A Phase IIa, Double-Blinded, Randomized Placebo-Controlled Trial of MAPKAPK2 Inhibition by ATI-450 in Treatment of Moderate-Severe COVID-19 Pneumonia

RATIONALE: The novel coronavirus disease 2019 (COVID-19) is a rapidly spreading global viral pandemic with a high-risk of mortality in selected populations (i.e. elderly, immunocompromised, cardiopulmonary diseases). A hyperinflammatory state caused by excessive inflammatory cytokine production (i.e. TNFα, IL-1β, IL6, IL-8) has been attributed to the pathobiology of COVID-19-mediated acute respiratory distress syndrome, worsened lung fibrosis and increased mortality. Inflammation and inflammatory disorders signal primarily through the MAPK pathway. Activation of p38α is important for regulating inflammation, and aberrant p38α activation is associated in the pathobiology of diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and tissue fibrosis. The downstream target of p38α is the protein MAPKAPK2 (MK2) and is responsible for transcriptional production of pro-inflammatory cytokines also elevated in COVID-19 inflammation. Further evidence in other severe viral illnesses (i.e. Dengue, Influenza, CMV) show activation of p38-MK2 signaling axis for mediating inflammation. Potentially, COVID-19 mediated inflammatory cytokine production may signal through p38α-MK2 axis and MK2 pathway blockade may suppress unwanted inflammation. However, it remains unknown whether reducing the inflammatory state can improve COVID-19 outcomes particularly in those with pre-existing conditions. We hypothesized that blockading this pathway would reduce inflammatory cytokine burden and improve respiratory failure-free survival in moderate-severe COVID-19 infected patients. Methods: We designed an investigator-initiated trial (IND#:149790;ClinicalTrials.gov Identifier: NCT04481685) using an oral MK2 inhibitor (ATI-450, Aclaris Pharmaceuticals) in COVID-19. This single-center trial is a Phase IIa, doubleblinded, randomized placebo-controlled proof-of-concept study. COVID-19 positive hospitalized patients with pulmonary signs and symptoms of moderate-severe hypoxic respiratory distress were randomized to ATI-450 or placebo twice-daily for up to 14 days. Results: Study enrollment is completed (n=20 subjects;n=11 male;median age 63 years old). The primary endpoint of this trial is respiratory failure-free survival at 14 days. Secondary endpoints include: changes in WHO-Ordinal scale, additional respiratory and survival outcomes, biochemical assays of circulating cytokines, and safety endpoints. Given the incomplete knowledge of MK2 pathway blockade effects on immune cell function, this study will further explore immune cell characterization in COVID-19 patients treated with ATI-450 via immunophenotyping and 10X Genomics single-cell gene expression analysis. We surmise that myeloid cell activation following COVID-19 infection contributes to localized and systemic tissue injury and will examine the effect of MK2 pathway blockade on eliciting myeloid cell inflammatory activation-suppression. Conclusion: Analyses of the safety, efficacy, and biology of MK2 inhibition, via ATI-450, in treating moderate-severe COVID-19 will be presented.