alirocumab. The trade name is currently pre-approved in the EU but not in other regions. 52 Q&A 53 BREAK Return in 15 Minutes 54 Agenda 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 55 There Is Need for an Improved Basal Insulin Experience to Get More Patients to Control(1) Frustration Imprisonment Embarrassment At start, a challenge ● Frustration of poor control ● Fear of hypoglycemia At stay, a variable experience ● Satisfaction? “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” (1) Motivation and characterization of insulin patients, patient interviews (2) Highs = Hyperglycemia / Lows = Hypoglycemia ● Motivation? 56 Despite Treatment, Many Patients with Diabetes Are Still not at A1c Goal(1) Diabetes Patients in the U.S. (Random Sample) T1D Patients T2D Patients 53% 53% Uncontrolled (>7%) Controlled (<=7%) 47% 47% 2013 (437) 2013 (2215) 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 57 Most Patients Delay Increasing their Dose After Initiation of Therapy Despite Not Being at Goal(1) Timing of Dose Increase after First Week on Basal Insulin 63% Patients wish for a quick titration experience to achieve immediate control but fear hypos 37% <1 month >1 month (1) Idea Exchange Report Toujeo® Titration Exploration (9.4.2014); Sanofi market research 58 Patients Respond to Hypoglycemia by Modifying their Dose or Discontinuing Therapy 4 in10 people experienced hypoglycemia within the first month(1) 6 in10 patients modify their insulin dose after experiencing a severe hypoglycemia event(2) 77% of people who experienced hypoglycemia within 6 months of initiation had discontinued within 1 year(3) (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 59 Inappropriate Diabetes Management Leads to Costly Consequences Risk of Complications and A1c(1) Microvascular Complications ● Diabetic Retinopathy Relative Risk in % 15 Retinopathy 13 Nephropathy Neuropathy 11 Microalbuminuria Macrovascular Complications ● Stroke 9 ● Diabetic Nephropathy 7 ● Heart Disease 5 ● Diabetic Neuropathy ● Peripheral Vascular Disease 3 1 6 7 8 9 10 11 12 A1c (%) 25% to 45% of diabetes-attributed medical expenditures spent treating complications of diabetes(2) (1) Endocrinol Metab Clin 1996;25:243 - 254 (DCC Trial) (2) Diabetes Care Publish Ahead of Print, published online March 6, 2013 60 Hypoglycemia Contributes to Poor Compliance and Affects Treatment Efficacy(1) 50% of basal 30% to 60% experience hypoglycemia insulin patients are not at A1c goal 59% of new to Lantus® patients in the U.S. have significant compliance gaps The launch of Toujeo® will offer opportunities to address unmet needs (1) IMS Lifelink; U300 segmentation; Sanofi market research; expert interviews; Sanofi analysis 61 Agenda 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 62 Patients Hate Hypoglycemia Mild to moderate hypoglycemia ● Very unpleasant and disruptive symptoms (e.g. blurry vision, rapid heartbeat, sudden mood changes, headache, trouble concentrating) Severe hypoglycemia ● A medical emergency that can result in fainting, seizures, unconsciousness, coma and death 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 Canadian Diabetes Association Clinical Practice Guidelines. Can J Diabetes. 2013;37(suppl 1):S1-212. 63 A Smoother and Prolonged PK/PD Profile vs. Lantus® Reduction of Volume by 2/3 More Constant PK/PD Profile(1) Median insulin concentration, µU/mL 20 Toujeo® 10 Lantus® 0 0 Lantus® Toujeo® 6 12 24 30 36 Glucose infusion rate, mg/kg/min 3 Lantus® 2 Reduction of Depot Surface Area by 1/2 18 1 Toujeo® 0 0 6 12 18 24 30 36 Blood glucose, mg/dL 160 Lantus® 140 Toujeo® 120 Lantus® Toujeo® 100 Time, h 0 6 12 18 24 30 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 36 64 Offering Greater Consistency Over the Course of the Day Type 1 Diabetes - Continuous Glucose Monitoring Study(1) Lantus® Toujeo® 11 Average 24-hour glucose profiles showed a more constant glucose level with Toujeo® vs Lantus® 10 9 8 7 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, h (1) Bergenstal RM et al. Poster presentation at EASD 2014; data combining morning and evening injections 65 All Studies of EDITION Phase III Program Met their Primary Endpoint(1,2) vs. Population EDITION 1 T2DM on basal and mealtime insulin + OADs EDITION 2 T2DM on basal insulin + OADs EDITION 3 T2DM insulin-naïve + OADs EDITION 4 T1DM on basal and mealtime insulin EDITION JP1 T1DM on basal and mealtime insulin EDITION JP2 T2DM on basal insulin + OAD Primary Endpoint Non inferiority (Change in A1c) (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 66 Benefit on Nocturnal Hypoglycemia Nocturnal Hypoglycemia(1,3) Pooled analysis of EDITION 1-2-3 % Participants with ≥1 Confirmed and/or Severe Hypoglycemia(2) Lantus® Toujeo® 50 RR 0.75 (0.68 to 0.83) 40 30 RR 0.80 (0.71 to 0.91) -25% RR 0.69 (0.58 to 0.81) -20% 20 -31% 10 0 Baseline to week 8 Baseline to month 6 (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 Week 9 to month 6 67 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 Lantus® Toujeo® Nocturnal(2) At any time(3) 3 10 -14% 8 2 6 -31% 1 4 2 p=0.0002 0 0 4 8 12 16 Time, weeks 20 24 p=0.0116 0 28 0 4 8 12 16 Time, weeks 20 24 (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 28 68 Hypoglycemia Benefit Consistently Demonstrated 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) (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% 69 Sustained Glycemic Control at 1 Year LS Mean (95% CI) Difference in A1c Between Groups at Month 12 A1c (%) mean ± SE 8,5 8.5 EDITION 1(1) 8,0 8.0 Lantus® 7,5 7.5 Toujeo® 7,0 7.0 8.5 8,5 EDITION 2(2) 8,0 8.0 Lantus® 7,5 7.5 7,0 7.0 −0.17% p=0.0074 0.06% p=0.4932 Toujeo® BL W12 LS: Least Squares (1) Type 2 Diabetic patients uncontrolled with basal bolus (2) Type 2 Diabetic patients uncontrolled with Basal + OAD M6 M9 M12 70 Weight Change Difference Maintained Over Time Mean Weight Change (kg ± SE)(1) Pooled analysis of EDITION 1-2-3 1.5 LS mean difference: –0.28 kg p=0.039 1.0 Lantus® Toujeo® 0.5 0.0 -0.5 BAS Week Week 2 4 Week 8 Week 12 Month 4 (1) Type 2 Diabetic patients; Ritzel R et al. Poster presentation at EASD 2014; Abstract 963 Month 6 71 Flexibility in Injection Time (24 hours ± 3 hours) 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) EDITION 1 EDITION 2 Percentage of patients experiencing ≥1 event, % 70 Flexible dosing 60 Fixed dosing 50 40 30 20 10 0 Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L]) Confirmed or severe nocturnal (≤70 mg/dL [3.9 mmol/L]) (1) Riddle MC et al. Poster presentation at ADA 2014; Abstract 919-P Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L]) Confirmed or severe nocturnal (≤70 mg/dL [3.9 mmol/L]) 72 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 PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile 73 Agenda 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 74 The Next Generation of Basal Insulin with a Smoother PK/PD Profile than Lantus® TOUJEO • Smoother PK/PD LANTUS • Once daily • Less hypos NPH than NPH • Treat to target PK/PD Profile: Pharmacokinetic/Pharmacodynamic Profile profile than Lantus® • Full 24h coverage • Less hypos than Lantus • Improved patient experience 75 Total Addressable U.S. Basal Insulin Market for Toujeo® Is ~6m Patients(1) Estimated Annual New Basal Insulin Naïve Patients Existing Patients Total Addressable Market Million patients Million patients 5m + Levemir® 1m/year ~6m ● 14.3m insulin naïve drug-treated patients ● 1m new basal insulin starts every year (1) Sanofi market research, expert interviews 76 A Compelling Value Proposition (1) (2) (3) (4) Jax T et al. Poster presented at EASD 2013; Abstract 1029. Available at http://www.easdvirtualmeeting.org/resources/6226 Accessed May 2014 Ritzel R, et al. Diabetes 2014;63 (suppl 1A) Riddle MC et al. Poster presentation at EASD 2014; Abstract 980 ORIGIN Trial Investigators. N Engl J Med. 2012 Jul 26;367(4):319-28 77 Scientific Data Communication Created Strong Pre-launch Awareness and Willingness to Prescribe Aided Awareness of Toujeo®(1) Willingness to Prescribe Toujeo®(1) % of Endocrinologist Aware % of Endocrinologist Willing to Prescribe 77% 75% 60% 52% 50% 40% US EU Top 5 (1) Sanofi Market Research – Awareness and Trial Tracking (August 2014) US EU Top 5 78 Target Switch Segments Represent Almost 60% of Existing Basal Insulin Patients Pre-Launch(1) Segment size % Receptive to Concerned ® (2) basal insulin pop Toujeo TPP about hypos Frustrated and challenged: Type 2 (Uncontrolled) 29% Frustrated and challenged: Type 1 (Uncontrolled) 6% Natural switchers Motivated but are falling short (Type 2 basal bolus, controlled w/ hypos) Engaged and satisfied (Type 1 / Type 2 controlled) Looking for better options 22% Require convincing 43% May become unsatisfied over time More limited drivers for engaged and satisfied patients to switch from current treatment (1) Toujeo® segmentation survey: Segmentation solutions and expert interviews (2) Target Patient Profile 79 An Enhanced SoloStar® Device: Accurate, Precise and Easier to Use Toujeo® SoloStar®: Adapted for the Next-Generation Basal Insulin ● Smaller injection volume(1) ● Ergonomic design improvements ● No additional training needed(1) ● 50% more units per pen (450 IU)(1) (1) Compared to Lantus® SoloStar® 80 Toujeo® and Customized Patient Support Program Intended to Ensure a Smoother Start and Better Stay Regular touch points ● Support successful initiation of Toujeo® following prescription ● Mix of face to face/ phone/ webinar interactions 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) Adapted locally ● Motivate patients to stay on therapy A Customized Patient Support Program to achieve personalized glycemic goals (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) 81 Ensuring U.S. Sales Force Readiness for Launch Enhancement of U.S. commercial effectiveness to improve Lantus® performance and prepare for the Toujeo® launch 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 Achieving Payor Access is Necessary for Franchise Conversion Toujeo® is a better insulin vs. Lantus® based on the EDITION program ● 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 83 Preparing for Launch Regulatory Timelines: 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 Our Diabetes Team is Focused on Improving Patient Outcomes Ambition for 1 Become the preferred basal insulin 2 Convert basal insulin users, especially Lantus®, to Toujeo® 3 Ensure Toujeo® patients have an improved insulin experience to generate a substantial proportion of Sanofi’s glargine volume in the U.S. within 3 years after launch 85 Agenda 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 86 The Majority of Patients on 2+ OADs Resist Starting Insulin Therapy(1,2) Patients on 2+ OADs Are Resistant to Starting Insulin Therapy % of Patients 39% 66% Resistant to starting66% insulin 27% Resistant because of injections Resistant not because of injections Not Resistant to taking insulin (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 87 A New and Innovative Treatment Option for Diabetes Afrezza® (insulin human) Product Label Indication ● ● Dosage & Administration Afrezza® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes Not recommended for patients who smoke Warnings & Precautions 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 Black Box ● Most common adverse event is cough ● Should not be used in patients with active lung cancer ● ● ● 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 Large 5-year safety study to assess potential risk of pulmonary malignancy to be conducted COPD: Chronic Obstructive Pulmonary Disease 88 Many Diabetes Patients Are Not at A1c Goals Due to Delayed Insulin Initiation and Intensification Focus of Initial Commercial Strategy for Afrezza®(1,2,3) Insulin Initiation Insulin Intensification Patients on 2+ OADs or GLP1 ± OADs Patients on Basal Insulin or Basal ± GLP1 ± OAD ~3.1m Diabetes Patients ~2.0m ~1.1m Uncontrolled patients(1) (A1c > 7%) Controlled patients (A1c < 7%) Smokers, patients with asthma & COPD(2,4) (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 89 Device is Unique and Innovative ● 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 90 Afrezza® Delivers a Distinctly Different Patient Experience than the Previous Inhaled Insulin Exubera® Afrezza® Lower bioavailability and slower clearance Higher bioavailability and faster clearance Large device Small device Complicated titration system Easy to use Doses were in milligrams Time consuming in-office training Doses equivalent to insulin units Less training required No cleaning requirement Device required weekly cleaning 91 Majority of Patients Surveyed Prefer Afrezza® over Insulin Pen Device or Injectable Mealtime Insulins(1) Insulin Initiation Insulin Intensification Preference for Afrezza® vs. Insulin Pen Device Preference for Adding Afrezza® vs. Injectable Mealtime Insulins (% of patients on 2+ OADs) (% of basal patients) 60% 57% 66% 32% 17% 23% 11% Preference for Afrezza® Preference for Afrezza® No preference No preference Preference for insulin pen device 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. 92 Physician Survey Indicates Afrezza® Would Be an Appealing Option for Insulin Initiation and Intensification(1) Insulin Initiation Insulin Intensification “The product will make it significantly easier to initiate insulin among my uncontrolled oral patients” “I would be comfortable using the product instead of injectable rapid acting insulin for my basal bolus patients” (% of physicians) (% of physicians) 62% 56% 66% 25% 23% 15% Agree Agree Neither agree nor disagree Neither agree nor disagree Disagree Disagree 19% (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. 93 The Launch Will Occur in Two Phases Expansion Drivers 2015 U.S. Launch ● Novel product delivery ● Early adopters ● Current label ● Potential ex-U.S. launches ● Supply of Sanofi insulin ● Label enhancement studies ● Safety study completed 94 Agenda 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 95 A Strong Drug Profile Emerging from PoC Study in Type 2 Diabetes Proof-of-Concept Study of Fixed-Ratio Once-Daily LixiLan in Type 2 DM on Metformin ● 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 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 (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) 96 High Proportion of Type 2 Diabetes Patients Reached A1c Target in PoC Study 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 (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 97 Combining Insulin Glargine with Lixisenatide in a Single Daily Injection U.S. Target Populations of T2D Patients for ● 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) 1st injectable drug Patients Not at Target on OAD ~5.5m patients Basal Intensification Patients Uncontrolled with basal therapy ~4m 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 Number of patients estimated for the U.S. (2017 projections based on internal model adapted from Adelphi) 98 Agenda 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 99 Broadening our Portfolio to Sustain a Leadership Position in Diabetes 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 4 Expand access to Lantus® in developing countries 5 Drive better outcomes through integrated care solutions 100 Q&A 101 Agenda 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 102 Dengue: A Mosquito-Borne Disease Dengue Is the Most Important Vector-Borne Viral Disease of Humans(1) ● 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 Aedes mosquito Humans 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) (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. 103 Spread of Dengue Follows Growing Trend of Urbanization Important Determinants of the Dengue Disease Epidemiology(1) ● Urbanization ● Travel and globalization ● Vector control effectiveness and sustainability ● Factors adding to the proliferation of dengue(2,3) ● Seasonal trends (1) Kyle, 2008, Ann Rev Microbiol. (2) Higa, 2011, Trop Med Health (3) Descloux, 2012, PLoS Negl Trop Dis. 104 Dramatic Expansion of Dengue with a 30-Fold Increase in Dengue Incidence over the Last 50 Years(1) WHO Estimates Estimates Based on 2013 Modeling(5) 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 WHO objective: estimate true disease burden by 2015(4) 96 million symptomatic infections per year 390 million infections per year Contributes to a large reservoir of infection that influences disease burden die Four distinct serotypes with unpredictable distribution(5) (1) (2) (3) (4) (5) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control World Health Organization, 2014, Dengue factsheet ~12,500 people or 2.5% people with severe dengue die each year WHO, 2012, Global Strategy for Dengue Prevention and Control Bhatt, 2013, Nature 105 Every Year, an Estimated 2 Million People with Dengue Require Hospitalization(1) Characteristics of Severe Dengue(2) ● Plasma leakage ● Severe gastrointestinal involvement ● Severe organ impairment ● Significant bleeding ~2.5% of severe dengue cases result in death ● Altered level of consciousness (1) Beatty 2009 (2) World Health Organization, 2009, Dengue guidelines for diagnosis, treatment, prevention and control 106 Dengue Has an Adverse Economic and Societal Impact in Endemic Regions Dengue Disease Is Estimated to Cost Between US$6.3bn(1) and US$12bn Each Year in Endemic Countries(2) Dengue “phobia”(4) Overcrowded healthcare facilities(3) Fear of infection(4) Community disruption(4) Lost productivity(3) Economic cost(3,4,6,7) Decrease in tourism(5) Perceived government failure(4) Dengue can affect anyone, regardless of age and socioeconomic status(4,8) (1) (2) (3) (4) Shepard et al. 2014, poster ASTMH 2014 Infectious Disease Cost Calculator, Accessed Nov 2014 Gubler, 2002, Trends Microbiol. Douglas, 2013, PLoS Negl Trop Dis. (5) (6) (7) (8) Mavalankar, 2009, IIMA Shepard, 2013, PLoS Negl Trop Dis. Shepard, 2011, Am J Trop Med Hyg. OK DoH website, 2013, Oklahoma Department of Health 107 Sanofi Pasteur Dengue Vaccine Can Make the 2020 Objectives of WHO Achievable WHO Objectives(1) Estimate true burden of disease by 2015 Reduce dengue mortality by ≥50% by 2020* Reduce dengue morbidity by ≥25% by 2020* Technical elements Diagnosis & case management Integrated surveillance & outbreak preparedness Sustainable vector control Future vaccine implementation Basic operational & implementation research Vaccination is a crucial element in achieving the WHO objectives *2010 is baseline year. (1) WHO, 2012, Global Strategy for Dengue Prevention and Control 108 Agenda 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 A Significant Technological Advance(1,2) ● 4 genetic constructs, 1 for each serotype Dengue Dengue 17D yellow fever 17D Yellow fever ● 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) YFV 17D VIRUS C NS DENV-1 PrM E DENV-2 PrM E DENV-3 PrM E DENV-4 PrM Chimeric Virus Recombinant virus RECOMBINANT DENV-1, -2, -3, and -4 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 110 More than 41,000 Individuals Included in Sanofi’s Dengue Vaccine Clinical Trial Program(1) Phase III Evaluation Provides Complementary and Pivotal Data for Efficacy, Safety, and Immunogenicity of the Dengue Vaccine(2,3) CYD14 Phase III Efficacy Study Asia Countries: Thailand, Indonesia, Malaysia, Viet Nam, Philippines Sites : 11 Age group: 2–14 years Sample size: 10,278 CYD15 Phase III Efficacy Study in LatAm(2) CYD14 Phase III Efficacy Study in Asia(3) ● Countries: Colombia, Mexico, Honduras, Puerto Rico and Brazil ● Countries: Thailand, Indonesia, Malaysia, Vietnam and Philippines ● Sites: 22 ● Sites: 11 ● Age group: 9 to 16 years ● Age group: 2 to 14 years ● Sample size: 20,875 ● Sample size: 10,278 (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 111 Phase III Studies Design: Randomized 2:1, Observer-Blind, Placebo-Controlled, Multicenter(1,2) 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 R A N D O M I Z A T I O N 2:1 Vaccination with Dengue Vaccine Months 0 6 12 13 18 25 Year 6 Hospital Phase Vaccination with Placebo* Active Phase Active Surveillance/Detection of Dengue Cases ● Per-protocol analysis: follow-up from month 13–25. ● Intent-to-treat analysis: follow-up from month 0–25. Additional followup for safety of hospitalized dengue cases for 4 years after the end of the active phase 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. 112 Meta-Analysis Demonstrates Significant Reduction in Dengue across All Serotypes after 3 Doses Schedule(1,2) EFFICACY and 95% CI STUDY (n episodes) Any Serotype ASIA / CYD14 (n=251) 52.0 Pooled (n=647) 52.3 ASIA / CYD14 (n=67) DENV-2 61.5 35.0 -9.2 61.0 42.3 14.0 LATAM / CYD15 (n=108) 18.7 61.1 39.6 55.2 78.4 52.9 ASIA / CYD14 (n=33) 61.9 LATAM / CYD15 (n=125) 65.1 Pooled (n=158) DENV-4 65.0 65.2 50.2 35.6 68.0 66.8 50.3 29.1 Pooled (n=175) DENV-3 59.2 50.0 24.6 LATAM / CYD15 (n=132) Pooled (n=233) 66.4 60.8 LATAM / CYD15 (n=397) ASIA / CYD14 (n=101) DENV-1 56.5 43.8 65.0 (1) Capeding, 2014, Lancet (2) Villar, 2014, N Engl J Med. 0 20 40 74.9 82.0 60 87.0 77.7 60.2 Pooled (n=109) -20 82.4 75.3 54.5 ASIA / CYD14 (n=51) LATAM / CYD15 (n=58) 74.0 90.8 76.6 80 88.0 84.4 100 113 Higher Efficacy Demonstrated Against Severe Dengue, Including Reduction in Hospitalized Cases(1,2) Overview of Efficacy Results Against Virologically Confirmed Dengue (Severe and Hospitalized)(1,2,3) EFFICACY and 95% CI STUDY (n episodes) Vaccine Efficacy on Dengue Hemorrhagic Fever (DHF) cases 80.0 52.7 ASIA / CYD14 (n=28) Vaccine on hospitalized dengue cases 67.2 50.3 ASIA / CYD14 (n=101) Efficacy(4) 64.7 LATAM / CYD15 (n=60) 0 20 95.0 99.9 64.9 LATAM / CYD15 (n=11) (WHO 1997 definition) 92.4 40 60 78.6 80.3 80 89.5 100 Results relevant in public health context (ie, vaccine could help reduce disease burden)(1,2) (1) (2) (3) (4) Capeding, 2014, Lancet Villar and al., 2014, NEJM Intent to Treat analysis (25m follow-up from months 0–25) 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) 114 Higher Efficacy Observed in Those Previously Exposed to Dengue, During the Active Phase Efficacy According to Dengue Serostatus at Baseline(2) in Asia & Latam(1,2) EFFICACY and 95% CI STUDY (n episodes) 74.3 DENV + (n=52) ASIA / CYD14 35.5 DENV – (n=41) 83.7 LATAM / CYD15 DENV + (n=31) 43.2 DENV – (n=18) -80 -60 -40 -20 0 20 40 60 80 100 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. 115 Favorable Safety Profile in Vaccinated Subjects during the Active Phase of Phase III Efficacy Studies CYD14 & CYD15 Safety Results (Active Phase)(1,2) Safety analyses* showed similar reporting rates between the vaccine and control groups during the studies * 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 (1) Capeding, 2014, Lancet (2) Villar and al., 2014, NEJM Safety profile over the 25-month is favorable and consistent with the favorable safety profile documented in previous studies (Phase I, II, III) 116 Both Efficacy Studies in Asia and LatAm Consistently Demonstrate a Reduction in Dengue Disease Both Studies Met their Primary Efficacy Endpoints and Showed Consistent Safety Profile for the Observed Active Phase(2,3) Key Study Results 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 CYD 14, Asia(2) CYD 15, LatAm(3) 56.5% 60.8% Reduction in symptomatic dengue(4) Reduction in symptomatic dengue(4) 80%* 95%† Reduction in severe disease(5) Reduction in severe disease(5) 67.2%‡ 80.3%§ Reduction in hospitalized cases(6) Reduction in hospitalized cases(6) 2.5%(1) of people with severe dengue die *95% CI: 52.7-92.4 (1) World Health Organization, 2014, Dengue factsheet (2) Capeding, 2014, Lancet (3) Villar and al., 2014, NEJM †95% CI: 64.9-99.9 ‡95% CI: 50.3-78.6 (4) Post Dose 3 (5) DHF, WHO 1997 criteria, intent to treat (6) Intent To Treat §95% CI: 64.7-89.5 117 Agenda 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 A Broad Vaccination Program Has the Potential to Lead to a Significant Reduction in Hospitalizations Modeling the Prevention of Hospitalized Dengue Cases by Adding Multiple Catch-up Cohorts to a Routine Vaccination Program in a Given Population(1) 40 19% 35 Number of hospitalized cases (per 100,000 dengue cases) 34% 30 53% 25 73% 20 81% Prevented hospitalized cases (%) 15 10 5 0 No vaccination Hospitalized cases 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 (1) Sanofi internal analysis, based on Coudeville & Garnett [2010]; prevented cases in the first 10 years of vaccine introduction ILLUSTRATIVE 119 From Vaccine Efficacy to Vaccination Impact(1-7) Vaccine Efficacy Direct protection & indirect protection x Vaccination Coverage # cohorts x coverage in each cohort = ƒ Disease Endemicity Vaccination Impact % Population Protected by Vaccination (1) (2) (3) (4) Chao, 2012, PLoS Negl Trop Dis. Coudeville, 2012, PLoS One Durham, 2013, Vaccine Rodriguez-Barraquer, 2013, Vaccine (5) Dasbach, 2006, Epidemiol Rev. (6) Farrington, 2003, Math Biosci. (7) McLean, 1998, Dev Biol Stand. 120 A Successful Vaccination Program Defined by Several Factors 1 Age for routine vaccination Define the optimal age range for routine vaccination population in an endemic country 2 Catch-up cohort size Determine the optimal catch-up cohort size to maximize impact of vaccination (range of age) 3 Geographic breadth Agree on the geographic breadth of the vaccination program with local government 4 Compliance Ensure highest impact through compliance with 3-dose schedule 5 Outbreaks Incorporate the outbreak nature of the disease into an integrated strategy 121 An Unprecedented Industrial Commitment to Ensure the Success of Large Scale Vaccination Programs Ready to Produce >1bn Doses over the Next 10 Years ● 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 Manufacturing Site, Neuville-sur-Saone, France 122 The Global Roll-out of Sanofi’s Dengue Vaccine 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 2015 2020 ILLUSTRATIVE 123 Dengue Vaccine Launch Expected to Start by End of 2015 Make Dengue the Next Vaccine- Preventable Disease 124 Agenda ● Elias Zerhouni, MD, President, Global R&D Sarilumab Dupilumab Wrap-up and Q&A Session 125 Immunology & Inflammation Set to Become a New Growth Platform for Sanofi Immuno-Modulation is at the core of Sanofi’s R&D strategy Rheumatoid Arthritis Systemic Lupus Erythematosus Atopic Dermatitis Asthma Inflammatory Bowel Disease Multiple Sclerosis 126 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) (1) World Health Organisation. Chronic rheumatic conditions (2) Patient UK. Rheumatoid arthritis 127 Incomplete Response or Intolerance Leads Patients to Cycle through Multiple Biologics MTX/DMARDS 1st line treatment RA Combination Tx Market ~70% Add Anti-TNF 1st line biologic Switch to Other MOA’s (Add on to MTX) T cell Current guidelines make no distinction between which biologic to start on IL-6R JAK CD 20 MTX/DMARDS 1st line treatment RA Mono Tx Market IL-6R ~30% JAK TNF MTX: Methotrexate DMARD: Disease-Modifying Anti-Rheumatic Drugs Humira® (adalimumab) is marketed by AbbVie Actemra® (tocilizumab) is marketed by Roche Remicade® (infliximab) is marketed by J&J Simponi® (golimumab) is marketed by J&J Orencia® (abatacept) is marketed by BMS Xeljanz® (tofacitinib) is marketed by Pfizer (1) EULAR guidelines Current guidelines recommend using IL-6R as a 1st choice monotherapy(1) Enbrel® (etanercept) is marketed by Amgen Cimzia® (certolizumab) is marketed by UCB Rituxan® (rituximab) is marketed by Roche 128 Sarilumab: An Investigational IL-6R mAb for RA ● Fully human, high affinity, IL-6R mAb sarilumab ● 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 129 A Broad Clinical Development Program Aiming for a Robust Label at Launch Study MOBILITY TARGET ASCERTAIN EXTEND ONE MONARCH EASY Design n sarilumab + MTX 1,197 MTX IR patients sarilumab + DMARD 546 Anti-TNFα IR patients sarilumab + MTX Anti-TNFα IR patients Safety calibrator vs. 200 Actemra® sarilumab + DMARD 2,000 Long-term extension study sarilumab monotherapy (open-label) 120 DMARD-IR patients sarilumab monotherapy vs. Humira® MTX-IR, intolerant and inappropriate patients sarilumab + MTX Auto-injector real-life use 340 200 Objectives ● 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 ● Evaluation of use with or without DMARD (MTX) ● Assessment of pre-filled syringe vs. autoinjector Status Completed 2015 2015 Ongoing 2015 2016 2015 ~2,500 RA patients targeted in SARIL-RA program MTX: Methotrexate DMARD-IR: Disease-Modifying Anti-Rheumatic Drugs Inadequate Responders Actemra® (tocilizumab) is marketed by Roche Humira® (adalimumab) is marketed by AbbVie 130 Significant Improvements in Signs and Symptoms of RA with Sarilumab(1) SARIL-RA-MOBILITY - ACR Scores (% of Patients) ACR Response at Week 24 ACR Response at Week 52 66* 58* 54* 59* 53* 46* 40* 37* 33 32 20* 17 25* 25* 18* 7 ACR 20** * p<0.0001 vs. placebo ** Co-primary endpoint ACR 50 28* 9 ACR 70 ACR 20 ACR 50 Placebo + MTX Sarilumab 150mg + MTX Sarilumab 200mg + MTX (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 ACR 70 131 Inhibiting Progression of Structural Damage in RA with Sarilumab SARIL-RA-MOBILITY - Change from Baseline in mTSS 3 mTSS: modified Total Sharp Score Sarilumab: van der Heijde modified Total Sharp Score (0-448) Placebo + MTX 2.5 2 70% 90% 1.5 1 Sarilumab 150 mg + MTX* 0.5 Sarilumab 200 mg + MTX* 0 Week 0 13 26 36 52 * p<0.0001 vs Placebo 132 Safety Findings Consistent with Prior Investigational Studies with Sarilumab SARIL-RA-MOBILITY - Safety Data ● 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 13.9% 12.5% TEAEs leading to withdrawal 4.7% Sarilumab 150mg Sarilumab 200mg + MTX +MTX 40.1% 39.6% 31.1% Infections of which serious infections 2.6% 4.0% Sarilumab 150mg Sarilumab 200mg +MTX +MTX TEAEs – Treatment Emergent Adverse Events (1) Sarilumab and placebo, both in combination with MTX Placebo +MTX 2.3% Placebo +MTX 133 Further Establish the IL-6R Class in an $18bn Rheumatoid Arthritis Biologic Market Rheumatoid Arthritis - Worldwide Sales of Biologics(1) ~$18bn IL-6R 5% ~$21bn IL-6R IL-6R 19% Other(2) Anti-TNFα ● 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 2013 2021 Develop sarilumab to become the preferred IL-6R mAb (1) Decision Resources - Internal estimates (2) Other includes: JAK inhibitors, B Cell, Co-stimulation, IL-17, IL-1 134 Agenda ● Elias Zerhouni, MD, President, Global R&D Sarilumab Dupilumab Wrap-up and Q&A Session 135 Dupilumab Offers Potential to Change Management of Multiple Th2-Mediated Allergic Inflammatory Diseases Dupilumab is a fully human monoclonal antibody targeting IL-4Rα blocking intracellular signaling of both IL-4 and IL-13 1 IL‐4 DERMATOLOGY Moderate-to-Severe Atopic Dermatitis IL‐13 or c IL‐4R Type I Receptor IL‐4R IL‐13R1 2 PULMONOLOGY Moderate-to-Severe Asthma Type II Receptor 3 OTOLARYNGOLOGY Chronic Sinusitis with Nasal Polyps IL-4/IL-13 pathway may be a fundamental driver in allergic diseases Dupilumab is developed in collaboration with Regeneron Th2: T-helper 2 cells, involved in “humoral-mediated” immunity 136 Atopic Dermatitis Is a Serious, Chronic, Inflammatory Skin Condition Atopic Dermatitis (AD) ● >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 (1) Adapted from White Book on Allergy published in 2011, http://www.worldallergy.org/UserFiles/file/WAO-White-Book-on-Allergy_web.pdf 137 137 The Negative Impact of Atopic Dermatitis on Quality of Life Is Largely Underestimated 1 Low self-esteem • Impact on social life Negative impact on QoL 2 Greater risk for psychological distress • Mood disorders, such as anxiety and depression(1) • Suicidal ideation(2,3) 3 Similar or higher than in psoriasis Determined by degree of skin involvement, severity and localization Sleep disturbance and fatigue(4) (1) (2) (3) (4) Journal of Psychomatic Research 57 (2004) 195-200 Acta Derm Venereol 2004;84(3):205-12 Suicide Life Threat Behav 2006 2006 Feb;36(1):120-4 J Allergy Clin Immunol 2006 Jul;118(1):226-32 138 Dose-Dependent Efficacy in Adults with Moderate-toSevere Atopic Dermatitis Uncontrolled by Topicals Phase IIb Study in AD - Mean Percent Change in EASI At Week 16 Placebo Over 16 Weeks 100 mg 300 mg 200 mg 300 mg 300 mg q4w q4w q2w q2w qw 0 0 0 -10 -10 -20 -20 -30 -30 -40 -40 -50 -50 -60 -60 -70 -70 -80 p < 0.0001 vs placebo -80 -90 -90 EASI=Eczema Area Severity Index IL-4Rα – Interleukin-4 receptor sub-unit α 2 4 6 8 10 12 14 16 Placebo 100mg q4w p<0.0001 vs placebo at Week 16 All other time points p<0.05 vs placebo 300mg q4w 200mg q2w 300mg q2w 300mg qw 139 Dupilumab Significantly Improved Signs and Symptoms in Moderate-to-Severe AD Patients Uncontrolled by Topicals 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% p<0.0001 vs placebo for all parameters 300mg qw and 300mg q2w dose regimens selected for Phase III program (1) (2) (3) (4) (5) Mean percent change in EASI (Eczema Area Severity Index) Proportion of patients achieving EASI-50/70/90 Proportion of patients achieving IGA ≤ 1 (Investigator’s Global Assessment score of 0 “clear” or 1 “almost clear”) Mean percent change in pruritus NRS (Numeric Rating Scale) weekly averaged Mean percent change 5-D Pruritus Score 140 Safety Findings in Moderate-to-Severe Atopic Dermatitis Phase IIb Study in Moderate-to-Severe Atopic Dermatitis - Safety Data Nasopharyngitis Headache Injection site reactions 21% 23% 15% 18.5% 12% 8% 9.5% 5% Dupilumab Placebo Dupilumab Placebo 3% Dupilumab Placebo ● 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 141 Dupilumab Leads Development of Biologics in AD with Recent Start of Phase III Program LIBERTY - Phase III Clinical Program of Dupilumab in Moderate-to-Severe AD CHRONOS Combination with topical corticosteroids in adults(1) SOLO 1 SOLO 2 Monotherapy in adults(2) OLE Open-label extension study in adults(3) (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 142 Moderate-to-Severe Asthma Negatively Impacts the Lives of Patients and Is Associated with High Burden to Society Moderate-to-Severe Asthma ● 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 (1) WHO, http://www.who.int/mediacentre/factsheets/fs307/en/ 143 143 Dupilumab Shows Improvement in Lung Function in Phase IIb in Moderate-to-Severe Asthma Phase IIb - Mean Improvement in FEV1 (mL and % Change from Baseline) mL 500 400 25.9%(1) (2) 25.8% (1) 18.0% 300 200 (1) 17.7% Placebo 200mg Q2W 10.4% 6.2% 300mg Q2W 100 0 (1) p<0.001 vs placebo High Eosinophils Population Overall population (2) p<0.01 vs placebo 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 144 Dupilumab Shows a 64-75% Reduction in Exacerbations in Phase IIb in Moderate-to-Severe Asthma Phase IIb: Annualized Rate of Severe Exacerbation Events 0,9 0.9 0,8 0.8 0,7 0.7 0,6 0.6 0,5 0.5 0,4 0.4 (1) Placebo (2) -64% -67% (1) -75% (3) -67% 200mg Q2W 300mg Q2W 0.3 0,3 0.2 0,2 0,1 0.1 (1) p<0.05 vs placebo 0 (2) p<0.01 vs placebo High Eosinophils Population Overall population (3) p<0.001 vs placebo 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 145 Safety Profile in Moderate-to-Severe Asthma Phase IIb Study in Moderate-to-Severe Asthma - Safety Data Infections Severe AEs 46% 45% 42% Injection site reactions 25% 7% 5% 12% 13% 3% Dupilumab Placebo Dupilumab Placebo Dupilumab Placebo ● 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 Phase III start in moderate-to-severe uncontrolled asthma expected in 2015 146 Prevalence of Chronic Sinusitis with Nasal Polyps Is Estimated at 3% to 5% in EU and the U.S.(1) Chronic Sinusitis with Nasal Polyps (CSwNP) ● 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) (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) 143,147-151 147 147 Dupilumab Delivers Positive Results in PoC Study in Patients with Nasal Polyposis and Chronic Symptoms of Sinusitis ● Strong efficacy of dupilumab 300mg qw vs. placebo, on top of Nasonex® Chronic Sinusitis with Nasal Polyps(3) ● Rapid, clinically and significant reduction size of nasal polyposis(1) Nasal Polyp Score (NPS) Mean change +/- SE 0.5 0.0 -0.5 ● 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 (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 -1.0 -1.5 -2.0 Placebo -2.5 -3.0 Dupilumab Baseline 4 8 12 16 Week 148 Dupilumab Has the Potential to Change Management of Patients Severely Affected by Various Allergic Diseases(1) 1● Execute Phase III program in Atopic Dermatitis as first-in-class biologic 2● Design Phase III program in Asthma to potentially position as best-in-class biologic 3● Accelerate development in Chronic Sinusitis with Nasal Polyps 4● Expand development program with new indications (1) Atopic Dermatitis, Asthma, Nasal Polyposis 149 Agenda ● Elias Zerhouni, MD, President, Global R&D Sarilumab Dupilumab Wrap-up and Q&A Session 150 New R&D Strategy Expected to Continue to Lead to Innovative New Medicines and Vaccines Reaching Market Multiple new product launches underway or imminent High potential late stage projects Promising early stage development pipeline 151 Q&A 152 APPENDICES R&D Pipeline 153 Late Stage Pipeline – Pharma & Vaccines Registration Phase III LixiLan alirocumab lixisenatide + insulin glargine Fixed-Ratio / Type 2 diabetes Anti-PCSK-9 mAb Hypercholesterolemia Lyxumia® (lixisenatide) N GLP-1 agonist Type 2 diabetes, U.S. sarilumab Toujeo® (U300) Mild-to-severe dengue fever vaccine Insulin glargine Type 1+2 diabetes, U.S., EU Metastatic prostate cancer (1L) N N Lemtrada® (alemtuzumab) Clostridium difficile Jevtana® (cabazitaxel) Anti-IL4Rα mAb Atopic dermatitis patisiran Kynamro® (mipomersen) Apolipoprotein B-100 antisense Severe HeFH, U.S. Dengue Toxoid vaccine Anti-CD52 mAb Multiple sclerosis, U.S. Rotavirus Cerdelga™ (eliglustat tartrate) Live attenuated tetravalent Rotavirus oral vaccine Glucosylceramide synthetase inhibitor Gaucher disease, EU N Anti-IL-6R mAb Rheumatoid arthritis dupilumab N SYNVISC-ONE® VaxiGrip® QIV IM PR5i Medical device Pain in hip OA Quadrivalent inactivated influenza vaccine DTP-HepB-Polio-Hib Pediatric hexavalent vaccine, U.S. N N Fluzone® QIV ID mRNA inhibitor Familial amyloid polyneuropathy Quadrivalent inactivated influenza vaccine intradermal Quadracel® Diphtheria, tetanus, pertussis & polio vaccine; 4-6 y of age N New Molecular Entity Oncology Diabetes Solutions Rare Diseases Biosurgery Immune Mediated Diseases Infectious Diseases Cardiovascular / Renal Diseases Vaccines Ophthalmology Age Related Degenerative Diseases 154 Early Stage Pipeline – Pharma & Vaccines Phase II dupilumab SAR391786 Anti-IL4Rα mAb Asthma; Nasal polyposis Anti-GDF8 mAb Sarcopenia vatelizumab Anti-VLA 2 mAb Multiple sclerosis SAR156597 N N N N Combination Meningitis ACYW conj. 2nd generation meningococcal conjugate infant vaccine N Maytansin-loaded anti-CD19 mAb B-cell refractory/relapsed malignancies Tuberculosis Recombinant subunit vaccine N SAR245409 (XL765) / MSC1936369B RNAi Familial amyloid cardiomyopathy Oral dual inhibitor of PI3K & mTOR / pimasertib Ovarian cancer Combination sarilumab N ferroquine / OZ439 Anti-IL-6R mAb Uveitis fresolimumab SAR3419 Rabies VRVg Purified vero rabies vaccine Anti-CD38 naked mAb Multiple myeloma IL4/IL13 Bi-specific mAb Idiopathic pulmonary fibrosis SAR438714 (ALN-TTRsc) SAR650984 N Antimalarial Malaria N TGFβ antagonist Focal segmental glomerulosclerosis N New Molecular Entity Oncology Diabetes Solutions Rare Diseases Biosurgery Immune Mediated Diseases Infectious Diseases Cardiovascular / Renal Diseases Vaccines Ophthalmology Age Related Degenerative Diseases 155 Early Stage Pipeline – Pharma & Vaccines Phase I N SAR405838 (MI-773) N SAR408701 Anti-CEACAM5 ADC Solid tumors HDM2 / p53 antagonist Solid tumors N SAR566658 Maytansin-loaded anti-CA6 mAb Solid tumors GZ402663 (sFLT-01) Gene therapy N SAR113244 StarGen® N SAR252067 UshStat® Anti-LIGHT mAb Crohn’s disease Solid tumors N SAR260301 PI3K β selective inhibitor PTEN – Deficient tumors SAR228810 N Anti-ANG2 mAb Solid tumors N SAR245408 (XL147) SAR425899 N GZ402665 HSV-2 vaccine N N (rhASM) Niemann-Pick type B N GZ402671 GLP-1 / GCGR agonist Diabetes Oral GCS Inhibitor Fabry Disease SAR342434 GZ402666 Oral PI3K inhibitor Solid tumors Insulin Lispro Diabetes neo GAA Pompe Disease Combination SAR438584 (REGN2222) SAR405838 / MSC1936369B Herpes Simplex Virus Type 2 Gene therapy Usher syndrome 1B Anti-protofibrillar AB mAb Alzheimer’s disease SAR307746 N Gene therapy Stargardt disease N Streptococcus pneumonia Meningitis & pneumonia vaccine Age-related macular degeneration (AMD) Anti-CXCR5 mAb Systemic lupus erythematosus SAR125844 C-MET kinase inhibitor N N N N anti-RSV-F protein mAb Respiratory syncytial virus Solid tumors N New Molecular Entity Oncology Diabetes Solutions Rare Diseases Biosurgery Immune Mediated Diseases Infectious Diseases Cardiovascular / Renal Diseases Vaccines Ophthalmology Age Related Degenerative Diseases 156 R&D Pipeline Summary Table(1) 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 20 12 9 5 TOTAL 32 (1) Excluding life cycle management programs 14 34 46 NMEs & Vaccines 157 Expected R&D Milestones 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 158 Expected R&D Milestones (cont’d) 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 Lyxumia® (lixisenatide) Expected U.S. regulatory submission in Diabetes Q3 2015 159 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 Discovery activities ● 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. 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 codevelops 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 codeveloped drug candidate, subsequent Phase III trial-related costs for that drug candidate are funded 80% by Sanofi and 20% by Regeneron. Accounting treatment in Sanofi’s income statements ● 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. ● 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. 162 Commercial Activities with Regeneron Commercial activities ● ● ● 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 12month 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. Accounting treatment in Sanofi’s income statements ● 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. 163 Record of Sanofi Holding in Regeneron ● 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. Accounting treatment in Sanofi’s income statements ● 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 164
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