Rusfertide Approval Aims to Close PV Hematocrit Control Gaps

Nearly 8 in 10 patients with polycythemia vera (PV) still have hematocrit levels above the recommended 45% threshold despite existing therapy, according to Andrew Kuykendall, MD, associate member in the Department of Hematology at Moffitt Cancer Center. Kuykendall, who was the lead investigator for the VERIFY trial (NCT05210790) that supported the FDA’s August 28 approval of rusfertide (Mimrylo; Takeda), explained that the 45% threshold dates back to the 1970s and was reinforced by the CYTO-PV trial (NCT01645124), which linked higher hematocrit targets to a greater risk of cardiovascular events.

In practice, sustaining that target through cytoreductive therapy and aggressive phlebotomy schedules “just doesn’t happen,” he said, leaving many patients walking around with hematocrit above goal and at constant risk for thrombotic events. Rusfertide, a first-in-class hepcidin mimetic, is designed to remove that volatility, comparing inconsistent hematocrit control to repeatedly bailing water out of a leaking boat rather than sealing the leak itself.

“It’s easier to have a boat with no holes in it,” Kuykendall said, rather than keep pouring water out as it comes back in.

How Does Rusfertide’s Approval Change the Treatment Paradigm?

In the VERIFY trial, 76.9% of patients treated with rusfertide achieved a clinical response without phlebotomy from weeks 20 to 32 compared with 32.9% of patients on placebo, according to the FDA. Uncontrolled hematocrit has been linked to as much as a 4-fold higher risk of cardiovascular death or major cardiovascular events, and thrombosis has long been a central concern in PV management.

Much of that excess risk, Kuykendall said, stems from a lack of consistent control rather than from the choice of cytoreductive therapy itself. By reliably keeping hematocrit below 45%, he added, rusfertide could let clinicians shift their attention to optimizing other elements of care, such as selecting and dosing cytoreductive therapy appropriately, without worrying that hematocrit control has slipped and put patients back at risk.

“I think that this kind of closes down, if you will; if there are multiple doors of entry, this closes one of those doors, [allowing] us to focus on the others,” Kuykendall said.