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 a 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 supports its assessment in randomized trials in hospitalized COVID-19 patients.
Author Information
Justin Stebbing1, Venkatesh Krishnan *,8, Stephanie de Bono8, Silvia Ottaviani, Giacomo Casalini1,3, eter J. Richardson4, Vanessa Monteil5, Volker M. Lauschke5, Ali Mirazimi5, Sonia Youhanna5, Yee‐Joo Tan6, Fausto Baldanti7, Antonella Sarasini7, Jorge A. Ross Terres8, Brian J. Nickoloff8, Richard E. Higgs8, Guilherme Rocha8, Nicole L. Byers8, Douglas E. Schlichting8, Ajay Nirula8, Anabela Cardoso8, Mario Corbellino
21Department of Surgery and Cancer, Imperial College, London, UK
2Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy
3Luigi Sacco Department of Clinical and Biomedical Sciences, University of Milan, Milan, Italy
4BenevolentAI, London, UK
5Department of Laboratory Medicine, Unit of Clinical Microbiology, and Department of Physiology and Pharmacology, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden
6National University of Singapore, Infectious Diseases Programme, Immunology Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore & Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
7Department of Clinical, Surgical, Diagnostics and Pediatric Sciences, University of Pavia, Molecular Virology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
8Eli Lilly and Company, Indianapolis, Indiana, USA
*Corresponding AuthorVenkatesh Krishnan, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, United States of AmericaEmail: krishnan_gary@lilly.com