Neumora Therapeutics’ KOASTAL-1 study of navacaprant for MDD falls short on primary endpoint

Neumora Therapeutics, Inc. (Nasdaq: NMRA), a clinical-stage biopharmaceutical company specialising in neuroscience, has announced results from the KOASTAL-1 Phase 3 study evaluating navacaprant as a potential monotherapy for moderate-to-severe major depressive disorder (MDD). The findings revealed that navacaprant, a highly selective kappa opioid receptor (KOR) antagonist, did not achieve statistically significant improvements in primary or secondary efficacy endpoints compared to placebo.

The KOASTAL-1 trial, which forms part of a broader pivotal Phase 3 program, assessed navacaprant’s ability to reduce depressive symptoms based on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score over six weeks. Despite its innovative mechanism targeting dopamine and reward pathways associated with mood regulation, the trial outcomes underscored the complexity of treating MDD effectively across diverse patient populations.

What Is Navacaprant and Why Does It Matter?

Navacaprant represents a novel approach to treating MDD, leveraging its ability to modulate the kappa opioid receptor system—a pathway implicated in depressive-like states. Unlike conventional antidepressants, navacaprant aims to influence mood, cognition, and behaviour through targeted interaction with dopamine signalling. This mechanism has raised hope for addressing treatment-resistant cases of MDD and improving overall outcomes.

However, the KOASTAL-1 trial, which enrolled 383 adult participants in the U.S., yielded neutral results. The primary endpoint—reduction in MADRS scores—showed no significant difference between the navacaprant and placebo groups. Similarly, secondary endpoints, such as the Snaith-Hamilton Pleasure Scale (SHAPS) measuring anhedonia, also failed to demonstrate statistical superiority.

Promising Gender-Specific Trends in Navacaprant’s Efficacy

While the overall results may seem disappointing, subgroup analyses revealed intriguing efficacy signals among female participants. Women treated with navacaprant showed greater reductions in both depressive symptoms (MADRS scores) and anhedonia (SHAPS scores) compared to placebo, though these differences did not reach statistical significance. Conversely, male participants showed a less favourable response, with some outcomes even trending toward placebo superiority.

Rob Lenz, Executive Vice President of Research and Development at Neumora, noted that these trends warrant further exploration. The data suggest that sex-based differences in kappa opioid receptor function could play a role in navacaprant’s variable effectiveness, opening avenues for more tailored therapeutic strategies.

Safety Profile Reinforces Navacaprant’s Potential

Despite mixed efficacy results, navacaprant’s safety profile remains a key strength. The drug was generally well-tolerated, with treatment-emergent adverse events (TEAEs) such as headaches and diarrhoea occurring at rates comparable to placebo. Crucially, no serious adverse events or increased risks of suicidal ideation were reported, a significant consideration in the treatment of depressive disorders.

Furthermore, 83.3% of patients completing the KOASTAL-1 trial opted to enrol in the long-term KOASTAL-LT extension study, reflecting patient confidence in the treatment’s tolerability.

The Broader KOASTAL Program: What Comes Next?

The KOASTAL-1 trial is the first of three pivotal studies evaluating navacaprant in MDD. The ongoing KOASTAL-2 and KOASTAL-3 trials, which include international sites, aim to validate the initial findings and explore potential regional or demographic variations in treatment response. Neumora’s comprehensive program also includes the KOASTAL-LT open-label extension study, focused on long-term safety and patient outcomes.

Neumora plans to present further updates, including insights from the KOASTAL program, at the J.P. Morgan Healthcare Conference on January 14. The company’s leadership remains optimistic, citing a strong financial position with $342 million in cash reserves as of Q3 2024, ensuring runway into mid-2026.

Expert Opinions Reflect Measured Optimism

Henry Gosebruch, President and CEO of Neumora, acknowledged the unexpected results but emphasised the company’s commitment to addressing unmet needs in neuroscience. He highlighted the importance of refining their understanding of navacaprant’s efficacy signals, particularly in specific subgroups, to maximise its potential impact.

What This Means for MDD Treatment Innovation

The KOASTAL-1 trial’s mixed results highlight the challenges of developing novel therapies for MDD, a condition characterised by its multifaceted and heterogeneous nature. While navacaprant’s broad efficacy remains uncertain, its safety profile and promising gender-specific trends underscore the importance of continued investigation.

Neumora’s commitment to redefining neuroscience drug development and their pipeline of seven clinical-stage programs reflect their determination to confront brain disease challenges with innovative precision medicine approaches.