急性间歇性卟啉症的 RNAi 治疗药物 Givosiran 的 3 期临床试验。

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

机构信息

From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).

出版信息

N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147.

DOI:10.1056/NEJMoa1913147

PMID:32521132

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. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

摘要

背景

肝δ-氨基-γ-酮戊酸合酶 1（ALAS1）的上调，导致δ-氨基-γ-酮戊酸（ALA）和卟胆原的积累，是急性肝性卟啉症急性发作和慢性症状的发病机制的核心。吉维司他是一种 RNA 干扰疗法，可抑制 ALAS1 的表达。

方法

在这项双盲、安慰剂对照的 3 期临床试验中，我们将有症状的急性肝性卟啉症患者随机分为皮下注射吉维司他（2.5mg/公斤体重）或安慰剂组，每月一次，共 6 个月。主要终点是急性间歇性卟啉症患者的复合卟啉症发作的年化率，急性肝性卟啉症最常见的类型。（复合卟啉症发作导致住院、紧急医疗就诊或在家中静脉内给予血红素。）主要次要终点是 ALA 和卟胆原的水平以及急性肝性卟啉症患者的年化发作率，以及急性间歇性卟啉症患者的血红素使用和每日最严重疼痛评分。

结果

共有 94 名患者接受了随机分组（吉维司他组 48 名，安慰剂组 46 名）。在 89 名急性间歇性卟啉症患者中，吉维司他组的年化发作率为 3.2，安慰剂组为 12.5，吉维司他组降低了 74%（P<0.001）；94 名急性肝性卟啉症患者的结果相似。在急性间歇性卟啉症患者中，吉维司他组的尿 ALA 和卟胆原水平较低，血红素使用天数较少，每日疼痛评分较好。吉维司他组观察到的更频繁的主要不良事件是血清转氨酶水平升高、血清肌酐水平和估计肾小球滤过率变化以及注射部位反应。