Rilzabrutinib (WAYRILZ) is a first-in-class, oral, reversible BTK inhibitor developed by Sanofi for the treatment of immune thrombocytopenia (ITP). The drug originated from Sanofi’s acquisition of Principia Biopharma in 2020 and was subsequently advanced into an approved therapy by Sanofi’s R&D organization. Unlike conventional therapies that primarily manage symptoms or increase platelet production, rilzabrutinib targets the underlying immune mechanisms of ITP through multi-immune modulation, reducing platelet destruction and helping restore immune balance. The therapy has received Orphan Drug Designation (ODD) in the US, EU, and Japan, as well as Fast Track Designation (FTD) from the FDA, highlighting its potential to address a significant unmet need in patients with persistent or chronic ITP.

Building on its clinical development program, rilzabrutinib received FDA approval in August 2025 for adults with persistent or chronic ITP who have had an insufficient response to prior treatment, followed by European Commission approval in December 2025 for adult patients refractory to other therapies. Both approvals were supported by results from the pivotal Phase III (LUNA 3) trial, which met its primary and key secondary endpoints, demonstrating significant improvements in sustained platelet responses and other ITP-related outcomes with a manageable safety profile. Following approvals in the US and Europe, Sanofi is seeking to expand the drug’s global reach, with a regulatory decision in Japan anticipated in H2 2026.

Key Efficacy Highlights:

• Clinically meaningful platelet responses were maintained for a mean of 80% of treatment weeks during the LTE

• 59% of patients achieved a complete response (platelet count ≥100 × 10⁹/L on two consecutive visits)

• Median platelet counts were maintained between 83–139 × 10⁹/L during the first two years of follow-up

• Improvements in physical fatigue and bleeding outcomes were sustained throughout the LTE

• 26% of patients discontinued concomitant ITP medications and remained on rilzabrutinib monotherapy; 50% reduced corticosteroid doses by >50%, and 44% reduced or discontinued TPO-RA therapy

Key Safety Highlights

• TREAs were reported in 22% of patients

• The most common TRAEs were nausea (7%) and diarrhea (4%), predominantly mild in severity

• One patient experienced Grade 3 cellulitis, which resolved without dose modification

• No deaths, thromboembolic events, or treatment-related Grade ≥2 bleeding or gastrointestinal adverse events were reported

KOL insights -

“Rilzabrutinib introduces a differentiated mechanism in ITP with a favorable safety profile and meaningful improvements in bleeding, fatigue, and quality of life. While its efficacy may not yet match the durable response rates achieved with TPO-RAs, its lack of thrombotic risk, convenient oral administration, and activity in heavily pretreated patients position it as an attractive option for patients who are unsuitable for or refractory to existing second-line therapies.” – Expert Opinion

“The long-term positioning of rilzabrutinib will depend on whether ongoing studies can demonstrate deeper and more durable responses, potentially enabling competition with established TPO-RAs. In the absence of predictive biomarkers, treatment selection remains empirical, and future adoption will be driven by real-world effectiveness, combination strategies, cost considerations, and the evolving competitive landscape in ITP.”– Expert Opinion

Conclusion -

Immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder, with an estimated 67,000 prevalent cases in the United States in 2025, characterized by immune-mediated platelet destruction and impaired platelet production. Persistent and chronic ITP remain particularly challenging to manage, with many patients experiencing recurrent thrombocytopenia, bleeding complications, and long-term dependence on corticosteroids, rituximab (RITUXAN), splenectomy, or thrombopoietin receptor agonists such as eltrombopag (PROMACTA/REVOLADE) and avatrombopag (DOPTELET), despite multiple available treatment options. Within this landscape, other key comparators include the SYK inhibitor fostamatinib (TAVALISSE), FcRn inhibitor efgartigimod (VYVGART), and additional emerging antibody- and B-cell–targeted agents. Pipeline therapies such as ianalumab (anti-CD19/BAFF-R) and mezagitamab (anti-CD38) are also under investigation, but they act through distinct immune pathways and remain largely investigational. Long-term results from the Phase III (LUNA 3) study demonstrate that rilzabrutinib delivers durable platelet responses, sustained improvements in fatigue and bleeding outcomes, and reduced reliance on concomitant ITP medications while maintaining a favorable safety profile. As the first BTK inhibitor approved for ITP, rilzabrutinib introduces a novel disease-modifying approach that targets the underlying immune mechanisms driving platelet destruction, supporting its potential to become an important new treatment paradigm for patients with persistent or chronic ITP.