Navacaprant: A Novel and Highly Selective Kappa Opioid Receptor Antagonist Evaluated in a Phase 2 Trial in Patients with Major Depressive Disorder

Introduction: This Phase 2 study assessed efficacy and safety of navacaprant, a highly selective kappa opioid receptor antagonist, in adults with major depressive disorder (MDD).
Methods: Patients (18-65y) were randomized 1:1 to once-daily navacaprant (80mg) or placebo in this 8-week, double-blind, placebo-controlled study. Primary endpoint was change from baseline (CFB) to Week 8 in 17-item Hamilton Depression Rating Scale (HAMD-17). Secondary endpoints included CFB in Snaith-Hamilton Pleasure Scale (SHAPS). The primary analysis used mixed-models-repeated-measures (MMRM). Due to ≥10% missing data, a prespecified last-observation-carried-forward (LOCF) analysis was also used.
Results: 204 patients (31 US sites) were randomized. For HAMD-17 CFB (n=171), navacaprant was superior to placebo at Week 4 (LSMD [SE] -2.7 [0.90], P=0.003) but not Week 8 (primary endpoint; -1.7 [1.08], P=0.121; MMRM). For LOCF analyses, navacaprant was superior to placebo for HAMD-17 CFB at Weeks 4 and 8 (-2.9 [0.88], P=0.002 and -2.2 [0.98], P=0.024). For SHAPS CFB, navacaprant was superior to placebo at Weeks 4 and 8 (-2.8 [0.96], P=0.004 and -3.4 [1.10], P=0.002). In patients with baseline HAMD-17 ≥22 (n=100), navacaprant was superior to placebo for HAMD-17 CFB at Weeks 4 and 8 (prespecified analysis; -3.0 [1.20], P=0.015 and 2.8 [1.33], P=0.037). For SHAPS CFB in this subgroup, a significant difference was seen at Week 8 (-4.8 [1.35], P=0.001). TEAE incidence was lower with navacaprant (35.3%) vs placebo (44.1%).
Conclusions: Statistically significant reductions in depressive symptoms including anhedonia with navacaprant in patients with moderate-to-severe MDD, along with a favorable safety profile, support its further study in MDD.