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: 9208595
• 负责人: Angela Hansen
• 金额: $ 30万
• 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/9208595
• 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% 会被诊断出患有神经病变，其特征是神经退化。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。因此，对于开发更有效的糖尿病神经病治疗方法存在巨大的未满足的需求。 WinSanTor 的创始人已经找到了一种有前途的候选药物，它可以预防和逆转啮齿动物模型中的神经病变。候选分子哌仑西平是使用公司创始人实验室开发的新型筛选方法进行鉴定的。随后，哌仑西平在十多项体内测试中进行了评估，并证明了其改善表皮纤维损失和热痛觉减退的独特能力。哌仑西平是美国以外国家批准用于其他适应症的药物，因此作为候选药物开发的风险大大降低。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，我们提出了一个快速通道项目，以快速推进该分子的临床前开发。第一阶段的具体目标是： 1) 评估局部给药哌仑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) 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。成功进入第二阶段的衡量标准是：1) 鉴定出至少一种制剂，其中局部给药（猪模型）后组织和血浆中存在足够量的活性成分，以及 2) 无显着毒性责任 第二阶段的具体目标是：1) 开发分析技术并获得 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。第二阶段成功的衡量标准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。