Pre-Clinical Development of Topical Pirenzepine for Treating Diabetic Neuropathy

局部哌仑西平治疗糖尿病神经病变的临床前开发

• 批准号: 9097695
• 负责人: Angela Hansen
• 金额: $ 59.17万
• 依托单位: WINSANTOR, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097695
• 关键词: American; Animals; Biological Assay; Canis familiaris; Cardiovascular system; Cavia; Cells; Clinical Trials; Country; Cutaneous; Data; Dermal; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Diagnosis; Diffusion; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Evaluation; FDA approved; Family suidae; Fiber; Formulation; Funding; Goals; Health; High Prevalence; In Vitro; Insulin-Dependent Diabetes Mellitus; Maximum Tolerated Dose; Measures; Methodology; Methods; Micronucleus Tests; Miniature Swine; Modeling; Nerve Degeneration; Nerve Regeneration; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oryctolagus cuniculus; Pain; Participant; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phototoxicity; Pirenzepine; Plasma; Public Health; Radiolabeled; Rattus; Risk; Rodent Model; Safety; Small Business Innovation Research Grant; Streptozocin; Techniques; Telemetry; Testing; Therapeutic; Tissues; Topical application; Toxic effect; Toxicology; United States National Institutes of Health; Work; acute toxicity; base; drug development; effective therapy; genotoxicity; in vivo; irritation; mouse model; novel; novel therapeutics; pre-clinical; preclinical study; prevent; programs; radiotracer; respiratory; screening; success

 DESCRIPTION (provided by applicant): The objective of this SBIR fast-track project is to expediently advance pre-clinical development of a new therapeutic for diabetic neuropathy. Of the 25 million Americans who suffer from diabetes, approximately 50% will be diagnosed with neuropathy, which is characterized by nerve degeneration. Despite the high prevalence of the disease, there is currently no FDA-approved treatment to either prevent diabetes-induced nerve degeneration or promote nerve regeneration. Thus, there is a substantial unmet need to develop more effective treatments for diabetic neuropathy. The founders of WinSanTor have identified a promising candidate which both prevents and reverses neuropathy in rodent models of the disease. The candidate molecule, pirenzepine, was identified using a novel screening methodology developed in the labs of the company's founders. Pirenzepine has subsequently been evaluated in over a dozen in vivo tests, and has demonstrated the unique ability to ameliorate both epidermal fiber loss and thermal hypoalgesia. Pirenzepine is an approved drug for other indications in non-US countries, and so it is substantially de-risked as a drug development candidate. Based on the molecule's significant potential as a first-in-class molecule for treating diabetic neuropathy, we propose a fast-track project to rapidly advance pre-clinical development of the molecule. Phase I Specific Aims are: 1) Assess in vitro release and retention, single dose pharmacokinetics, and tissue distribution of topically administered pirenzepine. 2) Determine acute toxicity under non-GLP conditions. 3) Evaluate genotoxicity and hERG under non-GLP conditions. 4) Conduct dermal toxicity studies under non-GLP conditions. The metrics of success to advance to Phase II are: 1) Identification of at least one formulation in which sufficient quantities of active ingredient are present in the tissues and plasma following topical administration (porcine model), and 2) No significant toxicity liabilities Phase II Specific Aims are: 1) Develop analytical techniques and obtain GMP material. 2) Conduct acute toxicity and 3-month toxicity studies with two animal species under GLP conditions. 3) Conduct safety toxicology and genotoxicity studies under GLP conditions. 4) Conduct dermal toxicity studies under GLP conditions. The metric of success of Phase II is to develop a complete safety package that will be submitted to the FDA as part of an IND filing.

 描述（由申请人提供）：该 SBIR 快速通道项目的目标是迅速推进糖尿病神经病变新疗法的临床前开发。在 2500 万患有糖尿病的美国人中，大约 50% 将被诊断患有神经病变。其特点是神经变性，尽管这种疾病的患病率很高，但目前尚无 FDA 批准的治疗方法来预防糖尿病引起的神经变性或促进神经再生。 WinSanTor 的创始人发现了一种有前途的候选分子，可以预防和逆转糖尿病神经病变的啮齿动物模型中的神经病变，该分子是使用实验室开发的新型筛选方法确定的。该公司创始人的哌仑西平随后经过十多项体内测试的评估，并显示出改善表皮纤维损失和热痛觉减退的独特能力。哌仑西平是一种在非美国国家批准用于其他适应症的药物，因此作为药物开发候选药物的风险大大降低，基于该分子作为治疗糖尿病神经病变的一流分子的巨大潜力，我们提出了一种药物。快速推进该分子的临床前开发的快速通道项目具体目标是：1) 评估最高给药哌伦西平的体外释放和保留、单剂量药代动力学和组织分布。 2) 确定非 GLP 条件下的急性毒性 3) 评估非 GLP 条件下的遗传毒性和 hERG 4) 在非 GLP 条件下进行皮肤毒性研究 成功进入 II 期的指标是： 1) 鉴定。至少一种制剂，其中局部给药后组织和血浆中存在足够量的活性成分（猪模型），并且 2) 无明显毒性 第二阶段的具体目标是： 1)开发分析技术并获取 GMP 材料。 2) 在 GLP 条件下对两种动物进行急性毒性和 3 个月毒性研究。 4) 在 GLP 条件下进行皮肤毒性研究。第二阶段成功的关键是开发一个完整的安全包，该包将作为 IND 备案的一部分提交给 FDA。