The US Food and Drug Administration (FDA) granted the second-generation investigational RNA interference (RNAi) therapeutic ARO-AAT (TAK-999) Breakthrough Therapy designation for the treatment of liver disease associated with alpha-1 antitrypsin deficiency (AATD).

The therapy being developed by Arrowhead Pharmaceuticals and Takeda Pharmaceuticals aims to knock down the production of faulty alpha-1 antitrypsin (AAT) protein in liver cells, which causes progressive liver disease. There is currently no treatment available for AATD apart from a liver transplant. 

“Being granted Breakthrough Therapy designation from the FDA is an important milestone for the investigational ARO-AAT program,” said Javier San Martin, MD, chief medical officer at Arrowhead, in a press release. “We intend to utilize the benefits that [the designation] provides, including enhanced access to and guidance from senior management and experienced review staff at the FDA, to expedite the development of ARO-AAT,” he added, saying he hopes to bring the treatment to patients rapidly.

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The potential treatment is being investigated in 2 phase 2 clinical trials in patients with AATD. Interim results presented at the 2021 European Association for the Study of the Liver (EASL) International Liver Congress suggest ARO-AAT may be able to reduce the production of the toxic AAT protein in patients, leading to important signs of healing liver disease.

AATD is a rare genetic disease estimated to affect between 1 in 3000 and 1 in 5000 people in the US and 1 in 2500 people in Europe.

Breakthrough Therapy designation is intended to expedite the development and review of treatments for serious or life-threatening conditions. To receive the designation, a treatment must have shown preliminary clinical evidence of substantial improvement on at least a single clinically significant endpoint over available therapies, if applicable.


Arrowhead Pharmaceuticals receives Breakthrough Therapy designation from US FDA for ARO-AAT for the treatment of alpha-1 antitrypsin deficiency associated liver disease. News release. Arrowhead Pharmaceuticals; July 29, 2021.

Safety, tolerability and pharmacodynamic effect of ARO-AAT (SEQUOIA). US National Library of Medicine. Last updated July 20, 2021. Accessed July 30, 2021.

Study of ARO-AAT in patients with alpha-1 antitrypsin deficiency associated liver disease (AATD). US National Library of Medicine. Last Updated April 1, 2021. Accessed July 30, 2021.