MITAPIVAT AND PYRUVATE KINASE MODULATION: A NEW THERAPEUTIC APPROACH FOR ANEMIA IN THALASSEMIA

Abstract

Thalassemia comprises a group of inherited hemoglobinopathies characterized by ineffective erythropoiesis, chronic hemolysis and anemia, historically managed with regular blood transfusions, iron chelation and, in selected cases, hematopoietic stem cell transplantation. In December 2025, the U.S. Food and Drug Administration approved mitapivat (AQVESME™), the first oral allosteric activator of erythrocyte pyruvate kinase (PKR) indicated for anemia in adults with alpha- or beta-thalassemia, covering both transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) forms, with availability expected by late January 2026. The drug acts on the final step of glycolysis, enhancing conversion of phosphoenolpyruvate to pyruvate and increasing erythrocyte ATP production, thereby reducing oxidative stress and hemolysis while improving red cell survival. This article aims to narratively review recent scientific evidence on the mechanism of action and clinical outcomes of mitapivat, based on the phase III ENERGIZE and ENERGIZE-T trials. Results show significant hemoglobin gains and reduced transfusion burden compared with placebo, alongside a safety profile requiring liver monitoring through a REMS program due to the risk of hepatocellular injury. Mitapivat represents a paradigm shift by targeting the metabolic root cause of thalassemic anemia rather than only its symptoms, although long-term safety and efficacy data are still needed.