November 14, 2019
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FDA panel unanimously supports CV event risk reduction indication for icosapent ethyl

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The Endocrinologic and Metabolic Diseases Advisory Committee of the FDA voted 16-0 in favor of the safety and efficacy of icosapent ethyl, based on available data, to support its approval for an indication to reduce risk for CV events.

“Even with all the caveats, I’m still comfortable with this being approved for both primary and secondary prevention,” Susan S. Ellenberg, PhD, professor of biostatistics and of medical ethics and health policy at University of Pennsylvania Perelman School of Medicine, said during a discussion after the vote. “I think that if there’s sufficient hesitation in the community about the primary prevention indication, that may show up in terms of reluctance to prescribe it. There may be motivation then to do another trial. I think it would be ethical to do another trial even if the drug is approved. I think there’s certainly examples where that’s been done in the past. I think it would be a good idea to have some kind of postmarketing study or maybe an observational cohort.”

The meeting of the committee was held to discuss the risks and benefits of icosapent ethyl (Vascepa, Amarin) with regards to a supplemental new drug application. If approved, icosapent ethyl would now be indicated to reduce the risk for CV events in addition to statin therapy in adults with elevated triglycerides — greater than 135 mg/dL — and other CVD risk factors based on results from the REDUCE-IT trial. The drug was originally approved in 2012 for use with diet for the reduction of triglycerides in adults with severe hypertriglyceridemia, defined as greater than 500 mg/dL.

“Elements that informed [my vote] were albeit one study, one that was large with a large degree of internal validity and I would argue a large amount of external validity,” panel member Walter K. Kraft, MD, professor of pharmacology, medicine and surgery at Thomas Jefferson University in Philadelphia, said after the vote.

As Healio previously reported in November 2018, the REDUCE-IT trial found that icosapent ethyl was superior to placebo for reducing risk for ischemic events in patients with elevated triglycerides at high CV risk despite statin therapy. In March 2019, new data from the REDUCE-IT trial demonstrated a 30% reduction in total ischemic events, including first and subsequent events, in high-risk patients with elevated triglycerides.

Before the vote, the committee discussed three questions during the meeting. Regarding interpretation of the REDUCE-IT trial, there was a consensus that the benefit in patients with high risk and for secondary prevention was clear, but the benefit for primary prevention was not as clear. The committee also agreed that an indication for CV death would not be justified. Questions remained about the long-term effect of mineral oil, which may require further studies.

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Another question focused on the new safety findings: increased risk for atrial fibrillation/atrial flutter and bleeding events. The committee agreed that the risk for AF and atrial flutter is something that can be monitored and treated, although the risk was increased in patients who previously had either of the conditions. Further studies may be needed that focuses on minor bleeding, which could be addressed by postmarket surveillance, panel members said.

The last question was dedicated to the indication itself. The committee had some debate on the use of icosapent ethyl for secondary prevention vs. primary prevention. Most members thought that age, triglycerides and LDL should be limited to what was established in the REDUCE-IT trial.

Industry, FDA presentations

The FDA has several concerns with regards to results from the REDUCE-IT trial, including that it was a single trial; the observed patterns of lipid and inflammatory biomarkers, which may have shown an interaction of mineral oil with statins; the robustness of the data, and the appropriate indicated population beyond patients with established CVD, Jay Sharretts, MD, acting deputy director of the division of metabolism and endocrinology products for the office of Drug Evaluation II and of the Office of New Drugs for the FDA, said during the Agency’s introductory remarks.

Deepak L. Bhat

Cardiology Today Editorial Board Member Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs and professor at Brigham and Women’s Hospital and Harvard Medical School, and study chair and principal investigator of the REDUCE-IT trial, addressed these concerns during a presentation on behalf of Amarin. He mentioned how the mineral oil placebo was selected in conjunction with FDA input based on the need to match the consistency and color of icosapent ethyl, and that it had similar effects on patients compared with icosapent ethyl.

“Regardless of how you look at it, overall, the 30,000-foot view is that this drug was tolerated as well as placebo and was as safe as a placebo,” Bhatt said during his presentation. “On the flip side, overall, the mineral oil placebo was not causing any evident harm either.”

Although there was an increase in minor bleeding associated with icosapent ethyl in the REDUCE-IT trial, Bhatt mentioned it did not show an increase in major bleeding.

“As someone who has done a number of antithrombotic trials through the years, ... there is a small increase in minor bleeding, but no significant excess in the forms of bleeding we worry about the most such as gastrointestinal, intracranial or fatal bleeding, including in those on dual antiplatelet therapy or on anticoagulants,” Bhatt said during his presentation. “As a practicing physician, I think the REDUCE-IT trial shows that icosapent ethyl is an extremely useful addition to our armamentarium for cardiovascular risk reduction across the continuum of secondary prevention and high-risk primary prevention. It’s a drug that’s easy to take, [has] side effects that can be addressed in labeling and is generally as well tolerated as a placebo.”

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Ann Marie Navar, MD, PhD, assistant professor of medicine and member in the Duke Clinical Research Institute at Duke University School of Medicine and Cardiology Today Next Gen Innovator, presented on clinical perspectives on behalf of Amarin. She mentioned that the increased risk for bleeding and AF found in the REDUCE-IT trial “can be adequately detected and then managed in the clinical setting.”

She also discussed the potential impact an FDA approval of this expanded indication, saying, “I hope that with the approval of icosapent ethyl, I will have the ability to offer this therapy to my patients immediately to start to further reduce their risk of important cardiovascular events.”

Presentations by the FDA addressed its concerns and concluded that despite the increased risk for AF and bleeding events with icosapent ethyl compared with placebo, the drug has a favorable benefit-risk profile. In addition, the potential effect with mineral oil as a placebo may not have as big of an impact as initially believed.

“We therefore concluded that the observed LDL-C increase in placebo patients is unlikely to render the study conclusion on the primary endpoint invalid since a 20% increase is needed to tip the study conclusion,” Roberto Crackel, PhD, mathematical statistician in the division of biometrics II in the Office of Biostatistics and of the Office of Translational Sciences (OTS) at the FDA, said during the FDA’s presentation.

Potential implications

If approved, icosapent ethyl has the potential to address a serious unmet need, according to the committee.

“There was a favorable safety profile, and this compared with an unmet medical need has the potential given the number of people with the underlying condition to have a large societal impact for the indication of secondary prevention is clear,” Kraft said after the vote. “For primary prevention, I would argue that there is also not a risk for extending too far, but not extending the indication far enough when you think about the societal need.”

Michael Miller

Healio spoke with Michael Miller, MD, professor of cardiovascular medicine, epidemiology and public health and director of the Center for Preventative Cardiology at University of Maryland School of Medicine in Baltimore, before the meeting about the importance of this potential approval.

He said, “[If approved,] it would be an important step towards trying to further reduce the risk of cardiovascular disease in this particularly high-risk group. ... We’ve known that a patient with high triglycerides are at increased risk. Now we finally have an established therapy to help reduce their excess risk.”

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“Today, we moved an important step closer to potentially helping millions of patients who are at risk for cardiovascular events despite being on standard-of-care statin therapy,” John F. Thero, president and chief executive officer of Amarin, said in a press release from the company. “Vascepa is positioned to be the first approved treatment to reduce cardiovascular events in the group of at-risk patients studied in the landmark REDUCE-IT clinical trial.” – by Darlene Dobkowski

For more information:

Michael Miller, MD, can be reached at Cardiovascular Medicine, 110 South Paca St., Suite 7N-124, Baltimore, MD 21201; email: mmiller@som.umaryland.edu; Twitter: @mmillermd1.

Disclosures: The REDUCE-IT trial was funded by Amarin Pharmaceuticals. Bhatt reports he received research funding from Amarin to Brigham and Women’s Hospital for his role as a study chair and principal investigator of the REDUCE-IT trial. Crackel and Sharretts are employees of the FDA. Miller reports he is a steering committee member for the REDUCE-IT trial and a scientific advisor for Amarin. Navar reports she received research support to Duke University for research studies of triglyceride epidemiology and personal fees including advisory board participation from Amarin. Thero is an employee of Amarin. The members of the Endocrinologic and Metabolic Diseases Advisory Committee report no relevant financial disclosures.