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- Title
Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
- Authors
Roschewski, Mark; Lionakis, Michail S.; Sharman, Jeff P.; Roswarski, Joseph; Goy, Andre; Monticelli, M. Andrew; Roshon, Michael; Wrzesinski, Stephen H.; Desai, Jigar V.; Zarakas, Marissa A.; Collen, Jacob; Rose, Keith M.; Hamdy, Ahmed; Izumi, Raquel; Wright, George W.; Chung, Kevin K.; Baselga, Jose; Staudt, Louis M.; Wilson, Wyndham H.
- Abstract
Taming cytokine storm: Hyperactivation of immune cells leading to "cytokine storm" contributes to acute lung injury in patients with COVID-19 pneumonia. Host signaling proteins and effector molecules contributing to cytokine storm are potential targets for pharmacotherapy of COVID-19. Roschewski et al. conducted an observational study evaluating off-label use of acalabrutinib, an inhibitor of the Bruton tyrosine kinase (BTK) enzyme, in 19 hospitalized COVID-19 patients requiring oxygen supplementation. Biomarkers of inflammation reverted toward normal in most treated patients. Correlative studies of blood monocytes from patients with severe COVID-19 showed increases in BTK activation and production of interleukin-6, a key driver of cytokine storm, compared with healthy control monocytes. These findings helped inform the design of a randomized controlled clinical trial to further test the therapeutic potential of acalabrutinib in COVID-19. 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.
- Publication
Science Immunology, 2020, Vol 5, Issue 48, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abd0110