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 Industry Relationships and Institutional Affiliations Author Christopher P. Cannon Bertrand Cariou Dirk Blom James M. McKenney Christelle Lorenzato Robert Pordy Umesh Chaudhari Helen M. Colhoun Disclosure Grants from Accumetrics, Arisaph, Astra Zeneca, Boehringer-Ingelheim, Janssen; grants and personal fees from GlaxoSmithKline, Merck, and Takeda; and consulting fees from BMS, CSL Behring, Essentialis, Lipimedix, Pfizer, Regeneron and Sanofi. Received research funds from Sanofi Aventis. Consultant/advisory panel for Amgen, AstraZeneca, DebioPharm, Janssen, Eli Lilly, Genfit, Novo-Nordisk and Sanofi-Aventis. Consultant/advisory panel for Aegerion, Amgen, AstraZeneca, MSD and Sanofi Aventis. D.B. s institution has received payment for conducting clinical trials from Aegerion, Amgen, Eli Lilly, Novartis, and Sanofi/Regeneron. D.B. has participated in a lecture/speaker s bureau or received honoraria from Aegerion, Amgen, AstraZeneca, MSD, Pfizer, Sanofi Aventis, Servier and Unilever. Research grants from Sanofi and Regeneron. Employee of Sanofi. Employee of Regeneron Pharmaceuticals, Inc. Employee of Sanofi. Consultant/advisory panel for Pfizer, Sanofi Aventis, Novartis and Eli Lilly. Received research support from Roche, Pfizer, Eli Lilly, Boehringer Ingelheim, AstraZeneca and JDRF. Participated in a lecture/speaker s bureau and received honorarium from Pfizer. Shareholder in Roche. 2 1
ODYSSEY COMBO II Study Design High CV-risk patients on max-tolerated statin LDL-C 1.81 mmol/l [70 mg/dl] (history of CVD) or 2.59 mmol/l [100 mg/dl] (no history of CVD) R n=479 n=241 Double-blind treatment period (104 weeks) 75 mg with potential to 150 mg Q2W SC + placebo ezetimibe PO (single 1-mL injection using prefilled pen for self-administration) 10 mg/day PO + placebo Q2W SC Per-protocol dose possible based on pre-specified LDL-C level Follow-up (8 weeks) Assessments W4 W0 W8 W16 W12 W24 W36 W52 W64 W76 W88 W104 Dose if LDL-C >70 mg/dl at W8 Primary endpoint Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W102 (all patients at least W52) 3 Other LLT not allowed. Clinicaltrials.gov identifier: NCT01644188. All patients on background max tolerated statin (n=479) (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. 4 High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily. 2
Significantly Reduced LDL-C from Baseline to Week 24 versus 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% LS mean difference (SE) vs. ezetimibe: 29.8% (2.3); P<0.0001 5 Intent-to-treat (ITT) analysis Maintained Consistent LDL-C Reductions over 52 Weeks Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin LDL-C, LS mean (SE), mmol/l 3 2.8 2.6 2.4 2.2 2 1.8 1.6 1.4 1.2 1 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Dose if LDL-C >70 mg/dl at W8 2.1 mmol/l 82.5 mg/dl 20.7% 1.3 mmol/l 51.6 mg/dl 50.6% Week 2.2 mmol/l 85.3 mg/dl 18.3% 1.4 mmol/l 53.3 mg/dl 49.5% 116 109 102 95 88 81 74 67 60 53 46 39 mg/dl 6 Intent-to-treat (ITT) analysis 3
Most of These High CV-Risk Patients Receiving on Background Statin Achieved LDL-C Goal Proportion of Patients Reaching LDL-C <1.81 mmol/l (70 mg/dl) at Week 24 90 80 All patients on background of maximally-tolerated statin 77.0% Proportion of Patients Reaching LDL-C <1.3 mmol/l (50 mg/dl) at Week 24 90 80 % patients 70 60 50 40 30 20 % patients 45.6% 70 60 50 40 30 20 60.3% 14.2% 10 10 0 P<0.0001 0 Post hoc 7 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 (n=479) (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) 8 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. 4
Safety Analysis (Baseline-W102) TEAEs Occurring in 5% of Either or Patients % (n) of patients All patients on background max tolerated statin (n=479) (n=241) Upper respiratory tract infection 6.5% (31) 5.8% (14) Accidental overdose 6.3% (30) 6.6% (16) Dizziness 4.8% (23) 5.4% (13) Myalgia 4.4% (21) 5.0% (12) 9 Accidental overdose is an event suspected by the Investigator or spontaneously notified by the patient (not based on systematic injection/capsule counts) and defined as at least twice the intended dose within the intended therapeutic interval (i.e., 2 injections from the double-blind treatment kit administered in <7 calendar days or 2 capsules from the double-blind treatment kit are administered within 1 calendar day). Statistical analyses have not been performed. Conclusions In this population of high CV-risk patients who had poorly controlled LDL-C on maximally-tolerated statin therapy: LDL-C from baseline maintained with alirocumab: significantly greater vs. ezetimibe at W24, 51% vs 21% (P<0.0001) Self-administered alirocumab had good compliance and was well-tolerated This treat-to-target approach with alirocumab resulted in ~80% pts not requiring a dose to 150 mg at W12 77% of alirocumab pts achieved LDL-C <1.81 mmol/l (70 mg/dl) at W24 Mean achieved LDL-C levels of 1.4 mmol/l (53.3 mg/dl) at W52 with alirocumab TEAEs similar between alirocumab and ezetimibe arms 10 5
Thank you to all principal investigators and national coordinators! Canada: 4 sites France: 4 sites Hungary: 5 sites Russia: 15 sites Ukraine: 2 sites Denmark: USA: 9 sites Israel: 58 sites 7 sites South Korea: 14 sites South Africa: 8 sites 126 sites worldwide 11 6