Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria
Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria
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DOI：
10.1056/nejmoa1913147
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发表时间：
2020-06-11
影响因子：
158.5
通讯作者：
Gouya, Laurent
中科院分区：
文献类型：
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作者：
Balwani, Manisha;Sardh, Eliane;Gouya, Laurent
肝δ-氨基乙酰丙酸合成酶1（ALAS 1）的上调，导致δ-氨基乙酰丙酸（ALA）和胆色素原的积累，是急性肝卟啉症急性发作和慢性症状的发病机制的核心。Givosiran是一种RNA干扰疗法，可抑制ALAS 1表达。方法在这项双盲、安慰剂对照、III期试验中，我们将有症状的急性肝卟啉症患者随机分配至皮下注射givosiran（2.5 mg/kg体重）或安慰剂，每月一次，持续6个月。主要终点是急性间歇性卟啉症（急性肝性卟啉症最常见的亚型）患者复合卟啉症发作的年发生率。（复合卟啉症发作导致住院治疗，紧急医疗保健访问，或在家中静脉注射氯化血红素。关键的次要终点是急性肝性卟啉症患者的ALA和胆色素原水平以及年发病率，沿着氯化血红素的使用以及急性间歇性卟啉症患者每日最严重疼痛评分。结果共有94例患者接受随机分组（givosiran组48例，安慰剂组46例）。在89例急性间歇性卟啉症患者中，吉伏西兰组的平均年发作率为3.2，安慰剂组为12.5，代表吉伏西兰组的发病率低74%（P
Background Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. Results A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P