Alkermes rebuffed by FDA on antidepressant

Alkermes is facing a significant delay for its ALKS 5461 candidate for major depressive disorder after the FDA turned down its marketing application.

The negative outcome for the review isn’t surprising given that an FDA advisory committee voted by 21-2 in November that the drug’s benefit-risk profile is not adequate to support its approval for treatment-resistant MDD. However, the outcome is something of a worst-case scenario for Alkermes as it seems the US regulator wants a new clinical trial of the drug, and that could hold up approval by a couple of years.

Alkermes announced the FDA’s decision after trading halted on Friday, but its stock fell almost 5% after-hours.

In its statement, the Dublin drugmaker said the FDA had requested “additional clinical data to provide substantial evidence of effectiveness of ALKS 5461” in the adjunctive treatment of MDD. The agency refused to accept Alkermes’ first filing attempt last year, but agreed to the submission later after it received additional clarifications about the data.

ALKS 5461 is a combination of buprenorphine, a mixed mu opioid receptor agonist/kappa opioid receptor antagonist, and an opioid antagonist called samidorphan.

Buprenorphine is thought to have an antidepressant effect via the kappa receptor, but its stimulation of the mu receptor means it has addictive potential which Alkermes says can be overcome by giving it alongside samidorphan.

The drug is vying to be the first in an entirely new class of drugs for MDD, and some analysts had forecast peak sales in excess of $1 billion if it gained approval.

The problem is that Alkermes’s drug missed the mark in one of three trials submitted in support of the marketing application, and also opted for an unorthodox, to-stage clinical trial design – known as sequential parallel comparison design (SPCD) – about which the FDA and advisory committee had serious concerns.

SPCD involves re-randomising placebo non-responders to either the drug or placebo again and has never been used in an FDA submission before. The regulator has doubts about its validity, and that was shared by the advisory committee members.

Alkermes is now planning to meet with the FDA in the coming months to work out its next steps – and see if there is a potential path forward for the antidepressant programme. CEO Richard Pops said a few weeks back that Alkermes has another phase IIIb trial ongoing in MDD that, in the event of an FDA rejection, could be “tuned” to provide additional data.

The setbacks means Alkermes is even more reliant on a schizophrenia drug candidate – ALKS 3831 – that is designed to sidestep one of the main side effects with current treatment for the disease. That’s due for filing this year, but is also a two-drug combination, this time combining olanzapine with samidorphan to prevent the weight gain caused by the primary drug.

The company also has a Biogen-partnered oral candidate for multiple sclerosis called BIIB098 (diroximel fumarate) which was filed in December in the US and is pitched as a more tolerable alternative to Biogen’s big-selling Tecfidera (dimethyl fumarate) MS drug.

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