Background/Purpose: IgG4-RD is a progressive, immune-mediated fibrotic disease with limited treatment options. Rilzabrutinib is a reversible, orally available inhibitor of Bruton’s tyrosine kinase (BTKi). Here, we conducted an open label proof-of-concept safety and efficacy study of rilzabrutinib in adult patients with IgG4-RD, stratified by prior rituximab treatment history.

Methods: The study (NCT04520451) included patients with active IgG4-RD whose last dose of rituximab was >6 months prior to screening (or with evidence of B cell reconstitution)[rituximab-experienced] or naïve to rituximab [rituximab-naïve]. During the 4-week screening period, prednisone (20 mg/day to 40 mg/day) was prescribed according to the investigator’s assessment of organ(s) involved and level of disease activity . Over the first 4 weeks of rilzabrutinib treatment, prednisone was tapered off and rilzabrutinib continued for up to 52 weeks. Disease activity was tracked with the IgG4-RD Responder Index (RI). Efficacy endpoints included proportion of participants without disease flare (defined as an increase in RI >2 or initiation of rescue treatment with glucocorticoid or immunomodulator), RI Total Activity score (observed and change from baseline) at each visit, and proportion of participants with a reduction in RI Total Activity score ≥2 at each visit.

Results: A total of 27 participants (15 rituximab-experienced, 12 rituximab-naïve) were enrolled. At baseline, 10/15 (67%) rituximab-experienced participants had a history of flaring on treatment, 1 (7%) without response to rituximab, 3 (20%) with adverse reaction to rituximab, and 1 (7%) with prior response to rituximab. The proportion of participants on rilzabrutinib monotherapy without a disease flare at the end of treatment was 19/27 (70%), and was similar in both the rituximab-experienced subgroup (73%) and the rituximab-naïve subgroup (67%). Rituximab-naïve participants had a higher total activity score at baseline vs rituximab-experienced participants (mean±SD: 15.7±7.6 vs. 10.1±5.7), By Week 12 the total activity scores were 3.0±2.0 (77% reduction from baseline) and 4.3±3.4 (52% reduction from baseline) in the rituximab-naïve and rituximab-experienced groups, respectively. At Week 52, the total activity score (mean±SD) in the rituximab-naïve subgroup was 1.7±1.5 (an 88% reduction from baseline) and 3.1±3.7 (71% reduction from baseline) in rituximab-experienced group. At Week 52, all participants in the rituximab naïve-subgroup and 88% in the rituximab-experienced subgroup had a reduction of >2 points in IgG4-RD RI Total Activity score.

Conclusion: Following withdrawal of oral prednisone, disease activity as measured by the RI Total Activity score declined rapidly, substantially, and was sustained during the 52-week treatment period. Although comparisons are limited by the small sample size, and differences in disease characteristics at baseline, the proportions without flare or rescue and reductions in disease activity were substantial in both the participants who were previously treated with rituximab (including those refractory to rituximab) and naïve to rituximab.

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-rilzabrutinib-was-associated-with-rapid-and-sustained-reduction-in-disease-activity-in-patients-with-igg4-rd-previously-treated-or-naive-to-b-cell-depletion/