Polycythemia vera is driven by abnormal blood-cell production, but the disease still depends on something much more basic: iron. Hepcidin, the hormone that controls how iron moves through the body, has become a new treatment target because limiting iron availability can restrain red blood cell production even when the underlying JAK2-driven disease remains active.
Polycythemia vera is driven by JAK2, but red blood cells still need iron
Polycythemia vera, or PV, is a chronic myeloproliferative neoplasm in which the bone marrow produces too many blood cells, especially red blood cells. In most patients, the disease is driven by activating mutations in JAK2, which keep growth signaling switched on even without the normal physiologic cues.
That constitutive signaling explains why the marrow keeps trying to make blood cells. But erythropoiesis still requires iron because every new red blood cell must synthesize hemoglobin. No matter how strong the growth signal becomes, red blood cell production cannot proceed indefinitely without access to iron.
This creates a useful distinction between the driver of PV and the raw material the marrow needs to carry out that signal. JAK2 drives the disease clone. Iron helps determine how much erythrocytosis that clone can produce.
Hepcidin is the body’s master regulator of iron traffic
Hepcidin is a peptide hormone made primarily by the liver. Its key target is ferroportin, the main iron-export protein on intestinal cells, macrophages, and other cells that release iron into the bloodstream.
When hepcidin binds ferroportin, the transporter is internalized and degraded. Less iron then moves from intestinal cells into plasma, and less recycled iron is released from macrophages that have broken down old red blood cells.
The result is lower circulating iron availability. Iron can still be present in the body, but less of it is accessible to developing red blood cells in the bone marrow.
PV creates an unusual combination of erythrocytosis and iron deficiency
Polycythemia vera is unusual because many patients are iron deficient even while producing too many red blood cells. The disease itself consumes large amounts of iron through excessive erythropoiesis, and treatment with repeated phlebotomy removes additional iron from the body.
That creates a physiologic paradox: the marrow is overproducing red blood cells while the patient becomes increasingly iron depleted.
Phlebotomy has long exploited this biology indirectly. Removing blood immediately lowers the red cell mass, but it also removes iron. Over time, iron deficiency itself helps slow new red blood cell production.
The problem is that repeated phlebotomy can be burdensome and may worsen symptoms associated with iron deficiency. A therapy that reproduces the iron-restricting effect without repeatedly removing blood therefore has obvious appeal.
Hepcidin mimetics deliberately create functional iron restriction
A hepcidin mimetic is designed to reproduce the biologic action of natural hepcidin. Instead of removing iron from the body, the drug changes where iron is allowed to move.
Rusfertide binds ferroportin and reduces iron export into the circulation. That decreases iron delivery to the bone marrow and limits the amount available for hemoglobin synthesis and red blood cell production.
This is best described as functional iron restriction. Total body iron is not necessarily being depleted to the same degree as with phlebotomy. Instead, iron becomes less available to the erythroid compartment.
That mechanism is why rusfertide can control hematocrit without directly killing the abnormal PV clone.
The phase 2 REVIVE trial showed the mechanism could translate into hematocrit control
REVIVE was an international phase 2 study of rusfertide in patients with phlebotomy-dependent polycythemia vera. Seventy patients entered an initial 28-week dose-finding phase, and 59 later entered a randomized withdrawal phase in which they received either rusfertide or placebo.
Before treatment, the estimated mean number of phlebotomies was 8.7 per year. During the initial rusfertide treatment period, that fell to 0.6 per year. Mean maximum hematocrit was 44.5% during treatment compared with 50.0% in the 28 weeks before the first dose.
During the randomized withdrawal phase, 60% of patients continuing rusfertide met the composite response endpoint versus 17% of those switched to placebo (P=0.002).
The investigators wrote that rusfertide “appears to represent a step forward” in PV treatment. The reason was not that it eliminated the disease clone, but that it controlled one of the disease’s most clinically important outputs: erythrocytosis.
Phase 3 data led to the first FDA approval of a hepcidin mimetic
FDA approved Mimrylo (rusfertide) in August 2026 for the treatment of erythrocytosis in adults with polycythemia vera. It became the first approved therapy in PV that directly mimics hepcidin.
The phase 3 VERIFY trial randomized 293 adults who still required frequent phlebotomy despite standard treatment. FDA reported that 76.9% of patients receiving rusfertide required no phlebotomy during the 32-week treatment period, compared with 32.9% receiving placebo.
Our Mimrylo approval article covers the dosing, phase 3 results, and safety information in detail.
Hematocrit matters because thrombosis is a major risk in PV
One of the central treatment goals in polycythemia vera is maintaining hematocrit below 45%. Excess red blood cells increase blood viscosity and contribute to the elevated risk of thrombosis, including stroke, myocardial infarction, and venous thromboembolism.
That is why therapies are judged partly by their ability to keep hematocrit controlled and reduce the need for rescue phlebotomy.
Our thrombosis and cardiovascular risk explainer discusses how platelet activation and clot formation can translate into heart attack and stroke risk through a different biological pathway.
Hepcidin therapy does not replace JAK2-directed or clone-directed treatment
The hepcidin approach acts downstream of the disease-driving mutation. It limits the resources available for erythropoiesis rather than directly suppressing the abnormal hematopoietic clone.
That means rusfertide should not be interpreted as a molecular cure for JAK2-mutant disease. Patients may still need cytoreductive or disease-directed therapy depending on age, thrombotic risk, blood counts, symptoms, and prior treatment.
This distinction is similar to the difference between controlling a signaling pathway and controlling a downstream consequence. Our JAK pathway explainer shows how kinase signaling can drive disease biology, although PV is primarily associated with JAK2 rather than TYK2 or JAK1.
What the evidence cannot yet answer
The strongest evidence for rusfertide is that it lowers hematocrit and reduces phlebotomy requirements. Those are clinically meaningful outcomes, but they are still surrogate hematologic endpoints.
Current trials have not yet established whether hepcidin mimetic therapy reduces long-term rates of thrombosis, progression to myelofibrosis, transformation to acute leukemia, or overall mortality. A 2026 review of the hepcidin-ferroportin axis in PV emphasized that disease modification remains unproven.
REVIVE was small, with 70 patients in the initial phase and 59 in the randomized withdrawal phase. VERIFY was larger, but the development program was sponsored by Protagonist Therapeutics and Takeda, the companies developing and commercializing rusfertide.
The mechanism also raises an important biological question: restricting iron can control red blood cell production without eradicating the clone, so long-term studies are needed to determine how disease biology evolves when erythrocytosis is controlled through iron trafficking rather than by suppressing the malignant population itself.
Hepcidin turns iron metabolism into a druggable control point
The importance of hepcidin in polycythemia vera comes from separating cause from dependency. JAK2 signaling causes the marrow to overproduce cells, but erythrocytosis still depends on iron. By closing the ferroportin gate and restricting iron delivery to the marrow, hepcidin mimetics can reduce red blood cell output without directly targeting the malignant clone.
That makes iron metabolism more than a side effect of PV or phlebotomy. It is now a therapeutic pathway in its own right.
References
- Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. N Engl J Med. 2024;390:723-735. DOI: 10.1056/NEJMoa2308809.
- U.S. Food and Drug Administration. FDA Approves First Drug of Its Kind for Polycythemia Vera, a Rare Blood Disorder. August 28, 2026. FDA press release.