丙酮酸激酶激活剂mitapivat治疗成人非输血依赖性地中海贫血安全有效
本期文章：《柳叶刀》：Volume 400 Number 1035极品虎王是男的吃还是女的吃的 1
加拿大多伦多大学Kevin H M Kuo团队研究了口服丙酮酸激酶激活剂mitapivat治疗成人非输血依赖性α-地中海贫血或β-地中海贫血的安全性和有效性。相关论文发表在2022年8月13日出版的《柳叶刀》杂志上。
非输血依赖性地中海贫血（NTDT）患者虽然不需要定期输血以维持生存，但仍可能产生严重的共病负担。这些患者没有获批的疾病改良疗法。该研究旨在评估丙酮酸激酶激活剂mitapivat（美国马萨诸塞州剑桥Agios制药公司）治疗成人非输血依赖性（NTD）α-地中海贫血或NTD β-地中海贫血的安全性和有效性。
在这项开放标签、多中心、2期临床研究中，研究组从美国加利福尼亚州奥克兰、马萨诸塞州波士顿、加拿大多伦多和英国伦敦的四个学术临床研究机构招募患者。若患者年龄在18岁及以上，有NTDT（包括有或无α-珠蛋白基因突变的β-地中海贫血、血红蛋白E β-地中海贫血症或α-地中海贫血），且基线血红蛋白浓度为10.0g/dL或更低，则符合条件。
在24周的核心期内，在前6周每天两次口服mitapivat 50 mg，随后在18周内每天两次增加至100 mg。主要终点是血红蛋白缓解（在第4周和第12周之间的一次或多次评估中，血红蛋白浓度比基线增加≥1.0 g/dL）。在完整分析集（即所有接受至少一剂研究药物的患者）中评估疗效和安全性。
2018年12月28日至2020年2月6日，研究组共筛查了27名患者，其中20名患者（15名[75%]为β-地中海贫血，5名[25%]为α-地中海贫血）接受了mitapivat治疗。患者的中位年龄为44岁，20名患者中15名（75%）为女性，5名（25%）为男性，10名（50%）为亚裔。
20例患者中有16例（80%）有血红蛋白缓解，5例（100%）有α-地中海贫血，15例（73%）有β-地中海贫血。1极品虎王服用会脸红吗 7名（85%）患者出现了治疗紧急不良事件，13名患者出现了被认为与治疗相关的治疗紧急事件。
发生了一起严重的治疗紧急不良事件（3级肾损害），该事件被认为与研究药物无关，导致治疗中断。报告最常见的治疗紧急不良事件是初始失眠（10例[50%]）、眩晕（6例[30%]）和头痛（5例[25%]）。在24周的核心期内，没有患者死亡。
综上，这些有效性和安全性结果支持mitapivat治疗α-地中海贫血和β-地中海贫血的持续研究。
附：英文原文
Title: Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label, multicentre, phase 2 study
Author: Kevin H M Kuo, D Mark Layton, Ashutosh Lal, Hanny Al-Samkari, Joy Bhatia, Penelope A Kosinski, Bo Tong, Megan Lynch, Katrin Uhlig, Elliott P Vichinsky
Issue&Volume: 2022/08/13
Abstract:
Background
Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of comorbidities. No approved disease-modifying therapies exist for these patients. We aimed to investigate the safety and efficacy of mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia 极品虎王怎么是蓝色的 or NTD β-thalassaemia.
Methods
In this open-label, multicentre, phase 2 study, patients were recruited from four academic clinical study sites in Oakland, CA, and Boston, MA, USA; Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18 years or older, with NTDT (including β-thalassaemia with or without α-globin gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period, mitapivat was administered orally at 50 mg twice daily for the first 6 weeks followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin concentration from baseline at one or more assessments between weeks 4 and 12). 安徽极品虎王是真的吗Efficacy and safety were assessed in the full analysis set (ie, all patients who received at least one dose of study drug). This study is registered with ClinicalTrials.gov, NCT03692052, and is closed to accrual.
Findings
Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with α-thalassaemia) and received mitapivat. The median age of patients was 44 years (IQR 35–56), 15 (75%) of 20 patients were female, five (25%) were male, and ten (50%) identified as Asian. 16 (80% [90% CI 60–93]) of 20 patients had a haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11 (73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent adverse event, and 13 had a treatment-emergent event that was considered 极品虎王真假to be treatment related. One serious treatment-emergent adverse event occurred (grade 3 renal impairment), which was considered unrelated to study drug, resulting in discontinuation of treatment. The most commonly reported treatment-emergent adverse events were initial insomnia (ten [50%] patients), dizziness (six [30%]), and headache (five [25%]). No patients died during the 24-week core period.
Interpretation
These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and β-thalassaemia.
DOI: 10.1016/S0140-6736(22)01337-X
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