Fazirsiran and Screening for AATD Liver Disease, With Pavel Strnad, MD

Fazirsiran 200 mg reduced intrahepatic Z-AAT by approximately 90% and improved liver enzymes and portal inflammation 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 2026.¹

Pavel Strnad, MD, of University Hospital RWTH Aachen, presented the data and discussed them in an interview with HCPLive. He noted the individual phase 2 trials of the small interfering RNA (siRNA) therapy were small, and pooling them made the treatment effect clearer.

How Did Fazirsiran Affect Z-AAT Burden and Portal Inflammation?

The pooled analysis included 56 adults (median age, 56 years; 57% male) from AROAAT-2001 (NCT03945292) and AROAAT-2002 (NCT03946449), of whom 38 entered the OLE.¹ Patients received placebo or fazirsiran 25, 100, or 200 mg on Day 1, at Week 4, and every 12 weeks through Week 48, followed by fazirsiran in the OLE through up to 196 weeks.¹

At the end of the primary phase, fazirsiran 200 mg (n = 19) reduced median intrahepatic Z-AAT by 89.6% vs a 25.5% increase with placebo (n = 9; P < .001) and serum Z-AAT by 92.3% vs 6.9% (P < .001).¹ Fazirsiran also lowered alanine aminotransferase (−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), and portal inflammation scores favored fazirsiran (P = .003).¹

Strnad highlighted the inflammation finding as especially relevant to AATD-LD.

“The alpha-1 antitrypsin liver disease is actually particularly strong in the portal area. So seeing a decrease in inflammation is particularly meaningful for this disease,” Strnad said.

Changes in METAVIR fibrosis score (−1.0 vs 0.0; P = .74) and FibroScan liver stiffness (−1.5 vs 0.3 kPa; P = .11) favored fazirsiran but were not statistically significant.¹ In the OLE, patients maintained on 200 mg had sustained serum Z-AAT reductions through approximately Week 60, followed by a plateau through Week 140. During the OLE, 34 patients (90%) reported treatment-emergent adverse events, most mild or moderate and unrelated to study drug.¹

Why Does Screening for AATD Liver Disease Matter Now?

Strnad pointed to recent multisociety consensus guidance published in Gastroenterology, which he coauthored, defining AATD-LD and establishing a framework for diagnosis, staging, and clinical trial endpoints.² The guidance identifies liver stiffness of 8 kPa or higher by vibration-controlled transient elastography as a threshold for clinically significant fibrosis and endorses a 1-stage or greater improvement in fibrosis as the consensus primary efficacy endpoint for trials.²

AATD-LD has no distinguishing clinical features, Strnad said, making broad screening essential as treatment options emerge.

“You have to screen everybody, and of course even more so if you have family history of disease, because it’s an inherited disease,” he said.

Strnad cautioned clinicians to expect a long road ahead, noting the ongoing phase 3 trial of fazirsiran 200 mg is designed for 2 to 4 years, with an interim analysis at 2 years. He described fazirsiran as the most advanced siRNA in development for a liver disease, with safety data from patients with advanced liver disease, and said its progress may also inform the broader use of siRNA therapies in this population.

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. Loomba R, Clark VC, Mandorfer M, et al. Multi-society expert panel consensus guidance regarding clinical assessment and clinical trial endpoints in adults with alpha-1 antitrypsin deficiency-associated liver disease. Gastroenterology. 2026;170(4):829-842. doi:10.1053/j.gastro.2025.12.012