Fazirsiran Reduces Liver Z-AAT Burden in AATD Liver Disease

Fazirsiran 200 mg reduced intrahepatic and serum mutant Z alpha-1 antitrypsin (Z-AAT) by approximately 90% compared with placebo in adults with alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD) and a Pi*ZZ genotype, according to pooled analyses of 2 phase 2 trials presented at AASLD The Liver Meeting 2026. Treatment also lowered liver enzymes, while pulmonary function remained stable through up to 196 weeks of follow-up.¹

Pavel Strnad, MD, of RWTH Aachen University Hospital, presented the pooled data from AROAAT-2001 (SEQUOIA; NCT03945292) and AROAAT-2002 (NCT03946449).¹ The findings build on SEQUOIA results in which the investigational small interfering RNA (siRNA) therapy reduced serum and liver Z-AAT concentrations and improved hepatic globule burden.² No pharmacologic therapy is approved for AATD-LD.

How Did Fazirsiran Affect Z-AAT Burden and Liver Enzymes?

The pooled analysis included 56 patients (median age, 56 years; 57% male), of whom 38 entered the open-label extension (OLE). In AROAAT-2001, patients received placebo or fazirsiran 25, 100, or 200 mg, while AROAAT-2002 evaluated fazirsiran 100 or 200 mg. Dosing occurred on Day 1, at Week 4, and every 12 weeks through Week 48, with liver biopsies at Weeks 24 (AROAAT-2002 only), 48, 72, and/or 96.¹

At the end of the primary study phase, fazirsiran 200 mg (n = 19) produced a median 89.6% reduction in intrahepatic Z-AAT (IQR, −94.5% to −79.7%), compared with a median 25.5% increase with placebo (n = 9; IQR, −35.4% to 93.2%; P < .001).¹ Median serum Z-AAT declined by 92.3% with fazirsiran vs 6.9% with placebo (P < .001), and the periodic acid-Schiff with diastase (PAS-D) composite score fell by a median of 5.0 points vs no change (P < .001).¹

Fazirsiran 200 mg also reduced alanine aminotransferase (median, −35.6% vs 12.0%; P = .023), aspartate aminotransferase (−19.2% vs 10.5%; P = .008), and gamma-glutamyl transferase (−33.3% vs 8.0%; P = .003) compared with placebo. Higher doses produced numerically, but not significantly, greater reductions in PAS-D score and intrahepatic Z-AAT than the 25 mg and 100 mg doses.¹

How Did Fazirsiran Affect Fibrosis, Lung Function, and Safety?

Portal inflammation scores favored fazirsiran 200 mg over placebo (P = .003). Median METAVIR fibrosis score declined by 1.0 point with fazirsiran compared with no change with placebo, and FibroScan liver stiffness decreased by a median 1.5 kPa versus an increase of 0.3 kPa, though neither difference was statistically significant (P = .74 and P = .11, respectively).¹

In the OLE, switching to fazirsiran 200 mg reduced geometric mean serum Z-AAT from OLE baseline to Week 24 by 86% among patients previously on placebo, 54% among those on 25 mg, and 40% among those on 100 mg (all nominal P < .05).¹ Patients maintained on 200 mg had continuous reductions in serum Z-AAT through approximately Week 60, followed by a plateau through Week 140.

Liver enzymes broadly declined toward normal ranges, and pulmonary function, assessed by FEV1, FVC, and DLCO, remained stable across all doses in both study phases.¹ During the OLE, 34 patients (90%) reported treatment-emergent adverse events, most of which were mild or moderate and unrelated to study drug. The authors reported no safety signals.¹

These results align with earlier OLE findings presented at The Liver Meeting 2024 by Virginia Clark, MD, a coauthor of the current analysis. In an interview with HCPLive at the time, Clark said the results “really support further development of this drug for treatment of alpha-1.”³

A phase 3 trial evaluating fazirsiran 200 mg in AATD-LD is ongoing.¹

References

1. Strnad P, Clark V, Wan YW, et al. Efficacy and safety of fazirsiran treatment in alpha-1 antitrypsin deficiency-associated liver disease: pooled analyses from two phase 2 clinical trials. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

2. Brooks A. SEQUOIA: fazirsiran reduces serum, liver Z-AAT concentrations, improves hepatic globule burden. HCPLive. Published July 10, 2024. Accessed November 6, 2026. https://www.hcplive.com/view/sequoia-fazirsiran-reduces-serum-liver-z-aat-concentrations-improves-hepatic-globule-burden

3. Clark V. Virginia Clark, MD: understanding fazirsiran’s potential in AATD liver disease. HCPLive. Published December 17, 2024. Accessed November 6, 2026. https://www.hcplive.com/view/virginia-clark-md-understanding-fazirsiran-potential-aatd-liver-disease