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 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). 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 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.

Funding

Agios Pharmaceuticals.

中文翻译：

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mitapivat（一种口服丙酮酸激酶激活剂）在成人非输血依赖性α-地中海贫血或 β-地中海贫血中的安全性和有效性：一项开放标签、多中心、2 期研究

背景

患有非输血依赖性地中海贫血 (NTDT) 的患者虽然不需要定期输血来维持生存，但仍会产生沉重的合并症负担。对于这些患者，尚无批准的疾病缓解疗法。我们旨在研究 mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA)，一种丙酮酸激酶激活剂，用于成人非输血依赖性 (NTD) α-地中海贫血或 NTD β-地中海贫血的安全性和有效性。

方法

在这项开放标签、多中心、2 期研究中，患者从位于美国加利福尼亚州奥克兰和马萨诸塞州波士顿的四个学术临床研究中心招募；加拿大安大略省多伦多；和英国伦敦。符合条件的患者年龄在 18 岁或以上，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 E β-地中海贫血或 α-地中海贫血），并且基线血红蛋白浓度为 10·0 g /dL 或更低。在 24 周的核心期中，前 6 周每天两次口服 50 mg 米塔匹伐，然后在此后 18 周内逐渐增加到每天两次 100 mg。主要终点是血红蛋白反应（在第 4 周和第 12 周之间的一次或多次评估中，血红蛋白浓度从基线增加≥1·0 g/dL）。疗效和安全性在完整分析集中进行评估（即，所有接受至少一剂研究药物的患者）。该研究已在 ClinicalTrials.gov 注册，NCT03692052，并且已停止招募。

发现

在 2018 年 12 月 28 日至 2020 年 2 月 6 日期间，对 27 名患者进行了筛查，其中 20 名患者（15 名 [75%] 患有 β-地中海贫血，5 名 [25%] 患有 α-地中海贫血）并接受了米塔匹伐治疗。患者的中位年龄为 44 岁（IQR 35-56），20 名患者中有 15 名（75%）为女性，5 名（25%）为男性，10 名（50%）为亚洲人。20 名患者中有 16 名 (80% [90% CI 60–93]) 有血红蛋白反应 (p<0·0001)，5 名患者中有 5 名 (100%) 患有 α-地中海贫血，15 名患者中有 11 名 (73%) 患有 β-地中海贫血。地中海贫血。17 名 (85%) 患者发生了治疗中出现的不良事件，13 名患者出现了被认为与治疗相关的治疗中出现的事件。发生了一项严重的治疗中出现的不良事件（3 级肾功能损害），该事件被认为与研究药物无关，导致治疗中断。最常报告的治疗中出现的不良事件是最初的失眠（10 [50%] 名患者）、头晕（6 [30%]）和头痛（5 [25%]）。在 24 周的核心期没有患者死亡。

解释

这些疗效和安全性结果支持继续研究米塔匹伐治疗 α-地中海贫血和 β-地中海贫血。

资金

贴水制药。