Stebbing J, Krishnan V, de Bono S, Ottaviani S, Casalini G, Richardson PJ, Monteil V, Lauschke VM, Mirazimi A, Youhanna S, Tan YJ, Baldanti F, Sarasini A, Terres JAR, Nickoloff BJ, Higgs RE, Rocha G, Byers NL, Schlichting DE, Nirula A, Cardoso A, Corbellino M, Sacco Baricitinib Study Group
EMBO Mol Med 12 (8) e12697 [2020-08-07; online 2020-06-24]
Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.