Acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, appears to reduce respiratory distress as well as the hyperinflammatory immune response associated with coronavirus disease 2019 (COVID-19), according to a study led by researchers at the Center for Cancer Research at the National Cancer Institute and the National Institute of Allergy and Infectious Diseases, both part of the National Institutes of Health (NIH).
The prospective study included 19 patients with confirmed COVID-19 who required hospitalization for hypoxemia and had evidence of inflammation. Patients received acalabrutinib 100mg twice daily for 10 days (supplemental oxygen cohort n=11) or 14 days (mechanical ventilation cohort n=8) plus best supportive care. A subset of patients in both cohorts received concomitant treatment with steroids and/or hydroxychloroquine.
Results showed that by the end of treatment, 8 of the 11 patients in the supplemental oxygen group had been discharged from the hospital. “The oxygenation and clinical status of most patients on supplemental oxygen improved relatively rapidly following acalabrutinib initiation, which was temporally associated with a normalization of inflammatory markers,” the investigators reported. In the ventilator group, which included patients who had been on mechanical ventilation for prolonged periods of time and who had organ dysfunction, the response to acalabrutinib was found to be more variable, with 4 of the 8 patients being able to come off the ventilator.
Additionally, treatment with acalabrutinib was associated with changes in several biomarkers of inflammation, including a normalization or decrease in C-reactive protein and interleukin-6 (IL-6), as well as improvement in lymphopenia. These results suggest that the treatment may have been effective because it targets BTK, which the investigators found to be significantly elevated in blood samples of patients with severe COVID-19 in a separate analysis.
“Our clinical and correlative laboratory studies have revealed that BTK is a likely instigator of the pathological inflammatory response in severe COVID-19,” the investigators concluded. They added that “Given the activation of BTK and production of IL-6 that we detected in COVID-19 monocytes, we propose that BTK inhibitors target pathological monocyte/macrophage activation and dampen the cytokine storm, which consequently may improve outcomes in these patients.”
The safety and efficacy of acalabrutinib in patients with severe COVID-19 will be further examined in a randomized controlled trial (CALAVI) sponsored by AstraZeneca.
Acalabrutinib is currently approved under the brand name Calquence (AstraZeneca) for the treatment of mantle cell lymphoma and chronic lymphocytic or small lymphocytic lymphoma.
For more information visit nih.gov.