Abstract

Improvement in Depressive Symptoms with Zuranolone Treatment in Patients with Major Depressive Disorder With or Without Elevated Anxiety: Pooled Analysis From the MDD-201B, MOUNTAIN, and WATERFALL Studies

Czysz A, Nemeroff C, Schatzberg AF, Lasser R, Park L, Toubouti Y, Forrestal F, Iovin R, Jonas J
61st Annual Meeting of the American College of Neuropsychopharmacology. 2022.

Abstract

Background: Patients having major depressive disorder (MDD) with elevated anxiety often have more severe depression and are less responsive to standard-of-care antidepressants than those without elevated anxiety. Zuranolone, a positive allosteric modulator of both synaptic and extrasynaptic GABA(A) receptors and a neuroactive steroid, is thought to upregulate GABA(A) receptor expression and enhance inhibitory GABAergic signaling. Zuranolone is hypothesized to rapidly restore network balance in brain areas dysregulated in depression. Zuranolone is investigational and in clinical development as an oral, once-daily, 14-day treatment course for adults with MDD. Clinical trials have demonstrated that treatment with zuranolone (30 or 50 mg) vs placebo leads to improvements in depressive symptoms as measured by change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression total score (HAMD-17). This pooled analysis of 3 completed studies of zuranolone evaluated the effect of zuranolone on depressive symptoms in patients having MDD with or without elevated anxiety at baseline.

Methods: MDD-201B (NCT03000530; zuranolone 30 mg), MOUNTAIN (NCT03672175; zuranolone 20 or 30 mg [20 mg Cohort not included here]), and WATERFALL (NCT04442490; zuranolone 50 mg) were randomized, double-blind, placebo-controlled trials. MDD with elevated anxiety was defined as having a Hamilton Anxiety Rating Scale (HAM-A) total score ≥20 at baseline. The primary outcome (CFB in HAMD-17 at Day 15) and secondary outcome (CFB in HAM-A at Day 15) in individual studies were analyzed in a pooled analysis using the Mixed Model for Repeated Measures. Only patients with non-missing HAM-A scores at baseline were included. Analyses were not adjusted for multiplicity and p values reported here are nominal. Safety and tolerability were evaluated by incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

Results: Of the 1007 patients included in this analysis, 508 (50.4%) met the criterion for MDD with elevated anxiety (zuranolone: n = 260; placebo: n = 248) and 499 did not (zuranolone: n = 245; placebo: n = 254). In the MDD with elevated anxiety subgroup, mean (SD) HAMD-17 (zuranolone vs placebo) was 27.3 (2.8) vs 27.6 (2.9) at baseline and 12.4 (8.0) vs 15.1 (8.2) at Day 15. This represented a least squares mean (LSM) (SE) CFB of −14.8 (0.6) vs −12.5 (0.6) (p = 0.002) at Day 15. In the MDD without elevated anxiety subgroup, mean (SD) HAMD-17 (zuranolone vs placebo) was 25.2 (2.2) vs 25.2 (2.1) at baseline and 12.1 (7.9) vs 13.6 (7.6) at Day 15. This represented a LSM (SE) CFB of −13.0 (0.6) vs −11.4 (0.6) (p = 0.038) at Day 15. In both subgroups, zuranolone separated from placebo at the first measured time point (Day 3; p < 0.0001). In the MDD with elevated anxiety subgroup, LSM (SE) CFB in HAM-A (zuranolone vs placebo) was −13.5 (0.6) vs −11.5 (0.6) at Day 15 (p < 0.0027). The proportions of patients who reported TEAEs were similar in both subgroups (MDD with elevated anxiety: zuranolone, 62.3% vs placebo, 47.6%; MDD without elevated anxiety: zuranolone, 55.5% vs placebo, 48.0%). Most patients reported TEAEs that were mild or moderate in severity, regardless of elevated anxiety status at baseline (MDD with elevated anxiety: zuranolone, 96.3% vs placebo, 97.5%; MDD without elevated anxiety: zuranolone, 96.3% vs placebo, 98.4%). Rates of SAEs were low and consistent across treatment groups, regardless of elevated anxiety status at baseline (MDD with elevated anxiety: zuranolone, 1.5% vs placebo, 0.4%; MDD without elevated anxiety: zuranolone, 0.8% vs placebo, 1.2%).

Conclusions: In this pooled analysis of 3 randomized, double-blind studies—MDD-201B, MOUNTAIN, and WATERFALL—improvement in depressive symptoms with zuranolone was observed in patients with MDD, regardless of elevated anxiety status at baseline. Zuranolone was generally well tolerated and had a consistent safety and tolerability profile in patients having MDD with or without elevated anxiety at baseline. This analysis supports zuranolone as a potential treatment for the difficult-to-treat subpopulation of patients who have MDD with elevated anxiety.