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.