Pavel Strnad1, Mattias Mandorfer1, Gourab Choudhury1, William Griffiths1, Christian Trautwein1, Rohit Loomba1, Thomas Schluep1, Ting Chang1, Min Yi1, Bruce D Given1, James C Hamilton1, Javier San Martin1, Jeffery H Teckman1. 1. 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.).
Abstract
BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
Authors: Lorenz Balcar; Bernhard Scheiner; Markus Urheu; Patrick Weinberger; Rafael Paternostro; Benedikt Simbrunner; Lukas Hartl; Mathias Jachs; David Bauer; Georg Semmler; Claudia Willheim; Matthias Pinter; Peter Ferenci; Michael Trauner; Thomas Reiberger; Albert Friedrich Stättermayer; Mattias Mandorfer Journal: JHEP Rep Date: 2022-08-20