Background

Mucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints.

Methods

A retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases.

Results

Of the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%.

Conclusions

In this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.

中文翻译：

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黏多糖多糖患者尿糖胺聚糖排泄和酶替代治疗的长期临床结局的回顾性图表回顾。

背景

粘多糖酶（MPS）是一组罕见的，遗传性的代谢性疾病，其是逐步糖胺聚糖（GAG）降解所必需的几种溶酶体酶之一的缺乏导致的，导致GAG积累，广泛的细胞病理学和临床疾病。尽管疾病表现是异质性的，但是在几种MPS亚型中，临床特征在很大程度上是可比的。大量数据表明，高于正常水平的尿GAG（uGAG）排泄水平与MPS疾病的疾病严重程度和临床结果密切相关。因此，uGAG排泄的变化可能作为MPS疾病临床试验中潜在的主要终点指标具有重要价值，而使用传统的临床终点指标很难进行MPS疾病的临床试验。

方法

对长期接受酶替代疗法（ERT）治疗的MPS I，II和VI患者进行回顾性医学图表审查。评估了uGAG降低与这些MPS疾病主要临床表现相关的临床结局之间的关系。计算了多域响应者指数（MDRI）分数，测量了以下4个域：6分钟步行测试，肺功能，生长速率和临床医生对变化的整体印象。对于每个领域，根据MPS和其他疾病中这些结局指标的公开信息定义了最小重要差异（MID）。

结果

在评估的50名患者中，有18名（36％）患有MPS I，23名（46％）患有MPS II，9名（18％）患有MPS VI。临床实践患者42例，其中8例参加了临床试验。在所有MPS亚型中，基线时的uGAG平均水平（±SD）为66.0±51.5 mg / mmol肌酐（n  = 48），ERT后平均降低54.6％。根据针对每个域定义的MID对MDRI评分进行的分析显示，与所有评估的uGAG阈值均降低了uGAG的患者相比，降低了uGAG的患者的改善幅度更大，并且趋势为阳性平均可能性更高uGAG降低≥40％的患者的MDRI评分。

结论

在这项回顾性研究中，通过多种方法评估，uGAG的降低与长期临床结局相关，支持将uGAG的降低用作生物标志物的主要终点指标。