Salford Royal NHS Foundation Trust, Salford, UK; University of Pretoria, Department of Paediatrics and Child Health, Pretoria, South Africa.
Azienda Ospedaliera San Gerardo, Monza, Italy.
Mol Genet Metab. 2018 Feb;123(2):127-134. doi: 10.1016/j.ymgme.2017.11.015. Epub 2017 Dec 5.
Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver-assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years.
Mean baseline MPS-HAQ domain scores showed impairments in mobility, self-care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domain least square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years.
Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL.
ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered.
在为期 96 周、开放性、多中心、3 期 MOR-005 扩展研究中，对 173 名黏多糖贮积症 A 型（Mucopolysaccharidosis IVA，MPS IVA）患者进行了长达 96 周的elosulfase alfa 酶替代疗法（ERT）的长期安全性和疗效评估，该研究是关键性 24 周、安慰剂对照研究（MOR-004）的延续。在从 MOR-004 基线到 MOR-005 第 96 周的 120 周内，评估了疗效终点的变化。我们报告了 ERT 对三个领域（移动性、自我护理和护理人员协助）的日常生活活动（ADL）的影响，使用黏多糖贮积症健康评估问卷（MPS-HAQ）在 72 周和 120 周或大约 1 年和 2 年后进行评估。
基线时的平均 MPS-HAQ 域评分显示移动性、自我护理和独立性受损。MOR-005 意向治疗人群（ITT；N=169，包括 158 人有 2 年随访）在 1 年和 2 年时显示出移动性和自我护理域最小平方（LS）均值评分相对于基线的持续显著降低（代表改善），而在 2 年时护理协助域的评分没有显著下降。在第 120 周时，与基线相比，LS 均值（SE）的变化为移动性为-0.5（0.1）（P=0.002），自我护理为-0.4（0.1）（P=0.001），和护理协助为-1.0（0.5）（P=0.06）（ITT 人群）。与基线相比，1 年和 2 年时 MPS-HAQ 域评分的改善在连续接受每周剂量方案治疗的患者中大于 MOR-005 总人群，并且在所有域中均具有统计学意义。来自黏多糖贮积症 A 临床评估计划（MorCAP）自然史研究的可比未治疗队列（ITT 人群，N=94，包括 37 人有 2 年随访）在 2 年内没有改善，三个域中有两个域恶化（LS 均值（SE）从基线的变化：移动性为 0.3（0.3），自我护理为 0.4（0.2），护理协助为-0.5（0.8））。在 2 年时，与 MorCAP 相比，MOR-005 与移动性域（-0.7（SE 0.4），P=0.0490）和自我护理域（-0.7（SE 0.3），P=0.0146）的 LS 均值评分与基线相比有统计学意义上的差异。
这些发现表明，长期的 elosulfase alfa ERT 与部分恢复功能能力有关，改善了黏多糖贮积症 A 型患者进行日常生活活动的能力。
ClinicalTrials.govNCT01415427。2011 年 8 月 8 日注册，回顾性注册。
