FDA Grants Breakthrough Therapy Designation to Rusfertide for Erythrocytosis in Polycythemia Vera

The FDA has granted breakthrough therapy designation to rusfertide, a potential first-in-class hepcidin-mimetic peptide, for the treatment of erythrocytosis in patients with polycythemia vera (PV) who have an unmet need for therapies that can reduce phlebotomy burden and improve hematologic control.1

The FDA’s decision was supported by positive efficacy findings from the phase 3 VERIFY trial (NCT05210790), which evaluated rusfertide plus current standard of care (SOC) vs placebo plus current SOC in patients with PV. Data from the 32-week analysis, presented as a late-breaking abstract during the plenary session at the 2025 ASCO Annual Meeting, showed that among evaluable patients who received rusfertide plus SOC (n = 147), the response rate during weeks 20 to 32 was 76.9% vs 32.9% among those who received placebo plus SOC (n = 146; P < .0001).2 The response benefit with rusfertide was maintained across several patient subgroups, including PV risk category and concurrent therapy.

Patients who received rusfertide also required a statistically significant lower mean number of phlebotomies from weeks 0 to 32 compared with those who received placebo, at 0.5 (SD, 1.2) vs 1.8 (SD, 1.5; P < .0001). Additionally, during weeks 0 to 32, 72.8% of patients in the rusfertide arm did not require phlebotomies vs 21.9% of those in the placebo arm. Notably, patients who received rusfertide were also more likely to maintain hematocrit levels lower than 45% from weeks 0 to 32 vs those who received placebo (P < .0001).

Rusfertide previously received orphan drug designation and fast track status from the FDA in 2020.1

“In the VERIFY trial, rusfertide demonstrated positive results across all primary and key secondary end points, including hematocrit control, decreased phlebotomy dependence, and patient-reported outcomes, including improvement in fatigue,” Arturo Molina, MD, MS, FACP, chief medical officer at Protagonist Therapeutics, explained in a news release. “The comprehensive data provide compelling evidence of the potential for rusfertide to address unmet medical needs in patients with PV who are unable to achieve adequate hematocrit control with standard-of-care or currently available treatments.”

VERIFY Trial Breakdown and Eligibility Criteria

The VERIFY trial is an ongoing, 3-part, global, randomized, placebo-controlled study evaluating the efficacy and safety of rusfertide in patients with PV. A total of 293 patients were enrolled to receive once-weekly, subcutaneously self-administered rusfertide or placebo over a 156-week treatment period.

The trial includes a 32-week double-blind period in which patients receive either rusfertide or placebo added to their ongoing PV therapy, which may consist of phlebotomy alone or phlebotomy combined with stable doses of hydroxyurea, interferon, and/or ruxolitinib (Jakafi).3 Patients who complete the 32-week blinded phase transition to an open-label extension phase, during which they receive rusfertide for an additional 124 weeks. Poststudy safety follow-up is conducted approximately 6 and 12 months after the last dose of rusfertide.

Individuals 18 years and older with a diagnosis of PV per revised 2016 World Health Organization criteria were eligible for enrollment. Patients were required to have inadequate hematocrit control, defined as at least 3 phlebotomies in the 6 months or at least 5 phlebotomies in the year prior to random assignment. Key laboratory parameters at baseline included hematocrit levels lower than 45%, white blood counts of 4000/μL to 20,000/μL, and platelet counts of 100,000/μL to 1,000,000/μL. Patients receiving cytoreductive therapy had to be on a stable regimen; patients treated with phlebotomy alone were required to have discontinued cytoreductive therapy 2 to 6 months before screening.

Exclusion criteria included clinically meaningful laboratory abnormalities, need for phlebotomy at hematocrit levels below 45%, significant thrombosis or active/chronic bleeding within 2 months, a history of invasive malignancy within 5 years (except localized cured prostate or cervical cancer), untreated in situ or stage I skin cancers identified at screening, and prior use of busulfan, pipobroman, or ³²phosphorus within 7 months before screening.

The trial’s primary end point is the proportion of patients achieving a response during weeks 20 through 32, defined as the absence of “phlebotomy eligibility.” Phlebotomy eligibility criteria include a confirmed hematocrit level of at least 45% that was at least 3% higher than baseline or a hematocrit level of at least 48%.1

“We are very pleased with the FDA’s decision to grant breakthrough therapy designation to rusfertide, which underscores its potential to demonstrate substantial improvement over available PV therapies,” Dinesh V. Patel, PhD, president and CEO of Protagonist Therapeutics, added in the news release. “We remain on track for new drug application submission [for] rusfertide in PV by the end of [2025].”

References

1. Rusfertide receives breakthrough therapy designation for treatment of erythrocytosis in patients with polycythemia vera. News release. Access Newswire. August 25, 2025. Accessed August 25, 2025. https://www.accessnewswire.com/newsroom/en/healthcare-and-pharmaceutical/rusfertide-receives-breakthrough-therapy-designation-for-treatment-of-1064560
2. Kuykendall A, Pemmaraju N, Pettit K, et al. Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). J Clin Oncol. 2025;43(suppl 17):LBA3. doi:10.1200/JCO.2025.43.17_suppl.LBA3
3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated August 7, 2025. Accessed August 25, 2025. https://clinicaltrials.gov/study/NCT05210790