Neumora halts navacaprant after Phase 3 MDD failures, refocusing pipeline on Alzheimer’s agitation, schizophrenia, and obesity with cash runway into 2027.
Written By: Fariha Sameen, PharmD
Reviewed By: Pharmacally Editorial Team
Neumora Therapeutics has discontinued development of navacaprant after the investigational treatment failed to meet primary and key secondary endpoints in two Phase 3 studies in adults with major depressive disorder (MDD). The setback halts Neumora’s lead neuropsychiatric program, shifting focus to a broader pipeline that includes assets targeting Alzheimer’s disease agitation, schizophrenia, and cardiometabolic disorders.
The Phase 3 KOASTAL-2 (NCT06058013) and KOASTAL-3 (NCT06058039) trials evaluated navacaprant 80 mg as a treatment for MDD. Neither study demonstrated a statistically significant improvement over placebo on the primary endpoint, change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Based on the results, Neumora will halt further development of the drug.
Navacaprant is an oral selective kappa opioid receptor (KOR) antagonist. The mechanism has attracted interest as a potential approach to treating depression by modulating stress, mood regulation, and reward pathways in the brain. However, the outcome highlights the ongoing challenge of translating promising KOR antagonist biology into consistent late-stage clinical benefit in depression.
MDD remains one of the leading causes of disability worldwide, and many patients fail to achieve adequate symptom control with currently available antidepressants. The continued need for novel treatment approaches has fueled interest in mechanisms beyond traditional monoamine-based therapies.
KOASTAL-2 and KOASTAL-3 Fail to Demonstrate Efficacy
KOASTAL-2 enrolled 430 adults with MDD, while KOASTAL-3 enrolled 422 participants. The primary endpoint in both studies was change from baseline in MADRS score at Week 6.
In KOASTAL-2, patients receiving navacaprant (n=217) achieved a mean MADRS reduction of 12.2 points compared with 12.0 points for placebo-treated patients (n=213), resulting in a least-squares mean difference (LSMD) of -0.3 (p=0.813).
KOASTAL-3 produced similar results. Patients treated with navacaprant (n=212) experienced a 10.1-point reduction in MADRS scores versus a 10.8-point reduction with placebo (n=210), corresponding to an LSMD of 0.7 (p=0.480).
Neumora also reported pre-specified analyses of 426 patients enrolled after study optimizations implemented in early 2025. In that subgroup, both treatment arms achieved identical 12.1-point reductions in MADRS scores, with no meaningful difference between navacaprant and placebo (LSMD 0.0; p=0.976).
Despite the lack of efficacy, navacaprant remained generally well tolerated, with a safety profile consistent with previous studies and no new safety signals identified.
Leadership Highlights Pipeline Priorities
Neumora leadership acknowledged the disappointing outcome while emphasizing progress across the broader portfolio. Chief Operating and Development Officer Bill Aurora thanked patients, caregivers, investigators, and study teams who participated in the KOASTAL program.
Chief Executive Officer Paul Berns pointed to recent advances across the company’s remaining pipeline and highlighted several anticipated milestones over the next 12 months.
The company expects to complete a multiple ascending dose study of NMRA-511, a vasopressin V1a receptor antagonist for Alzheimer’s disease agitation, in healthy elderly volunteers during the fourth quarter of 2026. The data will support dose selection for a planned Phase 2b dose-ranging study expected to begin before year-end.
For NMRA-898, an M4 positive allosteric modulator being developed for schizophrenia, Phase 1 data are expected in the second half of 2026.
Neumora is also advancing NMRA-215, an NLRP3 inhibitor for obesity and related cardiometabolic disorders. The company expects to complete a repeat 13-week rat toxicology study by mid-2026, provide a program update with second-quarter financial results in August, and initiate clinical studies before the end of 2026.
Cash Runway Extended Into 2027
To prioritize its remaining pipeline, Neumora will reduce its workforce by approximately 35%, generating about $10 million in annualized savings and extending its cash runway into the third quarter of 2027, despite roughly $2 million in one-time restructuring costs.
The company expects existing cash and cash equivalents to support operations through multiple upcoming clinical milestones across its remaining development programs.
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About the Writer
Fariha Sameen, PharmD (LinkedIn), is a clinical pharmacy professional with hands-on experience in patient counselling, medication review, therapeutic monitoring, and clinical documentation across multiple departments. She has experience identifying and assessing drug-related problems and supporting medication safety practices. Her interests include pharmacovigilance, ADR reporting, clinical research, and medical writing focused on clear, evidence-based communication.