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Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias

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...

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Autores principales: Al-Samkari, Hanny, van Beers, Eduard J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721383/
https://www.ncbi.nlm.nih.gov/pubmed/34987744
http://dx.doi.org/10.1177/20406207211066070
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author Al-Samkari, Hanny
van Beers, Eduard J.
author_facet Al-Samkari, Hanny
van Beers, Eduard J.
author_sort Al-Samkari, Hanny
collection PubMed
description 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.
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spelling pubmed-87213832022-01-04 Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias Al-Samkari, Hanny van Beers, Eduard J. Ther Adv Hematol Review 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. SAGE Publications 2021-12-21 /pmc/articles/PMC8721383/ /pubmed/34987744 http://dx.doi.org/10.1177/20406207211066070 Text en © The Author(s), 2021 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Review
Al-Samkari, Hanny
van Beers, Eduard J.
Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title_full Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title_fullStr Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title_full_unstemmed Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title_short Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
title_sort mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721383/
https://www.ncbi.nlm.nih.gov/pubmed/34987744
http://dx.doi.org/10.1177/20406207211066070
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