Phase 3 VERIFY trial results demonstrate breakthrough efficacy for this first-in-class hepcidin mimetic
For thousands of patients living with polycythemia vera (PV), a rare and chronic blood cancer, life revolves around a centuries-old treatment: therapeutic phlebotomy. This modern-day bloodletting, necessary to reduce dangerously high red blood cell counts, creates a relentless cycle where patients become trapped between the risks of thrombosis from too much blood and the debilitating symptoms of iron deficiency caused by frequent blood removal 1 .
"We thought a critical aspect of this study was to assess fatigue and how this could change, given the mechanism of action of rusfertide on iron regulation" - Dr. Andrew Kuykendall of Moffitt Cancer Center 2
But a breakthrough has emerged from the latest clinical research—an investigational drug called rusfertide that may fundamentally transform PV treatment. In March 2025, the oncology community welcomed stunning results from the phase 3 VERIFY trial, demonstrating that this first-in-class "hepcidin mimetic" not only dramatically reduced the need for phlebotomy but significantly improved patients' quality of life 2 4 .
76.9%
Response Rate with Rusfertide
0.5
Mean Phlebotomies (vs 1.8 with placebo)
73%
Patients Required No Phlebotomy
Polycythemia vera is one of a group of blood cancers known as myeloproliferative neoplasms. At its core, PV is driven by genetic mutations, most commonly in the JAK2 gene, that cause the bone marrow to produce excessive numbers of red blood cells 3 . This overproduction leads to thickened blood that flows less freely, dramatically increasing the risk of blood clots, strokes, and heart attacks 3 .
Here lies the paradox: while phlebotomy controls the immediate danger of thick blood, it creates another problem—systemic iron deficiency. Though this iron deficiency somewhat dampens red blood cell production, it also causes severe fatigue, cognitive issues, and other symptoms that profoundly impact quality of life 3 . Even more problematic, patients spend significant periods with hematocrit levels above the safety threshold of 45% between clinic visits, leaving them vulnerable to thrombotic events 1 .
Enter rusfertide, a novel investigational drug that represents an entirely different approach to PV treatment. Rather than simply removing excess blood or suppressing bone marrow function, rusfertide addresses the fundamental iron dysregulation at the heart of PV.
To understand rusfertide's mechanism, we must first meet hepcidin, a hormone produced by the liver that serves as the body's master regulator of iron metabolism 3 . Hepcidin controls iron availability by binding to ferroportin—the main protein responsible for exporting iron from cells into the bloodstream. When hepcidin binds to ferroportin, it triggers the degradation of this iron exporter, effectively locking iron inside storage sites like macrophages and liver cells while reducing iron absorption from the diet 2 3 .
Rusfertide is a first-in-class peptide mimetic of hepcidin that replicates the function of the natural hormone 2 . When administered via weekly subcutaneous injections, rusfertide achieves what has been dubbed "chemical phlebotomy" because it controls hematocrit without removing blood or depleting iron stores 3 .
The VERIFY trial (NCT05210790) was a global, randomized, placebo-controlled phase 3 study designed to confirm the promising results seen in earlier phase 2 trials 2 4 . This rigorous investigation involved 293 PV patients across multiple centers who required frequent phlebotomies despite standard care.
Randomized 1:1 to rusfertide or placebo as add-on therapy
Primary EndpointOpen-label phase where all participants received rusfertide
Open-label, long-term safety assessment
The VERIFY trial results, presented during the Plenary Session of the 2025 ASCO Annual Meeting, demonstrated remarkable efficacy across all primary and secondary endpoints 2 .
The most striking finding was how effectively rusfertide reduced the need for therapeutic phlebotomy. For the primary endpoint, 76.9% of rusfertide-treated patients achieved response (absence of phlebotomy eligibility) during weeks 20-32 compared to only 32.9% in the placebo group (p<0.0001) 2 4 .
Mean phlebotomies with Rusfertide
Mean phlebotomies with Placebo
Patients required no phlebotomy
Beyond the laboratory values, rusfertide delivered meaningful improvements in patients' quality of life. Using the PROMIS Fatigue Short Form instrument, researchers found that rusfertide-treated patients experienced significantly greater improvement in fatigue scores compared to placebo (p=0.0268) 2 .
Rusfertide demonstrated a manageable safety profile consistent with earlier studies. The most common adverse events were injection site reactions and anemia, consistent with the drug's mechanism of action 2 .
55.9%
Mostly mild to moderate15.9%
Mechanism-relatedNote: Serious adverse events were reported in 3.4% of rusfertide patients compared to 4.8% in the placebo group, with none considered related to rusfertide 2 .
Based on the VERIFY results, Protagonist Therapeutics and their development partner Takeda plan to file for global marketing approvals for rusfertide 2 . The drug has already received orphan drug and fast track designations from the FDA, which may expedite its review process 4 .
First-in-human studies established that rusfertide exhibits dose-dependent pharmacokinetics and pharmacodynamics, with single doses of 1-80 mg producing dose-dependent decreases in serum iron and transferrin-iron saturation .
The development of rusfertide represents a paradigm shift in polycythemia vera management. For the first time, patients and clinicians have a therapy that specifically targets the underlying iron dysregulation of PV, offering simultaneous control of hematocrit levels and improvement of debilitating symptoms.
"VERIFY is a practice-changing study. Rusfertide should become part of the standard of care for these patients" - Dr. Katherine Walsh of Vanderbilt University Medical Center 2
The remarkable success of rusfertide in the VERIFY trial marks more than just the arrival of a new medication—it validates an entirely new approach to treating polycythemia vera. By understanding and restoring the natural iron regulation that PV disrupts, rusfertide offers patients freedom from the ancient cycle of bloodletting and a path toward better quality of life.