An expert panel convened by the Food and Drug Administration to review Alkermes’s regulatory approval application for an opioid-based antidepressant has raised issues in a briefing document that some investors say could present a hurdle to the drug’s approval.
In a briefing document, the FDA’s Psychopharmacologic Drugs Advisory Committee, or PDAC, expressed concerns about the safety of the drug, ALKS 5461, and the primary endpoint used in the Phase III study to measure its efficacy. ALKS 5461 is a combination of the opioid buprenorphine and samidorphan, an opioid antagonist, for which Alkermes is seeking approval as an adjunctive treatment for major depressive disorder. The documents were posted online ahead of PDAC meeting about the drug, which will take place on Thursday. The FDA is expected to decide whether or not to approve the drug in January 2019.
Shares of Dublin-based Alkermes, which had reached $42.64 in midday trading Monday before closing at $40.37, were down 5.6 percent when markets opened Tuesday, but had partially recovered by Wednesday morning. While votes from AdComs like PDAC are not binding, the FDA usually follows them.
Alkermes declined to comment.
The company had submitted four studies to demonstrate ALKS 5461’s efficacy: The Phase III FORWARD-3, FORWARD-4 and FORWARD-5 trials and a Phase II study. However, analysts from B. Riley FBR noted, the FDA only accepted FORWARD-5, given that the other two Phase III trials were negative, and Phase II was designed for proof of concept, not efficacy. The briefing documents indicate hurdles to convincing PDAC of the drug’s efficacy and could result in the agency declining to approve the drug should the AdCom vote against it, the analysts wrote, calling the documents’ negativity “not overly surprising.” However, the analysts have maintained their “Buy” rating for Alkermes’s stock.
In particular, concerns were raised about potential safety issues.
A Deep-dive Into Specialty Pharma
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According to the briefing document, while PDAC said it agreed with Alkermes the inclusion of samidorphan meant ALKS 5461 carried fewer opioid effects than it would if it comprised buprenorphine only, “there remains some evidence of a mild opiate effect (including mild withdrawal effects) from the trials.” Phase III data published Monday in the Nature journal Molecular Psychiatry showed “minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by [adverse events] or objective measures.” The most frequent side effects reported more frequently in the ALKS 5461 treatment group than in the placebo group included nausea, constipation, dizziness, vomiting, somnolence, fatigue and sedation.
The document also pointed to disagreements between the FDA and the company about FORWARD-5’s primary endpoint.
Although the FDA accepted FORWARD-5 for submission, PDAC pointed to uncertainty about how the trial measured the drug’s efficacy. Most antidepressant studies, the document noted, assess efficacy endpoints following six to 12 weeks of treatment, but Alkermes took a different approach, averaging values from each patient over several weeks. While the FDA did not prospectively agree with that approach, PDAC stated that it seems worthy of consideration, as it could potentially decrease the variability in mood disorder symptoms that tend to fluctuate over time. At the same time, scores at the final time point can carry less weight, meaning loss of efficacy at the end of treatment is less important in the analysis.
Against the FDA’s advice, Alkermes had chosen the six-point Montgomery-Åsberg Depression Rating Scale, or MADRS-6, in addition to the more standard MADRS-10, for FORWARD-5. The agency said MADRS-6 excludes important measures of reduced sleep, reduced appetite, difficulty concentrating and suicidal thoughts. A protocol amendment also changed how the second stage of the study measured the timing of response, from change in baseline to week 5 through end of treatment – which occurred at week 6 – to change in baseline to week 3 through end of treatment. However, the agency had criticized the apparent lateness of the change and also the measurement of patient responses as an average over multiple time periods rather than a single efficacy measure at the end of the study.
According to the published Phase III data, FORWARD-5 showed the drug was effective on MADRS-6 and MADRS-10 from the start of the trial, at week 3 and through end of treatment. However, FORWARD-4 did not show the drug was effective in MADRS-10 at week 5.
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