Rusfertide Targets Iron Availability to Help Control Hematocrit in PV

For patients with polycythemia vera (PV), controlling excessive red blood cell production can mean frequent blood tests, therapeutic phlebotomies, and persistent symptoms. Andrew Kuykendall, MD, associate member of the Department of Hematology at Moffitt Cancer Center and lead investigator of the VERIFY trial (NCT05210790), said rusfertide, a hepcidin mimetic, offers a way to address the underlying relationship between iron availability and erythrocytosis.

PV is primarily characterized by uncontrolled production of red blood cells, but other cell types can also be overproduced. This erythrocytosis increases thrombotic risk and can require repeated phlebotomies to keep blood counts at acceptable levels, Kuykendall explained.

But the disease also creates a paradox: patients can be iron deficient while continuing to produce too many red blood cells. Because red blood cell production requires iron, ongoing erythrocytosis can deplete iron stores, contributing to symptoms such as decreased concentration, brain fog, and fatigue. Patients must also repeatedly return to the health care system for blood counts and phlebotomies, which themselves can be fatigue-inducing and can cause fluid shifts that some patients tolerate poorly.

The mechanism of rusfertide centers on hepcidin, a hormone that regulates iron availability. Normally, when a person becomes iron deficient, hepcidin levels decrease, allowing more iron to enter the bloodstream and reach the bone marrow for red blood cell production.

“In polycythemia vera, you’re iron deficient, but you’re making too many red blood cells,” Kuykendall said.

Low hepcidin, therefore, allows iron to continue reaching the bone marrow, supporting further red blood cell production and perpetuating the cycle of erythrocytosis and iron deficiency. Rusfertide essentially reverses that process by mimicking hepcidin. By increasing hepcidin activity, it downregulates iron availability to the bone marrow and restricts the amount of red blood cell production. The dose can then be titrated to allow for consistent control of hematocrit at goal levels, Kuykendall said.

For patients, that mechanism could translate into less reliance on repeated phlebotomies and fewer health care visits, while potentially avoiding the continued iron depletion associated with uncontrolled erythrocytosis. Rather than simply removing blood after red blood cell production has occurred, rusfertide works by limiting the iron available to support that production in the first place.