TOPLINE
In patients with immunoglobulin (Ig)G4-related disease, treatment with rilzabrutinib — an oral, reversible Bruton tyrosine kinase inhibitor (BTKi) — resulted in around 70% of patients remaining flare-free and off glucocorticoids (GCs) or immunosuppressants for up to 52 weeks. Reductions in disease activity were observed in those with prior rituximab exposure and those who were naive to rituximab.
METHODOLOGY
- Researchers conducted a phase 2a, open-label, 52-week study at nine sites across five countries to evaluate the efficacy and safety of rilzabrutinib in adults with IgG4-related disease.
- They enrolled 27 participants (median age, 60 years; 78% men): 13 participants from the US who were refractory to or unable to tolerate rituximab and 14 participants from four countries regardless of prior rituximab exposure.
- Participants refractory to rituximab were randomly assigned in a 3:1 ratio to rilzabrutinib 400 mg twice daily plus a 2- to 4-week GC taper or a 12-week GC monotherapy taper, with eligible participants permitted to cross over to rilzabrutinib.
- Participants enrolled regardless of prior rituximab exposure received rilzabrutinib 400 mg twice daily with a 2- to 4-week GC taper.
- The primary efficacy endpoint was remaining free of disease flares from the first rilzabrutinib dose through week 52, with a disease flare defined as either an increase of > 2 points in the IgG4-related disease Responder Index (RI) total activity score or initiation of rescue therapy for recurrent disease. Safety endpoints were the type, frequency, and severity of adverse events (AEs).
TAKEAWAY
- Overall, 70.4% of the participants were free of disease flares and off glucocorticoids or immunosuppressants; flare-free rates were 76.9% among participants refractory to rituximab and 64.3% among participants enrolled regardless of prior rituximab exposure.
- The mean IgG4-related disease RI activity score decreased by 8.3 points at week 12; among the 14 participants who completed 52 weeks of treatment, the mean reduction was 10.7 points, with a greater reduction among participants enrolled regardless of prior rituximab exposure than among those refractory to rituximab (15.0 vs 7.5 points).
- Among the 14 participants who completed 52 weeks of treatment, 13 had a reduction of ≥ 2 points in the IgG4-related disease RI score from baseline; mean serum IgG4 levels declined by 37.6% from baseline.
- Overall, 85.2% of the participants reported at least one treatment-emergent AE, most commonly diarrhea, COVID, and dizziness (reported by 40.7%, 18.5%, and 18.5% of participants, respectively); two participants experienced serious treatment-emergent AEs, including one death, but neither event was considered related to rilzabrutinib.
IN PRACTICE
“[T]he data from this phase 2 trial suggest that rilzabrutinib treatment resulted in clinically meaningful improvements in disease activity, deserving further evaluation of its potential efficacy and safety in patients with IgG4-related disease,” the authors of the study wrote.
SOURCE
This study was led by John H. Stone, Harvard Medical School, Massachusetts General Hospital in Boston. It was published online on July 21, 2026, in the Annals of the Rheumatic Diseases.
LIMITATIONS
The sample size was small, and placebo control was lacking, thereby limiting generalizability. Disease diagnosis and flares were not independently adjudicated. The primary efficacy endpoint definition excluded participants who discontinued for reasons other than flare, potentially inflating efficacy estimates.
DISCLOSURES
This study was funded by Sanofi. Four authors disclosed being Sanofi employees and may hold company stock and stock options; one author was a former Sanofi employee. Several other authors reported serving as consultants, receiving research grants or honoraria, or having advisory roles with Sanofi and other pharmaceutical companies, including AbbVie, Amgen, and Bristol-Myers Squibb. One of the authors reported being an executive chairman of IgG4ward! Foundation.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
