AFA-281: A Novel Dual Modulator for Neuropathic Pain and CNS Disorders – Preclinical Profile and Clinical Development Trajectory

1. Executive Summary

AFA-281 is an orally bioavailable, small molecule New Chemical Entity (NCE) developed by AfaSci, Inc., a biotechnology company based in Burlingame, California.[1] The compound's primary pharmacological distinction is its dual mechanism of action, functioning as a modulator of T-type calcium channels (Cav3) and an inhibitor of soluble epoxide hydrolase (sEH).[3] This dual activity is hypothesized to normalize neuronal excitability and enhance endogenous anti-inflammatory processes, respectively.[1]

AFA-281 has successfully completed Phase I clinical trials, and its Investigational New Drug (IND) application (IND 157314) for the treatment of neuropathic pain received acceptance from the U.S. Food and Drug Administration (FDA) in November 2022.[1] Building on this, AfaSci is advancing AFA-281 into Phase II clinical development for painful lumbosacral radiculopathy (under trial NCT06649747) and Alcohol Use Disorder (AUD) (trial NCT06710431). A dedicated Phase I drug-alcohol interaction study (NCT06719908) is also planned to support the AUD program.[2] Preclinical evidence further supports its potential utility in Cocaine Use Disorder (CUD), osteoarthritis, cancer pain, and various forms of inflammatory pain.[3]

The development of AFA-281 as a non-opioid, non-steroidal therapeutic agent is significant, given the substantial unmet medical need for safer and more effective treatments for chronic pain and other central nervous system (CNS) disorders.[1] The compound's dual-target mechanism represents a novel therapeutic strategy, potentially offering broader efficacy and an improved side-effect profile compared to single-mechanism agents.