Fazirsiran and the Future of RNA Therapy in AATD Liver Disease, With Pavel Strnad, MD

RNA therapeutics have rapidly emerged as a transformative approach in modern medicine, offering the ability to selectively target disease at the genetic level. In hepatology, this precision is particularly valuable, as many RNA-based agents are naturally directed to the liver.

Among these novel therapies, fazirsiran stands out as a promising siRNA-based treatment for liver disease caused by alpha-1 antitrypsin deficiency (AATD), an area of significant unmet clinical need. A hepatocyte-targeted investigational RNA interference therapeutic, fazirsiran is designed to degrade alpha-1 antitrypsin and mutant misfolded Z alpha-1 antitrypsin (Z-AAT) messenger RNA in hepatocytes, subsequently reducing protein synthesis and inhibiting further accumulation of Z-AAT polymers to allow normal cellular mechanisms to dispose of mutant proteins.

At the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, Pavel Strnad, MD, a full professor and leading physician at the University Hospital Aachen, presented data highlighting the promise of RNA therapeutics and fazirsiran in AATD liver disease across a broad spectrum of liver injury.

Targeting the Root Cause of AATD Liver Disease

AATD is a rare inherited disorder caused by mutations in the SERPINA1 gene, which encodes the AAT protein. These mutations lead to the accumulation of misfolded AAT protein within hepatocytes, causing liver injury and fibrosis. Because the defective protein cannot be secreted into the bloodstream, patients also experience systemic complications, most notably progressive lung disease.

Although augmentation therapy is available to treat the pulmonary manifestations of AATD, there is currently a major unmet need for approved therapy for its hepatic complications. Fazirsiran, an siRNA therapeutic, aims to fill this gap by directly silencing the SERPINA1 gene to reduce production of the misfolded, hepatotoxic protein.

Efficacy in Patients With Advanced Liver Disease

“The key aim of this study and of this talk was to see whether these RNA therapeutics work equally well in patients with and without advanced liver disease,” Strnad explained to HCPLive.

He and a group of investigators used liver tissue bulk transcriptomics and single nuclei/cell (sn/sc) RNA sequencing to identify genes dynamically modulated in advanced fibrosis from 10 studies of several fibrotic liver diseases. Overall ASGR1 and SERPINA1 expression was assessed in samples from: AATD-LD with Pi*ZZ vs healthy controls with a Pi*MM genotype; PSC vs healthy controls; advanced MASH (F3/4) vs MASLD or healthy controls. ASGR1 and SERPINA1 expression in hepatocytes was evaluated using snRNAseq from patients with MASLD or MASH, and scRNAseq from other cirrhosis etiologies vs healthy controls.

Analysis of fazirsiran phase 2 studies investigated whether fazirsiran’s effects on silencing SERPINA1, reducing Z-AAT burden, improving liver function and reducing fibrosis were affected by baseline fibrosis status.

Results showed that across bulk transcriptomic datasets, SERPINA1 expression was maintained while ASGR1 expression was reduced in advanced fibrosis (F3/4). However, investigators noted sn/sc RNAseq data demonstrated that expression of both ASGR1 and SERPINA1 in hepatocytes was sustained in advanced fibrosis, even in cirrhosis.

In fazirsiran phase 2 studies, hepatic Z-AAT burden was elevated in patients with AATD liver disease and advanced fibrosis (median 62 and 33 nmol/g for F3/4 vs F0–2, respectively; Wilcoxon test, P = .09). Advanced baseline fibrosis (F3/4 [n = 23] vs F0–2 [n = 8]) did not impair fazirsiran's effects versus baseline on reducing the following measures:

• Serum Z-AAT (–89 vs –90%; P = .58)
• Hepatic Z-AAT burden (–94 vs –89%; P = .28)
• Portal inflammation (–0.5 vs 0.0; P = .86)
• Liver enzymes (ALT –54 vs –28%; P = .02; AST –32 vs –14%; P = .09; GGT –40 vs –13%; P = .03)
• Liver stiffness measured by FibroScan (–1.38 vs –1.12 kPa; P = .44).

“Fazirsiran is basically the pioneer that hopefully paves the way and shows that this whole class of siRNA therapeutics, or RNA therapeutics in general, where we have now more than 30 compounds in different clinical trials, can potentially be used even in subjects with already existing liver disease,” Strnad said. “This opens up a large amount of opportunities in future clinical trials, and shows that this emerging class really has potential in all stages of liver disease.”

Editors’ note: Strnad reports relevant disclosures with Arrowhead Pharmaceuticals, CSL Behring, Grifols Inc, Alnylam Pharmaceuticals, Takeda Pharmaceuticals, Novo Nordisk, and more.

References

1. Brooks A. Virginia Clark, MD: Understanding Fazirsiran’s Potential in AATD Liver Disease. HCPLive. December 14, 2024. Accessed November 12, 2025. https://www.hcplive.com/view/virginia-clark-md-understanding-fazirsiran-potential-aatd-liver-disease

2. Strnad P, Chuang JC, Wan YW, et al. Fazirsiran is effective in early and advanced fibrosis in patients with alpha-1 antitrypsin deficiency-associated liver disease. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.