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

TY - JOUR

T1 - Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

AU - Roschewski, Mark

AU - Lionakis, Michail S.

AU - Sharman, Jeff P.

AU - Roswarski, Joseph

AU - Goy, Andre

AU - Monticelli, M. Andrew

AU - Roshon, Michael

AU - Wrzesinski, Stephen H.

AU - Desai, Jigar V.

AU - Zarakas, Marissa A.

AU - Collen, Jacob

AU - Rose, Keith M.

AU - Hamdy, Ahmed

AU - Izumi, Raquel

AU - Wright, George W.

AU - Chung, Kevin K.

AU - Baselga, Jose

AU - Staudt, Louis M.

AU - Wilson, Wyndham H.

N1 - Publisher Copyright: Copyright © 2020 The Authors, some rights reserved.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85086007909

U2 - 10.1126/SCIIMMUNOL.ABD0110

DO - 10.1126/SCIIMMUNOL.ABD0110

M3 - Article

C2 - 32503877

SN - 2470-9468

VL - 5

JO - Science immunology

JF - Science immunology

IS - 48

M1 - eabd0110

ER -