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

项目总结 化疗引起的周围神经病变(CIPN)是一种使人衰弱的疾病，70%的癌症患者 患者接受化疗，并限制治疗剂量和持续时间。症状范围从感官到 丧失为痛性神经病变，并伴有神经损害的电生理和结构指标。 美国临床肿瘤学会目前没有关于预防或逆转的建议 仅为症状性疼痛缓解提供了适度的建议。因此，CIPN是一个主要的 未得到满足的临床关切。温三通创始人S发表的临床前研究显示，外围设备 胆碱能抑制在体外和体内条件下对神经代谢和生长的再训练 通过神经元M1受体发挥作用的线粒体活性。毒扁豆碱对胆碱能“刹车”的作用 在多种糖尿病动物模型中，拮抗剂促进神经生长并预防神经病变， 化疗和艾滋病毒引起的神经病。通过NIH R21基金获得的概念验证临床数据 结果表明，用M受体拮抗剂局部治疗可显著逆转细胞内钙离子丢失。 糖尿病神经病变患者皮肤中的表皮神经纤维及改善的多项指标 改善神经功能和生活质量，以及缓解糖尿病神经病理性疼痛。由我们资助的 NCI第一阶段和第二阶段STTR拨款和WST的内部资助，WST实现了四个主要里程碑 在开发选择性M1R拮抗剂吡伦西平(PZ)的新局部制剂中：1)临床1期 试验于2018年11月在澳大利亚完成，2)糖尿病患者的第二阶段临床试验已经完成 2019年7月在加拿大发起(NCT04005287)，3)与FDA的IND前会议于9月完成 2019年，FDA明确通知我们，WST将能够在CIPN中根据 要求的IND，以及4)于2020年7月29日完成的IND申请，用于双盲随机第二阶段临床 对患有痛性神经病变的糖尿病患者进行试验，IND于2020年8月28日获得批准(IND 144090)。我们的临床前和探索性临床数据鼓励目前的SBIR直接进入II期 局部PZ方案在肿瘤患者顺铂联合化疗中的应用 紫杉醇预防剂量限制性CIPN。该项目的结果将导致临床证明- 支持FDA首次注册试验的额外投资和合作伙伴关系的概念数据 疼痛的CIPN的疾病修正治疗。

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.