ORLANDO, Fla. — Rusfertide, a weekly self-injected peptide, maintained control of hematocrit levels and reductions in phlebotomy requirements through 52 weeks in patients with polycythemia vera (PV), according to extended data from the phase 3 VERIFY study.

Hematologist-oncologist Andrew Kuykendall, MD, an assistant member with the Moffitt Cancer Center, Tampa, Florida, presented the results at the American Society of Hematology (ASH) 2025 Annual Meeting.

Of 147 patients initially assigned to rusfertide who had a durable response and continued on the drug past 32 weeks, 61.9% were not eligible for phlebotomy over the entire 52-week period, reported Kuykendall and colleagues in the meeting abstract. Of 140 patients who crossed over from placebo to rusfertide at 32 weeks, 77.9% were not eligible for phlebotomy from week 40 to 52, up from 32.9% (n = 48/146) during the initial 32 weeks. Mean hematocrit was < 43% in both groups.

Rusfertide, a peptide mimetic of the hormone hepcidin, is key to the body’s regulation of iron. Although it is not approved by the FDA for PV, it has shown “the ability to safely and consistently control blood counts that put patients at risk for cardiovascular events that could result in significant symptoms or death if uncontrolled,” Kuykendall said during an interview.

“Additionally,” he said, “this therapy has the ability to improve disease-related symptoms that are currently exacerbated by the treatments this therapy would be replacing.”

Patients with PV overproduce red blood cells, causing symptoms such as pruritus, night sweats, difficulty concentrating, and potentially, severe fatigue.

As Kuykendall explained, “Hematocrit control at a threshold of less than 45% has been associated with a reduced risk for major cardiovascular events,” and this is typically achieved via therapeutic phlebotomy with the occasional use of cytoreductive therapy. 

“While repeated therapeutic phlebotomy can maintain hematocrit, it often exacerbates iron deficiency, ties patients to the healthcare system, and isn’t always well-tolerated,” he said. “Moreover, real-world studies show that therapeutic phlebotomy is rarely administered optimally, and patients are often not maintained at their goal.” 

Methods and Results

In June 2025, Kuykendall and colleagues released the 32-week results of the VERIFY trial. Patients randomly assigned to receive rusfertide had a mean number of 0.5 phlebotomies vs 1.8 among those assigned to placebo (P < .0001). In a key secondary endpoint, 62.6% of patients taking rusfertide maintained hematocrit below 45% vs 14.4% of the placebo group (P < .0001).

The new analysis showed that from weeks 32 to 52, median time to first phlebotomy was not reached in either the initial rusfertide or placebo groups.

Improvements in PROMIS Fatigue SF-8a and Myelofibrosis Symptom Assessment Form (MFSAF) TSS7 from baseline in the initial rusfertide group were durable over weeks 32 to 52. Among those treated with rusfertide (n = 285), the most common treatment-emergent adverse events were injection-site reactions (47.4%), anemia (25.6%), and fatigue (19.6%). Most were grade 1 or 2.

From weeks 0 to 32, fatigue occurred in 15.9% of the rusfertide group and 15.8% of the placebo group; from weeks 32 to 52, the percentages were 9% and 9.3%, respectively.

Among rusfertide-treated patients, serious adverse events occurred in 8.1%. Non-PV malignancies occurred in 2.1% and 5.5% of patients in the rusfertide and placebo groups, respectively, from weeks 0 to 32 weeks and in 2.2% of all patients from weeks 32 to 52. 

“Given the propensity of our patients with PV to develop non-PV related malignancies, we felt like it was very important to monitor this, especially when we’re thinking about non-melanoma skin cancers that are quite frequent and exacerbated by some of our PV therapies,” said Kuykendall during the presentation.

Injection-site reactions get better over time, he said.

Two patients in the rusfertide group had thrombotic events, one during the initial period and the other during the extension period. 

Response From Expert Not Involved With Study

In response to the presentation, an audience member inquired about the benefits of concurrent cytoreductive therapy.

Kuykendall said: “One of the potential positives of this type of an agent is it allows you to optimize the dose of the cytoreductive therapy the patients are receiving.”

He added: “We have some patients on excessive doses of hydroxyurea or other cytoreductive therapies to achieve phlebotomy independence and improve their ability to stay away from the cancer center. But sometimes, we’d like them to be on a lower dose. It’s a little bit better tolerated.”

Hematologist-oncologist Gabriela S. Hobbs, MD, of Harvard Medical School and Massachusetts General Hospital, Boston, who was familiar with the findings but did not participate in the research, said the study is well done with “excellent” results. 

Compared to those initially taking rusfertide, “those who crossed over to the therapy from the placebo arm saw similarly impressive improvements in blood counts as those that had started on rusfertide from the start,” she said. 

Hobbs added that the extension data show “that responses are durable and that there are no new safety signals.”

In the big picture, “rusfertide is the first of several medications in development that have the promise to eliminate therapeutic phlebotomy,” Hobbs said. “Therapeutic phlebotomy may seem trivial to people that don't think a lot about PV, but it’s a significant burden for PV patients, logistically difficult, and time-consuming.”

What’s Next? 

The VERIFY study is ongoing. During a presentation at ASH, Kuykendall said FDA approval is being pursued. 

Protagonist Therapeutics funded the study. Kuykendall has disclosed relationships with Karyopharm, PharmaEssentia, Janssen, Bristol Myers Squibb, Deciphera/Ono, and Incyte. Other authors have disclosed various relationships with industry. Hobbs has disclosed relationships with Takeda and Disc Medicine.