Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

Abstract

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallelcomparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/ SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

“…As buprenorphine and buprenorphine/samidorphan combination have shown evidence of antidepressant efficacy in some (but not all) clinical trials (Ehrich et al, 2015;Fava et al, 2018;Karp et al, 2014;Peckham et al, 2018), our results support the use of the OB model to study antidepressants with different pharmacological mechanisms. In the OB rat model, an increase of met-enkephalin mRNA expression was detected in limbic brain regions (Primeaux & Holmes, 2000).…”

“…Samidorphan is a functional antagonist at the mu-opioid receptor (Bidlack et al, 2018). Evidence from some (but not all) clinical studies suggests the combination of buprenorphine with samidorphan reduces depressive symptoms in patients with MDD and an inadequate response to their current therapy, when administered as an adjunct treatment to monoaminergic antidepressants (Ehrich et al, 2015;Fava et al, 2018;Peckham, De La Cruz, & Dufresne, 2018). In non-clinical studies, acute and subacute administration of buprenorphine with samidorphan induces behavioural changes indicative of antidepressant-like activity (Burke et al, 2019;Smith et al, 2019).…”

Keeping up with the clinical advances: depression

“…Of particular relevance, there were no reported adverse events associated with abuse or dependence, and there were no reports of opioid withdrawal. 92…”

Sequential parallel comparison design with two coprimary endpoints

“…For each of the six cases and ρ 12 values, we considered three situations, that is, ρ PE = ρ PP =.5, , and (equal correlations); ρ PP =.5, ρ PE =.3, , and (unequal correlations); and ρ PE = ρ PP =.5 and w 1 = w 2 =.5 (equal weights). The reason we included the equal weights situation is that this situation has often been used in actual SPCD trials …”

“…The SPCD has already been applied to some clinical trials . Two examples are the FORWARD‐4 and FORWARD‐5 trails, which are two phase 3, randomized, double‐blind, placebo‐controlled SPCD trials for the combination drug formulation of buprenorphine and samidorphan (BUP/SAM) in patients with major depressive disorder . Although the FORWARD‐4 trial did not demonstrate that the new therapy was significantly better than the placebo with respect to primary endpoint (change from baseline for 10 items in the Montgomery‐Asberg Depression Rating Scale [MADRS] total score at week 5 vs placebo: −1.8, P =.109), the FORWARD‐5 trial achieved the primary endpoint (average difference change from baseline to week 3 through end of treatment for six items in the MADRS and 10 items in the MADRS vs placebo: −1.5, P =.018; −1.9, P =.026, respectively).…”