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首页> 外文期刊>Neuromuscular disorders: NMD >Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study
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Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study

机译：新型酶替代治疗的安全性，可耐药性，药代动力学，药效学和探索性疗效脂肪溶酶酶Alfa（Neogaa）在治疗 - 野生和alglucosidase Alfa治疗的晚期开发型Pompe疾病患者中：1期，开放标签，多中心，跨国公司 ，上升剂量学习

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This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid alpha-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients >= 18 years, alglucosidase alfa naive (Naive) or previously receiving alglucosidase alfa for >= 9 months (Switch), with baseline FVC >= 50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naive and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naive patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naive patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t(1/2z)similar to 1.0h). AUC was 5-6 x higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naive groups and over time. Baseline quadriceps muscle glycogen was low (similar to 6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. (C) 2018 The Authors. Published by Elsevier B.V.
机译：这种多中心/跨国公司，开放式标签，上升剂量研究（NCT01898364）评估了重复剂量抗血糖溶胶酶Alfa（Neogaa），第二代，重组酸α-葡糖苷酶替代治疗的安全性，耐受性，药代动力学，药效学和探索性疗效，在晚期疾病（LOPD）中。患者> = 18岁，Alglucosidase Alfa Naive（天真）或以前接受alglucosidase Alfa> = 9个月（开关），基线FVC> = 50％预测和独立的动态，接受每周雪葡萄糖酶Alfa 5,10，或20毫克/千克超过24周。 9/10 Naive和12/14交换患者完成了这项研究。 Avalglucosidase Alfa是耐受良好的;没有死亡/危及生命的严重不良事件（SAES）。一个天真的患者被撤回研究药物相关的Saes（呼吸窘迫/胸部不适）。输液相关的反应（IARS）影响8名患者。大多数治疗紧急的AES / IAR是非严重的，温和至中等强度。在筛选时，5名Switch患者测试抗抗蔓延酶Alfa抗体阳性;治疗，2个开关和9名静止患者Seroconverted。输注后，Avalglucosidase Alfa等离子体浓度下降单均为（T（1 / 2z），类似于1.0h）。在20 vs 5 mg / kg组中，AUC在5-6 x较高。药代动力学在开关和天真的组之间和随时间之间相似。在大多数患者中，基线Quadriceps肌肉糖原低（类似于6％），通常仍然保持不变。探索性疗效参数（肺功能/功能容量）通常保持稳定或改善。 Avalglucosidase Alfa的耐受性良好的安全性曲线和探索性疗效结果支持进一步的雪葡糖苷酶Alfa发育。 （c）2018作者。 elsevier b.v出版。

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