Background

Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1.

Methods

We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only).

Findings

315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7–28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment.

Interpretation

Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy.

Funding

Swedish Orphan Biovitrum (Sobi).

中文翻译：

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使用尼替西农治疗 1 型遗传性酪氨酸血症的长期安全性和结果：一项为期 15 年的非干预性多中心研究

背景

自 2005 年欧盟批准尼替西农以来，1 型遗传性酪氨酸血症患者的预后发生了巨大变化，患有该疾病的患者现在有史以来第一次进入成年期。本研究旨在评估尼替西农治疗 1 型遗传性酪氨酸血症患者的长期安全性和结果。

方法

我们在欧洲 17 个国家的 77 个地点进行了一项非干预性、非比较性、多中心研究，并收集了研究期间（2005 年 2 月 21 日）接受口服尼替西农治疗的 1 型遗传性酪氨酸血症患者的回顾性和前瞻性纵向数据。 ，至 2019 年 9 月 30 日）。没有特定的排除标准。只要患者接受治疗，或直到研究结束，至少每年由一名研究人员对患者进行随访。主要终点，即与肝、肾、眼、血液或认知或发育功能相关的不良事件的发生，在完整集中进行评估（所有患者在索引日期 [2 月 21 日，

发现

研究期间共招募了 315 名患者（全套）。此外，还检索了 24 名接受肝移植或在上市后监测计划期间死亡的患者的数据（扩展分析集；339 名患者）。中位治疗时间为 11·2 年（范围 0·7–28·4）；累积尼替西农暴露量为 3172·7 患者年。通过新生儿筛查诊断出的患者在中位年龄 0·8 个月时开始尼替西农治疗，而临床表现的患者则为 8·5 个月。肝脏、肾脏、眼科、血液学或认知或发育不良事件的发生率很低。开始治疗的时间越晚，肝移植或死亡的发生率越高（70 名在 <28 天时开始治疗的患者中无一例与268 名患者中有 35 名 [13%] 在年龄≥28 天时开始治疗）。315 名患者中有 279 名 (89%) 被评估为具有非常好的或良好的尼替西农治疗依从性。随着患者年龄的增长，治疗和饮食依从性下降。观察到次优血浆苯丙氨酸和酪氨酸水平。据报道，大多数患者在整个治疗过程中总体临床状况良好；整个研究期间 203 人中有 176 人 (87%)，治疗 1 年后为 98%。

解释

长期尼替西农治疗耐受性良好，未发现新的安全性信号。早期治疗开始似乎可以预防限制生命的肝病。新生儿筛查是确保早期治疗的最有效方法。血液酪氨酸、苯丙氨酸和尼替西农水平的标准化监测有可能指导个体化治疗。

资金

瑞典孤儿生物玻璃（Sobi）。