New data might have led to a different result for Amarin fish oil drug, FDA panelists say
Two members of an expert panel that recommended the Food and Drug Administration approve a fish-oil-based heart drug, Vascepa, said recently released data would have led them to reconsider their votes.
The concern stems from the suggestion that a substantial benefit the drug showed in a large clinical trial might have been in part due to harm caused by the placebo it was compared to in the study. A new analysis published in the medical journal Circulation on June 28 indicated that in the group that received the placebo, which contained mineral oil, volunteers had blood test results that might indicate heightened risk of heart attacks and strokes.
The experts’ comments raise concerns not only about the use of one drug, but about processes at the FDA and the future of fish-oil-derived medicines as heart treatments. They are a further headache for the drug’s maker, Amarin, which is also facing generic competition in the U.S. for Vascepa, its only product.
“Certainly this changes my interpretation of the potential harms of mineral oil placebo,” said James de Lemos, a professor of medicine at UT Southwestern in Dallas. He is an editor at Circulation but was not involved in the review of the recent paper. “This recent paper clearly shows that this mineral oil placebo is not inert, it’s not a placebo. If we had known this during the panel, that would have affected our assessment of the study result.”
De Lemos added: “As a clinician, it really leaves me at a loss. I really don’t know what to do with this drug anymore.”
Marvin Konstam, the chief physician executive of the CardioVascular Center at Tufts University School of Medicine, echoed those concerns.
“I think I might well have voted differently,” Konstam said. “I’ve been on innumerable panels and innumerable data monitoring committees. I can’t remember a situation like this where retrospectively there was a question about the risk of the placebo.”
The November 2019 hearing of the FDA advisory committee had a big impact on Vascepa use. Between 2019 and 2021, prescriptions for the drug or its generic counterpart increased 45% to 3.3 million, according to data from health information firm IQVIA. In the first five months of 2022, 30% of prescriptions were generic.
At that advisory committee meeting, 16 panelists voted unanimously to recommend the agency approve Vascepa to reduce the risk of first heart attacks and other heart problems in patients with high triglycerides.
It was known then that patients receiving the mineral oil placebo had increased in LDL, the so-called “bad cholesterol,” and C-reactive protein, or CRP, another blood test result that is an indicator of cardiovascular inflammation, which also indicates a risk of heart attacks and strokes. But the FDA presented its own analysis arguing that the changes in LDL and CRP could not explain the substantial benefit seen in the Vascepa study.
“I think most of us in the room were in virgin territory, and we’re taking in the information as we did, and we all had a certain trust in the FDA,” Konstam said. “And I had a willingness to accept what came out of their assumptions as pretty reasonable.”
But Konstam said that even as the panel ended he began to have doubts about whether the mineral oil placebo could explain all or some of the drug’s benefits. Perhaps a small, daily dose of mineral oil could be interfering with the absorption of cholesterol-lowering medicines. But what, Konstam wondered, if it were interfering with other medicines, too?
Other hypothetical explanations have been offered, too. Mouse data indicate that chronic mineral oil use may allow toxins produced by bacteria in the gut to enter the bloodstream. The Cleveland Clinic’s Steven Nissen, who is a critic of the use of mineral oil in the Amarin study, is a co-author of the paper.
Whatever the reason, Konstam said, modeling how much of the result of the study is due to mineral oil and how much is due to a benefit from Vascepa is a difficult prospect, and only becomes more difficult with more data. There is a vast amount of data on how changes in LDL affect heart risk, but it is more difficult to create a model for some of the other blood test results that were heightened in the results published in Circulation.
For instance, in the mineral oil group, blood levels of interleukin-1ß, a protein involved in inflammation, increased 28.9%. In a previous study by the researcher who led the new analysis, Paul Ridker of Brigham and Women’s Hospital in Boston, a drug that targeted Interleukin-1ß reduced the risk of heart attacks and strokes by 14%.
“Whether that negates the results of the study or mitigates the results to sort of discount the effect, who knows,” said de Lemos. “I think the trial result was always implausibly large. The magnitude of the risk reduction was frankly very surprising. My guess is it’s somewhere in between, that there may be a beneficial effect of the drug that’s magnified by the effects of the mineral oil placebo.”
In a statement, Amarin said it was “very surprised” that members of the advisory panel would comment based on the Circulation paper and said that the company stands behind its pivotal trial of Vascepa.
In an interview, Steve Ketchum, Amarin’s president of R&D, said that the company does not believe that there is new evidence that mineral oil, not Vascepa, could explain the differences seen in the study. He said that in absolute terms, the blood test results in the Circulation study did not change enough to explain the benefit. “We think that it’s also important to look at the absolute changes and in our view they are small and they do not correlate to any meaningful changes in outcomes,” Ketchum said.
Ketchum also said that important analyses were not accepted as part of the circulation manuscript. He said those concerned by the results “do not have the benefit of seeing the more complete information. That’s what gives us confidence.”
In an editorial accompanying the Circulation paper, Robert Harrington, chairman of the department of medicine, wrote: “The hard reality is that we are left with uncertainties and the questions raised by use of the mineral oil as placebo can only be answered by another [randomized controlled trial].”
Another member of the panel, Susan Ellenberg from the University of Pennsylvania, said that her expertise was in statistics and she would defer to experts in cardiology on the new effect, but that any analysis could, of course, have affected her vote. Several other members of the panel did not return requests for comment.
Scientists have thought fish oil preparations might reduce heart disease for decades, since experts hypothesized that the omega-3 fatty acids in fish explained surprisingly low rates of heart attacks in the Inuit. Even that claim has come to be questioned since. Many clinical trials have failed to show a benefit of various fish oil preparations. One that did, conducted in Japan, used a preparation that only included one very specific omega-3 fatty acid – eicosapentaenoic acid, or EPA.
Amarin decided to develop its own EPA-containing fish oil supplement more than a decade ago. Initially, like other prescription fish oil supplements, the drug was approved to treat patients with very high levels of triglycerides, or particles of fat in the blood. At very high levels, triglycerides can cause pancreas problems; lower elevated levels may mean patients have an increased risk of heart disease.
Issues about the mineral oil placebo were raised at FDA advisory panels that discussed earlier trials. But Amarin chose to use the mineral oil placebo in its major trial, with the FDA’s approval, because it closely resembled Vascepa in appearance.
De Lemos and Konstam, along with other cardiologists, say that another clinical trial may be required to settle questions of Vascepa’s benefit. But it seems unlikely that Amarin will conduct such a study, which would cost hundreds of millions of dollars. The company likely does not have the money.
Amarin’s shares on the NASDAQ have fallen more than 94% from their December 2019 peak.
“The FDA is aware of the publication,” an agency spokesperson said in a statement. “In general, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
But questions around Vascepa also have larger ramifications for the FDA because in recent years there have been cases where critics have worried that the FDA has gone too easy on companies, resulting in big unanswered questions about new drugs. For instance, a new muscular dystrophy made by Sarepta was approved in 2016 based on levels of an important muscle protein; six years later, data confirming the drug’s benefit are still not available.
Last year, the agency overruled one of its advisory committees to grant accelerated approval to Aduhelm, a new Alzhiemer’s drug. Before the advisory committee meeting, the FDA had taken the unusual step of presenting a single document from both the agency and the drug’s maker, Biogen, instead of two independent analyses of the data.
AI
