聚乙二醇化天冬氨酸酶治疗成人苯丙酮尿症的长期安全性和疗效：PAL-003 扩展研究的综合 2 期结果。
Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study.
机构信息
Department of Pediatrics, Division of Medical Genetics, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.
Division of Genetics and Metabolism, University of Florida, PO Box 100296 UFHSC, Gainesville, FL, 32610, USA.
出版信息
Orphanet J Rare Dis. 2018 Jul 4;13(1):108. doi: 10.1186/s13023-018-0858-7.
BACKGROUND
Deficiency of phenylalanine hydroxylase causes phenylketonuria (PKU) with elevated phenylalanine (Phe) levels and associated neuropsychiatric and neurocognitive symptoms. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an investigational agent to lower plasma Phe in adults with PKU. This study aimed to characterize the long-term efficacy, safety, and immunogenicity of pegvaliase in adults with PKU.
METHODS
PAL-003 is an ongoing, open-label, long-term extension study of the pegvaliase dose-finding parent phase 2 studies. Participants continued the dose of pegvaliase from one of three parent studies, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 μmol/L.
RESULTS
Mean (standard deviation [SD]) plasma Phe at treatment-naïve baseline for 80 participants in the parent studies was 1302.4 (351.5) μmol/L. In the 68 participants who entered the extension study, plasma Phe decreased 58.9 (39)% from baseline, to 541.6 (515.5) μmol/L at Week 48 of treatment. Plasma Phe concentrations ≤120 μmol/L, ≤360 μmol/L, and ≤ 600 μmol/L were achieved by 78.7, 80.0, and 82.5% of participants, respectively. Mean (SD) protein intake at baseline was 69.4 (40.4) g/day (similar to the recommended intake for the unaffected population) and remained stable throughout the study. All participants experienced adverse events (AEs), which were limited to mild or moderate severity in most (88.8%); the most common AEs were injection-site reaction (72.5%), injection-site erythema (67.5%), headache (67.5%), and arthralgia (65.0%). The AE rate decreased from 58.3 events per person-year in the parent studies to 18.6 events per person-year in the extension study.
CONCLUSIONS
Pegvaliase treatment in adults with PKU produced meaningful and persistent reductions in mean plasma Phe concentration with a manageable safety profile for most subjects that continued with long-term treatment.
TRIAL REGISTRATION
ClinicalTrials.gov , NCT00924703. Registered June 18, 2009, https://clinicaltrials.gov/ct2/show/NCT00924703.
背景
苯丙氨酸羟化酶缺乏导致苯丙酮尿症（PKU），使苯丙氨酸（Phe）水平升高，并伴有神经精神和神经认知症状。聚乙二醇化苯丙氨酸氨裂解酶（PEGylated phenylalanine ammonia lyase）是一种研究性药物，可降低 PKU 成人的血浆 Phe 水平。本研究旨在描述 pegvaliase 在 PKU 成人中的长期疗效、安全性和免疫原性。
方法
PAL-003 是 pegvaliase 剂量发现的父母期 2 期研究的一项正在进行的、开放标签、长期扩展研究。参与者继续接受来自三项父母期研究之一的 pegvaliase 剂量，剂量调整以实现血浆 Phe 浓度在 60 至 600μmol/L 之间。
结果
在父母期研究中，80 名参与者在治疗前基线时的平均（标准差 [SD]）血浆 Phe 为 1302.4（351.5）μmol/L。在 68 名进入扩展研究的参与者中，与基线相比，血浆 Phe 下降了 58.9（39）%，治疗 48 周时降至 541.6（515.5）μmol/L。分别有 78.7%、80.0%和 82.5%的参与者达到血浆 Phe 浓度≤120μmol/L、≤360μmol/L 和≤600μmol/L。基线时的平均（SD）蛋白质摄入量为 69.4（40.4）g/天（与未受影响人群的推荐摄入量相似），整个研究期间保持稳定。所有参与者均发生不良事件（AE），大多数（88.8%）AE 为轻度或中度严重程度；最常见的 AE 是注射部位反应（72.5%）、注射部位红斑（67.5%）、头痛（67.5%）和关节痛（65.0%）。AE 发生率从父母期研究中的 58.3 例/人年降至扩展期研究中的 18.6 例/人年。
结论
在 PKU 成人中使用 pegvaliase 治疗可显著且持续降低平均血浆 Phe 浓度，大多数接受长期治疗的患者具有可管理的安全性。
试验注册
ClinicalTrials.gov，NCT00924703。2009 年 6 月 18 日注册，https://clinicaltrials.gov/ct2/show/NCT00924703。
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