It would appear that patients suffering from moderate to severe COVID-19 present a certain hyperinflammatory immune response, which suggests macrophage activation. The bruton tyrosine kinase (BTK) is responsible for the regulation of macrophage signaling and macrophage activation. Acalabrutinib, which is a selective BTK inhibitor, was administered off-label to 19 patients, all of them hospitalized with severe COVID-19. Out of these 19, 11 were on supplemented oxygen and 8 were on mechanical ventilation. 18 of the 19 patients had increasing oxygen requirements at baseline. Over the period of 10-14 days, which was the duration of the treatment, acalabrutinib increased oxygenation in most of the patients. The increase usually occurred within 1 to 3 days and it would appear that there was no related toxicity.
Inflammation, which was measured through the amount of C-reactive protein and IL-6, ended up normalizing quite fast in most of the patients. Lymphopenia normalized quickly as well, at the same pace as the increase in oxygenation. Once the acalabrutinib treatment was finished, 8 out of 11 (72.7%) of the patients in the supplemental oxygen cohort had been discharged and left only on room air and 4 out of 8 (50%) of the patients in the mechanical ventilation cohort had been successfully extubated, 2/8 (25%) even being discharged on just the room air. An ex vivo analysis was performed and it revealed that BTK activity was significantly elevated, the autophosphorylation and the increased IL-6 production in blood monocytes from patients that had been suffering form a severe case of COVID-19 compared with blood monocytes from healthy volunteers extensively demonstrate.
The results of these study are promising. They seem to indicate that targeting host inflammation using a BTK inhibitor is a therapeutic strategy when being confronted by severe COVID-19 and it has led to a confirmatory international prospective randomized controlled clinical trial.