Background. To reduce the incidence of thrombotic events, polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per National Comprehensive Cancer Network guidelines. Since patients are seen periodically, PV patients spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is also associated with systemic symptoms with fatigue found to be the most prevalent and severe symptom in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients present with iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018] which worsens after repeated TP. Ultimately, this leads to suppression of hepcidin, the body’s main negative regulator of iron metabolism, resulting in increased iron absorption and iron recycling, fueling expanded erythropoiesis resulting in a continued need for TP and exacerbating patients’ iron deficiency. Thus, we explored if the therapeutic administration of a hepcidin mimetic agent (rusfertide) would be useful in achieving HCT control in PV patients. This presentation will introduce Protagonist’s platform as applied to the discovery of rufertide and summarise the Phase 2 clinical trial of 63 PV patients who have been dosed for 8-92 weeks.