The Emergence of Baricitinib: A Story of Tortoises Versus Hares

Baricitinib is a once daily orally administered JAK1/2 inhibitor, which inhibits the signaling of many cytokines and has been approved for the treatment of moderate to severe rheumatoid arthritis (RA) based on long-term randomized dosing against both placebo and standard of care [1], notably tumor necrosis factor (TNF)-alpha blockade. Its use for the treatment of coronavirus disease 2019 (COVID-19) was originally suggested after a search of the extensive BenevolentAI knowledge graph for approved drugs that could be used in this pandemic [2]. An advantage of approved drugs is that they have a known safety profile and can therefore be rapidly approved in fast moving pandemics. The artificial intelligence algorithms predicted that baricitinib would inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of cells [2], (an effect later confirmed in human liver spheroids) [3], combined with its better-known anti-inflammatory properties. The doses required were predicted to be the same as used for the treatment of RA. At these doses, interleukin 6 (IL-6) levels were reduced both in COVID19 patients as well as dose dependently in RA patients in a previous phase 2b randomized RA trial, the first time this was shown in humans [4]. What was more intriguing was its inhibition of members of the numb associated kinase family, thought in turn to translate to reduced AP-2 mediated viral propagation early in the infectious cycle, suggesting antiviral activity; this was shown in liver spheroid models, which express detectable albeit low levels of the ACE2 receptor...