Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

J Immunol. 2019 May 15;202(10):2888-2906. doi: 10.4049/jimmunol.1800583. Epub 2019 Apr 15.


Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor-mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. We evaluated evobrutinib in preclinical models of RA and SLE and characterized the relationship between BTK occupancy and inhibition of disease activity. In mouse models of RA and SLE, orally administered evobrutinib displayed robust efficacy, as demonstrated by reduction of disease severity and histological damage. In the SLE model, evobrutinib inhibited B cell activation, reduced autoantibody production and plasma cell numbers, and normalized B and T cell subsets. In the RA model, efficacy was achieved despite failure to reduce autoantibodies. Pharmacokinetic/pharmacodynamic modeling showed that mean BTK occupancy in blood cells of 80% was linked to near-complete disease inhibition in both RA and SLE mouse models. In addition, evobrutinib inhibited mast cell activation in a passive cutaneous anaphylaxis model. Thus, evobrutinib achieves efficacy by acting both on B cells and innate immune cells. Taken together, our data show that evobrutinib is a promising molecule for the chronic treatment of B cell-driven autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / immunology
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Lymphocyte Activation / drug effects*
  • Mice
  • Piperidines / pharmacology*
  • Pyrimidines / pharmacology*
  • U937 Cells


  • Piperidines
  • Pyrimidines
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse
  • evobrutinib