INTEGRATED PAIN PRECLINICAL PLATFORM:<EM > IN VITRO</EM> AND <EM>IN VIVO </EM>MODELS TO STUDY THE VOLTAGE GATED SODIUM CHANNEL NAV1.8

Acute and neuropathic pain represent highly prevalent and substantial global health burdens, affecting individuals across the lifespan and in a wide range of clinical conditions. Opioids have long been the cornerstone of pain management. However, their use raises serious concerns and provides poor analgesia in neuropathic pain, underscoring the urgent need for safer, non-opioid treatment options. Voltage‑gated sodium channel 1.8 (Nav1.8) represents a genetically and pharmacologically validated analgesic target. Suzetrigine (VX‑548), is an oral highly selective Nav1.8 inhibitor, recently approved for the treatment of moderate to severe acute pain. Here, we report the characterization of VX-548 in an integrated neuropharmacology platform combining in vitro, pharmacokinetic (PK) and in vivo efficacy studies across different preclinical models of acute and neuropathic pain. In vitro electrophysiological studies using cell lines expressing human Nav1.8, dorsal root ganglion (DRG) neurons from multiple species and human iPSC-derived sensory neurons demonstrated potent and selective inhibition of Nav1.8. Oral dosing of VX-548 in rodents resulted in dose‑dependent plasma exposure. In mice, VX‑548 markedly reduced writhing in the acetic acid visceral pain model and exhibited anti-allodynic efficacy in a diabetic neuropathy model. In rats, VX-548 produced a significant reduction in mechanical allodynia in peripheral nerve injury models of neuropathic pain. Finally, VX-548 demonstrated transient inhibition of heat‑induced nociceptive responses in Cynomolgus monkeys. These data establish VX-548 as a potent and selective Nav1.8 inhibitor with analgesic efficacy. Our integrated neuropharmacology platform provides a comprehensive framework for evaluating pain therapeutics and accelerating drug development.