Journal of Clinical Oncology October 13, 2026

VERIFY: A Phase III Trial of Rusfertide Versus Placebo in Phlebotomy-Dependent Patients With Polycythemia Vera Receiving Standard-of-Care Therapy

Andrew T. Kuykendall, Aniket Bankar, Kristen M. Pettit, et al.

Bottom Line

In the phase III VERIFY trial, the addition of the hepcidin mimetic rusfertide to standard-of-care therapy in phlebotomy-dependent polycythemia vera patients significantly improved hematocrit control, nearly eliminated the need for phlebotomy, and reduced patient-reported fatigue compared to placebo.

Key Findings

1. Rusfertide significantly increased the rate of clinical response (defined as the absence of phlebotomy eligibility during weeks 20-32), with 77% (n = 113) of patients in the rusfertide arm achieving this primary endpoint compared to 33% (n = 48) in the placebo arm (P < .0001).

2. The mean number of phlebotomies required between baseline and week 32 was significantly reduced in the rusfertide group (0.5 ± 1.2) compared to the placebo group (1.8 ± 1.5) (P < .0001).

3. Rusfertide demonstrated superiority in continuously maintaining a hematocrit level <45%, achieved by 63% (n = 92) of patients receiving the drug versus only 14% (n = 21) receiving placebo (P < .0001).

4. The intervention led to significant improvements in patient-reported symptom burdens, specifically the PROMIS Fatigue SF-8a T-score (P = .0252) and the MFSAF TSS7 (P = .0240) versus placebo.

5. The most common adverse events in the rusfertide group included injection site reactions, anemia, and fatigue, with no deaths reported in the study.

Study Design

Design

Phase III RCT

Double-Blind

Sample

293

Patients

Duration

32 weeks

Median

Setting

Multicenter

Population Phlebotomy-dependent adult patients with polycythemia vera and poorly controlled hematocrit despite receiving standard-of-care therapy.

Intervention Subcutaneous rusfertide (a hepcidin mimetic peptide) in addition to background standard-of-care therapy (with or without cytoreductive therapy).

Comparator Subcutaneous placebo in addition to background standard-of-care therapy (with or without cytoreductive therapy).

Outcome Clinical response, defined as the absence of phlebotomy eligibility during weeks 20 to 32 of the study.

Study Limitations

• The initial 32-week double-blind follow-up (Part 1a) is relatively short for a chronic indolent condition, leaving long-term safety, durability of response, and the impact on major cardiovascular/thrombotic events to be determined in subsequent extensions.

• A high incidence of injection site reactions associated with the active subcutaneous drug may have inadvertently compromised blinding, potentially introducing subjective bias into patient-reported symptom and fatigue outcome measures.

• The primary endpoint focused on short-term surrogate laboratory markers (hematocrit control and phlebotomy elimination) rather than hard clinical endpoints like thrombosis-free survival or overall survival.

Clinical Significance

Rusfertide represents a first-in-class, disease-modifying approach for polycythemia vera (PV) by mimicking the endogenous master iron regulator hepcidin. By suppressing iron availability for erythropoiesis without causing the severe systemic tissue iron depletion associated with chronic phlebotomies, rusfertide successfully halts runaway red blood cell production. Its robust efficacy in maintaining hematocrit <45% (the critical threshold for mitigating thrombotic risk in PV) and reducing both phlebotomy burden and fatigue positions it as a major advance for patients inadequately controlled by standard cytoreductive therapies.

Historical Context

The cornerstone of polycythemia vera (PV) management for decades has been minimizing the risk of major thrombotic events by maintaining a hematocrit level strictly below 45%. This is traditionally achieved via therapeutic phlebotomy, often combined with cytoreductive agents (such as hydroxyurea, pegylated interferons, or the JAK inhibitor ruxolitinib) for high-risk patients. However, chronic phlebotomy inherently induces absolute systemic iron deficiency, which perversely drives PV-associated symptoms such as profound fatigue and cognitive deficits. Rusfertide was developed to exploit the hepcidin-ferroportin axis; as a hepcidin mimetic, it therapeutically restricted iron specifically from the bone marrow's erythroid lineage. After highly promising Phase 2 data showed the feasibility of substituting systemic iron depletion with targeted iron restriction, the VERIFY Phase 3 trial was launched to definitively validate this novel mechanism of action, culminating in rusfertide becoming the first therapeutic option explicitly targeting the hepcidin pathway in PV.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of a hepcidin mimetic like rusfertide specifically target the pathophysiology of polycythemia vera to reduce the need for phlebotomy?

Key Response

Hepcidin is the master regulator of iron homeostasis. It binds to ferroportin on enterocytes and macrophages, inducing its internalization and degradation. This prevents iron absorption and traps iron in macrophages. In polycythemia vera, continuous erythropoiesis requires high iron turnover. By mimicking hepcidin, rusfertide induces a functional iron deficiency, restricting the iron supply necessary for excess red blood cell production, thereby controlling hematocrit without the volume shifts of phlebotomy.

Resident

In a patient with polycythemia vera who remains phlebotomy-dependent despite maximum tolerated hydroxyurea, how does the addition of rusfertide alter the clinical management of hematocrit targets and iron deficiency symptoms compared to traditional therapeutic phlebotomy?

Key Response

Traditional phlebotomy controls hematocrit but exacerbates systemic iron deficiency, which often causes profound fatigue in polycythemia vera patients. Rusfertide manages hematocrit by trapping iron rather than removing it from the body, achieving stable hematocrit control and preventing the cyclical peaks and troughs seen with intermittent phlebotomies. This shifts the treatment paradigm from treating the symptom via red cell removal to modulating substrate availability, improving the fatigue associated with true iron depletion.

Fellow

While the VERIFY trial demonstrated improved hematocrit control, how might prolonged systemic iron restriction and macrophage iron loading via hepcidin agonism impact long-term disease progression, such as clonal evolution or thrombotic risk in polycythemia vera?

Key Response

Fellows must consider the downstream consequences of chronic ferroportin degradation. While limiting iron restricts erythropoiesis, it also traps iron within reticuloendothelial macrophages. The long-term effects of this macrophage iron loading and systemic functional iron restriction on other marrow lineages, immune function, or the inflammatory microenvironment in a myeloproliferative neoplasm require careful study. Furthermore, evaluating if rusfertide impacts leukocyte or platelet counts is critical, as these are also implicated in polycythemia vera thrombosis.

Attending

Given the nearly complete elimination of phlebotomy and reduction in fatigue with rusfertide in the VERIFY trial, how should clinicians balance the financial toxicity and potential novel toxicities of this drug class against the established, inexpensive standard of therapeutic phlebotomy?

Key Response

Attendings must weigh clinical efficacy against healthcare value and practical implementation. While rusfertide significantly improves quality of life and eliminates a cumbersome procedure, it requires regular injections and carries a high cost. The critical teaching point focuses on patient selection, specifically identifying those with severe phlebotomy intolerance, refractory symptoms, or extreme fatigue who will derive the most meaningful benefit, rather than adopting it uniformly for all patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The VERIFY trial evaluates patient-reported fatigue as a key endpoint. From a trial design perspective, what are the methodological challenges regarding unblinding and placebo effects when the active intervention dramatically alters the frequency of a tangible procedure like therapeutic phlebotomy?

Key Response

A core methodological critique is that patients in the placebo arm will continue requiring frequent phlebotomies, whereas the rusfertide arm will not. Even with blinded drug administration, the downstream effect of frequent versus no phlebotomy is highly visible to both patient and investigator, effectively unblinding the study. This dynamic severely confounds the assessment of subjective endpoints like patient-reported fatigue, necessitating complex statistical sensitivity analyses and objective corroborating biomarkers.

Journal Editor

As a peer reviewer, how would you critically evaluate the standardization of the standard-of-care background arm in the VERIFY trial, and what threat does heterogeneous baseline cytoreductive therapy pose to the validity of the hematocrit control outcomes?

Key Response

Editors must scrutinize the control arm. If standard-of-care allowed heterogeneous use of hydroxyurea, interferon, or ruxolitinib with variable dose titrations during the study, it could introduce significant confounding. A tough reviewer would flag whether the placebo group received truly optimized cytoreductive dosing or if investigators held back on maximizing standard therapy, which could artificially inflate the apparent delta in efficacy between the rusfertide and placebo groups.

Guideline Committee

How should the findings of the VERIFY trial influence the next iteration of the ELN and NCCN guidelines for polycythemia vera management, specifically regarding the sequencing of hepcidin mimetics versus second-line cytoreductive agents for patients failing first-line hydroxyurea?

Key Response

Current NCCN and ELN guidelines recommend strict hematocrit control below 45 percent using phlebotomy and cytoreduction. The committee must determine if rusfertide should be an add-on therapy solely for phlebotomy-dependent patients, or if its efficacy in fatigue management elevates it above or alongside ruxolitinib in the second-line setting. The recommendation strength will heavily depend on long-term safety data, particularly regarding thrombosis prevention, which remains the primary goal of therapy.

Clinical Landscape

Noteworthy Related Trials

2013

CYTO-PV Trial

n = 365 · NEJM

Tested

Strict hematocrit control target under 45 percent

Population

Patients with polycythemia vera

Comparator

Less strict hematocrit target of 45 to 50 percent

Endpoint

Time until cardiovascular death or major thrombotic events

Key result: Maintaining a hematocrit target of less than 45 percent resulted in a significantly lower rate of cardiovascular death and major thrombosis.

2015

RESPONSE Trial

n = 222 · NEJM

Tested

Ruxolitinib 10 mg twice daily

Population

Polycythemia vera patients resistant or intolerant to hydroxyurea

Comparator

Best available therapy

Endpoint

Composite of hematocrit control and at least 35 percent reduction in spleen volume at week 32

Key result: Ruxolitinib was significantly more effective than standard therapy in controlling hematocrit, reducing spleen volume, and improving symptom burdens.

2021

PROUD-PV Trial

n = 254 · Lancet Haematol

Tested

Ropeginterferon alfa-2b

Population

Patients with early-stage polycythemia vera

Comparator

Hydroxyurea

Endpoint

Complete hematological response with normal spleen size at 12 months

Key result: Ropeginterferon alfa-2b demonstrated high rates of long-term disease modification and molecular responses compared to hydroxyurea over a multi-year continuation phase.

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