Navacaprant Improves Symptoms of Major Depressive Disorder in a Phase 2 Trial, Including in Participants With Comorbid Anxiety at Baseline

Introduction: Navacaprant is a highly selective kappa opioid receptor antagonist with promising efficacy and safety findings in a Phase 2 major depressive disorder (MDD) study. This post-hoc analysis aimed to characterize the efficacy of navacaprant in a subgroup of Phase 2 participants with moderate-to-severe comorbid anxiety at baseline.
Methods: Participants (18-65y) were randomized to 8 weeks of once-daily navacaprant (80mg) or placebo in this double-blind, placebo-controlled study. A post-hoc analysis in participants with baseline Hamilton Anxiety Rating Scale (HAM-A) scores equal to or above the median of 17 assessed change from baseline (CFB) in 17-item Hamilton Depression Rating Scale (HAMD-17) and Snaith-Hamilton Pleasure scale (SHAPS), and HAMD-17 response (≥50% decrease from BL) and remission (score ≤7) rates, at Weeks 4 and 8. Since ≥10% had missing data, last-observation-carried-forward analysis was used.
Results: In participants with baseline HAM-A ≥17 (navacaprant n=48, placebo n=45), HAMD-17 CFB with navacaprant was statistically significant vs placebo at Week 4 (LSMD [SE], -3.8 [1.22], P=0.002) but not Week 8 (-2.7 [1.38], P=0.052). Rates for HAMD-17 response (Week 4) and remission (both timepoints) were statistically significantly improved with navacaprant versus placebo. SHAPS CFB with navacaprant was statistically significant vs placebo at both timepoints (-3.7 [1.32], P=0.007 and -4.5 [1.39], P=0.002). TEAE incidence in this post-hoc subgroup was 42.9% (navacaprant, n=56) and 41.5% (placebo, n=53).
Conclusions: In this post-hoc analysis, navacaprant was associated with statistically significant improvements in symptoms of depression, including anhedonia, in participants with moderate-to-severe anxiety at baseline, a population that often experiences poorer acute outcomes.