Treatment with Janus kinase (JAK) inhibitor baricitinib may reduce inflammation and substantially improve outcomes in patients with severe coronavirus disease 2019 (COVID-19), according to study results published in Science Advances.
Using artificial intelligence models, baricitinib was indicated to reduce viral infectivity by the inhibition of numb-associated kinases and viral endocytosis. Baricitinib has also been known to have an anti-inflammatory mechanism by JAK inhibition. The objective of the current study was to determine the mechanistic action and clinical effect of baricitinib against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
The study included 601 patients with moderate to severe or severe disease, including 179 participants from the University of Pisa, Italy, and 422 aged 70 years or more from the Albacete Hospital, Spain.
In the Pisa cohort, baricitinib was administered to 37 patients at a dose of 4 mg per day for 14 days, along with standard treatment; 37 control participants were age- and sex-matched with those who received baricitinib. In the Spanish cohort, because of age-related factors, baricitinib was administered to 46 patients at lower doses of 2 or 4 mg per day for 3 to 11 days; 376 control participants were matched with those who received baricitinib.
In the merged matched population, the primary composite end point of mortality or invasive mechanical ventilation was more common among patients who received baricitinib compared with the control participants (16.9% vs 34.9%, respectively; P <.001). Multivariate Cox-regression analyses in the propensity score matched populations from both cohorts showed a 71% lower risk for mortality (hazard ratio, 0.29; 95% CI, 0.15-0.58; P = <.001). The protective effect of baricitinib appeared early and was maintained until the end of follow-up.
The most common adverse event related to baricitinib was elevated liver transaminases. Additional probable or possible adverse events included oral candidiasis, bacteremia, bacterial pneumonia, atrial fibrillation, hypertension, heart failure, urinary obstruction, diarrhea, and gastrointestinal bleeding.
Baricitinib was shown to inhibit viral entry into liver cell spheroids and reduced inflammatory markers in patients with COVID-19. Baricitinib was also found to restrain abnormally high expression of the angiotensin-converting enzyme 2 (ACE2) receptor required for the entry of SARS-CoV-2 and may reduce viral infection of the liver and other organs and tissues that do not normally express high levels of the ACE2 receptor.
The study had several limitations, including its nonrandomized design, small sample size, and performance of multiple statistical tests without an adjustment for multiplicity.
“This [study] reveals mechanistic actions of a [JAK]-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that [incentivize] further randomized controlled trials,” the researchers concluded.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Stebbing J, Sánchez Nievas G, et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. Published online 13 November, 2020. doi:10.1126/sciadv.abe4724