Selection of a lead LPAR1 antagonist for treatment of diabetic neuropathy

项目总结 糖尿病神经病变(DPN)是一个尚未得到满足的主要健康问题，在估计的3300万人中，超过一半的人 在美国，患有1型或2型糖尿病的人会患上神经病变。没有FDA批准的疾病修改 预防或减缓糖尿病神经病变进展的治疗，但建议维持的除外 血糖控制和目前的治疗仅限于对以下症状后果的管理 神经病变，如疼痛。越来越多的人认识到，糖尿病还会损害脊髓 (脊髓病)和脑(脑病)，因此糖尿病被认为是 发展为认知功能障碍和阿尔茨海默病14。因此，阻止或逆转 糖尿病期间周围神经和/或中枢神经系统的侮辱是有兴趣的，无论是作为单独的药物还是作为辅助因素 与对症治疗一起使用。EpiGen围绕着发现和开发 用于治疗纤维化疾病的新型溶血磷脂酸受体1型(LPAR1)拮抗剂。并行的 对糖尿病肾病的研究获得的数据表明，在埃皮根发现的先导化合物 在模型中，糖尿病神经病变的终点对于神经损伤和认知能力下降的标志物也是有益的。 这项提议建立在这些数据的基础上，以确定是否可以开发一种这样的先导化合物EPGN2154 治疗糖尿病神经病变。这种直接到第二阶段应用的目标是进行详细的临床前疗效 EPGN2154在大鼠DPN模型中的应用，以及筛选安全性，以允许提名开发候选人。 化合物将在加州大学圣地亚哥分校进行测试之前在埃皮根进行准备和表征 (UCSD)在奈杰尔·卡尔卡特博士的指导下。卡尔卡特博士的实验室将建立和维护 糖尿病啮齿动物，用爱普根公司提供的测试剂治疗，并测量生理、行为和 在整个研究过程中不同时间的外周和中枢神经病变的结构指数。经过研究 完成组织将被解剖和处理以进行组织学和生化评估，以支持 行为测量。EpiGen将进行额外的领导概况分析，以支持EPGN2154的候选人资格。药效 还将对分配进行评估，以支持机械学研究。复合分析将包括安全 EPGN2154的评估。这些研究将支持将EPGN2154推进到IND使能研究 作为进入DPN临床试验的前奏。

PROJECT SUMMARY Diabetic neuropathy (DPN) is a major unmet health concern where over half of the estimated 33 million people in the US with type 1 or type 2 diabetes will develop neuropathy1. There is no FDA-approved disease modifying treatment for preventing or slowing progression of diabetic neuropathy other than a recommendation to maintain glycemic control2 and current treatments are restricted to management of the symptomatic consequences of neuropathy such as pain. It is becoming increasingly appreciated that diabetes also injures both the spinal cord (myelopathy) and brain (encephalopathy) such that diabetes is recognized as a prominent risk factor for developing cognitive dysfunction and Alzheimer’s disease14. Accordingly, agents that prevent or reverse peripheral nerve and/or CNS insults during diabetes are of interest either as standalone agents or for adjunctive use with symptomatic treatments. Epigen has developed expertise around the discovery and development of novel lysophosphatidic acid receptor type 1 (LPAR1) antagonists for the treatment of fibrotic disease. In parallel to the study of diabetic nephropathy data was obtained to suggest that lead compounds discovered at Epigen also benefit endpoints of diabetic neuropathy for both nerve injury and markers for cognitive decline in models. This proposal builds on these data to determine if one such lead compound, EPGN2154, may be developed to treat diabetic neuropathy. The goal of this direct to phase 2 application is to conduct detailed pre-clinical efficacy of EPGN2154 in rat DPN models, along with screening safety to allow nomination of a development candidate. Compounds will be prepared and characterized at Epigen prior to testing at University of California San Diego (UCSD) under the guidance of Dr. Nigel Calcutt. Dr. Calcutt’s laboratory will establish and maintain colonies of diabetic rodents, treat them with test agents provided by Epigen and measure physiological, behavioral and structural indices of peripheral and central neuropathy at assorted times throughout the study. Upon study completion tissue will be dissected and processed for histological and biochemical evaluation to support behavioral measurements. Epigen will conduct additional lead profiling to support candidacy of EPGN2154. Drug distribution will also be evaluated to support mechanistic studies. Compound profiling will include a safety assessment of EPGN2154. These studies will support the advancement of EPGN2154 to IND enabling studies as a prelude to entry into clinical trials for DPN.