近日，美国麻省总医院Hanny Al-Samkari团队比较了Engasertib与安慰剂治疗遗传性出血性毛细血管扩张症出血的效果。该研究于2025年11月27日发表在《新英格兰医学杂志》上。

遗传性出血性毛细血管扩张（HHT）可引起复发性、严重的鼻出血，以及贫血和生活质量下降。这种疾病在世界范围内仍然没有获得许可的治疗方法。

在这项概念验证、多中心、双盲、安慰剂对照试验中，研究组评估了口服engasertib（一种新的、变构的、选择性AKT抑制剂）治疗HHT患者的安全性和有效性。患者以1:1:1的比例随机分配，接受30mg的engasertib剂量，40mg的engasertib剂量或安慰剂，每天一次，持续12周。主要结局是不良事件发生的频率和严重程度。主要的次要结局包括鼻出血的频率和持续时间。开放标签扩展正在进行中。

共有75名患者被分配到30mg engasertib组（24名患者）、40mg engasertib组（25名患者）或安慰剂组（26名患者）。在接受至少一剂试验方案的患者中，与engasertib相关的最常见靶外不良事件包括轻至中度皮疹（30 mg engasertib组5例[21%]，40 mg engasertib组10例[42%]，安慰剂组2例[8%]）和轻至中度高血糖（40 mg engasertib组3例[12%]，其他两组无患者），这是可逆的。两个engasertib组的严重不良事件发生率与安慰剂组相似。从基线到第12周，30 mg engasertib组鼻出血频率的平均（±SD）下降为26.5±26.5%，40 mg engasertib组为27.8±35.1%，安慰剂组为18.0±36.0%；鼻出血时间平均缩短29.9±53.2%、41.4±41.0%、23.8±53.4%。、

研究结果表明，除轻度至中度皮疹外，engasertib的安全性与安慰剂相似，大多数继续服用该药的患者皮疹消退。Engasertib治疗与鼻出血频率和持续时间的减少有关。

附：英文原文

Title: Engasertib versus Placebo for Bleeding in Hereditary Hemorrhagic Telangiectasia

Author: Hanny Al-Samkari, Josefien Hessels, Antoni Riera-Mestre, Sophie Dupuis-Girod, Thibaut Van Zele, Vicente Gómez del Olmo, Pamela G. Hodges, Raquel Torres-Iglesias, Roberto Bertè, Pierre Saint-Mezard, Hedvika Lazar, Nicholas Benedict, Debra Barker, Corrado Bernasconi, Damien Picard, Elisabetta Buscarini, Hans-Jurgen Mager

Issue&Volume: 2025-11-27

Abstract:

BACKGROUND

Hereditary hemorrhagic telangiectasia (HHT) can cause recurrent, severe epistaxis, as well as anemia and reduced quality of life. The disease remains without licensed therapies worldwide.

METHODS

In this proof-of-concept, multicenter, double-blind, placebo-controlled trial, we evaluated the safety and efficacy of oral engasertib, a new, allosteric, selective AKT inhibitor, in patients with HHT. Patients were randomly assigned in a 1:1:1 ratio to receive engasertib at a dose of 30 mg, engasertib at a dose of 40 mg, or placebo once daily for 12 weeks. The primary outcomes were the frequency and severity of adverse events. Key secondary outcomes included the frequency and duration of epistaxis. An open-label extension is ongoing.

RESULTS

A total of 75 patients were assigned to 30-mg engasertib (24 patients), 40-mg engasertib (25 patients), or placebo (26 patients). Among the patients who received at least one dose of the trial regimen, the most common on-target adverse events associated with engasertib included mild-to-moderate rash (5 patients [21%] in the 30-mg engasertib group, 10 [42%] in the 40-mg engasertib group, and 2 [8%] in the placebo group) and mild-to-moderate hyperglycemia (3 patients [12%] in the 40-mg engasertib group and no patients in the other two groups), which were reversible. The incidence of serious adverse events in each of the two engasertib groups was similar to that in the placebo group. From baseline to week 12, the mean (±SD) decrease in epistaxis frequency was 26.5±26.5% with 30-mg engasertib, 27.8±35.1% with 40-mg engasertib, and 18.0±36.0% with placebo; the mean decrease in epistaxis duration was 29.9±53.2%, 41.4±41.0%, and 23.8±53.4%, respectively.

CONCLUSIONS

The safety profile of engasertib was similar to that of placebo except for mild-to-moderate rash, which resolved in most patients who continued to receive the drug. Engasertib treatment was associated with decreases in epistaxis frequency and duration.

DOI: NJ202511273932111

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2504411