Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain

There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (NaV1.8) is a genetically and pharmacologically validated pain target that is selectively expressed in peripheral pain-sensing neurons and not in the central nervous system (CNS). Suzetrigine (VX-548) is a potent and selective inhibitor of NaV1.8, which has demonstrated clinical efficacy and safety in multiple acute pain studies. Our study was designed to characterize the mechanism of action of suzetrigine and assess both nonclinical and clinical data to test the hypothesis that selective NaV1.8 inhibition translates into clinical efficacy and safety, including lack of addictive potential. Preclinical pharmacology and mechanism of action studies were performed in vitro using electrophysiology and radiolabeled binding methods in cells recombinantly expressing human NaV channels, human proteins, and primary human dorsal root ganglion (DRG) sensory neurons. Safety and addictive potential assessments included in vitro secondary pharmacology studies, nonclinical repeat-dose toxicity and dependence studies in rats and/or monkeys, and a systematic analysis of adverse event data generated from 2447 participants from phase 3 acute pain studies of suzetrigine. Suzetrigine is selective against all other NaV subtypes (≥ 31,000-fold) and 180 other molecular targets. Suzetrigine inhibits NaV1.8 by binding to the protein's second voltage sensing domain (VSD2) to stabilize the closed state of the channel. This novel allosteric mechanism results in tonic inhibition of NaV1.8 and reduces pain signals in primary human DRG sensory neurons. Nonclinical and clinical safety assessments with suzetrigine demonstrate no adverse CNS, cardiovascular or behavioral effects and no evidence of addictive potential or dependence. The comprehensive pharmacology assessment presented here indicates that suzetrigine represents the first in a new class of non-opioid analgesics that are selective NaV1.8 pain signal inhibitors acting in the peripheral nervous system to safely treat pain without addictive potential.