Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia (heFH) not adequately controlled with current lipid- lowering therapy: Results of ODYSSEY FH I and FH II studies 1 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 - H ȏ pital Nord Laennec, Saint-Herblain, France; 9 Point Médical, Dijon, France

AuthorDisclosure John J.P. Kastelein Consultant/honoraria for Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Isis, Genzyme, Aegerion and Esperion Henry N. Ginsberg Research support from Genzyme (Sanofi) and Sanofi-Regeneron, is a consultant on an advisory board for Sanofi and Regeneron and is or has been a consultant for Amarin, Amgen, AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, ISIS, Kowa, Merck, Novartis, and Pfizer Gisle LangsletAdvisory board fees from Amgen, Sanofi-Aventis and Janssen Pharmaceuticals G. Kees Hovingh KHs institution has received payment for conducting clinical trials from Sanofi, Regeneron, Amgen, Pfizer, Kowa, Genzyme, ISIS, Genzyme, Roche, Ely Lilly, Aegerion, Synageva, AstraZeneca and for lectures and/or advisory panel participation of KH from Amgen, Sanofi, Pfizer and Roche Richard CeskaConsultant/honoraria for Regeneron, Sanofi, Amgen, Genzyme, Aegerion, Kowa Robert DufourReceived consultancy fees from Sanofi Dirk Blom Consultant or on an advisory panel for Aegerion, Amgen, AstraZeneca, MSD, and Sanofi Aventis. DB’s institution has received payment for conducting clinical trials from Aegerion, Amgen, Eli Lilly, Novartis, and Sanofi/Regeneron; DB has participated in a lecture/speaker’s bureau or received honoraria from Aegerion, Amgen, AstraZeneca, MSD, Pfizer, Sanofi Aventis, Servier, and Unilever Fernando CiveiraGrants, consulting fees and/or honoraria from Amgen, Merck, Pfizer and Sanofi Aventis Michel Krempf Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Astra Zeneca, BMS, Merck and Co, Novartis, Pfizer, Roche, Sanofi-Aventis Michel Farnier Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Boehringer- Ingelheim, Genzyme, Kowa, Merck and Co, Novartis, Pfizer, Recordati, Roche, Sanofi-Aventis, and SMB Industry Relationships and Institutional Affiliations 2

 HeFH is one of the most common genetic diseases (prevalence 1/200 to 1/500) characterised by: –extremely high levels of low-density lipoprotein cholesterol (LDL-C) 1 –premature atherosclerosis and cardiovascular disease (CVD) 1  A large proportion (~80%) of adult patients with heFH on lipid-lowering treatment do not reach the LDL-C goal of <2.5 mmol/L (100 mg/dL) 2  The treatment goal for adult patients with heFH who also have coronary heart disease or diabetes is <1.8 mmol/L (70 mg/dL) 1 Heterozygous Familial Hypercholesterolaemia (heFH) 3 1.Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90 2.Pijlman AH et al. Atherosclerosis. 2010;209(1):

4 Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT ; ODYSSEY FH II: NCT Placebo Q2W SC R n=323 (FH I); n=167 (FH II) n=163 (FH I); n=82 (FH II) HeFH patients on max tolerated statin ± other lipid- lowering therapy OLE/8 week FU Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC (single 1-mL injection using prefilled pen for self-administration) Assessments W0W8W16W36 W52 Double-Blind Treatment Period (78 Weeks) Primary efficacy endpoint W64 W4W12W24W78 LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD) or 2.59 mmol/L [100 mg/dL] (no history of CVD) Dose ↑ if LDL-C >70 mg/dL at W8 Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52) Per-protocol dose ↑ possible based on pre-specified LDL-C level ODYSSEY FH I and FH II Study Design

All patients on background of max-tolerated statin ± other lipid-lowering therapy FH IFH II Alirocumab (N=323) Placebo (N=163) Alirocumab (N=167) Placebo (N=82) Diagnosis of heFH †, % (n) Genotyping Clinical criteria 39.9% (129) 59.8% (193) ‡ 38.0% (62) 62.0% (101) 70.1% (117) 29.9% (50) 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) † 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. Baseline Characteristics

6 Any statin †, % (n)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)] All patients on background of max-tolerated statin ± other lipid-lowering therapy FH IFH II Alirocumab (N=323) Placebo (N=163) Alirocumab (N=167) Placebo (N=82) † Patients should receive either rosuvastatin mg, atorvastatin 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 mg or rosuvastatin mg daily. Lipid Medication and LDL-C at Baseline

Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo 7 LS mean (SE) % change from baseline to Week 24 LS mean difference (SE) vs. placebo: N=163 Alirocumab N=322 −57.9% (2.7) P< N=81N=166 −51.4% (3.4) P< FH I Placebo FH II 43.4% had dose increase at W % had dose increase at W12 Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy Intent-to-treat (ITT) Analysis

LDL-C, LS mean (SE), mmol/L 3.5 mmol/L 1.8 mmol/L 3.7 mmol/L 1.9 mmol/L mg/dL 1.8 mmol/L 1.7 mmol/L 4.0 mmol/L Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks 8 Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT Placebo: FH I FH II Alirocumab: FH I FH II Week Intent-to-treat (ITT) Analysis LLT = lipid-lowering therapy Dose ↑ if LDL-C >70 mg/dL at W8

Most heFH Patients Receiving Alirocumab on Background Statin  Other LLT Achieved LDL-C Goals 9 P< % patients Placebo † Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy. Proportion of patients reaching LDL-C goal † at Week 24 FH IFH II Alirocumab Intent-to-treat (ITT) Analysis

Safety Analysis (Pooled Data from FH I and FH II) All Data Collected Until Last Patient Visit at Week % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) TEAEs74.8% (366)75.4% (184) Treatment-emergent SAEs10.0% (49)9.0% (22) TEAEs leading to death0.8% (4)0 TEAEs leading to discontinuation3.1% (15)3.7% (9) Adverse Events of Interest Adjudicated CV events † 1.6% (8)1.2% (3) Injection-site reactions11.5% (56)9.0% (22) Neurocognitive disorders0.2% (1)1.2% (3) ALT >3 x ULN2.1% (10/488)1.2% (3/244) Creatine kinase >3 x ULN3.5% (17/483)6.2% (15/243)  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.

11 % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) Injection-site reaction 11.5% (56)9.0% (22) Nasopharyngitis 10.2% (50)11.1% (27) Influenza 8.8% (43)6.1% (15) Headache 5.5% (27)6.6% (16) Safety Analysis TEAEs Occurring in ≥5% of Either Alirocumab or Placebo Patients Collected Until Last Patient Visit at Week 52 (Pooled Data from FH I and FH II) Statistical analyses have not been performed.

 In heFH patients not well controlled on maximally- tolerated statin ± other lipid-lowering therapy: –Self-administered alirocumab produced significantly greater LDL-C ↓ vs. placebo at W24 (LS mean difference of %) –Majority of pts (>70%) achieved their LDL-C goals at W24 –Mean achieved LDL-C levels of mmol/L ( mg/dL) at W52 with alirocumab –~50% did not require a dose ↑ to alirocumab 150 mg Q2W –Safety and tolerability were generally comparable in alirocumab and placebo groups Conclusions 12

13 Thank you to all principal investigators and national coordinators! Canada: 5 sites USA: 23 sites FHI ‒ 89 sites worldwide FHII – 26 sites worldwide Austria: 3 sites Czech Republic: 4 sites Denmark: 3 sites France: 4 sites Israel: 4 sites Netherlands: 8 sites Sweden: 2 sites Russia: 10 sites Spain: 9 sites Norway: 1 site South Africa: 9 sites UK: 4 sites 2 sites 6 sites 13 sites 1 site