Vesatolimod

Vesatolimod (GS-9620) is a potent, selective and orally active agonist of Toll-Like Receptor (TLR7) with an EC₅₀ of 291 nM. IC50 & Target:EC50: 291 nM (TLR7), 9 μM (TLR8)^[3] In Vitro:Vesatolimod (GS-9620) rapidly internalizes into cells and preferentially localizes to and signals from endo-lysosomal compartments. To test this hypothesis, the kinetics of cellular uptake of the compound in Daudi cells using tritiated Vesatolimod (³H-GS-9620) is measured. The kinetics of ³H-GS-9620 accumulation is rapid, reaching concentration-dependent steady-state equilibrium in approximately thirty minutes. Measured intracellular concentration of ³H-Vesatolimod is 5-fold higher than the extracellular concentration of ³H-GS-9620 used to treat cells. Increases in intracellular ³H-Vesatolimod concentrations are roughly proportional with increasing concentrations of ³H-GS-9620^[1]. In Vivo:Single oral doses of Vesatolimod (GS-9620) at 0.3 and 1 mg/kg in uninfected chimpanzees demonstrates a dose- and exposure-related induction of serum IFN-α, select cytokines/chemokines, and IFN-stimulated genes (ISG) in the peripheral blood and liver. Following oral administration at 0.3 (n=3), and 1 mg/kg (n=3 and n=4), Vesatolimod (GS-9620) C_max is 3.6±3.5, 36.8±34.5, and 55.4±81.0 nM, respectively. Peak serum IFN responses occur at 8 h post-dose. The mean peak levels of induced serum IFN-α are 66 and 479 pg/mL at doses of 0.3 and 1 mg/kg, respectively. Vesatolimod (GS-9620) treatment induces ISG transcripts including ISG15, OAS-1, MX1, IP-10 (CXCL10), and I-TAC (CXCL11) in peripheral blood mononuclear cells (PBMC) at 0.3 mg/kg and in both PBMC and the liver at 1 mg/kg^[2].