FDA Grants Orphan Drug Designation to Sanofi’s Rare Disease Drug Rilzabrutinib for wAIHA & IgG4-RD

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The FDA has granted Orphan Drug designation to Sanofi’s rilzabrutinib for warm autoimmune hemolytic anemia (wAIHA) and IgG4-related disease (IgG4-RD), both of which currently lack approved treatment options. The treatment showed clinically meaningful improvements in response rates and disease markers in a Phase IIb study of patients with wAIHA, while a Phase IIa study demonstrated reduced disease flares and steroid use over a 52-week treatment period in patients with IgG4-RD.¹

“Orphan drug designation for these two rare, immune-mediated conditions validates our ongoing commitment to pursuing potential first- and best-in-class medicines for diseases that affect small populations but persist with unmet medical need,” said Karin Knobe, MD, PhD, global head, development, rare diseases, Sanofi, in a press release. “Our continued exploration of rilzabrutinib across multiple indications speaks to our belief in its potential for multi-immune modulation, as well as our belief in supporting treatment options, no matter how rare a condition.”

A multicenter, open-label Phase IIb study enrolled 22 adult patients with primary wAIHA, including one patient who was later found to be misclassified with cold agglutinin disease. Participants received 400 mg of rilzabrutinib twice daily for 24 weeks, with an optional long-term extension.

All patients were required to be relapsed, refractory, or dependent on corticosteroids (CS). Additional eligibility criteria included hemoglobin (Hb) levels of <10 g/dL, at least one abnormal hemolytic marker, positive direct antiglobulin test, Eastern Cooperative Oncology Group performance status 0–2, and an unsustained response to CS. The primary endpoint was overall Hb response, defined as an increase of ≥2 g/dL or achieving ≥11/12 g/dL without recent transfusion or rescue therapy. Secondary endpoints included time to response, durable Hb response, and fatigue as measured by the FACIT-Fatigue scale.

Results showed that 64% of patients achieved the overall Hb response, and 41% achieved a durable response. The mean baseline FACIT-Fatigue score was 30, with clinically meaningful improvements observed by weeks 12 and 24. The most common adverse events (AEs) included nausea, diarrhea, and abdominal pain and no AEs led to discontinuation or death.²

A multicenter, open-label, two-arm Phase IIa study evaluated approximately 25 patients with active IgG4-RD. Patients were randomly assigned in a 3:1 ratio to receive either rilzabrutinib 400 mg twice daily plus a glucocorticoid (GC) taper or GC alone for 12 weeks. All patients were refractory to rituximab and eligible for GC tapering. The primary endpoint was GC-free remission at week 12, defined by clinical response, absence of disease flare, and complete discontinuation of glucocorticoids.

At the time of data cut-off, full clinical results were not yet available. However, preclinical and mechanistic data demonstrated that rilzabrutinib blocks Bruton’s tyrosine kinase and B-cell receptor signaling in B cells, Fc gamma receptor activation in monocytes and macrophages, and IgG/IgM antibody production through both T-cell–dependent and –independent pathways.³

According to Sanofi, wAIHA affects approximately one to three per 100,000 people in the United States annually, with a median age of onset of 52 years, with mortality estimated at 5%.^1,4

The incidence of IgG4-RD in the United States increased from 0.78 per 100,000 people to 1.39 per 100,000 by 2019. While approximately 75% of reported cases occur in individuals of Japanese background, the disease has been observed across all ethnic groups.⁵

Rilzabrutinib is also under regulatory review in the United States, European Union, and China for immune thrombocytopenia. A final FDA decision is expected by August 29, 2025.¹

References

1. Press Release: Rilzabrutinib granted orphan drug designation in the US for two rare diseases with no approved medicines. Sanofi. April 3, 2025. Accessed April 8, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-04-03-05-00-00-3054815

2. 3836 Part a Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Patients with Warm Autoimmune Hemolytic Anemia (wAIHA): Multicenter, Open-Label, Phase 2b Study. ASH. December 9, 2024. Accessed April 8, 2025. https://ash.confex.com/ash/2024/webprogram/Paper200325.html

3. AB0756 IMMUNE-MEDIATED BASIS FOR A PHASE 2A CLINICAL STUDY COMPARING RILZABRUTINIB VS GLUCOCORTICOIDS IN RITUXIMAB-REFRACTORY PATIENTS WITH IGG4-RELATED DISEASE. BMJ. Accessed April 8, 2025. https://ard.bmj.com/content/80/Suppl_1/1406.1

4. Warm Autoimmune Hemolytic Anemia. NORD. Accessed April 8, 2025. https://rarediseases.org/rare-diseases/warm-autoimmune-hemolytic-anemia/#symptoms

5. IgG4-Related Disease (IgG4-RD). Rare Disease Advisor. Accessed April 8, 2025. https://www.rarediseaseadvisor.com/disease-info-pages/immunoglobulin-g4-related-disease-epidemiology/#:~:text=Incidence%20and%20Prevalence%20of%20IgG4%2DRD%20in%20the%20United%20States&text=The%20incidence%20of%20IgG4%2DRD%20increased%20from%200.78%20per%20every,5.3%20per%20every%20100%2C000%20persons.