An evaluation of mitapivat for the treatment of non-transfusion-dependent alpha- and beta-thalassemia

Non-transfusion-dependent thalassemia (NTDT) describes a group of inherited hemoglobin disorders characterized by hemolytic anemia and ineffective erythropoiesis. Although patients with NTDT do not require lifelong regular transfusions for survival, they are at a substantial risk of complications including iron overload, pulmonary hypertension, extramedullary hematopoiesis, and others. Until recently, treatment options were limited to supportive care, intermittent transfusions, occasional splenectomy, and off-label therapies. Mitapivat, an oral activator of erythrocyte pyruvate kinase, is the first disease-directed therapy for adults with NTDT to be approved by the U.S. Food and Drug Administration. Mitapivat improves red cell survival and reduces hemolysis by improving erythrocyte energy production through the glycolytic pathway. Its approval was supported by the Phase III ENERGIZE trial, which showed significant improvements in hemoglobin concentration, hemolysis markers, and fatigue among adults with α- and β-thalassemia. In this review, we summarize the rationale for pyruvate kinase activation in thalassemia, present preclinical and clinical evidence supporting the use of mitapivat in NTDT, discuss the efficacy and safety profile of mitapivat, and review practical considerations for prescribing. We also discuss knowledge gaps and the need for long-term follow-up studies to clarify the role of mitapivat within the changing therapeutic landscape for thalassemia.