A randomized, double-blind, placebo-controlled trial of a novel BTK inhibitor (rilzabrutinib) in patients with sickle cell disease (SCD) aged 10–65 years: LIBRA Study

Abstract Sickle Cell Disease (SCD) is a multisystem disorder caused by mutations in the HBB gene, leading to hemoglobin S polymerization following deoxygenation, red blood cell sickling, and chronic hemolysis. Therapies to prevent vaso-occlusive crises (VOC), improve anemia and prevent end-organ damage are limited and of variable efficacy. Hence, there is a significant unmet medical need for new therapies for patients with SCD. SCD is increasingly recognized as a chronic inflammatory, systemic, degenerative disorder. The pathophysiology of SCD involves oxidative stress, endothelial activation, and innate immune-driven inflammation, contributing to multiorgan dysfunction. Neutrophils, monocytes, mast cells, and platelets promote vascular occlusion via neutrophil extracellular trap (NET) formation, thrombosis, and increased adhesion. VOCs cause tissue ischemia, pain, organ damage, and reduced quality of life (QoL). Targeting inflammation in SCD holds the promise of preventing VOC and end-organ damage and may also reduce anemia and fatigue. Bruton's tyrosine kinase (BTK) is a key regulator of multiple immune and inflammatory pathways implicated in SCD. Rilzabrutinib, a highly selective, reversible BTK inhibitor, acts through multi-immune modulation, targeting key immune pathways central to SCD. In the phase 3 LUNA study, conducted in heavily pretreated patients with long-standing immune thrombocytopenia, rilzabrutinib demonstrated sustained platelet responses with favorable safety profile. A phase 2b study in patients with warm autoimmune hemolytic anemia further supported its therapeutic potential as evidenced by the observed robust efficacy and reduced inflammatory biomarkers. SCD treatment with rilzabrutinib may result in a global anti-inflammatory effect. In preclinical studies in SCD mouse-models, rilzabrutinib significantly reduced microvascular stasis, spleen weight, leukocytosis, nuclear factor-κB activation, and expression of adhesion molecules. Transcriptomic analysis showed downregulation of genes involved in inflammasome signaling, adhesion, NETosis, and thrombosis. The efficacy and safety of rilzabrutinib as a potential oral therapy for patients with SCD will be evaluated in the LIBRA study. LIBRA (NCT06975865) is a phase 3, multicenter, randomized, double-blind, placebo-controlled, group-sequential trial evaluating rilzabrutinib in pediatric and adult patients with SCD. Eligible participants will include both male and female individuals (aged 10 to 65 years) with confirmed HbSS or HbS/β0 thalassemia and 2–10 episodes of acute VOC in the previous 12 months. Additionally, participants may be on hydroxyurea and/or L-glutamine (if treated ≥6 months, on a stable dose ≥3 months, with ≥1 VOC while on stable dose); those not receiving these medications must not plan to initiate them during the study. Key exclusion criteria include a history of stroke or abnormal transcranial doppler, and the use of crizanlizumab within 90 days and/or voxelotor within 30 days prior to screening. After a 4-week screening period, approximately 192 participants will be randomized (2:1) to receive either rilzabrutinib or placebo orally twice daily during a 52-week double-blind (DB) period (Part A). Participants completing the DB period may enter an open-label, long-term extension (LTE) period (Part B) of ≥52 weeks plus 2-week follow-up (total duration: ≥106 weeks). The primary endpoint is the annualized rate of clinical VOC during the 52-week double-blind period to assess efficacy of rilzabrutinib. Statistical analysis will be two-sided at the significance level of 0.05. Secondary endpoints are time to first clinical VOC, annualized rate of visits due to SCD-related complications and home-managed VOCs, change from baseline in fatigue and hemoglobin, and overall safety. Other endpoints include change from baseline in QoL, patient global impression of fatigue and health status, and biomarkers (biomarkers of inflammation, endothelial activation, and oxidative stress). This study aims to address a significant unmet need in SCD by evaluating rilzabrutinib as a novel potential treatment option to reduce VOC burden and improve outcomes in SCD.