Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With Major Depressive Disorder: A Randomized, Double-Blind Phase 2 Clinical Trial.

PURPOSE/

BACKGROUND

This phase 2a randomized, double-blind, placebo-controlled, 8-week trial assessed the efficacy and safety of navacaprant, a highly selective kappa opioid receptor antagonist, in adults with major depressive disorder (MDD).

METHODS/PROCEDURES: Participants with 17-Item Hamilton Depression Rating Scale (HAMD-17) scores of 14 to 30 were randomized 1:1 to once-daily navacaprant 80 mg or placebo (n = 102 each). The primary endpoint was HAMD-17 change from baseline (CFB) to week 8. Secondary endpoints included CFB in Snaith-Hamilton Pleasure Scale (SHAPS). No adjustment for multiple comparisons was made.

FINDINGS/

RESULTS

At week 8, HAMD-17 CFB was not statistically significantly improved with navacaprant vs placebo (least squares mean difference -1.7 [standard error, 1.08], P = 0.121; mixed-models repeated-measures) in the efficacy population. In a prespecified sensitivity analysis using last-observation-carried-forward, navacaprant statistically significantly improved HAMD-17 CFB (-2.9 [0.88], P = 0.002; -2.2 [0.98], P = 0.024) and SHAPS CFB (-2.8 [0.96], P = 0.004; -3.4 [1.10], P = 0.002) vs placebo at weeks 4 and 8. In the prespecified subgroup with moderate-to-severe MDD (baseline HAMD-17 score ≥22; n = 100), navacaprant statistically significantly improved HAMD-17 CFB at both timepoints (-3.0 [1.20], P = 0.015; -2.8 [1.33], P = 0.037) and SHAPS CFB at week 8 (-4.8 [1.35], P = 0.001) vs placebo. Most frequently reported adverse events (AEs) included headache (4.9% both) and nausea (4.9% navacaprant, 1.0% placebo); no serious AEs were reported with navacaprant.

IMPLICATIONS/

CONCLUSIONS

Although the primary endpoint was not met in the efficacy population, which included participants with mild depression, statistically significant improvements with navacaprant on depressive symptoms including anhedonia in the moderate-to-severe MDD subgroup, along with a favorable safety profile, support further study of navacaprant for the treatment of MDD.