New Drug Application Approved for Rusfertide for Adults with Polycythemia Vera

Takeda and Protagonist Therapeutics announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) and granted Priority Review for rusfertide, an investigational, first-in-class hepcidin mimetic peptide therapy for adults with polycythemia vera (PV).*

Rusfertide is an investigational, first-in-class subcutaneous treatment for the treatment of adult patients diagnosed with polycythemia vera. The drug 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, which binds to ferroportin and decreases iron delivery to bone marrow, 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.

Unmet medical need
Polycythemia vera (PV) is a rare chronic hematological cancer where the bone marrow overproduces red blood cells, a condition known as erythrocytosis. The condition causes hyperviscosity and is linked to a JAK2 gene mutation.** [1][2]

Polycythemia vera is a slow-growing condition that raises risks for blood clots, stroke, or organ damage. Although there is no known cure for the disease, treatment focuses on reducing red blood cell volume to prevent thrombosis and managing symptoms. Primary treatments include regular therapeutic phlebotomy (blood removal), low-dose aspirin, and cytoreductive therapies (e.g., hydroxyurea, ropeginterferon) to lower blood counts.

Currently available treatment options are limited, and patients often struggle to control hematocrit and manage 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,” explained 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 FDA’s acceptance of the NDA for rusfertide brings patients one step closer to accessing a novel, first-in-class treatment that could meaningfully improve quality of life and outcomes throughout the PV treatment journey.

Studies
The NDA submission was supported by positive results from the ongoing, randomized, placebo-controlled Phase 3 VERIFY study (NCT05210790), including the 32-week primary analysis and the 52-week data, in which rusfertide met its primary endpoint and all four key secondary endpoints.  Early results of the study, presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held May 30 to June 3, 2025, in Chicago, Il.[3][4]

The VERIFY study, which included 293 patients with polycythemia vera (male, 73.0%; median age, 57 [27-86] years), is designed to evaluate the efficacy and safety of once-weekly, subcutaneously self-administered rusfertide over a 156-week period, with a treatment extension for participants who continue to derive benefit from rusfertide beyond the 156-week treatment period. The participating patients were randomized to receive rusfertide (n=147) or placebo (n=146).

The patients participating in the study were diagnosed with uncontrolled hematocrit and were phlebotomy-dependent despite current standard-of-care treatment, which could include phlebotomy, hydroxyurea, interferon, and/or ruxolitinib (Jakafi®; Incyte). The primary endpoint of the study was the proportion of patients who achieved a response during Weeks 20-32, defined as the absence of ‘phlebotomy eligibility.’ To meet phlebotomy eligibility, patients in the study were required to have a confirmed hematocrit ≥45% that was ≥3% higher than their baseline hematocrit, or a hematocrit ≥48%.

Rivive and Thrive
Two other studies evaluating rusfertide included the Phase 2 REVIVE study (NCT04057040) in adult patients with polycythemia vera, which consisted of three parts, which enrolled 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 open-label expansion Part 3 (52 weeks), and the THRIVE study (NCT06033586).

The THRIVE study is an ongoing, open-label extension study evaluating the long-term durability of response and safety profile of rusfertide in patients with polycythemia vera. This 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.

Outcomes
The outcomes of studies in which patients participating received rusfertide in combination with the current standard of care (SOC) demonstrated a higher response rate than with SOC alone. This included hematocrit control, reduced phlebotomy requirements, and improvements in pre-specified patient-reported outcomes of fatigue and symptom burden. Rusfertide was generally well-tolerated through 52 weeks of treatment. The observed rapid and sustained control of hematocrit reduced the need for therapeutic phlebotomy and, in turn, may reduce thrombotic and cardiovascular events over the long term in patients diagnosed with PV. [4]

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%), with most grade 1 or 2. Serious AEs occurred in 8.1% of patients treated with rusfertide.

In addition to Priority Review, Rusfertide has also received Breakthrough Therapy, Orphan Drug, and Fast Track designations from the FDA. The acceptance of this NDA marks a major milestone for Takeda and Protagonist, representing the culmination of a decade of innovation at Protagonist. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date for the third quarter of this calendar year. 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, Orphan Drug, and Fast Track designations from the U.S. FDA.

“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,” Patel concluded.

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Note: * Myeloproliferative neoplastic disorders are a group of slow-growing hematological cancers in which the bone marrow makes too many red blood cells, white blood cells, or platelets. The three main, classic BCR-ABL1-negative types are Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Chronic Myelogenous Leukemia (CML) is also a major subtype.

** The JAK2 gene mutation is an acquired, non-inherited genetic alteration causing overactive signaling in bone marrow, leading to excessive, uncontrolled production of blood cells, including red cells, white cells, or platelets. This mutation is the primary driver of myeloproliferative neoplasms (MPNs) such as polycythemia vera (in nearly 100% of cases), essential thrombocythemia (30-50%), and primary myelofibrosis (50%).

Clinical trials
A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera (VERIFY) – ClinicalTrials.gov ID NCT05210790
Hepcidin Mimetic in Patients With Polycythemia Vera (REVIVE) – ClinicalTrials.gov ID NCT04057040
Study to Evaluate the Long-term Safety of Rusfertide (PTG-300) in Subjects With Polycythemia Vera (THRIVE) – ClinicalTrials.gov ID NCT06033586

Highlights of prescribing information
Ruxolitinib (Jakafi®; Incyte)[Prescribing Information]

Reference
[1] James C. The JAK2V617F mutation in polycythemia vera and other myeloproliferative disorders: one mutation for three diseases? Hematology Am Soc Hematol Educ Program. 2008:69-75. doi: 10.1182/asheducation-2008.1.69. PMID: 19074061.
[2] Patel AB, Masarova L, Mesa RA, Hobbs G, Pemmaraju N. Polycythemia vera: past, present and future. Leuk Lymphoma. 2024 Nov;65(11):1552-1564. doi: 10.1080/10428194.2024.2361836. Epub 2024 Jun 13. PMID: 38871488.
[3] Kuykendall AT, Pemmaraju N, Pettit KM, Shatzel JJ, Lucchesi A, García-Gutierrez V, Mayer J, Yacoub A, Gill H, Hlusi A, Sasca D, Scandura JM, Kremyanskaya M, Dinh P, Khanna S, Gupta SK, Molina A, Bankar A. Results From VERIFY, a Phase 3, Double-Blind, Placebo (PBO)-Controlled Study of Rusfertide for Treatment of Polycythemia Vera (PV). Oral presentation at: American Society of Clinical Oncology (ASCO) Annual Meeting, June 1, 2025. Chicago, IL. LBA3; J Clin Oncol 43, 2025 (suppl 17; abstr LBA3)
[4] Chew LP, Ginzburg YZ, Kirubamoorthy K, Lee SE, Lee JH, Modi NB, Khanna S, Dinh P, Valone F, Molina A, Gupta S. Rusfertide rapidly decreases hematocrit in patients with suboptimally controlled polycythemia vera. Leuk Res. 2025 Dec;159:108132. doi: 10.1016/j.leukres.2025.108132. Epub 2025 Oct 29. PMID: 41175501.
[5] Kuykendall AT, Bankar A, Pettit K, Shatzel J, Lucchesi A, Gutiérrez VG, Mayer J, Yacoub A, Gill H, Hlusi A, Sasca D, Scandura J, Kremyanskaya M, Ross D, Palandri F, Fox ML, Vannucchi AM, Haque T, Koschmieder S, Sosa A, Oyuela P, Dinh P, Xiao J, Gupta S, Khanna S, Molina A, Pemmaraju N. Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study. Blood. 2025;146(suppl 1): 81. doi:10.1182/blood-2025-8

Featured image by Aakash Dhage on Unsplash. Licensed under the Unsplash+ License. Used with permission.

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