The investigational therapy ARO-AAT (TAK999) is able to reduce serum and liver levels of poorly secreted alpha-1 antitrypsin protein (Z-AAT) in patients with alpha-1 antitrypsin deficiency (AATD), according to interim data from the AROAAT2002 phase 2 clinical trial (NCT03946449).

The results were presented as a late-breaking poster at The Liver Meeting 2021, hosted by the American Association for the Study of Liver Diseases (AASLD). They showed that treatment improved liver fibrosis and biomarkers of liver health and reduced globule burden.

“These data demonstrate that removal of the causative factor, Z-AAT, in AATD liver disease ameliorates liver injury, and can lead to an improvement in fibrosis,” the authors said.

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ARO-AAT, a second-generation RNA interference therapy being codeveloped by Arrowhead Pharmaceuticals and Takeda Pharmaceutical Company, is believed to silence liver Z-AAT mRNA to reduce Z-AAT protein synthesis. At 24 or 48 weeks after treatment initiation, patients showed a 72% to 100% decrease in total liver levels of Z-AAT, as well as a 79% to 99% reduction in soluble Z-AAT.

Of the 14 patients analyzed from the interim data, 6 had a 1 point or greater improvement in liver fibrosis (all of whom received 200 mg doses) while 6 had no change from baseline (3 of whom received only 100 mg doses) as measured by the METAVIR score. Two patients did have worsening scores, increasing from F2 at baseline to F3 at week 48 of the study.

All patients showed a decrease in PAS+D total globule burden with a mean score at baseline of 7.3 compared to 2.5 at their last observation (week 24 or 48). Alanine transaminase (ALT) and gamma-glutamyl transferase (GGT) levels also decreased to normalized levels following treatment. ALT reduced by 42% to 56% from baseline while GGT reduced between 33% and 54% from baseline.

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No treatment-emergent adverse events related to pulmonary status or function were reported, and none lead to changes in drug dose, discontinuation, or withdrawal from the study. Four serious adverse events were reported, including Epstein-Barr virus-related myocarditis, diverticulitis, dyspnea, and vestibular neuronitis, but these were deemed to be related to confounding factors or alternative etiology.

The AROAAT2002 study recruited a total of 16 patients with AATD and divided them into 3 cohorts. The first cohort of 4 patients (Group 1) received 200 mg of ARO-AAT while the second cohort of 4 patients (Group 1b) received only 100 mg. The third cohort (Group 2) also received 200 mg. All patients received doses subcutaneously at weeks 1, 4, and then every 12 weeks.

Biopsies were collected at baseline and at postbaseline timepoints of week 24 for Groups 1/1b and week 48 for Group 2. Biopsies were not collected from 2 patients and they were excluded from the analysis.


Arrowhead presents additional clinical data on investigational ARO-AAT treatment at AASLD Liver Meeting. News Release. Arrowhead Pharmaceuticals; November 12, 2021.

Strnad, P, Mandorfer M, Choudhury G, et al. ARO-AAT treatment reduces intra-hepatic Z-AAT leading to improved parameters of liver health and fibrosis regression. Presented at: The Liver Meeting 2021: November 12-15, 2021; Virtual.