Background Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder characterized by symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in observational case studies and animal and cellular models of NPC. Therefore, the effects of the active L-enantiomer, N-acetyl-L-leucine (NALL, Sponsor Code IB1001) were evaluated in pediatric and adult patients with NPC. Methods We conducted a 9-center, multinational, open-label, rater-blinded Phase 2 study to assess the safety and efficacy of NALL for the treatment of pediatric (6 years and older) and adult patients with NPC (IB1001-201 clinical trial). Eligible patients were assessed during three study phases: a baseline period (with or without a study run-in), a 6-week treatment period (dosage of NALL 4 g/d in patients aged 13 years and older; weight tiered doses for patients aged 6-12 years based on approximately 0.1 g/kg/day), and a 6-week post-treatment washout period. The primary outcome was based on the Clinical Impression of Change in Severity (CI-CS) assessment (assessed on a 7-point Likert scale) performed by blinded, centralized raters who compared videos of patients performing a pre-defined primary anchor test - either the 8-Meter Walk Test (8MWT) or 9-Hole Peg Test of the Dominant Hand (9HPT-D) - at different study periods. Secondary outcomes included the cerebellar function evaluations, namely the Scale for Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), and the Clinical Global Impression Scales (CGI) as well as the EuroQol-5D/VAS. Results Thirty-three subjects aged 7 to 64 years with a confirmed diagnosis of NPC were enrolled according to the trial protocol between 04 September 2019 and 30 January 2020. Thirty-two patients were included in the modified intention-to-treat analysis. IB1001 met its CI-CS primary endpoint (mean difference 0.86 ((90% CI 0.25,1.75, p=0.029). IB1001 also met secondary endpoints, including improvement during treatment on the SARA scale (mean difference -1.19, 90% CI -1.8, -0.5, p=0.001), investigators CGI-C assessment (mean difference from baseline to the end of treatment 0.6, 90% CI 0.5, 1.0, p<0.001), clinically worsening over the washout period on the SARA (mean difference 1.45, 90% CI 0.5, 2.0, p=0.002) and investigators CGI-C assessment (washout mean difference -0.5, 90% CI -1.0, 0.0, p=0.006). IB1001 was well-tolerated with no treatment-related serious adverse reactions occurring. Conclusions Consistent with its pharmacological action, IB1001 rapidly improved symptoms, functioning, and quality of life in 6-weeks, the clinical effect of which was lost after the 6-week, post-treatment washout period. High consistency and statistical significance between the primary and secondary endpoints demonstrate a clear, clinically meaningful improvement with IB1001. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk/benefit profile for the treatment of NPC (Funded by IntraBio; ClinicalTrials.gov number, NCT03759639; EudraCT number 2018-004331-71).

中文翻译：

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乙酰L-亮氨酸用于C型尼曼-皮克：一项跨国，双盲，II期试验

背景C型尼曼-皮克病（NPC）是一种罕见的常染色体隐性遗传性神经退行性疾病，其特征是进行性小脑性共济失调和认知能力下降等症状。在观察性案例研究以及NPC的动物和细胞模型中，修饰的氨基酸N-乙酰-亮氨酸已与阳性症状和神经保护，疾病缓解作用相关。因此，在儿童和成人NPC患者中评估了活性L-对映体N-乙酰基-L-亮氨酸（NALL，发起人代码IB1001）的作用。方法我们进行了一项9个中心，跨国，开放标签，盲目评估的2期研究，以评估NALL在儿科（6岁及以上）和成人NPC患者中的安全性和有效性（IB1001-201临床试验）。在三个研究阶段中评估了合格的患者：基线期（有或没有研究磨合期），6周治疗期（13岁及以上患者的NALL剂量为4 g / d； 6-12岁患者的体重分级剂量基于约0.1 g / kg /天），以及治疗后6周的清除期。主要结果基于盲人集中评估者进行的临床严重程度变化印象（CI-CS）评估（以7点李克特量表评估），该评估者比较了进行预定义主要锚定测试的患者的视频-在不同的学习阶段进行优势手的8米步行测试（8MWT）或9孔挂钩测试（9HPT-D）。次要结果包括小脑功能评估，即共济失调评估和评定量表（SARA），脊髓小脑共济失调功能指数（SCAFI），以及临床总体印象量表（CGI）以及EuroQol-5D / VAS。结果根据试验方案，在2019年9月4日至2020年1月30日期间招募了33例年龄在7至64岁，确诊为NPC的受试者。其中32例患者纳入了改良的意向治疗分析。IB1001达到其CI-CS主要终点（平均差异0.86（（90％CI 0.25,1.75，p = 0.029）。IB1001也达到次要终点，包括在治疗期间改善了SARA量表（平均差异-1.19，90％CI- 1.8，-0.5，p = 0.001），研究者CGI-C评估（从基线到治疗结束的平均差异0.6，90％CI 0.5，1.0，p <0.001），在SARA清除期间临床恶化（平均差异1.45，90％CI 0.5，2.0，p = 0。002）和研究者的CGI-C评估（洗脱平均差异-0.5，90％CI -1.0，0.0，p = 0.006）。IB1001的耐受性良好，没有发生与治疗相关的严重不良反应。结论IB1001与其药理作用一致，可在6周内迅速改善症状，功能和生活质量，在治疗后6周冲洗期后，其临床疗效消失。主要终点和次要终点之间的高度一致性和统计学意义证明了IB1001具有明显的临床意义的改进。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001的耐受性良好，没有发生与治疗相关的严重不良反应。结论IB1001与其药理作用一致，可在6周内迅速改善症状，功能和生活质量，在治疗后6周冲洗期后，其临床疗效消失。主要终点和次要终点之间的高度一致性和统计学意义证明了IB1001具有明显的临床意义的改进。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001的耐受性良好，没有发生与治疗相关的严重不良反应。结论IB1001与其药理作用一致，可在6周内迅速改善症状，功能和生活质量，在治疗后6周冲洗期后，其临床疗效消失。主要终点和次要终点之间的高度一致性和统计学意义证明了IB1001具有明显的临床意义的改进。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC的风险/获益情况良好（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001在6周内迅速改善了症状，功能和生活质量，在6周治疗后清除期后，其临床效果消失了。主要终点和次要终点之间的高度一致性和统计学意义证明了IB1001具有明显的临床意义的改进。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001在6周内迅速改善了症状，功能和生活质量，在6周治疗后清除期后，其临床效果消失了。主要终点和次要终点之间的高度一致性和统计学意义证明了IB1001具有明显的临床意义的改进。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001具有临床意义的改善。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。IB1001具有临床意义的改善。IB1001具有良好的耐受性，未报告与药物相关的严重不良事件，这表明治疗NPC具有良好的风险/益处（由IntraBio资助; ClinicalTrials.gov号，NCT03759639; EudraCT号2018-004331-71）。