Development of TP-352 for the Treatment of Pediatric Non-alcoholic Steatohepatitis

摘要 非酒精性脂肪性肝病(NAFLD)指的是一系列与代谢有关的疾病 以脂肪变性为特征的综合征，脂肪在肝脏内堆积。非酒精性 脂肪性肝炎(NASH)，最具侵袭性的NAFLD亚型，指炎症和 以脂肪变性为背景的坏死，并与肝纤维化有关。纳什的健康状况很严重 可能导致严重的长期健康问题的问题，包括肝纤维化、肝硬变和肝细胞 癌症。在过去的几十年里，NASH已经成为最常见的肝病之一 儿童和青少年患者。尽管美国约有200万儿童受到影响， 目前还没有批准的治疗NASH的方法。 为了满足这一未得到满足的医疗需求，西蒂斯制药公司(Thetis PharmPharmticals)提议开发镁 L-赖氨酸双二十二碳六烯酸酯，或TP-352，作为一种安全的口服疗法，用于解决儿童NASH 病人。TP-352提供二十二碳六烯酸(DHA)，一种欧米茄-3多不饱和脂肪酸(PUFA) 对儿童NASH有较好的临床疗效。TP-352克服了物理化学和 DHA固有的商业缺陷使开发一种安全有效的NASH治疗方法成为可能。 在这个SBIR快速通道项目中，Thetis将完成 向FDA提交研究用新药(IND)并启动临床研究。这个目标将是 通过执行五个具体目标来实现。第一阶段的目标是获得初步的证据 概念通过使用已建立的NASH(特定的)小鼠模型进行疗效研究 目的#1)，并研究TP-352在小鼠体内的药代动力学特征(特定目的#2)。第二阶段的目标是 完成启动临床研究所需的关键商业支持的临床前活动。初步努力将 重点开展毒物学计划(具体目标3)。一旦疗效和可接受的毒性 展示了TP-352的配置文件，西蒂斯将生产通过GMP认证的良好制造规范 第一阶段计划的临床试验材料(特定目标#4)。完成此快速通道SBIR后 项目，Thetis将完成所有必要的研究，提交IND申请并启动第一阶段 临床研究。正如该国一些领先的纳什专家的支持信所表明的那样，这 SBIR项目对于开发TP-352方案以解决#年未得到满足的医疗需求至关重要 这些脆弱的儿科人群。

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of diseases related to metabolic syndrome that are characterized by steatosis, the accumulation of fat within the liver. Non-alcoholic steatohepatitis (NASH), the most aggressive NAFLD subtype, refers to the presence of inflammation and necrosis in a background of steatosis, and is associated with hepatic fibrosis. NASH is a serious health problem that can lead to serious long-term health issues, including liver fibrosis, cirrhosis and hepatocellular carcinoma. In the last few decades, NASH has emerged as one of the most common liver disorders amongst pediatric and adolescent patients. Despite affecting approximately two million children in the United States, there are currently no approved therapies for NASH. To answer this unmet medical need, Thetis Pharmaceuticals (Thetis) proposes to develop magnesium L-lysinate bis docosahexaenoate, or TP-352, as a safe, oral therapy for resolution of NASH in pediatric patients. TP-352 delivers docosahexaenoic acid, (DHA), an Omega-3 polyunsaturated fatty acid (PUFA) shown to have clinical efficacy for treatment of pediatric NASH. TP-352 overcomes the physico-chemical and commercial deficits inherent to DHA to enable development of a safe and effective treatment for NASH. In this SBIR Fast-Track project, Thetis will complete the preclinical activities required for an investigational new drug (IND) submission to the FDA and initiation of clinical studies. This goal will be achieved through the execution of five Specific Aims. The objective of Phase I is to obtain initial proof of concept by performing an efficacy studies using an established mouse model of NASH (Specific Aim #1) and characterizing TP-352 pharmacokinetics in mice (Specific Aim #2). The objective of Phase II is to complete key commercially-enabling preclinical activities required to initiate clinical studies. Initial efforts will focus on conducting a toxicological program (Specific Aim #3). Once the efficacy and acceptable toxicity profile of TP-352 are demonstrated, Thetis will manufacture good manufacturing practice (GMP) certified clinical trial material for the Phase 1 program (Specific Aim #4). Upon completion of this Fast-Track SBIR project, Thetis will have completed all requisite studies to submit an IND application and initiate Phase 1 clinical studies. As indicated by letters of support from some of the country’s leading NASH specialists, this SBIR project is critical to enabling development of the TP-352 program to address the unmet medical need in this vulnerable pediatric population.