Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial

Abstract

AimsTo compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia.Methods and resultsCOMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012–May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe (difference 29.8 ± 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events.ConclusionIn patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile.Trial registrationclinicaltrials.gov Identifier: NCT01644188.

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials

“…This post‐hoc pooled analysis included individuals with a medical history of Type 1 or Type 2 DM and ASCVD who participated in 9 randomized, double‐blind, placebo‐ or ezetimibe‐controlled ODYSSEY Phase 3 trials with subcutaneous alirocumab administered every 2 weeks (Q2W), with trial durations of 24‐104 weeks (LONG TERM [NCT01507831],26 FH I [NCT01623115],23 FH II [NCT01709500],23 HIGH FH [NCT01617655],22 COMBO I [NCT01644175],24 COMBO II [NCT01644188],20 OPTIONS I [NCT01730040],19 OPTIONS II [NCT01730053]21 and ALTERNATIVE [NCT01709513]) 25. Individual trial results have been published previously.…”

“…Alirocumab is a PCSK9 inhibitor that signficantly reduced LDL‐C and other atherogenic lipid parameters in participants with hypercholesterolaemia in Phase 3 ODYSSEY trials,19, 20, 21, 22, 23, 24, 25, 26 including dedicated trials involving individuals with DM who were receiving insulin therapy27 or with mixed dyslipidaemia,28 with a safety profile comparable to controls. Alirocumab has also been demonstrated to reduce major adverse cardiovascular events vs placebo in patients with recent acute coronary syndrome in the ODYSSEY OUTCOMES trial 29.…”

Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study

“…Alirocumab, a fully human monoclonal antibody that specifically binds to PCSK9, has been shown to significantly lower LDL‐C levels across a range of dosing regimens, whether as monotherapy12 or on a background of statin±other lipid‐lowering therapies 13, 14, 15, 16. A monthly dosing regimen may be convenient and effective,17, 18 with different doses being appropriate when used as monotherapy compared with background statin therapy.…”

“…This study also employed an alirocumab dosing regimen of 75 mg every 2 weeks (Q2W; with possible dose adjustment to 150 mg Q2W; referred to as “75Q2W”) as a calibrator arm, a dose that has been extensively investigated across the phase 3 ODYSSEY clinical trials program 12, 13, 14, 15, 16. CHOICE II followed a “treat‐to‐target” dosing strategy, based on the LDL‐C reduction needed to provide best achievement of target LDL‐C level at the lowest alirocumab dose.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Alirocumab and evolocumab, either alone or in combination with statins and/or other lipid‐lowering therapies, have been shown in their respective phase 3 clinical trial programs (ODYSSEY and PROFICIO [Program to Reduce LDL‐C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations]) to significantly reduce LDL‐C levels by up to 60% from baseline (depending on dosing regimen; Table) in patients with hypercholesterolemia, including those with familial hypercholesterolemia, moderate to very high cardiovascular risk, and statin intolerance 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62. The inclusion/exclusion criteria and other details of each phase 3 ODYSSEY and PROFICIO trial are shown in Table S2.…”