Children's Memorial Hospital, Chicago, IL, USA.
Mol Genet Metab. 2011 Aug;103(4):315-22. doi: 10.1016/j.ymgme.2011.03.020. Epub 2011 Mar 31.
Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH(4), the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration.
To evaluate the safety of long-term treatment with sapropterin in PKU subjects who participated in previous Phase 3 sapropterin trials.
PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of sapropterin in patients with PKU who were classified as sapropterin responders and participated in prior Phase 3 sapropterin studies: 111 subjects aged 4-50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements.
Average exposure during PKU-008 was 658.7±221.3 days (range, 56-953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0±237.5 days (range, 135-1151). The mean sapropterin dose was 16.2±4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with sapropterin.
Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of sapropterin as long-term treatment for patients with PKU.
苯丙酮尿症（PKU）是由于苯丙氨酸羟化酶（PAH）活性缺陷导致苯丙氨酸（Phe）分解受损引起的。盐酸沙丙蝶呤（sapropterin，Kuvan®）是唯一获得美国和欧盟批准的天然 6R-BH（4）的药物制剂，6R-BH（4）是 PAH 活性所必需的辅因子。沙丙蝶呤可增强沙丙蝶呤反应性 PKU 患者的残余 PAH 活性，与饮食管理相结合，有助于降低血液 Phe 浓度以实现最佳控制。批准是基于四项国际临床研究的积极安全性和疗效结果，其中最长的研究持续了 22 周。
评估先前参加过 3 期 sapropterin 试验的 PKU 受试者接受 sapropterin 长期治疗的安全性。
PKU-008 是一项 3b 期、多中心、多国家、开放性、3 年扩展试验，旨在评估 sapropterin 在被归类为 sapropterin 反应者且先前参加过 sapropterin 3 期研究的 PKU 患者中的长期安全性：111 名年龄为 4-50 岁的受试者完成了先前的研究，随后被纳入研究 PKU-008。每 3 个月进行一次常规安全性监测，包括不良事件报告、血液 Phe 监测、临床实验室评估、体格检查和生命体征测量。
在 PKU-008 中的平均暴露时间为 658.7±221.3 天（范围 56-953；中位数 595）。在多个研究（PKU-001、PKU-003、PKU-004 和 PKU-008；或 PKU-006 和 PKU-008）中的平均总参与时间为 799.0±237.5 天（范围 135-1151）。平均 sapropterin 剂量为 16.2±4.7mg/kg/天。大多数不良事件被认为与治疗无关，为轻度或中度严重程度，与 sapropterin 的先前研究一致。未观察到与年龄相关的不良事件报告差异。有 3 名受试者因被认为可能或极可能与研究治疗相关的不良事件而停止治疗（各有 1 例注意力集中困难、血小板计数减少和间歇性腹泻）。无死亡报告。7 例报告的严重不良事件中，有 1 例被认为可能与研究治疗有关（胃食管反流）。没有需要医疗干预的实验室或体格检查异常。对于大多数受试者，血液 Phe 浓度始终保持在目标范围内，证实了在接受 sapropterin 延长治疗的受试者中反应的持久性。
在 5 至 20mg/kg/天的剂量下，sapropterin 的暴露时间平均为 659 天，被发现是安全且耐受良好的。这项研究支持 sapropterin 作为 PKU 患者长期治疗的安全性和耐受性。
