Small Molecule · NMRA-140
Navacaprant (NMRA-140)
Oral, once-daily (80 mg), potent and highly selective kappa-opioid receptor (KOR / OPRK1) antagonist with >100-fold selectivity over mu- and delta-opioid receptors and no agonist properties. Designed to modulate dopaminergic reward and anhedonia circuitry. Developed by Neumora (originated at BlackThorn Therapeutics) as a novel-mechanism monotherapy for major depressive disorder; the Phase 3 KOASTAL program failed and development was discontinued in June 2026.
Also known as: NMRA-140, NMRA-335140, BTRX-335140, CYM-53093, navacaprant, 2244614-14-8
Key facts
- Modality
- Small molecule
- Chemical class
- quinoline, 1,2,4-oxadiazole, piperidine, tetrahydropyran
- Chemistry
- Achiral
- Mechanism
- KOR antagonist
- Highest phase
- Discontinued
- Lead indication
- Major depressive disorder
- Developer
- Neumora Therapeutics, Inc. (NMRA)
- Trials
- 4 tracked · 247 sites
Mechanism of action#
Potent, selective, reversible kappa-opioid receptor (KOR / OPRK1) antagonist. Antagonist IC50 ~0.8 nM at human KOR (pIC50 9.1), with ~138-fold selectivity over mu-opioid receptor (IC50 ~110 nM) and ~8000-fold over delta-opioid receptor (IC50 ~6500 nM); no agonist activity implicated in opioid abuse. KOR blockade is hypothesized to relieve anhedonia and depressive symptoms by disinhibiting mesolimbic dopamine signaling.
Formulations#
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Navacaprant 80 mg oral tablet 80 mg once daily | Oral | Once daily | — |
Development timeline#
- KOASTAL Phase 3 program initiated after End-of-Phase 2 FDA meeting.↗
- Phase 2a proof-of-concept (NCT04221230, n=204) completed; primary HAMD-17 endpoint not met in the overall efficacy population (included mild MDD), but significant improvement in the moderate-to-severe subgroup.
Navacaprant (NMRA-140) for Major depressive disorder#
DiscontinuedDiscontinuedMajor depressive disorder indication →
Phase 3 KOASTAL monotherapy program in moderate-to-severe MDD (three replicate studies KOASTAL-1/-2/-3 plus long-term KOASTAL-LT). KOASTAL-1 (NCT06029426) missed its primary MADRS and key secondary SHAPS endpoints (reported 2 Jan 2025). On 15 Jun 2026 Neumora reported KOASTAL-2 (NCT06058013) and KOASTAL-3 (NCT06058039) also failed to reach statistical significance on the primary or key secondary endpoints and announced it was discontinuing development of navacaprant (with an ~35% workforce reduction). Navacaprant was safe and generally well tolerated throughout.
Clinical trials#
NCT06058039NMRA-335140-303Phase 3Discontinuedn=422
KOASTAL-3: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder
United StatesBulgariaPolandFrance
missedprimaryMADRS change from baseline at Week 6 — LSMD 0.7 (navacaprant -10.1 vs placebo -10.8) (0.480)
Failed to separate from placebo on the primary MADRS endpoint. Reported 15 Jun 2026; ~422 enrolled.
NCT06058013NMRA-335140-302Phase 3Discontinuedn=430
KOASTAL-2: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder
United StatesBrazilChileCanada
missedprimaryMADRS change from baseline at Week 6 — LSMD -0.3 (navacaprant -12.2 vs placebo -12.0) (0.813)
Failed to separate from placebo on the primary MADRS endpoint. Reported 15 Jun 2026; ~430 enrolled.
NCT06029426NMRA-335140-301Phase 3Completedn=383
KOASTAL-1: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder
United States
missedsecondarySHAPS (anhedonia) change from baseline at Week 6 — LSMD -0.3 (navacaprant -5.8 vs placebo -5.5) (0.648)
Key secondary anhedonia endpoint also not met.
missedprimaryMADRS change from baseline at Week 6 — LSMD 0.0 (navacaprant -12.5 vs placebo -12.5) (0.993)
No separation from placebo on the primary endpoint; both arms improved -12.5. Female participants showed a numerical advantage (-14.0 vs -11.4); males did worse than placebo.
NCT04221230K2-MDD-201Phase 2Completedn=204
A Phase 2a, Randomized, Double-blind, Placebo-controlled Proof of Concept Study of Oral BTRX-335140 (NMRA-335140) Versus Placebo in Subjects With Major Depressive Disorder
United States
missedprimaryHAMD-17 change from baseline to Week 8 (overall efficacy population)
Primary endpoint not met in the overall population (which included mild MDD). Navacaprant 80 mg vs placebo, 1:1, ~102 per arm.
metsecondaryHAMD-17 change in moderate-to-severe MDD subgroup (0.002 (wk4); 0.024 (wk8))
Statistically significant improvement in depressive symptoms vs placebo in the moderate-to-severe subgroup at weeks 4 and 8, with improvement in anhedonia (SHAPS); favorable safety profile supported Phase 3.
Sources#
- KOASTAL-1 Phase 3 (NCT06029426) — ClinicalTrials.gov
- KOASTAL-2 Phase 3 (NCT06058013) — ClinicalTrials.gov
- KOASTAL-3 Phase 3 (NCT06058039) — ClinicalTrials.gov
- Navacaprant (NMRA-140) ligand page — IUPHAR/BPS Guide to Pharmacology
- Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With MDD: Phase 2 (oral 80 mg once daily, monotherapy) — J Clin Psychopharmacol (PMC)
- Neumora announces initiation of Phase 3 KOASTAL program for navacaprant in MDD — Neumora Therapeutics / IR
- Neumora reports KOASTAL-1 data (endpoints not met) — Neumora Therapeutics / IR
- Neumora Therapeutics Reports Data from Phase 3 KOASTAL Program and Provides Business and Pipeline Update — Neumora Therapeutics / IR
- Neumora Therapeutics, Inc. Form 424B4 (IPO Prospectus) — U.S. Securities and Exchange Commission (EDGAR)
- Phase 2a study of BTRX-335140/NMRA-335140 vs placebo in MDD (NCT04221230) — ClinicalTrials.gov