Industry Relationships and Institutional Affiliations Author - PDF document

8/31/2014 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 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 1 Industry Relationships and Institutional Affiliations Author Disclosure Consultant/honoraria for Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Isis, Genzyme, Aegerion and John J.P. Kastelein Esperion Research support from Genzyme (Sanofi) and Sanofi-Regeneron, is a consultant on an advisory Henry N. Ginsberg 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 Langslet Advisory board fees from Amgen, Sanofi-Aventis and Janssen Pharmaceuticals KHs institution has received payment for conducting clinical trials from Sanofi, Regeneron, Amgen, G. Kees Hovingh 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 Ceska Consultant/honoraria for Regeneron, Sanofi, Amgen, Genzyme, Aegerion, Kowa Robert Dufour Received consultancy fees from Sanofi 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, Dirk Blom 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 Civeira Grants, consulting fees and/or honoraria from Amgen, Merck, Pfizer and Sanofi Aventis Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Astra Zeneca, Michel Krempf BMS, Merck and Co, Novartis, Pfizer, Roche, Sanofi-Aventis Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Boehringer- Michel Farnier Ingelheim, Genzyme, Kowa, Merck and Co, Novartis, Pfizer, Recordati, Roche, Sanofi-Aventis, and SMB 2 1

8/31/2014 Heterozygous Familial Hypercholesterolaemia (heFH)  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 1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90 2. Pijlman AH et al. Atherosclerosis. 2010;209(1):189-194. 3 ODYSSEY FH I and FH II Study Design Double-Blind Treatment Period (78 Weeks) HeFH patients on Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC max tolerated statin (single 1-mL injection using prefilled pen for self-administration) ± other OLE/8 week FU n=323 (FH I); n=167 (FH II) lipid-lowering therapy Per-protocol dose ↑ possible based R on pre-specified LDL-C level LDL-C ≥ 1.81 mmol/L [70 mg/dL] n=163 (FH I); n=82 (FH II) (history of CVD) or Placebo Q2W SC 2.59 mmol/L [100 mg/dL] (no history of CVD) W0 W8 W16 W36 W64 Assessments W4 W12 W24 W52 W78 Dose ↑ if Primary Pre-specified analysis LDL-C >70 mg/dL efficacy Efficacy: All Patients To W52 at W8 endpoint Safety: Baseline-W78 (all patients at least W52) Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500. 4 2

8/31/2014 Baseline Characteristics FH I FH II All patients on background of max-tolerated statin ± Alirocumab Placebo Alirocumab Placebo other lipid-lowering therapy (N=323) (N=163) (N=167) (N=82) Diagnosis of heFH † , % (n) Genotyping 39.9% (129) 38.0% (62) 70.1% (117) 81.7% (67) Clinical criteria 59.8% (193) ‡ 62.0% (101) 29.9% (50) 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. Lipid Medication and LDL-C at Baseline FH I FH II All patients on background of max-tolerated statin ± other Alirocumab Placebo Alirocumab Placebo lipid-lowering therapy (N=323) (N=163) (N=167) (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 3.7 (1.3) 3.7 (1.2) 3.5 (1.1) 3.5 (1.1) [mg/dL] [144.7 (51.2) ] [144.4 (46.8) ] [134.6 (41.3)] [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. 6 3

8/31/2014 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 max-tolerated statin ± other lipid-lowering therapy Alirocumab FH I FH II 20 Placebo LS mean (SE) % change from baseline 9.1% 10 2.8% 0 N=322 N=163 N=166 N=81 -10 to Week 24 -20 43.4% 38.6% had dose had dose -30 increase at increase at -40 W12 W12 -50 -48.8% -48.7% -60 LS mean − 57.9% (2.7) − 51.4% (3.4) difference (SE) P <0.0001 P <0.0001 vs. placebo: Intent-to-treat (ITT) Analysis 7 Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ± Other LLT FH I FH I Placebo: Alirocumab: FH II FH II 4.5 174 4.0 mmol/L 4.0 mmol/L LDL-C, LS mean (SE), mmol/L 4 155 3.5 135 3.7 mmol/L 3.5 mmol/L 3 116 mg/dL 2.5 97 1.9 mmol/L 1.8 mmol/L 2 77 58 1.5 1.8 mmol/L 1.7 mmol/L 39 1 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Dose ↑ if LDL-C >70 mg/dL at W8 Intent-to-treat (ITT) Analysis LLT = lipid-lowering therapy 8 4

8/31/2014 Most heFH Patients Receiving Alirocumab on Background Statin  Other LLT Achieved LDL-C Goals Proportion of patients reaching LDL-C goal † at Week 24 FH I FH II 90 81.4% 80 Alirocumab 72.2% 70 Placebo 60 % patients 50 40 30 20 11.3% 10 2.4% 0 P <0.0001 † Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy. Intent-to-treat (ITT) Analysis 9 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 Alirocumab Placebo tolerated statin ± other lipid-lowering (N=489) (N=244) therapy 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) 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. 10 5