Final Results from the Phase 2 Revive Study Investigating the Hepcidin Mimetic Rusfertide in Patients with Polycythemia Vera (PV)

Background: PV is a myeloproliferative neoplasm that leads to excessive production of erythrocytes and increased platelet and leukocyte counts. The current standard of care is to use therapeutic phlebotomy (TP) with or without cytoreductive therapy (CRT) to treat PV. Over time, the CRT dose often needs to be increased to treat PV progression. Preliminary results from the phase 2 REVIVE study (NCT04057040) demonstrated that rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for TP in patients who were phlebotomy-dependent prior to study entry (Kremyanskaya et al. EHA2023. [Abstract LB2710]; Kremyanskaya et al. New Engl J Med 2024;390:723-35).Final data from REVIVE will be presented.

Methods: In Part 1 (Weeks 1-29), subcutaneous rusfertide (starting dose: 20 mg q1w) was initiated and titrated to control Hct to <45%. In Part 2 (Weeks 29-41; blinded randomized withdrawal phase), patients were randomized to receive rusfertide or placebo. Randomized patients were eligible to participate in the open-label extension (OLE) portion of the study (Part 3), in which all patients could receive rusfertide and investigators could make CRT dose adjustments.

Results: In Part 1, 70 patients were enrolled; 59 were randomized in Part 2. Fifty-eight patients continued to Part 3. As of 9 July 2024, 50 (71.4%), 37 (52.9%), and 17 (24.3%) patients received rusfertide for ≥2, ≥2.5, or ≥3 years, respectively.Overall, median (range) patient age was 57.5 years (27-77); the majority were male (70%) and had high-risk disease (55.7%). Overall, 52.9% and 47.1% of patients were treated with TP alone or TP plus CRT, respectively. Prior to enrollment, the estimated average (mean) phlebotomy rate (EAPR) in patients who enrolled on study was 8.5/year, which was reduced to <1.0/year in Part 1. In Part 2, the EAPR was <1.0/year and 6.6/year in the rusfertide and placebo groups, respectively. For patients who continued onto Part 3 and received rusfertide, the EAPR remained at <1.0/year. In Parts 1, 2, and 3, the mean (SD) weekly average rusfertide dose was 30.7 mg (12.2), 38.5 mg (21.3), and 44.9 mg (20.3), respectively. Rusfertide consistently maintained Hct <45%, including in patients receiving therapy for ≥3 years. Platelets increased following initiation of rusfertide therapy and stabilized over time; mean leukocyte counts remained stable. Prior to enrollment, iron-related parameters were consistent with systemic iron deficiency. Throughout the study, rusfertide resulted in the normalization of mean serum ferritin levels, increased mean transferrin saturation, and increased mean serum iron levels. Overall, mean corpuscular volume increased slightly over the duration of the study. Throughout the study, there was no evidence of increased markers of inflammation (eg, C-reactive protein or interleukin 6). The most common (≥20%) treatment-emergent adverse events (TEAEs) were injection site reactions (85.7%), fatigue (38.6%), COVID-19 (32.9%), pruritus (34.3%), arthralgia (30.0%), dizziness (30.0%), nausea (24.3%), headache (24.3%), and anemia (21.4%). Grade 3 TEAEs occurred in 25.7% of patients.There were no Grade 4 or 5 TEAEs. One patient developed acute myeloid leukemia after treatment discontinuation. After more than 150 patient-years of rusfertide exposure, malignancies (most of which were skin cancers) were reported in 11 patients (all had risk factors that may have contributed to the development of these malignancies). There was no obvious correlation between increasing exposure to rusfertide and malignancies reported. Six thrombotic events (5 arterial and 1 venous) occurred in 5 patients with high-risk PV.

Conclusions: In REVIVE, rusfertide added to TP with or without CRT provided long-term durable control of Hct and decreased the need for TP. Patients are eligible to roll over to the phase 2 THRIVE OLE study (NCT06033586), which will continue to assess the long-term safety and efficacy of rusfertide for a total period of up to 5.8 years. The randomized phase 3 VERIFY study (NCT05210790) is ongoing and will evaluate rusfertide vs placebo in PV patients.

Gerds:Agios: Consultancy; PharmaEssentia: Consultancy; Disc Medicine: Consultancy; Rain Oncology: Consultancy; GSK: Consultancy; AbbVie: Consultancy; BMS: Consultancy. Kuykendall:PharmaEssentia: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Protagonist Therapeutics: Honoraria, Research Funding. Kremyanskaya:Agios: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Silence Therapeutics: Consultancy; Constellation/MorphoSys: Consultancy; Protagonist Therapeutics: Consultancy; Disc Medicine: Consultancy. Ritchie:Ariad: Speakers Bureau; NS Pharma: Research Funding; Pfizer: Consultancy, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Bristol Myers Squibb: Consultancy, Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy. Pettit:BMS: Research Funding; Imago: Research Funding; Blueprint Medicines: Research Funding; Sierra Oncology: Consultancy; Protagonist Therapeutics: Consultancy, Research Funding; PharmaEssentia: Consultancy; Incyte: Consultancy; AbbVie: Consultancy, Research Funding; Kura Oncology: Research Funding; Merck: Research Funding. Yacoub:Notable Labs: Consultancy; Incyte: Consultancy; Gilead: Consultancy; CTI Pharma: Consultancy; BMS: Consultancy; Apellis: Consultancy; Acceleron: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; PharmaEssentia: Consultancy; Servier: Consultancy; Celgene: Consultancy. Gupta:Protagonist Therapeutics: Current Employment. Khanna:Protagonist Therapeutics: Current Employment. Molina:Protagonist Therapeutics: Current Employment. Pemmaraju:LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Triptych Health Partners: Consultancy; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Plexxikon: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; CTI BioPharma: Consultancy; Neopharm: Honoraria; CareDx: Honoraria; Bristol-Myers Squibb: Consultancy; Immunogen: Consultancy; Incyte: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Aptitude Health: Honoraria; Pacylex: Consultancy; Blueprint Medicines: Consultancy, Honoraria; Samus Therapeutics: Research Funding; Roche Molecular Diagnostics: Honoraria; DAVA Oncology: Honoraria, Other: Travel Expenses; ClearView Healthcare Partners: Consultancy; Protagonist Therapeutics: Consultancy; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated.