Efficacy, Safety, and Tolerability of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 as Monotherapy in Patients With Hypercholesterolaemia (MENDEL): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Study
Does a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) lower lipids among patients with hypercholesterolemia who are not taking concurrent lipid-lowering therapy such as statins?
The MENDEL study was a phase 2 clinical trial conducted from 52 centers in Europe, the United States, Canada, and Australia. Participants were ages 18-75 years with low-density lipoprotein cholesterol (LDL-C) concentrations ≥2.6 mmol/L and <4.9 mmol/L. Participants were randomized to subcutaneous injections of AMG 145 (a PCSK9 monoclonal antibody), placebo, or ezetimibe 10 mg/day. Doses of AMG 145 examined included 70 mg, 105 mg, or 140 mg every 2 weeks, and 280 mg, 350 mg, or 420 mg every 4 weeks. Analysis was intention to treat, and both study personnel and participants were blinded to treatment assignment for the AMG 145 and placebo arms. Ezetimibe assignment was open label. The primary outcome of interest was percentage change in LDL-C from baseline to week 12. Funding for the study was provided by Amgen.
A total of 406 participants were randomized to the AMG 145 treatment arms, placebo arms, and the ezetimibe arm, with approximately 45 participants per arm. The mean age of the patients was 51 years, 34% were men, and 79% were white. Mean LDL-C concentration at baseline was 3.7 mmol/L. Of the patients enrolled, 21% of patients had two or more cardiovascular risk factors, 32% had metabolic syndrome, and no one had a history of coronary artery disease. AMG 145 significantly reduced LDL-C concentrations in all dose groups. The changes from baseline were –41.0% (95% confidence interval –46.2 to –35.8) for the AMG 70 mg/2-week dose; –43.9% (–49.0 to –38.7) for the 105 mg/2-week dose; and –50.9% (–56.2 to –45.7) for the 140 mg/2-week dose. Doses given every 4 weeks also resulted in reduced LDL-C. The changes from baseline were –39.0% (–44.1 to –34.0) for the 280 mg/4-week dose; –43.2% (–48.3 to –38.1) for the 350 mg/4-week dose; and –48.0% (–53.1 to –42.9) for the 420 mg/4-week dose. The placebo groups had changes in LDL-C including placebo every 2 weeks –3.7% (–9.0 to 1.6); placebo every 4 weeks 4.5% (–0.7 to 9.8). For the ezetimibe group, the change from baseline was –14.7% (–18.6 to –10.8). Reductions observed in the AMG 145 arms were statistically different from either of the placebo arms and the ezetimibe arm (p < 0.001). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported.
The investigators concluded that AMG 145, a monoclonal antibody to PCSK9, demonstrated significant reductions in LDL-C over a 12-week period.
Antibodies to PCSK9 offer significant LDL-C lowering potential. Phase 2 studies such as the current study suggest that such therapies are well tolerated. However, as the authors suggest, longer-term studies that include more diverse study populations will be needed. In addition, outcomes that include cardiovascular endpoints are warranted.
Keywords: Proprotein Convertases, Cholesterol, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Australia, Canada, Cardiovascular Diseases, Europe, Hypercholesterolemia, Subtilisin
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