ACC.17: FOURIER trial meets primary endpoint, but investors are not impressed

Although patients with atherosclerotic cardiovascular disease and high levels of low-density lipoprotein (LDL) cholesterol benefited from receiving evolocumab plus statin therapy, the results of the randomized FOURIER trial did not impress Wall Street as shares of the drug’s manufacturer, Amgen, declined shortly after the findings were announced.

Patients in the evolocumab group had a statistically significant 15 percent reduction in the risk of the composite primary endpoint of cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization compared with a placebo group.

Adding evolocumab to optimal statin therapy also led to a statistically significant 20 percent reduction in the composite secondary endpoint of first MI, stroke or cardiovascular death. The rates of adverse events and serious adverse events were similar between the evolocumab and placebo groups.

Lead researcher Marc S. Sabatine, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School, presented the results in a late-breaking clinical trial session at the ACC scientific session on March 17 in Washington, D.C. The findings were simultaneously published online in The New England Journal of Medicine.

As of 11:45 a.m. (EST) on March 17, Amgen’s stock price had declined nearly 7 percent to $167.58 per share since the news was released earlier in the morning. Amgen funded the study.

In August 2015, the FDA approved evolocumab (Repatha), making the injectable drug the second in a class of cholesterol-lowering medications called proprotein convertase subtilisin kexin type 9 inhibitors.

Although evolocumab has been shown to significantly lower LDL cholesterol, the medication has a wholesale acquisition cost of $14,100 per year. The high price has limited the drug’s sales as payers and physicians have chosen to cover and prescribe cheaper alternatives such as statins.

During a press conference, Roxana Mehran, MD, and Valentin Fuster, MD, each expressed caution about the results considering the high cost of evolocumab. Fuster recommended that researchers examine evolocumab’s cost-effectiveness. Mehran and Fuster were not involved in the trial.

“We have to very sure that we identify the right people in which this approach is meaningful,” Fuster said.

“We have to figure out how to pay for this,” Mehran said. “This is an important cost issue.”

The drug’s FDA approval was based on results of trials that found patients with primary hyperlipidemia who received evolocumab had an average LDL cholesterol reduction of approximately 60 percent compared with the placebo group. However, the FDA required that Amgen conduct a postmarketing trial to determine if evolocumab reduced cardiovascular outcomes, which had not been tested in previous studies.

In the FOURIER trial, which was presented at the ACC scientific session, researchers enrolled 27,564 patients with atherosclerotic cardiovascular disease and fasting LDL cholesterol levels of 70 mg/dL or higher who were already treated with statins. The study took place at 1,242 sites in 49 countries from February 2013 through June 2015.

The researchers randomized the patients to receive 140 mg of evolocumab every two weeks or 420 mg of the medication each month or to a matching placebo group. They defined atherosclerotic cardiovascular disease as a history of MI, nonhemorrhagic stroke or symptomatic peripheral artery disease plus additional characteristics that made them of high cardiovascular risk.

The mean age was 63 years old, and 24.6 percent of the patients were women. All of the patients were between 40 and 85 years old. The median LDL cholesterol level at baseline was 92 mg/dL.

At baseline, 69.3 percent of patients were taking high-intensity statins, 30.4 percent were taking moderate-intensity statins and 5.2 percent were also taking ezetimibe. In addition, 92.3 took antiplatelet therapy, 75.6 percent took beta-blockers and 78.2 percent took and ACE inhibitor or an ARB inhibitor or both.

During a median follow-up period of 26 months, the primary composite endpoint occurred in 9.8 percent of patients in the evolocumab group and 11.3 percent of patients in the placebo group. The primary composite endpoint was cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization.

The researchers mentioned that the magnitude of the risk reduction in the primary endpoint increased from 12 percent in the first year to 19 percent beyond the first year.

In addition, the key secondary composite endpoint occurred in 5.9 percent of patients in the evolocumab group and 7.4 percent of patients in the placebo group. The key secondary composite endpoint was cardiovascular death, MI or stroke. The risk reduction for the key secondary endpoint increased from 16 percent in the first year to 25 percent beyond the first year.

The results for the primary and key secondary endpoints were consistent across most subgroups based on age, sex, type of atherosclerotic vascular disease, LDL cholesterol levels and intensity of statin therapy, according to the researchers.

The researchers added that evolocumab had no observed effect on cardiovascular mortality, rates of hospitalization for unstable angina, cardiovascular death or hospitalization for worsening heart failure or death from any cause. However, patients who received evolocumab had a 21 percent to 27 percent reduced risk of MI, stroke and coronary revascularization.

After 48 weeks of treatment, the researchers found there was a statistically significant 59 percent least-squares mean percentage reduction in LDL cholesterol levels with evolocumab compared with placebo. In addition, 87 percent of patients who received evolocumab reduced their LDL cholesterol level to 70 mg/dL or lower, 67 percent reduced their LDL cholesterol level to 40 mg/dL or lower and 42 percent reduced their LDL cholesterol level to 25 mg/dL or lower.

The researchers mentioned that the study’s main limitation was that it had a shorter follow-up period than previous lipid-lowering trials. They noted that the study was originally scheduled to have a median follow-up period of approximately four years, but the event rate was approximately 50 percent higher than expected, so they had a shorter required duration of follow-up to accrue the prespecified number of events.

“With this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely,” Sabatine said in a news release. “I think these results are very good news for patients with atherosclerotic disease, who remain at high risk for these events.”