Phase 3 KOASTAL-1 Trial Fails to Show Navacaprant Significantly Improves MDD

The phase 3 KOASTAL-1 trial failed to show that navacaprant brought statistically significant improvements in depression symptoms, announced by Neumora Therapeutics on January 2, 2025.1 However, the study demonstrated female participants had a better response rate to navacaprant than male participants.

“We are disappointed by the results from KOASTAL-1 as they were not consistent with the body of evidence supporting this mechanism in MDD,” said Rob Lenz, MD, PhD, executive vice president, head of research and development, Neumora, in a statement. “There is a lot to investigate from this study, in particular the contrast in drug and placebo responses in depressed mood and anhedonia in female participants compared to male participants.”

These results follow a previously positive phase 2 trial which found navacaprant brought statistically significant reductions in symptoms of depression and anhedonia compared with placebo following 4 (P = .002) and 8 (P = .024) weeks of treatment, measured by the 17-point Hamilton Depression Rating Scale (HAMD-17).2

KOASTAL-1, a randomized, placebo-controlled, double-blind trial, evaluated the efficacy and safety of navacaprant, a novel, oral, once-daily highly selective kappa opioid receptor antagonist, among 383 adult patients with moderate-to-severe major depressive disorder (MDD).1 At baseline, participants had a MADRS total score ≥ 25.

The primary endpoint of KOASTAL-1 was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. The secondary endpoint was the change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS).

By week 6, the change from baseline in the MADRS total score was – 12.5 for both participants on navacaprant 80 mg (n = 191) and placebo (n = 192), and this finding was not statistically significant (P = .993). Females on navacaprant 80 mg (n = 105) compared with placebo (n = 106) had a greater change from baseline in the MADRS (-14.0 vs -11.4; P = .072), as well as more improvements than the male population for those on navacaprant (-10.6; n = 86) and placebo (-13.8; n = 86). As seen here with the male population, those on placebo had greater improvements in depression symptoms than those on navacaprant 80 mg.

As for the SHAPS Total score which assesses pleasure in the last few days, participants on navacaprant (n = 191) had greater change from baseline scores than participants on placebo (n = 192) (-5.8 vs -5.5; P = .648). Female participants on navacaprant (n = 105) demonstrated greater improvements than those on placebo (n = 106) (-7.2 vs -4.9; P = .015). Like the MADRS total score, males on navacaprant had less improvement in this score than females; males on navacaprant had a lower change from baseline in the SHAPS total score than males on placebo (-4.3 vs - 6.3).

Nevertheless, navacaprant was demonstrated to be safe and generally well-tolerated with no reported serious adverse events. Investigators did not observe signs of increased suicidal ideation or suicidal behavior compared with the placebo, as evaluated by the Columbia Suicide Severity Rating Scale.

Common adverse events included headache and diarrhea, occurring among 6.8% and 5.2% of participants on navacaprant, respectively. Headaches and diarrhea occurred among 7.3% and 2.1% of participants on placebo, respectively. Another treatment-related adverse event included pruritus which included 3.7% of participants on navacaprant and 2.1% of participants on placebo. Investigators observed low discontinuation rates due to treatment-related adverse events, which was 2.1% among participants on navacaprant and 3.1% among participants on placebo.

Despite the discouraging findings, 83.3% of participants who took navacaprant 80 mg for 6 weeks enrolled in KOASTAL-LT, the open-label extension study. The phase 3 trials KOASTAL-2, KOASTAL-3, and KOASTAL-LT are ongoing.

“The outcome of KOASTAL-1 is not what we expected, but there are encouraging trends in the data that we are analyzing,” said Henry Gosebruch, president and chief executive officer, Neumora, in the press release. “Our strong financial foundation and cash balance of $342 million as of the end of the third quarter provides runway into mid-2026, and we look forward to providing additional updates on the navacaprant development program and our pipeline at the J.P. Morgan Healthcare Conference.”

References

1. Neumora Therapeutics Reports Data from KOASTAL-1 Study of Navacaprant in Major Depressive Disorder. Neumora. January 2, 2025. https://ir.neumoratx.com/news-releases/news-release-details/neumora-therapeutics-reports-data-koastal-1-study-navacaprant. Accessed January 2, 2025.
2. Mathew, S, Cutler, A, Visitacion, N, et al. Navacaprant (NMRA-140), A Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Patients with Major Depressive Disorder: A Randomized Placebo-Controlled Phase 2 Trial. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://neumoratx.com/wp-content/uploads/2024/08/ACNP23_Ph2_Poster_Final.pdf. Accessed January 2, 2025.