Pavel Strnad, MD: Exploring Circulating Z-Polymer as a Biomarker in AATD Liver Disease

In the absence of biomarkers specific to alpha-1 antitrypsin deficiency (AATD)-associated liver disease, underdiagnosis and misdiagnosis are common, especially among adults with the PiZZ genotype.¹

However, recent research suggests circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) levels may have prognostic value as a biomarker of clinically relevant disease, potentially offering a noninvasive indicator of risk of AATD-related liver disease. While previous research has shown elevated circulating Z-polymer levels among adults with the PiZZ genotype are associated with increased liver fibrosis on biopsy, this study is the first to demonstrate its link to long-term clinically relevant adverse outcomes.¹

“If you have a condition that you have your whole life, and often you meet people when they are, for example, in their 20s, and you need to somehow follow up with them for the next 50, 60, or 70 years, you need noninvasive biomarkers,” Pavel Strnad, MD, full professor and senior physician at University Hospital Rheinisch–Westfälisch Technische Hochschule Aachen in Germany, said to HCPLive, explaining how patients with AATD generally are not open to the repeated invasive tests that are currently necessary for disease management. “Circulating Z polymer is basically the only disease-specific shot at a noninvasive biomarker that we have so far.”

Emphasizing the small sample sizes and limited longitudinal data available in previous studies, Strnad described how this new research overcomes some of these limitations to provide more concrete evidence of circulating Z polymer’s viability as a biomarker in AATD liver disease.

“The major finding is that Z polymers do somehow correlate with the extent of liver disease and also with adverse outcomes, so they have at least some ability to predict whether you your future will be bright or not bright,” Strnad explained. “That would be helpful, especially when we are getting potential drugs like fazirsiran, to potentially stratify patients, because we do believe that not every patient with AATD needs liver treatment, and noninvasive biomarkers can help us with that.”

Although there is currently no US Food and Drug Administration-approved pharmacologic treatment for AATD-associated liver disease, fazirsiran may be on its way to becoming the first. Recently published 1-year findings from the phase 2b SEQUOIA trial demonstrate its impact on serum and liver concentrations of mutant misfolded Z-AAT as well as histological measures of liver disease in adult patients with the PiZZ genotype of AATD and liver fibrosis.²

Despite these findings suggesting the potential prognostic value of circulating Z-polymer, Strnad was careful to emphasize the need for future research, ideally with larger cohorts and longer follow-ups, to confirm and build upon the results from this study.

“We are kind of still at the beginning of this road, so maybe in 5 years we will know a little bit more about the usefulness of these biomarkers,” he concluded.

References

1. ^{Brooks, A. Circulating Z-Polymer Levels Show Potential as Prognostic Biomarker in AATD. HCPLive. July 30, 2024. Accessed August 14, 2024. https://www.hcplive.com/view/circulating-z-polymer-levels-potential-prognostic-biomarker-aatd}
2. ^{Brooks, A. SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden. HCPLive. July 10, 2024. Accessed August 14, 2024. https://www.hcplive.com/view/sequoia-fazirsiran-reduces-serum-liver-z-aat-concentrations-improves-hepatic-globule-burden}