Clinical investigation of topical delivery of a muscarinic receptor antagonist for the prevention of chemotherapy-induced peripheral neuropathy

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PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition that afflicts 70% of cancer patients undergoing chemotherapy and limits the dose and duration of treatment. Symptoms range from sensory loss to painful neuropathy and are accompanied by electrophysiological and structural indices of nerve damage. The American Society of Clinical Oncology currently makes no recommendations for the prevention or reversal of CIPN and provides only a moderate recommendation for symptomatic pain relief. CIPN is therefore a major unmet clinical concern. WinSanTor (WST)’s founders have published preclinical studies revealing that peripheral nerve metabolism and growth is retrained under both in vitro and in vivo conditions by cholinergic suppression of mitochondrial activity acting via neuronal M1 receptors. Removal of this cholinergic “brake” by muscarinic antagonists promotes nerve growth and protects against neuropathy in multiple animal models of diabetes, chemotherapy and HIV-induced neuropathy. Proof of concept clinical data obtained via NIH R21 funding demonstrates that topical treatment with a muscarinic receptor antagonist can significantly reverse loss of intra- epidermal nerve fibers (IENF) in the skin of patients with diabetic neuropathy and improve multiple indices of neurological function and quality of life, as well as relieving diabetic neuropathic pain. Supported by our funded NCI Phase I and II STTR grants and WST's internal funding, WST has achieved four major milestones in developing a novel topical formulation of Pirenzepine (PZ), 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, 3) Pre-IND meeting with FDA was completed in September 2019, and FDA clearly informed us that WST will be able to conduct exploratory studies in CIPN under the requested IND, and 4) IND filing completed on July 29, 2020 for a double-blind, randomized Phase 2 clinical trial in diabetic patients with painful neuropathy, and IND was approved on August 28, 2020 (IND 144090). Our preclinical and exploratory clinical data encourages the present SBIR Direct-to-Phase II application to evaluate the safety and efficacy of topical PZ in oncology patients administered cisplatin and paclitaxel for the prevention of dose-limiting CIPN. The results of this project will result in clinical proof-of- concept data to support additional investments and partnerships for an FDA registration trial of the first disease-modifying treatment for painful CIPN.