Pavel Strnad, MD: Noninvasive Testing, Candidate Biomarkers in AATD-Associated Liver Disease

Research presented at the European Association for the Study of the Liver (EASL) Congress in Milan, Italy, is calling attention to the benefits of noninvasive testing and biomarkers for the diagnosis and monitoring of alpha-1 antitrypsin deficiency (AATD)-associated liver disease.

A pair of poster presentations leveraged data from 2 phase 2 clinical trials for fazirsiran to determine the correlations of noninvasive tests with liver disease burden in patients with AATD-LD and identify biomarkers relevant for therapeutic targeting.^1,2

Currently, no pharmacologic treatments for AATD-LD exist. An ​​investigational RNA interference therapy, fazirsiran is undergoing phase 3 development for AATD-LD. It is designed to reduce the production of mutant alpha-1 antitrypsin protein (Z-AAT) and subsequently halt the progression of liver disease, allowing the liver to regenerate and repair. Fazirsiran was granted Orphan Drug Designation in February 2018 and Breakthrough Therapy Designation in July 2021.³

Regarding the diagnosis and monitoring of AATD-LD, Pavel Strnad, MD, full professor and senior physician at University Hospital Rheinisch–Westfälisch Technische Hochschule Aachen in Germany, pointed to inherent issues with the underrecognition of AATD due to the fact that it is a rare disease. Indeed, according to the National Organization for Rare Diseases, approximately 100,000 Americans are believed to have AATD, but estimates indicate 10% or fewer of these individuals with severe deficiency of alpha-1 antitrypsin have been diagnosed.⁴

Strnad also called attention to issues with the current reliance on liver biopsy for assessing fibrosis in patients with AATD-LD, pointing out that although it is widely considered the “gold standard” for assessing key prognostic features of liver disease, it is often painful and not entirely accurate.

“Usually, you can convince a person to do 1 liver biopsy, but you cannot convince anybody to do a liver biopsy every 5 years,” he explained to HCPLive, citing transient elastography, blood tests, and serum-based tests as promising alternatives. “Liver biopsy is really out of the question for long-term monitoring.”

Apart from assessing fibrosis, Strnad explained the importance of understanding the process of alpha-1 antitrypsin accumulation in the liver and whether any of the currently used noninvasive features can measure this process. Ultimately, he and a team of researchers determined this was the case, finding that markers known in other disorders also apply to AATD.

Specifically, he described the utility of serum levels of the mutated alpha-1 antitrypsin as a surrogate for activity in the liver, saying “This is a new piece of information made possible by the recent developments where we are now able to measure the mutated protein, which is important because some of these patients actually receive an augmentation therapy which means an addition of human purified alpha-1 antitrypsin. This makes it important to recognize the endogenous protein from the added protein.”

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

References:

1. ^{Chuang JC, Hou R, Hong F, et al. Correlation of non-invasive tests with histological features and intrahepatic Z-alpha-1 antitrypsin burden in patients with alpha-1 antitrypsin deficiency-associated liver disease. Abstract presented at European Association for the Study of the Liver Congress 2024. Milan, Italy. June 5 - 8, 2024.}
2. ^{Chuang JC, Hou R, Hong F, et al. Proteomic analysis identified fazirsiran treatment-responsive protein biomarkers in patients with alpha-1 antitrypsin deficiency-associated liver disease. Abstract presented at European Association for the Study of the Liver Congress 2024. Milan, Italy. June 5 - 8, 2024.}
3. ^{Takeda. Arrowhead and Takeda Announce Topline Results from SEQUOIA Phase 2 Study of Fazirsiran in Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease. Newsroom. January 9, 2023. Accessed June 10, 2024. https://www.takeda.com/newsroom/newsreleases/2023/arrowhead-and-takeda-announce-topline-results-from-sequoia-phase-2-study-of-fazirsiran-in-patients-with-alpha-1-antitrypsin-deficiency-associated-liver-disease/}
4. ^{NORD. Alpha-1 antitrypsin deficiency - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. March 22, 2024. Accessed June 10, 2024. https://rarediseases.org/rare-diseases/alpha-1-antitrypsin-deficiency/#complete-report.}