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

TLDR

Severe COVID‑19 triggers a hyperinflammatory macrophage‑driven response, and Bruton tyrosine kinase is a key regulator of macrophage signaling. Acalabrutinib, a selective BTK inhibitor, was given off‑label to 19 hospitalized severe COVID‑19 patients (11 on supplemental oxygen, 8 on mechanical ventilation), most of whom had rising oxygen needs at baseline. Acalabrutinib rapidly improved oxygenation, reduced inflammatory markers, and resolved lymphopenia in most patients without toxicity, with 73 % of oxygen‑dependent and 50 % of ventilated patients discharged or extubated, and ex vivo data showed heightened BTK activity driving IL‑6 production, supporting BTK inhibition as a therapeutic strategy and prompting a confirmatory randomized trial.

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.