Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Adults with Previously Treated Immune Thrombocytopenia (ITP): A Phase 3, Placebo-Controlled, Parallel-Group, Multicenter Study (LUNA 3)

Introduction: Patients with primary ITP who are not sufficiently responsive or intolerant to available therapies experience higher rates of morbidity, mortality, and impaired quality of life (QoL). Phase 2 results with covalent, reversible BTKi rilzabrutinib in ITP showed rapid and durable platelet responses with favorable safety. Methods: The phase 3 LUNA 3 study enrolled adults ≥18 y and pediatrics 10-<18 y with primary persistent/chronic ITP and platelet counts <30×109/L within 2 wk of study initiation (NCT04562766; 2020-002063-60). Patients had response (platelet count ≥50×109/L) to previous IVIg/anti-D or corticosteroids (CS) that was not sustained and documented as intolerance, insufficient response, or any contraindication to any standard-of-care ITP therapy. Patients were stratified by splenectomy status (yes/no) and thrombocytopenia severity (averaged platelet counts <15×109/L or ≥15×109/L) and randomized 2:1 to oral rilzabrutinib 400 mg bid or placebo for up to 24 wk (double-blind), followed by rilzabrutinib only in the 28-wk open-label period (+4-wk safety follow-up) or long-term extension, if eligible. After the initial 12 wk, non-responders could join the open-label part or discontinue. Stable baseline doses of concomitant CS and/or TPO-RA, and rescue medication use were permitted. The primary endpoint was durable platelet response: platelet counts ≥50×109/L for ≥8 of the last 12 wk of the 24 wk blinded period without rescue therapy. This is the first report of efficacy and safety of the adult population. Results: As of March 14, 2024, 202 randomized adults (n=133 rilzabrutinib, n=69 placebo) had a similar overall median baseline age of 47 y (range, 18-80), median baseline platelet count of 15×109/L, and 46% received ≥5 prior ITP therapies (including 28% splenectomized in both arms). Median duration of ITP was longer for rilzabrutinib-treated patients at 8.1 y (range, 0.3-52.2) vs placebo at 6.2 y (range, 0.3-35.8). Platelet response (ie, responders: ≥50×109/L or ≥30-<50×109/L and doubled from baseline) was achieved in 86 (65%) rilzabrutinib vs 23 (33%) placebo patients. The primary endpoint of durable response was met in 31 (23%) rilzabrutinib vs 0 placebo patients (P<0.0001). For double-blind and open-label periods combined, durable response was met in 38/133 (29%) rilzabrutinib-randomized patients. Significant improvements with rilzabrutinib over placebo were seen in all secondary efficacy endpoints. Median time to first platelet count ≥50×109/L or ≥30-<50×109/L and ≥doubled from baseline was 36 d (95% CI, 22-44) for rilzabrutinib vs not achieved for placebo (HR=3.1 [95%, 1.9-4.9]; P<0.0001). Among patients who randomized to rilzabrutinib and achieved response, median time to first platelet response was 15 d (range, 2-99). Rilzabrutinib significantly reduced the need for rescue therapy by 52% vs placebo (P=0.0007). Significant and clinically meaningful improvements were observed with rilzabrutinib vs placebo, respectively, in physical fatigue (ITP-PAQ item 10) with a mean change (SE) from baseline at week 13 of 7.95 (2.13) vs -0.13 (2.86; P=0.01), and bleeding (per IBLS) with a mean change (SE) from baseline at week 25 of -0.04 (0.02) vs 0.05 (0.02; P=0.0006). During the double-blind part, rilzabrutinib and placebo patients received treatment for a median of 98 days (range, 22-182) and 84 days (range, 17-173), respectively, with a median compliance rate of ≥98% for both. A similar percentage of rilzabrutinib and placebo patients had all-cause, any-grade adverse events (AEs) and serious AEs (SAEs); grade ≥2 GI AEs were comparable at 6% vs 4%. The most common treatment-related AEs for rilzabrutinib vs placebo were diarrhea (23% vs 4%), nausea (17% vs 6%), headache (8% vs 1%), and abdominal pain (6% vs 1%), all grade 1 or 2. All other related AEs were ≤5%. In the rilzabrutinib arm, 1 patient with multiple risk-factors had a treatment-related grade 3 peripheral embolism (SAE) and 1 patient died due to pneumonia unrelated to treatment. Conclusion: Pivotal LUNA 3 phase 3 study results in patients with ITP showed that first-in-class BTKi rilzabrutinib has a robust therapeutic effect as shown by rapid and durable platelet response, reduced bleeding and need for rescue therapy, improved physical fatigue and QoL, and favorable safety and tolerability.