Baricitinib

Baricitinib is an orally available small molecule with potential anti-inflammatory, immunomodulating, antineoplastic and antiviral activities. Baricitinib (Other names INCB28050, LY3009104) was discovered by Incyte and developed under license by Eli Lilly and Company (Lilly). Baricitinib is approved in the US under the brand name Olumiant for treatment of rheumatoid arthritis. Baricitinib (Olumiant) is an orally-administered, small-molecule, janus-associated kinase (JAK) inhibitor developed for rheumatoid arthritis, atopic dermatitis and systematic lupus erythematosus. Baricitinib is also under investigation for psoriasis, diabetic kidney disease and COVID-19.

Image source: National Center for Biotechnology Information

Janus-associated kinases (JAKs) transduce intracellular signals from receptors on the cell surface that are activated by signaling molecules such as cytokines and growth factors. Since cytokines and growth factors are involved in inflammation and immune function, JAK inhibitors have potential therapeutic benefits in inflammatory conditions. When circulating proinflammatory cytokines bind to cell surface receptors, JAKs are phosphorylated and activate signal transducers and activators of transcription (STATS). Baricitinib modulates signaling pathways by selectively and reversibly inhibiting JAK1 and JAK2.

Baricitinib potently inhibits JAK1 and JAK2 (IC₅₀ 5.9 and 5.7 nmol/L, respectively) but has lower potency against Tyk2 and JAK3 (IC₅₀ of 53 and approximately 560 nmol/L, respectively) in vitro. Assays in human T-cells show inhibition of phosphorylation of STAT3 (IC₅₀ 20–50 nmol/L) and subsequent production of MCP-1, and IL-23 induced STAT3 phosphorylation and subsequent production of IL-17 and IL-22. Baricinib is effective in murine models of arthritis. In an in vivo rat arthritis study, 14 days of treatment with baricitinib was associated with reductions of disease scores compared with delivery vehicle alone.

Baricitinib was established to have efficacy for treatment of rheumatoid arthritis in four pivotal phase III trials, which are RA-BEGIN (NCT01711359), RA-BUILD (NCT01721057), RA-BEAM and RA-BEACON (NCT01721044).

Use of baricitinib to treat eczema (atoptic dermatitis), a chronic inflammatory skin condition, showed long-term efficacy and safety in the phase II BREEZE-AD3 trial.

COVID-19 is a respiratory disease caused by the SARS-CoV-2 coronavirus. Baricitinib has the potential to treat COVID-19 as an anti-inflammatory by inhibiting JAK and also through blocking viral entry. Baricinitinib was identified in a search for approved drugs that could block the viral infection process for SARS-CoV-2 using BenevolentAI, a large repository of structured medial information with connections extracted from scientific literature by machine learning. Baricitinib inhibits AP2-associated protein kinase (AAK1), a regulator the endocytosis, the process by which most viruses enter cells. Baricitinib also binds cyclin G-associated kinase (GAK), another regulator of endocytosis. AAK1 and GAK are members of the numb-associated kinase (NAK) family.

In the Adaptive COVID-19 Treatment Trial (ACTT-2) sponsored by the NIAID, baricitinib in combination with remdesivir (Gilead Science) reduced the time to recovery and improved clinical outcomes for COVID-19 patients compared with remdesivir alone. The data, presented at the International Society for Influenza and other Respiratory Virus Diseases Antiviral Group (isirv-AVG) Virtual Conference on ‘Therapeutics for COVID-19’, showed the largest benefits to patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation. The overall patient population treated with baricitinib and remdesivir had a recovery time improved from 8 days to 7 days (12.5% improvement) compared to remdesivir alone. The combination treatment showed a decrease in death by 35% through Day 29. The decrease in death rate was 60% for those requiring oxygen.

Baricitinib is compared with background therapy in hospitalized patients in the phase 3 COV-BARRIER trial in hospitalized patients in the US, Europe, Asia and Latin America which began in June, 2020.

Baricitinib (Olumiant) received FDA emergency use authorization for use in combination with remdesivir (Veklury) to treat COVID-19 in November, 2020.

As of 2017 Incyte had issued and pending patents for baricitinib in the USA, EU and Japan that will expire in 2029.

Baricitinib | C16H17N7O2S | CID 44205240 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.