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

Sci Immunol. 2020 Jun 5;5(48):eabd0110. doi: 10.1126/sciimmunol.abd0110. Epub 2020 Jun 5.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Aged
  • Aged, 80 and over
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use*
  • Betacoronavirus*
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Critical Illness
  • Female
  • Follow-Up Studies
  • Humans
  • Inflammation / drug therapy
  • Inflammation / virology
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Monocytes / metabolism
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • Prospective Studies
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use*
  • Respiration, Artificial
  • Treatment Outcome

Substances

  • Benzamides
  • IL6 protein, human
  • Interleukin-6
  • Pyrazines
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • acalabrutinib

Supplementary concepts

  • COVID-19
  • COVID-19 drug treatment
  • severe acute respiratory syndrome coronavirus 2