Rusfertide Combo Enhances Responses in Polycythemia Vera

The VERIFY study met its primary end point of decreasing phlebotomy eligibility, with 76.9% of patients in the rusfertide arm achieving a response, which was more than double that seen in the placebo arm.

Rusfertide, a hepcidin mimetic, in combination with standard of care (SOC) therapy significantly enhanced the clinical response rate and improved quality of life vs placebo plus SOC in patients with polycythemia vera, meeting the primary end point and key secondary end points of part 1A of the phase 3 VERIFY study (NCT05210790), according to a findings presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

These data, presented by Andrew Kuykendall, MD, associate member in the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center, showed that rusfertide significantly reduced phlebotomy eligibility, improved hematocrit control, and yielded statistically significant improvements in symptoms across 2 patient-reported outcome instruments, while maintaining a manageable safety profile that was consistent with prior studies.

“Based on these data, we believe [rusfertide] represents a potential new treatment option [in] polycythemia vera,” Kuykendall said during the presentation.

About the VERIFY Study

VERIFY is a global, ongoing phase 3 study designed to confirm the benefit of adding rusfertide to the current standard of care for patients with polycythemia vera requiring frequent therapeutic phlebotomies.

The study design includes:

• Part 1A (weeks 0-32): Patients with polycythemia vera requiring frequent phlebotomies were randomly assigned in a 1:1 fashion to receive either rusfertide or placebo, in addition to their 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 could roll over into an open-label portion of the study.
• Part 2: This is an open-label, long-term safety assessment portion.

The primary and key secondary end points from week 0 to 32 included mean number of phlebotomies, proportion of patients maintaining a hematocrit less than 45%, and patient-reported outcomes.

Nearly 400 patients were screened, and 293 were ultimately randomized. Baseline demographics and disease characteristics were well matched between the placebo and rusfertide groups, with 1 exception: a small proportion of heavily phlebotomized patients (7 or more therapeutic phlebotomies in the 28 weeks prior to study) were slightly more represented in the rusfertide arm (16 vs 7). Over half of patients in both arms received concurrent cytoreductive therapy, predominantly hydroxyurea (39.2%), with some patients receiving interferons (13.3%) and ruxolitinib (Jakafi; 2.7%).

The VERIFY study met its primary end point of decreasing phlebotomy eligibility, with 76.9% of patients in the rusfertide arm achieving a response, which was more than double that seen in the placebo arm (32.9%; P <.0001). There were no disparate responses were observed across subgroups based on demographics, risk, or concurrent cytoreductive therapy.

Regarding the key secondary end points, rusfertide was associated with a lower mean phlebotomy rate over weeks 0 to 32 compared with placebo at 0.5 (standard deviation [SD], 1.2) vs 1.8 (SD, 1.5). Hematocrit control under 45%, a highly relevant secondary end point shown to decrease the incidence of cardiac events, was also improved with rusfertide, with 62.6% of patients maintaining hematocrit under 45% in the rusfertide arm vs 14.4% in the placebo arm (P <.0001). Patients receiving rusfertide also maintained more consistent hematocrit levels, while patients receiving placebo had sharp spikes before eventually returning to baseline.

As patients with polycythemia vera often experience high levels of fatigue, often linked to systemic iron deficiency, quality of life and symptom reduction also served as key secondary end points. According to the PROMIS Fatigue Short Form, patients receiving rusfertide showed an improvement in their fatigue score from baseline to week 32 when compared with placebo, and rusfertide was also associated with a significant improvement in the Total Symptom Score 7, with fewer complaints of myelofibrosis-associated symptoms like 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 (TEAEs) 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.

Patients with polycythemia vera are at higher risk of nonhematologic secondary malignancies, particularly skin malignancies, which are often exacerbated with treatments like hydroxyurea and ruxolitinib. Dermatologic screening exams were mandated by study protocol. Ten skin malignancies were detected during prior to randomization, and during part 1A, cancer events other than polycythemia vera were reported in 7 patients (4.8%) in the placebo arm vs 1 patient (0.7%) in the rusfertide arm.

Serious AEs were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm, with none of these considered related to rusfertide. One thromboembolic event of acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.

Rusfertide: A Novel Approach to Iron Regulation

Hepcidin is the master regulator of systemic iron homeostasis. It controls iron through ferroportin, a transmembrane protein responsible for delivering iron from hepatocytes, enterocytes, and splenic macrophages. Hepcidin binds to ferroportin, leading to its internalization and degradation. In iron deficiency, hepcidin levels are low, allowing iron to flow freely into the bloodstream.

In polycythemia vera, there is an overproduction of red blood cells despite systemic iron deficiency. Consequently, hepcidin levels are low, allowing iron to flow freely to the bone marrow at the expense of other iron-requiring tissues.

Rusfertide is a first-in-class, peptide mimetic of hepcidin, administered via subcutaneous injection. It binds to ferroportin, triggering its degradation and restricting iron from reaching the bone marrow, thereby controlling hematocrit.

Limitations and Future Directions

The VERIFY study enrolled a diverse patient population with different cytoreductive strategies, baseline symptom burdens, and disease durations. While this makes the trial relevant to a broad range of patients with polycythemia vera, it presents challenges for analyzing patient-reported outcomes from varied baselines.

“Ultimately, we plan to interrogate this further in upcoming analyses,” Kuykendall said during his presentation.

Additionally, the placebo-controlled portion of VERIFY was only 32 weeks long.

“Given this chronic malignancy, we are very focused on more long-term treatment outcomes, such as transformation, safety, as well as thrombosis, and ultimately, we will have to follow patients in this ongoing study during parts 1B and 2 to see how these play out,” Kuykendall added.

Reference

Kuykendall AT, Pemmaraju N, Pettit KM, 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):abstr LBA3. doi:10.1200/JCO.2025.43.17_suppl.LBA3