Arrowhead Presents Additional Clinical Data on Investigational ARO-AAT Treatment in Patients with Alpha-1 Liver Disease at EASL International Liver Congress
The results demonstrate that, in the AROAAT2002 study, investigational ARO-AAT treatment led to improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT protein (Z-AAT). In addition, ARO-AAT treatment was generally well tolerated after up to 1 year of treatment.
Pharmacodynamics and Efficacy
After 24 weeks (cohort 1, n=4) and 48 weeks (cohort 2, n=5) of treatment with investigational ARO-AAT in the AROAAT2002 study, the following results were observed:
- Serum Z-AAT levels decreased in all patients
Median decrease in intra-hepatic Z-AAT levels were:
- Total Z-AAT -80.1% (range -72 to -97%)
- Monomer -90% (range -79 to -97%)
Polymer -81% (range* -42 to -97%)
- *Excluding 1 subject in cohort 1 that had very low Z-AAT polymer levels at baseline that increased at week 24
- Histological globule burden was reduced in all nine patients, with two achieving full resolution (total aggregate globule burden score=0)
Six of the nine patients (2/4 after 24 weeks and 4/5 after 48 weeks) achieved a 1 or greater stage improvement in Metavir fibrosis stage, with no worsening of fibrosis in the other three patients
- Two patients had baseline F4 fibrosis (cirrhosis), with one patient achieving a two-stage improvement to F2 and the other patient achieving a one-stage improvement to F3
- Multiple biomarkers of liver health improved, including liver stiffness (FibroScan), liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), and PRO-C3, a marker of collagen formation
Safety and Tolerability
In AROAAT2002, investigational ARO-AAT demonstrated an acceptable safety profile and was generally well tolerated after up to 1 year of treatment. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or study withdrawal. Lung function was assessed throughout the study and there were no clinically meaningful changes in percent predicted forced expiratory volume in 1 second (ppFEV1). Three serious adverse events (SAEs) were reported, but none were considered related to the study drug. All SAEs were moderate in severity and all resolved.
AROAAT2002 (NCT03946449) is a pilot open-label, multi-dose, Phase 2 study to assess the response to investigational ARO-AAT in 16 patients with AATD associated liver disease and baseline liver fibrosis. All eligible participants receive a pre-dose biopsy and an end of study biopsy. Treated participants will also be offered the opportunity to continue treatment in an open-label extension (OLE). Including the OLE, interim assessments will be made after 6 months, 12 months, 18 months, and 24 months of treatment with ARO-AAT.
Title: ARO-AAT an investigational RNAi therapeutic demonstrates improvement in liver fibrosis with reduction in intra-hepatic Z-AAT burden
Type: Late-Breaking Oral Presentation
Date and Time:
A copy of the presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.
About Arrowhead and Takeda Collaboration
About Alpha-1 Antitrypsin-Associated Liver Disease
Alpha-1 Antitrypsin-Associated Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is estimated to affect 1 per 3,000-5,000 people in
Individuals with the homozygous PiZZ genotype have severe deficiency of functional AAT leading to pulmonary disease and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant, with its attendant morbidity and mortality, is currently the only available cure.
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