Amgen has announced a new analysis from the Repatha (evolocumab) cardiovascular outcomes study (FOURIER) that showed a statistically significant relationship between lower achieved low-density lipoprotein cholesterol (LDL-C) levels and lower cardiovascular event rates in patients with established atherosclerotic cardiovascular disease. There was no evidence of a leveling off of effect and no new safety concerns were identified in this analysis.

The results were presented in a Late-Breaking Clinical Trials session at the European Society of Cardiology (ESC) Congress 2017 in Barcelona, Spain and simultaneously published in The Lancet.

"With this analysis, we've further demonstrated the safety and efficacy of achieving an LDL-C well below current targets," said Robert P. Giugliano, M.D., S.M., Brigham and Women's Hospital and Harvard Medical School, Boston and lead author on the analysis. "These findings from the first analysis of a large cohort of patients to achieve such ultra-low LDL-C levels support the use of intensive lipid-lowering therapies, such as the combination of evolocumab and statin therapy, in high-risk patients to safely reduce the risk of another cardiovascular event."

Approximately 26,000 patients from the Repatha cardiovascular outcomes study were followed for a median of 2.2 years and stratified post-randomization into five prespecified groups irrespective of treatment allocation based on achieved LDL-C at week four from baseline: <0.5 mmol/L (which converts to less than 20 mg/dL), 0.5-<1.3 mmol/L, 1.3-<1.8 mmol/L, 1.8-<2.6 mmol/L, and =2.6 mmol/L (see footnote for conversions of all groups to mg/dL). Rates for the primary and secondary composite endpoints and cognitive function testing, as well as safety events, including cancer, hemorrhagic stroke, new onset diabetes, cataract, neurocognitive dysfunction and non-cardiovascular death were compared across these five groups.

The analysis demonstrated that there was a highly significant progressive relationship between lower LDL-C and a lower risk of the primary composite endpoint (ptrend<0.0001). A similar progressive reduction in the key secondary composite endpoint, which included heart attack, stroke or cardiovascular death, was also observed across all five groups (p=0.0001 for a monotonic relationship). There was no meaningful difference in the safety profile across the five groups, including the group with the lowest achieved LDL-C level. Lastly, patients were more likely to achieve very low LDL-C levels when treated with Repatha and statin therapy versus statin alone.

"Scientific evidence demonstrating the strong progressive association between lowering LDL-C and the risk reduction of cardiovascular events in patients with established atherosclerotic cardiovascular disease continues to grow," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "For patients who have already experienced an event, such as a heart attack or stroke, this analysis reinforces that the intensive LDL-C lowering provided with Repatha helps patients reduce their risk of another cardiovascular event."

Relationship of Achieved LDL-C and Primary and Secondary Efficacy Composite Endpoints

The risk of the primary composite efficacy endpoint, which included cardiovascular death, heart attack, stroke, coronary revascularization or hospitalization for unstable angina, was progressively lower as the achieved LDL-C at week 4 was reduced.

Based on Kaplan-Meier event rates at three years, Repatha reduced the risk of the composite primary endpoint across all five groups (24 percent in patients with LDL-C <0.5 mmol/L; 15 percent in patients with LDL-C of 0.5-<1.3 mmol/L; 6 percent in patients with LDL-C of 1.3-<1.8 mmol/L; and 3 percent in patients with LDL-C of 1.8-<2.6 mmol/L, using the group with LDL-C =2.6 mmol/L as the referent [ptrend<0.0001]).

In a post-hoc analysis, 504 patients who achieved an LDL-C of less than 0.26 mmol/L, or 10 mg/dL, experienced a 31 percent risk reduction in the primary composite endpoint (p=0.035)  and a 41 percent risk reduction in the secondary composite endpoint (p=0.020).

Relationship of Achieved LDL-C and Safety

Across the five groups, there was no significant association between achieved LDL-C and safety outcomes for all serious adverse events (AEs) and other AEs of interest: aspartate transaminase or alanine transaminase >3x the upper limits of normal (ULN), creatine kinase >5x ULN, neurocognitive events, new onset diabetes, cancer, hemorrhagic stroke, cataracts, and non-cardiovascular death. Serious AEs after week four occurred in 24 percent of patients, with less than four percent leading to drug discontinuation. There were no differences observed in serious AEs by achieved LDL-C at four weeks.

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.

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 low-density lipoprotein cholesterol (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.