Takeda and Protagonist Announce U.S. Food and Drug Administration Accepts New Drug Application and Grants Priority Review for Rusfertide as a Potential First-in-Class Therapy for Polycythemia Vera

(BUSINESS WIRE)--Takeda (TSE:4502/NYSE:TAK) and Protagonist Therapeutics, Inc. (“Protagonist”) (NASDAQ:PTGX) today announced that the U.S. Food and Drug Administration (FDA) accepted the New Drug Application (NDA) and granted Priority Review for rusfertide. Rusfertide is an investigational, first-in-class hepcidin mimetic peptide therapeutic for the treatment of adults with polycythemia vera (PV). The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date in the third quarter of this calendar year. In addition to Priority Review, rusfertide has received Breakthrough Therapy designation, Orphan Drug designation and Fast Track designation from the U.S. FDA.

PV is characterized by the overproduction of red blood cells (erythrocytosis), which increases blood viscosity, or thickness, and can result in life threatening thrombotic events. Hematocrit is the ratio of red blood cells to the total amount of blood in the body. Achieving and maintaining controlled hematocrit levels of <45% is the primary treatment goal in PV to prevent thrombotic events and alleviate burdensome symptoms.

“There is an urgent need for innovative treatment options in polycythemia vera, where patients currently face limited therapeutic choices to control their hematocrit and significant symptom burden,” said Andy Plump, M.D., Ph.D., president of R&D at Takeda. “The FDA's acceptance of our NDA brings us closer to potentially offering a first-in-class therapy that could meaningfully improve clinical outcomes and quality of life. This milestone is a reflection of our successful partnership with Protagonist and Takeda’s unwavering commitment to advancing innovative treatments in hematologic cancers where significant unmet needs persist.”

The NDA for rusfertide was primarily based on the positive 32-week primary analysis and 52-week results from the Phase 3 global randomized VERIFY study (NCT05210790), as well as four-year efficacy and safety data from the Phase 2 REVIVE study (NCT04057040) and long-term extension THRIVE study (NCT06033586). In the VERIFY study, rusfertide met the primary endpoint and all four key secondary endpoints. Patients receiving rusfertide plus current standard of care demonstrated a higher response rate compared to current standard of care. This included hematocrit control, a reduction in phlebotomy requirements and improvement in pre-specified patient reported outcomes of fatigue and symptom burden. Rusfertide was generally well-tolerated through 52 weeks of treatment. The most common treatment-emergent adverse events (AEs) in rusfertide-treated patients were injection site reactions (47.4%), anemia (25.6%) and fatigue (19.6%), which were mainly grade 1 or 2. Serious AEs occurred in 8.1% of overall rusfertide-treated patients.

“Rusfertide exemplifies Protagonist’s end-to-end expertise, from exploring a novel hepcidin mimetic mechanism to address unmet needs in polycythemia vera to discovering the peptide and driving its clinical development through NDA filing. We are very pleased with the FDA granting rusfertide Priority Review and look forward to its potential approval in 2026,” said Dinesh V. Patel, Ph.D., Protagonist President and CEO. “We have identified a great partner in Takeda as rusfertide progresses toward this milestone, thereby bringing a successful closure to our more than decade-long journey from concept-to-commercialization.”

In January 2024, Protagonist and Takeda entered into a worldwide license and collaboration agreement for rusfertide. Protagonist discovered rusfertide and led its development through Phase 3 studies, with Takeda responsible for implementing the regulatory strategy for the U.S. NDA filing and for leading any future global regulatory filings. Protagonist holds an option to co-commercialize in the U.S. through a 50/50 profit and loss share structure or to opt-out of this structure, providing Takeda with a worldwide license pursuant to the license and collaboration agreement.

About Rusfertide
Rusfertide is a first-in-class investigational subcutaneous treatment that mimics the action of hepcidin, a natural hormone that regulates iron homeostasis and red blood cell production. By targeting the underlying mechanism of iron dysregulation in polycythemia vera, rusfertide aims to reduce excess red blood cell production and help patients achieve sustained hematocrit control. Rusfertide is administered once weekly via subcutaneous self-injection and has been generally well-tolerated in clinical trials to date.

About VERIFY
The Phase 3 VERIFY study (NCT05210790) is an ongoing, three-part, global, randomized, placebo-controlled study evaluating rusfertide in 293 patients with polycythemia vera over a 156-week period, with treatment extension for participants who are continuing to derive benefit from rusfertide beyond the 156-week treatment period. The study is evaluating the efficacy and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy-dependent despite current standard of care treatment, which could include phlebotomy, hydroxyurea, interferon and/or ruxolitinib. The primary endpoint of the study was the proportion of patients achieving a response during Weeks 20-32, which was defined as the absence of “phlebotomy eligibility.” To meet phlebotomy eligibility, patients in the study were required to have: confirmed hematocrit ≥45% that was ≥3% higher than their baseline hematocrit value, or hematocrit ≥48%.

All patients have completed their participation in the randomized, placebo-controlled portion of the study evaluating the efficacy and safety of rusfertide plus current standard of care versus placebo plus current standard of care and are now in the open-label portions of the study.

About REVIVE and THRIVE
The Phase 2 REVIVE study (NCT04057040) evaluated rusfertide in adult patients with polycythemia vera and consisted of three parts, including 70 patients in the dose-finding Part 1 (28 weeks), 59 patients in the blinded, placebo-controlled, randomized withdrawal Part 2 (13 weeks) and 58 patients in the Part 3 open-label expansion (52 weeks). The THRIVE study (NCT06033586) is an ongoing, open-label extension study evaluating the long-term durability of response and safety profile of rusfertide in patients with polycythemia vera. The study includes 46 patients who previously participated in REVIVE. Patients eligible to transition to the THRIVE study completed the open-label extension portion of REVIVE, ≥12 months of rusfertide therapy and had an end-of-treatment visit. THRIVE is designed to further assess the maintenance of hematocrit control, reduction in the need for therapeutic phlebotomy and overall safety of once-weekly, subcutaneous rusfertide over an additional two-year treatment period.

About Polycythemia Vera (PV)
Polycythemia vera (PV) is characterized by the overproduction of red blood cells (erythrocytosis), which increases blood viscosity, or thickness, and can result in life threatening thrombotic events such as stroke, deep vein thrombosis and pulmonary embolism. Hematocrit is the ratio of red blood cells to the total amount of blood in the body. Achieving and maintaining controlled hematocrit levels of <45% is the primary treatment goal in PV to prevent thrombotic events and alleviate burdensome symptoms, including severe fatigue, difficulty in concentrating, night sweats and pruritus.

About Takeda
Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

About Protagonist
Protagonist Therapeutics is a discovery through late-stage development biopharmaceutical company. Two novel peptides derived from Protagonist's proprietary discovery platform are currently in advanced Phase 3 clinical development, with NDAs for both ICOTYDE™ (icotrokinra) and rusfertide under review at the FDA. ICOTYDE is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor ("IL-23R"), which is licensed to Janssen Biotech, Inc., a Johnson & Johnson company. Following ICOTYDE's joint discovery by Protagonist and Johnson & Johnson scientists pursuant to the companies' IL-23R collaboration, Protagonist was primarily responsible for the development of ICOTYDE through Phase 1, with Johnson & Johnson assuming responsibility for development in Phase 2 and beyond.

Rusfertide is a first-in-class hepcidin mimetic peptide that is being co-developed with Takeda Pharmaceuticals pursuant to a worldwide license and collaboration agreement entered in 2024. Protagonist holds an option to co-commercialize rusfertide in the U.S. through a 50/50 profit and loss share structure or can opt-out of this structure. The Company also has a number of preclinical stage drug discovery programs addressing clinically and commercially validated targets including an oral IL-17 peptide antagonist, obesity dual and triple agonists, an oral hepcidin functional mimetic, and the recently announced IL-4 and amylin programs.

More information on Protagonist, its pipeline drug candidates, and clinical studies can be found on the Company's website at https://www.protagonist-inc.com.

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This press release contains forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include statements regarding the potential benefits of rusfertide. In some cases, you can identify these statements by forward-looking words such as "anticipate," "believe," "may," "will," "expect," or the negative or plural of these words or similar expressions. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, our ability to develop and commercialize our product candidates, our ability to earn milestone payments under our collaboration agreements with Janssen and Takeda, our ability to use and expand our programs to build a pipeline of product candidates, our ability to obtain and maintain regulatory approval of our product candidates, our ability to operate in a competitive industry and compete successfully against competitors that have greater resources than we do, and our ability to obtain and adequately protect intellectual property rights for our product candidates. Additional information concerning these and other risk factors affecting our business can be found in our periodic filings with the Securities and Exchange Commission, including under the heading "Risk Factors" contained in our most recently filed periodic reports on Form 10-K and Form 10-Q filed with the Securities and Exchange Commission. Forward-looking statements are not guarantees of future performance, and our actual results of operations, financial condition, and liquidity, and the development of the industry in which we operate, may differ materially from the forward-looking statements contained in this press release. Any forward-looking statements that we make in this press release speak only as of the date of this press release. We assume no obligation to update our forward-looking statements, whether as a result of new information, future events, or otherwise, after the date of this press release.

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