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.

摘要 急性呼吸窘迫综合征（ARDS）是一种危及生命的肺损伤，其特征是急性呼吸窘迫综合征（ARDS）。 炎症反应导致肺和器官衰竭。据估计，多达190，000例ARDS发生在 每年在美国造成74,000人死亡。ARDS可由呼吸道感染引起，包括COVID- 19，它是死亡的主要原因。ARDS患者的治疗创造了显著的医疗保健 和经济负担，因为患者需要进入重症监护室和长时间的机械 通风.尽管最近的数据表明皮质类固醇在降低老年人死亡率方面有一定的疗效， COVID-19 ARDS患者，对安全有效的治疗方法的需求仍然显著未得到满足。 Thetis Pharmaceuticals寻求通过以下方式解决对ARDS有效治疗的需求： 开发TP-317，一种受专利保护的Resolvin E1盐，一种影响 与ARDS有关的多种机制为了支持这一应用，Thetis提供了初步数据， 显示：1）RvE 1增强了肺损伤的消退并改善了ARDS小鼠模型的存活率; 2） 静脉注射大鼠中TP-317给药导致RvE 1有效递送至肺组织; 3）RvE 1证实 在大鼠、犬和人中具有良好的耐受性和安全性; 4）TP-317具有优异的稳定性，降低了成本， 药物制剂的风险。这些数据支持TP-317通过拟议的快速通道计划的发展 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实现以下目标来实现： 第一阶段，目标1。LPS小鼠急性肺模型中的药代动力学/药效学（PK/PD）研究 损伤（ALI）。将在ALI小鼠模型中评估TP-317多次i. v.给药，以确定临床剂量。 第一阶段目标2。犬剂量范围确定耐受性研究。的耐受性和毒代动力学特征 将在成年犬连续3天i. v.注射后的非GLP研究中评估TP-317。 I期Go/No-Go Milketone：在ALI模型中证明疗效，在 犬，其中所有不良结果在临床上可逆，临床上不严重，与人类无关或相关 但在诊所里是可以监控的预计高剂量代表无明显不良作用水平。 第二阶段，具体目标3。评价大鼠和犬中TP-317静脉给药的毒理学。的毒性和 将在GLP条件下在大鼠和犬中连续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1期临床试验的良好生产规范（GMP）条件下生产。 II期试验：证明两个种属的毒性特征均可接受，其中所有不良结果 临床上可逆、临床上不严重、与人类无关或相关但可在临床上监测。 根据ICH 1期研究指导原则生产足够的GMP临床试验材料。