MPN-469 Rusfertide (PTG-300) Treatment Interruption Reverses Hematological Gains and Upon Reinitiation, Restoration of Clinical Benefit Observed in Patients With Polycythemia Vera

Context: Polycythemia vera (PV) patients are routinely treated with periodic therapeutic phlebotomy (TP) alone or combined with cytoreductive therapy to maintain hematocrit (HCT) <45% and reduce the incidence of thrombosis. TP may not adequately control HCT and results in iron deficiency. Rusfertide, a hepcidin mimetic, eliminates phlebotomy requirements and improves iron deficiency. We examined the impact of rusfertide dosing interruption on TP requirements, HCT, and iron homeostasis in 2 studies during FDA-mandated clinical hold in response to pre-clinical and clinical safety findings. Design and Patients: The REVIVE study (NCT04057040), in phlebotomy-dependent PV patients consisted of 3 parts: (1) 28-week dose-finding; (2) 12-week blinded randomized withdrawal (1:1) rusfertide vs placebo; and (3) 52-week open-label extension. The PACIFIC study (NCT04767802) in PV patients with high HCT (>48%), consisted of 2 parts, (1) Induction with 40mg SQ twice weekly until HCT<45%, and (2) Continuation, typically with weekly dosing. Interventions: Subcutaneous rusfertide 10-120 mg weekly added to the existing regimen and adjusted to maintain HCT <45%. During treatment interruption, patients received their baseline cytoreductive regimens with TP to maintain HCT <45%. Main Outcome Measures: Iron homeostasis, HCT control, and TP requirements. Results: In the REVIVE study, all participants were essentially phlebotomy free, HCTs maintained at <45%, and ferritin normalized, when rusfertide was added to their treatment. In the PACIFIC study, participants with an average baseline HCT of 51% had their HCT reduced to and maintained at <45% within ~6 weeks of treatment initiation. When a clinical hold necessitated rusfertide dosing interruption, participants had significant (p<0.01) increases in TPs, HCT, and RBC count, and a decrease in serum ferritin. Reinitiating rusfertide normalized hematologic parameters, eliminated TP, and restored ferritin demonstrating the potential effectiveness of rusfertide. Most adverse events (AEs) were grade 1-2. The most frequent AEs were transient injection site reactions reported in 59% of participants. Conclusions: Rusfertide maintains HCT at <45%, essentially eliminates TP requirements, and reverses iron deficiency in PV patients with/without cytoreductive agents. Reversal of hematological parameters during dosing interruption further confirms the effect of rusfertide on erythrocytosis and iron homeostasis. A global Phase 3 trial, VERIFY (NCT05210790), has been initiated.