Rusfertide, an investigational, first-in-class, self-injected peptide targeting the hepcidin pathway, shows efficacy in significantly reducing the need for phlebotomy in patients with polycythemia vera (PV) while improving quality-of-life symptoms, potentially representing an important new standard of care for the commonly undertreated condition.

“Rusfertide is the first agent to prospectively demonstrate a statistically significant improvement in the PROMIS Fatigue SF-8a and MFSAF patient-reported outcomes in patients with PV,” said lead investigator Andrew Tucker Kuykendall, MD, of the Moffitt Cancer Center, in Tampa, Florida, in presenting the findings at American Society of Clinical Oncology (ASCO) 2025 annual meeting.

“Rusfertide had a safety and tolerability profile consistent with rusfertide in prior studies.”

In PV, characterized by the overproduction of red blood cells, patients have an increased risk for thromboembolic events, along with symptoms ranging from pruritus, night sweats, difficulty concentrating and fatigue.

Patients with PV, characterized by an overproduction of blood cells in bone marrow, are at an increased risk for cardiovascular and thrombotic events, while also experiencing symptoms including potentially severe fatigue.

The traditional standard treatment includes phlebotomy to reduce excess red blood cells, and patients also often receive cytoreductive agents, mainly hydroxyurea, but also including interferon alfa-2b, ruxolitinib, and busulfan.

Despite those efforts, the treatment is often not sufficient in achieving or maintaining hematocrit control of < 45%, which is recommended to reduce the risk for a thromboembolic event.

Furthermore, phlebotomy is not just burdensome in requiring reliance of the health system, but the treatment can exacerbate iron deficiency, posing further quality of life issues.

If achieved, however, maintaining hematocrit control is associated with as much as a fourfold decreased risk for major events, Kuykendall explained.

Rusfertide, a hepcidin-mimetic compound, is meanwhile designed to mimic endogenous hepcidin, key in regulating levels of iron in the body.

With the drug showing favorable hematocrit control in the phase 2 REVIVE study, Kuykendall conducted the phase 3, double-blind VERIFY trial, enrolling 293 patients who required frequent phlebotomy, with or without stable cytoreductive therapy to control hematocrit.

The patients were randomized to treatment either with once-weekly rusfertide (n = 147) or placebo (n = 146) for the first 32 weeks of the study. All who completed that phase were eligible to join the open-label rusfertide phase from weeks 32 to 52.

About half of the patients in the study were treated with cytoreductive therapies to prevent thrombotic events.

In weeks 0 through 32, 56.5% of patients in the rusfertide group and 55.5% in the placebo group received concurrent cytoreductive therapy.

During the period from weeks 20 to 32, as many as 76.9% of patients receiving rusfertide achieved a clinical response compared with 32.9% of those who had received placebo (P < .0001).

During weeks 0-32, those receiving rusfertide had a mean number of 0.5 phlebotomies vs 1.8 with placebo (P < .0001).

As many as 72.8% of patients in the rusfertide group required no phlebotomies during the first 32 weeks compared with only 21.9% in the placebo group. Of note, the responses were consistent across subgroups, including based on level of risk or the type of concurrent cytoreductive therapy.

“Rusfertide reduced the mean number of phlebotomies vs placebo in weeks 0 through 32 by a statistically significant margin across subgroups, including PV risk category, geographic region and the use of concurrent cytoreductive therapy,” Kuykendall said.

For the key secondary endpoint, 62.6% of patients in the rusfertide group were able to successfully maintain hematocrit below 45% from weeks 0 to 32 compared with just 14.4% of those in the placebo group (P < .0001).

Patients treated with rusfertide also demonstrated statistically significant improvement in measures of fatigue and other symptoms, as assessed on the PROMIS Fatigue SF-8a total T-score and MFSAF Total Symptom Score (P < .03).

The most common treatment-emergent adverse events (AEs) in the rusfertide and placebo groups, respectively, were injection site reactions (55.9% and 32.9%), anemia (15.9% and 4.1%), and fatigue (15.2% and 15.8%).

Serious AEs occurred in 3.4% of those on rusfertide and 4.8% of patients on placebo; however, none were considered related to rusfertide treatment.

Importantly, cancer events were reported in just 1 patient on rusfertide and 7 patients on placebo.

Kuykendall noted that ongoing research will evaluate longer-term outcomes.

“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’ll have to follow patients in this ongoing study during [subsequent phases] to see how these play out,” he said.

“Rusfertide demonstrated a manageable safety profile; it was consistent with prior studies, and based on this data we believe it represents a potential new treatment option for polycythemia vera,” Kuykendall added, noting that “these data will ultimately be used to file marketing authorizations throughout the world.”

Commenting on the study at the meeting, discussant Katherine Walsh, MD, an associate professor of medicine in the Division of Hematology and Oncology, Vanderbilt University Medical Center, in Nashville, Tennessee, called the results “practice changing,” agreeing that “rusfertide should become a standard of care for us for our patients in the near future.”

“The ability to reduce the need for phlebotomy, which can carry a heavy burden, causing severe fatigue, visual disturbances and iron deficiency, is a highly important goal for patients with PV,” she explained.

“These patients live with a high risk of thrombosis over time and that has significant impact on their survival, impact on quality of life, and can be fatal in and of itself from those thrombotic events.”

In discussing further potential benefits, Kuykendall noted that rusfertide is of interest to patients who may not be responding well to cytoreductive therapy.

“I think our cytoreductive therapy options are limited in what they can offer to patients,” he noted in discussion of the study.

“They certainly reduce thrombotic events, they can control some blood counts, but they do have long term side-effect profile issues, tolerability issues and they don’t do as much as I would like for patients on in terms of quality of life,” he added.

“So I think this is where we can add to our current cytoreductive therapies that brings something else to the table.”

Walsh agreed, noting that “I have a number of patients who are referred because they don’t want to go on a cytoreductive agent if they can avoid it, and I think having this option with this different mechanism of action will be appealing to [those] patients wanting to avoid cytoreduction.”

Further commenting on the study in an ASCO Daily News report, Julie Gralow, MD, ASCO’s chief medical officer, noted the importance of the cancer results.

“We know that acute myeloid leukemia (AML) and other malignancies can occur in patients with polycythemia,” she explained. “AML occurs in about 3% of these patients over 10 years.”

“With just one cancer in the rusfertide group, and seven in the placebo arm, [AML] clearly did not increase and may, although not significantly, have decreased.”

Considering the reductions in the need for phlebotomy and other benefits, Gralow agreed that “this really should become a new standard of care for patients who are requiring phlebotomy that have polycythemia.”

This study was sponsored by Protagonist Therapeutics, Inc. Walsh had no disclosures to report.