Submission of Investigational New Drug application to the Federal Drug Administration to support clinical development of topical pirenzepine for CIPN.

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many first-line chemotherapeutic drugs. Depending on the specific drug and dose regimen, CIPN can afflict between 20-85% of cancer patients receiving these drugs at standard doses and nearly 100% of patients at high drug doses. Many patients with CIPN experience neuropathic pain, and there are no FDA-approved treatments to prevent or reverse CIPN other than those to limit associated neuropathic pain. Emerging appreciation that mitochondrial dysfunction is involved in the underlying pathogenesis of CIPN suggests a potential therapeutic approach. The founders of WinSanTor (WST) have demonstrated in in vitro and in vivo preclinical studies that peripheral neurons are under a tonic, cholinergic-mediated, constraint of mitochondrial function. Release of this metabolic brake by muscarinic receptor type 1 (M1R) antagonists enhances mitochondrial function, promotes nerve growth and both prevents onset of neuropathy and reverses established neuropathy and reduces neuropathic pain in rodent models of CIPN. Consistent with the idea that regulating peripheral nerve growth represents a promising target for therapy, pilot clinical trials using a non-selective muscarinic receptor antagonist confirmed reversal of intra-epidermal nerve fiber (IENF) loss in type 2 diabetes patient (ADA abstract 2018) and reduction of pain (unpublished results). WinSanTor’s preclinical proof-of-concept studies and IND enabling studies have been funded through various mechanisms, including an NIDDK STTR Fast Track grant awarded to WinSanTor in 2014 (1R44DK104512), an NCI Phase I STTR grant awarded to WinSanTor in 2017 (R41CA213555), and a NCI Phase II STTR grant awarded to WinSanTor in 2018 (R42CA213555). Supported by these grants, WinSanTor has achieved three major milestones in developing a novel topical formulation of Pirenzepine, a selective M1R antagonist: 1) Phase 1 clinical trial was completed in Australia in November 2018, 2) A Phase 2 clinical trial in diabetic patients has been initiated (NCT04005287) in Canada in July 2019, and 3) Pre-IND meeting with FDA schedule in September 2019, and IND filing anticipated in November 2019 for a double blind, randomized Phase 2 clinical trial in diabetic patients with painful peripheral neuropathy. To support our clinical development for CIPN, we propose to develop a regulatory strategy to assemble the documentation needed for the FDA IND submission and design a double blind, randomized Phase 2 clinical trial in gynecologic cancer patients with CIPN. Our preclinical studies demonstrated that topical pirenzepine is effective against the development of CIPN and neuropathic pain and is effective at reversing the established CIPN and neuropathic pain. We have completed GMP manufacturing and IND-enabling safety and toxicology studies. Our Phase I trial data demonstrated that topical delivery of Pirenzepine achieved target distribution of pirenzepine in skin tissue with extremely low levels of systemic exposure in humans. These data will be included in our IND submission and support the Phase 2 trial design. 1PROJECT NARRATIVE Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many first-line chemotherapeutic drugs, and there are no FDA-approved treatments to prevent or reverse CIPN other than those to limit associated neuropathic pain. WinSanTor, Inc is developing a proprietary topical formulation of selective M1R antagonist for CIPN. 1