Rusfertide Maintains Hematocrit Control Through 52 Weeks in VERIFY

New 52-week data from the phase 3 VERIFY study continue to strengthen the case for rusfertide as a potential first-in-class therapy for patients with polycythemia vera (PV). Presented at the 2025 ASH Annual Meeting, the updated results demonstrate sustained hematocrit control below 45%, high rates of phlebotomy ineligibility, and a consistent safety profile for the hepcidin mimetic across both the randomized and open-label portions of the trial.

"Rusfertide met the primary and all 4 secondary end points in VERIFY from baseline to week 32 and continued to provide durable, sustained control of hematocrit below 45% and phlebotomy ineligibility through week 52," lead investigator Andrew Kuykendall, MD, at Moffitt Cancer Center in the Department of Malignant Hematology, said during a presentation of the results. "After 52 weeks of treatment in VERIFY, rusfertide was well tolerated with a safety profile that was consistent with prior observations."

The VERIFY study enrolled patients receiving standard-of-care PV management, defined as phlebotomy with or without cytoreductive therapy, and randomized them 1:1 to rusfertide or placebo for 32 weeks (part 1a). After the primary end-point assessment window at weeks 20 to 32, patients in the placebo arm crossed over to receive open-label rusfertide plus standard therapy through week 52 (part 1b). Durability of hematocrit control and phlebotomy independence were the key measures in the extension period.

The newly reported findings show that patients maintained on rusfertide experienced continued benefit, and those who switched from placebo rapidly caught up. Among participants who received rusfertide throughout, the rate of phlebotomy ineligibility increased from 76.9% at week 32 to 84.1% at week 52. For patients who switched from placebo to rusfertide, the phlebotomy ineligibility rate rose from 32.9% to 77.9% during the same timeframe. Hematocrit levels declined quickly in the crossover cohort by week 52, both groups achieved similar levels of control.

"Rusfertide lowered hematocrit levels without exacerbating systemic iron deficiency," said Kuykendall.

During the randomized period (part 1a), rusfertide showed superiority over placebo across all major clinical outcomes. Hematocrit control below 45% was achieved in 62.6% of patients receiving rusfertide versus 14.4% on placebo (P <.0001). Patients in the rusfertide arm required far fewer phlebotomies, with a mean of 0.5 versus 1.8 for placebo (P <.0001). Patient-reported outcomes also favored rusfertide, including improvements in fatigue and symptom burden. On the PROMIS Fatigue SF-8a, patients receiving rusfertide reported a 1.78-point decline in fatigue compared with a slight increase in the placebo group.

VERIFY Study Findings and Design

Baseline characteristics were well balanced between arms in part 1a. In the extension, the median patient age was 57 years, and the majority were male. Nearly half of participants met criteria for high-risk PV, defined by age ≥60 years and/or a history of thromboembolic events. Use of cytoreductive agents remained consistent between study phases, with hydroxyurea as the most common therapy.

Physiologic markers tracked throughout the study demonstrated biologic activity consistent with hepcidin mimetic therapy. Ferritin levels remained low and unchanged for placebo recipients in the randomized phase and increased steadily once patients crossed over to rusfertide. Transferrin levels decreased while transferrin saturation and serum iron rose modestly, suggesting improved iron homeostasis without indications of worsening systemic iron deficiency. Leukocyte counts remained stable and platelet counts showed modest improvement in rusfertide-treated patients.

Safety findings remained favorable and aligned with earlier trial experience. At data cutoff, 86.7% of patients continued receiving open-label rusfertide. Discontinuations were infrequent: 7.5% during randomized treatment and 2.6% in the open-label phase. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2. Injection-site reactions were the most common TEAE, occurring in more than half of rusfertide-treated patients during the randomized portion but decreasing notably between weeks 32 and 52 among those who continued treatment.

Secondary malignancies were less common in the rusfertide group than in the placebo group in part 1a (3 vs 8 events) and remained low in part 1b following crossover.

"Optimistically, you can see that some of the injection site reactions actually go down in the rusfertide arm from week 32 to 52, suggesting it may lessen over time," said Kuykendall.

A regulatory submission for rusfertide in PV is planned, supported by VERIFY and results from the REVIVE trial, in which rusfertide achieved a 60% response rate compared with 17% for placebo. VERIFY parts 2 and 3 will continue to evaluate long-term efficacy, safety, and treatment durability over multiple years. Results from REVIVE also support rusfertide's efficacy.

References:

1. Kuykendall A, Bankar A, Pettit K, et al. Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study. Blood. 2025;146(Supplement 1):abstract 81. doi:10.1182/blood-2025-8.
2. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. N Engl J Med. 2024;390:723-735.