Alkermes Issues Positive Results from Phase 2 Study of ALKS 5461

Alkermes plc

today announced the presentation of positive phase 2 data for ALKS 5461, a novel opioid modulator, in patients with major depressive disorder (MDD) and inadequate response to standard therapies. In the phase 2 study, ALKS 5461 met its primary endpoint, met key secondary endpoints and demonstrated significant reduction in depressive symptoms versus placebo. The study is being presented in an oral session at the 53^rd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting in Hollywood, Fla., by Maurizio Fava, M.D., of Massachusetts General Hospital and Harvard Medical School. “The magnitude of effect seen with ALKS 5461 in this study is highly significant. These results are very encouraging for ALKS 5461 as a potential new treatment approach, with substantial reductions in depressive symptoms demonstrated and rapid onset of action observed,” stated Maurizio Fava, M.D., Director of the Depression Clinical and Research Program at Massachusetts General Hospital and Slater Family Professor of Psychiatry at Harvard Medical School. The phase 2 study of ALKS 5461 utilized a sequential parallel comparison design (SPCD), designed to reduce the impact of clinically meaningful response to treatment with placebo. The study included two four-week, randomized, double-blind stages run in sequence: an Initial Study Stage and a Successive Study Stage. The Successive Study Stage randomized only those patients who were non-responders to placebo in the Initial Study Stage. Both stages of the phase 2 study evaluated two doses of ALKS 5461, a lower dose and a higher dose. Overall, the combined analysis of both doses at both stages showed statistically significant efficacy on multiple endpoints compared to placebo. Overall, the lower dose showed greater efficacy than the higher dose and, as a result, will be the top end of the dose range employed in future studies. Results for the lower dose from the Successive Study Stage of the study included: * ALKS 5461 significantly reduced Hamilton Depression Rating Scale (HAM-D17) scores from baseline (p=0.013), with a reduction of 5.3 points, compared to a reduction of 1.2 points in the placebo group at the end of the four-week treatment period. ALKS 5461 also significantly reduced Montgomery–Åsberg Depression Rating Scale (MADRS) scores from baseline (p=0.004), with a reduction of 8.7 points, compared to a reduction of 1.8 points in the placebo group at the end of the four-week treatment period. * ALKS 5461 had an onset of effect, as measured by MADRS, evident after one week of treatment. In the phase 2 results for the overall study population, including both the Initial Study Stage and the Successive Study Stage, patients who received either dose of ALKS 5461 for a treatment period of four weeks showed a significant reduction in depressive symptoms from baseline in HAM-D17 (p=0.026) and MADRS (p=0.004) scores, compared to placebo. The primary endpoint of the phase 2 study was the change from baseline in depressive symptoms over a four-week treatment period in the overall study population, as measured by HAM-D17, compared to placebo. Data from the study showed that ALKS 5461 was generally well tolerated. The most common adverse events observed in the study were nausea, headache and dizziness. “ALKS 5461 reflects a new approach to the treatment of major depressive disorder based on modulation of the opioid system in the brain. With these compelling data in hand, we are planning to meet with the U.S. FDA as we work to advance ALKS 5461 to pivotal clinical development,” stated Elliot Ehrich, M.D., Chief Medical Officer of Alkermes. “ALKS 5461, one of several product candidates in our advancing clinical pipeline, is an excellent example of how Alkermes is leveraging our unique understanding of opioid biology and pharmacology to develop medications that address unmet medical needs for central nervous system disorders.” Study Design This phase 2, randomized, double-blind, multicenter, placebo-controlled study assessed the efficacy and safety of once-daily ALKS 5461 as adjunctive treatment in 142 patients with MDD who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Two doses of ALKS 5461 were evaluated, each with a 1:1 ratio of buprenorphine and ALKS 33 (lower dose of 2mg/2mg and higher dose of 8mg/8mg). The primary endpoint of the study was the change from baseline in depressive symptoms over a four-week treatment period, as measured by HAM-D17. Secondary endpoints included additional analyses of patient responses based on HAM-D17, MADRS and Clinical Global Impression – Severity Scale (CGI-S) scores. The study utilized a sequential parallel comparison design (SPCD), a design developed ten years ago by Drs. Fava and Schoenfeld at Massachusetts General Hospital and now widely utilized in clinical trials. A SPCD trial involves two randomized, double-blind stages run in sequence. In the Initial Study Stage (stage 1), patients are randomized to either drug treatment or placebo. In the ALKS 5461 phase 2 study, the Initial Study Stage was a four-week treatment period. At the end of the Initial Study Stage, patients were reassigned treatment groups for the Successive Study Stage (stage 2), which in the ALKS 5461 phase 2 study was a second four-week treatment period. In the Successive Study Stage, patients who had been on drug in the Initial Study Stage were put on placebo. Patients who had been administered placebo in the Initial Study Stage were determined to be either responders, i.e., they responded positively to placebo treatment, or non-responders. Placebo responders were assigned to remain on placebo in the Successive Study Stage. Placebo non-responders were re-randomized to either placebo or drug treatment in the Successive Study Stage. SPCD studies are particularly useful in studies of depression, anxiety and other difficult psychiatric diseases to reduce the impact of placebo effect on the assessment of treatment response.