0239: Safety of Rilzabrutinib, a BTK Inhibitor, in Adult Patients with IgG4-related disease (IgG4-RD) in a 52-week Phase 2 Open-label Study

Background/Purpose: IgG4- related disease (IgG4-RD) is a chronic, progressive, immune-mediated fibrotic disease with limited treatment options. Rilzabrutinib is an orally available, reversible, inhibitor of Bruton's tyrosine kinase (BTKi). We conducted an open label proof-of-concept safety and efficacy study of rilzabrutinib orally twice daily in patients diagnosed with active IgG4-RD. As of Jan 2, 2025, the cumulative exposure to rilzabrutinib in interventional clinical trials is estimated to be 1186 participants and 672 patient-years (PY). Across the completed and ongoing studies in multiple indications (IgG4-RD, immune thrombocytopenia, warm autoimmune hemolytic anemia, focal segmental glomerulosclerosis/minimal change disease, pemphigus vulgaris, asthma, atopic dermatitis, and chronic spontaneous urticaria) rilzabrutinib was well tolerated, including at single and multiple doses

Methods: The safety of rilzabrutinib was evaluated in a 52-week, phase 2 proof-of-concept study (NCT04520451) including adult patients with active IgG4-RD. Two cohorts were included. Cohort A included participants in the United States and Cohort B included participants in Canada, France, Italy, and Spain. Safety parameters included spontaneously reported treatment emergent adverse events (TEAE), serious TEAE, TEAE leading to discontinuation, adverse events of special interest (AESI), and death

Results: The most frequently reported TEAEs by primary SOC (≥20% of participants) were: Gastrointestinal disorders (16 of 27 [59.6%], infections and infestations (12 of 27 [44.4%]), skin and subcutaneous tissue disorders (11 of 27 [40.7%]) and nervous system disorders (8 of 27 [29.6%]) (Table). Overall, 2 of 27 (7.4%) participants experienced serious TEAE (1 participant with campylobacter infection; and 1 death due to aspiration pneumonitis while hospitalized for acute kidney injury, reported as not related to study intervention, in a participant with history of chronic kidney failure, oesophagitis, and hiatal hernia). Overall, 5 of 27 (18.5%) reported TEAEs leading to permanent treatment discontinuation (Table). There were no reports of pregnancy, symptomatic overdose, tuberculosis, or uveitis; nor drug related AESI associated with other BTKi: major hemorrhagic events, severe or serious cytopenia, or atrial fibrillation.

Conclusion: Although this study included participants with a multi-organ, chronic, relapsing disease, with the exception of the unrelated fatal event, the safety profile was consistent with that reported for other clinical trials of rilzabrutinib. No participant experienced a TEAE associated with other BTKi, e.g., bleeding, cytopenia, or atrial fibrillation.