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

作者：Virginia Clark, Charlie Strange, Pavel Strnad, Antonio J. Sanchez, Paul Y. Kwo, Vítor Magno Pereira, Bart van Hoek, Igor Barjaktarević, Angelo Guido Corsico, Mònica Pons, Monica Goldklang, Meagan Gray, Brooks Kuhn, Hugo E. Vargas, John M. Vierling, Raj Vuppalanchi, Mark Brantly, Naomi Kappe, Ting Chang, Thomas Schluep, Rong Zhou, James Hamilton, Javier San Martín, Rohit Loomba · 发表于：Gastroenterology · 年份：2024 · DOI：10.1053/j.gastro.2024.06.028 · 被引用次数：29 · 研究领域：Protease and Inhibitor Mechanisms、Protein Kinase Regulation and GTPase Signaling、Blood Coagulation and Thrombosis Mechanisms

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...