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Editorial
. 2025 May 30;87(7):4014-4016.
doi: 10.1097/MS9.0000000000003393. eCollection 2025 Jul.

Fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease findings from the SEQUOIA phase 2 trial

Talha Liaquat  1 , Bareera Tanveer Malik  1 , Tayyab Habib Hashmi  1 , Huzaifa Arain  1 , Mohammad Haris Ali  1 , Md Ariful Haque  2   3
Affiliations
Editorial

Fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease findings from the SEQUOIA phase 2 trial

Talha Liaquat et al. Ann Med Surg (Lond). .

Abstract

Alpha-1 antitrypsin deficiency (AATD) is a prevalent autosomal recessive disorder affecting approximately 3 million people worldwide, caused by mutations in the SERPINA1 gene leading to low alpha-1 antitrypsin (AAT) levels. This deficiency predisposes individuals to chronic obstructive pulmonary disease, bronchiectasis, neonatal cholestasis, and liver cirrhosis. The most common pathogenic mutation, PI*ZZ allele, produces misfolded Z-AAT protein accumulating in hepatocytes. Currently, there are no specific treatments for AATD-related liver disease, with management focusing on preventing complications. Fazirsiran, an investigational RNA interference therapeutic, targets hepatocytes to reduce Z-AAT synthesis. Preclinical studies and an open-label phase 2 trial showed promising results. The subsequent phase 2 SEQUOIA trial, a randomized controlled study, evaluated Fazirsiran's efficacy and safety in 40 PiZZ homozygous patients. Results demonstrated significant dose-dependent reductions in serum Z-AAT levels (-61% to -94%) and liver Z-AAT concentrations, improved liver histopathology, and a favorable safety profile. These findings support Fazirsiran's potential as a therapeutic option for AATD-associated liver disease.

Keywords: RNA interference (rNAi); SEQUOIA trial; alpha-1 antitrypsin (AAT); alpha-1 antitrypsin deficiency (AATD); fazirsiran; phase 2 trial.

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Conflict of interest statement

Authors stated no conflicts of interest.

Figures

Figure 1.
Figure 1.
Diagrammatic representation of mechanism of action of Fazirsiran.
See this image and copyright information in PMC

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