B10 | EFFICACY AND SAFETY OF ORAL BRUTON TYROSINE KINASE INHIBITOR RILZABRUTINIB IN ADULTS WITH PREVIOUSLY TREATED IMMUNE THROMBOCYTOPENIA: A PHASE 3, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER STUDY (LUNA 3)

Rilzabrutinib, a covalent, reversible Bruton’s tyrosine kinase inhibitor(BTKi) that acts through multi-immune modulation, showed rapid and durable platelet (PLT) responses with favorable safety in ITP patients in previous phase ½ LUNA 2 studies. In phase 3 LUNA 3 study (NCT04562766), adults with primary persistent/chronic ITP and PLT counts <30×109/L, with unsustained response to previous IVIg/anti-D or corticosteroids and insufficient response or contraindications to standard of care ITP therapy, were randomized 2:1 to oral rilzabrutinib 400 mg BID or placebo (PBO) for 24 weeks(wk) in double blind (DB) period, followed by rilzabrutinib only in the 28-wk open-label (OL) phase. Primary endpoint: durable PLT response (PLT counts ≥50×109/L for ≥8 of last 12wk of DB without rescue therapy). 202 adults (rilzabrutinib,n=133;PBO,n=69) included with similar baseline (BL) characteristics: median age: 47 years; median PLT counts: 15×109/L;≥5 prior ITP therapies: 46%(28% splenectomized in both arms). Overall, 86(65%) rilzabrutinib vs 23(33%) PBO patients had PLT response (PLT counts ≥50×109/L or ≥30–<50×109/L and doubled from BL). Primary endpoint was achieved in 31(23%) rilzabrutinib vs 0 PBO patients (P<0.0001). For DB and OL periods combined, durable response met in 38/133(29%) rilzabrutinib-randomized patients. All secondary efficacy endpoints were met compared to PBO. Median time to first PLT count was 36 days for rilzabrutinib vs not met for PBO(HR=3.1;P<0.0001); 15 days (range 2-99) in rilzabrutinib responders. Rilzabrutinib significantly reduced need for rescue therapy by 52% (vs PBO; P=0.0007). Significant and clinically meaningful improvements from BL observed with rilzabrutinib vs PBO in physical fatigue (ITQ-PAQ item 10) at Wk13(mean change:7.95vs–0.13; P=0.01), and bleeding(per IBLS) at Wk25 (–0.04vs 0.05; P=0.0006). Rilzabrutinib and PBO patients had similar all-cause, any-grade adverse events (AEs) and serious AEs; grade ≥2 gastrointestinal AEs were comparable (6%vs4%). Diarrhea (23%vs4%), nausea (17%vs6%), headache (8%vs1%), and abdominal pain (6%vs1%) were most common related AEs of rilzabrutinib; all grade 1/2. One patient with multiple risk-factors had treatment-related grade 3 peripheral embolism and 1 patient died (pneumonia) unrelated to rilzabrutinib. In patients with ITP rilzabrutinib showed robust therapeutic effect (rapid and durable PLT response), reduced bleeding and need for rescue therapy, improved physical fatigue and QoL, favorable safety and tolerability.