Development of a novel lipase inhibitor for the treatment of acute pancreatitis

项目概要/摘要 该提案旨在开发一种治疗急性胰腺炎的新疗法，这是一个主要的未满足的问题。 没有有效治疗的医疗需求。我们的方法建立在临床和临床前数据的基础上， 强烈暗示脂解和脂毒性是将轻度急性胰腺炎转化为 重症急性胰腺炎，其定义为持续性器官衰竭。此外，这项工作得到了 数据表明，脂肪酶活性的抑制消除了器官衰竭和全身性炎症的指标， 在重症急性胰腺炎的临床相关模型中发现的炎症反应综合征（SIRS）。我们 作为一家公司，我们有一种先导化合物，已经在初步的安全性研究中得到验证， 多个临床前疗效模型，疗效突出。此外，我们还设立了一个专家小组， 临床前和临床转化研究，胰腺炎研究和治疗， 创业、业务发展、制药合作和临床试验。我们的首要目标是 快速，有效，并通过翻译途径努力推进这种疗法。鉴于我们强大的 可行性数据，我们将其作为直接进入第二阶段的提案提交，这将使我们能够最迅速地， 有效地将该化合物推进临床试验（计划在本奖项结束时进行）。当前 将这种治疗方法投入临床试验的差距是完成提交临床试验所需的安全性研究。 研究性新药（IND）申请。因此，下一阶段的发展是完成IND- 进行安全性研究。本提案的目标是完成以下具体目标： 目的1：完成剂量范围确定、ADME、体外安全性和7天毒性和毒代动力学（TK） 问题研究第1年里程碑：1）完成剂量范围探索、ADME、遗传毒理学、7天毒性和 毒代动力学研究，2）完成IND前提交和IND前会议。 目的2：完成体内毒理学和安全药理学研究。第二年里程碑：1）完成 GLP毒理学和安全药理学研究，2）IND提交。 在完成本提案后，我们将拥有一个IND就绪的资产， 成功的临床开发团队准备通过临床试验。

Project summary/abstract This proposal seeks the development of a novel therapeutic for acute pancreatitis, which is a major unmet medical need with no effective treatment. Our approach builds upon a body of clinical and preclinical data that strongly implicate lipolysis and lipotoxicity as major driving factors in converting mild acute pancreatitis to severe acute pancreatitis, which is defined by sustained organ failure. In addition, this work is supported by data demonstrating that inhibition of lipase activity abrogates the organ failure and indicators of systemic inflammatory response syndrome (SIRS) found in clinically relevant models of severe acute pancreatitis. Our status as a company is that we have a lead compound that has been validated in preliminary safety studies, and multiple preclinical efficacy models with outstanding efficacy. We further have in place an expert team in the fields of preclinical and clinical translational research, pancreatitis research and treatment, entrepreneurship, business development, pharmaceutical partnering, and clinical trials. Our primary goal is to rapidly, efficiently, and diligently advance this therapy through the translational pathway. In light of our strong feasibility data, we are submitting this as a Direct-to-Phase 2 proposal, which will allow us to most rapidly and efficiently move this compound forward into clinical trials (planned at the conclusion of this award). The current gap in moving this treatment into clinical trials is to complete the safety studies needed to submit an investigational new drug (IND) application. As such, the next phase of development is to complete the IND- enabling safety studies. The objectives of this proposal are the completion of the following specific aims: Aim 1: Complete dose range finding, ADME, in vitro safety and 7-day toxicity and toxicokinetics (TK) studies. Year 1 milestones: 1) completion of dose range finding, ADME, genetic toxicology, 7-day toxicity and toxicokinetic studies, 2) completion of pre-IND submission and pre-IND meeting. Aim 2: Complete in vivo toxicology and safety pharmacology studies. Year 2 milestones: 1) completion of GLP toxicology and safety pharmacology studies, 2) IND submission. At the completion of this proposal, we will have an IND-ready asset, with a committed, experienced, and successful clinical development team ready to take it through clinical trials.