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

Mark Roschewski, Michail S. Lionakis, Jeff P. Sharman, Joseph Roswarski, Andre Goy, M. Andrew Monticelli, Michael Roshon, Stephen H. Wrzesinski, Jigar V. Desai, Marissa A. Zarakas, Jacob Collen, Keith M. Rose, Ahmed Hamdy, Raquel Izumi, George W. Wright, Kevin K. Chung, Jose Baselga, Louis M. Staudt, Wyndham H. Wilson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

268 Scopus citations

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 and 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10- to 14-day treatment course, initiation of acalabrutinib treatment was associated with improved oxygenation in a majority of patients, often within 1 to 3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and interleukin-6 (IL-6) - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8 of 11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4 of 8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2 of 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.

Original languageEnglish
Article numbereabd0110
JournalScience Immunology
Volume5
Issue number48
DOIs
StatePublished - Jun 2020
Externally publishedYes

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