Background: Buprenorphine/samidorphan (BUP/SAM) is an investigational opioid system modulator for adjunctive treatment of major depressive disorder. To account for differences in treatment standards across geographic regions, this post-hoc analysis evaluated BUP/SAM among United States (US) participants across 3 multicenter, placebo-controlled studies.
Methods: US populations from 1 phase 2 (ALK5461-202) and 2 phase 3 studies (FORWARD-4 and FORWARD-5) were analyzed. All studies used Sequential Parallel Comparison Design and a 2 mg/2 mg dose. Efficacy was evaluated with the Montgomery-Åsberg Depression Rating Scale at end-of-treatment (MADRS-10EOT) and from baseline to average of Week 3 through EOT (MADRS-10AVG). Adverse events (AEs), Columbia-Suicide Severity Rating Scale scores, and Clinical Opiate Withdrawal Scale scores were assessed.
Results: Baseline characteristics were similar across ALK5461-202 (n=98 placebo, n=24 BUP/SAM), FORWARD-4 (n=218 placebo, n=52 BUP/SAM), and FORWARD-5 (n=229 placebo, n=52 BUP/SAM). Statistically significant improvements in MADRS scores were observed with BUP/SAM versus placebo in all 3 studies at multiple time points. For ALK5461-202, FORWARD-4, and FORWARD-5, respectively, least squares mean differences for MADRS-10EOT scores were -5.2, -3.5, and -2.4; MADRS-10AVG scores were -3.6, -2.7, and -2.7, (P<0.05 for all). Most AEs were of mild or moderate severity. Common (≥5% and ≥2 times placebo) BUP/SAM-associated AEs included nausea, constipation, dizziness, vomiting, sedation, and fatigue. There was no indication of opioid dependence, opioid withdrawal, suicidal ideation, or suicidal behavior.C
Conclusions: BUP/SAM 2 mg/2 mg demonstrated consistent, statistically significant efficacy in US patients across 3 independent, placebo-controlled studies, was well tolerated, and showed minimal evidence of abuse potential and no withdrawal.