Integrating Novel Agents: Clinical Positioning of Hepcidin Mimetics

Summary for Physicians: Complementary Role of Hepcidin Mimetics in PV Therapy

Hepcidin mimetics, such as rusfertide, offer a novel mechanism of action that can complement existing therapeutic approaches in the management of polycythemia vera (PV). These agents help regulate iron metabolism, which can be beneficial in managing symptoms related to iron overload and erythropoiesis in PV patients.

How Hepcidin Mimetics Complement Current Therapies:

1. Complementing Cytoreductive Therapies:

• Cytoreductive agents (eg, hydroxyurea, ruxolitinib) help control hematocrit and reduce blood viscosity. However, these treatments often lead to iron deficiency or overload due to phlebotomy or increased erythropoiesis.

• Hepcidin mimetics, like rusfertide, can help by reducing iron availability, thus lowering excessive RBC production and preventing iron overload, which is commonly seen in patients on long-term phlebotomy or with refractory disease.

1. Managing Iron Overload:

• Phlebotomy is a cornerstone of PV management to reduce hematocrit levels. However, frequent phlebotomy can cause iron deficiency or, in some cases, iron overload.

• Rusfertide mimics hepcidin, which regulates iron by reducing iron absorption and trapping iron in cells. This action helps to balance iron levels, potentially reducing the need for iron chelation therapy and minimizing symptoms associated with iron overload.

1. Enhancing Quality of Life:

• Patients with PV may experience symptoms related to both iron deficiency and excess erythropoiesis, such as fatigue or splenomegaly.

• By improving iron homeostasis and reducing erythropoiesis, rusfertide can help alleviate these symptoms, potentially improving overall quality of life and reducing the frequency of phlebotomies required for symptom control.

1. Targeting Disease Features Beyond Hematocrit Control:

• In addition to addressing hematocrit control, ruxolitinib and other JAK inhibitors are often used for managing splenomegaly and PV-associated symptoms (eg, pruritus, fatigue). Hepcidin mimetics may provide additional benefit by helping regulate iron levels, reducing the risk of secondary complications like iron overload, which can worsen fatigue and other systemic symptoms.

1. Potential for Long-Term Disease Control:

• By addressing iron dysregulation, hepcidin mimetics like rusfertide may help optimize the effects of other long-term treatments, such as hydroxyurea or interferon, and provide more durable control over PV symptoms and complications.

• This complementary action might lead to improved management of disease burden over time, reducing the risk of progression and enhancing overall disease outcomes.

Conclusion: Hepcidin mimetics offer a promising complementary approach to existing PV therapies by managing iron metabolism and erythropoiesis. When used alongside traditional cytoreductive therapies, these agents can improve iron homeostasis, reduce the risk of iron overload, and potentially enhance quality of life for PV patients, making them a valuable addition to the therapeutic arsenal.