第一阶段试验的RNA干扰治疗急性间歇性卟啉病。

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Sardh E,哈珀P, Balwani M,斯坦P,里斯D,比塞尔DM, Desnick R,帕克C,菲利普J, Bonkovsky霍奇金淋巴瘤,Vassiliou D, Penz C, Chan-Daniels,他问,Querbes W,菲茨杰拉德K金JB,加戈P, Vaishnaw,西蒙•AR安德森柯

第一阶段试验的RNA干扰治疗急性间歇性卟啉病。

郑传经地中海J。2019年2月7日,380 (6):549 - 558。doi: 10.1056 / NEJMoa1807838。

PubMed ID

30726693 (在PubMed

]

文摘

背景:感应δaminolevulinic酸合酶1 (ALAS1)基因表达和神经毒性中间体积累导致脑脊髓交感神经系统攻击和疾病症状在急性间歇性卟啉病的病人,血红素生物合成的一种罕见的遗传疾病。Givosiran是一个临床实验的RNA干扰治疗剂,抑制肝ALAS1合成。方法:我们进行了第一阶段试验givosiran患者急性间歇性卟啉病。在审判的一个部分,没有最近的卟啉症袭击(即病人。前6个月,没有攻击基线)被随机分配接受一个5升的皮下注射剂量的givosiran(0.035、0.10、0.35、1.0或2.5毫克每千克体重)或安慰剂。在B部分中,病人没有最近的攻击被随机分配接受每月注射两种剂量的givosiran(0.35或1.0毫克每千克)或安慰剂(共有两注射28天)。在C部分,患者反复发作被随机分配接受注射两种剂量的givosiran(2.5或5.0毫克每千克)或安慰剂一次每月注射(共四个)或一次季度(共两个注射)在12周内,开始在0天。安全、药代动力学、药效学和探索性的疗效结果进行评估。结果:A和B部分地区共有23个患者和17例患者部分C进行了随机化。常见的不良事件包括鼻咽炎、腹痛和腹泻。 Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).

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药物

Givosiran