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Improving AATD care with early diagnosis and management

CE / CME

Improving AATD Care Through Early Diagnosis and Multidisciplinary Management: A Call to Action

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners/Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: June 12, 2025

Expiration: June 11, 2026

Rohit Loomba
Rohit Loomba, MD, MHSc
CME/CE Information

Activity

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Current Management Strategies

Current AATD management strategies include lifestyle modifications. For example, smoking accelerates lung disease so patients should be directed to stop smoking. Obesity and alcohol promote liver fibrosis, so maintaining a healthy body weight and avoiding alcohol is recommended.

As previously mentioned, augmentation therapy is indicated for specific patients with AATD-related lung disease. Several vaccinations can be considered in terms of preventing lung infection and liver disease (hepatitis A and hepatitis B viruses).14

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Which of the following statements regarding the current evidence for fazirsiran is most accurate?

Clinical Trial Landscape for AATD-LD

In the clinical trial landscape for AATD-related liver disease, we have some gene editing approaches that are currently in play. NTLA-2003 uses CRISPR technology (no longer in development) and BEAM-302 uses adenine base editing. There are RNA interference and editing small interfering RNA (siRNA) therapies like fazirsiran in development. In addition, RNA editing with WVE-006 and KRRO-110 is being studied. Then there are fold correctors, such as BMN 349. So there is a lot of activity in new drug development across a spectrum of genetic platforms, folding correctors, and small molecules.41

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siRNA Approach: Pi*Z Is a Liver Toxin

This slide illustrates how the Pi*ZZ genotype is associated with transcription and the development of the mutant Z-AAT protein. Accumulation of this Z-AAT protein in lysosome leads to endoplasmic reticulum stress and hepatocyte injury. This then leads to increased risk for hepatic fibrosis and the activation of hepatic stellate cells. The mutant Z protein is not able to be secreted, so it is retained inside the hepatocyte. Reduced levels of serum Z-AAT protein can help diagnose AATD.

When using an siRNA like fazirsiran, the transcription of the Pi*ZZ gene is blocked, leading to the reduced formation of the mutant Z-AAT protein. It is not formed because that gene is silenced, and the protein that exists in the liver can degrade gradually, improving liver disease homeostasis over time because there is less Z protein accumulation.42

The hypothesis with fazirsiran is that it will lead to liver disease improvement, which is being tested now in a phase III study.43

Click below to listen to Dr. Loomba’s comments on this topic.

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AROAAT-2002: Fazirsiran for Patient With AATD-LD

This slide shows data from the open-label, phase II AROAAT-2002 trial that studied fazirsiran in patients with AATD-related liver disease. Sixteen patients were evaluated across 3 cohorts, and biopsy samples were collected after 24 and 48 weeks.

This study found that patients’ mean Z-AAT protein levels in the liver decreased with fazirsiran treatment from baseline to posttreatment. There was a pretty significant reduction when comparing baseline levels with posttreatment levels. There was an absolute 47.9 nmol/g reduction with a relative delta change of 83. This is a significant reduction in Z-AAT, which later led to improvements in histology, liver enzymes, and fibrosis.44

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SEQUOIA (AROAAT-2001): Safety

Note that when considering fazirsiran safety data the phase II SEQUOIA trial was conducted during the COVID-19 pandemic and looked at fazirsiran vs placebo. You can see that adverse events (AEs) were higher for COVID-19 infection and headache, among others. Some of the other AEs were similar across both the placebo and fazirsiran arms. Overall, fazirsiran was well tolerated.45

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SEQUOIA (AROAAT-2001): Safety (cont’d)

Treatment-related AEs in the SEQUOIA trial are listed here. There were 5 reported serious AEs: 2 patients in the fazirsiran 200 mg arm and 3 patients in the placebo arm. The 2 serious AEs in the fazirsiran 200 mg arm comprised 2 patients receiving AATD augmentation therapy with pre-existing pulmonary disease who had infective exacerbations of bronchiectasis. The 3 serious AEs in the placebo arm included 1 patient with influenza, acute pancreatitis, and staphylococcal wound infection; 1 patient receiving AATD augmentation therapy had hypertensive crisis and decreased pulmonary function test; and 1 patient with presyncope. No AEs resulted in discontinuation, dose interruption, study withdrawal, or death.45

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OLE Fazirsiran: Long-term Efficacy and Safety in AATD-LD

There is an open-label extension study for fazirsiran, which is a multicenter phase III trial. Adults with AATD-related liver disease and prior participation in AROAAT-2001/2002 studies who met specific requirements were nonsmokers and did not have HCC or other chronic liver diseases. They started on fazirsiran 200 mg subcutaneously administered every 12 weeks and will continue treatment until regulatory approval and commercial availability, withdrawal, or study termination.

The primary endpoints are safety, pulmonary function, vitals, and labs. Key secondary endpoints include progression of fibrosis, Z-AAT protein polymer burden, inflammation, and liver stiffness (NCT05899673).

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Investigational Therapies

There are other investigational therapies. Autophagy enhancements with investigational agents (carbamazepine and rapamycin) may improve misfolded AAT degradation and fibrosis in mouse models, but carbamazepine’s phase II trial was terminated in 2017. Chaperone molecules like kifunensine (a mannosidase I/II inhibitor) and castanospermine (a glucosidase inhibitor) may stabilize the folding and/or secretion of AAT. Then histone deacetylase inhibitors like 4-phenylbutyric acid 4-PBA and suberoylanilide hydroxamic acid were found to increase AAT secretion, but 4-phenylbutyric acid was determined to be ineffective in a previous clinical trial.

Monoclonal antibodies are also a potential agent type since monoclonal antibodies of 4B12 block AAT polymer formation without compromising their inhibitory activity. And potential possibilities in future gene therapy are being evaluated. Pluripotent stem cells with corrected Z allele mutations both in vitro and in vivo have been created using CRISPR/Cas9 technology, but there is a risk of off-target mutagenesis (NCT01379496).13,46,47 Again, this could be more developed, and the most important thing would be to document the safety of these approaches before looking into their efficacy.

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Key Takeaways

AATD is caused by deficiency in the AAT protein, leading to liver damage because of protein accumulation and lung damage related to low AAT levels. Timely recognition and testing are crucial for effective AATD management. Fazirsiran shows promise as a specific treatment for AATD-related liver disease, and additional studies are needed before its clinical use and FDA assessment. Furthermore, multiple therapies are undergoing investigation for treating AATD and may receive FDA approval in the future.

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