Update (November 5, 2018): After years of development, two FDA advisory committees have voted 21-2 against approving Alkermes’ major depressive disorder treatment, ALKS-5461. The advisory committee members found that the company failed to provide sufficient evidence of the drug’s efficacy.
Originally published on January 26, 2016:
A new depression drug – ALKS-5461 – in development by biopharmaceutical company Alkermes, has failed the first two of three Phase III clinical trials. In an effort to get more positive results, the company is reworking their trial design for the final Phase III clinical trial.
The results of the previous trials found that ALKS-5461 could not beat the placebo in terms of patient response. A higher placebo response is one of the most common reasons why experimental antidepressant drugs fail in advanced clinical trials.
“We are gaining important insights as we proceed with the FORWARD program for ALKS-5461. The third pivotal efficacy study, FORWARD-5, is ongoing and we plan to adapt it to incorporate findings from FORWARD-3 and FORWARD-4,” said Dr. Elliot Ehrich, Chief Medical Officer of Alkermes. “Clinical trials of new medicines for the treatment of major depressive disorder are complicated by significant placebo response. We designed the FORWARD pivotal program to include three efficacy studies as we recognize that this is a challenging disease state where multiple clinical studies and expansive analyses are generally necessary to confirm the efficacy of a new medicine.”
The results come just one week after the J.P. Morgan conference where Alkermes CEO Richard Pops was very optimistic about the drug’s chances of passing the trial. He even went so far as to call the Phase III results a “seismic” event for the company.
Pops attributed his enthusiasm to the company’s uncommon clinical trial design in which those patients that failed to respond to treatment in the initial placebo group were subsequently randomized between the drug and placebo groups again. Biopharmaceutical companies that develop antidepressants tend to organize three Phase III clinical trials in the hopes that the drug would pass at least two of the three studies, and gain regulatory approval.
Despite the two failed Phase III clinical trials, Alkermes isn’t giving up on ALKS-5461 yet. According to the company, further analysis of the last trial showed a trend towards statistical significance. The company even identified that patients in the drug treatment group of the trial – known as FORWARD-4 – were successful at achieving the endpoint on the Montgomery–Åsberg Depression Rating Scale (MADRS) scores.
While post hoc analyses are sometimes conducted during drug development, conclusions drawn from such analyses can be considered invalid in the eyes of regulators. Alkermes has now reconfigured their last Phase III clinical trial, by adding new patients and altering the statistical analysis plan.
“We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families,” said Pops. “Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS-5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.”
If the FORWARD-5 trial is a success, the company plans to submit data from both it and FORWARD-4 to the Food and Drug Administration (FDA). ALKS-5461 is a combination drug of both buprenorphine and samidorphan.