1. Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.
- Author
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Langrish, Claire L, Bradshaw, J Michael, Francesco, Michelle R, Owens, Timothy D, Xing, Yan, Shu, Jin, LaStant, Jacob, Bisconte, Angelina, Outerbridge, Catherine, White, Stephen D, Hill, Ronald J, Brameld, Ken A, Goldstein, David M, and Nunn, Philip A
- Subjects
Kidney ,Blood Platelets ,Basophils ,Mast Cells ,Animals ,Dogs ,Humans ,Mice ,Nephritis ,Purpura ,Thrombocytopenic ,Idiopathic ,Pemphigus ,Disease Models ,Animal ,Immunoglobulin E ,Anti-Inflammatory Agents ,Protein Kinase Inhibitors ,Drug Evaluation ,Preclinical ,Mice ,129 Strain ,Agammaglobulinaemia Tyrosine Kinase ,Autoimmune Disease ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Inflammatory and immune system ,Immunology - Abstract
Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.
- Published
- 2021
