Anti-PCSK9 Monotherapy for Hypercholesterolemia – The MENDEL-2 Randomized, Controlled Phase 3 Clinical Trial of Evolocumab

Study Questions:

What is the relative efficacy of biweekly and monthly subcutaneous (SC) evolocumab, a monoclonal antibody-based PCSK9 inhibitor, with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase 3 trial?

Methods:

Patients ages 18–80 years with fasting low-density lipoprotein cholesterol (LDL-C) ≥100 and <190 mg/dl and Framingham risk scores ≤10% were randomized (1:1:1:1:2:2) to: oral placebo and placebo SC biweekly, oral placebo and placebo SC monthly, ezetimibe and placebo SC biweekly, ezetimibe and placebo SC monthly, oral placebo and evolocumab 140 mg biweekly, or oral placebo and evolocumab 420 mg monthly.

Results:

A total of 614 patients were randomized and dosed, and 97% completed the study. Mean age was 53 years, approximately 35% were male, average LDL-C was 142 mg/dl, and high-density lipoprotein (HDL)-C was 55 mg/dl. Evolocumab treatment reduced LDL-C from baseline, on average, by 55-57% more than placebo and 38-40% greater than ezetimibe (p < 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoproteins. Treatment-emergent adverse events, muscle-related adverse events, and laboratory abnormalities were comparable across treatment groups. Evolocumab demonstrated consistent LDL-C effects regardless of age, gender, race, region, or baseline levels of LDL-C, triglycerides, or PCSK9.

Conclusions:

In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe, and was well tolerated in hypercholesterolemic patients.

Perspective:

The safety and efficacy data of the PCSK9 inhibitors in this 12-week trial and the longer duration studies have been impressive thus far. The Food and Drug Administration (FDA) recently expressed concern about the potential for neurocognitive side effects from a PCSK9 inhibitor that could potentially result from the drug per se, or the very low LDL-C achieved. Neurocognitive stability will need to be part of the assessment in the large and long-term placebo-controlled studies of lipid-lowering agents. The issue still remains a question to some within the statin family of drugs.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet

Keywords: Cholesterol, United States Food and Drug Administration, Azetidines, Pharmaceutical Preparations, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipidemic Agents, Hypercholesterolemia, Triglycerides, Fasting, ACC Annual Scientific Session


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