First Patient Treated in Alpha-1 Antitrypsin Deficiency Liver Disease Phase 3 Study Triggering $40 Million Milestone Payment from Takeda to Arrowhead

Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced that the first patient has been dosed in Takeda’s (TSE:4502/NYSE:TAK) Phase 3 REDWOOD clinical study of fazirsiran (TAK-999/ARO-AAT) for the treatment of alpha-1 antitrypsin deficiency associated liver disease (AATD-LD). The start of this pivotal study triggers a $40 million milestone payment from Takeda to Arrowhead.

Fazirsiran is an investigational RNA interference (RNAi) therapy designed to reduce the production of mutant alpha-1 antitrypsin protein (Z-AAT) as the first potential treatment for AATD-LD, a rare genetic disease. Z-AAT accumulation is believed to be the cause of progressive liver disease in patients with alpha-1 antitrypsin deficiency (AATD). Reducing production of the mutant Z-AAT protein is expected to halt the progression of liver disease and potentially allow the liver to regenerate and repair. Fazirsiran was granted Breakthrough Therapy Designation in July 2021 and Orphan Drug Designation in February 2018 for the treatment of AATD-LD from the U.S. Food and Drug Administration.

The REDWOOD (TAK-999-3001) clinical study (NCT05677971) is a randomized, double-blind, placebo-controlled, Phase 3 trial to evaluate the efficacy and safety of fazirsiran in the treatment of AATD-LD. Approximately 160 adult patients with METAVIR stage F2 to F4 fibrosis will be randomized 1:1 to receive fazirsiran or placebo. The primary endpoint of the study is a decrease from baseline of at least 1 stage of histologic fibrosis METAVIR staging in the centrally read liver biopsy done at Week 106 in patients with METAVIR stage F2 and F3 fibrosis. The REDWOOD study is now recruiting across several sites in the U.S.; additional information can be found at https://theredwoodliverstudy.com/.

About Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

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 the United States and 1 per 2,500 in Europe, of which 35% may develop liver disease. 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 that may lead 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.

About Takeda and Arrowhead Collaboration and License Agreement

In October 2020, Arrowhead and Takeda announced a collaboration and licensing agreement to develop fazirsiran. Under the terms of the agreement, Arrowhead and Takeda will co-develop fazirsiran, which, if approved, will be co-commercialized in the U.S. under a 50/50 profit-sharing structure. Outside the U.S., Takeda will lead the global commercialization strategy and receive an exclusive license to commercialize fazirsiran with Arrowhead eligible to receive tiered royalties of 20-25% on net sales. Arrowhead received an upfront payment of $300 million and is eligible to receive potential development, regulatory and commercial milestones up to $740 million.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.

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Source: Arrowhead Pharmaceuticals, Inc.

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