Abstract and Introduction
Objectives: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia.
Design: Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL).
Patients: Hospitalized adults with severe COVID-19 pneumonia.
Interventions: Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28.
Measurements and Main Results: The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active.
Conclusions: Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.
In 2020, COVID-19 was the third leading cause of death in the United States. Most COVID-19–associated deaths are due to severe interstitial pneumonia, which progresses to acute respiratory distress syndrome (ARDS) and hypoxemic respiratory failure. ARDS, characterized by increased epithelial and endothelial permeability leading to alveolar edema, has been observed in 16–42% of patients with severe COVID-19.[1–5] Hyperinflammatory responses, including elevated pro-inflammatory cytokines, are associated with increased mortality in patients with COVID-19. COVID-19 treatment includes direct antiviral therapeutics and anti-inflammatory agents.
Interleukin (IL)-33, an alarmin released upon epithelial injury in response to allergens, irritants, and infections in the lung, binds the suppression of tumorigenicity 2 (ST2) (IL-1 receptor-like 1) receptor on multiple immune cell types driving pulmonary inflammation, which triggers downstream cytokine release. Patients with ARDS have elevated serum IL-33. IL-33 production increases with disease severity[8,9] and independently predicts poor outcomes in COVID-19. We hypothesized that astegolimab (MSTT1041A), a fully human immunoglobulin (Ig) G2 monoclonal antibody that binds ST2, blocks IL-33 signaling, and significantly reduces asthma exacerbations in patients with severe asthma, may reduce hyperinflammation during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
IL-22, an IL-10 family cytokine, acts directly on epithelial tissue. By working through regenerative and protective mechanisms, IL-22 may protect and repair lung epithelial tissue from ventilation-induced damage and acute lung injury following viral infections.[14,15] Patients with ARDS show reduced IL-22 levels in bronchoalveolar lavage fluid compared with mechanically ventilated patients without lung injury. Based on this, we hypothesized that efmarodocokin alfa (UTTR1147A), a fusion of human IL-22 and the IgG4 crystallizable fragment, may promote lung recovery in SARS-CoV-2 infection. The COVID-astegolimab-interleukin (COVASTIL) trial independently investigated the reduction in hyperinflammation via IL-33 blockade with astegolimab and prevention/repair of lung damage by IL-22 pathway activation with efmarodocokin alfa in patients with severe COVID-19 pneumonia.
Crit Care Med. 2023;51(1):103-116. © 2023 Lippincott Williams & Wilkins