EMA Grants Orphan Designation to Rilzabrutinib for IgG4-Related Disease

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The European Medicines Agency (EMA) has granted orphan designation to rilzabrutinib, an investigational oral Bruton’s tyrosine kinase (BTK) inhibitor from Sanofi (1). The designation applies to the treatment of IgG4-related disease (IgG4-RD). Orphan designation is granted to therapies targeting rare, serious, or debilitating conditions affecting no more than five in 10,000 people in the European Union, underscoring the unmet medical need in this patient population (1).

Clinical data support potential in rare immune-mediated disorders

EMA’s decision is based on results from a Phase II clinical trial (NCT04520451) in which patients received rilzabrutinib for 52 weeks (2). The study reported reductions in disease flare frequency, improvements in other clinical markers, and decreased reliance on glucocorticoids. According to the study data, safety outcomes were consistent with those of previous rilzabrutinib studies, with no new safety signals identified. These results were presented at the 2025 European Alliance of Associations for Rheumatology Congress, held on June 11–13 in Barcelona (1).

Rilzabrutinib is being investigated across multiple rare immune-mediated and inflammatory diseases. In addition to IgG4-RD, the drug has orphan designations for treating immune thrombocytopenia in the United States, European Union (EU), and Japan, as well as for warm autoimmune hemolytic anemia, sickle cell disease, and IgG4-RD in the US (1). In addition, fast track designation has been granted in the US by FDA for both immune thrombocytopenia and IgG4-RD.

Regulatory reviews for rilzabrutinib in immune thrombocytopenia are ongoing in the US, EU, and China. A regulatory decision is expected from FDA by Aug. 29, 2025 (1).

Mechanism and Implications for pharmaceutical development

Rilzabrutinib’s mechanism of action targets BTK, a signaling protein expressed in B cells, macrophages, and other innate immune cells (1). BTK is implicated in multiple immune-mediated disease pathways. Rilzabrutinib’s reversible covalent binding approach, which is enabled by Sanofi’s Tailored Covalency technology, is designed to maintain BTK selectivity while potentially minimizing off-target effects.

The development of rilzabrutinib reflects two broader trends in drug manufacturing and discovery: the application of structure-based drug design to improve target specificity, and the strategic expansion of BTK inhibitors beyond oncology into autoimmune and inflammatory indications. Orphan designation status also provides incentives, such as market exclusivity and regulatory support, which can influence development timelines and commercialization strategies.

IgG4-RD: challenges in diagnosis and treatment

IgG4-RD is a progressive, chronic immune-mediated condition that can affect nearly any organ, causing irreversible organ damage and potentially fatal outcomes (3). The disease course often includes recurrent flares marked by exacerbated symptoms. Although U.S. prevalence is estimated at eight cases per 100,000 adults annually, global epidemiology remains unclear due to diagnostic challenges (3).

Given the limited treatment options and the need to balance efficacy with long-term safety in chronic immune-mediated disorders, pharmaceutical advances in this area carry significance for both patient care and manufacturing innovation. The development of rilzabrutinib demonstrates how targeted immune modulation strategies may open new therapeutic pathways for rare and difficult-to-treat conditions.

References

1. Sanofi. Sanofi’s Rilzabrutinib Earns Orphan Designation in the EU for IgG4-Related Disease. Press Release. Aug. 14, 2025.
2. National Library of Medicine. Open Label Two-Arm Study to Evaluate Rilzabrutinib in IgG4-RDParticipants. clinicaltrials.gov, last updated Feb. 21, 2025 (accessed Aug. 15, 2025). https://clinicaltrials.gov/study/NCT04520451
3. Wallace, Z. S.; Miles, G.; Smolkina, E.; et at. Incidence, Prevalence and Mortality of IgG4-Related Disease in the USA: A Claims-Based Analysis of Commercially Insured Adults. Ann. Rheum. Dis. 2023, 82 (7), 957–962. DOI: 10.1136/ard-2023-223950