Efficacy and safety of MAS825 (anti-IL-1β/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function
Alex D Hakim, Mustafa Awili, Hollis R O’neal, Omar Siddiqi, Naseem Jaffrani, Richard Lee, Jeffrey S Overcash, Ann Chauffe, Terese C Hammond, Bela Patel, Michael Waters, Gerard J Criner, Alok Pachori, Guido Junge, Rafael Levitch, Jen Watts, Philip Koo, Tirtha Sengupta, Lili Yu, Michael Kiffe, Anne Pinck, Richard R Stein, Jamie Bendrick-Peart, Janet Jenkins, Marianna Rowlands, Frank Waldron-Lynch, Jesse Dean Matthews
Clinical and Experimental Immunology, doi:10.1093/cei/uxad065
MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasomemediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1β and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.
Supplementary data Supplementary data is available at Clinical and Experimental Immunology online.
Ethical Approval The study was conducted in accordance ICH GCP and Declaration of Helsinki. Patients or their legal representatives provided signed informed consent. The study was approved by the institutional review board and ethical committees of participating institutes. Additional details have been provided in the manuscript.
Conflict of Interests
Author Contributions The study was designed by G.J., M.K., R.R.S., M.R., R.L., T.S. and F.W.L. A.D.H., M.A., H.O.N., O.S., N.J., R.L., J.O., A.C., T.H., B.P., M.W., G.J.C., A.P., J.W., P.K., T.S., A.P., J.B.P., J.J., G.J., M.K., R.R.S., M.R., R.L., T.S., and F.W.L. contributed to the conduct of these studies. Data were acquired by A.D.H., M.A., H.O.N., O.S., N.J., R.L.,J.O., A.C., T.H., B.P., M.W., G.J.C. and analyzed by A.D.H., G.J., M.K , P.K., M.R., T.S., F.W.L. All authors contributed equally to the interpretation of data. A.D.H. is the principal investigator for this study. All authors contributed to the intellectual content of the manuscript and approved it for publication.
Permission to Reproduce This manuscript does not contain data that requires permission to reproduce.
Clinical Trial Registration ClinicalTrials.gov, NCT04382651
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doi:10.1016/S0140-6736(20)30566-3DOI record:
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