Rusfertide Improves Hematocrit Control vs Placebo in Polycythemia Vera

Rusfertide (Mimrylo) significantly improved hematocrit control, reduced the need for phlebotomy, and improved patient-reported symptoms compared with placebo in phlebotomy-dependent populations with polycythemia vera who were also receiving standard-of-care therapy, according to updated results from part 1a of the phase 3 VERIFY trial (NCT05210790) published in the Journal of Clinical Oncology.

What were the key efficacy data from the VERIFY trial?

A clinical response, defined as the absence of phlebotomy eligibility with no intercurrent events during weeks 20 to 32, was achieved by 113 patients (77%) in the rusfertide group vs 48 patients (33%) in the placebo group (P <.0001), corresponding to a common risk difference of 43.8% (95% CI, 33.5%-54.2%). The treatment effect was consistent across prespecified subgroups, including patients treated with phlebotomy alone (82% vs 33%) and those receiving concomitant cytoreductive therapy (CRT; 73% vs 33%).

Rusfertide also met the key secondary end points of the trial. Compared with placebo, rusfertide reduced the mean number of phlebotomies between baseline and week 32 (0.5 ± 1.2 vs 1.8 ± 1.5; P <.0001) and was superior in maintaining a hematocrit of less than 45%, with 92 patients (63%) vs 21 patients (14%) maintaining that threshold (P <.0001; common risk difference, 48.2% [95% CI, 38.4%-57.9%]). More than 3 times as many patients in the rusfertide group were phlebotomy free during part 1a (73% vs 22%).

Rusfertide led to significant improvements vs placebo in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8a T score (least squares mean difference, –2.0 [95% CI, –3.7 to –0.3]; P = .0252) and the Myelofibrosis Symptom Assessment Form Total Symptom Score–7 items (least squares mean difference, –1.9 [95% CI, –3.5 to –0.3]; P = .0240). Among the 113 rusfertide responders, 84% maintained their response during weeks 32 to 52.

What did the safety of rusfertide look like in the VERIFY trial?

The most common adverse events (AEs) were localized injection site reactions, anemia, and fatigue, which were primarily grade 1 or 2 in severity. Grade 3 AEs occurred in 13 patients (9%) in the rusfertide group and 10 patients (7%) in the placebo group during part 1a; 1 grade 4 event (diabetic ketoacidosis, unrelated to treatment) occurred in the rusfertide group, and no deaths were reported. Serious AEs occurred in 3% and 5% of the rusfertide and placebo groups, respectively, and none were treatment related.

Two patients who received rusfertide (less than 1%) had thromboembolic events, which include a grade 3 myocardial infarction and a grade 2 deep vein thrombosis. Both events were considered unrelated to rusfertide.

“The phase [3] VERIFY trial demonstrated that rusfertide with current standard-of-care therapy provided rapid, consistent, and durable hematocrit control [of less than 45%] in the absence of increased phlebotomy or CRT burden in phlebotomy-dependent patients with [polycythemia vera] and poorly controlled hematocrit despite standard-of-care therapy,” lead author Andrew T. Kuykendall, MD, a medical oncologist in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida, wrote in the publication with study coinvestigators. “Better hematocrit control significantly reduced the need for therapeutic phlebotomy and improved patient-reported symptoms.”

How was the VERIFY trial designed?

VERIFY is an ongoing, 3-part phase 3 trial conducted at 102 centers across 19 countries. Part 1a was a randomized, double-blind, placebo-controlled period in which patients were randomly assigned 1:1 to receive subcutaneous rusfertide or placebo weekly, each titrated to achieve and maintain a hematocrit of less than 45%, with or without CRT. Investigators enrolled 293 patients (rusfertide, n = 147; placebo, n = 146) between April 11, 2022, and May 1, 2024.

Eligible adults met 2016 WHO criteria for polycythemia vera and had phlebotomy-dependent disease, defined as at least 3 phlebotomies within 28 weeks or at least 5 within 1 year before random assignment. Across the study population, 47% had high-risk disease, and 96% were positive for the JAK2 V617F mutation.

The primary end point was the proportion of patients achieving a clinical response during weeks 20 to 32. Key secondary end points included the mean number of phlebotomies, the proportion of patients maintaining a hematocrit of less than 45%, and changes from baseline in patient-reported fatigue and total symptom score.

Consistent with rusfertide’s mechanism of action, clinical improvements were temporally associated with increases in ferritin, normalization of mean corpuscular volume (81.8 to 86.7 fL by week 52), and improvements in other iron parameters, suggesting an effect on iron deficiency–related symptoms. The authors noted that rusfertide is not expected to directly address symptoms driven by underlying myeloproliferative disease biology.

The investigators acknowledged that the 32-week placebo-controlled period precludes definitive assessment of long-term outcomes such as thrombotic events, secondary malignancies, and disease progression. They noted that ongoing follow-up in VERIFY and the phase 2 THRIVE extension study (NCT06033586) will further characterize these outcomes. The findings confirm and extend those of the phase 2 REVIVE trial (NCT04057040), which previously demonstrated that rusfertide met its primary response end point vs placebo in patients with polycythemia vera.

The FDA previously approved rusfertide for adult patients with polycythemia vera in August 2026 based on data from the VERIFY trial.²

References

1. Kuykendall AT, Bankar A, Pettit KM, et al. VERIFY: a phase III trial of rusfertide versus placebo in phlebotomy-dependent patients with polycythemia vera receiving standard-of-care therapy. J Clin Oncol. Published online October 13, 2026. doi:10.1200/JCO-26-00992
2. FDA approves first drug of its kind for polycythemia vera, a rare blood disorder. News release. FDA. August 28, 2026. Accessed November 5, 2026. https://tinyurl.com/yeavrkc4