Navacaprant for Major Depressive Disorder Fails in Late-Stage Study

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The oral kappa opioid receptor antagonist navacaprant for the treatment of major depressive disorder (MDD) has failed in a phase 3 study as part of Neumora Therapeutics' pivotal KOASTAL program.^1,2

“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, head of research and development at Neumora Therapeutics.

Investigators in the KOASTAL-1 trial enrolled 383 adults with moderate-to-severe MDD, who were randomized to receive navacaprant as a monotherapy at a dose of 80 mg or placebo. According to topline results, both navacaprant and placebo led to a 12.5-point improvement from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6, thus missing the study's primary endpoint.

Additionally, the study failed on its key secondary endpoint of change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) scale. The difference between navacaprant and placebo was 0.3 points, and while this favors navacaprant, it was not a statistically significant improvement.

Interestingly, in women, navacaprant was associated with a 14-point improvement in MADRS, vs 11.4 points for placebo. The change in women as measured by the SHAPS scale was 7.2 and 4.9 points, respectively.

"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 said.

Concerning safety, navacaprant was generally well tolerated, with no serious adverse events reported and no increased suicidal ideation or suicidal behavior when compared with placebo, as measured by Columbia Suicide Severity Rating Scale (C-SSRS). Treatment emergent adverse events in either treatment group that were ≥5% included headache (navacaprant, 6.8%; placebo, 7.3%) and diarrhea (navacaprant, 5.2%; placebo, 2.1%). Rates of discontinuation due to treatment-emergent adverse events were 2.1% for navacaprant and 3.1% for placebo.

The KOASTAL Program also includes an open-label extension study, KOASTAL-LT, which is designed to evaluate the long-term safety of navacaprant. A significant portion of patients who received navacaprant 80 mg (83.3%) in the KOASTAL-1 study elected to enroll in KOASTAL-LT. Patients can also enroll in the KOASTAL-LT study following participation in the KOASTAL-2 and KOASTAL-3 studies, results of which are due in the first half of 2025.

“We will not waver on our mission to make a difference for people living with brain diseases, which our broad pipeline of novel programs has the potential to address. The outcome of KOASTAL-1 is not what we expected, but there are encouraging trends in the data that we are analyzing,” said CEO Henry Gosebruch. “We look forward to providing additional updates on the navacaprant development program and our pipeline at the J.P. Morgan Healthcare Conference. We would like to express our appreciation to the patients, families, and investigators who participated in this trial.”

References

1. Neumora Therapeutics reports data from KOASTAL-1 study of navacaprant in major depressive disorder. News release. January 2, 2025. Accessed January 2, 2025. https://www.biospace.com/press-releases/neumora-therapeutics-reports-data-from-koastal-1-study-of-navacaprant-in-major-depressive-disorder

2. Dennis M. Neumora's major depression drug fails first of three pivotal studies. News release. January 2, 2025. Accessed January 2, 2025. https://firstwordpharma.com/story/5924641