EULAR 2025: Rilzabrutinib Shows Promise in IgG4-Related Disease — Reduction in Flares and Disease Activity
Rilzabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor currently in clinical development, demonstrated a significant and sustained reduction in disease flares and key disease activity markers in patients with IgG4-related disease (IgG4-RD), according to new data presented at the European Alliance of Associations for Rheumatology (EULAR) 2025 Congress in Barcelona, Spain (June 11–14).
The results come from a open-label, proof-of-concept, Phase 2 study (NCT04520451) and highlight rilzabrutinib’s potential as a disease-changing treatment option for a condition that currently has limited and non-specific treatment options and involves substantial patient suffering due to its chronic and progressive course.
IgG4-Related Disease: An Unmet Medical Need
IgG4-related disease is a immune-mediated condition that involves organ dysfunction and mass-like formations due to infiltration by IgG4-positive plasma cells and fibrosis. This can manifest in a range of symptoms, depending on which organ is involved — the pancreas, lacrimal and salivary glands, kidneys, aorta, or even the nervous system — and can lead to permanent, irreversible damage if left unchecked.
Current standard treatments predominantly rely upon high-dose glucocorticoids (GCs). While these can be effective in reducing disease activity, their side effects — osteoporosis, diabetes, weight gain, and susceptibility to infections — alongside their limited ability to enable long-term disease control — create a significant unmet need for new therapeutic options.
John Stone, MD, MPH, Professor of Medicine at Harvard Medical School, the Edward A. Fox Chair in Medicine at Massachusetts General Hospital, and Executive Chairman of The IgG4ward! Foundation, explained during the EULAR 2025 presentation:
“IgG4-related disease is a progressive, immune-mediated condition with a significant unmet patient need. While it can cause irreversible organ damage and can even be fatal in some cases, there are limited approved treatments for this disease. The data presented at EULAR are promising as they support the potential of rilzabrutinib to help manage chronic fibro-inflammatory symptoms, notably by reducing flares and reliance on glucocorticoids in people with IgG4-related disease.”
Phase 2 Study: Meaningful Reduction in Disease Activity and Glucocorticoid-Sparing Benefit
The open-label, proof-of-concept Phase 2 study (NCT04520451) evaluated rilzabrutinib’s efficacy and safety in adult patients with IgG4-related disease. All participants met the ACR/EULAR 2019 diagnostic criteria for IgG4-RD and had a minimum IgG4-RD Responder Index (RI) score of 2 or greater at baseline. Importantly, most participants presented with active disease in at least one organ, with the exception of the lymph nodes.
The study’s treatment regimen involved rilzabrutinib 400mg administered twice daily alongside a brief glucocorticoid taper over the first four weeks. Subsequently, rilzabrutinib was continued as monotherapy for the rest of the 52-week study period. This design was meant to enable clinician-researchers to gauge the ability of rilzabrutinib to control disease activity after the withdrawal of standard therapy.
Key results from the study include:
- Flare-free Disease Control: 70% of patients treated with rilzabrutinib remained flare-free through 52 weeks without needing additional treatments, such as high-dose glucocorticoids or other immunosuppressants.
- Clinically Meaningful Improvement in Disease Activity: Disease activity, measured by the IgG4-RD Responder Index, fell by at least two points by Week 52, reflecting remarkable disease control and improvement in symptoms.
- Rapid and Sustained Benefit: Reductions in disease activity were observable as early as Week 12 and remained sustained through Week 52.
- Safety Profile Consistent with Previous Studies: The safety profile of rilzabrutinib was well-understood from previous trials, with no new safety signals. The most frequently reported treatment-emergent adverse events (reported by greater than 10% of patients) included diarrhea, COVID-19, dizziness, dry mouth, and nausea — all of which were predominantly mild to moderate in severity.
Sanofi’s Commitment to Innovation in Rare Disease
Alyssa Johnsen, MD, PhD, Global Therapeutic Area Head for Immunology and Oncology Development at Sanofi, stressed the significance of these results for both patients and their families:
“Sanofi is committed to advancing new medicines in immune-mediated rare diseases, including IgG4-related disease. The promising Phase 2 study results presented at EULAR strengthen our confidence in rilzabrutinib and its potential to make a meaningful impact on IgG4-related disease symptoms and disease progression. We look forward to further evaluating rilzabrutinib in subsequent phases of its clinical development.”
Fast Track and Orphan Drug Designations from FDA
The U.S. Food and Drug Administration (FDA) recognized the significance of rilzabrutinib’s potential by granting Fast Track designation in May 2025 and Orphan Drug designation in April 2025 for its development in IgG4-related disease.
Fast Track designation is a process designed by the FDA to facilitate the development and expedite the review of medicines for the treatment of serious conditions with high unmet need. This process helps bring promising new treatments to patients faster, while retaining rigorous standards for safety and efficacy.
Orphan Drug designation is meant to aid in the development of treatments for rare disorders — those affecting fewer than 200,000 people in the USA — by offering incentives to sponsor companies.
Clinical Development
Looking forward, rilzabrutinib’s further clinical development is underway, with plans to initate a Phase 3 trial later this year. The aim is to further define its efficacy, safety, and tolerability in a larger population of patients with IgG4-related disease.
While rilzabrutinib’s safety and efficacy remain under investigation and have not yet been evaluated by regulators, these new data suggest that rilzabrutinib may become a much-needed treatment option for patients battling IgG4-related disease — offering symptom relief, disease control, and hopefully, a chance for an improved quality of life.
