Navacaprant Fails Late-Stage MDD Trials
Key Clinical Summary
- Navacaprant did not meet the primary endpoint in the phase 3 KOASTAL-2 or KOASTAL-3 studies in adults with major depressive disorder (MDD).
- The 80 mg dose showed no statistically significant improvement versus placebo in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 6.
- Neumora Therapeutics said it will discontinue navacaprant development after the late-stage MDD trial failures.
Navacaprant, a kappa opioid receptor antagonist for major depressive disorder treatment, failed to show statistically significant efficacy in two phase 3 trials, manufacturer Neumora Therapeutics reported. In a press release, the company said KOASTAL-2 and KOASTAL-3 did not achieve statistical significance on the primary or key secondary endpoints.
Study Findings
The KOASTAL-2 and KOASTAL-3 studies each evaluated navacaprant 80 mg in approximately 430 and 422 adults with major depressive disorder, respectively.
The primary endpoint in both studies was change from baseline to week 6 on the MADRS, a clinician-rated measure of depressive symptom severity. In KOASTAL-2, patients assigned to navacaprant (n = 217) had a change from baseline of -12.2 points, compared with -12.0 points for placebo (least-squares mean difference (LSMD) = -0.3; p = 0.813). KOASTAL-3 also failed to demonstrate benefit. Patients treated with navacaprant (n = 212) had a change from baseline of -10.1 points, compared with -10.8 points for placebo (LSMD = 0.7; p = 0.480).
Neumora stated that the drug was safe and generally well tolerated, with a safety profile consistent with prior studies, but the lack of efficacy led the company to discontinue development.
The manufacturer previously announced the failure of KOASTAL-1 in January 2025, a development that prompted the pause and reworking of the other 2 studies.
Clinical Implications
For clinicians following investigational treatments for MDD, the KOASTAL findings are a negative late-stage signal for this specific kappa opioid receptor antagonist program. The failure is particularly relevant because MDD remains an area with substantial unmet need, especially for patients who do not adequately respond to existing antidepressant therapies.
Expert Commentary
“While we are disappointed with the results of the KOASTAL-2 and -3 studies, we want to extend our gratitude to the patients, families, dedicated investigators, Neumora team and others who contributed meaningfully to the KOASTAL program,” said Bill Aurora, PharmD, chief operating and development officer, Neumora Therapeutics.
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