Novel Pharmacological Interventions for ARDS of COVID-19 Patients: Investigational New Drug-Enabling Studies

Acute respiratory distress syndrome (ARDS) is a major complication of Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV-2) infection, contributing to morbidity, mortality, and potential long-term disability in COVID-19 patients. As COVID-19 spreads rapidly throughout the world, there is a pressing unmet need for novel pharmacological strategies to mitigate the severity of this devastating disease that has become common in military personnel, veterans, and civilians. The proposed studies aim to develop a novel therapeutic agent for treating respiratory complications in COVID-19 patients. This novel drug candidate, VT-109, is a synthetic cyclic peptide (901 Da) that treats many pathological manifestations of the severe form of SARS-CoV-2 infection. It restores function to injured lung, heart, and liver; reduces levels of circulating inflammatory cytokines; and improves survival in septic mice. Based on these preclinical findings, we hypothesize that VT-109 represents a useful pharmacologic approach to treat pulmonary edema and systemic inflammation in COVID-19 patients. To support the advancement of this novel drug candidate to a first-in-man clinical trial, a set of Investigational New Drug (IND)-enabling preclinical efficacy, pharmacology, and toxicology studies to support an IND submission are proposed here. Aim 1 establishes the efficacy of the novel drug candidate VT-109 in treating pulmonary edema, lung inflammation, and injury associated with SARS-CoV-2 infection using two animal models: transgenic mice expressing human angiotensin-converting enzyme 2 receptor and cynomolgus monkeys. Whereas mice will be used to establish the dose-response effect as well as to determine the therapeutic window in treating respiratory illness associated with SARS-CoV-2 infection, non-human primates will provide a near clinical model to validate findings in mice. The time-course of virus shedding will also be determined in nasal and throat swabs to characterize any potential effect of the drug candidate on the duration of SARS-CoV-2 infection. Aim 2 characterizes the potential mutagenicity of VT-109 using bacterial mutagenesis (Ames) and mammalian cell DNA damage using an in vitro chromosomal aberration in TK lymphoma cell assay and an in vivo mammalian erythrocyte micronucleus test. These studies will provide a critical "Go/No Go" point in early development for non-oncology indications. Aim 3 evaluates safety pharmacology and pharmacokinetic (PK) profiles of the drug candidate, key elements of IND submissions, in rats and cynomolgus monkeys. These studies will include the effects of VT-109 on in vitro ventricular repolarization, in vitro protein binding and plasma stability, in vivo cardiovascular effects in telemetrized monkeys, as well as characterize in vivo PK profiles in rats and monkeys. Aim 4 characterizes the toxicity of the drug candidate in single and repeat dose (7-day) range-finding toxicity studies in cynomolgus monkeys. These studies will define the No Observed (Adverse) Effect Level (NO[A]EL) after repeat-dose administration. If the drug candidate demonstrates suitable PK profiles and acceptable toxicity, we will conduct a pre-IND meeting to solicit FDA's guidance on the acceptability of a proposed IND-enabling program involving 28-day repeat-dose Good Laboratory Practice (GLP) studies (with recovery). Aim 5 implements a pilot Good Manufacturing Practice (GMP) production of the drug candidate for initial clinical trials using liquid combinatorial synthesis. We will perform chemistry process development and optimization as well as scale-up feasibility for the most effective synthetic route. We will also develop analytical and quality control methodology as well as conduct required chemical stability studies. A GMP-compliant process will be developed, and sufficient material will be synthesized to complete a first-in-human clinical trial. Aim 6 develops analytical methods for GLP studies in rats and monkeys. To facilitate the quantitative analysis of the drug candidate in dosage formulations, we will develop an assay using high performance liquid chromatography (HPLC) with UV detection and validate this assay as required by the FDA for IND submissions. In addition, to enable drug level and PK analysis of plasma from rats and monkeys, we will develop and validate a liquid chromatography - tandem mass spectrometry (LC-MS/MS) method. Aim 7 characterizes the toxicity and PK profile of the drug candidate in 28-day repeat dose toxicity/PK GLP studies (with recovery) in rats and cynomolgus monkeys. Three dose levels and a vehicle control will be assessed in both species. Animals will be dosed for 28 days and necropsied on day 29 for pathology, clinical chemistry, hematology, coagulation, and histopathology assessment. Additional animals in the high dose and control groups will be allowed to recover for 2 weeks after the last dosing and then evaluated for recovery of toxicity. We expect these studies to lay the groundwork for a novel therapeutic approach in treating acute respiratory distress syndrome (ARDS) associated with SARS-CoV-2 infection, thereby improving the survival rates and quality of life of COVID-19 patients-our long-term goal. Less