Pavel Strnad, MD: Fazirsiran’s Potential in AATD-Associated Liver Disease

Phase 2b data suggest fazirsiran may be on its way to becoming the first pharmacologic treatment for alpha-1 antitrypsin deficiency (AATD)-related liver disease, highlighting its impact on serum and liver concentrations of mutant misfolded Z alpha-1 antitrypsin (Z-AAT) as well as histological measures of liver disease.¹

Results from the ongoing randomized, placebo-controlled, phase 2 SEQUOIA study highlight sustained, dose-dependent reductions in Z-AAT concentration and improved histological findings, including periodic acid-Schiff staining with diastase digestion globule burden, with fazirsiran, building upon previous clinical trial data to reinforce the hepatocyte-targeted investigational RNA interference therapeutic’s potential in AATD.¹

“For liver disease, there is really nothing. We have a lung-related treatment, which is augmentation therapy, but for the liver, it’s purely supportive,” Pavel Strnad, MD, full professor and senior physician at University Hospital Rheinisch–Westfälisch Technische Hochschule Aachen in Germany, said to HCPLive, explaining current approaches to liver disease care with weight loss, patient awareness of liver-damaging drugs, monitoring alcohol consumption, and, in severe cases, liver transplantation.

“The very first published fazernan data were about 2 years ago, which showed what you would expect,” Strnad said. “If you block the production of the alpha-1 antitrypsin, the accumulation of alpha-2 antitrypsin in the liver goes down, and these [data] were really what made a big splash.”

However, Strnad acknowledged weaknesses of the study, including its open-label design, the lack of a placebo comparator, the small sample size, and the inclusion of 2 relatively high and efficient fazirsiran doses.² SEQUOIA sought to address these shortcomings to confirm and expand upon the understanding of fazirsiran’s potential in AATD-associated liver disease. Specifically, Strnad cited the inclusion of a placebo arm and 3 different fazirsiran doses, noting how these aspects of the study informed the drug’s safety and dose-dependent responses with fazirsiran.

“Obviously, the big remaining questions need to be answered in phase 3, which will be an even bigger trial and the treatment will go for a longer time,” Strnad said. “As time goes on, we will know more and more about this compound, but basically, things look good. I would say things look great, but obviously there is still some way to go.”

Editors' note: Strnad has relevant disclosures with Arrowhead Pharmaceuticals, Takeda, Grifols, and others.

References

1. ^{Brooks, A. SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden. HCPLive. July 10, 2024. Accessed August 5, 2024. https://www.hcplive.com/view/sequoia-fazirsiran-reduces-serum-liver-z-aat-concentrations-improves-hepatic-globule-burden}
2. ^{Strnad P, Mandorfer M, Choudhury G, et al. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. N Engl J Med. doi:10.1056/NEJMoa2205416}