Baricitinib

Baricitinib inhibits IL-6–stimulated phosphorylation of the canonical substrate STAT3 (pSTAT3) and subsequent production of the chemokine MCP-1 with IC50 values of 44 nM and 40 nM, respectively, in PBMCs. Baricitinib also inhibits pSTAT3 stimulated by IL-23 with IC50 od 20 nM in isolated naive T-cells. ^[1]

Baricitinib inhibits IL-6–stimulated phosphorylation of STAT3 in whole blood with an IC50 of 128 nM. Baricitinib (10 mg/kg p.o.) is expected to inhibit JAK1/2 signaling (by ≥50%) in rats for about 8 hours. Baricitinib (10 mg/mL, p.o.) inhibits disease scores in dose-dependent manner in rats with established disease in the adjuvant arthritis model. Baricitinib treatment, compared with vehicle, inhibits the increase in hind paw volumes during the 2 weeks of treatment by 50% at a dose of 1 mg/kg and >95% at doses of 3 mg/kg or 10 mg/kg. Baricitinib treatment, compared with vehicle, also inhibits composite score of immune infiltrate, edema, and periarticular tissue appearance by 27% at a dose of 1 mg/kg, 64% at doses of 3 mg/kg and 82% at doses of 10 mg/kg in rats with established disease in the adjuvant arthritis model. Baricitinib reduces bone resorption by 15%, 61%, and 67% with increasing dose level (1, 3, and 10 mg/kg) in rats with established disease in the adjuvant arthritis model. Baricitinib (10 mg/kg, daily for 2 wk, p.o.) results in radiographic improvements with restoration of the normal architecture and appearance to the ankle and tarsals in rats with established disease in the adjuvant arthritis model. Baricitinib reduces levels of pSTAT3 in a dose- and time-dependent manner in the peripheral blood of rAIA animals. Baricitinib (10 mg/mL, p.o.) improves a composite score of joint damage by 47% in the murine CIA model. Baricitinib (10 mg/kg) reduces pannus (74%) and bone damage (78%) and improves cartilage damage (43%) and signs of inflammation (33%), resulting in a 53% improvement in an aggregate score of disease in the collagen Ab-induced arthritis (CAIA) murine model. Baricitinib (10 mg/kg) inhibits the delayed-type hypersensitivity response by 48% in both the CIA and CAIA models. ^[1]

Baricitinib is efficacious in active rheumatoid arthritis patients refractory to disease modifying drugs and biologics. ^[2]

Baricitinib preferentially inhibits JAK1 and JAK2, with 10-fold selectivity over Tyk2 and 100-fold over JAK3. The observed effects of GLPG-0634 on the ACR20, albeit in a smaller study, appear to be at least as good as that seen with tofacitinib and superior to that of baricitinib, since baricitinib only moderately affect the ACR20 values in Phase IIa clinical studies. ^[3]

Baricitinib has the dose-limiting side-effect of inducing anaemia which has been attributed to its effects on JAK2 but has clearly shown efficacy. ^[4]

• Biochemical assays

  Enzyme assays are performed using a homogeneous time-resolved fluorescence assay with recombinant epitope tagged kinase domains (JAK1, 837-1142; JAK2, 828-1132; JAK3, 718-1124; Tyk2, 873-1187) or full-length enzyme (cMET and Chk2) and peptide substrate. Each enzyme reaction is performed with or without test compound (11-point dilution), JAK, cMET, or Chk2 enzyme, 500 nM (100 nM for Chk2) peptide, ATP (at the Km specific for each kinase or 1 mM), and 2.0% DMSO in assay buffer. The calculated IC50 value is the compound concentration required for inhibition of 50% of the fluorescent signal.

• Animal Models

  Collagen-induced arthritis (CIA) mice

• Dosages

  10 mg/mL

• Administration

  orally