Any remaining hopes for an expanded indication for Amarin's Vascepa were largely dashed today by the FDA. Although it hasn't yet rejected the proposed indication, the FDA today essentially overturned the foundation of the application, leaving little doubt as to the ultimate fate of the proposed new indication. As veteran biotechnology reporter Adam Feuerstein tweeted:
"The chance of FDA approval for Anchor went from 0.00000001% to 0.00000000001%."
By way of background, as I reported two weeks ago, an FDA advisory panel recommended against an expanded indication for Vascepa, the purified EPA fish oil product from Amarin. Vascepa is currently indicated only for the relatively small number of people with severe hypertriglyceridemia (>500 mg/dl). The proposed new indication would have greatly expanded the patient population eligible to receive Vascepa to the 20% of the US population who have elevated triglycerides (>200 mg/dl) and existing CV disease or who are at high risk for CV disease.
The supplemental new drug application (sNDA) for the indication was based on the ANCHOR trial, which showed that Vascepa lowered triglycerides in the target patient population. The ANCHOR design was based on a special protocol assessment (SPA) agreement between Amarin and the FDA. On the basis of the SPA Amarin believed that if the trial demonstrated that Vascepa lowered triglycerides safely and effectively then it would gain the expanded indication. But SPAs are not ironclad contracts, and a series of clinical trials that came to completion following the start of the ANCHOR trial has placed in question the value of lowering triglycerides in this population.
Today Amarin disclosed that it had received written notification from the FDA that in fact the SPA was no longer valid:
...the FDA has rescinded the ANCHOR study special protocol assessment agreement because the FDA has determined that a substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began. Specifically, consistent with discussion at the Advisory Committee meeting, the FDA cited results from the ACCORD-Lipid and AIM-HIGH outcome trials, as well as the publicly presented results from the HPS2-THRIVE outcome trial, which the FDA stated in its October 29, 2013 notice to Amarin, fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). Thus, the FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL.
The PDUFA date for the Vascepa sNDA is December 20, but any hope that the FDA might reject the recommendation of the advisory panel now seems even more unlikely.
The Fate of REDUCE-IT
One additional uncertainty and potential source of controversy has emerged since the panel hearing. As reported by Matt Herper, after the FDA panel meeting Amarin executives raised the possibility that to save money the company would discontinue the ongoing REDUCE-IT trial, which is a large cardiovascular outcomes trial that was designed to provide a definitive answer to the question of the value of triglyceride lowering in people with triglyceride levels between 200-499 mg/dL.
In fairness to Amarin, the company is now caught between a rock and a hard place. It's unclear whether the company will have enough money to finish the trial. (Sales of Vascepa for the current limited indication are unlikely to improve after the panel hearing.) In his article, Herper makes a strong case for why it would be ethically wrong and commercially stupid for Amarin to stop the trial prematurely.
But if Amarin does abandon the trial, is there an alternative? Some cholesterol experts I've spoken with believe the NHLBI should pick up the trial if it is abandoned. It's unclear how this could happen, or if it's even possible, but the fact is that the REDUCE-IT trial is testing a very important hypothesis, with significant implications for many other drugs besides Vascepa. There are no other trials on the horizon that are likely to shed so much light on this vital topic.
