Rusfertide Gains Breakthrough Therapy Designation for Polycythemia Vera

The investigational agent PTG-300 (Rusfertide; Protagonist, Takeda), a hepcidin mimetic, has emerged as a novel therapeutic option and was recently granted breakthrough therapy designation by the FDA for the treatment of polycythemia vera (PV), reflecting its potential to transform management of this disease. PV is a chronic myeloproliferative neoplasm characterized by the overproduction of red blood cells, leading to elevated hematocrit and increased risk of thrombosis. Standard treatment has historically relied on therapeutic phlebotomy and cytoreductive therapy, both of which carry burdens and risks for patients.¹

Image Credit: Luciano Luppa | stock.adobe.com

The FDA’s breakthrough therapy designation is created for drugs that potentially offer substantial improvements over existing therapies in serious conditions. The designation for PTG-300 builds on its previous breakthrough, fast track, and orphan drug statuses, indicating the development of its clinical evidence and the agency’s acknowledgment of its promise.²

"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, said in a news release. "We remain on track for [new drug application (NDA)] submission of rusfertide in PV by the end of this year."¹

Clinical Outcomes from VERIFY

The designation is primarily supported by results from the phase 3 VERIFY trial (NCT05210790), a randomized, placebo-controlled study evaluating PTG-300 in patients with PV who require frequent phlebotomy.^1,2

"In the VERIFY phase 3 trial, rusfertide demonstrated positive results across all primary and key secondary endpoints, including hematocrit control, decreased phlebotomy dependence, and patient-reported outcomes, including improvement in fatigue," Arturo Molina, MD, MS, chief medical officer at Protagonist, said. "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."¹

According to VERIFY data, patients treated with PTG-300 had a substantial proportion that achieved stable hematocrit control without phlebotomy during weeks 20 to 32 of the treatment, notably exceeding those patients under placebo. Specifically, about 77% of patients on PTG-300 did not require phlebotomy compared to 33% in the placebo group. Patients’ self-reports indicated improvements in fatigue, pruritus, and night sweats, with most adverse events limited to mild injection site reactions.²

These results are especially meaningful because frequent phlebotomy can worsen iron deficiency and contribute to fatigue, negatively affecting quality of life. By mimicking hepcidin, a natural regulator of iron metabolism, PTG-300 acts as a chemical phlebotomy, lowering red blood cell production while avoiding the drawbacks of repeated blood removal.³ This mechanism represents a major innovation in the management of PV.

Conclusion

The FDA’s breakthrough therapy designation for PTG-300 highlights its potential as a novel treatment that addresses significant unmet needs in PV. PTG-300, through continuous hematocrit management, lowering the reliance on phlebotomy, and enhancing patient-reported outcomes, can represent a paradigm shift in PV therapy. With Protagonist on track to file an NDA by the end of 2025, patients may soon benefit from a therapy designed to ease the burden of this chronic disease.¹

REFERENCES

1. Protagonist Therapeutics. Rusfertide Receives Breakthrough Therapy Designation for Treatment of Erythrocytosis in Patients with Polycythemia Vera. ACCESSWIRE Newsroom. 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. Rusfertide Demonstrates Promising Results in Phase 3 VERIFY Trial in Polycythemia Vera. Takeda.com. March 3, 2025. Accessed August 25, 2025. https://www.takeda.com/newsroom/newsreleases/2025/positive-topline-results-from-verify-study/

3. Spindler S. Rusfertide Cuts Number of Needed Blood Draws to Treat PCV - NCI. www.cancer.gov. March 28, 2024. Accessed August 25, 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2024/rusfertide-polycythemia-vera-fewer-phlebotomies