8 October 2020 - - Japanese pharmaceutical company Takeda Pharmaceutical company Ltd. (TSX: 4502) (NYSE: TAK) and US-based Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) have forged a collaboration and licensing agreement to develop ARO-AAT, a Phase 2 investigational RNA interference therapy in development to treat alpha-1 antitrypsin-associated liver disease (AATLD), the company said.

ARO-AAT is a potential first-in-class therapy designed to reduce the production of mutant alpha-1 antitrypsin protein, the cause of AATLD progression.

Under the terms of the agreement, Takeda and Arrowhead will co-develop ARO-AAT which, if approved, will be co-commercialized in the United States under a 50/50 profit-sharing structure.

Outside the US, Takeda will lead the global commercialisation strategy and receive an exclusive license to commercialise ARO-AAT with Arrowhead eligible to receive tiered royalties of 20-25% on net sales.

Arrowhead will receive an upfront payment of USD 300m and is eligible to receive potential development, regulatory and commercial milestones up to USD 740m.

Closing of the transaction is contingent on completion of review under antitrust laws, including the Hart-Scott-Rodino Antitrust Improvements Act of 1976 in the US.

Alpha-1 Antitrypsin-Associated Deficiency 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 the United States and 1 per 2,500 in Europe.

The protein 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.

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.

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.