Assessment of chronic toxicity to support the use of topical pirenzepine for treating diabetic neuropathy

项目摘要 该SBIR商业化准备项目（CRP）的目的是评估慢性毒性 一种新的糖尿病神经病变治疗方法，以支持IND申请。在2500万美国人中， 患有糖尿病，大约50%将被诊断为神经病变，其特征在于神经 退化尽管该疾病的患病率很高，但目前还没有FDA批准的治疗方法， 预防糖尿病引起的神经退化或促进神经再生。因此，有一个 因此，开发更有效的糖尿病神经病变治疗方法的需求大量未得到满足。 WinSanTor的创始人已经确定了一个有前途的候选人，既防止和逆转 在啮齿类动物模型的疾病。候选分子哌仑西平是用一种新的 公司创始人在实验室开发的筛选方法。哌仑西平随后被 在十几个体内试验中进行了评估，并证明了其独特的能力，以改善表皮 纤维丢失和热痛觉减退。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， 因此其作为药物开发候选物的风险大大降低。在SBIR快速通道计划中， WinSanTor成功执行了加速临床前项目，包括：1）开发和 生物分析方法的验证; 2）药代动力学分析; 3）优化制剂以增强 递送; 4）产生安全性特征;和5）哌仑西平的GMP制造。这些努力充分支持 通过评价慢性毒性评估，继续执行临床前项目。 本CRP项目的重点是评价哌仑西平局部应用9 个月选择9个月研究以满足NDA的9个月慢性毒性研究要求 提交并支持预期的II期临床试验方案的持续时间， 给药至少5个月。本研究将在小型猪中进行，并将使用多种毒性试验 终点，如死亡率观察结果、临床观察结果、Draize评分、临床病理学和 组织病理学，以充分确定哌仑西平的毒理学特征。这一目标的成功标准是 在暴露水平下达到NOAEL，使人体安全裕度高达10倍 问题研究本研究的完成对于向FDA提交IND以支持后续临床试验至关重要。 审判

PROJECT SUMMARY The objective of this SBIR Commercialization Readiness Program (CRP) project is to evaluate chronic toxicity of a new therapeutic for diabetic neuropathy in support of an IND submission. 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. In a SBIR Fast-track program, WinSanTor successfully executed an expedited pre-clinical program that included: 1) development and validation of bioanalytical methods; 2) pharmacokinetic analyses; 3) optimization of formulation to enhance delivery; 4) generation of a safety profile; and 5) GMP manufacturing of pirenzepine. These efforts fully support the continued execution of the pre-clinical program through the evaluation of chronic toxicity assessments. The focus of this CRP program will be to evaluate the toxicity of pirenzepine when applied topically for 9 months. A 9-month study was chosen to fulfill the 9-month chronic toxicity study requirement for an NDA submission and to support the duration of the anticipated Phase 2 clinical trial protocol that will involve administration for at least 5 months. This study will be executed in mini-pigs and will use a number of toxicity end points, such as mortality observations, clinical observations, Draize scoring, clinical pathology, and histopathology, to fully define a toxicological profile of pirenzepine. The metric of success for this Aim is to achieve to achieve a NOAEL at an exposure level such that there is up to a 10x safety margin for human studies. The completion of this study is critical to an IND submission to the FDA to support subsequent clinical trials.