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

局部给药毒蕈碱受体拮抗剂预防化疗引起的周围神经病变的临床研究

• 批准号: 10324216
• 负责人: Angela Hansen
• 金额: $ 110.14万
• 依托单位: WINSANTOR, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324216
• 关键词: Adjuvant Analgesic; Adverse event; American Society of Clinical Oncology; Amitriptyline; Animal Model; Ankle; Area; Australia; Award; Canada; Cancer Patient; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Cisplatin; Clinical; Clinical Data; Clinical Trials; Common Terminology Criteria for Adverse Events; Data; Dermal; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease; Dose; Dose-Limiting; Double-Blind Method; Drug Kinetics; Electrophysiology (science); Excision; FDA approved; Formulation; Funding; Grant; Growth; Gynecologic Oncology Group; HIV; Hand; In Vitro; Incidence; Interruption; Investments; Laboratories; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modification; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Muscarinic M1 Receptor; National Institute of Diabetes and Digestive and Kidney Diseases; Nerve; Nerve Fibers; Nervous System Physiology; Neurologic Symptoms; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oncology; Paclitaxel; Pain; Pathogenesis; Patient Outcomes Assessments; Patients; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physical Function; Pirenzepine; Placebos; Plasma; Prevention; Publishing; Quality of life; Randomized; Recommendation; Regimen; Research; Rodent Model; Safety; Sensory; Skin; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; Symptoms; Testing; Therapeutic; Topical application; Toxicology; United States National Institutes of Health; Visual; analog; base; chemotherapy; cholinergic; clinical care; clinical investigation; density; diabetic; diabetic patient; duloxetine; experience; foot; gabapentin; improved; in vivo; indexing; meetings; mitochondrial dysfunction; nerve damage; novel; novel therapeutic intervention; pain outcome; pain reduction; pain relief; painful neuropathy; pedometer; peroneal nerve; pre-clinical; preclinical study; pregabalin; prescription pain reliever; prevent; sensory neuropathy; side effect; standard of care; statistics; sural nerve; targeted treatment; treatment duration; vibration perception

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.

项目摘要 化疗引起的周围神经病变（CIPN）是一种使人衰弱的疾病， 患者接受化疗，并限制剂量和治疗持续时间。症状从感觉到 疼痛性神经病变的损失，并伴有神经损伤的电生理和结构指标。 美国临床肿瘤学会目前没有提出预防或逆转的建议。 的CIPN，并提供了只有一个温和的建议，症状疼痛缓解。因此，CIPN是一个主要的 未满足的临床问题。WinSanTor（WST）的创始人已经发表了临床前研究，揭示了外周 在体外和体内条件下通过胆碱能抑制抑制神经代谢和生长 线粒体活性通过神经元M1受体起作用。通过毒蕈碱清除这种胆碱能“制动器” 拮抗剂在多种糖尿病动物模型中促进神经生长并防止神经病变， 化疗和HIV引起的神经病变。通过NIH R21基金获得的概念验证临床数据 表明用毒蕈碱受体拮抗剂的局部治疗可以显著地逆转内- 表皮神经纤维（IENF）在糖尿病神经病变患者的皮肤，并改善多个指标， 神经功能和生活质量，以及缓解糖尿病神经性疼痛。由我们资助的 NCI第一和第二阶段STTR赠款和WST的内部资金，WST已经实现了四个主要里程碑 在开发哌仑西平（PZ）（一种选择性M1 R拮抗剂）的新型局部制剂中：1）1期临床 试验于2018年11月在澳大利亚完成，2）糖尿病患者的2期临床试验已 2019年7月在加拿大启动（NCT 04005287），3）9月完成与FDA的IND前会议 2019年，FDA明确通知我们，WST将能够根据CIPN进行探索性研究。 申请的IND，以及4）2020年7月29日完成的双盲、随机II期临床试验的IND申报 在患有疼痛性神经病变的糖尿病患者中进行试验，并于2020年8月28日批准IND（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 应用于评价局部PZ在给予顺铂的肿瘤患者中的安全性和疗效， 紫杉醇用于预防剂量限制性CIPN。该项目的结果将导致临床证明- 概念数据，以支持FDA首次注册试验的额外投资和合作伙伴关系 缓解疼痛性CIPN的疾病治疗。