Sustained, long-term renal stabilization after 54 months of agalsidase β therapy in patients with Fabry disease
Sustained, long-term renal stabilization after 54 months of agalsidase β therapy in patients with Fabry disease
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DOI：
10.1681/asn.2006080816
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发表时间：
2007-05-01
影响因子：
13.6
通讯作者：
Guffon, Nathalie
中科院分区：
文献类型：
--
作者：
Germain, Dominique P.;Waldek, Stephen;Guffon, Nathalie
法布里病是一种遗传性溶酶体α -半乳糖苷酶A缺乏症，可导致球三烷基神经酰胺（GL-3）在溶酶体内进行性积累，并因肾脏、心脏和脑血管表现而过早死亡。为了确定重组人α -半乳糖苷酶A的长期安全性和有效性，进行了一项开放标签的III期扩展研究，涉及58名患有经典法布里病的患者，他们完成了一项为期20周、双盲、随机、安慰剂对照的agalsidase β III期研究，并过渡到一项扩展试验，每两周接受1mg /kg agalsidase β，持续最多54个月。肾和心脏。评估肾功能。到第54个月，所有选择肾活检的患者（n = 8）在肾毛细血管内皮细胞和多种细胞类型中保持完全的GL-3清除。继续，皮肤（36例中31例）和心脏（8例中6例）毛细血管内皮完全清除。平均血浆GL-3水平仍在正常范围内下降。在第54个月（n = 41）有肾脏数据的患者中位血清肌酐和估计GFR保持稳定（正常）。6例患者出现肾脏疾病进展；大多数（6人中的4人）年龄超过40岁，基线时有明显的蛋白尿，并有硬化性肾小球预处理的证据。不良事件一般轻微，与治疗无关。最常见的治疗相关不良事件是输液相关反应，随着时间的推移而减少。长期的agalsidase - β治疗可以稳定基线时无肾受累患者的肾功能，维持血浆GL-3的降低，并维持毛细血管内皮细胞和多种肾细胞类型中GL-3的清除。
Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.