Phase 3 Study to evaluate the efficacy and safety of rilzabrutinib in primary warm autoimmune hemolytic anemia (wAIHA): LUMINA 3 Study design Free

Warm autoimmune hemolytic anemia (wAIHA) is the most common subtype of AIHA, accounting for ~60-70% of cases. It results from immune dysregulation, with loss of self-tolerance inducing pathogenic IgG autoantibodies (in ≥95% of patients) that target and drive premature RBC destruction. wAIHA often follows a chronic, relapsing course, with symptoms such as jaundice, fatigue, dyspnea, high risk of thromboembolism and impaired quality of life (QoL). Currently, no approved therapies exist for patients with wAIHA. Treatment goals include improving hemoglobin (Hb) levels, alleviating symptoms, and achieving transfusion independence. Most patients initially respond to corticosteroids (CS), nearly two-thirds require additional therapy within the first year due to relapse or CS dependence, resistance, or intolerance.

Rilzabrutinib is a reversible covalent, highly selective Bruton tyrosine kinase inhibitor that acts through multi-immune modulation, targeting key mechanisms in wAIHA pathophysiology. Preclinical studies showed rilzabrutinib inhibits B-cell activation, autoantibody production, Fcγ receptor signaling in macrophages, and reduces inflammatory pathways. Clinical studies in immune thrombocytopenia have shown sustained platelet responses and a favorable safety profile in Phase 2 and 3 trials. Recently, a Phase 2b study (NCT05002777) in wAIHA demonstrated its robust efficacy based on overall and durable Hb responses and good tolerability. Among patients who continued rilzabrutinib for up to 50 weeks, 80% achieved a durable Hb response. These responses were accompanied by sustained improvements in hemolytic markers, inflammatory biomarkers and fatigue scores, with a favorable safety profile.

The LUMINA 3 study (NCT07086976) is a phase 3, multicenter, randomized, double-blind (DB), placebo-controlled, parallel-group trial designed to evaluate the efficacy and safety of rilzabrutinib in adult patients with wAIHA who are either relapsed/refractory to, dependent on, or intolerant/ineligible to CS therapy. Eligible participants must be ≥18 years with confirmed primary wAIHA, baseline averaged Hb level <10 g/dL, evidence of hemolysis, and a positive direct antiglobulin test. Key exclusion criteria include history of malignancy within 5 years; secondary wAIHA; active infections; prednisone >20mg/day or >10% dose change within 14 days; rituximab use within 12 weeks; and immunosuppressants within 30 days. After a 4-week screening period, approximately 90 participants will be randomized in a 2:1 ratio to receive either oral rilzabrutinib or placebo BID during a 24-week DB period. All participants who complete 24 weeks of treatment in the DB may enter the open-label (OL) period for a duration of 28 weeks during which all participants will receive rilzabrutinib BID. Responders in the OL period may enter a long-term extension (LTE) period which is planned to continue until the last patient in completes 52 weeks. The use of rescue medications to treat participants with severe hemolysis to maintain satisfactory Hb levels will be allowed.

The primary endpoint is the proportion of participants achieving a durable Hb response, defined as an increase of ≥2 g/dL from baseline at ≥ two-thirds of evaluable scheduled visits between Week 12 and 24. A durable Hb response requires ≥4 evaluable Hb assessments (Week 12–Week 24), ≥1 qualifying response during Weeks 20–24, no rescue medication within 6 weeks prior to durable response through Week 24, and no transfusions within 14 days before each qualifying Hb response. Secondary endpoints include overall Hb response (defined as the proportion of participants achieving either a Response [Hb increase ≥2 g/dL from baseline, without recent transfusion or rescue medications] or a Complete Response [CR; Hb ≥11 g/dL for women or ≥12 g/dL for men, without recent transfusion or rescue medications or no evidence of hemolysis]), time to response, fatigue (FACIT-Fatigue scale), use of rescue therapy, and overall safety and tolerability. In the LTE, participants with a CR sustained for ≥24 weeks may discontinue rilzabrutinib to assess off-treatment durability. If maintained for 24 weeks, they complete the EOS visit and withdraw; if Hb declines earlier, treatment may be resumed.

This study aims to address a significant unmet need in patients with wAIHA by evaluating rilzabrutinib as a potential treatment option to improve Hb levels, reduce hemolysis, improve fatigue and overall QoL.