Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease

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 dosedependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcgR 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, Fc«R-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.

Management of Adult Patients with Immune Thrombocytopenia (ITP): A Review on Current Guidance and Experience from Clinical Practice

“…There is ongoing research involving Bruton's tyrosine kinase inhibitors in the potential treatment of immunerelated diseases. 96 Rilzabrutinib is an oral, reversible small molecule selective BTK inhibitor that has shown preclinical efficacy in rapidly inhibiting antibody mediated innate immune response as well as antibody production, exhibiting potential for ITP treatment. 96 Rilzabrutinib was also shown to be safe and well tolerated in a phase I trial, with favorable pharmacokinetics that could result in fast onset of effect.…”

“…96 Rilzabrutinib is an oral, reversible small molecule selective BTK inhibitor that has shown preclinical efficacy in rapidly inhibiting antibody mediated innate immune response as well as antibody production, exhibiting potential for ITP treatment. 96 Rilzabrutinib was also shown to be safe and well tolerated in a phase I trial, with favorable pharmacokinetics that could result in fast onset of effect. 97 Bortezomib is a proteasome inhibitor that was shown in a preclinical study to improve thrombocytopenia in ITP by inducing apoptosis in long-lived plasma cells which were thought to play a role in corticosteroid resistant ITP.…”

Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors

“…The reactivity of this complex confers a possibility to reverse the reaction under in vitro and cellular conditions ( 47 , 48 ). Pre-clinical studies of rilzabrutinib indicated anti-inflammatory effect in animal models of immune-mediated diseases ( 49 ).…”

Bruton Tyrosine Kinase Inhibition and Its Role as an Emerging Treatment in Pemphigus

“…A significant advantage of rilzabrutinib is that only short exposure is required to get a clinical benefit ( 27 ). Low systemic exposure reduces side effects, increases tolerability and promotes effectiveness and drug survival.…”

“…The activation of macrophages and monocytes via cross-linking of IgG and FcgR is a BTK dependent function; the ability of rilzabrutinib to prevent IgG mediated FcgR activation was illustrated in rodent models of lupus nephritis and immune thrombocytopenia (ITP). Rilzabrutinib has shown a unique dual Ab mechanistic approach over the standard treatments for immune-mediated diseases, based on its fast action on halting self-reactive Ab signaling and its longer-term impact on the formation of new autoantibodies ( 27 ).…”