美国西奈山伊坎医学院Manisha Balwani团队探讨了RNAi治疗急性间歇性卟啉症的疗效，该成果发表在2020年6月11日出版的《新英格兰医学杂志》上。

肝δ-氨基乙酰丙酸合酶1（ALAS1）的上调会导致δ-氨基乙酰丙酸（ALA）和胆色素原的积聚，是急性肝卟啉症急性发作和慢性症状的重要机制。Givosiran，一种RNA干扰疗法，可抑制ALAS1的表达。

在这项双盲、安慰剂对照的3期临床试验中，研究组招募了94例有症状的急性肝卟啉症患者，将其随机分组，其中48例接受皮下注射Givosiran治疗，46例接受安慰剂治疗，为期6个月。主要终点是急性间歇性卟啉症（急性肝卟啉症最常见的亚型）患者复合性卟啉症的年发病率。

在89例急性间歇性卟啉症患者中，Givosiran组的年平均发作率是3.2次，安慰剂组是12.5次，Givosiran组降低了74％，差异显著，94例急性肝卟啉症患者的结果相似。在患有急性间歇性卟啉症的患者中，与安慰剂相比，Givosiran可降低尿液ALA和胆色素原的水平，减少使用氯高铁血红素的时间，并改善每日疼痛评分。Givosiran组发生的主要不良事件是血清转氨酶水平升高、血清肌酐水平变化和估计肾小球滤过率变化以及注射部位反应。

总之，对于患有急性间歇性卟啉症的患者，Givosiran治疗与安慰剂相比，可显著降低卟啉症的发作率，但肝肾不良反应有所增加。

附：英文原文

Title: Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria

Author: Manisha Balwani, M.D.,, Eliane Sardh, M.D., Ph.D.,, Paolo Ventura, M.D.,, Paula Aguilera Peiró, M.D.,, David C. Rees, F.R.C.P.,, Ulrich Stlzel, M.D.,, D. Montgomery Bissell, M.D.,, Herbert L. Bonkovsky, M.D.,, Jerzy Windyga, M.D., Ph.D.,, Karl E. Anderson, M.D.,, Charles Parker, M.D.,, Samuel M. Silver, M.D., Ph.D.,, Siobán B. Keel, M.D.,, Jiaan-Der Wang, M.D., Ph.D.,, Penelope E. Stein, M.D., Ph.D.,, Pauline Harper, M.D., Ph.D.,, Daphne Vassiliou, M.D.,, Bruce Wang, M.D.,, John Phillips, Ph.D.,, Aneta Ivanova, M.D., Ph.D.,, Janneke G. Langendonk, M.D., Ph.D.,, Raili Kauppinen, M.D., Ph.D.,, Elisabeth Minder, M.D.,, Yutaka Horie, M.D., Ph.D.,, Craig Penz, M.A.,, Jihong Chen, Ph.D.,, Shangbin Liu, Ph.D.,, John J. Ko, Pharm.D.,, Marianne T. Sweetser, M.D., Ph.D.,, Pushkal Garg, M.D.,, Akshay Vaishnaw, M.D., Ph.D.,, Jae B. Kim, M.D.,, Amy R. Simon, M.D.,, and Laurent Gouya, M.D., Ph.D.

Issue&Volume: 2020-06-10

Abstract: Abstract

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<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.

Conclusions

Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events.

DOI: 10.1056/NEJMoa1913147

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1913147