Navacaprant (BTRX-335140): A Comprehensive Report on an Investigational Kappa-Opioid Receptor Antagonist for Major Depressive Disorder

1. Executive Summary

Navacaprant (BTRX-335140) is an orally active, selective small-molecule antagonist of the kappa-opioid receptor (KOR) that has been under investigation primarily for the treatment of Major Depressive Disorder (MDD). Originally developed by BlackThorn Therapeutics and later acquired and advanced by Neumora Therapeutics, navacaprant aimed to address MDD, particularly symptoms of anhedonia, by modulating the KOR system, a novel mechanism of action in depression therapeutics.

The compound demonstrated a promising preclinical profile, including high selectivity for KOR, favorable pharmacokinetics with central nervous system (CNS) penetration, and efficacy in animal models. Early clinical development included a Phase 2 trial (NCT04221230) which, while not meeting its primary endpoint in the overall population, showed statistically significant and clinically meaningful improvements in depressive symptoms and anhedonia in a prespecified subgroup of patients with moderate-to-severe MDD.[1] These encouraging signals, coupled with a generally favorable safety and tolerability profile characterized by a low incidence of adverse events and no serious adverse events attributed to the drug, supported its progression to a large Phase 3 program known as KOASTAL.[2]