Journal Article

Mechanism of baricitinib supports artificial intelligence‐predicted testing in COVID‐19 patients

Higgs, Richard E, Krishnan, Venkatesh, Casalini, Giacomo, Baldanti, Fausto, Rocha, Guilherme, Cardoso, Anabela, Byers, Nicole L, Stebbing, Justin, Mirazimi, Ali, Tan, Yee‐Joo, Youhanna, Sonia, Nirula, Ajay, Nickoloff, Brian J, Schlichting, Douglas E, de Bono, Stephanie, Ottaviani, Silvia, Monteil, Vanessa, Sarasini, Antonella, Richardson, Peter J, Terres, Jorge A Ross, Lauschke, Volker M, Corbellino, Mario

2020

Overview

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. Synopsis This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients. Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor used to treat rheumatoid arthritis, was hypothesised using AI to be useful in COVID‐19. Baricitinib‐mediated inhibition of numb associated kinases utilized by SARS‐CoV‐2 for its propagation, led to reduced viral infectivity in primary liver spheroids. Baricitinib reduces levels of cytokines implicated in COVID‐19 and inhibits their signaling. In 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. Graphical Abstract This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Adult / Aged / Antiviral Agents - pharmacokinetics / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Antiviral drugs / anti‐cytokine / anti‐viral / Artificial Intelligence / Azetidines - pharmacokinetics / Azetidines - pharmacology / Azetidines - therapeutic use / baricitinib / Betacoronavirus / Cardiovascular disease / case series / Chronic obstructive pulmonary disease / Clinical trials / Coronavirus Infections - drug therapy / Coronaviruses / COVID-19 / COVID-19 Drug Treatment / Cytokines / Cytokines - antagonists & inhibitors / Disease transmission / Drug Evaluation, Preclinical / Drug Repositioning / Drugs / EMBO08 / EMBO23 / Enzyme inhibitors / Female / Hospitalization / Humans / Infections / Infectivity / Inflammation / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Janus kinase / Janus kinase 2 / Kinases / Leukocytes - drug effects / Liver / Male / Middle Aged / Mortality / Pandemics / Patients / Pharmacokinetics / Pneumonia / Pneumonia, Viral - drug therapy / Propagation / Protein Kinase Inhibitors - pharmacokinetics / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein Serine-Threonine Kinases - antagonists & inhibitors / Public health / Purines / Pyrazoles / Rheumatoid arthritis / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Spheroids / Spheroids, Cellular - drug effects / Spheroids, Cellular - virology / Sulfonamides - pharmacokinetics / Sulfonamides - pharmacology / Sulfonamides - therapeutic use