Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia: A Randomized, Phase 2 Trial*

Abstract

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). SETTING: Hospitals.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.

Editorial: The impact of COVID-19 on immune system-related complications in surgical patients

“…However, this conservative strategy represents a double-edged sword due to the risk associated with depriving patients from access to timely surgical care ( 23 ). There are currently multiple anti-inflammatory pharmacological agents available to attenuate the SARS-CoV-2-induced immune system derangements, including complement inhibitors ( 8 , 24 , 25 ) and monoclonal antibodies to pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-22 or IL-33 ( 26 – 28 ). Now at three years into the pandemic, the lessons learned from the COVID-related immunopathology will allow for more specifically targeted treatment modalities to inhibit SARS-CoV-2-induced hyperinflammation and the related immuno-thrombotic sequelae responsible for the high complication rates and increased mortality in surgical COVID-19 patients.…”

Lessons From a Negative Clinical Trial: Novel Immunological Targets for COVID-19 and Beyond*

“…It has been associated with inflammatory conditions including asthma and chronic obstructive pulmonary disease, and blocking this pathway may improve outcomes in asthma (5). Astegolimab is a human monoclonal antibody, which inhibits the IL-33 receptor, ST2 (2,5). In a phase 2b trial of patients with severe asthma, patients who received astegolimab subcutaneously had a significantly reduced number of exacerbations compared with placebo (5).…”

“…When COVID-19 arrived, many investigators logically prioritized finding therapies that might work earlier in the course of illness with the goal of preventing progression to late-stage disease. Here, Waters et al (2) intentionally limited the proportion of patients who were critically ill or requiring mechanical ventilation (a priori the enrollment of mechanically ventilated patients was limited to 25%). Ultimately, across all groups, the study randomized a total of 168 patients (42%) who were admitted to the ICU and 36 patients (9%) who were mechanically ventilated.…”

“…This research can provide the field with a forward step in the science of therapeutics beyond COVID-19, particularly in the broader realm of ARDS, which has seen few new treatments and no effective new pharmacotherapies in the past several decades (1). In this issue of Critical Care Medicine, Waters et al (2) report results from a clinical trial that investigated two intriguing and novel drug targets in COVID-19 in the interleukin (IL)-33 and IL-22 pathways. Their study, the COVIDastegolimab-interleukin trial, was a phase 2, randomized, double-blind, placebo-controlled trial containing two study drug arms: astegolimab (a human monoclonal antibody that binds the IL-33 receptor) and efmarodocokin alfa (a fusion of human IL-22 the IgG4 crystallizable fragment).…”

“…This study by Waters et al (2), conducted from June 2020 to March 2021, is in many ways a product of the pandemic times in which it was completed. The investigators facilitated expedited enrollment via a pooled placebo group to test two novel drugs, both administered by intravenous infusion, providing a time advantage compared with running two separate trials.…”