- Alkermes plc opened trading on Monday down more than 20% when the company revealed that the Food and Drug Administration issued a Refusal to File letter for the biotech's major depressive disorder drug ALKS-5461.
- The agency said the application did not have sufficient "evidence of overall effectiveness for the proposed indication" and requested Alkermes conduct further clinical trials, as well as a bioavailability study to show additional information about ALKS-5461 and its reference product buprenorphine.
- Alkermes said it "strongly disagrees with the FDA's conclusions and plans to appeal the FDA's decision," as well as request a Type A meeting to determine next steps.
Recent data disclosed to Biopharma Dive from the FDA showed that the agency issued more Refusal to File (RTF) letters in 2017 than any of the three years prior. Unlike a Complete Response Letter, RTFs are not a total rejection of a drug, but the agency's refusal to even review a New Drug Application.
It's unclear exactly what the FDA is looking for from Alkermes — companies are only required to reveal the details they choose about the letter (if they reveal it at all — many companies don't).
But this seems like a worst-case scenario for Alkermes; the biotech revealed the regulatory agency is requiring multiple late-stage studies to prove efficacy before it accepts the application for review.
Alkermes has already conducted several Phase 3 studies for ALKS-5461. The drug failed to show a positive result in two of the studies, but showed efficacy in a third – a fourth trial is already ongoing.
"We see the results as a positive surprise, as we were not sure that the modifications made to FORWARD-5 following the failures of FORWARD-3/-4 would be necessarily adequate for success," wrote Jefferies analyst Biren Amin in a note to investors in October 2016.
Amin estimated in a note to clients on Monday that approval of the drug could be delayed until 2021.
After the flop of the FORWARD-3 and FORWARD-4 studies, Alkermes modified the last late-stage study to include two different dosages of the drug, as well as two stages of the trial that separated out non-responders.
That study, the FORWARD-5 trial, only showed a statistically significant result at the higher dose. At the time, Alkermes planned to pool the data from two of the late-stage studies and submit that to the FDA.
"We strongly believe that the clinical development program, including data from more than 1,500 patients with MDD, provides substantial evidence of ALKS 5461's consistent antidepressant activity and a favorable benefit-risk profile," said Alkermes CEO Richard Pops in a statement.
The mixed results for ALKS-5461 are not so uncommon for depression indications. Clinical trials in this space are considered difficult to conduct because placebo responses tend to be particularly high, often dimming the strength of a positive efficacy result.
This is at least the second RTF issued by the FDA so far this year. About a month ago, the FDA refused to accept an application from Celgene Corp. for its blockbuster hopeful multiple sclerosis drug ozanimod.