Amgen has announced the submission of a supplemental Biologics License Application (sBLA) to the US Food and Drug Administration (FDA) and a variation to the marketing authorization to the European Medicines Agency (EMA) for Repatha (evolocumab), a PCSK9 inhibitor. The regulatory submissions are based on the 27,564-patient Repatha cardiovascular outcomes study (FOURIER), which showed that maximally reducing low-density lipoprotein cholesterol (LDL-C) levels with Repatha, beyond what is possible with the current best therapy alone, leads to a further reduction in major cardiovascular events, including heart attacks, strokes and coronary revascularizations.
"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," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "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."
The Repatha cardiovascular outcomes study demonstrated that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (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 cardiovascular death. The study found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.
The magnitude of risk reduction in both the primary and secondary composite endpoints grew over time, with the robust benefit starting as early as six months and accruing through the median 2.2 years of the study. For the secondary composite endpoint, an exploratory analysis showed a reduction in risk of 16 percent in the first year and 25 percent beyond the first year.
Patients on Repatha experienced a reduction in the risk of heart attack (27 percent, nominal p<0.001), stroke (21 percent, nominal p=0.01) and coronary revascularization (22 percent, nominal p<0.001). Consistent with recent trials of more intensive LDL lowering, there was no observed effect on cardiovascular mortality. Similarly, there was no observed effect on hospitalization for unstable angina.
No new safety concerns were identified in this large clinical trial with roughly 60,000 patient-years of follow-up; this included the assessment of patients who achieved very low levels of LDL-C. In particular, there were no notable differences seen between treatment arms in the overall rate of adverse events, serious adverse events or adverse events leading to study drug discontinuation. These results were presented during a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session (ACC.17) and simultaneously published in the New England Journal of Medicine.
The 27,564-patient Repatha cardiovascular outcomes study, FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), was a multinational phase 3 randomized, double-blind, placebo-controlled trial, designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. The primary endpoint was 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.
Eligible patients with high cholesterol (LDL-C =70 mg/dL or non-high-density lipoprotein cholesterol [non-HDL-C] =100 mg/dL) and clinically evident atherosclerotic cardiovascular disease at more than 1,200 study locations around the world were randomized to receive Repatha subcutaneous 140 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 at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event driven and continued until 1,630 patients experienced a key secondary endpoint.