Development of a Novel Resolvin-Based Therapy for the Prevention and Treatment of Acute Respiratory Distress Syndrome (ARDS)

摘要 急性呼吸窘迫综合征(ARDS)是一种危及生命的肺损伤，其特征是急性 导致肺和器官衰竭的炎症反应。据估计，发生的ARDS病例多达19万例 在美国每年造成7.4万人死亡。ARDS可由呼吸道感染引起，包括COVID- 19，它是导致死亡的主要原因。ARDS患者的治疗创造了重要的医疗保健 和经济负担，因为患者需要进入重症监护病房和延长机械治疗时间 通风。尽管最近的数据表明，皮质类固醇在降低儿童死亡率方面效果不大。 对于新冠肺炎急性呼吸窘迫综合征患者来说，对安全有效的治疗仍然有很大的需求没有得到满足。 西蒂斯制药公司寻求通过以下途径解决ARDS有效治疗的需求 受专利保护的内源性脂质介质Resolvin E1的盐TP-317的开发 ARDS涉及多种机制。为了支持这一申请，西蒂斯提供了初步数据 结果表明：1)RvE1提高了ARDS模型小鼠肺损伤的分辨率和存活率；2) 静脉注射(静脉注射)TP-317在大鼠体内的剂量导致RvE1有效地输送到肺组织；3)RvE1显示 对大鼠、狗和人类具有良好的耐受性和安全性；4)TP-317具有极好的稳定性，降低了成本和 药物配方的风险。这些数据支持通过拟议的快速通道方案开发TP-317 总体目标是完成临床前研究以支持IND应用并将TP-317推进到 治疗ARDS的临床试验。这一总体目标将通过执行以下目标来实现： 第一阶段，目的1.脂多糖小鼠急性肺损伤模型的药代动力学/药效学(PK/PD)研究 损伤(ALI)。静脉注射多剂量TP-317。将在ALI的小鼠模型中进行评估，以确定临床剂量。 第一阶段，目标2。狗的剂量范围发现耐受性研究。阿司匹林的耐受性和毒代动力学研究 TP-317将在成年犬静脉注射后的一项非GLP研究中进行评估。连续注射3天。 第一阶段Go/No Go里程碑：ALI模型的有效性演示和可接受的毒性分布 狗，所有不良结果在临床上是可逆的，临床上不严重，与人类无关，或相关 但在诊所里是可以监测的。高剂量预计代表未观察到的不良反应水平。 第二阶段，特定目标3.评价TP-317静脉注射对大鼠和狗的毒理作用毒性和 在大鼠和狗的GLP条件下，将连续14天评估TP-317的毒代动力学特征。 第二阶段，具体目标4.临床试验材料的开发和制造。临床试验材料将 在良好的生产规范(GMP)条件下生产，用于第一阶段临床试验。 第二阶段里程碑：显示两个物种的可接受毒性概况，其中所有不良发现 在临床上是可逆的，临床上不严重，与人类无关，或者相关但在临床上可监测。 根据ICH第一阶段研究指南制作足够的GMP临床试验材料。

ABSTRACT Acute Respiratory Distress Syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response leading to lung and organ failure. It is estimated that up to 190,000 cases of ARDS occur in the US each year resulting in 74,000 deaths. ARDS can be caused by respiratory infections, including COVID- 19, for which it is the leading cause of death. The treatment of patients with ARDS creates significant healthcare and economic burdens as patients require admission into intensive care units and prolonged mechanical ventilation. Although recent data suggests that corticosteroids have modest efficacy in reducing mortality in COVID-19 ARDS patients, there remains a significant unmet need for safe and effective therapies. Thetis Pharmaceuticals seeks to address the need for an effective treatment for ARDS through development of TP-317, a patent-protected salt of Resolvin E1, an endogenous lipid mediator that affects multiple mechanisms implicated in ARDS. In support of this application, Thetis presents preliminary data showing: 1) RvE1 enhances resolution of lung injury and improves survival in mouse models of ARDS; 2) intravenous (i.v.) TP-317 dosing in rat leads to efficient delivery of RvE1 to lung tissue; 3) RvE1 demonstrates good tolerability and safety in rats, dogs, and humans; 4) TP-317 exhibits excellent stability, reducing cost and risk of drug formulation. These data support development of TP-317 through the proposed Fast-Track program with the overall goal of completing preclinical studies to support an IND application and advance TP-317 into clinical trials for the treatment of ARDS. This overall goal will be met through the execution of the following aims: Phase I, Aim 1. Pharmacokinetic/Pharmacodynamic (PK/PD) Study in LPS Mouse Model of Acute Lung Injury (ALI). Multiple doses of TP-317 i.v. will be assessed in a mouse model of ALI to identify clinical doses. Phase I, Aim 2. Dose Range Finding Tolerability Study in Dog. The tolerability and toxicokinetic profile of TP-317 will be assessed in a non-GLP study in adult dogs following i.v. injections for 3 consecutive days. Phase I Go/No-Go Milestones: Demonstration of efficacy in the ALI model and an acceptable toxicity profile in dog, in which all adverse findings are clinically reversible, not clinically severe, irrelevant to humans, or relevant but monitorable in the clinic. The high dose is expected to represent the no-observed-adverse-effect-level. Phase II, Specific Aim 3. Evaluate intravenous TP-317 Toxicology in Rat and Dog. The toxicity and toxicokinetic profile of TP-317 will be assessed under GLP conditions in rats and dogs for 14 consecutive days. Phase II, Specific Aim 4. Development and Manufacture of Clinical Trial Materials. Clinical trial material will be produced under good manufacture practice (GMP) conditions for the Phase 1 clinical trial. Phase II Milestones: Demonstration of an acceptable toxicity profile in both species, in which all adverse findings are clinically reversible, not clinically severe, irrelevant to humans, or relevant but monitorable in the clinic. Manufacture of sufficient GMP clinical trial material according to ICH Guidelines for Phase 1 studies.