Alkermes has announced preliminary topline results from FORWARD-3 and FORWARD-4, the first two of three phase III efficacy studies to read out from the comprehensive FORWARD pivotal program for ALKS 5461, a once-daily, oral investigational medicine with a novel mechanism of action for the adjunctive treatment of major depressive disorder (MDD) in patients who have an inadequate response to standard therapies for clinical depression. Neither of the two studies met the prespecified primary efficacy endpoint, which compared ALKS 5461 to placebo on the change from baseline on the Montgomery–Åsberg Depression Rating Scale (MADRS).

FORWARD-4 tested two dose levels of ALKS 5461 (2mg/2mg and 0.5mg/0.5mg) compared to placebo. 385 patients entered the study. There was a clear trend toward efficacy with the 2mg/2mg dose of ALKS 5461 on the primary endpoint, and post hoc analyses achieved statistical significance for the entire 2mg/2mg dose group on the MADRS endpoint. Based on these analyses, Alkermes believes that FORWARD-4 provides supportive evidence of the efficacy of ALKS 5461 in the treatment of major depressive disorder.

FORWARD-3 tested ALKS 5461 (2mg/2mg) compared to placebo. 429 patients entered the study. Placebo response was greater than that observed in FORWARD-4 and no treatment effect of ALKS 5461 was observed. Negative trials due to significant placebo effect are not uncommon in the study of major depressive disorder.

FORWARD-5, the third pivotal efficacy study in the FORWARD program, is ongoing, testing two dose levels of ALKS 5461 (2mg/2mg and 1mg/1mg). FORWARD-5 shares common design and analysis features with FORWARD-4. Based on information gained from FORWARD-3 and FORWARD-4, patient enrollment in FORWARD-5 will be increased and the statistical analysis plan will be updated. Alkermes will provide an update later this quarter on the projected timing of completion of FORWARD-5.

In the case of a clear positive outcome for FORWARD-5, Alkermes believes that the evidence provided by it and the previously completed successful, randomized, placebo-controlled phase II study, together with supportive evidence from FORWARD-4, collectively could provide substantial evidence of efficacy for ALKS 5461 for the adjunctive treatment of MDD. In that case, Alkermes would request a meeting with the FDA’s Division of Psychiatric Products to discuss the regulatory path for this Fast Track designated medicine.

“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,” stated Elliot Ehrich, M.D., 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.”

“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 Richard Pops, chief executive officer of Alkermes. “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.”

In FORWARD-3, the most commonly reported adverse events were nausea, headache and fatigue, and in FORWARD-4 they were nausea, headache and dizziness. The safety and tolerability profile of ALKS 5461 was consistent with that reported for the phase II and FORWARD-1 studies.