Preclinical Pharmacology Characterization of Sovleplenib (HMPL-523), an Orally Available Syk Inhibitor

Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase in-volved in the signal transduction in immune cells mainly. Its aber-rant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibi-tion of Syk is considered a reasonable approach to treat autoim-mune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib, a novel, highly potent and selective, oral Syk inhibitor, in several rodent autoimmune disease models. Sovleplenib potently inhibited Syk activity in a recombinant enzymatic assay and Syk-dependent cellular functions in various immune cell lines and human whole blood in vitro. Furthermore, sovleplenib, by oral administration, demonstrated strong in vivo efficacies in murine models of im-mune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and chronic graft-versus-host disease (cGVHD), and a rat model of collagen induced arthritis (CIA) respectively, in a dose-dependent manner. Collectively, these results clearly supported sovleplenib as a therapeutic agent in the treatment of autoimmune diseases. Sovleplenib is being globally developed for ITP (Phase III, NCT05029635, Phase Ib/II, NCT03951623), wAIHA (Phase II/III, NCT05535933) and B-cell lymphoma (Phase I, NCT02857998, NCT03779113).