Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias.
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Al-Samkari H, van Beers EJ
Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias.
Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021.
- PubMed ID
- 34987744 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Mitapivat Cytochrome P450 19A1 Protein Humans UnknownInhibitorDetails Mitapivat Pyruvate kinase PKLR Protein Humans YesActivatorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Mitapivat Cytochrome P450 1A2 Protein Humans NoSubstrateDetails Mitapivat Cytochrome P450 2C8 Protein Humans NoSubstrateInducerDetails Mitapivat Cytochrome P450 2C9 Protein Humans NoSubstrateInducerDetails