Lenders Malte, Menke Elise Raphaela, Rudnicki Michael, Cybulla Markus, Brand Eva
Internal Medicine D (Nephrology, Hypertension and Rheumatology), and Interdisciplinary Fabry Center (IFAZ), University Hospital Muenster, Albert-Schweitzer-Campus 1, D-48149, Muenster, Germany.
Department of Internal Medicine IV - Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria.
BioDrugs. 2025 Jan;39(1):153-165. doi: 10.1007/s40259-024-00690-1. Epub 2024 Nov 30.
Pegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.
Pharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.
No infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.
The pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.
聚乙二醇化α-半乳糖苷酶α是一种新批准用于治疗法布里病的药物，旨在延长输注的α-半乳糖苷酶A（AGAL）的血浆半衰期并降低其免疫原性。除了行业发起的研究外，我们提供了首个全面的药代动力学和免疫原性数据。
在接受治疗的患者（11例转换治疗者，2例初治患者）中测量了聚乙二醇化α-半乳糖苷酶α、氨基酸以及聚乙二醇（PEG）特异性抗体和免疫复合物的药代动力学。在连续三至十次输注前后直接采集的血清样本中进行测量。只有三名患者直接从1.0 mg/kg体重开始治疗。
在观察期间，聚乙二醇化α-半乳糖苷酶α治疗下未报告与输注相关的反应。没有预先存在中和性抗AGAL抗体的患者显示出较高的酶促AGAL峰值活性，并且在下次输注前AGAL血清浓度持续存在，而有中和性抗AGAL抗体的患者未观察到这种情况。九名（69.2%）患者存在预先存在的抗PEG抗体（IgG或IgM），在观察期间这似乎对药代动力学没有影响。治疗开始后未观察到新的抗PEG或抗AGAL抗体形成。三名（75.0%）预先存在中和性抗AGAL抗体的患者滴度升高，一名（25.0%）患者滴度降低。在有抗AGAL抗体的患者（n = 4）中检测到免疫复合物形成。
聚乙二醇化α-半乳糖苷酶α的药代动力学根据预先存在的中和抗体的情况显示出不同的特征，有抗体的患者输注后血浆半衰期和酶活性峰值降低。聚乙二醇化α-半乳糖苷酶α半衰期缩短以及抗体阳性患者中免疫复合物形成的临床意义需要在未来的研究中进行分析。
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