NDA for Rusfertide Submitted to FDA for Polycythemia Vera

A new drug application (NDA) has been submitted to the FDA seeking approval of rusfertide, an investigational hepcidin mimetic, for the treatment of adult patients with polycythemia vera (PV).¹

The basis for NDA submission largely stems from the multi-part phase 3 VERIFY study (NCT05210790) of patients with PV, which met the first part’s primary end point of decreasing phlebotomy eligibility after 76.9% of patients receiving rusfertide achieved a clinical response compared with 32.9% receiving placebo (P <.0001), as first revealed at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Key secondary end points were also met, with rusfertide providing greater and more consistent hematocrit control under 45% in 62.6% compared with 14.4% in the placebo arm (P <.0001). Notably, rusfertide treatment was also associated with a lower mean phlebotomy rate over weeks 0 to 32 vs placebo (0.5 vs 1.8).

Updated 52-week results recently presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in December 2025 proved rusfertide’s continued high response rates and durability of hematocrit control below the 45% threshold.

Along with improvement in clinical outcomes, patient-reported outcomes with rusfertide were superior to that with placebo, with reduced fatigue and myelofibrosis symptoms.

The submission is also partially supported by the phase 2 REVIVE study (NCT04057040), a global randomized trial of approximately 80 patients with PV.²

“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, PhD, president and CEO of Protagonist, in a news release.¹

About Rusfertide and the Unmet Need in PV

Characterized by erythrocytosis, the excess of red blood cells produced in PV lends itself to an increased incidence of thrombotic events.² Therapeutic phlebotomies are standard practice for mitigating this risk; however, they are frequently associated with tolerability challenges and significant burden on the patient.

"The problem… is that while we do a lot of therapeutic phlebotomies, patients do not necessarily tolerate those well, and it is somewhat of an archaic way of controlling blood counts," Andrew Kuykendall, MD, Moffitt Cancer Center, explained in a previous interview with Targeted Oncology. "It ties them to the health care system, it causes fluid shifts that may make them lightheaded or pass out or feel terrible, and then it worsens and exacerbates iron deficiency, which is associated with a whole host of other symptoms that patients suffer with."

Rusfertide is a self-injectable agent that mimics hepcidin, a peptide hormone in the liver that regulates iron homeostasis and red blood cell production. By targeting iron dysregulation in PV, the agent aims to meet this need by providing sustained hematocrit control.

The agent has been awarded several FDA recognitions throughout its development, including breakthrough therapy designation, orphan drug designation, and fast track designation. If approved, rusfertide could help reduce treatment burden for patients, with ultimate hopes of reducing the need for phlebotomies in PV. In practice, the agent may also have utility across risk categories and lines of treatment, according to Aniket Bankar, MD.

“Rusfertide could have its place in both low-risk and high-risk patients and both as first-line and second-line treatment,” explained Bankar, hematologist at Princess Margaret Cancer Center in Toronto, Canada, in a 2024 interview with Targeted Oncology. “Right now, the standard of care for patients with PV who are low risk is either phlebotomy alone, or some patients may be on interferon or hydroxyurea. Most high-risk patients will be on some cytoreductive treatments. When these treatments are not adequate to control the hematocrit, produce toxicities, or are contraindicated, rusfertide could be useful.”

Safety Profile

Rusfertide was generally well-tolerated by patients. Treatment discontinuations were uncommon, with only 7.5% of patients discontinuing rusfertide due to adverse events (AEs) or study withdrawal in the first portion. More injection site reactions also occurred in over half of the rusfertide arm (55.9%) compared with 32.9% in the placebo arm.

Most AEs were grade 1 or 2, with 3.4% experiencing serious AEs. The most common grade 3 treatment-emergent AEs included anemia, asthenia, and hypertension.

VERIFY Study Design

The VERIFY study is a global, randomized, placebo-controlled study evaluating the efficacy and safety of rusfertide in 293 phlebotomy-dependent patients with PV over the course of 156 weeks.³ The primary end point of the trial is response during weeks 20 to 32, which is defined as the absence of phlebotomy eligibility.

The study is ongoing and consists of 3 parts:

• Part 1A (weeks 0-32): Patients have been randomized 1:1 to receive either once-weekly subcutaneous injections of rusfertide (n = 147) or placebo (n = 146) in addition to standard of care. Dosing was titrated over the first 20 weeks, with the primary end point assessed from weeks 20 to 32.
• Part 1B (weeks 32-52): Patients completing part 1A may roll over into an open-label portion (n = 274).
• Part 2: An open-label, long-term safety assessment portion.

REFERENCES

1. Takeda and Protagonist announce submission of new drug application (NDA) for rusfertide for treatment of polycythemia vera (PV). News release. Takeda Pharmaceutical Company. January 5, 2026. Accessed January 5, 2026. https://tinyurl.com/yc2uyker

2. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Eng J Med. 2024;390(8):723-735. doi:10.1056/nejmoa2308809

3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated August 7, 2025. Accessed January 5, 2026. https://clinicaltrials.gov/study/NCT05210790