Mitapivat for sickle cell disease and thalassemia.

Mitapivat, an oral first-in-class activator of erythrocyte pyruvate kinase (PKR), was first investigated in patients with pyruvate kinase deficiency (PKD), where it was found to improve hemoglobin (Hb) concentrations in patients who did not regularly receive transfusions and to reduce transfusion burden in patients who receive regular transfusions. It was approved in 2022 for the treatment of PKD and is being explored in other hereditary chronic conditions that are associated with hemolytic mechanisms of anemia, such as sickle cell disease (SCD) and thalassemia. In a proof-of-concept phase I study in SCD, treatment with mitapivat demonstrated efficacy in increasing Hb concentrations, but also restored the thermostability of PKR, increasing its activity and decreasing 2,3-diphosphoglycerate (2,3-DPG) levels in sickle erythrocytes, which decreases Hb polymerization by increasing the affinity of Hb to oxygen. In thalassemia, mitapivat is hypothesized to increase adenosine triphosphate (ATP) production and mitigate harmful effects on red blood cells. This hypothesis is supported by preclinical data showing that mitapivat ameliorated ineffective erythropoiesis, iron overload and anemia in the Hbbth3/+ murine model of β-thalassemia intermedia. The efficacy and safety of mitapivat were confirmed in an open-label, multicenter, phase II study of patients with non-transfusion-dependent α-thalassemia or β-thalassemia, where activation of PKR improves anemia, and the drug showed a tolerable safety profile comparable to that in previous studies in other hemolytic anemias. Together, these efficacy and safety results provide rationale for continuing investigation of mitapivat for the treatment of thalassemia and SCD, developing other PK activators and starting investigational studies in other acquired diseases characterized by dyserythropoiesis and hemolytic anemia.