THOUSAND OAKS, Calif., Sept. 15, 2017 — Amgen (NASDAQ:AMGN) today announced that a new analysis of the cardiovascular outcomes study (FOURIER) demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) levels with Repatha® (evolocumab) significantly and consistently reduced cardiovascular events in patients with and without diabetes at baseline.
The analysis showed that diabetes was independently associated with a substantially increased risk of cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Patients with diabetes tended to have a greater absolute risk reduction of cardiovascular events with Repatha treatment because of their heightened baseline risk. Consistent with recent trials of more intensive LDL lowering, Repatha has not shown an effect on cardiovascular mortality.1-5 The analysis also showed that Repatha was not associated with an increased risk of new-onset diabetes or worsening glycemia (increased presence of glucose in the blood) over a median of 2.2 years of follow-up in patients without diabetes or pre-diabetes. Additionally, no new safety concerns were identified in this analysis. The results were presented today at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Lisbon, Portugal and simultaneously published in The Lancet Diabetes & Endocrinology.
"This analysis further demonstrates the benefits of achieving LDL-C levels well below current targets among atherosclerotic cardiovascular disease patients both with and without diabetes, the former of whom are at significantly greater risk of cardiovascular events and thus tend to enjoy even larger absolute risk reductions," said Marc S. Sabatine, chairman of the TIMI Study Group, the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women's Hospital, and Professor of Medicine, Harvard Medical School, Boston, and lead author on the analysis. "Importantly, this analysis also provides additional evidence that evolocumab is equally safe in patients with and without diabetes."
As part of a pre-specified analysis of the Repatha cardiovascular outcomes study, diabetes status was defined on the basis of patient history, clinical events committee review of medical records, or baseline glycated hemoglobin (HbA1c) of 6.5 percent (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7.0 mmol/L (126 mg/dL) or greater. At study baseline, 40 percent of patients had diabetes (n=11,031) and 60 percent did not have diabetes (n=16,533), of whom 10,344 had pre-diabetes and 6,189 had normoglycemia. In this analysis, compared with placebo, the diabetes subgroup experienced a 57 percent mean reduction in LDL-C levels when treated with Repatha (95 percent confidence interval [CI], 56-58.0; p<0.0001), and in the non-diabetes subgroup, patients treated with Repatha experienced a 60 percent mean reduction at 48 weeks (95 percent CI, 60-61; p<0.0001), down to 0.8 mmol/L (30 mg/dL) in both groups.
The hazard ratio (HR) of Repatha treatment for the composite primary endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death, was 0.83 (95 percent CI, 0.75-0.93; p=0.0008) for those with diabetes, and 0.87 (95 percent CI, 0.79-0.96; p=0.0052) for patients without diabetes. Because of their greater baseline risk of cardiovascular events, patients with diabetes tended to have a greater absolute risk reduction with Repatha treatment than patients without diabetes (2.7 percent [95 percent CI, 0.7-4.8] versus 1.6 percent [95 percent CI, 0.1-3.2]), driven largely by a greater absolute risk reduction in coronary revascularisation (2.7 percent [95 percent CI, 1.1-4.2] versus 1.8 percent [95 percent CI, 0.6-3.1]). The HR of Repatha treatment for the secondary composite endpoint of heart attack, stroke or cardiovascular death was 0.82 (95 percent CI, 0.72-0.93; p=0.0021) for those with diabetes and 0.78 (95 percent CI, 0.69-0.89; p=0.0002) for those without diabetes. As was seen in the overall trial results, the magnitude of risk reduction in both the primary and secondary endpoints tended to increase over time beyond the first year in patients with and without diabetes.6
"Abnormally high lipids are common in patients with diabetes, which increases their risk of cardiovascular disease, and some patients continue to struggle with the critical task of managing their LDL-C levels despite treatment with high-intensity statins, which is the standard of care," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This analysis provides further evidence of a substantially increased risk of cardiovascular events in patients with diabetes, and reinforces the importance of Repatha as an appropriate treatment option in these higher risk patients by virtue of a greater absolute risk reduction with treatment."
Repatha, compared to placebo, did not increase the risk of new-onset diabetes in patients without diabetes at baseline (8.0 percent [663/8,256] versus 7.6 percent [631/8,254], respectively; HR 1.05, 95 percent CI, 0.94-1.17), including those with pre-diabetes (HR 1.00, 95 percent CI, 0.89-1.13). Levels of HbA1c and FPG were similar between the Repatha and placebo groups over time in patients with diabetes, pre-diabetes or normoglycemia.
The overall rates of adverse events and serious adverse events were similar between Repatha and placebo in patients with and without diabetes. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78.5 percent (4,327 of 5,513 patients) in the Repatha group and 78.3 percent (4,307 of 5,502 patients) in the placebo group. Among patients without diabetes at baseline, the proportions with adverse events were 76.8 percent (6,337 of 8,256 patients) in the Repatha group and 76.8 percent (6,337 of 8,254 patients) in the placebo group.
Primary Analysis of the Repatha Cardiovascular Outcomes Study
The primary analysis included 27,564 patients with established cardiovascular disease. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The study also 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.6
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.
The detailed results from the Repatha cardiovascular outcomes study were initially presented during a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session and simultaneously published in the New England Journal of Medicine.
Repatha Cardiovascular Outcomes (FOURIER) Study Design
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.
About Repatha® (evolocumab)
Repatha® (evolocumab) is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.7
Repatha is approved in more than 50 countries, including the U.S., Japan, Canada and in all 28 countries that are members of the European Union. Applications in other countries are pending.