ACC 2014 Report: Efficacy of evolocumab in the DESCARTES, MENDEL-2 and RUTHERFORD-2 Trials

by Bruce Sylvester  – On March 29, 2014, investigators presented results from three separate evolocumab trials at the American College of Cardiology annual meeting/ACC2014. Evolocumab is a human monoclonal antibody to PCSK9.

In the  DESCARTES trial, the investigators  studied monthly evolocumab treatment for 52 weeks. They found that, either as monotherapy or combined with a statin with or without ezetimibe (EZE), evolocumab treatment lowered LDL-C by 57 percent in subjects with a range of cardiovascular risk

All candidates for DESCARTES were screened for LDL-C and for NCEP-ATPIII risk.

The researchers randomized 901 subjects to one of four background lipid-lowering therapies (diet only, atorvastatin 10 mg/d, atorvastatin 80 mg/d, atorvastatin 80 mg/d with EZE 10 mg/d).

After a lipid therapy lead-in phase, the researchers randomized subjects with LDL-C ≥ 75 mg/dL (median baseline range 94–113 mg/dL) on a  2:1 basis  to subcutaneous monthly evolocumab 420 mg or to placebo.

They reported that, at 52 weeks, evolocumab treatment reduced mean LDL-C by 57 percent compared with placebo (P < 0.001).However, patient responses varied, from 49 percent to 62 percent, according to background treatment.

LDL-C reduction at week 12 and week 52 were comparable.

The study was published in the New England Journal of Medicine on March 29.

Investigators in the 12-week MENDEL-2 trial evaluated evolocumab as monotherapy for 614 randomized patients with hypercholesterolemia (HeFH) who were not treated with statins.

They found that subjects treated with evolocumab biweekly (140 mg) or monthly (420 mg) achieved fast and significant lowering of LDL-C over 12 weeks, compared with placebo or EZE. The reduction in LDL-C from baseline was, on average, 55 percent to 57 percent greater 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.

In the RUTHERFORD-2 trial, investigators evaluated the effect of PCSK9 inhibition with evolocumab on LDL-C levels in patients with heterozygous familial hypercholesterolemia (HeFH).

In this 12-week trial, the investigators randomized 331 subjects on a 2:2:1:1 ratio to evolocumab 140 mg subcutaneous biweekly, evolocumab 420 mg subcutaneous monthly, placebo subcutaneous  biweekly, or placebo subcutaneous monthly.

They reported that evolocumab treatment, 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 endpoint was 61 percent in the 140 mg biweekly group and 56 percent in the 420 mg monthly evolocumab group.

Mean reduction of LDL-C at weeks 10 and 12, respectively, was 61 percent in the 140 mg biweekly group and 63 percent in the 420 mg monthly evolocumab  group.

Evolocumab 140 mg biweekly and 420 mg monthly dosing regimens appeared to be equivalent in efficacy.