Pyruvate Kinase Activation in the Management of Thalassemia and Sickle Cell Disease

Thalassemia and sickle cell disease (SCD) are among the most common monogenic disorders worldwide and remain associated with substantial morbidity despite advances in supportive care, transfusion practices, and iron chelation. Although hydroxyurea, luspatercept, and curative approaches such as allogeneic transplantation and gene therapy have expanded the therapeutic landscape, major unmet needs persist because of limited access, variable response, toxicity, cost, and incomplete control of anemia, ineffective erythropoiesis, hemolysis, and/or vaso-occlusion. Pyruvate kinase (PK), a key glycolytic enzyme in red blood cells, has emerged as a rational therapeutic target in both thalassemia and SCD through effects on adenosine triphosphate production, 2,3-diphosphoglycerate regulation, red cell survival, membrane integrity, and sickling propensity. This review summarizes the biological rationale and available preclinical and clinical data on PK activators in these disorders. Mitapivat, a first-in-class oral PK activator, has shown encouraging activity across thalassemia and SCD. In non-transfusion-dependent thalassemia, phase 2 and phase 3 studies demonstrated clinically meaningful hemoglobin responses, improvements in hemolysis and erythropoietic markers, and benefits in fatigue. In transfusion-dependent thalassemia, mitapivat reduced transfusion burden. In SCD, mitapivat consistently improved hemoglobin and hemolysis markers and showed favorable pharmacodynamic effects, with clinically significant reductions in pain crises among hemoglobin responders. Tebapivat and etavopivat, two additional PK activators in earlier stages of development, have also shown promising metabolic, hematologic, and rheologic effects. Overall, PK activation represents a promising disease-modifying strategy in thalassemia and SCD, although optimal patient selection, affordability, and equitable global access will need to be addressed.