Amarin Heads Into Vascepa Expansion Labeling Talks After Positive US FDA Panel Review
Executive Summary
Focus of negotiations with agency will be on breadth of population encompassed by a cardiovascular risk reduction indication; most advisory committee members favored a broad claim for secondary and primary prevention reflecting the REDUCE-IT trial population, but some strongly opposed an indication that includes patients without established CV disease.
Amarin Corp. PLC could be facing extensive labeling negotiations with the US Food and Drug Administration given that an advisory committee's strong endorsement of a cardiovascular risk reduction claim for Vascepa (icosapant ethyl) came with misgivings about the appropriate target population for the triglyceride-lowering drug.
On 14 November, the Endocrinologic and Metabolic Drugs Advisory Committee unanimously recommended approval of Vascepa to reduce the risk of CV events based on the results of the 8,179-patient REDUCE-IT outcomes trial. (Also see "Amarin’s Vascepa Positioned For Broad CV Risk Reduction Claim Following US FDA Panel Nod" - Pink Sheet, 14 Nov, 2019.)
However, the 16-member expert panel was more divided on the target population for the new indication.
Even if the approved indication were to encompass primary prevention, the panel’s feedback and agency reviewer concerns about a disconnect between the proposed indication and the REDUCE-IT study population mean labeling could be more restrictive than Amarin has proposed.
Ten members favored approval for secondary prevention in patients with existing CV disease and primary prevention in diabetics with additional risk factors for CV disease. This recommendation was based on the overall efficacy results from REDUCE-IT, which consisted of patients with established CV disease (70%) and diabetics with at least one additional risk factor for CV disease (30%).
However, four panelists strongly opposed extending the claim to the primary prevention setting because they did not believe efficacy had been demonstrated in this lower risk population, while the remaining two panelists suggested they were on the fence.
Even if the approved indication were to encompass primary prevention, the panel’s feedback and agency reviewer concerns about a disconnect between the proposed indication and the REDUCE-IT study population mean labeling could be more restrictive than Amarin has proposed.
On The Brink Of Market Expansion
The advisory committee vote puts Amarin on the brink of a huge market expansion for its only commercialized drug, potentially opening the door to use by as many as 15m US patients, according to company estimates.
Vascepa, a purified ethyl ester of eicosapentaenoic acid derived from fish oil, has been approved since July 2012 for the narrow indication of reducing triglyceride levels in adults with severe (≥500mg/dL) hypertriglyceridemia.
The company now is seeking approval to reduce the risk of CV death, myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization as an adjunct to statin therapy in adults with elevated triglyceride levels (≥135mg/dL) and other risk factors for CV disease.
“We look forward to anticipated labeling discussions with the FDA, and we continue to prepare for the launch of Vascepa assuming FDA approval of our sNDA on or before the target PDUFA date of December 28,” the company said in a press release issued after the meeting.
Analysts were upbeat following the panel review.
In a same-day note, Jefferies analyst Michael Yee said the 16-0 positive vote for approval “is most important although predictably there was a (mixed) discussion about labeling. Our thesis and valuation are not based on specific ‘details’ of a label as we think docs will use this widely across patients.”
“Predictably there was a (mixed) discussion about labeling. Our thesis and valuation are not based on specific ‘details’ of a label as we think docs will use this widely across patients.” – Jeffries’ Michael Yee
On the panel’s debate over whether the primary prevention population should be included or whether labeling should be limited to secondary prevention only, Yee said: “This is nuanced because the actual label would not say ‘primary’ vs ‘secondary’ and FDA could work a label that just says established CV disease and let docs use it in patients deemed relevant based on the study (although payors might limit it).”
Yee noted that professional society guidelines that recommend Vascepa’s use for CV risk reduction do not differentiate between primary and secondary prevention.
SVB Leerink analyst Ami Fadia said that while a vote in favor of approval was likely expected following the release of the agency’s briefing documents two days earlier, “we also believe the AdCom was open minded about an indication for use in primary prevention.”
“However, the AdCom did not hammer out many specifics on inclusion criteria for primary prevention, so we believe Amarin will be in for a robust discussion with the FDA on just how the indication could read,” she said.
Fadia estimates the sNDA approval could increase Vascepa’s total market population from approximately 600,000 patients to approximately 10m, with sales potentially exceeding $4bn at peak in 2028.
Jeffries’ Yee estimates 5m-15m patients would meet the REDUCE-IT enrollment criteria and “even just 1m patients on therapy would be $2.5bn in sales in USA.”
Vascepa revenues for the first nine months of 2019 were $285.3m, up 89% over the prior year period. Amarin is in the process of doubling the size of its US sales force from approximately 400 to 800 sales professionals in anticipation of adding the broader indication. (Also see "Amarin's Vascepa Momentum Builds Ahead Of Next Week's FDA AdComm" - Scrip, 5 Nov, 2019.)
Concerns Warranting Public Discussion
The breadth of the indication was a key issue heading into the advisory committee meeting, the scheduling of which came as a surprise to Amarin and its investors late in the application’s priority review, resulting in a three-month extension in the user fee date. (Also see "An AdComm After All: Amarin's Vascepa Labeling Update Now Delayed By FDA " - Scrip, 8 Aug, 2019.)
The FDA review team generally agreed with Amarin’s conclusions on the major efficacy and safety findings from REDUCE-IT.
Compared to placebo, Vascepa reduced the risk of the primary endpoint – a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization and coronary revascularization – by 25%, a statistically significant finding in the overall REDUCE-IT population. Vascepa also reduced the risk of the key secondary endpoint – the three-point composite of CV death, nonfatal MI and nonfatal stroke – by 26%, also statistically significant.
Amarin’s drug reduced the risk of the individual components of the primary endpoint and secondary composite endpoints, and all results were statistically significant per the prespecified testing plan except for the final endpoint in the hierarchy, all-cause mortality, which trended favorably for Vascepa.
Nevertheless, John Sharretts, acting deputy director of the FDA Division of Metabolism and Endocrinology Products, said the agency had several concerns that warranted a public discussion. These included:
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Reliance upon a single trial for a first-in-class indication;
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Observed patterns of lipid and inflammatory biomarker changes in the placebo group that suggested a possible interaction between the mineral oil placebo used and statins, which could make Vascepa look more effective than it really is;
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Robustness of the data to support all individual components of the composite endpoint, particularly CV death; and
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Breadth of Amarin’s proposed indication.
Distinguishing Between Secondary And Primary Prevention
The FDA said REDUCE-IT provides strong evidence that Vascepa is beneficial in patients with established CV disease and persistently elevated triglycerides despite optimized statin therapy (the so-called secondary prevention group) and appears to provide benefit in a subset of patients with diabetes, additional CV risk factors and hypertriglyceridemia (the primary prevention group). However, “it is arguable how broadly this second population should be drawn,” the agency’s briefing document states. (Also see "Amarin’s Vascepa: US FDA Panel To Scrutinize Breadth Of CV Risk Reduction " - Pink Sheet, 12 Nov, 2019.)
In the Vascepa arm, the effect size for the primary endpoint was numerically lower for the primary prevention group versus the secondary prevention cohort (12% estimated risk reduction vs. 27%, respectively), with the benefit in the lower risk group not reaching statistical significance.
In addition, unlike the REDUCE-IT enrollment criteria, Amarin’s proposed indication is not limited by presence or absence of CV disease, diabetes in patients without CV disease, age, LDL-cholesterol or optimization of statin therapy, the agency said.
“As written, the indication for Vascepa would apply to a group of patients with a potentially different benefit/risk consideration than those studied in REDUCE-IT,” Sharretts said.
Amarin asserted it took longer for benefit to emerge in the primary prevention group, as would be expected. The risk/benefit profile for primary prevention is most positive in diabetics at highest risk of CV events, and a 10-year atherosclerotic CV disease (ASCVD) risk score can be used to identify these individuals for Vascepa treatment, Amarin and its experts told the committee.
The risk/benefit profile for primary prevention is most positive in diabetics at highest risk of CV events, and a 10-year ASCVD risk score can be used to identify these individuals for Vascepa treatment, Amarin said.
Panelists who favored a broad indication encompassing primary prevention did so on the basis of the robust results in the overall trial population, the underlying biology of CV disease, and the desire not to make at-risk patients wait until they have a heart attack before they can get Vascepa.
The panel’s consumer representative, Anna McCollister-Slipp, framed the issue as one of access.
“Given the significant adverse events that you see with statins and the significant need for cardiovascular risk reduction, and maybe not slam-dunk data but pretty good data about potential benefit, my inclination is to let something go onto the market that does have demonstrated benefit for which the data may not be perfect but certainly can be compelling, and let’s see what happens in the clinical setting,” McCollister-Slipp said.
“Indications matter in terms of access,” she continued, referencing open public hearing testimony from health care providers and patients who described their experience with payers declining to cover Vascepa for what currently is an off-label use. “How the agency decides to approve a medication has real implications on what patients have access to and what tools are available to them and their physicians.”
Marvin Konstam, a cardiologist at Tufts Medical Center, supported extending the indication to the primary prevention setting but said labeling should reflect there is less benefit in lower risk populations, particularly in the context of risks that include bleeding and atrial fibrillation/flutter.
“I would at least want to think about working into the labeling the issue of risk/benefit as you go to lower risk populations, and you’re not lowering the risk of bleeding,” Konstam said. “When clinicians are thinking about this, I think they should be thinking that as you go to that low risk population the risk may be catching up to the benefit.”
Those who opposed a broad indication said they were not convinced the drug was effective for primary prevention.
“In the secondary prevention population the data are overwhelming and convincing … but they are wholly unconvincing in the primary prevention” population, said James De Lemos, a cardiologist at UT Southwestern Medical Center.
Labeling Limitations
Numerous panelists said the indication should more closely match the inclusion and exclusion criteria of REDUCE-IT, including a requirement for either established CV disease or diabetes with other CV risk factors. Some panelists also favored a higher triglyceride threshold and minimum age limit, as well as language stating that patients should be on maximally tolerated statin therapy.
Several panelists recommended against a claim for reduction of CV death because the magnitude of benefit on that endpoint was not as large or statistically robust as other components in the five-point composite primary endpoint.
As for the mineral oil issue, panelists generally agreed with the agency’s view that while the potential for an interference with statins could not be excluded, any impact on the trial’s efficacy results would have been small and not enough to invalidate the otherwise robust efficacy findings.
Bleeding, A-fib Risks
Although there was increased bleeding with Vascepa in REDUCE-IT, there was no increase in the most worrisome types of bleeding, such as gastrointestinal or central nervous system bleeds, Amarin said. There was a statistically significant increase in atrial fibrillation/flutter, but the risk of more worrisome downstream effects, such as MI and stroke, were reduced, the company said.
The committee said the risks of bleeding and atrial fibrillation did not outweigh the CV benefits seen in REDUCE-IT, and these safety concerns could be addressed in labeling and further studied after approval.
“I’m not very concerned about the A-fib issue. I don’t think it has any major impact on the long-term effects in the population,” Konstam said. “I’m uneasy about the bleeding and … I would consider how do you mitigate that? How does the labeling read? Should there be a warning about that?”