In documents released Tuesday ahead of an advisory committee meeting on November 14, FDA staff said the agency's tests were inconclusive on whether the use of mineral oil as placebo in Amarin's REDUCE-IT  cardiovascular (CV) outcomes trial for Vascepa (icosapent ethyl) could have skewed results in the company's favour. Shares in the drugmaker jumped as much as 21% on the news.
Vascepa was approved  by the FDA in 2012 to reduce triglyceride levels in adults with severe hypertriglyceridaemia. Amarin is seeking  to extend the indicated use of the fish-oil-derived drug based on the REDUCE-IT results to include the prevention of CV events in statin-treated patients with controlled LDL cholesterol, but persistent elevated triglycerides and other CV disease risk factors.
The REDUCE-IT trial enrolled 8179 statin-treated adults with established CV disease or with diabetes and other risk factors. Participants were randomly assigned to receive Vascepa twice daily or a placebo containing mineral oil, and were followed for a median 4.9 years. In November last year, the company unveiled  detailed results showing that Vascepa was associated with a significant 25% relative risk reduction versus placebo in first occurrence of major adverse cardiovascular events (MACE) on a five-point primary composite endpoint.
However, the data also revealed that patients taking placebo saw their LDL levels rise 10%, which was 6% more than for the Vascepa group. The authors suggested at the time that the mineral oil in the placebo might have affected statin absorption in some patients, leading to the different outcomes in the two study arms. Although they also pointed out that the "relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25% lower risk observed with Vascepa."
In the FDA briefing documents, agency reviewers said they conducted a series of post hoc analyses to explore the potential mineral oil effect in REDUCE-IT, concluding "we do not agree that placebo influenced the...results." They added that "even if we are wrong, such potential influence cannot reasonably be estimated to account for a substantial portion of overall robust and consistent REDUCE-IT findings, including a 25% [relative risk reduction] in the primary endpoint that is consistent with the observed risk reduction in the JELIS study [of a similar medicine conducted in Japan], which did not administer a mineral oil placebo."
The FDA staff report also highlighted "a concerning safety signal" around atrial fibrillation/flutter, which happened significantly more often in the Vascepa group than placebo, occurring at rates of 5.8% and 4.5%, respectively, while the incidences of atrial fibrillation/flutter requiring hospitalisation occurred at respective rates of 3.1% and 2.1% between the two groups. However, agency reviewers noted that the observed increase in atrial fibrillation/flutter in REDUCE-IT is "consistent with trends observed for other omega-3 fatty acids," adding that while atrial arrhythmias can contribute to congestive heart failure (CHF), there were no changes in newly emergent CHF in the study. In addition, the documents noted that in the study, 11.8% of patients in the Vascepa arm experienced a bleeding event, such as gastrointestinal bleeding or contusions, versus 9.9% in the placebo arm.
Commenting on the news, Leerink analyst Ami Fadia said "the FDA has clearly taken its stance that mineral oil had minimal impact, which, in turn, likely makes it less likely the Vascepa discussion would go south on this point." She suggested that the main topic to be discussed at the upcoming advisory panel meeting is likely to be "how broad a label can Vascepa potentially get."
Earlier this week, Amarin unveiled  results from a US subgroup analysis of the REDUCE-IT trial, showing that Vascepa cut the relative risk of first occurrence of five-point MACE by 31% versus placebo. The FDA is expected to render its decision on the Vascepa label expansion by December 28, with its original goal date of September 28 pushed back by the announcement  earlier this year to hold an advisory committee meeting (for related analysis, see ViewPoints: Amarin caught off-guard by Vascepa AdCom ).