Bold claim: Rusfertide keeps hematocrit tightly controlled and dramatically reduces the need for phlebotomy in polycythemia vera, with these benefits persisting through 52 weeks. But here's where it gets controversial: is long-term safety truly as favorable as the data suggest, and will these results translate into real-world practice?
Rusfertide, a hepcidin mimetic, continued to maintain hematocrit below 45% and produced high rates of phlebotomy ineligibility through week 52 in patients with polycythemia vera (PV), according to updated findings from the phase 3 VERIFY study (NCT05210790) presented at the 2025 ASH Annual Meeting. The results indicate durable efficacy and a safety profile consistent with prior observations.
For participants who crossed over from placebo to rusfertide, hematocrit dropped rapidly and remained controlled within the first 4 weeks. By week 52, both randomized groups achieved similar hematocrit control, regardless of initial treatment assignment. Among those continuing rusfertide from part 1a into part 1b, the response rate—in this context, absence of phlebotomy eligibility—rose from 76.9% to 84.1%. For those switching from placebo in part 1a to rusfertide in part 1b, the response increased from 32.9% to 77.9%.
Lead investigator Andrew Kuykendall, MD (Moffitt Cancer Center, Department of Malignant Hematology), summarized: “Rusfertide met the primary and all four secondary endpoints from baseline to week 32 and continued to provide durable, sustained control of hematocrit below 45% and phlebotomy ineligibility through week 52. After 52 weeks of treatment in VERIFY, rusfertide was well tolerated with a safety profile consistent with prior observations.”
Updated VERIFY data highlight the following points:
- Rusfertide delivered durable hematocrit control under 45% and maintained high phlebotomy ineligibility through 52 weeks in PV patients.
- Patients switching from placebo experienced rapid, sustained hematocrit reduction and normalization of iron parameters without worsening systemic iron deficiency.
- The treatment remained well tolerated, with mostly mild-to-moderate adverse events, supporting continued long-term evaluation and planned regulatory submission.
Study design at a glance
- VERIFY Part 1a: 147 patients received rusfertide plus standard of care versus 146 received placebo for 32 weeks, with primary endpoints assessed between weeks 20 and 32.
- After week 32, placebo patients crossed over to rusfertide plus standard of care in Part 1b (open-label), continuing to week 52 to assess response durability.
- Standard of care was defined as phlebotomy with or without cytoreductive therapy. Long-term safety data are still being collected in subsequent parts.
Baseline characteristics were balanced in Part 1a. In Part 1b, the median age was 57, and the cohort was predominantly male (72.6%). Roughly 45% had high-risk PV (prior thromboembolic event and/or age ≥60). Median PV diagnosis age was 51, with a median disease duration of 2.9 years. About 45% of Part 1b patients were not on cytoreductive therapy, mirroring Part 1a; hydroxyurea was the most common cytoreductive therapy (38.3%), followed by interferons (13.9%), with a small subset on ruxolitinib (Jakafi) at 2.6%.
Part 1a results showed rusfertide outperformed placebo across all primary endpoints. Response rates were 76.9% for rusfertide versus 32.9% for placebo (P < .0001). Hematocrit below 45% occurred in 62.6% of rusfertide patients compared with 14.4% on placebo (P < .0001). Phlebotomies required were fewer with rusfertide (0.5) than with placebo (1.8) (P < .0001).
Patient-reported outcomes also favored rusfertide. PROMIS fatigue scores showed a decline (improvement) with rusfertide versus a small increase with placebo. Myelofibrosis symptom scores improved more with rusfertide than with placebo, reflecting better overall symptom control.
Part 1b provided further insights: time to first phlebotomy was not estimable in either arm, with similar times observed after crossover. Ferritin levels normalized over time with rusfertide, and transferrin saturation rose as ferritin improved. Serum iron rose modestly in both groups. These iron parameter shifts highlight that hematocrit reduction did not worsen systemic iron deficiency.
Overall safety data from VERIFY indicate most adverse events were grade 1–2, with similar overall TEAE rates between arms during Part 1b. The most common Grade 3 TEAEs were anemia, asthenia, and hypertension, each affecting a small number of patients. Serious adverse events were relatively uncommon. Injection or infusion site reactions were more frequent in the rusfertide arms but tended to decrease over time in some patients.
Safety signals and future plans
- Open-label rusfertide continuation beyond Part 1b showed ongoing tolerability, with relatively low discontinuation rates due to adverse events or lack of efficacy.
- A regulatory submission for rusfertide as a PV treatment is planned, incorporating VERIFY Part 1b results and data from the REVIVE study, which reported a 60% response rate with rusfertide compared with 17% for placebo (P = .002).
- Parts 2 and 3 of VERIFY will further explore long-term efficacy and safety, with Part 2 extending to week 156 and Part 3 following through the end of treatment.
Bottom line: Rusfertide continues to show strong, durable control of erythrocytosis in PV with tolerable safety, setting the stage for potential regulatory approval. Yet, questions remain about long-term iron homeostasis, real-world adherence, and how these results will influence clinical practice. Do these findings justify broad adoption, or are there concerns that warrant cautious optimism and additional real-world data?
References and disclosures: Data from the VERIFY trial were presented at the 2025 ASH meeting and published in Blood in 2025, with related NEJM data informing the broader context of rusfertide’s mechanism and efficacy.
