Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial.

Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C.

左旋乙酰亮氨酸（N-乙酰-L-亮氨酸）已被证明对于治疗神经系统表现有效，并且在尼曼-匹克病C型等溶酶体贮积病中具有疾病修饰作用。

We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.

我们旨在评估左乙拉西坦对于儿童和成人共济失调-毛细血管扩张症患者的疗效和安全性。

Methods

In this phase 3, randomised, double-blind, placebo-controlledcrossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA.

在这项第三阶段、随机、双盲、安慰剂对照的交叉试验中，参与者在德国、斯洛伐克、西班牙、瑞士、英国和美国的十个研究中心进行招募。

Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day).

符合条件的4岁及以上的患者，经基因确认患有共济失调-毛细血管扩张症，使用交互式响应技术以1:1的比例随机分配，接受每日两次或三次口服左乙酰酪氨酸或匹配安慰剂治疗，持续两个连续的12周治疗期（体重大于或等于35公斤的患者每天接受4克口服左乙酰酪氨酸或匹配安慰剂，每天三次；体重小于35公斤的患者根据大约每天每公斤体重0.1克的剂量，每天两次或三次口服重量分级剂量）。

All participants, investigators, and assessors were blinded to group assignment.

所有参与者、研究人员和评估者对分组分配情况均不知情。

The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo.

主要结果是评估基线和每个12周治疗期结束时，接受利巴韦林或安慰剂治疗的患者在小脑共济失调评估和评分量表（SARA）上的平均变化。

Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random.

所有随机分配并至少接受一次研究药物剂量的患者均进行了安全性和有效性的分析，并使用线性混合效应模型来处理随机缺失的数据。

The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.

该试验已在ClinicalTrials.gov注册，注册号为NCT06673056，并在CTIS注册，注册号为2024-517706-29；开放标签扩展阶段正在进行中。

Results

Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion.

在2025年3月18日至2025年6月30日期间，共有77名经基因确诊的共济失调-毛细血管扩张症患者被筛选以纳入研究。

Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older.

排除了四名不符合纳入标准的患者，共有73名患者被纳入并随机分配（36名接受左乙酰亮氨酸后给予安慰剂，37名接受安慰剂后给予左乙酰亮氨酸）。73名患者被纳入主要分析和安全集。73名患者中，38名（52%）为女性，35名（48%）为男性；55名（75%）为白人。47名（64%）患者年龄小于18岁，26名（36%）年龄为18岁或以上。

The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo.

左乙酰亮氨酸组的SARA总分平均变化为-1.92（标准差2.81），而安慰剂组为-0.14（标准差2.38）（线性混合模型治疗效果为-1.88 [标准差0.41]，95%置信区间为-2.70至-1.06；p<0.0001）。接受左乙酰亮氨酸治疗的29名患者中发生了54起不良事件，而接受安慰剂治疗的25名患者中发生了75起不良事件。

No treatment-related serious adverse events or deaths occurred.

未发生与治疗相关的严重不良事件或死亡。

interpretation

Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia.

左乙拉西坦显示出在功能上显著且具有临床意义的改善，并且安全且耐受性良好，为治疗共济失调-毛细血管扩张症提供了良好的风险-效益比。

An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.

该试验的持续开放标签扩展阶段将研究潜在的长期神经保护和疾病修饰效应。

funding

IntraBio.

IntraBio 公司。