- Alkermes chances of winning U.S. approval for an experimental depression drug look slim after an advisory panel to the Food and Drug Administration concluded clinical data presented by the company was insufficient to support a regulatory OK.
- Committee experts voted 21-2 against recommending approval, echoing many of the concerns raised by FDA staff in briefing documents issued ahead of the Thursday meeting. While the FDA does not have to follow the committee's advice, it typically does.
- Alkermes' pitch for its drug, called ALKS-5461, already faced long odds. Only one of three Phase 3 trials conducted by the company succeeded, while an unusual clinical trial design used in two of the studies had met resistance from the FDA early on.
Alkermes won't know the FDA's verdict on ALKS-5461 until late January of next year, when the agency is scheduled to make a decision on approval. Thursday's panel vote, however, makes a negative outcome more likely.
In making its case for ALKS-5461, Alkermes had acknowledged an approval would require flexibility from the FDA, which typically requires two positive studies from applicants.
The biotech argued that it cleared that bar with what it called positive results from a Phase 2 study and the one successful Phase 3 trial of ALKS-5461 in major depressive disorder (MDD) — despite significant misses in the other two late-stage tests.
Yet the advisory committee meeting made clear that the FDA didn't hold the same view. In its presentation, the regulator noted that it disagreed with the company's characterization of both of those studies as successful.
"The agency has in our view clearly shown its hand — outlining a belief that both 'positive' studies for ALKS5461 are actually 'negative'," wrote Stifel analyst Paul Matteis in a Nov. 1 note to investors.
"It was almost as if the FDA was so bluntly negative in its remarks so as to foster a panel vote that corroborated its skeptical viewpoint," he continued.
Committee experts were asked to vote on whether Alkermes had presented enough data to support ALKS-5461's efficacy, safety and overall risk-benefit profile.
On safety, panelists actually voted 13-10 in favor of ALKS-5461, which is a fixed dose combination of the opioid agonist buprenorphine and the mu opioid receptor antagonist samidorphan. But when considering the drug's efficacy, committee members were decidedly against in a 20-3 vote.
"We were disappointed and surprised by the FDA's characterization of the safety and efficacy data for ALKS-5461 and the resulting outcome of the Advisory Committee vote," said company CEO Richard Pops in an Oct. 31 statement.
Alkermes designed ALKS-5461 for patients with serious depression who don't respond well to standard therapies such as SSRI drugs. There are limited treatment options for use in this adjunctive setting, and Alkermes estimates that roughly 5 million of the 11.6 million MDD patients treated in the U.S. become resistant to therapy following second-line treatment.
Clinical studies of antidepressants can be challenging due to high placebo responses that are typically seen among patients with depression. In order to mitigate that risk, Alkermes opted to use an unusual trial design which re-randomizes placebo non-responders after an initial testing phase to either switch to the trial drug or receive placebo again.
The FDA, however, hasn't endorsed the use of this design in confirmatory trial settings. Alkermes' studies using this method were the first to come before the agency's division of psychiatry products.
Another sticking point for both the FDA and the committee experts was Alkermes' decision to modify the one successful Phase 3 study partway through.
"It was surprising to us today to hear the amount of disagreement the FDA has on fundamental issues related to the ALKS 5461 program such as how the studies should have been designed and how many of the trials were actually positive and supportive of approval," wrote Credit Suisse analyst Vamil Divan in a Nov. 1 note to investors.
Alkermes said it would continue to work with the FDA during the review process for ALKS-5461. Investors and analysts, though, may already be switching gears to the rest of Alkermes' pipeline, which features an upcoming Phase 3 readout for ALKS-3831 in schizophrenia.
The company is also conducting an ongoing study of ALKS-5461 that it could use to generate additional clinical data in the event of a rejection from the FDA. That trial, however, isn't expected to read out for several years yet.
Shares in Alkermes fell by more than 6% in Friday morning trading.
Johnson & Johnson, Allergan, Sage Therapeutics and Acadia Pharmaceuticals are also developing drugs for MDD or treatment-resistant depression. With ALKS-5461's fate now in doubt, attention in the depression space could shift to those candidates.