Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients.

7003 Background: Polycythemia (PV) patients with hematocrit (HCT) levels > 45% are at an increased risk of thrombosis and are treated with therapeutic phlebotomy (TP) alone or in combination with cytoreductive agents. Current therapies are not effective in reaching a HCT < 45% or uniformly tolerated. Rusfertide (PTG-300) is a hepcidin mimetic being developed as a non-cytoreductive option to consistently control HCT at < 45% in PV patients. Methods: We report results from two Phase 2 trials investigating the activity of rusfertide in PV patients. The first (NCT04057040) was conducted in patients with excessive erythrocytosis despite TP (3 or more in the 6 months prior to enrolling) ± cytoreductive therapy with a HCT < 45% at study entry. This study comprised 1) a 28-week open-label dose finding phase; 2) a 12-week double-blind randomized (1:1) withdrawal; and 3) a 3-year open-label extension with all subjects receiving rusfertide. Rusfertide doses,10-120 mg, were self-administered SQ weekly and adjusted monthly to maintain HCT < 45%. The second study (NCT04767802) enrolled poorly controlled PV patients with HCT > 48% at study entry despite TP ± hydroxyurea. Rusfertide dosing was initiated as 40 mg twice weekly and reduced to once weekly dosing when HCT < 45% was reached. Results: As of December 2021, 63 subjects were enrolled in Study 1. TP alone was the most common treatment (n = 30). The mean number of TP in the 28 weeks prior to enrollment was 4.63 and was 0.43 after treatment. On rusfertide, patients consistently maintained HCT < 45%, essentially eliminating TP, had normalization of serum ferritin, MCV values and iron deficiency. Rusfertide-treated patients also reported a statistically significant improvement in symptom burden at week 28. 20 subjects were enrolled in Study 2. TP with hydroxyurea was the most common treatment (n = 12). Mean HCT was 50.7% pre-treatment and mean time to reach HCT < 45% without TP was 4.79 weeks with persistently well controlled HCT thereafter. Rusfertide significantly reduced erythrocyte counts by ̃1.2x10 6 /μL within 8 weeks of treatment. In both trials rusfertide did not result in changes in the number of WBC; clinically not meaningful transient increases in platelet numbers were noted. Rusfertide was well tolerated, with mostly grade 1-2 adverse events (AE). The most common AEs were injection site reactions. These were typically transient, manageable with topical therapies, and did not lead to study withdrawal. Conclusions: Rusfertide, when added to standard therapy, demonstrated robust activity in managing PV patients with sub-optimally controlled erythrocytosis in 2 trials, enrolling patients with HCT < 45% (Study 1), and HCT > 48% (Study 2). Taken together, these data show that the non-cytoreductive rusfertide, is a promising novel agent for PV patients which leads to sustained HCT control < 45%. A pivotal Phase 3 study is scheduled to begin in 2022. Clinical trial information: NCT04057040 and NCT04767802.