Dr Kuykendall on the Development of Hepcidin-Upregulating Agents in Polycythemia Vera

[Hematocrit control with phlebotomy] is kind of like [having] a hole in your boat, and you’re just dumping out water. It keeps the boat dry to some extent, but it’s a continuous process, and it’s not super comfortable.

Andrew Kuykendall, MD, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the emergence of hepcidin-upregulating agents as a treatment class for patients with polycythemia vera and how these agents could address a central unmet need in the field: maintaining consistent control of hematocrit.

Maintaining a hematocrit level below 45% across a higher proportion of remains an unmet need in the management of PV, Kuykendall explained. That target has traditionally been pursued with therapeutic phlebotomy, but the approach is burdensome, uncomfortable, and often inadequate, leaving substantial numbers of patients in need of improved hematocrit control.

As such, research in the polycythemia vera space has focused on agents intended to upregulate hepcidin and control hematocrit levels, and this work has led to the introduction of 1 agent in clinical practice and a parade of agents deep along the developmental pathway. In August 2026, the FDA approved the hepcidin mimetic rusfertide (Mimrylo) for the treatment of adult patients with polycythemia vera. On top of the approved agent, Kuykendall highlighted others in development, including the antisense oligonucleotide sapablursen (formerly ISIS 702843), which produced strong data in the phase 2 IMPRSSION trial (NCT05143957) and is advancing to the phase 3 INTREPID trial (NCT07429266); the short interfering RNA therapy divesiran (SLN124), which met a response primary end point in the phase 2 portion of the SANRECO trial (NCT05499013); and the TMPRSS6-targeting monoclonal antibody DISC-3405, which lowered the rate of phlebotomies and maintained hematocrit control in the phase 2 RESTORE-PV trial (NCT06985147).

This development of these types of agents rests on iron biology, according to Kuykendall. Patients with polycythemia vera are iron deficient and therefore carry low hepcidin levels, which frees iron for delivery to the bone marrow and drives excess red blood cell production. Repeated phlebotomy deepens the iron deficiency and perpetuates the cycle. Agents that raise hepcidin restrict iron availability and erythropoiesis, allowing hematocrit to be held at goal without the fluctuations seen with phlebotomy, he said.