PROJECT SUMMARY Voltage-gated sodium ion channels (NaVs) are required for the transmission of electrical signals along pain sensing neurons. While a number of NaV isoforms are expressed in nociceptors, NaV1.8 is unique in that its distribution is highly restricted to dorsal root ganglia and trigeminal neurons, raising the intriguing possibility that isoform selective inhibitors could interfere with pain signaling without affecting other physiological functions. In support of this hypothesis, rodents treated with antisense oligonucleotides targeting NaV1.8 exhibit reduced mechanical allodynia in models of inflammatory and neuropathic pain. Recently, Vertex has demonstrated that NaV1.8 inhibitors effectively reduce pain in patients with small fiber neuropathy, osteoarthritis and following surgery (bunionectomy, abdominoplasty). Despite these promising results, due to molecule-specific challenges such as poor pharmacokinetics, accumulation of metabolites, idiosyncratic drug reactions and high cost of goods, no drug candidate targeting NaV1.8 has yet reached approval. SiteOne Therapeutics has identified a development candidate targeting NaV1.8 with exquisite potency (IC50 < 1 nM at hNaV1.8), selectivity over off-target NaV isoforms (>8000-fold), and pharmaceutical properties suitable for once daily oral dosing. The objective of this proposal is to advance the development candidate through a single and multiple ascending dose study in healthy volunteers (UG3 phase), and Phase 2 proof-of-concept studies in acute postsurgical and chronic neuropathic pain (UH3 phase). If successful, the program will deliver an oral analgesic medicine targeting NaV1.8 for the treatment of pain and replacement of opioids that is well- positioned to initiate pivotal Phase 3 trials.