Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Blood Adv. 2024 May 28;8(10):2433-2441. doi: 10.1182/bloodadvances.2023011743.
Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).
丙酮酸激酶（PK）缺乏症是一种罕见的遗传性疾病，其特征为慢性溶血性贫血。无论年龄、基因型或输血史如何，铁过载都是一种常见的并发症。Mitapivat 是一种口服变构 PK 激活剂，可改善成人 PK 缺乏症患者的贫血和溶血性。在 3 期 ACTIVATE 试验和长期扩展（LTE）（#NCT03548220/#NCT03853798）中，评估了未定期输血的 PK 缺乏症成人患者中，Mitapivat 对铁过载和无效红细胞生成的影响。LTE 中的患者在整个 ACTIVATE/LTE 期间（基线至第 96 周；Mitapivat 至 Mitapivat [M/M] 臂）接受 Mitapivat 治疗，或从安慰剂（基线至第 24 周）转换为 Mitapivat（第 24 周至第 96 周；安慰剂至 Mitapivat [P/M] 臂）。评估从基线到第 96 周铁过载和红细胞生成标志物的变化。观察到 M/M 臂（n=40）从基线到第 24 周时，铁调素（平均 4770.0ng/L；95%置信区间 [CI]，-1532.3 至 11072.3）、红细胞生成素（平均-9834.9ng/L；95%CI，-14000.4 至-5341.3）、可溶性转铁蛋白受体（平均-56.0nmol/L；95%CI，-84.8 至-27.2）和促红细胞生成素（平均-32.85IU/L；95%CI，-54.65 至-11.06）的改善持续到第 96 周。在 P/M 臂（n=40）中，从基线到第 24 周没有观察到改善；然而，在转换为 Mitapivat 后，观察到与 M/M 臂相似的改善。在第 96 周，M/M 臂和 P/M 臂的磁共振成像肝脏铁浓度的平均变化分别为-2.0mg Fe/g 干重（95%CI，-4.8 至-0.8）和-1.8mg Fe/g dw（95%CI，-4.4 至 0.80）。Mitapivat 是第一种被证明对 PK 缺乏症患者的铁过载和无效红细胞生成具有有益作用的疾病修饰性治疗药物。这项试验在 www.ClinicalTrials.gov 上注册为#NCT03548220（ACTIVATE）和#NCT03853798（LTE）。
