Neumora’s Kappa Opioid Antagonist Falters in Phase 3 Depression Trial
Neumora Therapeutics’ lead drug, navacaprant, failed to show efficacy in the Phase 3 "KOASTAL-1" trial for major depressive disorder (MDD), with results indicating no significant difference from placebo in reducing depression symptoms after six weeks of treatment. The announcement on January 2, 2025, sent the company’s shares plummeting by over 80%.
The KOASTAL-1 study enrolled 383 adults with moderate-to-severe MDD, comparing navacaprant to placebo over six weeks. Both groups showed an average 12.5-point decrease on a 60-point depression symptom scale, contradicting earlier Phase 2 findings from 2023, which suggested navacaprant could significantly improve symptoms like anhedonia.
Navacaprant, a kappa opioid receptor (KOR) antagonist, targets proteins linked to mood regulation and aims to increase dopamine release to alleviate depressive symptoms. While overall efficacy was lacking, gender-specific trends emerged: women showed a 14-point reduction in symptoms compared to 11.4 points for placebo (p=0.072) and a statistically significant improvement in anhedonia (p=0.015). Men, however, fared worse than those on placebo, complicating the interpretation.
Despite disappointing efficacy, navacaprant exhibited a favorable safety profile, with low discontinuation rates (2.1% for the drug versus 3.1% for placebo) and manageable adverse events. Additionally, 83.3% of participants remained in the long-term extension study, indicating good tolerability.
Strategic Implications for Neumora
This failure impacts Neumora’s strategic position, given its $1.71 billion market cap and $342 million in cash reserves, which provide runway through mid-2026. The ongoing KOASTAL-2 and KOASTAL-3 trials now carry heightened risk, and the gender-specific efficacy signals may necessitate a more targeted development approach, requiring protocol modifications and additional trials.
The results also raise broader concerns about the KOR antagonist drug class. Companies like Johnson & Johnson and AbbVie are pursuing similar therapies, but Neumora’s trial underscores the challenges of translating promising mechanisms into clinically meaningful outcomes. High placebo response rates and the complexity of diagnosing and treating mood disorders further complicate neuropsychiatric drug development.
Neumora’s Next Steps
Henry Gosebruch, Neumora’s CEO, has committed to analyzing the data further, with updates expected at the upcoming J.P. Morgan Healthcare Conference. The company aims to explore trends, including gender-specific responses, before deciding on the next steps for the navacaprant program.
Investor confidence, however, has declined. Neumora’s stock fell from $11 to just over $2, reflecting skepticism about the drug’s future. Analysts like Brian Abrahams from RBC Capital Markets described the results as a “worst-case scenario.” Reportedly, the trial was carefully designed to minimize placebo effects and maximize the drug’s chances of success, leading RBC analysts to conclude that the data likely reflect a genuine lack of efficacy rather than trial design flaws.
Rob Lenz, MD, PhD, Neumora’s head of research and development, 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.”
Neumora’s Phase 2 trial in 2023 provided early optimism, showing statistically significant improvements in moderate-to-severe MDD patients and highlighting navacaprant’s favorable safety profile compared to existing antidepressants. This included avoiding common side effects like weight gain and sexual dysfunction. However, the KOASTAL-1 results cast doubt over the remaining Phase 3 trials and navacaprant’s potential.
Beyond navacaprant, Neumora’s pipeline includes investigational drugs targeting bipolar depression, Alzheimer’s disease agitation, schizophrenia, Parkinson’s disease, and ALS, leveraging mechanisms such as V1aR antagonists, M4 and NMDA modulators, CK1δ inhibitors, and GCASE activators. This diversification offers some risk mitigation, but navacaprant’s failure dampens confidence in its neuropsychiatric portfolio.
The Future of Depression Drug Development
Navacaprant’s trial failure reflects broader challenges in developing novel depression therapies. Unlike diseases with objective biomarkers, psychiatry relies heavily on subjective measures like patient-reported outcomes, making trials susceptible to placebo effects and harder to interpret.
Despite these hurdles, hope remains for kappa opioid receptor modulation and other novel mechanisms. Lessons from navacaprant may inform future efforts, and ongoing studies by other companies in this space could refine the approach. Neuropsychiatric drug development, however, requires innovative trial designs to navigate the inherent complexities of the field.
Topics: Clinical Trials
