Arrowhead Pharma Moves ARO-AAT Into Phase 2/3 for Alpha-1 Liver Disease Following FDA Clearance

Apr 22, 2019 | Clinical Trials, FDA, Leading Pharma, Liver Disease, Pharma Watch, Phase 2

Arrowhead Pharmaceuticals received clearance from the U.S. FDA  to proceed with an adaptive Phase 2/3 trial of ARO-AAT, the company’s second generation subcutaneously administered RNA interference (RNAi) therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD).

The adaptive design, Phase 2/3 study of ARO-AAT in patients with AATD associated liver disease is expected to commence at various sites in the U.S. in the second quarter of 2019, followed by various international sites in Europe, pending regulatory submission and review. The proposed primary objectives are to evaluate safety and pharmacodynamic dose response, and to evaluate efficacy, defined as an improvement in a histologic grading scale of AATD associated liver disease, and no worsening of liver fibrosis based on Ishak score on end of study biopsy. The company plans to provide additional study details following its initiation. This study has the potential to serve as a pivotal registrational study.

A phase I trial of ARO-AAT was successfully completed in 45 healthy subjects. The most common adverse events were headache (22%) and rhinorrhea (13%). Single dose serum AAT mean nadir reductions from baseline of 79%, 87%, >91% and >91% were reported at 35, 100, 200 and 300 mg respectively. Multi-dose mean nadir serum AAT reductions were >91% at all dose levels with most subjects BLQ. Maximum AAT reduction across all cohorts was >94%. A greater than 90% reduction was sustained for at least 8 weeks following the last dose in the lowest multi-dose cohort (100 mg), the only cohort with data of this duration.

About alpha-1 antitrypsin deficiency (AATD)

AATD is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AAT is primarily synthesized and secreted by liver hepatocytes. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, the Z mutant, has a single amino acid substitution that results in improper folding of the protein. The mutant protein cannot be effectively secreted and accumulates in globules inside the hepatocytes. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.


ARO-AAT is designed to knock down the hepatic production of the mutant alpha-1 antitrypsin (Z-AAT) protein, the cause of progressive liver disease in AATD patients. Reducing production of the inflammatory Z-AAT protein is expected to halt the progression of liver disease and potentially allow it to regenerate and repair.