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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. Colhoun8

1Harvard Clinical Research Institute, Boston, MA, USA; 2L’Institut du Thorax, CHU de

Nantes, Nantes, France; 3Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa; 4Virginia Commonwealth University and National Clinical Research, Inc., Richmond, VA, USA;

5Sanofi, Paris, France; 6Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7Sanofi,

Bridgewater, NJ, USA; 8University of Dundee, Dundee, Scotland, UK

Author Disclosure Christopher P. Cannon 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. Bertrand Cariou Received research funds from Sanofi Aventis. Consultant/advisory panel for Amgen, AstraZeneca, DebioPharm, Janssen, Eli Lilly, Genfit, Novo-Nordisk and Sanofi-Aventis. Dirk Blom 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. James M. McKenney Research grants from Sanofi and Regeneron. Christelle Lorenzato Employee of Sanofi. Robert Pordy Employee of Regeneron Pharmaceuticals, Inc. Umesh Chaudhari Employee of Sanofi. Helen M. Colhoun 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.

Industry Relationships and Institutional Affiliations

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ODYSSEY COMBO II Study Design

3 †Other LLT not allowed. Clinicaltrials.gov identifier: NCT01644188.

Double-blind treatment period (104 weeks)

High CV-risk patients on max-tolerated statin† LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD)

• r

≥2.59 mmol/L [100 mg/dL] (no history of CVD) High CV-risk patients on max-tolerated statin† LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD)

• r

≥2.59 mmol/L [100 mg/dL] (no history of CVD) R

n=479 n=241

Assessments W0 W4 W8 W12 W16 W24 W36 W52

Primary endpoint

W64 W76 W104

Dose ↑ if LDL-C >70 mg/dL at W8

W88 Follow-up (8 weeks)

Alirocumab 75 mg with potential ↑ to 150 mg Q2W SC + placebo ezetimibe PO

(single 1-mL injection using prefilled pen for self-administration)

Ezetimibe 10 mg/day PO + placebo Q2W SC Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W102 (all patients at least W52)

Per-protocol dose ↑ possible based

• n pre-specified LDL-C level

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/m2, 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] 2.8 (0.9) [109 (37)] 2.7 (0.9) [105 (34)]

Baseline Characteristics

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.

‡High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily.

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Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Ezetimibe

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• 50.6%
• 20.7%
• 60
• 50
• 40
• 30
• 20
• 10

LS mean (SE) % change from baseline to Week 24 LS mean difference (SE) vs. ezetimibe: −29.8% (2.3); P<0.0001 n=467 n=240 Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background of maximally-tolerated statin Ezetimibe Alirocumab

Intent-to-treat (ITT) analysis

18.4% had dose increase at W12

Alirocumab Maintained Consistent LDL-C Reductions over 52 Weeks

LDL-C, LS mean (SE), mmol/L

Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin

39 46 53 60 67 74 81 88 95 102 109 116 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 4 8 12 16 20 24 28 32 36 40 44 48 52 Ezetimibe

Week

2.1 mmol/L 82.5 mg/dL 1.3 mmol/L 51.6 mg/dL

Alirocumab

2.2 mmol/L 85.3 mg/dL 1.4 mmol/L 53.3 mg/dL

mg/dL

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Intent-to-treat (ITT) analysis Dose ↑if LDL-C >70 mg/dL at W8

−20.7% −50.6% −18.3% −49.5%

8/31/2014 4 Most of These High CV-Risk Patients Receiving Alirocumab

• n Background Statin Achieved LDL-C Goal

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Proportion of Patients Reaching LDL-C <1.81 mmol/L (70 mg/dL) at Week 24

% patients

77.0% 45.6% 10 20 30 40 50 60 70 80 90

P<0.0001

Intent-to-treat (ITT) analysis

60.3% 14.2% 10 20 30 40 50 60 70 80 90 Proportion of Patients Reaching LDL-C <1.3 mmol/L (50 mg/dL) at Week 24

% patients

Ezetimibe Alirocumab

Post hoc All patients on background of maximally-tolerated statin

Safety Analysis (Baseline-W102)

Including All Data Collected Until Last Patient Visit at Week 52

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% (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)

†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.

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Safety Analysis (Baseline-W102)

TEAEs Occurring in ≥5% of Either Alirocumab or Ezetimibe Patients

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% (n) of patients All patients on background max tolerated statin Alirocumab (n=479) Ezetimibe (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)

†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.

 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

Conclusions

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Thank you to all principal investigators and national coordinators!

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