Lau Heather A, Viskochil David, Tanpaiboon Pranoot, Lopez Antonio Gonzalez-Meneses, Martins Esmeralda, Taylor Julie, Malkus Betsy, Zhang Lin, Jurecka Agnieszka, Marsden Deborah
NYU Grossman School of Medicine, Department of Neurology, New York, NY, USA.
University of Utah, Department of Pediatrics, Salt Lake City, UT, USA.
Mol Genet Metab. 2022 May;136(1):28-37. doi: 10.1016/j.ymgme.2022.03.002. Epub 2022 Mar 9.
Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.
黏多糖贮积症VII型（MPS VII）是一种极为罕见的常染色体隐性代谢疾病，由β-葡萄糖醛酸酶缺乏所致。β-葡萄糖醛酸酶是一种溶酶体酶，可水解糖胺聚糖（GAGs），包括硫酸皮肤素（DS）、硫酸软骨素和硫酸乙酰肝素（HS）。β-葡萄糖醛酸酶缺乏会导致未降解的GAGs在受影响组织的溶酶体中逐渐蓄积，这可能会导致胎儿水肿、身材矮小、肝脾肿大和认知障碍。一项开放标签、多中心、II期研究纳入了8名5岁以下患有MPS VII的儿科受试者。受试者每隔一周静脉输注重组人β-葡萄糖醛酸酶vestronidase alfa 4 mg/kg，共48周（治疗期）。完成48周治疗的受试者可继续接受vestronidase alfa 4 mg/kg治疗，最长可达240周，或直至撤回同意、停药或研究终止（延长期）。尿中排泄的GAGs（uGAG）高于正常水平已被证明与MPS疾病的疾病严重程度和临床结局相关。因此，本研究的主要疗效终点是确定从基线到第48周uGAG DS排泄的平均百分比变化。每次访视时均观察到uGAG DS较基线有统计学意义的降低（p < 0.0001），在第4周（基线后首次评估）最小二乘均值（标准误）百分比变化为-60%（6.6），在第48周（治疗期最终评估）为-61%（6.41）。次要疗效终点包括从基线到第48周生长和肝脾肿大的变化。观察到站立身高Z评分呈上升趋势（基线时均值[标准差]为-2.630 [1.17]，n = 8；第48周时为-2.045 [0.27]，n = 7）和生长速度（基线时均值[标准差]Z评分为-2.59 [1.49]，n = 4；第48周时为-0.39 [2.10]，n = 4；p = 0.27）。通过超声评估的3名受试者中有3名肝肿大得到缓解，通过体格检查评估的6名受试者中有5名缓解；通过超声评估的3名受试者中有1名脾肿大得到缓解，通过体格检查评估的2名受试者中有2名缓解。本研究期间未发现新的安全信号。4名（50%）受试者出现轻度至中度输液相关反应。总之，长期使用vestronidase alfa治疗可使5岁以下患有MPS VII的儿科受试者的uGAGs迅速且持续降低，维持生长，并改善肝脾肿大。试验注册号：NCT02418455。
