Matching-adjusted Indirect Treatment Comparison and Network Meta-Analysis of Zuranolone to Standard-of-care Antidepressant Therapies for the Acute Treatment of Adults with Major Depressive Disorder

Abstract: Background: Major depressive disorder (MDD) is a debilitating disease for which there is an unmet need for rapid-acting treatments. Zuranolone is an investigational oral, once-daily, 14-day treatment for adults with MDD and PPD. Given the rapid improvement in depressive symptoms observed in the zuranolone trials, we sought to indirectly compare efficacy data from the zuranolone Phase 3 WATERFALL Study (NCT04442490) against clinical trials of standard-of-care (SOC) antidepressants (ADTs) in MDD. Methods: A systematic literature review identified 60 studies to establish evidence networks for response and remission at Day 15 for both MADRS and HAM-D. Matching-adjusted indirect treatment comparison (MAICs) were conducted between zuranolone and placebo from comparable studies. MAIC results were subsequently included in a Bayesian Network Meta-Analysis which compared the relative effects of zuranolone versus SSRIs and SNRIs. Odds ratios (ORs) with 95% credible intervals were reported. Results: Zuranolone significantly improved the odds of response (MADRS) at Day 15 compared to SNRIs, SSRIs, and the placebo arms of the comparator studies: OR 4.20 (2.56-6.88); 4.07 (2.46-6.69); 6.03 (3.82-9.50), respectively. Odds of MADRS remission at Day 15 were also significantly higher for zuranolone compared to the SOC antidepressants: OR SNRIs 4.20 (1.64-10.29); SSRIs 4.37 (1.64-12.19); placebo 5.75 (2.67-12.43). The odds of HAM-D response and remission at Day 15 were also higher for zuranolone and support the effect measured by the MADRS outcomes. Conclusions: The results of this analysis suggest that zuranolone-treated patients demonstrated greater odds of achieving positive MDD outcomes at Day 15 of treatment compared to SOC ADTs.Short Description: Zuranolone is an investigational oral, once-daily, 14-day treatment for adults with MDD. Matching-adjusted indirect treatment comparisons and network meta-analyses were conducted to compare zuranolone (WATERFALL study (NCT04442490)) to standard-of-care (SOC) antidepressant therapies (ADTs) on response and remission at Day 15 for both MADRS and HAM-D measures. The results of this analysis suggest that zuranolone-treated patients demonstrated greater odds of achieving response and remission at Day 15 of treatment compared to SOC ADTs.Name of Sponsoring Organization(s): Sage Therapeutics, Inc., and Biogen Inc.