REVIVE: ​​Rusfertide Effective for Erythrocytosis Control in Polycythemia Vera

Marina Kremyanskaya, MD, PhD

Credit: Mount Sinai

Rusfertide therapy, a hepcidin mimetic, may be an effective treatment option for achieving and sustaining hematocrit control in patients with polycythemia vera, according to new results from the phase 2 REVIVE trial.¹

The REVIVE trial is an ongoing, three-part, international study conducted in 16 centers across the United States and India. In its initial 28-week phase (part 1), the trial explored the addition of rusfertide to ongoing phlebotomy therapy. After this ended, part 2 of the trial involved a 12-week withdrawal period where participants were randomized to receive either rusfertide or placebo.

Outcomes from the initial two parts of REVIVE demonstrated rusfertide effectively managed erythrocytosis, sustained a hematocrit of <45%, and decreased or eliminated the need for phlebotomy use among the population with polycythemia vera.

“Rusfertide appears to represent a step forward in the treatment of polycythemia vera, with a novel mechanism of action that could become an additional therapeutic tool for the control of this disease,” wrote the investigative team, led by Marina Kremyanskaya, MD, PhD, division of hematology and medical oncology, Tisch Cancer Institute, Ichahn School of Medicine at Mount Sinai.

Polycythemia vera is a myeloproliferative neoplasm characterized by erythrocytosis and variable increases in leukocyte and platelet counts.² The incidence of thromboembolic events is higher in those with polycythemia vera than those without the rare blood disorder. A therapeutic approach to reduce the risk of thromboembolic events is by maintaining a hematocrit of <45%,with current treatments ranging from phlebotomy to the addition of cytoreductive agents.

However, real-world evidence has shown currently used treatments are ineffective at maintaining a hematocrit of <45% in many patients with polycythemia vera, leaving them at high risk for complications.³ Rusfertide, an injectable peptide hepcidin-mimetic, restricts the availability of iron for erythropoiesis. The phase 2 REVIVE trial set out to evaluate the safety and efficacy of rusfertide in patients who met the 2016 World Health Organization (WHO) criteria for the diagnosis of phlebotomy-dependent polycythemia vera.¹

Between October 2019 and March 2022, 70 patients were enrolled in part 1 of REVIVE. In part 1 of the trial, the use of phlebotomy was found to decrease or cease altogether in all patients after initiation of rusfertide treatment. Estimates showed the mean phlebotomy rate was 8.7 ± 2.9 during the 28 weeks before the first dose of rusfertide and 0.6 ± 1.0 during part 1 of the trial (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was lower during part 1 (44.5 ± 2.2%) of the trial than the 28 weeks before the first dose of rusfertide (50.0 ± 5.8%).

Moreover, the primary end-point analysis in part 2 of REVIVE (weeks 29 to 41) included 59 patients, including 30 in the rusfertide group and 29 in the placebo group. In part 2 of the trial, a response occurred in 60% of patients receiving rusfertide compared with 17% of patients in the placebo group (P = .002).

The analysis additionally measured the change from baseline to week 29 in individual symptom scores on the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (score range, 0 [absent] to 10 [worst]).

At baseline, the mean total symptom score on the MPN-SAF was low (15.6 ± 15.3). Between baseline and the end of part 1, rusfertide was linked to a decrease in disease-related symptom scores in patients with moderate or severe symptoms. A comparison of the trial groups in part 2 was not possible due to the early nonresponse to placebo in most patients in the cohort.

Despite the maintenance of a hematocrit of <45% linked to a reduction in the risk of thrombotic events, Kremyanskaya and colleagues called for further research to confirm whether rusfertide therapy affects the incidence of thromboembolic events.

“Rusfertide is a potentially effective treatment option for achieving and sustaining hematocrit control in patients with polycythemia vera, reducing the use of phlebotomy and the occurrence of debilitating disease-related symptoms,” they wrote.

References

1. _{Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. New England Journal of Medicine, 2024; 390:723-735. DOI: 10.1056/NEJMoa2308809}
2. _{Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera: historical oversights, diagnostic details, and therapeutic views. Leukemia 2021;35:3339-51}
3. _{CarobbioA,VannucchiAM,DeStefano V, et al. Neutrophil-to-lymphocyte ratio is a novel predictor of venous thrombosis in polycythemia vera. Blood Cancer J 2022; 12:28.}