Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK.
Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
Mol Genet Metab. 2020 Aug;130(4):255-261. doi: 10.1016/j.ymgme.2020.06.004. Epub 2020 Jun 11.
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.
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.
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%.
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.
黏多糖贮积症（MPS）是一组罕见的遗传性代谢疾病，由几种溶酶体酶中的一种缺乏引起，这些酶对于逐步糖胺聚糖（GAG）降解至关重要，导致 GAG 积累和广泛的细胞病理学和临床疾病。尽管疾病表现存在异质性，但几种 MPS 亚型的临床特征基本相似。大量数据表明，尿 GAG（uGAG）排泄量超过正常水平与 MPS 疾病的严重程度和临床结局密切相关。因此，uGAG 排泄量的变化可能具有重要价值，可作为 MPS 疾病临床试验的潜在主要终点，这些疾病因太罕见而无法使用传统的临床终点进行研究。
对长期接受酶替代疗法（ERT）治疗的 MPS I、II 和 VI 患者进行了回顾性病历审查。评估了 uGAG 减少与这些 MPS 疾病主要临床表现相关的临床结局之间的关系。计算了多域应答指数（MDRI）评分，测量以下 4 个领域：6 分钟步行测试、肺功能、生长速度和临床医生整体变化印象。对于每个领域，根据这些结局测量在 MPS 和其他疾病中的已发表信息，定义了最小重要差异（MID）。
在评估的 50 名患者中，18 名（36%）患有 MPS I，23 名（46%）患有 MPS II，9 名（18%）患有 MPS VI。42 名是临床实践患者，8 名参加了临床试验。在所有 MPS 亚型中，基线时 uGAG 水平的平均值（±SD）为 66.0±51.5mg/mmol 肌酐（n=48），ERT 后平均降低 54.6%。基于为每个领域定义的 MID 对 MDRI 评分进行分析表明，与 uGAG 降低程度较低的患者相比，uGAG 降低程度较高的患者在所有评估的 uGAG 阈值下，MDRI 评分的改善幅度更大，并且在 uGAG 降低≥40%的患者中，MDRI 评分呈阳性的可能性更高。
在这项回顾性研究中，uGAG 减少与多种方法评估的长期临床结局相关，支持将 uGAG 减少作为生物标志物主要终点。
