FDA Advisors Recommend CVD Event Reduction Claim for Icosapent Ethyl

(UPDATED) Members of the US Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted unanimously today in favor of an expanded indication of icosapent ethyl (Vascepa; Amarin) for the reduction of cardiovascular events.

Icosapent ethyl, a prescription-grade omega-3 fatty acid, has been proposed as a treatment for adult patients with triglyceride levels greater than 135 mg/dL and additional risk factors for cardiovascular disease. In total, 16 advisory committee members stated that the study sponsor provided sufficient evidence of efficacy and safety to support the CVD event claim.

The proposed indication is based on results from REDUCE-IT, a large cardiovascular outcomes trial published almost exactly a year ago in the New England Journal of Medicine. As reported by TCTMD at that time, treatment with icosapent ethyl on top of statin therapy reduced the risk of the primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina, by 25% compared with placebo. Treatment with icosapent ethyl reduced the risk of the key secondary endpoint—cardiovascular death, nonfatal MI, or nonfatal stroke—by 26%.

EMDAC chair Kenneth Burman, MD (Medstar Washington Hospital Center/Georgetown University, DC), said that even among statin-treated patients who have achieved adequate LDL cholesterol-lowering, “there is a definite need for additional therapeutic approaches.” While “bothered a little bit” that the mechanism of action for reducing CVD events with icosapent ethyl isn’t clearly defined, Burman said the evidence suggests the drug is safe, effective, and clearly needed.

Despite Win, Issues Raised by EMDAC Members 

The advisory committee grappled with numerous issues throughout the daylong meeting, including whether to only approve icosapent ethyl for patients with established CVD given that subgroup analyses from REDUCE-IT showed the treatment benefit was largest (and statistically significant) in high-risk patients with existing disease. In contrast, in the primary prevention cohort—those with diabetes and at least one major cardiovascular risk factor—treatment with icosapent ethyl did not significantly reduce the risk of the primary endpoint.

“In the secondary prevention population, the data are overwhelming and convincing,” said committee member James de Lemos, MD (UT Southwestern Medical Center, Dallas, TX). “They are wholly unconvincing in primary prevention. We never really got the math, but it’s not really clear to me that there is a net benefit in the primary prevention cohort. I don’t think we should reward sponsors for enrolling small subsets of primary prevention patients in secondary prevention trials, reporting an interaction that’s not significant, and then given them a broad indication for which we really don’t have enough evidence.”

de Lemos said that if the drug gains a broad indication from the FDA to include primary prevention patients, there would be no incentive to further study it in a randomized trial in patients without CVD.

I don’t think we should reward sponsors for enrolling small subsets of primary prevention patients in secondary prevention trials, reporting an interaction that’s not significant, and then given them a broad indication for which we really don’t have enough evidence. James de Lemos

Marvin Konstam, MD (Tufts Medical Center, Boston, MA), also said that he remained “queasy” about the benefit of icosapent ethyl in primary prevention. However, while subgroup analyses are “fun to look at” and drive future research, his inclination is to view REDUCE-IT as a whole. “Taking it in its entirety, I would say that the higher the risk of the patient, the greater the benefit you get overall,” he said. “As you go down in risk, you’re going to see less benefit."  

In the end, the advisory committee, like Konstam, relied on the totality of the evidence and chose to recommend an expanded indication for all adult patients with elevated triglyceride levels (> 135/dL) and additional risk factors for CVD without regard for age, diabetes status, and LDL cholesterol levels. Many noted that icosapent ethyl is already available to physicians and patients without ASCVD, and suggested the updated FDA label, if it comes, could include language to highlight a greater benefit in secondary prevention.

Other Issues in REDUCE-IT  

While REDUCE-IT was largely hailed as a landmark trial when presented and published in 2018, there were a couple of flies in the ointment. One question raised was whether mineral oil, which was given as the placebo, was truly inert. There were concerns mineral oil interacted with statin therapy and contributed to an increase in LDL cholesterol and high-sensitivity C-reactive protein (hs-CRP) levels in the placebo group. In the trial, LDL levels in the placebo arm increased by roughly 10% from baseline while hs-CRP increased by more than 30%.

FDA reviewers grappled with this increase in lipids and inflammatory biomarkers, noting the same pattern was observed in the ANCHOR trial with icosapent ethyl. The reviewers performed multiple analyses in an effort to determine if the increase in LDL cholesterol and other biomarkers was due to the placebo and if it had any impact on CVD outcomes. Even in their “worst-case scenario” analysis, they concluded that the difference in LDL between the two study arms “could not account for the positive cardiovascular outcomes.”   

While committee members debated the potential role mineral oil might have played in the trial, most were satisfied with the reviewers’ conclusion, as well as analyses from Amarin showing similar results.

Committee member Cecilia Low Wang, MD (University of Colorado School of Medicine, Aurora), said the data presented showed a real signal of benefit of icosapent ethyl, specifically in the secondary prevention subgroup, “and the mineral oil probably affected the magnitude of that effect so that we probably have more of an effect in the trial than what’s real.” While that sentiment was shared by other committee members, they all remained convinced of the drug’s efficacy as studied in REDUCE-IT.

The advisory committee also debated the potential risks of icosapent ethyl, noting the omega-3 fatty acid was associated with an increased risk of atrial fibrillation/atrial flutter and bleeding events. Ultimately, the panel concluded that the benefits of treatment outweighed the risks and that these adverse events could be managed clinically and with patient/physician education.

When I move myself back to practice, it’s diet, it’s exercise, it’s smoking cessation, and it’s a statin. Now, for the first time, we have something else to add to that. Paul Ridker

Several high-profile cardiologists spoke during the session, all in support of an expanded label for icosapent ethyl. Paul Ridker, MD (Brigham and Women’s Hospital, Boston), who addressed the advisory committee’s concerns about the rise in hs-CRP with mineral oil, praised the REDUCE-IT trial and welcomed the addition of icosapent ethyl to the toolbox for combating CVD risk.

“When I move myself back to practice, it’s diet, it’s exercise, it’s smoking cessation, and it’s a statin,” said Ridker. “Now, for the first time, we have something else to add to that. At the end of the day, I think that’s really what this is all about.”

Several major societies have already made room in various guidelines, scientific statements, and advisories for icosapent ethyl, including the American Diabetes Association, American Heart Association, National Lipid Association, and the European Society of Cardiology/European Atherosclerosis Society.