Evobrutinib (M2951)

Evobrutinib, as an orally, highly selective, covalent Bruton's tyrosine kinase inhibitor, was well‐tolerated and effective.^[1] Evobrutinib was metabolized via hydroxylation, hydrolysis, O-dealkylation, glucuronidation, and GSH conjugation.^[4]

n vitro efficacy test it shown that evobrutinib inhibits Btk in vitro with IC₅₀ values in two studies 58 nM and 38 nM. Evobrutinib at concentrations of 10 µM did not increase bleeding time in vitro. ^[5] In U937 NF-κB–Luc reporter cells, evobrutinib inhibited NF-κB activation and, FcγR signaling with an IC₅₀ of 78 nM. Evobrutinib inhibited BTK and BMX with IC₅₀ values of 0.058 μM and 0.02 μM, respectively. Evobrutinib inhibited B cell activation in PBMCs with a mean IC₅₀ of 15.8 nM. Evobrutinib inhibited basophil activation with an average IC₅₀ of 1.66 μM. ^[2] In vitro, treatment with 100 to 1000 nM evobrutinib dose-dependently reduced calcium mobilization upon BCR ligation in a manner indistinguishable from the murine setting, while T cells again remained unaffected. In addition, production of IL-6, IFN-γ and IL-10 upon BCR ligation was reduced by 1000 nM evobrutinib.^[3]

In vivo, treatment with 1, 3 or 10 mg/kg evobrutinib in C57/BL6 mice orally inhibited expression of molecules involved in B-cell antigen presentation. Evobrutinib treatment (10 mg/kg) functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a remarkably decreased disease severity in mice.^[3]

References:
[1]Scheible H, et al. Evobrutinib, a covalent Bruton's tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants. Clin Transl Sci. 2021 Nov;14(6):2420-2430. 
[2]Haselmayer P, et al. Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models. J Immunol. 2019 May 15;202(10):2888-2906.
[3]Torke S, et al. Inhibition of Bruton's tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 2020 Oct;140(4):535-548. 
[4]Li Z, et al. Identification of metabolites of evobrutinib in rat and human hepatocytes by using ultra-high performance liquid chromatography coupled with diode array detector and Q Exactive Orbitrap tandem mass spectrometry. Drug Test Anal. 2019 Jan;11(1):129-139. 
[5]von Hundelshausen P, et al. Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. Cancers (Basel). 2021 Mar 4;13(5):1103.