Sci Immunol 5(48): eabd0110

PMC: PMC7274761

PMID: 32503877

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

Jigar Desai+10 authors

^{Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD;}^{Fungal Pathogenesis Section}_, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD; ^{Willamette Valley Cancer Institute and Research Center, US Oncology, Eugene, OR;}^{Hematology-Oncology Department, Walter Reed National Military Medical Center, Bethesda, MD;}^{John Theurer Cancer Center, Hackensack Meridian and School of Medicine at Seton Hall, NJ;}^{Rocky Mountain Cancer Center, US Oncology, Colorado Springs, CO;}^{Department of Emergency Medicine, Penrose-St. Francis Health Services, Colorado Springs, CO; US Acute Care Solutions, Canton, OH;}^{Department of Medicine, St. Peter’s Hospital and US Oncology, Albany, NY;}^{Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;}^{Acerta Pharma, South San Francisco, CA;}^{Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Bethesda, MD, USA}^{AstraZeneca, One MedImmune Way, Gaithersburg, MD}

^{These authors contributed equally to the manuscript.}

^{Co-senior authors}

^{Corresponding Author: Wyndham H. Wilson, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 4N115, National Institutes of Health, Bethesda, MD 20892. Email:}vog.hin.liam@wnosliw

Received 2020 May 26; Accepted 2020 Jun 3.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Abstract

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation – C-reactive protein and IL-6 – normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.

Acknowledgments

ACKNOWLEDGMENTS: The authors would like to thank all the patients and their caregivers who consented to release their clinical results for publication. We thank Norman E. “Ned” Sharpless for helpful discussions and advice. We acknowledge Michael Abers for illustration support. We would like to thank Dr. Daniel Chertow and Dr. Richard Davey from the NIAID/NIH and Dr. Marc Siegel from George Washington University Hospital for providing samples from COVID-19 patients for immunological analyses and Ms. Joie Davis from the NIAID/NIH for her assistance with obtaining informed consent from some of the COVID-19 patients who underwent immunological analyses at NIAID. We also would like to acknowledge additional health care providers who cared for these patients during their hospitalization and participated in the clinical decision-making process to use off-label acalabrutinib, including Jeffery Gray, Adam Barelski, and Jessica Bunin from Walter Reed National Military Medical Center; Caryn Baldauf, J. Daniel Monticelli, Russell M. Lee, Andrew Ingram, Elizabeth A. Kleiner, and Thomas J. Bartlett from Penrose Hospital; Timothy J. Murphy, and Matthew Logsdon from Rocky Mountain Cancer Center; Ihor Sawchuck, Robert Lee, Anuja Pradhan Ronak Shah, and Ali Nadeem from Hackensack University Medical Center; Ira Zackon, Lawrence Garbo, Qin Zen, John Phelan, Amy Zuchelkowski, and Nancy Egerton from New York Oncology Hematology and US Oncology; and Anwar Haque and Philip Palmieri from St. Peter’s Hospital. We specifically acknowledge all health care workers who have taken care of these patients and collected data. Funding: This work is supported by the Intramural Research Program of the National Institutes of Health: National Cancer Institute, Center for Cancer Research and National Institute of Allergy & Infectious Diseases. Individual hospitals provided commercial supply of the study drug for off-label use. Author contributions: The Lymphoid Malignancies Branch, National Cancer Institute, and the National Institute of Allergy & Infectious Diseases of National Institutes of Health provided academic input for this study. W.H.W, M.R., and L.M.S designed the study. M.R, J.P.S, J.R., A.G., M.A.M., M.R., S.W., K.R. J.C., and K.K.C. treated patients and collected data; M.S.L. designed and analyzed the correlative immunological experiments. J.V.D. and M.A.Z. performed the correlative laboratory experiments. M.R, J.P.S, J.R., A.G., M.A.M., M.R., S.W., J.C., A.H., R.I., K.K.C, M.S.L., J.B., L.M.S., and W.H.W. analyzed the data; W.H.W, M.R., and L.M.S wrote the paper. No medical writer was used. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Defense. Competing interests: A.H. and R.I. are current or past employees of Acerta Pharma, a majority-owned subsidiary of AstraZeneca, and have received salary and stock compensation from Acerta Pharma. A.H. and R.I. are listed as inventors on patents on acalabrutinib assigned to Acerta Pharma. R.I. also has an equity position in AstraZeneca. J.B. is an employee of AstraZeneca and has received salary, stock compensation and personal fees from AstraZeneca. The other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate and reproduce the conclusions in this paper are present in the main text or the Supplementary Materials. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

SUPPLEMENTARY MATERIALS

immunology.sciencemag.org/cgi/content/full/5/48/eabd0110/DC1

Supplementary Methods (instructions on preparation of acalabrutinib for an enteric feeding tube)

Figure S1. Gating strategy for flow cytometric analysis of phosphorylated and total BTK.

Figure S2. Gating strategy for flow cytometric analysis of IL-6.

Table S1. Treatment centers.

Table S2. Clinical course of supplemental oxygen cohort.

Table S3. Clinical course of mechanical ventilation cohort.

Table S4. Laboratory tests for inflammatory markers during acalabrutinib treatment in supplemental oxygen cohort.

Table S5. Laboratory tests for inflammatory markers during acalabrutinib treatment in mechanical ventilation cohort.

Table S6. Other laboratory tests during acalabrutinib treatment in supplemental oxygen cohort.

Table S7. Other laboratory tests during acalabrutinib treatment in mechanical ventilation cohort.

Table S8. Statistical analysis of laboratory changes related to oxygenation status.

Table S9. Adverse events of special interest during treatment with acalabrutinib.

Table S10. Characteristics of COVID-19 patients who underwent flow cytometry-based immunological analyses.

Table S11. Raw data file (Excel spreadsheet).