Background

Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease.

Methods

LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21–55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014–000418–75, and is now complete.

Findings

Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI –1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference –1·76% [95% CI –2·67 to –0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).

Interpretation

Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.

Funding

Teva Pharmaceutical Industries.

中文翻译：

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拉喹莫德治疗亨廷顿病 (LEGATO-HD) 的安全性和有效性：一项多中心、随机、双盲、安慰剂对照、2 期研究

背景

拉喹莫德调节中枢神经系统炎症通路，被认为与亨廷顿病的病理学有关。在亨廷顿病转基因啮齿动物模型中使用拉喹莫德的研究表明，拉喹莫德可改善运动功能、减少脑容量损失并延长生存期。我们的目的是评估拉喹莫德在改善亨廷顿病患者运动功能和减少尾状核体积损失方面的安全性和有效性。

方法

LEGATO-HD 是一项多中心、双盲、安慰剂对照的 2 期研究，在 10 个国家（加拿大、捷克共和国、德国、意大利、荷兰、葡萄牙、俄罗斯、西班牙、英国和美国）的 48 个地点进行。年龄 21-55 岁、胞嘧啶-腺苷-鸟嘌呤 (CAG) 重复长度在 36 至 49 之间、患有症状性亨廷顿舞蹈病且统一亨廷顿舞蹈病评定量表 - 总运动评分 (UHDRS-TMS) 高于 5 且总功能能力评分为 8 分或更高的患者通过集中互动反应技术随机分配 (1:1:1:1) 为拉喹莫德 0·5 mg、1·0 mg 或 1·5 mg，或匹配的口服安慰剂52 周内每天一次；参与随机化的人在研究中没有其他角色。参与者、研究人员和研究人员对治疗分配情况不知情。由于多发性硬化症研究中的心血管安全问题，1·5 mg 组在招募完成前停止。主要终点是 UHDRS-TMS 相对于基线的变化，次要终点是尾状核体积的百分比变化，两者均在第 52 周时将 1·0 mg 组与安慰剂组进行比较。主要终点和次要终点在完整分析集中进行评估（即所有接受至少一剂研究药物且至少进行过一次基线后 UHDRS-TMS 评估的随机患者）。安全性措施包括不良事件发生频率和严重程度以及临床和实验室检查，并在安全性分析组（即接受至少一剂研究药物的所有随机患者）中进行评估。该试验已在ClinicalTrials.gov、NCT02215616和 EudraCT、2014-000418-75 注册，现已完成。

发现

2014年10月28日至2018年6月19日期间，352名患有亨廷顿舞蹈病的成年人（179 [51%]名男性和173 [49%]名女性；平均年龄为43·9 [SD 7·6]岁和340 [97%]白色）被随机分配：107 名拉喹莫德 0·5 mg，107 名拉喹莫德 1·0 mg，30 名拉喹莫德 1·5 mg，108 名匹配安慰剂。第 52 周时 UHDRS-TMS 相对于基线的最小二乘平均变化在拉喹莫德 1·0 mg 组中为 1·98 (SE 0·83)，在安慰剂组中为 1·2 (0·82)（最小二乘平均差 0 ·78 [95% CI –1·42 至 2·98]，p=0·4853）。1·0 mg 组尾状核体积的最小二乘平均变化为 3·10% (SE 0·38)，安慰剂组为 4·86% (0·38)（最小二乘平均差 –1·76%） 95% CI –2·67 至 –0·85]；p=0·0002）。拉喹莫德耐受性良好，没有新的安全性发现。安慰剂组有 8 名 (7%) 患者报告严重不良事件，拉喹莫德 0·5 mg 组有 7 名 (7%) 患者报告严重不良事件，拉喹莫德 1·0 mg 组有 5 名 (5%) 患者报告，拉喹莫德 1·5 组有 1 名 (3%) 患者报告严重不良事件。毫克。安慰剂组有 1 例死亡，与治疗无关。所有拉喹莫德剂量组（0·5 mg、1·0 mg 和 1·5 mg）中最常见的不良事件是头痛（38 [16%]）、腹泻（24 [10%]）、跌倒（18 [18] 7%]）、鼻咽炎（20 [8%]）、流感（15 [6%]）、呕吐（13 [5%]）、关节痛（11 [5%]）、烦躁（10 [4%]）、疲劳（8 次 [3%]）和失眠（8 次 [3%]）。

解释

拉喹莫德对 UHDRS-TMS 评估的运动症状没有显示出显着影响，但与安慰剂相比，在第 52 周时尾状核体积损失显着减少。亨廷顿病有一个慢性且缓慢进展的病程，本研究没有解决是否会延长持续时间拉喹莫德治疗可能会在临床评估中产生可检测到的有意义的变化。

资金

梯瓦制药工业公司。