Rusfertide Continues to Show Strong Results for Polycythemia Vera

Treatment with the hepcidin mimetic rusfertide continued to demonstrate sustained hematocrit control below 45% and high rates of phlebotomy ineligibility through week 52 for patients with polycythemia vera (PV), according to updated findings from the phase 3 VERIFY study (NCT05210790) presented at the 2025 ASH Annual Meeting.¹

For those who crossed over from placebo to rusfertide, there was a rapid and durable drop in their hematocrit levels within the first 4 weeks. Both groups had similar levels of hematocrit control by week 52, regardless of having received a placebo or rusfertide in the first part of the study. For those continuing rusfertide from part 1a of the study to part 1b, the response rate, defined as absence of phlebotomy eligibility, went from 76.9% to 84.1%. For those who switched from placebo in part 1a to rusfertide in part 1b, the response went from 32.9% to 77.9%.

“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.”

What is the study design of VERIFY?

The phase 3 study was broken into several parts. In part 1a, patients were randomly selected to receive the current standard of care plus rusfertide (n = 147) or placebo (n = 146) for 32 weeks, with primary end points assessed at weeks 20 to 32. After this initial period, patients in the placebo group crossed over to receive rusfertide plus standard of care. This open-label part of the study (part 1b; n = 274) continued until week 52, at which point the durability of response was assessed. Standard of care was defined as phlebotomy with or without cytoreductive therapy. Subsequent parts of the study are ongoing to assess long-term safety. Results from ASH were for Part 1b.

Baseline characteristics were balanced between groups in part 1a of the study, Kuykendall noted. In part 1b, the median age was 57 years, and most patients were male (72.6%). Nearly half of patients had high-risk PV (44.9%), which was defined as having a prior thromboembolic event and/or age 60 or older. The median age at PV diagnosis was 51 years, and the median PV duration was 2.9 years.

Nearly half of patients were not on a cytoreductive therapy for part 1b of the study (44.9%), which was consistent with part 1a. For those on therapy, the most common was hydroxyurea (38.3%), followed by interferons (13.9%). There was a small subset of patients on ruxolitinib (2.6%; Jakafi).

What were the results from part 1a of the VERIFY study?

In part 1a of the study, rusfertide was superior to placebo across all key end points. For placebo and rusfertide, respectively, the response rates were more than doubled (32.9% vs 76.9%; P <.0001), and 62.6% of those on rusfertide had a hematocrit lower than 45% compared with 14.4% for placebo (P <.0001). There were fewer (P <.0001) mean phlebotomies required with rusfertide (n = 0.5) compared with placebo (n = 1.8).

In addition to clinical end points, patient-reported outcomes were also superior with rusfertide. For the PROMIS fatigue SF-8a T-score, there was a 0.17 increase at week 32 with placebo compared with a decline of 1.78 for rusfertide, suggesting less fatigue (-1.95 delta; P = .0268). Improvement was also seen in Myelofibrosis Symptom Assessment Form Version 4.0 Total Symptom Score 7 Items, with a 0.54 drop with placebo and a 2.40 drop for rusfertide (-1.87 delta; P = .0239).

What were the new rusfertide findings from part 1b of VERIFY?

The median time to phlebotomy was not reached in the rusfertide arm compared with 16 weeks in the placebo group for part 1a. In part 1b, the median time to phlebotomy was not estimable in both arms. "Once patients switched from placebo to rusfertide, time to first phlebotomy looked similar in both groups," Kuykendall said.

Ferritin levels normalized over time for those receiving rusfertide, with a continued improvement seen with rusfertide throughout the course of the study. There was no change with placebo in part 1a but a consistent climb in ferritin once patients crossed over to received rusfertide. There was only a small change in serum iron levels in both groups of patients (from ~6 µm ol/L at baseline increasing to ~10 µm ol/L). Transferrin levels decreased with rusfertide while transferrin saturation increased. As with all levels, a significant shift could be seen with patients moved from placebo to rusfertide.

“Rusfertide lowered hematocrit levels without exacerbating systemic iron deficiency,” added Kuykendall.

There was a modest improvement in mean corpuscular volume levels with rusfertide. Leukocytes counts were stable in both arms with a slight increase, and an improvement in platelet counts was seen with rusfertide.

What was the safety profile for rusfertide in VERIFY?

At the data cutoff, 86.7% of patients continued to receive open-label rusfertide, with discontinuations being uncommon, Kuykendall said. In part 1a, just 7.5% of patients discontinued rusfertide due to adverse events (AEs; n = 8) or study withdrawal (n = 3). This compares with a discontinuation rate of 4.1% in the placebo group for AEs (n = 5) and disease progression (n = 1). In part 1b, the discontinuation rate was 2.6%, with 3 from AEs, 2 from lack of efficacy, 1 for other reasons, and 1 for study withdrawal.

In part 1a, there were fewer secondary cancer events in the rusfertide group compared with placebo (3 vs 8, respectively). In part 1b, those who switched from placebo had 2 cancer events compared with 4 in the arm that was on rusfertide for both part 1a and 1b.

Most AEs were grade 1 or 2 in severity, with at least 1 treatment-emergent adverse events (TEAEs) occurring in 86.3% of those in the placebo group and for 90.3% of those in the rusfertide group in part 1a. In part 1b, TEAE rates were similar between groups at approximately 75%. The most common grade 3 TEAE were anemia, asthenia, and hypertension, Kuykendall noted. These occurred in 3 patients each. Serious AEs were experienced by 3.4% of patients in part 1a and by 2.6% in part 1b.

In part 1a of the study, injection site reactions occurred in 32.9% of those in the placebo group and in 55.9% in the rusfertide group. In part 1b, infusion site reactions were seen in 32.9% of those in the crossover group and for 9.7% in the rusfertide arm.

“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,” Kuykendall said.

What are the next steps for rusfertide?

A regulatory submission is being planned for rusfertide as a treatment for patients with PV. Data for the submission will come from the VERIFY study along with results from the REVIVE study (NCT04057040). In the REVIVE study,² the response rate with rusfertide was 60% compared with 17% for placebo (P = .002).

Parts 2 and 3 of the VERIFY study will continue to assess long-term efficacy and safety for rusfertide, with part 2 scheduled to go to week 156 and part 3 expending from the end of part 2 through the end of treatment.

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(suppl 1): 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(8):723-735. doi:10.1056/NEJMoa2308809