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.
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.)
Funding and Disclosures
Supported by Arrowhead Pharmaceuticals. Dr. Strnad is supported by the German Research Foundation (DFG) (grant STR1095/6-1) and by the DFG consortium CRC/SFB 1382 “Gut–liver axis” (ID 403224013).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on June 25, 2022, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the trial participants, pathologists (R. Saxena, D. Carpenter, and X. Liu), trial site staff, and Arrowhead Pharmaceuticals staff for their support of this trial; D. Christianson for support in the clinical program, including development of the semiquantitative histologic assessments used in this trial; and Hicham Naimy from Takeda and Esmie Lynn Wescott from Oxford PharmaGenesis for editorial assistance with an earlier version of the manuscript.
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