AB0756 IMMUNE-MEDIATED BASIS FOR A PHASE 2A CLINICAL STUDY COMPARING RILZABRUTINIB VS GLUCOCORTICOIDS IN RITUXIMAB-REFRACTORY PATIENTS WITH IGG4-RELATED DISEASE
Authors: Long L. , Baker M. , Carruthers M. , Meysami A. , Spiera R. , Reddy M. , Kavanagh M. , Francesco M. , Langrish C. , Neale A. , Arora P. , Stone J. H. 
Published: May 2021

Background:IgG4-related disease (IgG4-RD) is an immune-mediated disorder causing fibro-inflammatory lesions. Although the cause remains unknown, it may be driven by interactions between B lymphocytes and CD4+ cytotoxic and regulatory T cells and is characterized by an increase in short-lived plasmablasts, circulating antibodies, and macrophages. Standard therapy mainly includes glucocorticoids (GC), limited by toxicity with long-term use (> 6 mo), and to a lesser extent, immunosuppressives (eg, rituximab). Bruton tyrosine kinase (BTK) plays an important role in the activation of multiple immune effector cells such as B cells, mast cells, eosinophils, basophils, monocytes/macrophages, and neutrophils. Dysregulation of the activation of these immune cells results in autoimmune inflammation, tissue damage, and development of fibrosis. Rilzabrutinib is a highly selective oral BTK inhibitor that targets multiple pathways of innate and adaptive immunity (with direct effects on B-cell and FcR pathways) and has the potential to inhibit antigen presentation to autoreactive T cells.Objectives:To provide the biological rationale for rilzabrutinib in IgG4-RD.Methods:Rilzabrutinib has been evaluated in biochemical, in vitro studies, and in vivo models of inflammatory diseases. Additional support is provided by the phase 2 trial for oral rilzabrutinib in patients with pemphigus vulgaris and the phase 2 trial for oral rilzabrutinib in patients with immune thrombocytopenia (ITP).Results:Rilzabrutinib inhibited the activity of BTK and B-cell receptor in B cells (IC50 5-123 nM) and Fc gamma receptor in IgG/Fc gamma receptor-stimulated monocytes (IC50 56 nM) and blocked IgG- and IgM-mediated antibody production in enriched B cells when stimulated in T-cell dependent (anti-CD40+IL-21) and T-cell independent (TLR-9/CpG and TNP-LPS) pathways. The impact of rilzabrutinib on innate cell pathways was further confirmed by significant dose-dependent inhibition of macrophage and neutrophil-driven passive rat Arthus reaction (P < 0.01 vs vehicle) and antibody-induced murine ITP (P < 0.05 vs vehicle). In a 12-week phase 2 pemphigus vulgaris trial, 54% of patients achieved the primary endpoint, control of disease activity (CDA) on low-dose corticosteroids by week 4, and 73% achieved it by week 12. In the phase 2 trial of ITP patients (median 6 prior therapies), rilzabrutinib 400 mg bid showed rapid and sustained improvement in platelet counts and only grade 1/2-related adverse events1. In responders, platelet counts increased as early as day 8, potentially due to innate immune mechanisms. Collectively, results in both B and innate immune cells provide an initial basis for evaluating rilzabrutinib in IgG4-RD. The ongoing phase 2a study (NCT04520451) is investigating rilzabrutinib 400 mg bid (+tapered GC) vs GC control (3:1) for 12 weeks in IgG4-RD patients refractory to rituximab. The primary objective is to evaluate the safety and ability of rilzabrutinib to induce GC-free remission at week 12. Coupled with known preclinical/clinical findings, mechanistic analyses in this ongoing IgG4-RD study will profile B and other immune cell effects pre-/post-rilzabrutinib dosing to enhance the clinical understanding of rilzabrutinib in IgG4-RD.Conclusion:Studies of rilzabrutinib that show beneficial effects on both B-cell and innate cell pathways provide support for its therapeutic role in immune-mediated diseases and for targeting the underlying pathophysiological effects of IgG4-RD. Effective and safe therapies that rapidly induce and maintain clinical responses, while minimizing the need for continuous GC treatment, remain an unmet need for patients with IgG4-RD.References:[1]Kuter et al. Res Pract Thromb Haemost. 2020;4(suppl 1): PB1318.Disclosure of Interests:Li Long Employee of: Principia Biopharma, a Sanofi Company, Matthew Baker: None declared, Mollie Carruthers: None declared, Alireza Meysami: None declared, Robert Spiera Consultant of: research funding and personal fees for consulting from Chemocentryx, Formation Biologics, Roche-Genentech, and Sanofi, Grant/research support from: research funding fees from BMS, Boehringer Ingelheim, Corbus, GSK, and Inflarx; personal fees from AbbVie, CSL Behring, GSK, and Janssen, Mamatha Reddy Employee of: Principia Biopharma, a Sanofi Company, Marianne Kavanagh Employee of: Principia Biopharma, a Sanofi Company, Michelle Francesco Employee of: Principia Biopharma, a Sanofi Company, Claire Langrish Employee of: Principia Biopharma, a Sanofi Company, Ann Neale Employee of: Principia Biopharma, a Sanofi Company, Puneet Arora Employee of: Principia Biopharma, a Sanofi Company, John H. Stone Consultant of: research funding and personal fees for consulting from Principia and Sanofi