Takeda and Arrowhead Announce $1 Billion Collaboration to Develop Potential First-in-Class RNAi Therapy ARO-AAT for Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Takeda and Arrowhead Pharmaceuticals today announced that they have entered into a research collaboration agreement to jointly develop ARO-AAT, a potential first-in-class RNAi therapy, for the treatment of alpha-1 antitrypsin deficiency-associated liver disease (AATLD). ARO-AAT is designed to reduce the production of mutant alpha-1 antitrypsin (AAT) protein, which is the root cause of disease progression in AATLD.

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults, as well as lung disease in adults. The antitrypsin (AAT) protein is primarily synthesized and secreted by hepatocytes, and its function is to inhibit enzymes that break down normal connective tissue. The most common pathogenic variant is the Z variant, which causes improper protein folding due to a single amino acid substitution. The mutant protein is not effectively secreted and accumulates as globules within hepatocytes. This leads to persistent hepatocyte injury, resulting in fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma.

Patients homozygous for the Z mutation suffer from severe deficiency of functional alpha-1 antitrypsin (AAT), leading to pulmonary and hepatic diseases. For these patients, liver transplantation remains the only available treatment, indicating a significant unmet medical need.

ARO-AAT is designed to knock out the production of mutant alpha-1 antitrypsin (Z-AAT) protein that causes progressive liver disease. Reducing the production of inflammatory Z-AAT protein is expected to halt the progression of liver disease and may allow for liver regeneration and repair.

Under the terms of the agreement, Takeda and Arrowhead will jointly develop ARO-AAT and, if approved, co-commercialize it in the United States. Outside the United States, Takeda will lead the global commercialization strategy and hold the exclusive license for the commercialization of ARO-AAT. Arrowhead will receive a $300 million upfront payment and be eligible for up to $740 million in potential development, regulatory, and commercial milestone payments.

“AAT-associated liver disease is a devastating condition for which there are currently no effective treatments. Leveraging the mechanism of action of RNA interference, ARO-AAT has the potential to address the underlying cause of AATLD, thereby helping patients avoid liver transplantation and its associated comorbidities,” said Dr. Asit Parikh, Head of Gastroenterology Therapeutic Area at Takeda. “We are pleased to collaborate with Arrowhead Pharmaceuticals to bring this exciting late-stage investigational therapy to these patients.”

References:

[1] Takeda and Arrowhead Collaborate to Co-Develop and Co-Commercialize ARO-AAT for Alpha-1 Antitrypsin-Associated Liver Disease. Retrieved October 8, 2020, from https://www.takeda.com/newsroom/newsreleases/2020/takeda-and-arrowhead-collaborate-to-co-develop-and-co-commercialize-aro-aat-foralpha-1-antitrypsin-associated-liver-disease/

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