Preclinical Studies of PHP-303, a Neutrophil Elastase Inhibitor to Treat Severe COVID-19-Associated Acute Respiratory Distress Syndrome and Lung Injury
Abstract
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has circumnavigated the globe producing asymptomatic carriers, mildly and severely ill patients, and killed many people. While higher rates of mortality are observed in people of advanced age and those who had preexisting conditions, this pandemic has not spared the healthy and the young. The medical, emotional, and financial impact to civilians, warfighters, veterans, and their families is immeasurable. The illness produced by COVID-19 infections can be divided into two phases. In the initial phase, it causes relatively moderate respiratory symptoms including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and pneumonia, plus a variety of other symptoms. A second more life-threatening phase of the illness emerges a week or more later in a subset of patients and is the result of the body’s overactive immune response to the virus. This phase includes disease processes such as cytokine storm (which can lead to sepsis), blood clot formation, and severe lung damage. Neutrophils – human immune system cells, which normally play an important role in defense against foreign invaders such as viruses, play a critical role in this second phase. An enzyme released by neutrophils called neutrophil elastase (NE) degrades tissue allowing neutrophils to reach sites of infection, influences cytokine signaling pathways to dial up the immune response, and destroys pathogens. To oppose the potentially damaging effects of NE, the body produces proteins that bind and inhibit it. However, under states of very high inflammation in which large numbers of neutrophils are present, the excess NE is not adequately controlled by these proteins and the excess NE can damage the patient’s body. Indeed, this has been observed in patients with severe COVID-19 infection and is implicated in processes that are often lethal in patients such as sepsis, blood clot formation, and pneumonia and/or ARDS/ALI. Furthermore, patients that survive severe COVID-19 infection often have residual lung damage, and excess NE release may contribute to this damage. A drug that inhibits NE may reduce lung damage caused by COVID-19 and have long-term benefits to prevent residual lung function impairment in these patients. PHP-303 is a drug candidate that is the most potent NE inhibitor to enter clinical trials. The drug has been proved safe in multiple clinical studies, including a recently completed Phase 1 study that tested dose levels predicted to inhibit NE activity. PHP-303 can be taken orally in tablet form and should limit the detrimental effects of excess NE in COVID-19 patients. We propose preclinical studies to determine if PHP-303 can prevent some of the negative effects of neutrophils in cultured cells; reach effective concentrations in the lung; and demonstrate efficacy in preclinical animal models of pulmonary damage/infection. These include two models of ALI in rats and a model of SARS-CoV-2 infection in monkeys. If PHP-303 has positive effects on measures of lung damage and/or disease progression in these animal models, it will position PHP-303 for testing in Phase 2 clinical trials in severe COVID-19 patients. The long-term objective is to receive approval of PHP-303 by the FDA for the treatment of COVID-19 patients with severe pulmonary disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110042
Entities
People
- Patricia Finn
Organizations
- United States Army