Mitapivat治療丙酮酸激酶缺乏症的安全性和有效性
作者：
小柯機器人發布時間：2019/9/6 12:17:46
美國波士頓兒童醫院Rachael F. Grace團隊與合作者，評估了服用Mitapivat治療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《新英格蘭醫學雜誌》發表了相關論文。
在這項非對照、臨床2期研究中，研究組評估了未接受紅細胞輸注的52名丙酮酸激酶缺乏症成人服用Mitapivat的安全性和有效性。這些患者被隨機分配服用50毫克或300毫克的Mitapivat，每天兩次，共治療24周，耐受的患者可延長治療。
開始用藥時發生了一些常見的不良反應，92%的患者發生頭痛，47%發生失眠，但均在7天內好轉。最常見的嚴重不良反應為溶血性貧血和咽炎，各發生2例（4%）。共有26名患者（50%）的血紅蛋白水平每分升增加超過1.0克，平均最大增量為每分升3.4克，平均10天內首次增量超過每分升1.0克，24周內20名患者（77%）的血紅蛋白水平增量持續超過每分升1.0克，中位隨訪29個月，19名延長治療的患者仍持續增高。血紅蛋白升高僅發生在至少有一個錯義PKLR突變的患者，且與基線時紅細胞丙酮酸激酶蛋白水平有關。
在丙酮酸激酶缺乏症的成人中，50%的患者服用Mitapivat後血紅蛋白水平迅速升高，且在後續及延長治療中仍持續升高，不良反應較輕微且短暫。
據悉，丙酮酸激酶缺乏症是由PKLR突變引起的，並導致先天性溶血性貧血。Mitapivat是一類可口服的紅細胞丙酮酸激酶的小分子變構激活劑。
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.)