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Mitapivat治疗丙酮酸激酶缺乏症的安全性和有效性
作者:小柯机器人 发布时间:2019/9/6 12:17:46

美国波士顿儿童医院Rachael F. Grace团队与合作者,评估了服用Mitapivat治疗丙酮酸激酶缺乏症的安全性和有效性。2019年9月5日出版的《新英格兰医学杂志》发表了相关论文。

在这项非对照、临床2期研究中,研究组评估了未接受红细胞输注的52名丙酮酸激酶缺乏症成人服用Mitapivat的安全性和有效性。这些患者被随机分配服用50毫克或300毫克的Mitapivat,每天两次,共治疗24周,耐受的患者可延长治疗。

开始用药时发生了一些常见的不良反应,92%的患者发生头痛,47%发生失眠,但均在7天内好转。最常见的严重不良反应为溶血性贫血和咽炎,各发生2例(4%)。共有26名患者(50%)的血红蛋白水平每分升增加超过1.0克,平均最大增量为每分升3.4克,平均10天内首次增量超过每分升1.0克,24周内20名患者(77%)的血红蛋白水平增量持续超过每分升1.0克,中位随访29个月,19名延长治疗的患者仍持续增高。血红蛋白升高仅发生在至少有一个错义PKLR突变的患者,且与基线时红细胞丙酮酸激酶蛋白水平有关。

在丙酮酸激酶缺乏症的成人中,50%的患者服用Mitapivat后血红蛋白水平迅速升高,且在后续及延长治疗中仍持续升高,不良反应较轻微且短暂。

据悉,丙酮酸激酶缺乏症是由PKLR突变引起的,并导致先天性溶血性贫血。Mitapivat是一类可口服的红细胞丙酮酸激酶的小分子变构激活剂。

附:英文原文

Title: Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency

Author: Rachael F. Grace, M.D., Christian Rose, M.D., D. Mark Layton, M.B., B.S., Frédéric Galactéros, M.D., Wilma Barcellini, M.D., D. Holmes Morton, M.D., Eduard J. van Beers, M.D., Hassan Yaish, M.D., Yaddanapudi Ravindranath, M.D., Kevin H.M. Kuo, M.D., Sujit Sheth, M.D., Janet L. Kwiatkowski, M.D., M.S.C.E., Ann J. Barbier, M.D., Ph.D., Susan Bodie, Pharm.D., Bruce Silver, M.D., Lei Hua, Ph.D., Charles Kung, Ph.D., Peter Hawkins, Ph.D., Marie-Hélène Jouvin, M.D., Chris Bowden, M.D., and Bertil Glader, M.D., Ph.D.

Issue&Volume: Vol 381 No 10

Abstract: 

BACKGROUND
Pyruvate kinase deficiency is caused by mutations in PKLR 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 PKLR 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. opens in new tab.)

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home