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

Aims: To 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 results: COMBO 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.

Conclusion: In 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 registration: clinicaltrials.gov Identifier: NCT01644188.

Keywords: Alirocumab; Ezetimibe; Low-Density Lipoprotein Cholesterol; Monoclonal antibody.

Figure 1

Patient flow chart.

Figure 2

Distribution by 10 mg/dL increments of LDL-C concentration at baseline and at Week 24 in patients on maximally tolerated statins^a and alirocumab or ezetimibe. Comparison between Week 24 vs. baseline is descriptive and exploratory only, as data for all patients were not available at Week 24. ^aOne patients was not on maximally tolerated statin therapy.

Figure 3

LDL-C values achieved vs. study time-points (ITT analysis). Percentages above Weeks 12 and 24 data points indicate LS mean (SE) percent change from baseline. Values above Weeks 24 and 52 indicate achieved LDL-C.