IR Thematic Call on Alirocumab September 2 nd, 2014
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Regeneron Forward Looking Statements This presentation includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. ( Regeneron or the Company ), and actual events or results may differ materially from these forward-looking statements. Words such as anticipate, expect, intend, plan, believe, seek, estimate, variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of Regeneron s products, product candidates, and research and clinical programs now underway or planned, such as alirocumab, including the potential of alirocumab to demonstrate any cardiovascular benefit; unforeseen safety issues resulting from the administration of products and product candidates in patients, including serious complications or side effects in connection with the use of Regeneron s product candidates in clinical trials, such as the ODYSSEY global trial program evaluating alirocumab; the likelihood and timing of possible regulatory approval and commercial launch of Regeneron s late-stage product candidates, such as alirocumab, including the impact (if any) of the planned use of the U.S. Food and Drug Administration s Rare Pediatric Disease Priority Review Voucher in connection with the contemplated Biologics License Application submission for alirocumab; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron s ability to continue to develop or commercialize Regeneron s products and product candidates; competing drugs and product candidates that may be superior to Regeneron s products and product candidates; uncertainty of market acceptance and commercial success of Regeneron s products and product candidates; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; coverage and reimbursement determinations by third-party payers, including Medicare and Medicaid; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its sales or other financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license or collaboration agreement, including Regeneron s agreements with Sanofi and Bayer HealthCare LLC, to be cancelled or terminated without any further product success; and risks associated with intellectual property of other parties and pending or future litigation relating thereto. A more complete description of these and other material risks can be found in the Company s filings with the United States Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2013 and its Form 10-Q for the quarter ended June 30, 2014. The reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update publicly any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise. 3
Agenda Introduction Pascale Witz, Executive VP, Global Divisions & Strategic Development, Sanofi Cardiovascular Disease Burden Bill Sasiela, VP, Program Direction, Regeneron ODYSSEY Program Overview Jay Edelberg, M.D., Ph.D. VP, Head of the PCSK9 Development & Launch Unit, Sanofi ODYSSEY LONG TERM, FH I, FH II, and COMBO II Data Jennifer Robinson, M.D., MPH, University of Iowa Next Steps Robert Terifay, Senior VP, Commercial, Regeneron Q&A Session 4
INTRODUCTION Pascale Witz Executive Vice President, Global Divisions & Strategic Development 5
Alirocumab Illustrates Sanofi s Focus on Gearing Up to Successful Launches of Biologics 6
PCSK9 Inhibitors Have the Potential to Revolutionize LDL-C Management of High Cardiovascular (CV) Risk Patients High LDL-C and CV diseases remain an area of high unmet medical need Large and comprehensive Phase 3 ODYSSEY clinical program designed to assess the safety and efficacy of alirocumab in patients with hypercholesterolemia at high CV risk Detailed positive safety and efficacy results of four pivotal alirocumab studies (1) recently highlighted at a hotline session at ESC Submission planned in the U.S. and EU by end of 2014 (1) ODYSSEY LONG TERM, FH I & II, and COMBO II studies. 7
CARDIOVASCULAR DISEASE BURDEN Bill Sasiela VP, Program Direction, Regeneron 8
Cardiovascular Disease Remains an Area of High Unmet Need CVD: High Morbidity, Mortality, and Cost Cardiovascular disease (CVD) is the leading cause of death globally, accounting for ~30% of all deaths (1) By 2030, almost 24.3M people/year globally will die from CVD (2) High LDL-C = High CV Risk Cholesterol is the most well-established risk factor for CVD Continuous, positive relationship between cardiovascular risk and serum total cholesterol concentrations (2) Aggressive LDL-C goals for high-risk patients Despite best available treatment, including statins, many highrisk patients fail to reach LDL-C goals 21M very high-risk patients with elevated LDL-C in the US and EU5 Limited Treatment Options Beyond statins, existing agents provide only modest LDL-C reduction None shown to improve CV clinical outcomes on top of statins (1) WHO Top 10 Causes of Death. http://www.who.int/mediacentre/factsheets/fs310/en/index2.htmlaccessed August 2014 (2) Mathers CD, Loncar D. PLoS Med. 2006; 3(11):e442. doi:10. 1371/journal.pmed.0030442. LDL-C= Low density lipoprotein-cholesterol 9
Many Patients With High CV Risk Are Not Achieving Optimal LDL-C Levels Statins +/- ezetimibe are the standard of care for LDL-C management However, many patients are not reaching LDLC goals with standard-of-care therapy due to suboptimal reductions in LDL-C (1-3) High risk patients (1) HeFH patients (2,3) LDL-C Goal <100 mg/dl LDL-C Goal <70 mg/dl LDL-C Goal <100 mg/dl 23% not at goal 76% not at goal ~80% not at goal (1) Jones PH, et al. J Am Heart Assoc. 2012;1:e001800. doi: 10.1161/JAHA.112.001800. (2) Stein EA, et al. Am J Cardiol. 2003;92:1287-1293. (3) Pijlman AH, et al. Atherosclerosis.2010;209:189-194. 10
Despite Current Therapies, There Exists a Significant Population of Patients at High Cardiovascular Risk 36M Eligible Population (US+EU5 in 2016) 21M High Risk 1 M 1M recent recent CV CV events events SI SI High Risk FH Secondary Prevention w/o Diabetes Diabetes 2 risk factors with or w/o event Diabetes 0/1 risk factor 3.1M 2.7M 0.9M 9M 8.9M 11M SI: Statin intolerant - FH: Familial hypercholesterolemia Source: US NHANES, Market Scan US+EU5 inputs Recent CV event: EU5 volume extrapolated from US incidence rate 11
ODYSSEY PROGRAM OVERVIEW Jay Edelberg, M.D., Ph.D. VP, Head of the PCSK9 Development & Launch Unit, Sanofi 12
Key Features of The Phase 3 Alirocumab ODYSSEY Program Comprehensive clinical development 14 studies with primary endpoint evaluated at 24 weeks Double-blind for 6, 12, 18, 24 months Solid long-term double-blind exposure ( 5,000 patient years) at completion of studies Robust characterization of safety and efficacy prior to data from ODYSSEY OUTCOMES Dosing flexibility Q2W and Q4W dosing regimens 75mg and 150mg doses Up-titration treat to target approach provides physicians the ability to tailor therapy to suit individual patient needs Several patient populations studied HeFH patients (largest cohort of such patients) Hypercholesterolemic patients at high CV risk and poorly controlled LDL-C despite standard of care treatment, including statin intolerants State-of-the-art drug delivery systems Patient friendly single use, 1 ml, disposable pen device Ready to use, 1 ml, pre-filled syringe (1) Q2W = Every two weeks dosing (2) Q4W = Every four weeks dosing 13
Key Efficacy Findings From Alirocumab Phase 3 ODYSSEY Program (1) Primary efficacy endpoint achieved in all ten reported Phase 3 ODYSSEY trials EFFICACY 62% LDL-C reduction compared to placebo in 2,341 high CV risk patients treated with alirocumab 150mg Q2W in ODYSSEY LONG TERM 81% reaching LDL-C goal at Week 24 (2) Majority of patients treated in up-titration trials reached LDL-C goals on 75 mg Q2W dose (3) Approximately 50% reduction in LDL-C in patients using an up-titration approach and/or in monotherapy Efficacy consistent across trials testing alirocumab as monotherapy or in combination with statins and/or other lipid-lowering therapies vs. placebo or active comparator (1) Based on data presented to date in top line press release and data presentations at ESC (2) Pre-specified LDL-C goal: either 70 mg/dl or 100 mg/dl depending on patients baseline CV risk (3) In the FHI, FH II and COMBO II studies, patients receiving the low, 75mg dose every two weeks, could be up titrated to receive 150 mg if they did not achieve individual treatment goals 14
Key Safety Findings From Alirocumab Phase 3 ODYSSEY Program (1) Alirocumab was generally well-tolerated Most common adverse events were nasopharyngitis and upper respiratory tract infections, which were generally balanced between treatment groups SAFETY Safety well balanced across trials Injection site reactions were infrequent and occurred more often in the alirocumab group compared to placebo Key adverse events including deaths, musculoskeletal, neurocognitive and liver-related events were balanced between treatment groups From a pre-specified safety interim analysis of ODYSSEY LONG TERM, a post-hoc assessment showed fewer adjudicated major cardiovascular events* (cardiac death, myocardial infarction, stroke and hospitalization for unstable angina) in the alirocumab arm compared to placebo (1.4% vs. 3%, nominal p<0.01) * Same endpoint as ODYSSEY OUTCOMES. A pre-specified interim safety analysis was performed when all patients reached one year and approximately 25% of patients reached 18 months of treatment. (1) Based on data presented to date in top line press release and data presentations at ESC 15
ODYSSEY Phase 3 Clinical Trial Program: 14 Studies Including More Than 23,500 Patients High CV Risk MI, Stroke, T2D, CKD LONG TERM (1) (n=2,341) High CV Risk Recent CV Event COMBO I (n=316) COMBO II (n=720) OPTIONS I (n=355) OPTIONS II (n=305) CHOICE I (n=700, 300mg Q4W) HeFH Patients receiving statins FH I (n=486) FH II (n= 249) HIGH FH (n=107) OUTCOMES (n=18,000) OLE (Open-Label Extension, n 1,000) Patients not receiving statins Monotherapy MONO (n=103) Statin Intolerant ALTERNATIVE (n=314) CHOICE II (2) (n=200, 150mg Q4W) Except CHOICE I & II, all studies are investigating Q2W regimens: a dose titration scheme (75mg up-titrated to 150mg, based on LDL-C levels at Week 12) or a continuous treatment with 150mg for patients with LDL-C >160mg/dL (HIGH FH) n = Target enrollment (except for ODYSSEY MONO for which results are already reported). Chronic Kidney Disease (CKD) (1) LONG TERM includes a subset of FH patients (2) CHOICE II includes some patients on additional non-statin lipid-lowering therapy 16
Schema of ODYSSEY FH I, FH II, COMBO II And LONG-TERM Studies FH I N=486 FH II N=249 COMBO II N=720 LONG TERM N=2,341 Patient Population HeFH patients on max tolerated statin +/- other lipid-lowering therapy High CV risk patients on high intensity statins HeFH or high CV risk patients on max tolerated statin +/- other lipid-lowering therapy Baseline Characteristics 100% patients on statins Over 80% of patients on high dose statins 60% patients on ezetimibe 90% of patients had history of CHD 67% on high intensity statins 100% on statins 68% had a prior CHD 36% had Type 2 diabetes Dose Regimen Alirocumab 75 mg to 150 mg SC Q2W (1) Alirocumab 150 mg SC Q2W Comparator Arm Placebo Placebo Ezetimibe Placebo High intensity statin defined as atorvastatin 40 to 80 mg daily, rosuvastatin 20 to 40 mg daily, or simvastatin 80 mg SC= sub-cutaneous Q2W= every two weeks CHD= Coronary Heart Disease (1) FH I, FH II and COMBO II studies utilized a dose titration scheme: alirocumab-treated patients received an initial dose of alirocumab 75 mg every two weeks, increasing to 150 mg at Week 12 if needed to reach pre-specified LDL-C levels 17
ODYSSEY LONG-TERM, FH I & II, AND COMBO II Jennifer Robinson, M.D., MPH Professor, Departments of Epidemiology & Medicine (Division of Cardiology) Director of the Prevention Intervention Center University of Iowa 18
Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2,341 patients Jennifer G. Robinson, 1 Michel Farnier, 2 Michel Krempf, 3 Jean Bergeron, 4 Gérald Luc, 5 Maurizio Averna, 6 Erik Stroes, 7 Gisle Langslet, 8 Frederick J. Raal, 9 Mahfouz El Shahawy, 10 Michael J. Koren, 11 Norman Lepor, 12 Christelle Lorenzato, 13 Robert Pordy, 14 Umesh Chaudhari, 15 John J.P. Kastelein 7 1 University of Iowa, Iowa City, IA, USA; 2 Point Médical, Dijon, France; 3 CHU de Nantes - Hôpital Nord Laennec, Saint- Herblain, France; 4 Clinique des Maladies Lipidiques de Quebec Inc., Quebec, Canada; 5 University Hospital of Lille, Lille, France; 6 Università di Palermo Policlinico P.Giaccone, Palermo, Italy; 7 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; 8 Lipid Clinic, Oslo University Hospital, Oslo, Norway; 9 University of Witwatersrand, Johannesburg, South Africa; 10 Cardiovascular Center of Sarasota, Sarasota, FL, USA; 11 Jacksonville Center For Clinical Research, Jacksonville, FL, USA; 12 Westside Medical Associates of Los Angeles, Beverly Hills, CA, USA; 13 Sanofi, Chilly-Mazarin, France; 14 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 15 Sanofi, Bridgewater, NJ, USA 19
Baseline Characteristics All patients on background of max-tolerated statin ± other lipid-lowering therapy Alirocumab (n=1553) Placebo (n=788) Age, years, mean (SD) 60.4 (10.4) 60.6 (10.4) Male, % (n) 63.3% (983) 60.2% (474) Race, White 92.8% (1441) 92.6% (730) BMI, kg/m 2, mean (SD) 30.2 (5.7) 30.5 (5.5) HeFH, % (n) 17.8% (276) 17.6% (139) CHD history, % (n) 67.9% (1055) 70.1% (552) Type 2 diabetes, % (n) 34.9% (542) 33.9% (267) Any statin, % (n) 99.9% (1552) 99.9% (787) High-intensity statin, % (n) 44.4% (690) 43.4% (342) Any LLT other than statins, % (n) 28.1% (437) 27.9% (220) Ezetimibe, % (n) 13.9% (216) 15.0% (118) LDL-C, calculated mean (SD), mmol/l [mg/dl] 3.2 (1.1) [122.7 (42.6)] 3.2 (1.1) [121.9 (41.4)] Patients should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator 20 High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily.
Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background of maximally-tolerated statin ± other lipid-lowering therapy LS mean (SE) % change from baseline to Week 24 10 0-10 -20-30 -40-50 -60-70 N=1530 N=780-61,0 0,8 Alirocumab Placebo 21 Intent-to-treat (ITT) analysis LS mean difference (SE) versus placebo: 61.9% (1.3); P<0.0001
Alirocumab Maintained Consistent LDL-C Reductions over 52 Weeks Achieved LDL-C Over Time All patients on background of maximally-tolerated statin ±other lipid-lowering therapy LDL-C, LS mean (SE), mmol/l 4 3,5 3 2,5 2 1,5 1 Placebo Alirocumab 3.1 mmol/l 118.9 mg/dl 1.3 mmol/l 48.3 mg/dl 3.2 mmol/l 123.0 mg/dl 1.4 mmol/l 53.1 mg/dl 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week 151 137 123 109 95 81 67 53 39 mg/dl 22 Intent-to-treat (ITT) analysis
Most Patients Receiving Alirocumab on Background Statin ± Other LLT Achieved LDL-C Goals Proportion of patients reaching LDL-C goal at Week 24 % patients 90 P<0.0001 P<0.0001 81% 79% 80 70 60 50 40 30 Very high-risk: LDL-C <1.8 mmol/l (70 mg/dl) High-risk: <2.6 mmol/l (100 mg/dl) <1.8 mmol/l (70 mg/dl) regardless of risk Alirocumab Placebo 20 10 9% 8% 0 23 Intent-to-treat (ITT) analysis; LLT = lipid-lowering therapy
Significant Reductions in Secondary Lipid Parameters at Week 24 All patients on background of maximally-tolerated statin ± other lipid-lowering therapy Alirocumab Placebo 10 Non-HDL-C Apo B Lp(a) LS mean (SE) % change from baseline to Week 24 0-10 -20-30 -40-50 -60 LS mean difference versus placebo: 52% P<0.0001 54% P<0.0001 26% P<0.0001 24 Adjusted mean (SE) shown for Lp(a).
Treatment-Emergent Adverse Events Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) % (n) of patients All patients on background of max-tolerated statin ± other lipid-lowering therapy Alirocumab (n=1550) Placebo (n=788) TEAEs 78.6% (1218) 80.6% (635) Treatment-emergent SAEs 16.5% (255) 17.6% (139) TEAE leading to death 0.5% (7) 1.0% (8) TEAEs leading to treatment discontinuation 6.2% (96) 5.5% (43) Mean treatment duration: 65 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) completed 78 weeks 25 Statistical analyses have not been performed.
Adverse Events of Special Interest Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Treatment-emergent local injection site reactions Alirocumab (n=1550) Placebo (n=788) 5.8% (90) 4.3% (34) General allergic reaction events 9.0% (140) 9.0% (71) All cardiovascular events 4.0% (62) 4.4% (35) Neurological events 4.2% (65) 3.9% (31) Neurocognitive disorders 1.2% (18) 0.5% (4) Ophthalmological events 2.5% (38) 1.9% (15) Haemolytic anaemia 0 0 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 hospitalisation, congestive heart failure requiring hospitalisation, ischemia driven coronary revascularisation procedure [PCI, CABG]. Company MedDRA Queries (CMQ). 26 Statistical analyses have not been performed.
Post-hoc Adjudicated Cardiovascular TEAEs Safety Analysis (at least 52 weeks for all patients in ongoing study) Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (n=1550) Placebo (n=788) CV events confirmed by adjudication 1.4% (22) 3.0% (24) CHD death 0.2% (3) 0.8% (6) Non-fatal MI 0.7% (11) 2.2% (17) Fatal + non-fatal ischaemic stroke 0.5% (8) 0.3% (2) Unstable angina requiring hospitalisation 0 0.1% (1) Patients are censored at the end of TEAE period (last injection of study treatment + 70 days). 27 Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. Unstable angina requiring hospitalisation is limited to the UA events with definite evidence of progression of the ischemic condition (strict criteria).
No. at Risk Placebo Alirocumab 28 Cumulative probability of event Post-hoc Adjudicated Cardiovascular TEAEs Safety Analysis (at least 52 weeks for all patients in ongoing study) Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) 0.06 0.05 0.04 0.03 0.02 0.01 0.00 0 788 1550 Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01 12 776 1534 24 731 1446 Mean treatment duration: 65 weeks Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy 36 703 1393 48 682 1352 60 667 1335 72 321 642 84 127 252 Weeks
Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia (hefh) not adequately controlled with current lipidlowering therapy: Results of ODYSSEY FH I and FH II studies John J.P. Kastelein, 1 Henry N. Ginsberg, 2 Gisle Langslet, 3 G. Kees Hovingh, 1 Richard Ceska, 4 Robert Dufour, 5 Dirk Blom, 6 Fernando Civeira, 7 Michel Krempf, 8 Michel Farnier 9 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Columbia University, New York, NY, USA; 3 Lipid Clinic, Oslo University Hospital, Oslo, Norway; 4 Center of Preventive Cardiology, 1st School of Medicine and University Hospital, Charles University, Prague, Czech Republic; 5 Institut de Recherches Cliniques de Montréal, Montreal, Canada; 6 Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa; 7 Lipid Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain; 8 CHU de Nantes - Hȏpital Nord Laennec, Saint-Herblain, France; 9 Point Médical, Dijon, France 29
All patients on background of max-tolerated statin ± other lipid-lowering therapy Diagnosis of hefh, % (n) Genotyping Clinical criteria Baseline Characteristics Alirocumab (N=323) FH I Placebo (N=163) 39.9% (129) 38.0% (62) 59.8% (193) 62.0% (101) Alirocumab (N=167) 70.1% (117) 29.9% (50) FH II Placebo (N=82) 81.7% (67) 18.3% (15) Age, years, mean (SD) 52.1 (12.9) 51.7 (12.3) 53.2 (12.9) 53.2 (12.5) Male, % (n) 55.7% (180) 57.7% (94) 51.5% (86) 54.9% (45) Race, white, % (n) 92.9% (300) 88.3% (144) 98.2% (164) 97.6% (80) BMI, kg/m 2, mean (SD) 29.0 (4.6) 30.0 (5.4) 28.6 (4.6) 27.7 (4.7) CHD history, % (n) 45.5% (147) 47.9% (78) 34.1% (57) 37.8% (31) Current smoker, % (n) 12.1% (39) 18.4% (30) 21.6% (36) 15.9% (13) Hypertension, % (n) 43.0% (139) 43.6% (71) 34.1% (57) 29.3% (24) Type 2 diabetes, % (n) 9.6% (31) 15.3% (25) 4.2% (7) 3.7% (3) 30 Diagnosis of hefh must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score of >8 points. In FH I, one patient was categorised as probable FH by clinical criteria genotyping results for this patient are pending.
Lipid Medication and LDL-C at Baseline All patients on background of max-tolerated statin ± other lipid-lowering therapy Alirocumab (N=323) FH I Placebo (N=163) Alirocumab (N=167) FH II Placebo (N=82) Any statin, % (n) 100% 100% 100% 100% High-intensity statin, % (n) 80.8% (261) 82.8% (135) 86.2% (144) 87.8% (72) Ezetimibe, % (n) 55.7% (180) 59.5% (97) 67.1% (112) 64.6% (53) LDL-C, mean (SD), mmol/l [mg/dl] 3.7 (1.3) [144.7 (51.2)] 3.7 (1.2) [144.4 (46.8)] 3.5 (1.1) [134.6 (41.3)] 3.5 (1.1) [134.0 (41.6)] Patients should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator. High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily. 31
Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo LS mean (SE) % change from baseline to Week 24 32 Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy 20 10 0-10 -20-30 -40 N=322 9.1% N=163-50 -48.8% -48.7% -60 LS mean 57.9% (2.7) difference (SE) P<0.0001 vs. placebo: Intent-to-treat (ITT) Analysis FH I 43.4% had dose increase at W12 N=166 FH II 2.8% N=81 38.6% had dose increase at W12 51.4% (3.4) P<0.0001 Alirocumab Placebo
Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT LDL-C, LS mean (SE), mmol/l Placebo: FH I Alirocumab: FH I FH II FH II 4,5 4 3,5 3 2,5 2 1,5 1 4.0 mmol/l 4.0 mmol/l 3.7 mmol/l 3.5 mmol/l 1.9 mmol/l 1.8 mmol/l 1.8 mmol/l 1.7 mmol/l 0 4 8 12 16 20 24 28 32 36 40 44 48 52 174 155 135 116 97 77 58 39 mg/dl 33 Dose if LDL-C >70 mg/dl at W8 Week Intent-to-treat (ITT) Analysis LLT = lipid-lowering therapy
Safety Analysis (Pooled Data from FH I and FH II) All Data Collected Until Last Patient Visit at Week 52 % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) TEAEs 74.8% (366) 75.4% (184) Treatment-emergent SAEs 10.0% (49) 9.0% (22) TEAEs leading to death 0.8% (4) 0 TEAEs leading to discontinuation 3.1% (15) 3.7% (9) Adverse Events of Interest Adjudicated CV events 1.6% (8) 1.2% (3) Injection-site reactions 11.5% (56) 9.0% (22) Neurocognitive disorders 0.2% (1) 1.2% (3) ALT >3 x ULN 2.1% (10/488) 1.2% (3/244) Creatine kinase >3 x ULN 3.5% (17/483) 6.2% (15/243) 34 4 TEAE-related deaths were all in alirocumab arm, 2 due to metastatic cancer (non-small cell lung and pancreatic), 2 due to MI (1 acute, 1 sudden cardiac death) Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, ischaemia-driven revascularisation procedure (PCI, CABG). Statistical analyses have not been performed.
Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study Christopher P. Cannon, 1 Bertrand Cariou, 2 Dirk Blom, 3 James M. McKenney, 4 Christelle Lorenzato, 5 Robert Pordy, 6 Umesh Chaudhari, 7 Helen M. Colhoun 8 1 Harvard Clinical Research Institute, Boston, MA, USA; 2 L Institut du Thorax, CHU de Nantes, Nantes, France; 3 Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa; 4 Virginia Commonwealth University and National Clinical Research, Inc., Richmond, VA, USA; 5 Sanofi, Paris, France; 6 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7 Sanofi, Bridgewater, NJ, USA; 8 University of Dundee, Dundee, Scotland, UK 35
All patients on background max tolerated statin Alirocumab (n=479) Ezetimibe (n=241) Age, years, mean (SD) 61.7 (9.4) 61.3 (9.2) Male, % (n) 75.2% (360) 70.5% (170) Race, White, % (n) 84.3% (404) 85.5% (206) BMI, kg/m 2, mean (SD) 30.0 (5.4) 30.3 (5.1) CHD history, % (n) 91.2% (437) 88.0% (212) Hypertension, % (n) 79.7% (382) 82.2% (198) Type 2 diabetes, % (n) 30.3% (145) 31.5% (76) Any statin,% (n) 99.8% (478) 100% (241) High-intensity statin, % (n) 66.8% (320) 66.4% (160) LDL-C, calculated mean (SD), mmol/l [mg/dl] Baseline Characteristics 2.8 (0.9) [109 (37)] 2.7 (0.9) [105 (34)] Patients should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator. 36 High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily.
Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Ezetimibe Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background of maximally-tolerated statin 0 n=467 n=240 LS mean (SE) % change from baseline to Week 24-10 -20-30 -40-50 -60 18.4% had dose increase at W12-50.6% -20.7% Alirocumab Ezetimibe LS mean difference (SE) vs. ezetimibe: 29.8% (2.3); P<0.0001 37 Intent-to-treat (ITT) analysis
Safety Analysis (Baseline-W102) Including All Data Collected Until Last Patient Visit at Week 52 % (n) of patients All patients on background max tolerated statin Alirocumab (n=479) Ezetimibe (n=241) TEAEs 71.2% (341) 67.2% (162) Treatment-emergent SAEs 18.8% (90) 17.8% (43) TEAE leading to death 0.4% (2) 1.7% (4) TEAEs leading to discontinuation 7.5% (36) 5.4% (13) Adverse Events of Interest Adjudicated CV events 4.8% (23) 3.7% (9) Injection-site reactions 2.5% (12) 0.8% (2) Neurocognitive disorders 0.8% (4) 1.2% (3) ALT >3 x ULN 1.7% (8/470) 0.4% (1/240) Creatine kinase >3 x ULN 2.8% (13/467) 2.5% (6/236) 38 Both deaths in the alirocumab arm were due to CV events (cardiac arrest and sudden cardiac death). Of the four deaths in the ezetimibe arm, two were due to CV events (malignant lung neoplasm, suicide, defect conduction intraventricular, sudden cardiac death and sudden death one patient was counted in two categories) 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 hospitalisation, congestive heart failure requiring hospitalisation, ischemia driven coronary revascularisation procedure [PCI, CABG]. Statistical analyses have not been performed.
CLINICAL PERSPECTIVE ON ODYSSEY LONG-TERM, FH I & II, AND COMBO II Jennifer Robinson, M.D., MPH Professor, Departments of Epidemiology & Medicine (Division of Cardiology) Director of the Prevention Intervention Center University of Iowa 39
NEXT STEPS Robert Terifay Senior VP, Commercial, Regeneron 40
Phase 3 Clinical Trial Program: 10 Trials Form Core of Initial Regulatory Submission Double-Blinded Efficacy and Safety Evaluation Primary Endpoint Evaluation at Week 24 MONO (n=103) OPTIONS I (n=355) OPTIONS II (n=305) ALTERNATIVE (n=314) COMBO I (n=316) FH I (n=486) FH II (n= 249) HIGH FH (n=107) LONG TERM (n=2,341) 24 Weeks 52 Weeks 78 Weeks 5,000 double-blind patient years at completion of studies COMBO II (n=720) 104 Weeks (1) Does not include ODYSSEY OUTCOMES (event-driven) and ODYSSEY OLE (open label safety study; up to 120 weeks), ODYSSEY ALTERNATIVE will have an indefinite open label extension 41
Next Steps 1 Additional Phase 3 data to be presented at AHA, November 2014 (1) ODYSSEY OPTIONS I, OPTIONS II, HIGH FH, COMBO I and ALTERNATIVE 2 Regulatory submissions planned in the U.S. and EU by end of 2014 Companies plan to use Priority Review Voucher for BLA submission in the U.S. 3 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 4 ODYSSEY OUTCOMES ongoing (n=18,000) Tests the hypothesis that alirocumab improves CV outcomes after ACS (2) Study completion event-driven (2) ACS: Acute Coronary Syndrome (1) American Heart Association, Chicago, Nov 15-19, 2014 http://www.abstractsonline.com/pp8/#!/3547/session/5166 (2) http://www.sciencedirect.com/science/article/pii/s0002870314004943# 42
Summary Alirocumab well placed to address significant unmet medical need in the management of high cardiovascular risk patients Significant and sustained reductions in LDL-C over one year on top of existing therapies across different patient populations Balanced safety and tolerability profile across patient groups Flexible dosing provides options for physicians and patients Convenient 1-mL dosage forms 43
Q&A SESSION 44