Three separate trials presented March 29 as part of ACC.14 in Washington, DC, looked at the impacts of evolocumab, a human monoclonal antibody to PCSK9.

The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES) found that evolocumab administered monthly, either alone or in combination with a statin with or without ezetimibe (EZE), for 52 weeks lowered LDL-C by 57 percent in subjects with a range of cardiovascular risk.

Based on screening LDL-C and NCEP-ATPIII risk, 901 subjects were randomized to one of four background lipid-lowering therapies (diet alone, atorvastatin 10 mg/d, atorvastatin 80 mg/d, atorvastatin 80 mg/d with EZE 10 mg/d). Subjects with LDL-C ≥ 75 mg/dL following lipid therapy lead-in (median baseline range 94–113 mg/dL) were randomized 2:1 to subcutaneous monthly evolocumab 420 mg or placebo. Results showed evolocumab reduced LS mean (95 percent CI) LDL-C by 57 percent compared with placebo (P < 0.001) but responses varied, from 49 percent to 62 percent, among background therapies. LDL-C reduction at week 12 and week 52 were comparable. The trial was simultaneously published in the New England Journal of Medicine. 

Meanwhile, a separate trial, MENDEL-2, evaluated evolocumab as a monotherapy in 614 randomized patients with hypercholesterolemia (HeFH) not taking statins. Evolocumab biweekly (140 mg) or monthly (420 mg) rapidly and markedly lowered LDL-C over 12 weeks compared with placebo or EZE, reducing LDL-C from baseline, on average, by 55 percent to 57 percent more than placebo and 38 percent to 40 percent greater than EZE (P < 0.001 for all comparisons). The trial was simultaneously published in the Journal of the American College of Cardiology. 

A third trial, RUTHERFORD-2 investigated the effect of PCSK9 inhibition with evolocumab on LDL-C levels in patients with heterozygous familial HeFH. The 12-week, multi-center trial randomized 331 patients 2:2:1:1 to evolocumab 140 mg subcutaneous biweekly: evolocumab 420 mg subcutaneous monthly: placebo subcutaneous biweekly: placebo subcutaneous monthly. Results showed that evolocumab administered either biweekly or monthly yielded significant reductions in LDL-C in HeFH patients on statins with or without EZE. The mean reduction of LDL-C at week 12 was 61 percent in the 140 mg biweekly and 56 percent in the 420 mg monthly evolocumab dose groups, respectively. The mean reduction of LDL-C at the mean of weeks 10 and 12 was 61 percent in the 140 mg biweekly and 63 percent in the 420 mg monthly evolocumab dose groups, respectively. Evolocumab 140 mg biweekly and 420 mg monthly dosing regimens were clinically equivalent.

Keywords: Pyrroles, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Heptanoic Acids, Hypercholesterolemia