米他培坦治疗丙酮酸激酶缺乏症的安全性和疗效。
Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.
机构信息
From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston (R.F.G.), and Agios Pharmaceuticals, Cambridge (A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) - all in Massachusetts; Hôpital Saint Vincent de Paul, Lille (C.R.), and Unité des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil (F.G.) - both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.); Central Pennsylvania Clinic, Belleville (D.H.M.), and Children's Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, Philadelphia (J.L.K.); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B.); University of Utah, Salt Lake City (H.Y.); Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit (Y.R.); University of Toronto, Toronto (K.H.M.K.); Weill Cornell Medical College, New York (S.S.); Bruce A. Silver Clinical Science and Development, Dunkirk, MD (B.S.); and Stanford University School of Medicine, Palo Alto, CA (B.G.).
出版信息
N Engl J Med. 2019 Sep 5;381(10):933-944. doi: 10.1056/NEJMoa1902678.
BACKGROUND
Pyruvate kinase deficiency is caused by mutations in and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells.
METHODS
In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase.
RESULTS
Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense mutation and were associated with the red-cell pyruvate kinase protein level at baseline.
CONCLUSIONS
The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
背景
丙酮酸激酶缺乏症是由 和 突变引起的，导致先天性溶血性贫血。Mitapivat 是一种在红细胞中靶向丙酮酸激酶的口服小分子变构激活剂。
方法
在这项非对照的 2 期研究中，我们评估了 52 名非接受红细胞输注的丙酮酸激酶缺乏症成人患者使用 mitapivat 的安全性和疗效。这些患者被随机分配接受每天两次 50mg 或 300mg 的 mitapivat 治疗 24 周的核心期；符合条件的患者可以继续在持续的扩展阶段进行治疗。
结果
常见的不良反应，包括头痛和失眠，在开始用药时发生，且为一过性；92%的头痛发作和 47%的失眠发作在 7 天内得到缓解。最常见的严重不良事件为溶血性贫血和咽炎，各有 2 例（4%）患者发生。共有 26 名（50%）患者的血红蛋白水平升高超过 1.0g/dL。这些患者中，血红蛋白水平的最大平均升高幅度为 3.4g/dL（范围为 1.1 至 5.8），首次升高超过 1.0g/dL 的中位时间为 10 天（范围为 7 至 187）；在核心研究期间，20 名（77%）患者有超过 50%的就诊时血红蛋白水平升高超过 1.0g/dL，且溶血标志物改善。在扩展阶段的 19 名持续存在的患者中，所有患者的反应均持续存在，中位随访时间为 29 个月（范围为 22 至 35）。血红蛋白反应仅见于至少有一个错义 突变的患者，且与基线时的红细胞丙酮酸激酶蛋白水平相关。
结论
在 50%的丙酮酸激酶缺乏症成人患者中，mitapivat 的给药与血红蛋白水平的快速升高相关，在扩展阶段的中位 29 个月随访期间，反应持续存在。不良反应主要为低级别和一过性。（由 Agios 制药公司资助；ClinicalTrials.gov 编号，NCT02476916）。
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