Pre-Clinical Development of Topical Pirenzepine for Treating Diabetic Neuropathy

 描述(由申请人提供)：该SBIR快速通道项目的目标是促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，约50%将被诊断为神经病变，其特征是神经变性。尽管糖尿病的发病率很高，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退化或促进神经再生。因此，开发更有效的糖尿病神经病变治疗方法是一个巨大的未得到满足的需求。WinSanTor的创始人已经确定了一种有希望的候选药物，可以预防和逆转这种疾病的啮齿动物模型中的神经病变。候选分子吡伦西平是通过该公司创始人实验室开发的一种新的筛选方法确定的。随后，在十几个体内试验中对吡仑西平进行了评估，并证明了其独特的改善表皮纤维丢失和热痛觉减退的能力。哌仑西平是非美国国家批准的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)评估外用吡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)测定非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。成功进入第二阶段的衡量标准是：1)确定至少一种配方，在局部给药(猪模型)后，组织和血浆中存在足够数量的有效成分，以及2)没有重大毒性责任第二阶段的具体目标是：1)开发分析技术和获得GMP材料。2)在GLP条件下，对两种动物进行急性毒性试验和3个月毒性试验。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套完整的安全方案，该方案将作为IND文件的一部分提交给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.