OP0186 EFFICACY AND SAFETY OF RILZABRUTINIB, AN ORAL BRUTON'S TYROSINE KINASE INHIBITOR, IN PATIENTS WITH IgG4-RELATED DISEASE: RESULTS FROM A 52-WEEK, PHASE 2, OPEN-LABEL, PROOF-OF-CONCEPT STUDY

Abstract

<h2>Abstract</h2><h3>Background:</h3> Current treatment options for patients with IgG4-related disease (IgG4-RD) are limited to off-label use of high dose glucocorticoids (GC), disease-modifying antirheumatic drugs, and B cell depleting agents highlighting the large unmet need in these patients. Immune cells of B cell lineage play a central role in the pathophysiology of IgG4-RD. It is hypothesized that the activation of B cells by follicular helper T cells and of CD4⁺ cytotoxic T cells by B cells results in a feedback loop driving the inflammatory and fibrotic manifestations of IgG4-RD[1]. This model is supported by reported efficacy of B cell depletion in patients with IgG4-RD. Rilzabrutinib is an oral, covalent, reversible, and highly specific inhibitor of Bruton's tyrosine kinase (BTK), an intracellular signaling molecule expressed in monocytes, macrophages, neutrophils, mast cells, eosinophils, platelets, and essential for maturation, function, and differentiation of B cells[2]. <h3>Objectives:</h3> To evaluate the safety and efficacy of rilzabrutinib over 52-weeks in rituximab-refractory or rituximab-naïve patients with IgG4-RD. <h3>Methods:</h3> This Phase 2a (NCT04520451) multi-center, open-label, 52-week, clinical trial of oral rilzabrutinib 400 mg twice daily enrolled two cohorts: Cohort A included patients who previously failed rituximab and Cohort B included patients naïve to rituximab. Most patients in the two cohorts were treated with rilzabrutinib plus a 4-week GC taper followed by rilzabrutinib alone for up to 52 weeks. Primary efficacy endpoint was the proportion of participants without disease flare following the first dose of rilzabrutinib until the end of treatment. Disease flare was defined as an increase in IgG4-RD RI >2 or initiation of rescue treatment (glucocorticoids or immunomodulators). <h3>Results:</h3> A total of 27 patients with active IgG4-RD were included; of these 13 were previously treated with rituximab and had recurrent disease activity. The median age was 60 years old. Patients were predominantly male (78%). The median duration of IgG4-RD was 3.7 years, and most patients (85%) had 3 or more organs involved. At week 52, 19/27 (70%) of rilzabrutinib-treated patients were off GC or immunosuppressants and free of disease flare during the entire treatment period after GC discontinuation. Treatment-emergent adverse events reported by ≥10% of patients included diarrhoea, COVID-19, dizziness, dry mouth, and nausea. These were mostly self-limited and mild in intensity. One death due to aspiration pneumonitis of a patient with submandibular and pulmonary manifestations of IgG4-RD was reported but was determined as not related to study intervention by the investigator. <h3>Conclusion:</h3> These results suggest rilzabrutinib might be a promising oral treatment for prevention of disease flares in patients with IgG4-RD. <h3>REFERENCES:</h3> [1] Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nature Reviews Rheumatology. 2020;16(12):702-14. [2] Langrish CL, Bradshaw JM, Francesco MR, Owens TD, Xing Y, Shu J, et al. Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease. The Journal of Immunology. 2021;206(7):1454-68. <h3>Acknowledgements:</h3> This study was funded by Sanofi. <h3>Disclosure of Interests:</h3> John H. Stone Amgen, Bristol-Myers Squib, Hoffmann-La Roche, Horizon Pharma, IgG4ward! Foundation, Novartis Pharma, Q32 Bio, Sanofi, Sobi. Inc, Steritas, Zenas, Fernando Martinez Valle Amgen, Medpace, Novartis, Mollie Carruthers Abbvie, Amgen, Janssen, Pfizer, UCB, Roche, Sanofi, Matthew Baker Zenas Biopharma, Amgen, Tong Wu: None declared, Jeea Choi Sanofi, Sanofi, Vincent Mikol Sanofi, Sanofi, Leda Mannent Sanofi, Sanofi, Owen Hagino Sanofi, Sanofi. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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