Durability of Hematocrit Control in Polycythemia Vera with the First-in-Class Hepcidin Mimetic Rusfertide: Two-Year Follow up Results from the Revive Study

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with uncontrolled erythrocytosis, systemic symptoms, and an increased risk of thromboembolic and cardiovascular complications largely driven by uncontrolled hematocrit (HCT) levels. Rusfertide is a hepcidin mimetic that controls red blood cell production in PV patients by limiting iron availability. The REVIVE trial (PTG-300-04; NCT04057040) is investigating rusfertide and consists of three stages. Eligibility criteria: diagnosis of PV; ≥3 therapeutic phlebotomies (TP)s in the 28 weeks prior to enrollment with or without concurrent cytoreductive therapies (CYTO). As reported previously, adding rusfertide to standard of care PV treatments optimally controls HCT levels and decreases the need for TP (Kuykendall et al., HemaSphere, 2022;6:(S3):1766; Kremyanskaya et al. EHA2023; Abstract LB2710). Herein, we report results from the ongoing open-label extension (OLE) from REVIVE (Part 3) and explore the long-term durability of response to rusfertide.

Methods: During Part 1 (Week 1-29), treatment with rusfertide was initiated at 20 mg and individually titrated to control hematocrit (<45%); the median was 40 mg/wk and relatively stable after achieving a therapeutic dose. In Part 2 (Week 29-41), the blinded randomized withdrawal phase, patients were randomized to either continue rusfertide or to matching placebo. Any randomized patient who responded or did not respond was allowed to participate in Part 3 (3-yr OLE). The investigators can adjust doses of rusfertide and CYTO as needed to manage PV symptoms and blood counts. During Part 3, the hematocrit, erythrocytes, leukocytes, platelets, and ferritin are being assessed to determine long-term durability of response to rusfertide.

Results: In Part 1 of REVIVE, 70 patients were enrolled, 59 were randomized, and 58 continued into the OLE (Part 3). As of July 11, 2023, of the 70 enrolled patients, 57 (81.4%) patients have been treated for ≥1 year, 46 (65.7%) for ≥1.5 years, and 24 (34.3%) for ≥2 years. For subjects continuing in Part 3, the median age was 57 years (range, 27-77); 41 (70.7%) were men, and 17 (29.3%) were women. Thirty-two (55.2%) of the 58 subjects were treated with phlebotomy (PHL); 26 (44.8%) were receiving concurrent therapy with CYTO. All patients were essentially phlebotomy-free while on rusfertide treatment. Mean platelet counts increased initially on average within 4 weeks following initiation of rusfertide but subsequently stabilized at approximately 30% increase by week 9 (Figure 1); platelets didn’t increase with the increase in rusfertide doses either. The increased platelet counts were not associated with any bleeding or thrombotic events. Leukocyte counts remained stable. Treatment with rusfertide resulted in the consistent maintenance of hematocrit below 45% and an overall decrease in erythrocyte counts (Figure 2). This effect was lost temporarily for patients randomized to placebo during Part 2 and returned after resuming rusfertide treatment. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency (mean [±SE] ferritin 18.7 [±4.3] µg/L). Rusfertide treatment resulted in an improvement of serum ferritin towards normal levels (mean [±SE] ferritin 148.6 [±18.6] µg/L at Cycle 15 during the OLE) (Figure 2). Rusfertide was generally well tolerated; 80% of treatment-emergent adverse events (TEAEs) were grade 1-2, 20% were grade 3, and none were grade 4 or 5. The most common TEAEs were injection site reactions (ISRs), which were localized and grade 1-2 in severity and decreased in incidence with continued treatment. Six (8.6%) TEAEs led to treatment discontinuation.

Conclusions: The REVIVE OLE demonstrated that rusfertide can provide long-term control of HCT, without phlebotomy, in patients with PV receiving TP with or without CYTO. Ferritin improved with rusfertide dosing and other lineages, after an initial increase in platelet counts both platelets and leucocyte counts remained stable during rusfertide treatment. Rusfertide was added to the current standard of care and was generally well-tolerated; most TEAEs were grade 1 or 2.