VERIFY: A randomized controlled phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera (PV).

Abstract

<p><strong>Background:</strong> PV is a myeloproliferative neoplasm characterized by overproduction of red blood cells and increased risk of thrombosis. Patients may require frequent therapeutic phlebotomies (TP) alone or in combination with cytoreductive therapy to maintain hematocrit (HCT) <45%. Hepcidin regulates iron homeostasis but is downregulated in PV, increasing iron availability for erythropoiesis, which complicates TP optimization. In a phase 2 study (REVIVE, NCT04057040), rusfertide led to rapid, sustained, and durable HCT control with over 90% of patients achieving TP independence in part 2.¹ It was well tolerated; majority (77.1%) of treatment-emergent adverse events (TEAEs) had a maximum grade of 2. There were no Grade 4 or 5 TEAEs. The phase 3 study VERIFY (NCT05210790) aims to confirm efficacy and safety of rusfertide in patients with PV. <strong>Methods:</strong> VERIFY is a multicenter, global, randomized trial comparing efficacy and safety of rusfertide (starting dose: 20 mg subcutaneously once weekly) vs. placebo when added to ongoing therapy for PV. Patients with PV who require frequent TP with or without concurrent cytoreductive therapy to control HCT are included in this 3-part study: Part 1a: 1:1 randomized, double-blind, placebo-controlled, add-on parallel-group period lasting 32 weeks (Week 0-32); Part 1b: open-label treatment phase with cross-over for previous placebo-treated patients. During this phase, all patients who completed Part 1a successfully will receive rusfertide for 20 weeks (Week 32-52); and Part 2: long term extension phase where all patients who complete Part 1b will continue to receive rusfertide for 104 weeks (Week 52-156). <strong>Results:</strong> Major inclusion criteria prior to randomization include PV diagnosis by 2016 WHO criteria; ≥3 TP in the previous 28 weeks or ≥5 in the previous 12 months due to inadequate HCT control; HCT <45%, white blood cells 4-20 × 10⁹/L and platelets 100-1000 × 10⁹/L at Week 0; stable PV therapy regimen in patients receiving cytoreduction at randomization; and cessation of cytoreductive therapy 2-6 months before screening in patients treated with TP alone. Major exclusion criteria are thrombosis or bleeding (active and/or chronic) within 2 months before randomization and a history of invasive malignancy within the previous 5 years. Primary endpoint is the proportion of patients achieving a response in Part 1a from Week 20-32. A response is defined as absence of TP eligibility. TP eligibility: HCT ≥45% and ≥3% higher than baseline HCT or HCT ≥48%. Secondary endpoints are mean number of TPs from Week 0-32; proportion of patients with HCT <45% from Week 0-32; mean change from baseline to Week 32 in total fatigue score measured by PROMIS Short Form and in total symptom score measured by MFSAF v4.0. <strong>Conclusions:</strong> VERIFY opened in January 2022 and aims to enroll approximately 250 patients globally. <br></p>