Opinion|Videos|May 26, 2025
Hepcidin Mimetic Mechanism: Scientific Rationale in Polycythemia Vera
Panelists discuss how hepcidin mimetics like rusfertide offer a novel approach to managing polycythemia vera (PV) by regulating iron metabolism, reducing iron overload, and improving hematocrit control, particularly in patients with iron deficiency or refractory disease, while also potentially enhancing disease management and quality of life when used alone or in combination with standard therapies like hydroxyurea or ruxolitinib.
Episodes in this series
Summary for Physicians: Hepcidin Mimetics and Their Role in PV—Focus on Rusfertide
Hepcidin mimetics, such as rusfertide, represent an innovative approach to managing polycythemia vera (PV), particularly in patients with challenges related to iron overload or excess erythropoiesis. These agents function by mimicking the action of hepcidin, a key regulator of iron homeostasis.
Mechanism of Action of Rusfertide:
- Mimicking Hepcidin:
- Hepcidin is a natural regulator of iron metabolism, inhibiting iron absorption from the gut and trapping iron in macrophages, thus reducing available iron for red blood cell (RBC) production. Rusfertide, a synthetic hepcidin mimetic, acts similarly by binding to the ferroportin protein on cell membranes, promoting its internalization and degradation. This reduces iron efflux from cells and lowers serum iron levels.
- Iron Regulation and Erythropoiesis:
- In PV, excess erythropoiesis often leads to iron deficiency due to increased RBC production and phlebotomy. Rusfertide helps control iron levels by reducing iron availability, which may help normalize hematocrit and prevent iron overload, particularly in patients receiving frequent phlebotomy or those with symptomatic iron deficiency.
- Therapeutic Impact:
- By reducing iron availability, rusfertide can lower red blood cell production and improve hematocrit control in PV, especially in those with polycythemia-related iron overload or those who experience refractory disease despite standard therapies (eg, hydroxyurea).
- It may also help mitigate symptoms related to iron overload and reduce the need for frequent phlebotomy, potentially improving quality of life.
Clinical Role in PV:
- Iron Overload Management: Rusfertide may be particularly useful in patients with iron overload due to frequent phlebotomy or those at risk for hemochromatosis-like symptoms. By controlling iron levels, it could reduce the need for iron chelation therapy.
- Combination With Other Therapies: Rusfertide may be used in combination with standard cytoreductive treatments like hydroxyurea or ruxolitinib to address iron overload while simultaneously controlling hematocrit and disease progression.
Conclusion: Hepcidin mimetics like rusfertide offer a promising new mechanism to manage iron metabolism and hematopoiesis in PV patients, especially those with iron overload or refractory disease. By reducing iron availability, rusfertide helps control erythropoiesis and may improve disease management and quality of life for these patients.
