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

开发一种基于 Resolvin 的新型疗法，用于预防和治疗急性呼吸窘迫综合征 (ARDS)

• 批准号: 10323895
• 负责人: Frank Sciavolino
• 金额: $ 29.96万
• 依托单位: THETIS PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323895
• 关键词: Acute; Acute Lung Injury; Address; Admission activity; Adrenal Cortex Hormones; Adult; Adult Respiratory Distress Syndrome; Adverse effects; Affect; Area; Bronchoalveolar Lavage; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19/ARDS; Canis familiaris; Cause of Death; Cessation of life; Clinic; Clinical; Clinical Treatment; Clinical Trials; Complication; Coronavirus; Data; Development; Dose; Drug Formulations; Drug Kinetics; Economic Burden; Endotoxins; Escherichia coli; Exhibits; Feedback; Future; Goals; Guidelines; High Pressure Liquid Chromatography; Homeostasis; Human; Immune system; Immunization; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Injections; Intensive Care Units; Intravenous; Legal patent; Life; Liquid substance; Lung; Mechanical ventilation; Mediator of activation protein; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; No-Observed-Adverse-Effect Level; Organ failure; Oxygen; Particulate Matter; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebos; Pneumonia; Prevention therapy; Process; Rattus; Research; Residual state; Resolution; Respiratory Failure; Respiratory Tract Infections; Risk; Safety; Secondary to; Sepsis; Shock; Small Business Innovation Research Grant; Sodium Chloride; Solvents; Stomach Content; Structure of parenchyma of lung; Supportive care; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Toxic effect; Toxicokinetics; Toxicology; Trauma; Water; Weight; base; clinical investigation; clinical practice; cohort; cost; economic cost; effective therapy; health care economics; healthy volunteer; immunoreaction; improved; innovation; lipid mediator; lung injury; manufacturing scale-up; mortality; mouse model; neutrophil; novel; phase 1 study; phase I trial; preclinical study; primary endpoint; programs; research clinical testing; ventilation

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.

抽象的 急性呼吸窘迫综合征（ARDS）是一种危及生命的肺损伤，其特征是急性呼吸窘迫综合征。 炎症反应导致肺和器官衰竭。据估计，有多达 190,000 例 ARDS 病例发生 美国每年造成 74,000 人死亡。 ARDS 可能由呼吸道感染引起，包括新冠肺炎 (COVID-19) 19，这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 以及经济负担，因为患者需要进入重症监护病房并需要长期机械治疗 通风。尽管最近的数据表明皮质类固醇在降低死亡率方面效果有限 COVID-19 ARDS 患者对安全有效的治疗的需求仍然未得到满足。 Thetis Pharmaceuticals 致力于通过以下方式解决 ARDS 有效治疗的需求： 开发 TP-317，这是一种受专利保护的 Resolvin E1 盐，Resolvin E1 是一种内源性脂质介质，影响 ARDS 涉及多种机制。为了支持该应用，Thetis 提供了初步数据 显示：1) RvE1 增强 ARDS 小鼠模型肺损伤的消退并提高生存率； 2） 大鼠静脉内 (i.v.) TP-317 给药可将 RvE1 有效递送至肺组织； 3）RvE1演示 对大鼠、狗和人类具有良好的耐受性和安全性； 4) TP-317表现出优异的稳定性，降低成本和 药物配方的风险。这些数据支持通过拟议的快速通道计划开发 TP-317 总体目标是完成临床前研究以支持 IND 申请并将 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： I 期，目标 1：LPS 小鼠急性肺模型的药代动力学/药效 (PK/PD) 研究 损伤（ALI）。多剂量 TP-317 静脉注射将在 ALI 小鼠模型中进行评估以确定临床剂量。 第一阶段，目标 2。寻找狗的剂量范围耐受性研究。的耐受性和毒代动力学特征 TP-317 将在成年犬静脉注射后的非 GLP 研究中进行评估。连续注射3天。 I 期通过/不通过里程碑：在 ALI 模型中展示功效，在 ALI 模型中展示可接受的毒性特征 狗，其中所有不良结果在临床上都是可逆的，临床上不严重，与人类无关或相关 但可以在诊所进行监测。高剂量预计代表未观察到的不良反应水平。 II 期，具体目标 3。评估大鼠和狗的静脉注射 TP-317 毒理学。毒性和 将在 GLP 条件下对大鼠和狗连续 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：在两个物种中证明可接受的毒性特征，其中所有不良发现 临床上可逆，临床上不严重，与人类无关，或相关但可在临床中监测。 根据 ICH 第一阶段研究指南生产足够的 GMP 临床试验材料。