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.

项目摘要化学疗法引起的周围神经病（CIPN）是一种使癌症的70％的衰弱状况接受化疗并限制了治疗的剂量和持续时间。症状从感觉范围失去疼痛的神经病，并伴随着神经损伤的电生理和结构指标。美国临床肿瘤学会目前尚未提出预防或逆转的建议 CIPN的作品，仅提供症状缓解的现代建议。因此，CIPN是主要的未经临床关注。 Winsantor（WST）的创始人发表了临床前研究，揭示了外围通过胆碱能抑制，在体外和体内条件下，神经代谢和生长均经过重新培训通过神经元M1受体作用的线粒体活性。去除毒蕈碱的胆碱能“制动” 拮抗剂促进神经的生长并预防多种糖尿病动物模型的神经病，化学疗法和HIV诱导的神经病。通过NIH R21资金获得的概念证明临床数据证明毒蕈碱受体拮抗剂的局部治疗可以显着逆转糖尿病神经病患者皮肤的表皮神经纤维（IENF），并改善多个指数神经功能和生活质量以及缓解糖尿病神经性疼痛。得到我们资助的 NCI第一阶段和II STTR赠款以及WST的内部资金，WST取得了四个主要里程碑在开发新型吡renzepine（PZ）的新型局部配方时，选择性M1R拮抗剂：1）1阶段临床试验于2018年11月在澳大利亚完成，2）糖尿病患者的2期临床试验已是 2019年7月在加拿大发起（NCT04005287），3）与FDA的预定会议于9月完成 2019年，FDA清楚地告诉我们，WST将能够在CIPN进行探索性研究要求IND和4）IND申请于2020年7月29日完成，用于双盲，随机2阶段临床糖尿病患者的疼痛神经病患者的试验，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当前的SBIR直接到相关II 用于评估局部PZ在肿瘤学患者中的安全性和效率的应用紫杉醇预防剂量限制CIPN。该项目的结果将导致临床证明概念数据以支持第一个FDA注册试验的其他投资和合作伙伴关系疾病改良治疗疼痛的CIPN。