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Will mineral-oil placebo torpedo Vascepa's game-changing CV label? FDA committee will decide.

An FDA advisory committee will scrutinize a mineral-oil placebo used in a CV outcomes trial for Amarin's Vascepa. (Amarin)

Just two days before Amarin faces a pivotal FDA advisory committee to expand its label for fish-oil derivative Vascepa, the FDA has some questions about the key trial's placebo control—namely, whether it skewed the drug's "landmark" cardiovascular outcomes results. 

FDA documents posted ahead of Thursday's meeting show staff reviewers have zeroed in on the mineral oil placebo used in Vascepa's phase 3 Reduce-It trial. The choice of placebo may have flattered Vascepa's performance, said John Sharretts, acting deputy director of the FDA's division of metabolism and endocrinology products, in a briefing for Thursday's advisory committee meeting.

The trial tested Vascepa as an add-on to statin therapy, compared with the mineral oil placebo paired with statins. Sharretts said the FDA was examining whether that mineral oil interfered with patients' ability to absorb statin therapy, artificially raising patients' cholesterol levels and skewing Vascepa's results in the trial.

However, Sharretts noted that the FDA's own study of mineral oil's effects on statin absorption was "inconclusive." 

"Due to lack of certain key measurements, we could neither rule out the possibility that mineral oil––at least to some extent––interfered with statin absorption, nor estimate the magnitude of LDL-C or other biomarker increase that could be attributed to such an interaction," Sharretts wrote in the review documents.

He went on to instruct the committee to weigh the questions. "From the scientific perspective, therefore, it remains necessary to consider what impact the increase in LDL-C and other biomarkers had on CV outcomes, Sharretts said.

In a third-quarter earnings call with analysts last week, Amarin CEO John Thero downplayed the threat of the mineral oil line of questioning, arguing that any effect on statin absorption it would be negligible—if it's present at all. 

The FDA's "exploratory analysis indicates the effect, if any, of mineral oil ... is numerically small and unlikely to change the overall conclusion of treatment benefit," Thero said, according to a transcript.

So far, market watchers have agreed with Thero. On the heels of the FDA's document posting, Amarin's stock price opened up 15% on Tuesday to $19.68, underscoring investors' lack of concern about the committee's talking points. 

In the FDA briefing, Sharretts also outlined a number of label possibilities that should cheer Amarin shareholders, including treating patients with established CV disease or expanding treatment to high-triglyceride patients at risk of CV disease.

Cantor analyst Louise Chen said in a Tuesday note to investors the FDA's talking points showed the mineral-oil concern was "overdone" and forecast that the advisory committee meeting would mostly indicate how expansive Vascepa's label could be pending approval in December. 

That's good news for Amarin, which had expected a label decision by the FDA in September before the administration opted for an advisory committee instead. Amarin has already been forced to delay its plan to double its sales force to 800 in anticipation of Vascepa's new label. 

Apart from original Reduce-It data released in October 2018 showing the 25% CV risk cut, Amarin released follow-up data from that trial Monday showing even higher CV risk reduction in a pre-specified subgroup. Vascepa posted a 31% relative risk reduction and 6.5% absolute risk reduction in the first occurrence of a major CV event, and a 30% relative and 2.6% absolute risk reduction in all-cause mortality in that group.

Written by: Kyle Blankenship |

Published on: Nov 12, 2019 9:07am

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