Current Status of Baricitinib as a Repurposed Therapy for COVID-19

Abstract

The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment.

An updated overview of recent advances, challenges, and clinical considerations of IL-6 signaling blockade in severe coronavirus disease 2019 (COVID-19)

“…Baricitinib (olumiant) is a selective JAK1/2 inhibitor that was approved for anti-TNF-α-resistant RA patients [121] , [122] . Recently, it has also been shown to hinder the endocytosis and assembly of the SARS-CoV-2 to the host cell by inhibiting AP2-associated protein kinase 1 (AAK1) [123] , [124] , [125] . Considering the inhibitory effects of baricitinib on the JAK-mediated inflammatory process and the entrance of SARS-CoV-2 to the host cell, it has been thought to be investigated in COVID-19 patients to improve the cytokine storm [126] , [127] , [128] .…”

COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy

“…CCL4 and family members of tumor necrosis factor (TNF, TNFSF11) were enriched. Baricitinib treatment appears to suppress tissue regeneration, ion, and membrane transduction, as well as cellular responses ( 159 ). A study by Hasan et al showed that baricitinib could potentially suppress inflammatory cascades in severe COVID-19 pneumonia.…”

“…Interestingly, a study of individuals treated with baricitinib found that ACE2 and TMPRSS2 levels were significantly reduced. In addition, baricitinib inhibits the AAK2 virus by binding to anesthetics-related kinases, and GAK-induced endocytosis, ultimately reducing the viral load ( 159 ). The ability of baricitinib to reduce the production of these cytokines, and hence immunological factors, has been demonstrated to aid patients with COVID-19 dramatically.…”

The role of interleukin-6 and janus kinases in the pathogenesis, and treatment of SARS-CoV-2

“…Furthermore, transcriptomic analysis of baricitinib-treated model reveals a significant downregulation of ACE2, and TMPRSS2 in patients treated with baricitinib, thus slowing the entry of SARS-CoV-2 into target cells. 265 Moreover, through binding to numb-associated kinases, baricitinib further inhibits AAK1, and GAK-mediated endocytosis of the virus-ACE complex, thus leading to a reduction in the viral load. 266 Notewothy, baricitinib at therapeutically clinically-relevant levels has been shown to reduce infectivity of Covid-19 in human primary liver spheroid model.…”