University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Child and Adolescent Health (DZKJ), Hamburg, Germany.
Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.
Lancet. 2024 Oct 5;404(10460):1333-1345. doi: 10.1016/S0140-6736(24)01556-3.
Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria.
APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 μmol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin (forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days -1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640).
APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, ≥15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (-63%, SD 20) compared with placebo (1%, 29; least squares mean change -395·9 μmol/L, SE 33·8; p<0·0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events.
Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity.
PTC Therapeutics.
苯丙酮尿症是一种神经毒性苯丙氨酸（Phe）积累的遗传性疾病。APHENITY 评估了口服合成蝶呤在苯丙酮尿症儿童和成人中的疗效和安全性。
APHENITY 是一项在 13 个国家的 34 个诊所、医院和大学地点进行的 3 期、随机、双盲、安慰剂对照研究。所有年龄的个体，如果他们在研究入组时血液中 Phe 浓度为 360 μmol/L 或更高，且由于 GCH1、PTS、QDPR、SPR 和 PCBD1 的致病性变异而患有高苯丙氨酸血症，符合原发性 BH 缺乏症的诊断，则有资格入组。第 1 部分是蝶呤对血液 Phe 浓度反应的 14 天开放性评估。在第 2 部分中，蝶呤反应性参与者通过基于网页响应系统（基于 2 和 4 的随机分组大小的交替分组）随机分配（1:1）接受蝶呤（强制剂量递增：每天每公斤体重 20、40 和 60mg/kg，连续 2 周）或安慰剂。研究药物和安慰剂在外观和给药方式上是相同的。在第 2 部分中，无论是在诊所还是在家中，都采集干血样进行分析，以确定第 1 天（在给药前）、第 5 天、第 10 天、第 14 天、第 19 天、第 24 天、第 28 天、第 33 天、第 38 天和第 42 天的血液 Phe 浓度。第 2 部分的主要终点是在第 1 部分中至少有 30%的血液 Phe 浓度降低且至少服用过一剂第 2 部分药物的参与者中，从基线到第 6 周的平均血液 Phe 变化。在至少服用一剂治疗药物的所有参与者中评估安全性。该完成的研究在 EudraCT（2021-000474-29）和 ClinicalTrials.gov（NCT05099640）上注册。
APHENITY 于 2021 年 9 月 30 日至 2023 年 4 月 3 日进行。对 187 人进行了资格评估，其中 157 人入组。在第 1 部分中，对 156 名参与者进行了评估或评估，其中 114 名（73%）是蝶呤反应性的（即，血液 Phe 与基线相比降低了≥15%）。在第 2 部分中，98 名参与者（安慰剂组 49 名，蝶呤组 49 名）纳入主要分析组。与安慰剂相比，蝶呤治疗 6 周后血液 Phe 浓度显著降低（-63%，20%）（蝶呤组-395.9μmol/L，SE 33.8；p<0.0001）。在接受蝶呤治疗的 56 名参与者中有 33 名（59%）和接受安慰剂治疗的 54 名参与者中有 18 名（33%）报告了治疗相关不良事件。大多数治疗相关不良事件是轻度胃肠道事件（蝶呤组 11 例[20%]，安慰剂组 10 例[19%]），很快就解决了。没有死亡和严重或严重的不良事件。
蝶呤是一种有前途的治疗苯丙酮尿症的口服疗法，耐受性良好，可显著降低不同疾病严重程度的参与者的血液 Phe 浓度。
PTC 治疗公司。
