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Clinical Trial
. 2023 Jan 1;51(1):103-116.
doi: 10.1097/CCM.0000000000005716. Epub 2022 Nov 14.

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

Michael Waters  1 , James A McKinnell  2   3 , Andre C Kalil  4 , Greg S Martin  5 , Timothy G Buchman  6 , Wiebke Theess  7 , Xiaoying Yang  8 , Annemarie N Lekkerkerker  9 , Tracy Staton  9 , Carrie M Rosenberger  10 , Rajita Pappu  11 , Yehong Wang  12 , Wenhui Zhang  12 , Logan Brooks  12 , Dorothy Cheung  7 , Joshua Galanter  13 , Hubert Chen  7 , Divya Mohan  7 , Melicent C Peck  7 ; COVID-astegolimab-interleukin (IL) (COVASTIL) Study Group
Collaborators, Affiliations
Clinical Trial

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

Michael Waters et al. Crit Care Med. .

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.

Trial registration: ClinicalTrials.gov NCT04386616.

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Conflict of interest statement

Dr. Waters has received funding from Genentech paid to his institution for the conduct of this trial. Dr. McKinnell has received funding from Genentech paid to his institution for the conduct of this trial; he reports receiving research funding paid to his institution from Gilead, Eli Lilly and Company, and Duke University; and he received funding from Pfizer and ThermoFisher. Dr. Martin has received compensation for service as a monitor of the COVID-astegolimab-interleukin trial. Dr. Buchman serves as a Senior Advisor to Biomedical Advanced Research and Development Authority (BARDA), U.S. Department of Health and Human Services under an agreement between his employer, Emory University, and that agency; he also serves as Editor-in-Chief of Critical Care Medicine, and Emory University similarly receives payment for that service from the Society of Critical Care Medicine. Drs. McKinnell, Martin, Buchman, Theess, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck disclosed the off-label product use of Astegolimab and Efmarodocokin Alfa. Dr. Theess is currently an employee of F. Hoffmann-La Roche and owns Roche stock. Drs. Staton and Wang are former employees of Genentech and own Roche stock. Dr. Chen is a former employee of Genentech. Drs. Martin, Theess, Yang, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Cheung, Galanter, Chen, Mohan, and Peck received funding from Genentech. Drs. Theess’s, Lekkerkerker’s, Staton’s, Rosenberger’s, Wang’s, Zhang’s, Cheung’s, Chen’s, Mohan’s, and Peck’s institutions received funding from the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, and the BARDA (OT number: HHSO100201800036C). Drs. Theess, Yang, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck are employees of Genentech, a member of the Roche group, and own Roche stock. Drs. Theess and Brooks disclosed they are employed by F. Hoffman-LaRoche. Drs. Theess, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck disclosed work for hire. Dr. Brooks disclosed that he is a Principal Computational Researcher at Genentech. Dr. Kalil has disclosed that he does not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
COVID-astegolimab-interleukin study design and patient disposition. A, Study design. The second dose on day 15 (open triangles) was only given if the patient remained hospitalized and required supplemental oxygen. B, Patient disposition. aMatching placebo (PBO) groups for astegolimab and efmarodocokin alfa were pooled for all analyses. mITT = modified intent-to-treat, SOC = standard of care.
Figure 2.
Figure 2.
Primary endpoint (time to recovery) and clinical status. A, Time to recovery. B, Clinical status using the 7-category ordinal scale over time. p values were generated from the log-rank test, and hazard ratios (HRs) were generated from the Cox proportional hazard model. Both parameters were stratified by country and baseline mechanical ventilation. Eight patients had an ordinal score of 2 at baseline and therefore did not contribute to the primary endpoint analysis.
Figure 3.
Figure 3.
Effects of astegolimab and efmarodocokin alfa on activity biomarkers. Mean percent change from baseline through day 28 in serum soluble ST2 (sST2) (A), regenerating islet-derived protein 3A (REG3A) (B), and C-reactive protein (CRP) (C). Right-hand images shows magnification of timepoints through day 15. Error bars, se.
See this image and copyright information in PMC

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