Interim results from a study on the investigational treatment ARO-AAT showed improvements in multiple measures of liver health, including fibrosis, with a reduction in intrahepatic Z-AAT burden. ARO-AAT is being developed as a treatment for the rare genetic liver disease linked with alpha-1 antitrypsin deficiency (AATD)

“The results represent an important breakthrough for the field and are encouraging for patients with alpha-1 liver disease, who currently have no available treatment options other than a liver transplant,” said Javier San Martin, MD, chief medical officer at Arrowhead Pharmaceuticals.

Liver biopsy results from the open-label phase 2 trial indicate treatment with ARO-AAT reduces the production of the toxic mutant Z-AAT protein, which has been a cause of progressive liver disease in patients with AATD. ARO-AAT is the first investigational therapy to give such benefits in patients with AATD, Dr. San Martin said.

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ARO-AAT is a second-generation RNA interference (RNAi) therapeutic. After 24 weeks (n=4) and 48 weeks (n=5) of treatment with it, the study found:

  • Decreased serum Z-AAT levels in all 9 participants.
  • Median intrahepatic Z-AAT levels declined 80.1%.
  • Improved histological globule burden. 
  • Six patients showed an improvement of 1 or more in their Metavir fibrosis stage, while fibrosis did not worsen in the remaining 3 patients.
  • Several biomarkers of liver health — including stiffness, enzymes alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and PRO-C3, a collagen formation marker — improved.

ARO-AAT was well tolerated over up to 1 year of treatment, according to a statement from Arrowhead Pharmaceuticals. Researchers did not find any clinically meaningful changes in percent predicted forced expiratory volume in 1 second (ppFEV1). There were no treatment-related adverse effects that led to any interruptions during the study. Three serious adverse events were reported; they were moderate in severity and were not considered related to the study drug, according to Arrowhead.

The results were part of the AROAAT2002 pilot study, being conducted to determine response to ARO-AAT in 16 patients with AATD-associated liver disease and baseline liver fibrosis. Treated patients may continue treatment in an open-label extension. Interim assessments will be made every 6 months, for up to 24 months of therapy with ARO-AAT.


Arrowhead presents additional clinical data on investigational ARO-AAT treatment in patients with alpha-1 liver disease at EASL International Liver Congress. News release. Arrowhead Pharmaceuticals; June 26, 2021.