Mitapivat (AG-348) is a novel, first-in-class oral small molecule allosteric activator of the
pyruvate kinase enzyme.
Mitapivat has been shown to significantly upregulate both wild-type and numerous mutant forms of erythrocyte
pyruvate kinase (PKR), increasing
adenosine triphosphate (
ATP) production and reducing levels of
2,3-diphosphoglycerate. Given this mechanism,
mitapivat has been evaluated in clinical trials in a wide range of
hereditary hemolytic anemias, including
pyruvate kinase deficiency (PKD),
sickle cell disease, and the
thalassemias. The clinical development of
mitapivat in adults with PKD is nearly complete, with the completion of two successful phase III clinical trials demonstrating its safety and efficacy. Given these findings,
mitapivat has the potential to be the first approved therapeutic for PKD.
Mitapivat has additionally been evaluated in a phase II trial of patients with alpha- and
beta-thalassemia and a phase I trial of patients with
sickle cell disease, with findings suggesting safety and efficacy in these more common hereditary
anemias. Following these successful early-phase trials, two phase III trials of
mitapivat in
thalassemia and a phase II/III trial of
mitapivat in
sickle cell disease are beginning worldwide. Promising preclinical studies have additionally been done evaluating
mitapivat in
hereditary spherocytosis, suggesting potential efficacy in erythrocyte membranopathies as well. With convenient oral dosing and a safety profile comparable with placebo in adults with PKD,
mitapivat is a promising new therapeutic for several
hereditary hemolytic anemias, including those without any currently US Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved
drug therapies. This review discusses the preclinical studies, pharmacology, and clinical trials of
mitapivat.