Multinational biopharmaceutical company Amgen ($AMGN) has recently announced its submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) as well as request for marketing authorization to the European Medicines Agency (EMA) for their new drug, Repatha (evolocumab). Repatha is a PCSK9 inhibitor.

Regulatory submissions to both the FDA and EMA were based on the cardiovascular outcome studies of 27,564 patients taking Repatha. Studies showed a major reduction of low-density lipoprotein cholesterol (LDL-C) levels of patients taking Repatha compared to the best approved therapies that are currently available. The reduction of LDL-C levels leads to a lowered chance of major and potentially life-threatening cardiovascular events such as heart attacks, strokes, and coronary revascularizations.
Repatha’s cardiovascular outcomes study showed that adding Repatha to optimized statin therapy displayed a 20% (p<0.001) reduction in hard major adverse cardiovascular events (MACE) represented in the composite (secondary) endpoint of time to first heart attack, stroke, or other related cardiovascular death. A 15% reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint — which includes hospitalization for unstable angina, coronary revascularization, heart attack, stroke, or cardiovascular death — was seen.

Specifically, patients taking Repatha experienced a 27% reduction (p<0.001) in the risk of getting a heart attack, a 21% reduction of a stroke (p<0.001), and a 22% reduction of coronary revascularization (p<0.001). There were, however, no observed effect on unstable angina, or cardiovascular related deaths or hospitalization.

While the numbers look good, there were still some concerns. Executive vice president of Research and Development at Amgen, Sean E. Harper, M.D., noted, “Despite optimized therapy, including high-intensity statins, patients in our landmark cardiovascular outcomes study were still at high risk for an additional cardiovascular event. This demonstrates a significant unmet need, as event rates in the real world are typically two to three times higher than those seen in clinical trial settings.” Harper is hopeful to improve the drug after Amgen’s submission to the FDA and EMA, stating, “These regulatory submissions are important steps forward to helping improve access for patients who remain at high risk for cardiovascular events. We look forward to working with the FDA and EMA to update the labels for Repatha.”

There were no new safety concerns that were identified with the drug after about 60,000 patient-years of follow-ups, including patients that showed low levels of LDL-C after taking Repatha. As such, there were no notable differences and/or adverse events that lead to a discontinuation of the Repatha study.

Results of the study were presented during a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session (ACC.17). It is also published in the New England Journal of Medicine.

Repatha Cardiovascular Outcomes (FOURIER) Study Design

FOURIER, which stands for Further cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk, was a multinational Phase 3 study that was a randomized, double-blind, placebo-controlled trial that involved the participation of 27,564 patients. FOURIER was designed to determine whether or not treatment with Repatha, combined with statin therapy, reduced cardiovascular events. Primary endpoint was time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Key secondary endpoint was time to cardiovascular death, myocardial infarction, or stroke.

Eligible patients with high cholesterol (LDL-C higher or equal to 70 mg/dL, or non-high-density lipoprotein cholesterol higher or equal to 100 mg/dL) and/or have clinically evident atherosclerotic cardiovascular disease were randomly selected at more than 1,200 study locations internationally to participate in the study. Rapatha subcutaneous was given at 120 mg every two weeks, or 420 mg monthly plus optimized statin dose, or placebo subcutaneous every two weeks or monthly plus optimized statin dose.

Optimized statin therapy was defined as the patient taking at least 20 mg of atorvastatin (or equivalent) daily, with a recommendation for at least 40 mg of atorvastatin (or equivalent) daily where approved.

The study was event based, and continued until 1,630 patients experienced a key secondary endpoint (cardiovascular death, myocardial infarction, or stroke).

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