Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency.

Weekly intravenous AAT therapy (augmentation) is the only specific treatment available.

每周一次的静脉注射α1-抗胰蛋白酶治疗（增强疗法）是目前唯一可用的特定治疗方法。

Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy.

Alvelestat 是一种口服的中性粒细胞弹性蛋白酶(NE)抑制剂，作为一种针对 α1-抗胰蛋白酶缺乏症（AATD）治疗的新方法正在开发中。

Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD.

在这里，我们测试了 alvelestat 在严重 α1-抗胰蛋白酶缺乏症（AATD）中的安全性和机制性疗效。

Methods

We conducted two complementary, double-blind, randomised, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD.

我们进行了两项互补的、双盲的、随机的、安慰剂对照的12周试验，研究了两种剂量的alvelestat在α1抗胰蛋白酶缺乏症（AATD）中的应用。

ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 and 240 mg twice daily without augmentation.

ATALANTa研究了每日两次120毫克的剂量，包括一部分同时接受增强治疗的参与者；ASTRAEUS测试了每日两次120毫克和240毫克的剂量，没有增强治疗。

Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (Aα-Val360 and desmosine/isodesmosine) as well as safety and tolerability.

主要和次要终点是血液中去甲肾上腺素（假定的靶点）的变化及其在AATD（Aα-Val360和去甲基异戊二烯/异戊二烯）中的活性，以及安全性和耐受性。

Results

We enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS).

我们招募了161名参与者（ATALANTa项目63人，ASTRAEUS项目98人）。

Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at alvelestat 240 mg twice daily.

在这两项研究中，无论剂量如何，血液中NE均显著受到抑制，其中以每日两次240毫克阿维莱司特的效果最为显著（>90%的抑制）。

There was no effect of alvelestat 120 mg on disease activity biomarkers, while 240 mg demonstrated significant reduction in Aα-Val360 and desmosine.

120毫克阿维莱司特对疾病活动生物标志物没有影响，而240毫克则显著降低了Aα-Val360和脱敏素的水平。

The most common adverse eventwas headache, particularly at the 240 mg dose.

最常见的不良事件是头痛，特别是在240 mg剂量下。

No safety signals of concern were detected.

未检测到任何令人关注的安全信号。

Conclusions

Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice-daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile.

Alvelestat 有效地抑制了 NE 及其活性，在两种剂量下均有表现，但只有每日两次240 mg剂量在疾病活动生物标志物上与安慰剂相比显示出相关疗效，并具有良好的安全性特征。

These findings support progression of the 240 mg twice-daily dose into a clinical end-point study.

这些发现支持将每日两次240 mg剂量推进到临床终点研究。