Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA),Gastroenterology

当前位置： X-MOL 学术 › Gastroenterology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA)
Gastroenterology ( IF 25.7 ) Pub Date : 2024-07-02 , DOI: 10.1053/j.gastro.2024.06.028
Virginia C Clark ₁ , Charlie Strange ₂ , Pavel Strnad ₃ , Antonio J Sanchez ₄ , Paul Kwo ₅ , Vitor Magno Pereira ₆ , Bart van Hoek ₇ , Igor Barjaktarevic ₈ , Angelo Guido Corsico ₉ , Monica Pons ₁₀ , Monica Goldklang ₁₁ , Meagan Gray ₁₂ , Brooks Kuhn ₁₃ , Hugo E Vargas ₁₄ , John M Vierling ₁₅ , Raj Vuppalanchi ₁₆ , Mark Brantly ₁₇ , Naomi Kappe ₁₈ , Ting Chang ₁₉ , Thomas Schluep ₁₉ , Rong Zhou ₁₉ , James Hamilton ₁₉ , Javier San Martin ₁₉ , Rohit Loomba ₂₀

Affiliation

Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida.
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina.
Department of Internal Medicine III, University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen University, Health Care Provider of the European Reference Network on Rare Liver Disorders, Aachen, Germany.
Division of Gastroenterology and Hepatology, University of Iowa Hospital and Clinics, Iowa City, Iowa.
School of Medicine, Stanford University, Redwood City, California.
Hospital Central do Funchal, Madeira, Portugal; Universidade da Madeira, Madeira, Portugal.
Department of Gastroenterology and Hepatology and LUMC Transplantation Center, Leiden University Medical Center, Leiden, the Netherlands.
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; Division of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain.
Columbia University Irving Medical Center, New York, New York.
Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama.
Division of Pulmonary and Critical Care and Sleep Medicine, University of California, Davis, Sacramento, California; University of California, Davis, Alpha-1 Deficiency Clinic, University of California, Davis, Sacramento, California.
Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona.
Departments of Medicine and Surgery, Baylor College of Medicine, Houston, Texas.
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, Florida.
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
Arrowhead Pharmaceuticals, Inc, Pasadena, California.
Division of Gastroenterology and Hepatology, University of California, University of California San Diego School of Medicine, La Jolla, California.

Background & Aims

Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis.

Methods

This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4.

Results

At week 16, least-squares mean percent declines in serum Z-AAT concentration were −61%, −83%, and −94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable.

Conclusions

Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292)

中文翻译：

Fazirsiran 治疗 Alpha-1 抗胰蛋白酶缺乏症肝病成人患者：2 期安慰剂对照试验（SEQUOIA）

背景和目标

纯合子 ZZ α-1 抗胰蛋白酶（AAT）缺陷在肝细胞中产生突变的 AAT （Z-AAT）蛋白，导致进行性肝纤维化。我们评估了一种研究性 RNA 干扰治疗药物 fazirsiran 的安全性和有效性，该疗法可降解 Z-AAT 信使 RNA，减少有害蛋白质合成。

方法

这项正在进行的 2 期研究将 40 名患者随机分配到皮下注射安慰剂或 fazirsiran 25、100 或 200 毫克。主要终点是血清 Z-AAT 浓度从基线到第 16 周的百分比变化。基线肝活检纤维化患者在第 1 天、第 4 周和每 12 周接受治疗，并在第 48 、 72 或 96 周或之后进行第二次肝活检。无纤维化的患者在第 1 天和第 4 周接受了 2 剂。

结果

在第 16 周，与安慰剂相比，fazirsiran 25、100 和 200 mg 的血清 Z-AAT 浓度的最小二乘平均百分比下降分别为 -61% 、 -83% 和 -94% （均 P < .0001）。疗效持续到第 52 周。在给药后肝活检时，fazirsiran 将肝脏 Z-AAT 浓度中位数降低了 93%，而安慰剂组增加了 26%。所有 fazirsiran 治疗的患者肝球负荷的组织学水平均较基线降低。fazirsiran 组和安慰剂组 12 例患者中有 5 例和 8 例患者中有 0 例门静脉炎改善，基线评分分别为 >0。病毒性肝炎评分组织学数据的组织学荟萃分析显示，fazirsiran 组和安慰剂组 14 例中有 7 例和 8 例纤维化患者中有 3 例在基线时分别提高了 >F0 >1 分。无不良事件导致停药，肺功能检查保持稳定。