Anti-PCSK9 monoclonal antibody, clone MAFB4530

Cholesterol treatment guidelines have evolved in the United States from the 1988 Adult Treatment Panel (ATP) I, the ATP II guidelines, ATP III guidelines, the 2013 American College of Cardiology/American Heart Association guidelines, to the most recent 2016 recommendations from the United States Protective Services Task Force. The use of statins to treat hyperlipidemia has been widely accepted and recommended in adults aged 40-75 years old with at least one risk factor and a calculated 10-year cardiovascular disease risk of 10%. However, statin use is associated with myalgias, myopathy, musculoskeletal injury, liver injury, and increased diabetes risk. The evidence for non-statin treatments is mixed. Bile acid sequestrants and ezetimibe reduce cardiovascular events. There is no evidence that the addition of any fibric acid derivative to a statin improves cardiovascular outcomes. Available evidence suggests that the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme inhibitors likely leads to little or no difference in mortality despite lowering lipid levels.

Aim: In patients with hyperlipidemia, intolerance to statins presents a challenge in reducing the risk of events associated with cardiovascular disease. This phase 3, randomized, double-blind trial in Japanese patients with statin intolerance aimed to evaluate the efficacy and safety of evolocumab vs. ezetimibe in lowering low-density lipoprotein-cholesterol (LDL-C). Methods: This study was conducted in a 12-week, double-blind period followed by an open-label extension designed to characterize 1 year of evolocumab treatment. Statin intolerance was defined as failure of two or more statins due to myalgia, myositis, or rhabdomyolysis. Eligible patients were randomized at 2:2:1:1 into four groups: 420 mg evolocumab every 4 weeks (Q4W)+oral placebo daily, 140 mg evolocumab every 2 weeks (Q2W)+oral placebo daily, subcutaneous (SC) placebo Q4W+10 mg ezetimibe daily, and SC placebo Q2W+10 mg ezetimibe daily. Results: Sixty-one patients were randomized to evolocumab (n=40) or ezetimibe (n=21). For the co-primary endpoints of percent change from the baseline in mean LDL-C to the mean of weeks 10 and 12 and to week 12, the evolocumab-ezetimibe treatment differences were -39.4% (95% CI, -47.2% to -31.5%) and -40.1% (95% CI, -48.7% to -31.6%), respectively (adjusted p< 0.0001). The most common adverse events were diarrhea (9.5%) and nasopharyngitis (12.5%) in the ezetimibe and evolocumab groups, respectively, during the double-blind period and nasopharyngitis (29%) during the open-label extension. Conclusion: Evolocumab was superior to ezetimibe in reducing LDL-C during the 12-week double-blind period in this population of Japanese patients with statin intolerance, with efficacy and safety results maintained for 1 year.