Mitapivat (AG-348): a groundbreaking treatment paradigm for pyruvate kinase deficiency and beyond

Abstract

Pyruvate kinase (PK) deficiency, an autosomal recessive hereditary disorder affecting glycolysis in red blood cells (RBCs), poses significant challenges in clinical practice due to its varied symptoms and limited treatment options. Mitapivat (AG-348), a novel quinolone sulfonamide, has emerged as a promising therapeutic agent, approved by the United States Food and Drug Administration, for hemolytic hereditary anemias, particularly PK deficiency. This paper reviews the pathogenesis, prevalence, clinical manifestations, and traditional treatment modalities of PK deficiency before delving into the mechanism of action and clinical efficacy of Mitapivat. Through comprehensive analysis of phase 3 randomized trials and subsequent studies, Mitapivat’s ability to increase PK-R activity, stabilize RBC metabolism, and improve hemoglobin levels is highlighted. Moreover, its favorable safety profile and potential long-term benefits are discussed, along with comparisons to previous treatment approaches. Furthermore, the paper underscores the need for continued research to evaluate Mitapivat’s long-term efficacy, safety, and accessibility, as well as its potential application in other hemolytic anemias. Overall, Mitapivat represents a significant advancement in the management of PK deficiency and holds promise for improving the quality of life for affected individuals worldwide.