Neumora Therapeutics' Phase 3 trial of navacaprant for major depressive disorder (MDD) has failed to meet its primary endpoint. The KOASTAL-1 study, the first of three replicate Phase 3 trials, did not demonstrate a statistically significant improvement in depressive symptoms compared to placebo.
The trial enrolled 383 adult patients with moderate-to-severe MDD. Participants were randomized to receive either 80 mg of navacaprant or a placebo. The primary endpoint was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. The key secondary endpoint was the change from baseline in the Snaith-Hamilton Pleasure Scale (SHAPS), a measure of anhedonia.
Topline Results
Both the navacaprant and placebo groups showed a 12.5-point reduction in MADRS scores, resulting in no statistically significant difference (p = 0.993). Similarly, there was no significant difference between the groups in the SHAPS scores (p = 0.648).
Gender-Specific Analysis
Interestingly, a gender-specific analysis revealed that female participants treated with navacaprant showed a greater improvement in MADRS scores (-14.0) compared to those on placebo (-11.4), with a p-value of 0.072. Furthermore, female participants also showed a statistically significant improvement in SHAPS scores (p = 0.015). In contrast, male participants in the navacaprant group showed a smaller reduction in MADRS scores compared to the placebo group.
Rob Lenz, executive vice president and head of research and development at Neumora, stated, "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."
Safety and Tolerability
Navacaprant was generally well-tolerated, with no serious adverse events reported. There was no signal for increased suicidal ideation or suicidal behavior compared to placebo, as measured by the Columbia Suicide Severity Rating Scale (C-SSRS). Common adverse events included headache (6.8% in the navacaprant group vs. 7.3% in the placebo group) and diarrhea (5.2% vs. 2.1%).
Ongoing Studies and Future Plans
Despite the failure of the KOASTAL-1 trial, Neumora is continuing with its KOASTAL-2, KOASTAL-3, and KOASTAL-LT studies. A significant proportion (83.3%) of patients who completed the KOASTAL-1 study elected to enroll in the KOASTAL-LT long-term extension study.
Henry Gosebruch, president and chief executive officer of Neumora, said, "The outcome of KOASTAL-1 is not what we expected, but there are encouraging trends in the data that we are analyzing. 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."
About Navacaprant
Navacaprant is a highly selective, novel kappa opioid receptor (KOR) antagonist being developed as a potential monotherapy treatment for MDD. It is designed to modulate the dopamine and reward processing pathways, which play an important role in the regulation of mood, cognition, reward, and behavior.
Market Impact
The failure of the KOASTAL-1 trial has had a significant impact on Neumora's stock price, with shares plummeting over 80%. The company's future plans for navacaprant and its broader pipeline will be closely watched by investors and the medical community.
