Pb2535: trial in progress: a phase 2, double-blind, randomized, placebo-controlled, multicenter study to evaluate the efficacy and safety of luspatercept to treat anemia in adults with alpha-thalassemia

Topic: 27. Thalassemias Background: Alpha (α)-thalassemia hemoglobin H (HbH) disease is a blood disorder in which 3 of the 4 genes encoding α-globin are defective, leading to ineffective erythropoiesis and chronic anemia. Patients (pts) with non-deletional mutations have higher red blood cell (RBC) transfusion and iron chelation therapy (ICT) requirements, and some may become transfusion dependent (TD). Regular RBC transfusions are associated with increased risk of morbidity and mortality, emphasizing the need for effective treatments for anemia. Luspatercept, an erythroid maturation agent, is approved in the EU and USA to treat anemia in pts with beta (β)-thalassemia who require regular RBC transfusions. The efficacy of luspatercept in α-thalassemia has yet to be investigated. Aims: This actively enrolling, phase 2, double-blind, randomized, placebo-controlled, multicenter study will evaluate the efficacy and safety of luspatercept to treat anemia in pts with α-thalassemia HbH disease. Methods: Eligible pts will be ≥18 years of age with documented diagnosis of α-thalassemia HbH disease and ECOG score of 0 or 1; combination diagnosis of β-thalassemia is allowed if the patient has ≥1 non-mutated β-chain gene. Pts may be TD (receiving ≥6 RBC units/24 wk prior to randomization with no transfusion-free period >56 days) or non-transfusion dependent (NTD; receiving <6 RBC units/24 wk prior to randomization, not receiving RBC transfusions during ≥8 wk prior to randomization, and mean baseline (BL) Hb ≤10 g/dL based on ≥2 measurements taken ≥1 wk apart within 4 wk before randomization). Exclusion criteria include diagnosis of α-thalassemia trait, Hb Bart’s hydrops, ATR-X α-thalassemia, HbS/β-thalassemia, or an HbE homozygous β gene mutation; use of an erythropoiesis-stimulating agent or initiation of ICT in the 24 wk prior to randomization; history of deep vein thrombosis or stroke in the 24 wk prior to randomization; and anemia or episodes of hemolysis due to causes other than α-thalassemia. A target of 177 pts (93 TD and 84 NTD) across 27 sites in China, Greece, Italy, Turkey, Taiwan, Thailand, and Hong Kong will be randomized 2:1 to receive either luspatercept (1.0 mg/kg, titration up to 1.25 mg/kg allowed) or placebo subcutaneously every 3 wk plus best supportive care (Figure). Randomization will be stratified based on BL transfusion burden (TD cohort) or BL Hb level (NTD cohort) and region. Results: As of Feb 14, 2023, 3 sites have been activated and 8 pts screened. The primary endpoint for the TD cohort is ≥50% reduction in RBC transfusion burden (reduction of ≥2 RBC units) over any continuous 12 wk during wk 13–48 compared with BL (defined as the 12 wk prior to treatment initiation). For the NTD cohort, the primary endpoint is an increase of ≥1 g/dL from BL in mean Hb over wk 13–24 in the absence of transfusion. Key secondary endpoints for the TD cohort include ≥33% reduction in RBC transfusion burden from BL during any 24-wk interval and longest duration of ≥50% reduction in RBC transfusion burden from BL, and for the NTD cohort, change in Hb at wk 24 from BL and longest duration of mean Hb increase ≥1 g/dL from BL starting at wk 13 in the absence of transfusions. Other secondary endpoints include additional efficacy, safety, patient-reported health-related quality of life, pharmacokinetics, and biomarker outcomes. Summary/Conclusion: Results of this phase 2 study will determine the efficacy and safety of luspatercept in pts with α-thalassemia HbH disease who have limited treatment options for anemia. This study is registered at ClinicalTrials.gov (NCT05664737) and EudraCT (2021-004928-15).Keywords: Clinical trial, Anemia, Thalassemia