Pre-Clinical Development of Topical Pirenzepine for Treating Diabetic Neuropathy

 描述（由申请人提供）：该SBIR快速通道项目的目的是方便地推进糖尿病神经病变新治疗药物的临床前开发。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，其特征在于神经变性。尽管这种疾病的患病率很高，但目前还没有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变治疗存在大量未满足的需求。WinSanTor的创始人已经确定了一种有希望的候选药物，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该公司创始人实验室开发的一种新的筛选方法鉴定的。哌仑西平随后在十几个体内试验中进行了评估，并证明了其改善表皮纤维丢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显著潜力，我们提出了一个快速跟踪项目，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）评估局部施用的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)在非GLP条件下确定急性毒性。3)在非GLP条件下评价遗传毒性和hERG。4)在非GLP条件下进行皮肤毒性研究。进入II期的成功指标是：1）鉴定至少一种制剂，其中在局部给药后组织和血浆中存在足量的活性成分（猪模型），和2）无显著毒性倾向II期具体目标是：1）开发分析技术并获得GMP材料。2)在GLP条件下对两种动物种属进行急性毒性和3个月毒性研究。3)在GLP条件下进行安全性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，作为IND申请的一部分提交给FDA。

 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.