Abstract Topic: 16. Myeloproliferative neoplasms - Clinical
Background: Patients with polycythemia vera (PV) are treated with periodic therapeutic phlebotomy (TP) to maintain hematocrit levels <45% to reduce the incidence of thrombotic events. Since many patients with PV are seen irregularly, they may experience periods of time with hematocrit levels >45%, potentially increasing thrombosis risk, especially in patients with high TP requirements. Hepcidin is the body’s main iron homeostasis regulator hormone. Elevated hepcidin levels are expected to reduce iron availability and control excessive erythropoiesis. We hypothesized that rusfertide (PTG-300), a hepcidin-mimetic, could decrease erythropoiesis and phlebotomy requirements in PV patients, thereby alleviating PV-related symptoms.
Aims: To examine the impact of rusfertide therapy on TP and patient reported symptoms in PV
Methods: PTG-300-04 is a Phase 2 trial (NCT04057040) consisting of 3 parts: (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal rusfertide vs placebo (1:1); and (3) a 52-week open-label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit <45% in the 24 weeks prior to enrollment. Rusfertide was administered subcutaneously weekly and was added to each subject’s pre-study treatment for PV; rusfertide dose was adjusted to maintain hematocrit <45%. Patients completed the MPN-SAF TSS questionnaire at protocol specified visits. MPN-SAF TSS items are considered “moderate” if symptoms were rated as 4-6 on a scale of 0 to 10 and “severe” if symptoms were rated 7-10. The MPN-SAF TSS has a range of 0-100 based on the 10 questions each with a range of 0-10. Higher scores indicate higher severity.
Results: In Part 1, 70 patients were enrolled, 61 patients completed the dose titration through 28 weeks, and 9 patients discontinued. The most common reason for discontinuation was the withdrawal by subject. Mean number of TPs declined from 4.7 in 28 weeks prior to rusfertide treatment to 0.4 TP during the 28 weeks of rusfertide treatment (p=0.001) (Figure 2). Approximately 60% of the patients required no TP and 26% required one TP during 28 weeks of rusfertide treatment. Mean MPN- SAF TSS score was 15.6 at baseline compared to 14.1 at 16 weeks of treatment and 12 after 28 weeks of treatment (Figure 3). The mean change from baseline was -2.2 (n=57, p=0.056). Fatigue in patients with moderate baseline severity (Figure 4) showed statistically significant improvement by Week 28 (mean change =-1.5, p=0.006) and inactivity improved at Week 28 (mean change= -2, p=0.003). Subjects with moderate severity (Figure 5a) at baseline showed an improvement in problems with concentration at week 28 (mean change = -2, p= 0.077). Patients with high baseline severity (Figure 5b) experienced an improvement at week 28 (mean change = -4.2, p=0.012) in concentration at Week 28. The most frequent adverse events (AE) were injection site reactions (ISR) reported by 86% of the patients, the frequency of which decreased over time. Most of the ISR were grade 1 or 2 and transient in nature. One subject discontinued Part 1 due to an ISR. Two patients discontinued the drug due to an SAE, one during the double-blind randomized withdrawal and one during the open-label extension.
Summary/Conclusion: These clinical trial results indicate that rusfertide is a promising investigational drug for the treatment of PV in maintaining hematocrit <45%, reversing iron deficiency, potentially eliminating the need for TP, and improving PV-related symptoms.
Keywords: Rusfertide, Fatigue, Myeloproliferative disorder, Polycythemia vera