Navacaprant Phase III Trial Fails to Show Efficacy

The KOASTAL-1 Study is the first of three replicate Phase III studies that comprise the pivotal KOASTAL program. The study did not demonstrate a statistically significant improvement on the primary endpoint of change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 or the key secondary endpoint of a change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS) scale.

“We are disappointed by the results from KOASTAL-1 as they were not consistent with the body of evidence supporting this mechanism in MDD. 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,” said Rob Lenz, executive vice president, head of research and development, Neumora.

“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 Henry Gosebruch, president and chief executive officer, Neumora. “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. We’d like to express our appreciation to the patients, families, and investigators who participated in this trial.”

Results: 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, 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. 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

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.

About the KOASTAL Program; The KOASTAL program includes three replicate Phase III randomized, placebo-controlled, double-blind studies, KOASTAL-1, KOASTAL-2, and KOASTAL-3, designed to evaluate the efficacy and safety of navacaprant monotherapy in adult patients with moderate-to-severe MDD who have a MADRS total score ≥ 25 at baseline. The KOASTAL-1 Study was conducted in the U.S. The KOASTAL-2 and -3 studies include sites in the U.S. and other regions. The primary endpoint of these studies is change from baseline in MADRS total score at Week 6. Key secondary endpoints include change from baseline on the SHAPS at Week 6, a measure of anhedonia. The KOASTAL Program also includes an open-label extension study, KOASTAL-LT, designed to evaluate the long-term safety of navacaprant. As noted above, a significant portion of patients who received navacaprant 80 mg (83.3%) in the KOASTAL-1 study elected to enroll in KOASTAL-LT. Patients will also have the opportunity to enroll in the KOASTAL-LT study following participation in the KOASTAL-2 and KOASTAL-3 studies.