Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis

Abstract

Purpose of reviewDevelopment of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic, rusfertide, is in late-stage clinical development for treating polycythemia vera patients with a global phase 3 trial [NCT05210790] currently underway. Rusfertide serves as the first possible noncytoreductive therapeutic option to maintain haematocrit control and avoid phlebotomy in polycythemia vera patients. In this comprehensive review, we discuss the pathobiology of dysregulated iron metabolism in polycythemia vera, provide the rationale for targeting the hepcidin-ferroportin axis and elaborate on the preclinical and clinical trial evidence supporting the role of hepcidin mimetics in polycythemia vera.Recent findingsRecently, updated results from two phase 2 clinical trials [NCT04057040 & NCT04767802] of rusfertide (PTG300) demonstrate that the drug is highly effective in eliminating the need for therapeutic phlebotomies, normalizing haematological parameters, repleting iron stores and relieving constitutional symptoms in patients with polycythemia vera. In light of these findings, additional hepcidin mimetic agents are also being evaluated in polycythemia vera patients.SummaryHepcidin agonists essentially serve as a ‘chemical phlebotomy’ and are poised to vastly improve the quality of life for phlebotomy requiring polycythemia vera patients.

A randomized placebo−controlled clinical trial of oral green tea epigallocatechin 3−gallate on erythropoiesis and oxidative stress in transfusion−dependent β−thalassemia patients

“…Likewise, monotherapy of iron chelators and the relevant combinations were applied parenterally and/or orally to remove excessive iron depositions in tissues to prevent oxidative tissue damage and organ dysfunction. Therapeutic hepcidin mimetics (e.g., rusfertide) and hepcidin agonists (e.g., TMPRSS6 inhibitor and mini−hepcidin PR73 and mHS17) aim to reverse iron deficiency by targeting hepcidin−ferroportin axis, increase iron influx, mobilize tissue iron, and consequently normalize hematological parameters ( Chua et al, 2015 ; Makis et al, 2021 ; Handa et al, 2023 ). Furthermore, oral ferroportin inhibitors (e.g., vamifeport and substituted benzoimidazole compounds) can relieve ineffective erythropoiesis and improve body iron parameters in iron overload−associated TDT mice, as well as treat patients suffering from neurodegenerative and cardiac diseases ( Kadam et al, 2021 ; Kalleda et al, 2023 ).…”

Renin-angiotensin inhibitors reduce thrombotic complications in Essential Thrombocythemia and Polycythemia Vera patients with arterial hypertension

“…It may be worth considering certain classes of hypertensive drugs as electives for patients with MPN, such as ACEi and ARBs. Another interesting aspect is the potential use of new drugs in treating PV, such as the hepcidin mimetic [ 39 ]. Hepcidin is a peptide hormone primarily responsible for regulating the balance of iron in the body and also impacts erythropoiesis [ 40 ].…”

Iron restriction in sickle cell disease: When less is more

“…Numerous such agents have been developed and evaluated in vivo (Table S3). [70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] To date, these agents have generally been considered for diseases of iron overload, including β-thalassemia and hereditary hemochromatosis, but they are also undergoing human trials for the treatment of polycythemia vera.…”