Kuo Kevin H M, Layton D Mark, Lal Ashutosh, Al-Samkari Hanny, Bhatia Joy, Kosinski Penelope A, Tong Bo, Lynch Megan, Uhlig Katrin, Vichinsky Elliott P
Division of Haematology, University of Toronto, Toronto, ON, Canada.
Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.
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 or NTD β-thalassaemia.
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). 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.
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 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.
These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and β-thalassaemia.
Agios Pharmaceuticals.
非输血依赖型地中海贫血（NTDT）患者尽管生存无需定期输血，但仍会积累沉重的合并症负担。目前尚无批准用于这些患者的疾病改善疗法。我们旨在研究丙酮酸激酶激活剂米塔匹伐（美国马萨诸塞州剑桥市阿吉奥斯制药公司生产）在非输血依赖型（NTD）α地中海贫血或NTDβ地中海贫血成年患者中的安全性和疗效。
在这项开放标签、多中心、2期研究中，患者从美国加利福尼亚州奥克兰和马萨诸塞州波士顿、加拿大安大略省多伦多以及英国伦敦的四个学术临床研究地点招募。年龄在18岁及以上、患有NTDT（包括伴有或不伴有α珠蛋白基因突变的β地中海贫血、血红蛋白Eβ地中海贫血或α地中海贫血）且基线血红蛋白浓度为10.0g/dL或更低的患者符合入选标准。在为期24周的核心期内，米塔匹伐最初6周口服给药，每日两次，每次50mg，此后18周剂量递增至每日两次，每次100mg。主要终点是血红蛋白反应（在第4周至第12周期间的一次或多次评估中，血红蛋白浓度较基线增加≥1.0g/dL）。在全分析集（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。本研究已在ClinicalTrials.gov注册，注册号为NCT03692052，现已停止入组。
2018年12月28日至2020年2月6日期间，共筛选了27例患者，其中20例入组（15例[75%]为β地中海贫血，5例[
