From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.).
N Engl J Med. 2022 Aug 11;387(6):514-524. doi: 10.1056/NEJMoa2205416. Epub 2022 Jun 25.
Alpha-antitrypsin (AAT) deficiency results from carriage of a homozygous "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency.
We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry.
All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved.
In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).
α-1 抗胰蛋白酶（AAT）缺乏症是由携带纯合子“Z”突变（蛋白酶抑制剂[PI]ZZ）引起的。Z 等位基因产生一种称为 Z-AAT 的突变 AAT 蛋白，该蛋白在肝细胞中积累，可导致进行性肝病和纤维化。这项开放标签、2 期临床试验研究了 fazirsiran（一种 RNA 干扰治疗药物）在 AAT 缺乏症相关肝病患者中的安全性和疗效。
我们将 PIZZ 基因型且有肝纤维化的成年人按 200mg 剂量（队列 1[4 例]和队列 2[8 例]）或 100mg 剂量（队列 1b[4 例]）皮下注射，第 1 天和第 4 周，然后每 12 周一次。主要终点是从基线到第 24 周（队列 1 和 1b）或第 48 周（队列 2）肝脏 Z-AAT 浓度的变化，通过液相色谱-质谱法进行测量。
所有患者肝脏中 Z-AAT 的积累均减少（中位数减少 83%，第 24 或 48 周）。血清中的最低点减少了约 90%，治疗还与组织学珠母层负担的减少相关（从基线时的平均评分 7.4（评分范围为 0 至 9，评分越高表示珠母层负担越大）降至第 24 或 48 周时的 2.3）。所有队列的肝酶浓度均降低。24 或 48 周后，15 例患者中有 7 例观察到纤维化消退，有 2 例观察到纤维化进展。没有导致试验或药物停药的不良事件。4 例严重不良事件（病毒性心肌炎、憩室炎、呼吸困难和前庭神经元炎）已解决。
在这项小型试验中，fazirsiran 可使血清和肝脏中的 Z-AAT 浓度强烈降低，并同时改善肝酶浓度。（由 Arrowhead 制药公司资助；AROAAT-2002 ClinicalTrials.gov 编号，NCT03946449）。
