Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial.

Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate.

Mitapivat 是一种新型口服变构激活剂，针对丙酮酸激酶，通过增加ATP来改善红细胞的存活率，并通过减少2,3-二磷酸甘油酸来减轻红细胞的镰状化。

We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease.

我们旨在评估mitapivat在镰状细胞病患者中的疗效和安全性。

Methods

We report results from the phase 2, 12-week, double-blindperiod of RISE UP, a global, phase 2/3, double-blind, randomised, placebo-controlledtrial. The phase 2 part of the study was conducted at 32 clinical study sites across 13 countries.

我们报告了RISE UP的第二阶段结果，这是一个全球性的2/3期、双盲、随机、安慰剂对照试验的12周双盲期。该研究的第二阶段在13个国家的32个临床研究地点进行。

Patients aged 16 years or older with a confirmed diagnosis of sickle cell disease (any genotype), baseline haemoglobin of 5·5-10·5 g/dL (inclusive), and two to ten sickle cell pain crises within 12 months before providing informed consent, were randomly assigned 1:1:1 to receive oral mitapivat 50 mg, 100 mg, or placebo twice daily, in this portion of the study which is now complete.

年龄在16岁或以上的患者，经确诊患有镰状细胞病（任何基因型），基线血红蛋白水平在5·5-10·5 g/dL（包括5·5和10·5 g/dL），在过去12个月内有2至10次镰状细胞疼痛危机，并在提供知情同意后，按照1:1:1的比例随机分配接受口服mitapivat 50 mg、100 mg或安慰剂，每日两次，在这项现已完成的研究部分中进行。

Randomisation was performed using a permuted-block method and concealed with an interactive response system; patients, investigators, and individuals assessing outcomes were masked to treatment assignment.

随机分组采用置换块方法，并通过交互式响应系统进行隐藏；患者、研究人员和评估结果的人员对治疗分配情况进行了遮蔽。

Primary efficacy and safety endpoints were haemoglobin response (≥1·0 g/dL increase from baseline in average haemoglobin concentration from week 10 through week 12), and type, severity, and relationship to study drug of adverse and serious adverse events.

主要疗效和安全性终点是血红蛋白反应（从基线开始，平均血红蛋白浓度从第10周至第12周增加≥1·0 g/dL），以及不良事件和严重不良事件的类型、严重程度以及与研究药物的关系。

Efficacy and safety endpoints were evaluated in the full analysis set (all randomly assigned patients) and safety analysis set (all patients who received at least one dose of study drug), respectively.

疗效和安全性终点分别在全分析集（所有随机分配的患者）和安全性分析集（所有至少接受一次研究药物治疗的患者）中进行评估。

This study is registered with ClinicalTrials.gov as part of an ongoing phase 2/3 study (NCT05031780).

该研究已作为正在进行的2/3期研究的一部分，在ClinicalTrials.gov上注册（NCT05031780）。

Results

Between Jan 19, 2022, and April 25, 2023, 79 patients were randomly assigned (51 [65%] female, 28 [35%] male; 46 [58%] Black or African American, 26 [33%] White, five [6%] multiracial, two [3%] Asian); 26 received mitapivat 50 mg, 26 received mitapivat 100 mg, and 27 received placebo, twice daily.

在2022年1月19日至2023年4月25日期间，79名患者被随机分配（51名[65%]女性，28名[35%]男性；46名[58%]黑人或非裔美国人，26名[33%]白人，五名[6%]多种族，两名[3%]亚洲人）；26名患者接受50毫克的mitapivat，26名患者接受100毫克的mitapivat，另外27名患者接受安慰剂，每日两次。

Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 mg group and 13 [50%] of 26 patients in the mitapivat 100 mg group, versus one [4%] of 27 patients in the placebo group; two-sided p=0·0003 and p=0·0001, respectively).

两个治疗组与安慰剂组相比，血红蛋白反应率均有统计学显著性差异（50毫克米塔匹瓦组26名患者中有12名[46%]，100毫克米塔匹瓦组26名患者中有13名[50%]，而安慰剂组27名患者中只有1名[4%]；双侧p值分别为0·0003和0·0001）。

Mitapivat was generally well tolerated.

米塔匹瓦通常耐受性良好。

Serious adverse events were reported in two (8%) of 26 patients in the mitapivat 50 mg group, four (15%) of 26 patients in the mitapivat 100 mg group, and three (11%) of 27 patients in the placebo group; grade 3 or worse adverse events occurred in three (12%), five (19%), and two (7%) patients, respectively.

在50毫克米塔匹瓦组的26名患者中，有2名（8%）报告了严重不良事件，在100毫克米塔匹瓦组的26名患者中，有4名（15%）报告了严重不良事件，在安慰剂组的27名患者中，有3名（11%）报告了严重不良事件；3级或更严重的不良事件分别发生在3名（12%）、5名（19%）和2名（7%）患者中。

No serious or grade 3 or worse adverse events were considered treatment related and there were no treatment-related deaths.

没有被认为是与治疗相关的严重或3级或更严重的不良事件，并且没有与治疗相关的死亡事件。

The most common grade 3 or worse adverse events were infections and infestations, and included one patient in the placebo group with an infected skin ulcer, one patient in the mitapivat 50 mg group with meningitis and one with pelvic inflammatory disease, and one patient each with malaria, pneumonia, and tonsillitis in the mitapivat 100 mg group.

最常见的3级或更严重的不良事件是感染和寄生虫病，包括安慰剂组中一名患有感染性皮肤溃疡的患者，mitapivat 50 mg组中一名患有脑膜炎和一名患有盆腔炎症的患者，以及mitapivat 100 mg组中各有一名患者患有疟疾、肺炎和扁桃体炎。

interpretation

Mitapivat, through its dual effect of increasing ATP and decreasing 2,3-diphosphoglycerate, could provide clinical benefit to patients with sickle cell disease.

通过其双重作用，即增加ATP和降低2,3-二磷酸甘油酸，mitapivat可能为镰状细胞病患者提供临床益处。

These results support continued evaluation of mitapivat in the phase 3 portion of the study.

这些结果支持在研究的第3阶段继续评估mitapivat的疗效。

funding

Agios Pharmaceuticals.

Agios制药公司。