Preclinical development of an immunomodulatory agent capable of mitigating SARS-CoV-2 virus related hypercytokinemia

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Abstract CytoAgents is developing GP1681 (beraprost-314d) to regulate the uncontrolled inflammatory response that can result from viral infections. This inflammatory response is associated with increased disease severity, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and death. The emergence of novel viruses with pandemic potential poses a major threat to world health and security. In particular, the emergence of novel coronaviruses (CoVs) of animal origin in recent decades indicates that these viruses will continue to cross species boundaries and cause outbreaks in humans. The current outbreak of SARS-CoV-2, a highly pathogenic CoV that causes lower respiratory tract infections and severe pneumonia, represents a severe public health emergency and has been declared a global pandemic by the World Health Organization. SARS-CoV-2 has so far infected nearly 3M individuals in 185 countries, resulting in over 200K deaths, with the greatest number of confirmed cases in the U.S. While most individuals with COVID-19 report only mild illness, about 14% develop severe disease requiring hospitalization and oxygen support, and 5% require intensive care. This has resulted in a significant burden on healthcare systems in several countries, as well as a massive economic burden globally. Studies have revealed that the severity of viral disease and negative health outcomes are often associated with an overstimulated cytokine response, rather than the viral load per se. Overactivation of the inflammatory response results in the uncontrolled release of proinflammatory cytokines, known as hypercytokinemia, which contributes to the destruction of lung tissue, and in severe cases, leads to ARDS, multiorgan dysfunction, and death. GP1681 moderates hypercytokinemia and may reduce the duration and severity of many viral diseases, including COVID-19. Evaluation in mouse models has shown notable efficacy of GP1681 in the treatment of influenza. Knowledge of the mechanism of action of GP1681 suggests that it may be equally effective in treating COVID-19. CytoAgents has submitted an Investigational New Drug (IND) Application to the FDA for an influenza indication and received approval to proceed with a Phase 1 study. Additional NIH (NIAID)-funded preclinical studies are also underway in influenza models. To assess the potential of GP1681 for use against COVID-19, the aims of this project are 1) IND-enabling toxicology studies expanding the initial toxicology screens, as longer treatment may be needed given the typical COVID-19 disease course; 2) Pharmacokinetic (PK) analysis in a non-human primate (NHP) model; and 3) Assessment of the efficacy of delayed GP1681 treatment in an NHP model of COVID-19, as therapy in the clinic is typically initiated at some time after viral infection. The outcomes of this project will prepare CytoAgents for an IND application for the use of GP1681 in the treatment of COVID-19.