Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

By Peter J. Richardson, Ivan Griffin, C. Tucker, Daniel P. Smith, O. Oechsle, A. Phelan, M. Rawling, E. Savory, J. Stebbing. The Lancet, 2020

1,260 citations recorded by the source corpus.

Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins, have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination. BenevolentAI’s knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning. Together with customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. We identified baricitinib, which is predicted to reduce the ability of the virus to infect lung cells. Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cellsurface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure). These AT2 cells are particularly prone to viral infection. One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles. Of 378 AAK1 inhibitors in the knowledge graph, 47 have been approved for medical use and six inhibited AAK1 with high affinity. These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people. By contrast, one of the six highaffinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia.

Subfields: Epidemiology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/1ab0a64222e24f8eb56c76fb61955bc2f54edbe7

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In Epidemiology

1. Vincent C. Marconi

In Infectious Diseases

1. Ankita Srivastava
2. Aishwarya Kumar
3. Puneet Kumar Gupta

Citations in the corpus

• The cytokine storm and COVID‐19 (2020, background): “However, JAK inhibitors can also inhibit IFN‐α production, which helps us to fight viruses.(76) Intravenous im-”
• Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer (2023, background): “Baricitinib was also found to have a high affinity for numb-associated kinase (NAK) which enabled it to suppress NAK activity and block clathrin-mediated endocytosis to reduce viral infection in COVID-19.”
• A review of modern technologies for tackling COVID-19 pandemic (2020, background): “Numerous data driven drug repurposing (drug repositioning) approaches have been proposed with the point of identifying illnesses, conditions or groups of patients that could be treated with existing medications not known for this disease [31] .”
• Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases (2020, background): “35 A fixed dose of the anti-HIV combination, lopinavir−ritonavir, is currently in clinical trials with Arbidol or ribavirin.”
• COVID-19: consider cytokine storm syndromes and immunosuppression (2020, neutral): “10 All patients with severe COVID-19 should be screened for hyperinflammation using laboratory trends (eg, increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) and the HScore 11 ( ”
• The JAK/STAT signaling pathway: from bench to clinic (2021, background): “Moreover, baricitinib inhibits inflammation via JAK1/2-mediated cytokine signaling.(381,382) One of the most important effects was the rapid and remarkable inhibition of macrophage production of the cytokines and chemokines critical for inflammation and neutrophil recruitment.”
• Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 (2020, background): “The authors’ affiliations are as follows: the University of Nebraska Medical Center, Omaha (A.C.K., L.L.); University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio (T.F.P., P.O.P., B.S.T.), UT Southwestern Medical Center, Parkland Health”
• Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment (2020, background): “Baricitinib is also a NAK inhibitor, with a particularly high affinity for AAK [40, 51].”
• Building a knowledge graph to enable precision medicine (2022, background): “While drug repurposing remains the focus of knowledge graph development 32,36,38,41,59–61 , considerable effort has been devoted to building knowledge graphs from biomedical literature 27,30,39 and clinical records 28,29,33,62 .”
• Mapping the Landscape of Artificial Intelligence Applications against COVID-19 (2020, methodology): “Richardson et al. (2020) use this technique to identify Baricitinib, a drug which is commonly used to treat arthritis via inhibition of JAK1/2 kinases, as a promising therapy for COVID-19 because it inhibits the AP2-associated protein kinase 1 (AAK1) enzyme and may, therefore, make it harder for…”
• Deep learning in drug discovery: an integrative review and future challenges (2022, methodology): “They received FDA permission to use their planned Baricitinib medication in conjunction with Remdesivir, which resulted in a higher recovery rate for hospitalized COVID19 patients (Richardson et al. 2020).”
• The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China (2020, background): “Therapeutic dosage with either 2 mg or 4 mg once daily was sufficient to reach the plasma concentration of inhibition [29].”
• The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China (2020, neutral): “suggested that baricitinib may reduce both the viral entry and inflammation [134] .”