Fazirsiran Shows Promising Results in Treating Liver Disease Associated with Alpha-1 Antitrypsin Deficiency: Arrowhead and Takeda’s SEQUOIA Phase 2 Study

Arrowhead Pharmaceuticals announced positive results from the Phase 3 clinical trial of fazirsiran for the treatment of Alpha-1 Antitrypsin Deficiency (AATD). Patients receiving fazirsiran experienced a median reduction of 94% in Z-AAT accumulation in the liver and a mean reduction of 68% in histologic globule burden. Furthermore, 50% of patients experienced regression of fibrosis. Treatment emergent adverse events were generally well balanced between the fazirsiran and placebo groups. These results are consistent with the AROAAT-2002 open-label study previously published in The New England Journal of Medicine. To discuss the trial results in further detail, Arrowhead will host a webcast investor call today, January 9, 2023, at 8:30 a.m. ET.

Takeda (TSE: 4502/NYSE:TAK) and Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced the exciting topline results from the successful 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). In addition, they provided details of the Phase 3 study that was co-developed by Takeda and Arrowhead and will be conducted by Takeda. A comprehensive review of the Phase 2 data is planned to be presented at a future medical meeting and submitted for publication. To further discuss this news, Arrowhead will host a webcast call for investors today, January 9, 2023, at 8:30 a.m. ET.

The results from the SEQUOIA study bring great hope to those suffering from the rare genetic condition of alpha-1 antitrypsin deficiency, for which there is currently no treatment. According to Dr. Virginia Clark from the University of Florida’s Division of Gastroenterology, Hepatology, and Nutrition, blocking the production of the toxic protein that accumulates in the liver may provide a safe and effective therapy to help it heal. This breakthrough research offers much-needed relief to those affected by this debilitating condition.

Key SEQUOIA Results

Patients with baseline fibrosis who received 25 mg, 100 mg, or 200 mg of fazirsiran demonstrated a dramatic reduction in serum mutant alpha-1 antitrypsin protein (Z-AAT) concentration at week 48, of 74%, 89%, and 94%, respectively. This was further supported by a median reduction of 94% in total liver Z-AAT and a decrease in PAS-D globule burden from a baseline mean of 5.9 to a post baseline mean of 2.3 at the postbaseline liver biopsy visit. In addition, 42% of patients experienced improvement in portal inflammation, while 50% achieved an improvement in fibrosis of at least one point by METAVIR stage. Altogether, these results show that fazirsiran is an effective treatment for fibrosis.

At Aquestive, we remain optimistic about our current expectations as we focus on our product candidates, anticipated regulatory submissions and clinical program results, and our collaborations with other companies. However, we must remain mindful of the various risks and uncertainties that could impact our actual results. This includes the effects of the COVID-19 pandemic, decisions of regulatory authorities, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, our ability to successfully develop and commercialize drug candidates, the enforcement of our intellectual property rights, and more. We will continue to monitor and manage these risks, and adjust our forward-looking statements when necessary.

Fazirsiran has been found to be well tolerated, with treatment emergent adverse events reported to date being generally balanced between fazirsiran and placebo groups. In fact, no adverse event led to drug discontinuation, dose interruptions, or premature study withdrawals in any study group. Additionally, no dose-dependent or clinically meaningful changes were observed in pulmonary function tests over 1 year with fazirsiran compared to placebo.

The SEQUOIA study promises to further the findings of the Phase 2 AROAAT-2002 open-label study, which was previously published in The New England Journal of Medicine. More details on the study will be revealed at an upcoming scientific meeting, offering an exciting opportunity to see the results of this data-driven research.

The results of the SEQUOIA study, which evaluated the efficacy of fazirsiran in treating Alpha-1 Antitrypsin Deficiency (AATD) associated liver disease, were encouraging. Patients receiving fazirsiran experienced dramatic improvements in several markers of disease, such as fibrosis, Z-AAT accumulation in the liver, PAS-D globule burden, liver enzymes, and other important markers. This data gives Arrowhead Pharmaceuticals’ Chief Medical Officer, Javier San Martin, M.D., additional confidence that fazirsiran has the potential to provide physicians with a therapeutic strategy to treat AATD associated liver disease in the future. The company is grateful to the patients and investigators who participated in the study, as well as its partner, Takeda, for their support and collaboration.

Advancing the Fazirsiran Phase 3 Study

This month, Takeda will launch the TAK-999-3001 study – a randomized, double-blind, placebo-controlled Phase 3 trial – to assess the efficacy and safety of fazirsiran in treating alpha-1 antitrypsin deficiency-associated liver disease with METAVIR stage F2 to F4 fibrosis. A total of 160 patients will be split evenly into two groups to receive either fazirsiran or a placebo. The primary endpoint of this study is to determine whether fazirsiran can reduce the fibrosis METAVIR staging from baseline in patients with METAVIR stage F2 and F3 fibrosis after a 106-week period of central liver biopsy.

Takeda’s Head of Gastroenterology Therapeutic Area Unit, Chinwe Ukomadu, M.D., Ph.D., expresses his confidence in the Phase 2 data of fazirsiran, an RNAi therapy, which has the potential to reverse liver disease associated with AATD. With Takeda’s extensive experience in gastroenterology, the company is aiming to execute the Phase 3 study in a timely manner and make fazirsiran available to patients as soon as possible.

About Fazirsiran

Fazirsiran, a revolutionary RNAi therapy, is poised to revolutionize the treatment of alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD). By reducing the production of the inflammatory Z-AAT protein, Fazirsiran has the potential to halt the progression of this rare genetic condition and may even allow the liver to regenerate and repair. In recognition of its potential, Fazirsiran has been granted Breakthrough Therapy Designation (BTD) and Orphan Drug Designation by the US FDA in July 2021 and February 2018 respectively.

About SEQUOIA Phase 2 Study

SEQUOIA (NCT03945292) is an exciting Phase 2 study that explores the safety, tolerability, and pharmacodynamic effect of fazirsiran (TAK-999, ARO-AAT) in 42 individuals with AATD-LD. Participants were enrolled in three cohorts to receive fazirsiran at 25 mg, 100 mg, or 200 mg doses, or a matching placebo. To assess the impact of the treatment, eligible participants received a pre-dose biopsy and those with baseline fibrosis received a post-baseline biopsy at week 48. For those interested in continuing their treatment, an open-label extension (OLE) is available. Uncover the potential of fazirsiran and join us in the SEQUOIA study!

About Takeda and Arrowhead Collaboration and License Agreement

In October 2020, Arrowhead and Takeda made a groundbreaking move with their collaborative and licensing agreement to develop fazirsiran. Under the terms of the agreement, Arrowhead and Takeda will join forces to advance the development of the drug, with Takeda leading global commercialization strategy and Arrowhead eligible to receive tiered royalties. To kickstart the venture, Arrowhead was awarded $300 million upfront and has the potential to earn up to $740 million in development, regulatory, and commercial milestones. This agreement could prove to be an invaluable asset to both companies as fazirsiran’s success could be a game-changer for the industry.

About Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Alpha-1 Antitrypsin Deficiency (AATD) is a rare, yet serious, genetic disorder that affects an estimated 1 in 3,000-5,000 people in the US and 1 in 2,500 in Europe. It is characterized by a single amino acid substitution in the AAT protein, leading to improper folding and a buildup of globules inside the hepatocytes – triggering continuous injury and a heightened risk of developing liver disease, cirrhosis, and even hepatocellular carcinoma. AATD is a serious condition that should not be taken lightly, as it has the potential to cause devastating effects on the body.

Individuals with the homozygous PiZZ genotype suffer from severe deficiency of functional alpha-1 antitrypsin (AAT) and may develop both pulmonary and liver diseases. While augmentation therapy is available to treat the pulmonary manifestations, no specific therapy has been developed to address the hepatic consequences. As a result, liver transplant is the only available cure, yet this comes with a great risk of morbidity and mortality. There is a pressing need to develop new treatments to provide relief to this population.

About Takeda

Takeda, a global biopharmaceutical leader with a strong commitment to patients, our people and the planet, is dedicated to discovering and delivering life-changing treatments. We focus our R&D efforts on the four therapeutic areas of Oncology, Rare Genetics and Hematology, Neuroscience and Gastroenterology (GI), as well as investing in Plasma-Derived Therapies and Vaccines. Our team of experts in immune and inflammatory diseases is passionate about developing cutting-edge treatments that have the potential to make a real difference to people’s lives. We partner with healthcare providers in over 80 countries and regions, striving to bring our innovative solutions to those who need it most.

About Arrowhead Pharmaceuticals

At Arrowhead Pharmaceuticals, we are revolutionizing medicine by developing treatments that silence the genes that cause intractable diseases. Our advanced RNA chemistries and efficient delivery methods trigger the RNA interference process, resulting in a rapid, deep and long-lasting suppression of target genes. Through this natural mechanism of gene silencing, we are able to provide powerful solutions for some of the most difficult health challenges faced today.

Takeda Important Notice

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Takeda Forward-Looking Statements

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Arrowhead Safe Harbor Statement under the Private Securities Litigation Reform Act:

Forward-looking statements in this news release, such as those related to our product candidates, anticipated regulatory submissions and clinical program results, and prospects or benefits of our collaborations with other companies, are based on our current expectations. However, our actual results may be materially and adversely different from those expressed in the forward-looking statements due to numerous factors and uncertainties, including the impact of the ongoing COVID-19 pandemic on our business, the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and other risks and uncertainties described in our most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, among other documents filed with the Securities and Exchange Commission from time to time. We remain committed to monitoring and managing these risks, and will update or revise our forward-looking statements to reflect new events or circumstances, if and when necessary.

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