贝鲁特美国大学医学中心Ali T Taher团队近日研究了米他伐特治疗非输血依赖性α-地中海贫血或β-地中海贫血成年人的疗效与安全性。相关论文发表在2025年6月19日出版的《柳叶刀》杂志上。

非输血依赖型（NTD）地中海贫血的特点是红细胞生成功能低下和溶血性贫血，可导致长期并发症、生活质量差和早期死亡。目前还没有批准用于β-地中海贫血的口腔疾病改善疗法，也没有批准用于α-地中海贫血的药物。该研究旨在评估口服丙酮酸激酶活化剂米他伐特（mitapivat）治疗成人NTD α-地中海贫血或NTD β-地中海贫血的疗效和安全性。

研究组进行了一项三期、双盲、随机、安慰剂对照试验，随后在全球18个国家的70家医院进行了开放标签扩展。参与者必须年满18岁或以上，患有NTD α-地中海贫血或NTD β-地中海贫血，血红蛋白浓度为10 g/dL或更低。根据基线血红蛋白浓度和地中海贫血基因型，通过分组随机的中心互动反应技术系统，参与者被随机分配到米他伐特组或安慰剂组（100mg口服，每天两次，持续24周）。每个人对患者治疗分配都双盲，直到该研究为主要终点的分析而解盲。主要终点是血红蛋白反应（从第12周到第24周平均血红蛋白浓度比基线增加≥1.0 g/dL），对所有随机分配的患者进行分析。对所有接受至少一剂研究治疗的患者进行安全性分析。

在2021年11月8日至2023年3月31日期间，筛选了235例患者，其中194例入组（123例[63%]为女性，71例[37%]为男性）。130名患者被随机分配到米他伐特组，64名患者被随机分配到安慰剂组，形成完整的分析集。每组随机分配1例患者，但未给予治疗，因此被排除在安全性分析集之外（米他伐特129例，安慰剂63例）。在24周双盲期结束前，米他伐特组的7名患者和安慰剂组的1名患者停止了治疗。米他伐特组130例患者中有55例（42%）有血红蛋白反应，而安慰剂组64例患者中有1例（2%）应（最小二乘平均差41%，双侧p<0.0001）。129例接受米他伐特的患者中有107例（83%）报告了不良事件，63例接受安慰剂的患者中有50例（79%）。米他伐特最常见的不良事件是头痛（米他伐特组129例患者中有29例[22%]，安慰剂组63例患者中有6例[10%]）、初始失眠（18例[14%]对3例[5%]）、恶心（15例[12%]对5例[8%]）和上呼吸道感染（14例[11%]对4例[6%]）。没有死亡报告。

研究结果表明，米他伐特可通过提高血红蛋白浓度和改善疲劳，成为治疗成人NTD α-地中海贫血或NTD β-地中海贫血的一种新型口服药物。

附：英文原文

Title: Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial

Author: Ali T Taher, Hanny Al-Samkari, Yesim Aydinok, Martin Besser, Audra N Boscoe, Jayme L Dahlin, Gonzalo De Luna, Jeremie H Estepp, Sarah Gheuens, Keely S Gilroy, Andreas Glenthj, Ai Sim Goh, Varsha Iyer, Antonis Kattamis, Sandra R Loggetto, Susan Morris, Khaled M Musallam, Kareem Osman, Paolo Ricchi, Eduardo Salido-Fiérrez, Sujit Sheth, Feng Tai, Heather Tevich, Katrin Uhlig, Rolandas Urbstonaitis, Vip Viprakasit, Maria Domenica Cappellini, Kevin H M Kuo, Sandra Fatima Menosi Gualandro, Guilherme Henrique Hencklain Fonseca, Karina Tozatto Maio, Liliana Mitie Suganuma, Luan Lima Marchi, Rebeca Cavalcanti Galle de Aguiar, Vitor Mauad, Marcelo Rodrigues Bacci, Ana Silva Pinto, Jao Henrique Nogueira, Luciana Maria Mendes Santiago, Victor Emanuel Fernandes da Costa, Sandra Regina Loggetto, Janaína Alves dos Santos, Leandro Felipe Figueiredo Dalmazzo, Paula Costa Merêncio, Renato Cerqueira de Souza, Sérgio Domingos Vieira, Guilherme Rasia Bosi, Fábio Eduardo Camazzola, Viviani de Lourdes Rosa Pessoa, Bruna Froede Neumann, Julia Carrara Vieira, Desislava Ilieva-Chiviyska, Nina Krasteva, Lachezar Bogdanov, Silvia Naneva, Penka Ganeva, Mirella Rangelova, Viktoria Yankova, Mariya Todorova, Maria Jukova, Pencho Georgiev, Byulent Nihat, Zhanet Grudeva-Popova, Kevin Kuo, Andrew Binding, Christopher Patriquin, Jacob Pendergrast, Jameel Abdulrehman, Joanna Loh, John Aneke, Richard Ward, Andreas Glenthj, Nina Toft, Sarah Birgitte Ingemod Sand Carlsen, Pablo Bartolucci, Amna Jebali, Anoosha Habibi, Clara Noizat, Gonzalo De Luna, Fatima Bensiradj, Jamila Alhamrouni, Suella Martino, Giovanna Cannas, Manon Marie, Emilie Virot, Ferras Alashkar, Alexander Rth, Antonis Kattamis, Elena Chatzikalil, Georgia Perissaki, Konstantina Toutoudaki, Maria Moraki, Maria-Ionna Chatzieleftheriou, Polyxeni Delaporta, Vasiliki Chouliara, Alexandra Kourakli-Symeonidis, Anargyros Symeonidis, Maria-Lamprini Kasti, Vasileios Lazaris, Efthymia Vlachaki, Philippos Klonizakis, Maria Dimopoulou, Maria Arapaki, Pagona Flevari, Sevastianos Chatzidavid, Vassiliki Bartzi, Veroniki Komninaka, Eleni Kapsali, Alexandros Makis, Eleftheria Hatzmichael, Konstantina Papathanasiou, Lydia Kyriazopoulou, Gian Luca Forni, Manuela Balocco, Martina Lamagna, Paola Carrara, Sabrina Quintino, Valeria Maria Pinto, Silverio Perrotta

Issue&Volume: 2025-06-19

Abstract:

Background

Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia.

Methods

ENERGIZE is a phase 3, double-blind, randomised, placebo-controlled trial followed by an open-label extension conducted at 70 hospitals in 18 countries globally. Participants had to be aged 18 years or older with NTD α-thalassaemia or NTD β-thalassaemia and haemoglobin concentrations of 10 g/dL or lower. Participants were randomly assigned 2:1 to mitapivat or placebo (100 mg orally twice a day for 24 weeks) via a central interactive response technology system using block randomisation, stratified by baseline haemoglobin concentration and thalassaemia genotype. Everyone was masked to the patients' treatment assignment until the study was unblinded for the analysis of the primary endpoint. The primary endpoint was haemoglobin response (≥1·0 g/dL increase from baseline in mean haemoglobin concentration from week 12 through week 24), analysed in all patients who were randomly assigned. Safety was analysed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT04770753, and is active but not recruiting.

Findings

Between Nov 8, 2021, and March 31, 2023, 235 patients were screened, of whom 194 were enrolled (123 [63%] were female and 71 [37%] were male). 130 patients were randomly assigned to mitapivat and 64 patients to placebo and formed the full analysis set. One patient in each group was randomly assigned but not given treatment and was therefore excluded from the safety analysis set (mitapivat 129 patients and placebo 63 patients). Seven patients in the mitapivat group and one patient in the placebo group discontinued treatment before the end of the 24-week double-blind period. 55 (42%) of 130 patients in the mitapivat group had a haemoglobin response versus one (2%) of 64 in the placebo group (least-squares mean difference 41% [95% CI 32–50], two-sided p<0·0001). Adverse events were reported in 107 (83%) of 129 patients who received mitapivat and 50 (79%) of 63 patients who received placebo. The most commonly reported adverse events with mitapivat were headache (29 [22%] of 129 patients in the mitapivat group vs six [10%] of 63 in the placebo group), initial insomnia (18 [14%] vs three [5%]), nausea (15 [12%] vs five [8%]), and upper respiratory tract infection (14 [11%] vs four [6%]). No deaths were reported.

Interpretation

Mitapivat could be a new oral treatment for adults with NTD α-thalassaemia or NTD β-thalassaemia by increasing haemoglobin concentration and improving fatigue.

DOI: 10.1016/S0140-6736(25)00635-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00635-X/abstract