Rusfertide’s target in polycythemia vera (PV) is iron homeostasis, not the malignant clone. The first-in-class hepcidin mimetic limits the iron available for red cell production, and the phase III VERIFY trial tested whether that single action can control hematocrit in patients who remain phlebotomy-dependent despite standard care (Kuykendall et al., 2026).
An accompanying editorial places the drug within an increasingly individualized approach to PV, where goals now extend beyond hematocrit control to symptoms, complete hematologic response, and possible disease modification (Torre and Harrison, 2026).
Hematocrit Control and Its Cost
PV is a chronic myeloproliferative neoplasm marked by clonal erythrocytosis and a higher risk of arterial and venous thrombosis. The CYTO-PV trial showed that keeping hematocrit below 45% reduces major cardiovascular and thrombotic events compared with a 45%-50% target. Standard management combines low-dose aspirin and therapeutic phlebotomy, with hydroxyurea, interferon, or ruxolitinib added when cytoreduction is indicated.
Control is often inconsistent. Observational data cited by the VERIFY investigators show that only 14% of low-risk and 25% of high-risk patients kept hematocrit below 45% at every assessment. Repeated phlebotomy also depletes iron stores. Iron restriction helps limit erythrocytosis, but chronic iron deficiency may contribute to fatigue, impaired concentration, and reduced quality of life.
Hepcidin Mimicry
Rusfertide is a subcutaneous peptide that mimics hepcidin, the main regulator of systemic iron availability. Hepcidin inhibits ferroportin, the protein that exports iron from intestinal cells and macrophages into the circulation. Blocking that export limits the iron available for red cell production.
Hydroxyurea and interferon act on hematopoietic cell production, and ruxolitinib inhibits JAK signaling, which can improve blood counts, splenomegaly, and symptoms. Rusfertide targets erythrocytosis only. It isn’t designed to suppress the malignant clone, normalize leukocyte or platelet counts, or reduce spleen volume. The phase II REVIVE trial showed hematocrit control and fewer phlebotomies. VERIFY tested this in a larger placebo-controlled study.
Study Design
VERIFY is an ongoing international trial at 102 centers in 19 countries. It enrolled 293 adults with PV who had required at least three phlebotomies within 28 weeks or five within one year before randomization. All had hematocrit below 45% immediately before randomization, so the study measured maintenance of control in patients with a history of frequent phlebotomy.
Patients received weekly subcutaneous rusfertide or placebo for 32 weeks on top of standard care, with rusfertide doses adjusted to keep hematocrit below 45%. At baseline, 55% were receiving cytoreductive therapy (stable before enrollment) and 45% phlebotomy alone. About half had high-risk disease, and median age was 57 years.
The primary endpoint was clinical response during weeks 20-32, defined as no protocol-defined phlebotomy eligibility and no specified intercurrent events. Key secondary endpoints were phlebotomy number, sustained hematocrit control below 45%, fatigue, and overall symptom burden. Eligible patients then entered an open-label extension in which all received rusfertide.
Results: Response and Phlebotomy Burden
VERIFY met its primary endpoint: 77% versus 33%. The benefit was consistent across prespecified subgroups.
- Response rates were 82% versus 33% in patients on phlebotomy alone and 73% versus 33% in those on cytoreductive therapy.
- Sustained hematocrit control below 45% was achieved by 63% of rusfertide patients and 14% of placebo patients.
Before enrollment, both groups averaged about 4.5 phlebotomies over the preceding 32 weeks. During randomized treatment:
- The mean fell to 0.5 with rusfertide and 1.8 with placebo.
- No phlebotomy was needed in 73% of rusfertide patients versus 22% of placebo patients, regardless of background cytoreduction.
Durability Through 52 Weeks
Of patients who met the primary endpoint during weeks 20-32, 84% maintained response during weeks 32-52. Across the original rusfertide group, 62% met the stringent response definition throughout the full 52 weeks.
Patients who switched from placebo to rusfertide at week 32 had a rapid fall in hematocrit, and 78% had a clinical response during weeks 40-52. The open-label crossover supports consistency of effect but lacks the comparative strength of the randomized phase. Multiyear follow-up is needed.
Fatigue and Iron Parameters
At week 32, rusfertide improved fatigue on the PROMIS Fatigue Short Form versus placebo. The Myelofibrosis Symptom Assessment Form total symptom score, which covers fatigue, night sweats, pruritus, abdominal discomfort, early satiety, and other symptoms, also improved.
The between-group differences were modest, and the trial did not show a clinically meaningful improvement in every patient. Fatigue in PV is multifactorial, with inflammatory signaling, disease-related symptoms, and sleep disturbance contributing independently of iron status. Ferritin and other iron parameters rose during treatment, and MCV moved toward normal, including in patients who crossed over from placebo.
Which Patients Could Benefit Most From Rusfertide?
The editorial identifies two candidate groups. The first is patients with genuinely low-risk PV, usually managed with aspirin and phlebotomy, who have significant phlebotomy-related symptoms such as iron deficiency, fatigue, or difficult venous access. VERIFY did not compare rusfertide with starting cytoreduction in these patients.
The second is patients whose leukocyte and platelet counts are controlled on hydroxyurea, interferon, or ruxolitinib but who still need intermittent phlebotomy. Escalating cytoreduction solely to remove residual phlebotomy needs may add toxicity. The consistent benefit in VERIFY participants already on cytoreduction supports this use, but the trial did not test rusfertide against optimizing or changing cytoreductive therapy.
Hematocrit Control Versus Disease Modification
PV management has historically centered on preventing thrombosis through hematocrit control. Recent studies have broadened the goals. RESPONSE showed that ruxolitinib improved hematocrit control, spleen response, and symptoms in patients resistant or intolerant to hydroxyurea.
MAJIC-PV associated complete hematologic response with better event-free survival, and reduced JAK2V617F allele burden with better overall survival. Long-term PROUD-PV and CONTINUATION-PV data suggest ropeginterferon alfa-2b can produce sustained molecular responses, though molecular response is not yet a validated survival surrogate across PV treatments.
Rusfertide has not shown molecular disease modification, and its mechanism doesn’t predict reductions in leukocyte count, platelet count, or spleen volume. VERIFY therefore used absence of phlebotomy eligibility as its primary endpoint. The differing mechanisms and endpoints also preclude efficacy comparison across VERIFY, RESPONSE, MAJIC-PV, and the interferon studies. Where cytoreduction is indicated, rusfertide is more likely to complement it.
Safety
Most adverse events were grade 1-2. Grade 3 events occurred in 9% of rusfertide patients and 7% of placebo patients. Injection-site reactions were the most common, affecting 56% on rusfertide during the first 32 weeks versus 33% on placebo, and declined with continued treatment. Serious adverse events were uncommon, and no deaths occurred.
Two thromboembolic events occurred on rusfertide, an acute myocardial infarction and a deep vein thrombosis, investigators judged both unrelated to treatment.
Cancer events occurred in three rusfertide patients and eight placebo patients, most associated with prior skin cancer or concurrent hydroxyurea. Mandated dermatologic examinations also identified previously unrecognized lesions and cancers before treatment began.
Thrombosis and Long-Term Outcomes
Hematocrit below 45% is an established strategy for reducing thrombosis in PV, and rusfertide reached that target more consistently than placebo. The 32-week randomized period was too short to assess thrombosis, cardiovascular mortality, progression to myelofibrosis, or transformation to acute myeloid leukemia. The investigators also caution against extrapolating CYTO-PV results to VERIFY, since the interventions and endpoints differ.
Cost Implications
Phlebotomy is inexpensive per procedure, but repeated sessions require healthcare resources, travel, time away from work, and monitoring. A biologic adds medication, administration, and monitoring costs. Future evaluations should capture total cost of care, productivity, and quality-adjusted life years, including any reduction in cytoreduction escalation. VERIFY doesn’t support a cost-effectiveness conclusion.
Next Steps
The ongoing VERIFY extension and the phase II THRIVE study will add durability and safety data. Open questions include whether sustained erythrocytosis control affects thrombotic events and disease progression, how hepcidin-directed therapy redistributes iron, whether iron restoration directly relieves fatigue, and how iron-targeted therapy can be combined with disease-directed treatment without added toxicity.
Torre and Harrison identify iron homeostasis as an expanding area of development. Investigational strategies target TMPRSS6, a regulator of hepcidin production, as well as erythroferrone, bone morphogenetic proteins, hemojuvelin, and ferroportin. TMPRSS6-directed agents such as sapablursen and divesiran could differ in dosing frequency, duration of effect, and convenience, but their efficacy and safety in PV are unestablished.
