A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies
A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies
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DOI：
10.1086/318809
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发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Desnick, RJ
中科院分区：
文献类型：
--
作者：
Eng, CM;Banikazemi, M;Desnick, RJ
法布里病是由于α-半乳糖苷酶A(α-GalA)活性不足和球三糖神经酰胺(GL-3)及相关糖鞘糖脂的病理性堆积所致，主要是在血管内皮细胞溶酶体中。目前的治疗是姑息性的，受影响的患者通常在40多岁或50多岁时死亡。在基因敲除小鼠中输注重组人α-半乳糖A(r-hα-GALA)的临床前研究表明，组织和血浆中的GL-3减少，为1/2期临床试验提供了理论基础。在这里，我们报告了一项单中心、开放标记、剂量范围的r-hα-GALA治疗研究，在15名患者中，每个患者都接受了五种剂量方案中的一种的五次输液。静脉给药的r-hα-GALA通过可饱和和非饱和两种途径以剂量依赖的方式从循环中清除。生化、组织学和/或超微结构观察到血浆和组织中GL-3的迅速和显著减少。血浆GL-3清除量呈剂量依赖关系。在治疗前后的活检患者中，肝脏的GL-3平均含量下降了84%(n=13)，5名患者中有4名患者的肾脏明显下降，7名患者中有4名患者的心内膜在5剂治疗后略有下降。光镜和电子显微镜检查显示肝、皮肤、心脏和肾脏的血管内皮细胞中的GL-3沉积明显减少或接近正常。此外，患者报告疼痛减轻，出汗能力增加，生活质量指标改善。输液耐受性良好；4名患者出现轻至中度反应，提示有超敏反应，均予保守治疗。在15名患者中，8名(53%)产生了针对r-hα-Gala的抗体；然而，正如输液1和5的药代动力学值不变所表明的那样，抗体不是中和的。这项研究为Fabry病的酶替代疗法3期试验提供了基础。
Fabry disease results from deficient alpha -galactosidase A (alpha -Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha -Gal A (r-h alpha GalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-h alpha GalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-h alpha GalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n = 13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-h alpha GalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.