Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was −0.36 mL/min/1.73 m2/year [−2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of −3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

中文翻译：

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Pegunigalsidase alfa：一种新型聚乙二醇化重组 α-半乳糖苷酶，用于治疗法布里病

法布里病是一种罕见的 X 连锁遗传病，由致病性变异引起GLA，导致溶酶体α-半乳糖苷酶A酶活性缺陷和多器官表现。自 2001 年以来，使用阿加糖酶 α 或阿加糖酶 β 的酶替代疗法 (ERT) 一直是主要治疗方法，尽管存在快速清除和免疫原性等局限性。 Pegunigalsidase alfa 是一种新型聚乙二醇化重组 α-半乳糖苷酶，有望成为替代品。聚乙二醇化酶 alfa 在植物细胞中产生，由于聚乙二醇化而表现出增强的稳定性、延长的半衰期和降低的免疫原性。一项 1/2 期临床试验证明了 Gb3 从肾毛细血管内皮细胞中清除，其 48 个月的扩展研究显示了肾功能保存的显着结果。三个 3 期临床试验（BRIDGE、BRIGHT 和 BALANCE）显示出良好的疗效和安全性，但在解释缺乏对照组的 BRIDGE 和 BRIGHT 结果时需要谨慎。在 BALANCE 中，比较 Pegunigalsidase alfa 与 agalsidase beta 的关键 3 期试验，对 2 年来 eGFR 下降的意向治疗分析显示，中位斜率的组间差异 [95% 置信区间] 为 -0.36 mL/min /1.73米2/年[−2.44； 1.73]。置信区间的下限高于预设值 -3 mL/min/1.73 m2/年，包括零。尽管存在偶发的超敏反应和免疫复合物介导的肾小球肾炎等挑战，欧洲药品管理局和美国食品和药物管理局批准的聚乙二醇化酶 alfa 代表着法布里病治疗领域的重大补充，为接受当前酶替代疗法的患者提供了一种选择制剂耐受性差或效果差。