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（由适用提供）：这个SBIR快速轨道项目的目的是极端地促进糖尿病神经病新治疗的临床前开发。在患有糖尿病的2500万美国人中，大约有50％的神经病变将被诊断出患有神经变性。尽管该疾病的患病率很高，但目前尚无FDA批准的治疗方法可以预防糖尿病引起的神经变性或促进神经再生。那是次要的未满足需要开发更有效的糖尿病神经病治疗方法的。 Winsantor的创始人已经确定了一个承诺候选者，该候选者既可以阻止并逆转该疾病的啮齿动物模型中的神经病。使用在公司创始人实验室中开发的新型筛选方法鉴定出候选分子Pirenzepine。随后在多次体内测试中评估了Pirenzepine，并证明了改善表皮纤维损失和热差差的独特能力。 Pirenzepine是非美国国家中其他适应症的批准药物，因此它作为药物开发候选人的危险很高。基于该分子作为治疗糖尿病神经病的第一类分子的重要潜力，我们提出了一个快速轨道项目，以快速促进该分子的临床前发育。第一阶段的特定目的是：1）评估局部施用的吡伦zepine的体外释放和保留，单剂量药代动力学以及组织分布。 2）确定在非GLP条件下的急性毒性。 3）在非GLP条件下评估遗传毒性和HERG。 4）在非GLP条件下进行皮肤毒性研究。进入II期成功的指标是：1）识别至少一个公式，其中局部给药后的组织和血浆中呈现了足够数量的活性成分（猪模型），而2）无明显的毒性负责II期特异性目标是：1）开发分析技术并获得分析技术并获得GMP材料。 2）在GLP条件下对两种动物进行急性毒性和3个月的毒性研究。 3）在GLP条件下进行安全毒理学和遗传毒性研究。 4）在GLP条件下进行皮肤毒性研究。第二阶段成功的指标是开发一个完整的安全软件包，该包将作为IND申请的一部分提交给FDA。