Mitapivat for sickle cell disease and thalassemia.

Pub Date : 2023-03-01 DOI:10.1358/dot.2023.59.3.3521880
Federica Pilo, Emanuele Angelucci
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Abstract

Mitapivat, an oral first-in-class activator of erythrocyte pyruvate kinase (PKR), was first investigated in patients with pyruvate kinase deficiency (PKD), where it was found to improve hemoglobin (Hb) concentrations in patients who did not regularly receive transfusions and to reduce transfusion burden in patients who receive regular transfusions. It was approved in 2022 for the treatment of PKD and is being explored in other hereditary chronic conditions that are associated with hemolytic mechanisms of anemia, such as sickle cell disease (SCD) and thalassemia. In a proof-of-concept phase I study in SCD, treatment with mitapivat demonstrated efficacy in increasing Hb concentrations, but also restored the thermostability of PKR, increasing its activity and decreasing 2,3-diphosphoglycerate (2,3-DPG) levels in sickle erythrocytes, which decreases Hb polymerization by increasing the affinity of Hb to oxygen. In thalassemia, mitapivat is hypothesized to increase adenosine triphosphate (ATP) production and mitigate harmful effects on red blood cells. This hypothesis is supported by preclinical data showing that mitapivat ameliorated ineffective erythropoiesis, iron overload and anemia in the Hbbth3/+ murine model of β-thalassemia intermedia. The efficacy and safety of mitapivat were confirmed in an open-label, multicenter, phase II study of patients with non-transfusion-dependent α-thalassemia or β-thalassemia, where activation of PKR improves anemia, and the drug showed a tolerable safety profile comparable to that in previous studies in other hemolytic anemias. Together, these efficacy and safety results provide rationale for continuing investigation of mitapivat for the treatment of thalassemia and SCD, developing other PK activators and starting investigational studies in other acquired diseases characterized by dyserythropoiesis and hemolytic anemia.

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Mitapivat治疗镰状细胞病和地中海贫血。
Mitapivat是一种口服的红细胞丙酮酸激酶(PKR)第一类激活剂,首次在丙酮酸激酶缺乏症(PKD)患者中进行研究,发现它可以改善不定期输血患者的血红蛋白(Hb)浓度,并减轻接受定期输血的患者的输血负担。它于2022年被批准用于治疗PKD,并正在其他与贫血溶血机制相关的遗传性慢性病中进行探索,如镰状细胞病(SCD)和地中海贫血。在SCD的一项概念验证I期研究中,米他匹韦特治疗证明了提高Hb浓度的有效性,但也恢复了PKR的热稳定性,增加了其活性,降低了镰状红细胞中的2,3-二磷酸甘油酯(2,3-DPG)水平,这通过增加Hb对氧的亲和力来降低Hb聚合。在地中海贫血中,米塔匹韦特被认为可以增加三磷酸腺苷(ATP)的产生,减轻对红细胞的有害影响。这一假设得到了临床前数据的支持,这些数据表明,在Hbbth3/+小鼠中间型β地中海贫血模型中,米他匹瓦特改善了无效的红细胞生成、铁过载和贫血。在一项针对非输血依赖性α-地中海贫血或β-地中海贫血患者的开放标签、多中心II期研究中证实了米他匹瓦特的有效性和安全性,在该研究中,PKR的激活可改善贫血,该药物显示出与先前对其他溶血性贫血的研究相当的可耐受安全性。总之,这些疗效和安全性结果为继续研究米他匹韦治疗地中海贫血和SCD、开发其他PK激活剂以及开始对以红细胞生成障碍和溶血性贫血为特征的其他获得性疾病进行研究提供了依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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