Takeda and Protagonist Announce Submission of New Drug Application (NDA) for Rusfertide for Treatment of Polycythemia Vera (PV)

OSAKA, Japan & CAMBRIDGE, Mass. & NEWARK, Calif.--(BUSINESS WIRE)--Takeda (TSE:4502/NYSE:TAK) and Protagonist Therapeutics (Nasdaq: PTGX) (“Protagonist”) announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval of rusfertide for the treatment of adults with polycythemia vera (PV). Rusfertide is an investigational first-in-class subcutaneously administered hepcidin mimetic peptide designed to regulate iron homeostasis and red blood cell production to control hematocrit levels in patients with PV.

“This is an important milestone toward our goal of addressing critical gaps that patients living with polycythemia vera face today,” said Teresa Bitetti, President, Global Oncology Business Unit, Takeda. “The comprehensive VERIFY study data underscore rusfertide’s strong clinical profile and potential to provide sustained hematocrit control while reducing phlebotomy and symptom burden. Our collaboration with Protagonist exemplifies how partnerships can advance innovative science, with a focus on making a meaningful difference for patients.”

This NDA submission follows the positive 32-week primary analysis and 52-week results from the Phase 3 global randomized, placebo-controlled VERIFY study (NCT05210790), in which rusfertide met the primary endpoint and all four key secondary endpoints, as well as the Phase 2 REVIVE study (NCT04057040). In the VERIFY study, patients receiving rusfertide plus standard of care therapy demonstrated a substantially higher response rate compared to placebo plus standard of care, including durable hematocrit control, a reduction in phlebotomy requirements and improvement in pre-specified patient reported outcome (PRO) endpoints.

Rusfertide has received Breakthrough Therapy Designation, a regulatory milestone recognizing the potential of rusfertide to offer a substantial improvement over available therapies, as well as Orphan Drug Designation and Fast Track Designation from the U.S. FDA.

“Rusfertide has the potential to redefine the treatment paradigm for PV by offering patients a novel, first-in-class erythrocytosis-specific therapy that significantly reduces or eliminates the need for frequent phlebotomy,” said Dinesh V. Patel, Ph.D., Protagonist President and CEO. “Submitting this NDA marks a major inflection point in the decade long journey that started with a hepcidin mimetic program at Protagonist. Rusfertide has practice-changing potential that could become standard of care for patients with PV who currently rely on burdensome and often ineffective therapies.”

Under the terms of its January 2024 worldwide license and collaboration agreement with Takeda, the submission of the NDA triggers the start of a 120-day period, after which Protagonist can decide to exercise its opt-out right during a subsequent 90-day period. If Protagonist chooses to exercise this opt-out right, it would be eligible to receive up to $400 million in opt-out payments as well as enhanced milestone payments and 14-29% tiered royalty rates on worldwide net sales of rusfertide.

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 PV 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, that can result in life threatening thrombotic events such as stroke, deep vein thrombosis and pulmonary embolism. Hematocrit (HCT) is the ratio of red blood cells to total amount of blood in the body. Achieving and maintaining controlled HCT 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 a New Drug Application (NDA) for icotrokinra submitted to the FDA in July, and an NDA for rusfertide submitted in December 2025. Icotrokinra (formerly, JNJ-2113), 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 icotrokinra's joint discovery by Protagonist and Johnson & Johnson scientists pursuant to the companies' IL-23R collaboration, Protagonist was primarily responsible for the development of icotrokinra through Phase 1, with Johnson & Johnson assuming responsibility for development in Phase 2 and beyond. Rusfertide, a mimetic of the natural hormone hepcidin, is currently in Phase 3 development for the rare blood disorder polycythemia vera (PV). Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals pursuant to a worldwide collaboration and license agreement entered in 2024 under which the Company remains primarily responsible for development through NDA filing. The Company also has a number of preclinical stage drug discovery programs addressing clinically and commercially validated targets, including IL-17 oral peptide antagonist PN-881, obesity triple agonist peptide PN-477, and the oral hepcidin program.

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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