In patients with polycythemia vera requiring frequent phlebotomies, the investigational hepcidin mimetic rusfertide, given as a weekly subcutaneous injection, more than doubled the clinical response rate and significantly improved quality of life in the global phase III VERIFY study.¹ These findings were presented during the Plenary Session of the 2025 ASCO Annual Meeting by Andrew Kuykendall, MD, Associate Member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

Rusfertide significantly improved multiple endpoints: reducing the need for phlebotomy, improving hematocrit control, and reducing symptoms across two patient-reported outcome instruments. And it did so while maintaining a manageable safety profile that was consistent with prior studies, according to the investigators, thus meeting the primary endpoint and key secondary endpoints.

“Based on these data, we believe rusfertide represents a potential new treatment option in polycythemia vera,” said Dr. Kuykendall. The data will be used to file global marketing authorizations for the drug.

A Novel Approach to Iron Regulation

“Polycythemia vera represents a unique situation, where you have overproduction of red blood cells in the setting of systemic iron deficiency,” Dr. Kuykendall said. Rusfertide was designed to address this particular issue.

“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.”

— ANDREW KUYKENDALL, MD

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The endogenous hormone hepcidin is the principal regulator of systemic iron homeostasis, controlling iron through downregulation of ferroportin, a transmembrane protein responsible for delivering iron. In iron deficiency, and in polycythemia vera, hepcidin levels are low, and iron freely flows to the bone marrow at the expense of other iron-requiring tissues. Rusfertide, which is administered subcutaneously, is a first-in-class peptide mimetic of hepcidin. It binds to ferroportin, thereby triggering its degradation, restricting iron from the bone marrow, and controlling hematocrit, he explained.

About the VERIFY Trial

VERIFY is a global, ongoing phase III trial designed to confirm the benefit of adding rusfertide to the current standard of care for patients with polycythemia vera requiring frequent therapeutic phlebotomies. There were 293 patients in this three-part study:

• Part 1A (weeks 0–32): Patients with polycythemia vera requiring frequent phlebotomies were randomly assigned in a 1:1 fashion to receive either rusfertide, self-injected weekly, or placebo—both of which were added to standard therapy (cytoreductive therapy could continue). Dosing was titrated over the first 20 weeks, with the primary endpoint assessed from weeks 20 to 32.
• Part 1B (weeks 32–52): Patients completing part 1A could roll over into an open-label part of the study wherein all patients received rusfertide.
• Part 2: The open-label, long-term safety-assessment phase.

The presentation at the ASCO meeting focused on the results from part 1A. Although the primary endpoint focused on weeks 20 to 32, the key secondary endpoints were assessed from weeks 0 to 32 and included the mean number of phlebotomies, the proportion of patients maintaining a hematocrit less than 45%, and patient-reported outcomes.

Among the 293 patients, baseline demographics and disease characteristics were well matched between the placebo and rusfertide groups, with the exception that the rusfertide arm had slightly more heavily phlebotomized patients (16 vs 7). More than half of patients in both arms received concurrent cytoreductive therapy, including hydroxyurea (39.2%), interferon (13.3%), and ruxolitinib (2.7%).

Multiple Endpoints Met

The VERIFY study met its primary endpoint of decreasing “phlebotomy eligibility,” which was a confirmed hematocrit level ≥ 45% and ≥ 3% higher than baseline hematocrit or hematocrit ≥ 48%. Double the proportion of patients given rusfertide achieved this response, 76.9% vs 32.9% in the placebo arm (P < .0001). Higher response rates were consistent across subgroups based on demographics, risk, or concurrent cytoreductive therapy, according to Dr. Kuykendall.

Compared with placebo, rusfertide was associated with a lower mean phlebotomy rate over weeks 0 to 32 (0.5 vs 1.8; P < .0001) and a significant improvement in hematocrit control < 45%, which is considered “a highly relevant clinical endpoint,” he said, as this has been shown to decrease the risk of cardiac events; the rate was 62.6% vs 14.4%, respectively (P < .0001). Patients receiving rusfertide also maintained more consistent hematocrit levels, whereas patients receiving the standard care alone experienced “sharp spikes” during treatment, he noted.

“Patients with polycythemia vera have a critically unmet need in terms of quality of life and symptoms. The major symptom that plagues these patients is fatigue, and although this is multifactorial, we understand that some of this is likely due to systemic iron deficiency,” Dr. Kuykendall continued. “Because of that, we thought a critical aspect of this study was to assess fatigue and how this could respond, given the mechanism of action of rusfertide on iron regulation.”

Using the PROMIS Fatigue Short Form, investigators observed that patients treated with rusfertide had improved fatigue scores from baseline to week 32, as compared with the placebo arm; the mean difference between the arms was almost two points (P = .0268). Rusfertide was also associated with a significant improvement in the Total Symptom Score (ie, 7, which suggests mild symptoms)—again, an almost two-point difference (P = .0239)—with fewer complaints of disease-related symptoms such as fatigue, night sweats, itching, abdominal symptoms, and bone pain.

Safety Profile

The median treatment exposure in both groups was 32 weeks. The most common treatment-emergent adverse events in the rusfertide arm were localized injection-site reactions (55.9%) and anemia (15.9%), which were consistent with the drug’s administration route and mechanism of action. Serious adverse events were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm; none were considered to be related to rusfertide. An acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.

Patients with polycythemia vera are at higher risk of nonhematologic secondary malignancies, particularly skin malignancies, which are often exacerbated with treatments such as hydroxyurea and ruxolitinib, Dr. Kuykendall noted. During part 1A, new cancers were reported in one patient (0.7%) in the rusfertide arm and in seven patients (4.8%) in the placebo arm.

The other parts of the VERIFY study will report longer-term treatment and safety outcomes for this chronic malignancy. Patients will be followed for up to 3 years.

DISCLOSURE: Dr. Kuykendall has received honoraria from AbbVie/Genentech, Blueprint Medicines, BMS, GlaxoSmithKline, Incyte, MorphoSys, Opna Bio, PharmaEssentia, and Swedish Orphan Biovitrum (SOBI); has served as a consultant or advisor to GlaxoSmithKline, Karyopharm Therapeutics, Keros Therapeutics, MorphoSys, and Protagonist Therapeutics; institutional research funding from Blueprint Medicines, Bristol Myers Squibb/Celgene, Geron, GlaxoSmithKline, Janssen Oncology, Kartos Therapeutics, MorphoSys, Novartis, and Protagonist Therapeutics; and reimbursement for travel expenses from AbbVie, GlaxoSmithKline, PharmaEssentia, and Protagonist Therapeutics. For full disclosures of the other study authors, visit coi.asco.org.

REFERENCE

1. Kuykendall AT, Pemmaraju N, Pettit K, et al: Results from VERIFY, a phase 3, double-blind, placebo-controlled study of rusfertide for treatment of polycythemia vera. 2025 ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2025.

EXPERT POINT OF VIEW

The invited discussant of the phase III VERIFY trial was Katherine Walsh, MD, MEd, Associate Professor of Medicine in the Division of Hematology and Oncology and Hematology/Oncology Fellowship Program Director at Vanderbilt University Medical Center in Nashville. She deemed the findings meaningful and impactful for patients, who she said have been anticipating these data.

Katherine Walsh, MD, MEd

“We need to optimize our patients’ care, reduce their thrombotic risk, and give them better quality of life and peace of mind. VERIFY is a practice-changing study. Rusfertide should become part of the standard of care for these patients,” Dr. Walsh said.

“Why are we talking about this abstract at the ASCO Plenary, when we have so many malignancies and so many wonderful presentations here?” she asked. “It’s about how important this issue is to our patients—their high symptom burden, the amount of time these patients spend coming in for phlebotomies, the high risk of thrombosis they must live with throughout their lives, and the impact of these findings.”

The goal of treatment with rusfertide is one that most patients cannot achieve with phlebotomy alone, Dr. Walsh noted: to reduce hematocrit levels to below 45%. An effective medication would also help to avoid the complications patients experience as a result of the current standard therapy, which is symptomatic iron deficiency. In addition, patients must suffer the discomfort of having a peripheral intravenous line placed at each phlebotomy visit and the impact of frequent visits on quality of life, and rusfertide may help with this, too, she added.

Real-Life Benefits

The key takeaway from VERIFY is the high response rate achieved with rusfertide: approximately 73% of patients no longer required phlebotomies at any point of the study, and, Dr. Walsh said, similar success was shown for symptom improvement. “Not only was hematocrit better controlled and phlebotomy needs were lower, but patients just felt better, as they indicated on two different scoring instruments.” Additionally, she said, the ability to self-inject the drug is another win for this medication, “giving patients time back in their lives.”

A positive aspect of the study design, according to Dr. Walsh, was its inclusion of high-risk patients—those requiring cytoreductive therapy to keep their disease under control, which accounted for more than half the study population. “The study was unique in its ability to add this drug on to existing therapy…. This was very reflective of real life,” she said, noting the consistent benefit shown for these challenging patients. The hope now is that the addition of rusfertide will also reduce the need for cytoreductive therapies.

Although polycythemia vera will be gaining a new medication option, Dr. Walsh hopes it continues to be an active area of research. This way patients with this chronic malignancy may experience improved quality of life and perhaps be spared progression to myelofibrosis and acute myeloid leukemia.

DISCLOSURE: Dr. Walsh has received honoraria from Blueprint Medicines.