Insights From VERIFY: Rusfertide Shows Promise in Polycythemia Vera
A groundbreaking study reveals rusfertide's potential to transform polycythemia vera treatment, reducing phlebotomy needs and improving patient quality of life.
For patients with polycythemia vera (PV), a chronic myeloproliferative neoplasm characterized by an overproduction of red blood cells, the current treatment landscape often involves frequent therapeutic phlebotomies. While effective at reducing thrombotic risk, this approach is often burdensome, poorly tolerated, and exacerbates iron deficiency, leading to a host of debilitating symptoms.1
At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Andrew Kuykendall, MD, shed light on the promising results of the phase 3 VERIFY study (NCT05210790) of rusfertide, an investigational hepcidin mimetic, offering a potential paradigm shift in PV management.2
Understanding the Challenges of Polycythemia Vera
Andrew Kuykendall, MD
Driven by activating mutations in the JAK2 gene, PV leads to an overproduction of blood cells, primarily red blood cells, increasing a patient's hematocrit, explained Kuykendall, assistant member at Moffitt Cancer Center in the Department of Malignant Hematology.1 This elevated hematocrit significantly raises the risk of life-threatening cardiovascular events, including heart attacks, strokes, and blood clots. The primary goal of PV treatment is to mitigate this thrombotic risk.
“We'll put patients on antiplatelet therapy, so most are on a [low-dose] aspirin. Some patients will get cytoreductive therapy, so some sort of medication to help bring blood counts down or control blood counts. That could be hydroxyurea or interferon formulations or ruxolitinib [Jakafi], approved as a second-line agent,” Kuykendall said in an interview with Targeted OncologyTM.
However, the cornerstone of red blood cell control remains therapeutic phlebotomy, aiming to maintain a hematocrit below 45% to reduce thrombotic events fourfold.
"The problem with that is that while we do a lot of therapeutic phlebotomies, patients do not necessarily tolerate those well, and it is somewhat of an archaic way of controlling blood counts," Kuykendall explained. "It ties them to the health care system, it causes fluid shifts that may make them lightheaded or pass out or feel terrible, and then it kind of worsens and exacerbates iron deficiency, which is associated with a whole host of other symptoms that patients suffer with." The unmet need, therefore, lies in finding a more effective and tolerable way to control blood counts while improving patient quality of life.
The VERIFY Study: A Novel Approach
The VERIFY study investigates rusfertide, a hepcidin mimetic. Hepcidin is a master regulator of iron, controlling the distribution of iron into the bloodstream.3 By mimicking a high hepcidin state, rusfertide effectively withholds iron from the bone marrow, thereby restricting red blood cell production.
The study enrolled patients with PV who consistently required phlebotomies and randomized them 1:1 to receive either rusfertide or placebo, in addition to their existing standard of care therapy.2 The primary end point for part 1a (32 weeks) was the absence of phlebotomy eligibility between weeks 20 and 32. Key secondary end points included the mean number of phlebotomies, the proportion of patients maintaining a hematocrit less than 45% from week 0 to 32, and patient-reported outcome measures for fatigue (PROMIS fatigue score) and overall symptoms (Myelofibrosis Symptom Assessment Form).
Remarkable Findings: Doubled Response Rates and Symptom Improvement
The results from part 1a of the VERIFY study were highly encouraging.
"With the primary end point, we found that being on rusfertide more than doubled the response rate," Kuykendall said. Over 70% of patients receiving rusfertide achieved the absence of phlebotomy eligibility, compared with just over 30% in the placebo arm. Subgroup analyses showed a consistent benefit across various patient demographics, disease durations, and risk classifications.
Regarding secondary end points, rusfertide significantly reduced the mean number of phlebotomies at 0.5 for rusfertide vs 1.8 for placebo over 32 weeks, a more than 3-fold reduction. Over 60% of patients treated with rusfertide maintained a hematocrit below 45% for the duration of the study compared with only about 14% in the placebo group.
Beyond blood count control, rusfertide also demonstrated superiority in patient-reported outcomes. Patients treated with rusfertide experienced a greater decline in fatigue scores and improvement in their myelofibrosis symptom assessment compared to placebo.
"I think [it is] important to see [that] we are hitting the target as far as controlling hematocrit and reducing phlebotomy requirements, but also, patients had a trend, and a consistent trend towards feeling better too," Kuykendall said.
Reshaping the Patient Experience: Beyond Just Numbers
Kuykendall explained how rusfertide could transform the daily lives of patients with PV. While achieving numerical goals like hematocrit control is important, he stressed the significance of "disease experience modification."
"I think that they suffer from just kind of feeling like a patient, right? They are tied to the health care system," he said.
Many PV patients, despite living long lives, grapple with profound fatigue and the constant burden of phlebotomies and their associated iron deficiency.
"If this can move the needle and help patients that are struggling with that fatigue, that brain fog, that inability to participate in daily life, then I think this could be a real game changer for a lot of those folks as well,” Kuykendall added.
Rusfertide offers benefits for those struggling with phlebotomies due to discomfort, poor venous access, or the logistical challenges of frequent clinic visits. It also provides autonomy through self-administered subcutaneous injections.
Future Directions and Unanswered Questions
The VERIFY study continues with part 1b, where all patients, including those initially on placebo, will transition to rusfertide, followed by a long-term safety assessment in part 2.2 Researchers aim to understand if rusfertide allows for dose optimization of concomitant cytoreductive therapies, potentially reducing adverse events.
Long-term goals include monitoring thrombotic risk, disease progression, and comprehensive long-term safety data. While the initial 32-week findings are clinically significant, future research will delve deeper into patient-reported outcomes, exploring which subgroups derive the most symptomatic benefit.
Kuykendall also expressed interest in investigating rusfertide earlier in the disease course, particularly for patients with newly diagnosed disease and uncontrolled red blood cell counts and exploring its potential in combination with frontline cytoreductive therapy to achieve rapid and enhanced disease control. The VERIFY study's findings mark a significant step forward, offering a promising avenue to not only manage the clinical aspects of polycythemia vera but also profoundly improve the lived experience of patients.
