Virginia Clark, MD: Understanding Fazirsiran’s Potential in AATD Liver Disease

New data from the open-label extension of the phase 2b SEQUOIA study of fazirsiran support the investigational small interfering RNA therapy’s long-term safety and efficacy in patients with alpha-1 antitrypsin deficiency (AATD)-associated liver disease.

Findings were presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD) in San Diego, California, by Virginia Clark, MD, a professor of medicine and program director of the gastroenterology fellowship in the division of gastroenterology, hepatology, and nutrition at the University of Florida.

In an interview with HCPLive, Clark described AATD as being frequently overlooked and underdiagnosed, explaining the importance of establishing the presence of fibrosis and cirrhosis to determine the next steps in disease management.

In the absence of an approved therapeutic option for the treatment of AATD-associated liver disease, transplantation is the only choice for patients who develop more severe complications. For patients with stage 2 or 3 fibrosis who fall in the “gray zone” and are at high risk of progression, Clark pointed to the promise of investigational agents in clinical trials.

“These new therapeutic agents may have the potential to reduce the toxic burden of the alpha-1 within the liver, and that may change the trajectory of what their disease does over time,” she explained.

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.

The SEQUOIA trial enrolled 40 adults with Pi*ZZ AATD who were randomly assigned to receive fazirsiran at doses of 25 mg, 100 mg, or 200 mg, or placebo for ≤ 148 weeks. One-year findings showed treatment with fazisiran resulted in sustained, dose-dependent reductions in Z-AAT concentration and improved histological findings, including periodic acid-Schiff staining with diastase digestion (PAS+D) globule burden, a hallmark of AATD-associated liver disease.

Patients with fibrosis at screening and a post-dose liver biopsy at week 48, 72, and 96 entered the open-label extension and received fazirsiran 200 mg every 12 weeks for a total treatment period of ≤ 197 weeks. In total, 23 patients received ≥1 dose of fazirsiran during the open-label extension, 14 of whom received fazirsiran (FAZ–FAZ cohort) and 9 of whom received placebo (PBO–FAZ cohort) during the double-blind study phase.

“No real pulmonary complications were seen over placebo and the pulmonary function tests were stable, so that is very encouraging in the short-term,” Clark explained.

In addition to stable mean percent predicted pulmonary function in both cohorts and improved mean laboratory measures in the PBO–FAZ cohort, results showed serum Z-AAT levels reduced by a mean of 36.3% (Standard deviation [SD], 34.1) for the FAZ–FAZ cohort and 85.5% (SD, 13.1) for the PBO–FAZ cohort. Among the 20 patients who reported a treatment-emergent adverse event in the open-label extension, most were mild or moderate and 1 led to study withdrawal.

“The findings were very consistent with what we'd already seen in the first 2 studies, which was decreased liver tests and stain reduction in how much alpha-1 could be measured within the serum,” Clark said. “Overall, the results were very promising, quite consistent, and really support further development of this drug for treatment of alpha-1.”

Editors’ note: Clark has relevant disclosures with Vertex, Takeda, and Novo Nordisk.

References

1. Clark V, Strange C, Strnad P, et al. Long-term safety and efficacy of fazirsiran in patients with alpha-1 antitrypsin deficiency-associated liver disease enrolled in the phase 2 placebo-controlled SEQUOIA trial. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.
2. Brooks, A. SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden. HCPLive. July 10, 2024. Accessed December 17, 2024. https://www.hcplive.com/view/sequoia-fazirsiran-reduces-serum-liver-z-aat-concentrations-improves-hepatic-globule-burden