Inhibition of Bruton tyrosine kinase in patients with severe COVID-19
View ORCID ProfileMark Roschewski1,*, Michail S. Lionakis2,*, Jeff P. Sharman3,*, Joseph Roswarski4,*, Andre Goy5, M. Andrew Monticelli6, View ORCID ProfileMichael Roshon7, View ORCID ProfileStephen H. Wrzesinski8, View ORCID ProfileJigar V. Desai2, Marissa A. Zarakas2, Jacob Collen9, Keith Rose5, Ahmed Hamdy10, Raquel Izumi10, View ORCID ProfileGeorge W. Wright11, View ORCID ProfileKevin K. Chung9, View ORCID ProfileJose Baselga12, View ORCID ProfileLouis M. Staudt1,# and Wyndham H. Wilson1,#,†
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Science Immunology 05 Jun 2020:
Vol. 5, Issue 48, eabd0110
DOI: 10.1126/sciimmunol.abd0110
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.
