Mixed Results Reported for Repatha in Landmark Cardiovascular Outcomes Study

Monoclonal antibody reduces major cardiovascular events

In a large cardiovascular outcomes study, reducing low-density lipoprotein cholesterol (LDL-C) levels with evolocumab (Repatha, Amgen), beyond what is possible with the current best therapy alone, led to further reductions in major cardiovascular events, including heart attacks, strokes, and coronary revascularizations. The treatment had no observed effect, however, on cardiovascular mortality.

The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial––a multinational, phase 3, randomized, double-blind, placebo-controlled study––was designed to evaluate whether treatment with evolocumab in combination with statin therapy compared with placebo plus statin therapy reduces cardiovascular events. The primary endpoint was the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was the time to cardiovascular death, myocardial infarction, or stroke.

A total of 27,564 patients with high cholesterol (LDL-C levels greater than or equal to 70 mg/dL or non–high-density lipoprotein cholesterol [non–HDL-C] levels greater than or equal to 100 mg/dL) and clinically evident atherosclerotic cardiovascular disease at more than 1,200 study locations around the world were randomly assigned to receive subcutaneous (SC) evolocumab 140 mg every two weeks (420 mg monthly) plus an optimized statin dose; or SC placebo every two weeks or monthly plus an effective statin dose. Effective statin therapy was defined as at least atorvastatin 20 mg or its equivalent daily, with a recommendation for at least atorvastatin 40 mg or its equivalent daily where approved. The study continued until at least 1,630 patients experienced a key secondary endpoint.

The trial was statistically powered around the “hard” major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke, or cardiovascular death (the key secondary composite endpoint) and found that adding evolocumab to optimized statin therapy resulted in a statistically significant (P < 0.001) 20% reduction in those events. The benefit of evolocumab started as early as six months and continued to accrue through the median 2.2 years of the study.

The study also found a statistically significant (P < 0.001) 15% reduction in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke, or cardiovascular death.

Patients treated with evolocumab experienced a 27% reduction in the risk of heart attack (P < 0.001), a 21% reduction in the risk of stroke (P = 0.01), and a 22% reduction in the risk of coronary revascularization (P < 0.001) compared with those given placebo. In an exploratory analysis, the relative risk reduction for fatal and nonfatal heart attack or stroke was 19% in the first year (P = 0.003) and 33% beyond the first year (P < 0.00001).

Evolocumab had no observed effect on cardiovascular mortality. Similarly, there was no observed effect on hospitalization for unstable angina.

When added to statin therapy, evolocumab reduced LDL-C levels from a median of 92 mg/dL to a median of 30 mg/dL at week 48––a 59% reduction, which was sustained throughout the trial. At 48 weeks, LDL-C levels were reduced to at least 25 mg/dL in 42% of the patients treated with evolocumab compared with less than 0.1% of the placebo group (P < 0.001).

Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to LDL receptors (LDLRs), thereby preventing PCSK9-mediated LDLR degradation and permitting LDLRs to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLRs, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

Source: Amgen; March 17, 2017.