New Vascepa Approval Opens Up Treatment to Millions

The newly approved US indication for icosapent ethyl (Vascepa, Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.

The high-dose, purified eicosapentaenoic acid (EPA) product was approved last week by the US Food and Drug Administration (FDA) for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.

The approval is based largely on the REDUCE-IT trial's finding of a 25% reduction in risk for major adverse cardiovascular events vs placebo. The FDA stated that the approval is the first for an agent with this specific indication.

Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval "will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events."

The drug was unanimously recommended for approval by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary prevention population, who made up just 30% of patients in the study.

Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.

In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.

The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low high-density lipoprotein cholesterol, high C-reactive protein, body mass index above 25 kg/m², renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Ketchum said.

"So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes."

Craig Granowitz, MD, PhD, chief medical officer at Amarin, noted that: "It is difficult to precisely define the size of the population now eligible for Vascepa, but it is big."

He estimated that 38 million patients are on statins, of whom 12 million will have triglycerides over 150 mg/dL — and more than half of these will have established CVD or diabetes and multiple other risk factors. There are also millions more patients with a similar risk who are statin intolerant that would also be eligible for Vascepa, he added.

"Most Significant Event Since Statins"

Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as "the most significant event in the field of cardiovascular prevention since the introduction of statins nearly three decades ago."

He commended the FDA on "a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label," which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.

Bhatt, who is a professor of medicine at Brigham and Women's Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.

"The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels," he reported.

"In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort," Bhatt added. "On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria."

Multiple Billions in Sales

Amarin says it is expecting sales of Vascepa of around $700 million next year, mostly from the United States, and that beyond 2020 the drug could generate "multiple billions of dollars."

The drug is already on the market for patients with very high triglyceride levels and the company is not increasing the current price of about $300 a month, which it says is "relatively low compared to other new breakthrough drugs." However, it says it expects sales to grow from vastly increased volume based on the new indication.

The European approval application for Vascepa has recently been accepted for review, with a decision expected before the end of 2020.

Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association meeting, found the drug to be cost saving in the majority of cases. "That is something that is quite rare in cost-effectiveness research," he said.

"Now, the key challenge is to identify and treat appropriate patients," Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.

"I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use," he said. "Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl."

Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.

"The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit," Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, told theheart.org | Medscape Cardiology.

"We do not know if the key factor in the trial's success was the high-dose of EPA alone. In a year, we will likely have the results of the STRENGTH trial that looks at a different formulation of high-dose EPA with some [docosahexaenoic acid]," he added.

Some Still Unsure

But not everyone is in full agreement with the broad indication granted.

One expert who has reservations is James de Lemos, professor of medicine at UT Southwestern Medical Center in Dallas, Texas, who sat on the FDA advisory committee that assessed the drug last month.

"I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary prevention indication. We need an adequately powered randomized controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this," de Lemos commented to theheart.org | Medscape Cardiology.

"This is a slippery slope and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary and primary prevention patients, with the results driven by the secondary prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different," he added.

However, de Lemos acknowledged that he would use Vascepa for some high-risk primary prevention patients in his practice — those with diabetes, high triglycerides, and multiple risk factors. "I just wish we had more data coming so that I could be more certain of the benefit in this group," he said.

Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Blumenthal has disclosed no relevant financial relationships.

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