Engasertib versus Placebo for Bleeding in Hereditary Hemorrhagic Telangiectasia.

The disease remains without licensed therapies worldwide.

全球范围内，该疾病仍无获批准的治疗方法。

Methods

In this proof-of-concept, multicenter, double-blind, placebo-controlledtrial, we evaluated the safety and efficacy of oral engasertib, a new, allosteric, selective AKT inhibitor, in patients with HHT.

在这项概念验证、多中心、双盲、安慰剂对照试验中，我们评估了口服engasertib（一种新的别构、选择性AKT抑制剂）在HHT患者中的安全性和有效性。

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.

患者按1:1:1的比例随机分配，分别接受30 mg或40 mg的engasertib或安慰剂，每日一次，持续12周。

The primary outcomes were the frequency and severity of adverse events.

主要结果是不良事件的频率和严重程度。

Key secondary outcomes included the frequency and duration of epistaxis.

关键次要结果包括鼻出血的频率和持续时间。

An open-label extension is ongoing.

目前正在进行一项开放标签的扩展研究。

Results

A total of 75 patients were assigned to 30-mg engasertib (24 patients), 40-mg engasertib (25 patients), or placebo (26 patients).

共有75名患者被分配接受30毫克的engasertib治疗（24名患者）、40毫克的engasertib治疗（25名患者）或安慰剂治疗（26名患者）。

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.

在接受至少一次试验方案治疗的患者中，与engasertib相关的最常见的靶向不良事件包括轻度至中度皮疹（30-mg engasertib组5名患者[21%]，40-mg engasertib组10名患者[42%]，安慰剂组2名患者[8%]）和轻度至中度高血糖（40-mg engasertib组3名患者[12%]，其他两组无患者），这些不良事件是可逆的。

The incidenceof serious adverse events in each of the two engasertib groups was similar to that in the placebo group.

两个engasertib组的严重不良事件发生率与安慰剂组相似。

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.

从基线到第12周，使用30毫克恩加塞替布的患者鼻出血频率平均下降了26.5±26.5%，使用40毫克恩加塞替布的患者下降了27.8±35.1%，而安慰剂组下降了18.0±36.0%；鼻出血持续时间的平均下降分别为29.9±53.2%，41.4±41.0%和23.8±53.4%。

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.

恩加塞替布的安全性特征与安慰剂相似，除了轻度至中度皮疹，大多数继续接受药物治疗的患者症状得到了缓解。

Engasertib treatment was associated with decreases in epistaxis frequency and duration.

Engasertib治疗与鼻出血频率和持续时间的减少有关。

(Funded by Vaderis Therapeutics; ClinicalTrials.gov number, NCT05406362.).

(由Vaderis Therapeutics资助；ClinicalTrials.gov编号，NCT05406362。)