Background & Aims

Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION.

Methods

Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (n = 48) or placebo (n = 46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted.

Results

During givosiran treatment, the median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item short-form health survey physical and mental component summary scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lower urinary delta-aminolevulinic acid and porphobilinogen levels were sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran.

Conclusions

Long-term monthly givosiran treatment provides sustained and continued improvement in clinical manifestations of AHP.

ClinicalTrials.gov identifier

NCT03338816.

EudraCT number

2017-002432-17.

Impact and implications

Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders associated with overproduction and accumulation of neurotoxic heme intermediates (delta-aminolevulinic acid and porphobilinogen), sometimes resulting in recurrent acute attacks and long-term complications. Givosiran, a small-interfering RNA that prevents accumulation of delta-aminolevulinic acid and porphobilinogen, is approved for the treatment of AHP. These final 36-month results of ENVISION, a phase III study of givosiran in patients with AHP and recurrent attacks, show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in annualized attack rate and use of hemin over time, as well as improved quality of life, with an acceptable safety profile. These results are important for physicians, patients, families, and caregivers who are grappling with this debilitating and potentially life-threatening disease with few effective and tolerable treatment options.

中文翻译：

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givosiran 治疗急性肝卟啉症的疗效和安全性：随机 III 期 ENVISION 试验的最终结果

背景与目标

急性肝卟啉症 (AHP) 是由肝脏血红素生物合成缺陷引起的，导致急性神经内脏发作和慢性症状。在 ENVISION (NCT03338816) 中，与安慰剂相比，为期 6 个月的 givosiran 治疗减少了发作和其他疾病表现。在此，我们报告了 ENVISION 36 个月的最终分析数据。

方法

94 名患有 AHP（年龄≥12 岁）且反复发作的患者以 1:1 的比例随机分配至每月双盲皮下注射 givosiran 2.5 mg/kg (n = 48) 或安慰剂 (n = 46)，为期 6 个月。在开放标签延伸（OLE）期间，93 名患者接受 givosiran 2.5 或 1.25 mg/kg 治疗 6 个月或更长时间，然后过渡到 2.5 mg/kg。除非另有说明，终点都是探索性的。

结果

在 givosiran 治疗期间，中位年化发病率 (AAR) 为 0.4。到第 36 个月，连续使用 givosiran 组的年化血红素使用天数仍然较低（中位数为 0.0 至 0.4），而安慰剂交叉组则有所下降（16.2 至 0.4）。在 OLE 结束时，在连续 givosiran 和安慰剂交叉组中，分别有 86% 和 92% 的患者出现 0 次发作。AAR 分别低于历史 AAR（事后分析），分别为 98% 和 100%，并且分别有 88% 和 90% 的人使用 0 天血红素。12 项简短健康调查的身体和心理成分总结分数分别增加了 8.6 和 8.1（连续 givosiran）以及 9.4 和 3.2（安慰剂交叉）。EQ-5D 健康相关问卷分数增加了 18.9（连续 givosiran）和 9.9（安慰剂交叉）。尿δ-氨基乙酰丙酸和胆色素原水平持续较低。安全性研究结果表明 givosiran 具有持续的积极风险/效益特征。

结论

长期每月 givosiran 治疗可持续改善 AHP 的临床表现。

ClinicalTrials.gov 标识符

NCT03338816。

EudraCT 编号

2017-002432-17。

影响和影响

急性肝卟啉症 (AHP) 是一组罕见的慢性多系统疾病，与神经毒性血红素中间体（δ-氨基乙酰丙酸和胆色素原）的过量产生和积累有关，有时会导致反复急性发作和长期并发症。Givosiran 是一种小干扰 RNA，可防止 δ-氨基乙酰丙酸和胆色素原的积累，被批准用于治疗 AHP。ENVISION（一项 givosiran 在 AHP 和复发性发作患者中的 III 期研究）的这些最终 36 个月结果表明，长期每月使用 givosiran 治疗可导致年化发作率和氯高铁血红素的使用随着时间的推移持续不断地降低，如以及生活质量的提高和可接受的安全状况。这些结果对于医生、患者、家庭和护理人员来说非常重要，他们正在努力应对这种使人衰弱且可能危及生命的疾病，而有效且可耐受的治疗选择很少。