Research Project
10323895
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.
