Early multi-immune modulation with rilzabrutinib in patients with primary ITP after first-line treatment failure: A phase 3b study (LUNA 4)

Abstract Background: Immune thrombocytopenia (ITP) is driven by complex immune dysregulation involving both autoimmunity and inflammation, leading to increased platelet destruction and impaired production. In addition to bleeding, patients often experience fatigue, reduced quality of life, and increased risk of thromboembolism in selected individuals, burdens not consistently addressed by current therapies. While corticosteroids (CS) are the standard first-line (1L) therapy, the remission rate is often low. For patients not achieving adequate platelet counts (PC), second-line (2L) therapies include thrombopoietin receptor agonists, anti-CD20 antibodies, and spleen tyrosine kinase inhibitors, which can be effective but are associated with variable platelet response and durability, intolerance, and/or limited impact on the underlying immune imbalance. Rilzabrutinib is a highly selective, reversible, oral Bruton tyrosine kinase (BTK) inhibitor that acts through multi-immune modulation, targeting key immune pathways involved in ITP pathogenesis. In the LUNA 2/3 studies, conducted in heavily pretreated patients with long-standing ITP, rilzabrutinib demonstrated durable platelet responses, reduced bleeding, and improvements in fatigue and quality of life. Notably, improvements in fatigue were also observed among some non-responders. Its anti-inflammatory activity has also been reported in other immune-mediated hematologic conditions. These findings support the rationale that early multi-immune modulation with rilzabrutinib may improve clinical outcomes and help restore immune balance, potentially influencing disease progression if introduced earlier, when a more immunologically responsive disease course is expected. Study design: LUNA4 (NCT07007962; EU trial number: 2025-522070-36-00) is a phase 3b, open-label, single-arm, interventional study evaluating the effect of early multi-immune modulation with rilzabrutinib in adults with ITP. Eligible participants must have primary ITP and qualifying PC <30×109/L (no single count >35×109/L) after 1L therapy or require ongoing/repeated administration of CS for more than 6 weeks to maintain PC >30×109/L plus one PC <30×109/L after a new tapering attempt. Additionally, patients should have a history of platelet response (≥30x109/L) while on 1L therapy and must not have received any dose of 2L therapies for ITP, including splenectomy. During the study all participants will be treated with rilzabrutinib 400 mg bid. At week 16 during the 28-week Primary Analysis Period (PAP), participants who have not achieved ≥1 PC ≥30×109/L or an increase in PC ≥20×109/L in absence of rescue therapy will be discontinued. The proportion of participants achieving durable platelet response during the PAP is LUNA4 primary outcome, defined as PC ≥50x109/L or ≥30x109/L and <50x109/L and at least double from baseline in absence of rescue therapy, for ≥50% of 6 (and at least 4) biweekly platelet measurements in the last 12 weeks of PAP. Durable responders will continue into the Long-Term Extension (LTE) period, comprising additional 28 weeks. Concomitant CS are allowed in LUNA4, and participants can taper/discontinue CS early during PAP and during LTE. Participants on rilzabrutinib monotherapy achieving one PC ≥100x109/L and no PC <70x109/L for ≥6 weeks can discontinue rilzabrutinib during LTE. At week 56, those maintaining PC ≥30x109/L and double from baseline following rilzabrutinib discontinuation, with no bleeding or use of any therapy for ITP will be considered in sustained response off treatment (SROT) and will be followed for additional 24-weeks. Re-treatment with rilzabrutinib 400 mg bid after discontinuation is allowed. The LUNA4 study will evaluate other outcomes including overall response (two PC at least 5 days apart of ≥50x109/L or ≥30x109/L and <50x109/L and at least double from baseline without rescue therapy), cumulative number of weeks with platelet response, change from baseline in the immune thrombocytopenia bleeding scale score, proportion of participants able to discontinue or reduce CS dose by 50% or to <5 mg from baseline, proportion of participants achieving SROT, change from baseline in fatigue, levels of inflammatory markers, and frequency and severity of treatment emergent adverse events. This study will evaluate the effect of early multi-immune modulation with rilzabrutinib in ITP after failing 1L therapy and the ability of rilzabrutinib to modify ITP disease progression.