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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要化疗引起的周围神经病变 (CIPN) 是一种使人衰弱的疾病，影响 70% 的癌症接受化疗的患者会受到感觉症状的影响，并限制剂量和治疗持续时间。丧失疼痛性神经病，并伴有神经损伤的电生理学和结构指标。美国临床肿瘤学会目前没有提出预防或逆转的建议 CIPN 并仅提供缓解症状疼痛的中等建议，因此 CIPN 是主要的。 WinSanTor (WST) 的创始人发表了临床前研究，揭示了外周血中未得到满足的临床关注。通过胆碱能抑制在体外和体内条件下重新训练神经代谢和生长通过神经元 M1 受体作用的线粒体活性通过毒蕈碱消除这种胆碱能“刹车”。拮抗剂在多种糖尿病动物模型中促进神经生长并预防神经病变，通过 NIH R21 资助获得的概念验证临床数据。表明用毒蕈碱受体拮抗剂进行局部治疗可以显着逆转体内改善糖尿病神经病变患者皮肤中的表皮神经纤维（IENF）并改善多项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。 NCI 一期和二期 STTR 资助以及 WST 的内部资助，WST 实现了四个重大里程碑开发新型局部用哌仑西平 (PZ) 制剂（一种选择性 M1R 拮抗剂）：1) 1 期临床试验于 2018 年 11 月在澳大利亚完成，2）针对糖尿病患者的 2 期临床试验已在 2019年7月在加拿大启动（NCT04005287），3）9月完成与FDA的Pre-IND会议 2019年，FDA明确告知我们WST将能够在CIPN下进行探索性研究请求的 IND，以及 4) 于 2020 年 7 月 29 日完成的双盲、随机 2 期临床 IND 备案在伴有疼痛性神经病变的糖尿病患者中进行试验，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 直接进入第二阶段。应用来评估局部 PZ 在接受顺铂治疗的肿瘤患者中的安全性和有效性紫杉醇用于预防剂量限制性 CIPN 该项目的结果将产生临床证明- 概念数据，以支持第一个 FDA 注册试验的额外投资和合作伙伴关系针对疼痛 CIPN 的疾病缓解治疗。