Developers Submit NDA to FDA for Rusfertide in Polycythemia Vera

The FDA has received a submission of a new drug application (NDA) for rusfertide, a first-in-class subcutaneously administered hepcidin mimetic peptide, for the treatment of adult patients with polycythemia vera (PV), according to a press release from the developers Takeda and Protagonist Therapeutics.¹

Rusfertide recently demonstrated positive results in the randomized, placebo-controlled phase 3 VERIFY study (NCT05210790) and the phase 2 REVIVE study (NCT04057040).

“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,” Dinesh V. Patel, PhD, president and chief executive officer at Protagonist, stated in the news release.¹ “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.”

Previously, rusfertide was granted the FDA’s breakthrough therapy designation, orphan drug designation, and fast track designation for this PV patient group.

The VERIFY Study

According to data presented in an oral presentation at the 2025 American Society of Hematology Annual Meeting,the VERIFY trial met its primary end point, with 76.9% of the rusfertide group responding to treatment between weeks 20 and 32 compared with 32.9% of the placebo group (P <.0001).² Regarding secondary end points, the mean number of phlebotomies from baseline to week 32 was 0.5 (SD, 1.2) in the rusfertide group compared with 1.8 (SD, 1.5) in the placebo group (P <.0001). Additionally, 62.6% of patients who received rusfertide maintained hematocrit less than 45% compared with 14.4% of the placebo group (P <.0001).

Patients who received rusfertide also had an improvement in their PROMIS Fatigue SF-8a T-score, with LS means at week 32 of –1.78 vs 0.17 with placebo (P = .0268); an improvement in the Myelofibrosis Symptom Assessment Form Version 4.0 Total Symptom Score 7 Items (MFSAF TSS7) score was also observed, with LS means of –2.40 with rusfertide and –0.54 with placebo (P = .0239).

In part 1a of the trial, 293 patients were randomly assigned to receive either placebo plus current standard of care (n = 146) or rusfertide plus current standard of care (n = 147). A total of 93.5% of patients (n = 274) advanced to part 1b of the trial, where all patients received rusfertide plus current standard of care. Current standard of care was phlebotomy with or without cytoreductive therapy.

The median patient age in part 1b was 57 years (range, 27-86), 72.6% were male, and 44.9% were high risk, defined as at least 60 years old and/or a prior thromboembolic event. The median age at PV diagnosis was 51 years (range, 17-84), and the median duration of PV was 2.9 years (range, 0.21-29.2).

In part 1b, which lasted from weeks 32 to weeks 52, the response rate of patients increased to 84.1%. Additionally, from weeks 40 to 52, patients who transitioned from placebo to rusfertide had a response rate 77.9%.

Rusfertide also yielded a favorable safety profile through week 52. In part 1a, at least 1 treatment-emergent adverse event (TEAE) occurred in 86.3% of the placebo group and 90.3% of the rusfertide group. The most common TEAEs were injection site reactions (32.9% and 33.9%, respectively), fatigue (15.8% and 15.9%), and anemia (4.1% and 15.2%). In part 1b, at least 1 TEAE occurred in 76.4% of the placebo to rusfertide group and 75.4% of the rusfertide-only group. The most common TEAEs were injection site reactions (32.9% and 9.7%, respectively), fatigue (9.3% and 9.3%), and anemia (10.0% and 11.2%).

Notably, most TEAEs were grade 1 or 2, and the most common grade 3 TEAEs were anemia, asthenia, and hypertension, each of which occurred in 3 patients.

The REVIVE Study

Results from the REVIVE trial published in the New England Journal of Medicine in 2024 showed, in part 1, the use of phlebotomy decreased or was discontinued in all patients after the initiation of rusfertide; the estimated mean phlebotomy rate was 8.7 ± 2.9 phlebotomies during the 28 weeks before the first dose of rusfertide, then was 0.6 ± 1.0 during part 1 of the trial. The mean maximum hematocrit was 44.5% ± 2.2% during part 1 of the trial vs 50.5% ± 5.8% during the 28 weeks before the first dose of rusfertide. Furthermore, a response occurred in 83% of patients in the efficacy evaluable population.

In part 2 of the trial, 60% of the rusfertide group and 17% of the placebo group achieved responses (P = .002). The mean absolute change from baseline in the hematocrit was 0.3% ± 3.1% with rusfertide and 2.0% ± 2.6% with placebo.

A total of 70 patients were enrolled in part 1 of the trial. In part 2, 59 patients were randomly assigned to receive rusfertide or placebo. Eligible patients were 18 years or older with phlebotomy-dependent PV, defined as having received at least 3 phlebotomies during the 28 weeks before the first dose of rusfertide in part 1 of the trial.

Regarding safety, grade 3 or higher AEs occurred in 10% of patients in part 1. The most common any-grade AEs were injection-site reaction (86%), fatigue (23%), and pruritus (20%). In the rusfertide group of part 2, the most common any-grade AEs were injection site reaction (43%), pruritus (7%), hyperuricemia (7%), myalgia (7%), and paresthesia (7%).

References

1. Takeda and Protagonist announce submission of new drug application (NDA) for rusfertide for treatment of polycythemia vera (PV). News release. Takeda and Protagonist Therapeutics. January 5, 2026. Accessed January 6, 2026. https://tinyurl.com/bde99y9j
2. Kuykendall AT, Bankar A, Petit K, et al. 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. 146(suppl 1):81. doi:10.1182/blood-2025-81
3. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 2024;390(8):723-735. doi:10.1056/NEJMoa2308809