Neumora Therapeutics Reports Disappointing Results from Phase 3 Study of Navacaprant in MDD

Navacaprant, a novel kappa opioid receptor (KOR) antagonist being developed as a potential monotherapy treatment for major depressive disorder (MDD), returned disappointing results in the phase 3 KOASTAL-1 clinical trial, the first of 3 replicate phase 3 studies in the pivotal KOASTAL development program, according to a news release from Neumora Therapeutics, Inc.¹

_{©srdjan/stock.adobe.com}

Treatment with navacaprant did not lead to a statistically significant improvement of the study’s primary endpoint, change from baseline in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 6 weeks, or in the key secondary endpoint, identified as change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) scale.¹

“We are disappointed by the results…as they were not consistent with the body of evidence supporting this mechanism in MDD," Rob Lenz, Neumora executive vice president and head of R&D said in the company release.¹ His comment may reflect the positive findings from a recent phase 2 study that resulted in statistically significant reductions in symptoms of depression and anhedonia in the navacaprant- vs placebo-treated groups after 4 (P =.002) and 8 (P =.024) weeks of treatment, as measured by scores on the 17-point Hamilton Depression Rating Scale.²

KOASTAL-1

The KOASTAL-1 randomized, double blind, placebo controlled, multicenter study enrolled 383 adults with moderate to severe MDD, aged 18 to 65 years. Inclusion required a study candidate’s MDD symptoms to have been present for more than 4 weeks but fewer than 12 months prior to the screening visit. Also required were a MADRS total score of 25 or higher at study screening and baseline and a change of no more than 20% in MADRS score between screening and baseline.³ MDRAS score can range from 0 to 60, with higher scores reflecting treater severity of disease.

Participants were randomly assigned to receive 80 mg orally of navacaprant daily (n = 191) or placebo daily (n = 192).³

Results

At week 6 of treatment, the improvement from baseline in MADRS total score was identical for the navacaprant and placebo groups at 12.5-points (P =.993), missing the study’s primary endpoint. In women, however, navacaprant was associated with a 14-point improvement in MADRS score vs 11.4 points for placebo (P =.072). The improvement in MADRS score, which stratifies depression severity, was also greater for women compared with men treated with navacaprant (14.0 vs 10.6 points, respectively).¹

Analysis of SHAPS total score, an assessment of pleasure experienced in the past several days, also revealed a non-statistically significant improvement from baseline between navacaprant- and placebo-treated participants of 0.3 (5.8 points vs 5.5 points, respectively; P =.648). Reflecting the greater improvement among women on MADRS total score, women who received navacaprant also showed greater change from baseline on the pleasure scale than men, with a rise of 7.2 points for the former vs 4.3 for the latter.

There were no serious adverse events reported during KOASTAL-1, according to Neumora, nor was there an increased signal for suicidal ideation or behavior compared with placebo, based on a validated rating scale. Study discontinuation rates related to treatment emergent adverse events were low, at 2.1% for navacaprant and 31.% for placebo. A majority (83.3%) of participants treated with navacaprant who completed the 6-week study elected to enroll in the long-term extension trial, KOASTAL-LT, the company said.

The KOASTAL-2 and KOASTAL-3 studies will replicate the design and methods of KOASTAL-1 but will include participants from regions outside the US. Participants who complete these 2 studies will also be eligible to enroll in KOASTAL-LT, Neumora stated.

“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,” Lenz noted in the press release. And, although the outcome was unexpected, “there are encouraging trends in the data that we are analyzing,” Henry Gosebruch, president, and chief executive officer, Neumora, added. The KOR system is a well-characterized pathway known to mediate depressive-like states, according to the press statement. Modulating this system represents a novel approach to treating MDD and other major neuropsychiatric disorders.

The company plans to provide updates on the navacaprant development program at the upcoming JP Morgan Healthcare Conference, January 14, in San Francisco, CA.

References

1. Neumora Therapeutics reports data from KOASTAL-1 study of navacaprant in major depressive disorder. News release. Neumora Therapeutics. January 2, 2025. Accessed January 3, 2025. https://ir.neumoratx.com/news-releases/news-release-details/neumora-therapeutics-reports-data-koastal-1-study-navacaprant
2. Mathew SJ, Cutler AJ, Visitacion NC, Gold M, Yuan J, Aurora B. 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. Poster presented at: 62nd Annual Meeting of the American College of Neuropsychopharmacology; December 3-6, 2023; Tampa, FL. https://neumoratx.com/wp-content/uploads/2024/08/ACNP23_Ph2_Poster_Final.pdf
3. Study to evaluate the effects of oral NMRA-335140 versus placebo in participants with major depressive disorder. ClinicalTrials.gov ID NCT06029426. Updated September 19, 2024. Accessed January 2, 2024. https://clinicaltrials.gov/study/NCT06029426