Arrowhead Presents Updated Data from Phase 2 SEQUOIA Study of Investigational RNAi Therapy Fazirsiran in Patients with Alpha-1 Antitrypsin Deficiency Liver Disease

- Data Presented During Oral Session at EASL 2023 Demonstrate Fazirsiran’s Promising Impact on Key Markers of Liver Disease

- AATD-LD is a Rare Genetic Disease Affecting Children and Adults with no Approved Treatments

- Takeda and Arrowhead are Advancing Fazirsiran and Actively Enrolling in 160 patient Phase 3 REDWOOD Study

Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today presented updated results from the Phase 2 SEQUOIA clinical study of investigational fazirsiran (TAK-999/ARO-AAT) for the treatment of liver disease associated with alpha-1 antitrypsin deficiency (AATD-LD). The SEQUOIA Phase 2 data are consistent with the promising results from an open-label Phase 2 trial of fazirsiran (AROAAT2002) that were published in The New England Journal of Medicine. Takeda (TSE:4502/NYSE:TAK) and Arrowhead are further investigating fazirsiran in the ongoing pivotal Phase 3 REDWOOD clinical study which is actively recruiting a total of 160 patients.

The updated Phase 2 clinical data were presented at the European Association for the Study of the Liver (EASL) Congress 2023 in an oral presentation titled, “Fazirsiran reduces liver Z-alpha-1 antitrypsin synthesis, decreases globule burden and improves histological measures of liver disease in adults with alpha-1 antitrypsin deficiency: a randomized placebo-controlled phase 2 study,” which may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.

“The clinical results from the Phase 2 SEQUOIA study of fazirsiran were clear and compelling. Fazirsiran treatment demonstrated a substantial effect on several key markers of liver disease,” said Javier San Martin, M.D., chief medical officer at Arrowhead. “Together with our partners at Takeda, we are now conducting the Phase 3 REDWOOD study to further investigate fazirsiran’s potential in patients with AATD-LD and F2 to F4 liver fibrosis.”

Key findings from the SEQUOIA study include the following:

• Fazirsiran reduced serum Z-AAT concentration in a dose-dependent manner
  • At week 48, patients receiving 25, 100, or 200 mg fazirsiran (n=16) achieved serum Z-AAT reductions of 74%, 89%, and 94%, respectively, versus an increase of 9% observed in patients receiving placebo (n=9)
• Fazirsiran significantly reduced liver Z-AAT
  • Patients receiving 200 mg fazirsiran achieved a least-squares mean percentage difference (95% CI) versus placebo at post-dose biopsy of -141% (p = 0.0004)
• Fazirsiran consistently reduced hepatic globule burden
  • 100% of patients in the pooled fazirsiran treatment group achieved at least a 1-point improvement in PASD-positive globule burden
• Fazirsiran treatment reduced histological signs of hepatic inflammation
  • 42% of patients in the pooled fazirsiran treatment group achieved at least a 1-point improvement in portal inflammation versus 0% in the placebo group
  • 67% of patients in the pooled fazirsiran treatment group achieved at least a 1-point improvement in interface hepatitis versus 0% in the placebo group
• 50% of the pooled fazirsiran treated patients showed at least a 1-point improvement in METAVIR liver fibrosis versus 38% in the placebo group
• Fazirsiran has been well tolerated to date
  • No treatment-emergent adverse events related to study drug causing discontinuation, dose interruptions or premature study withdrawals
  • Treatment emergent adverse events reported to date generally well balanced between fazirsiran and placebo groups
• Pulmonary function test results (FEV1 and DLCO) for both fazirsiran and placebo were stable over time with no apparent dose-dependent effects

About Fazirsiran

Fazirsiran (TAK-999/ARO-AAT) 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.

About the Phase 3 REDWOOD Clinical Trial

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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