Department of Pediatrics in the College of Medicine, University of Florida, Gainesville, FL, USA.
Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Mol Genet Metab. 2018 Nov;125(3):217-227. doi: 10.1016/j.ymgme.2018.06.010. Epub 2018 Aug 23.
Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU.
Pegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 μmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 μmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment.
Baseline mean blood Phe for Group A and Group B were 1135 μmol/L and 1198 μmol/L, respectively. Mean blood Phe ≤ 600 μmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ± 483 μmol/L) and for Group B by Week 48 (mean blood Phe of 557 ± 389 μmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B.
Pegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.
苯丙酮尿症（PKU）是由苯丙氨酸羟化酶活性缺乏引起的，导致血液和大脑中苯丙氨酸（Phe）积累。血液 Phe 水平升高与成年人的并发症有关，包括神经、精神和认知问题。即使进行营养和药物管理，大多数 PKU 成年人也无法将血液 Phe 水平维持在或低于指南推荐的水平。Pegvaliase，聚乙二醇化重组鱼腥藻变异体苯丙氨酸氨裂解酶（PAL），将 Phe 转化为反式肉桂酸和氨，是一种研究性的酶替代疗法，用于降低 PKU 成年人的血液 Phe 水平。
在从未接受过 pegvaliase 治疗的 PKU 成年人中，使用诱导、滴定和维持剂量方案给予 pegvaliase。逐渐增加剂量，直到血液 Phe≤600μmol/L 为止。维持剂量是指参与者在至少 4 周内实现并维持血液 Phe≤600μmol/L 而无需调整剂量的剂量。对在研究治疗的前 24 周内达到（A 组，n=11）和未达到（B 组，n=13）维持剂量的参与者进行了分析。
A 组和 B 组的基线平均血液 Phe 分别为 1135μmol/L 和 1198μmol/L。A 组在第 11 周（平均血液 Phe 为 508±483μmol/L）和 B 组在第 48 周（平均血液 Phe 为 557±389μmol/L）达到≤600μmol/L。最常见的不良事件涉及过敏反应，大多数为轻度至中度，且随着时间的推移而减少。B 组中有一名参与者发生了四次全身性过敏反应的过敏反应，符合临床过敏与传染病研究所/食物过敏与过敏反应网络的标准；所有事件均非 IgE 介导，且无后遗症，在第四次事件后停止了 pegvaliase 给药。与 B 组相比，A 组的抗药物抗体的发生率和滴度通常较低。
在 A 组和 B 组中，pegvaliase 采用诱导、滴定和维持剂量方案进行治疗，在第 48 周时均显著降低了血液 Phe 水平，大多数参与者的安全性特征可管理。pegvaliase 降低血液 Phe 似乎与剂量、治疗持续时间和个体免疫反应有关；在接受额外的治疗时间和剂量滴定后，较晚的 Phe 反应者（B 组）获得了与早期 Phe 反应者（A 组）相似的益处，且长期安全性相似。
