In the phase II REVIVE trial reported in The New England Journal of Medicine, Marina Kremyanskaya, MD, PhD, and colleagues found that the hepcidin mimetic rusfertide reduced the number of phlebotomies (during a dose-finding phase) and improved response rate vs placebo (during a randomized phase) in patients with polycythemia vera.
Rusfertide is an injectable peptide mimetic of the master iron regulatory hormone hepcidin that restricts the availability of iron for erythropoiesis.
Marina Kremyanskaya, MD, PhD
Study Details
Patients from sites in the United States and India were enrolled in the trial between October 2019 and March 2022. In part 1 of the trial, 70 patients were enrolled in a 28-week dose-finding phase and received weekly subcutaneous rusfertide at doses of 10 to 120 mg, adjusted to maintain a hematocrit of < 45%. Part 2 was a 12-week, double-blind, randomized withdrawal period (weeks 29 to 41) in which patients were assigned to receive rusfertide (n = 30) or placebo (n = 29). The primary endpoint was response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2.
Key Findings
Among patients in part 1, the estimated mean (standard deviation) number of phlebotomies per year was 8.7±2.9 during the 28 weeks prior to the first dose of rusfertide vs 0.6±1.0 during the 28 weeks of rusfertide treatment (estimated difference = 8.1 phlebotomies per year). Corresponding mean maximum hematocrit levels were 50.0±5.8% vs 44.5±2.2%.
During part 2, response was observed in 18 (60%) of 30 patients in the rusfertide group vs 5 (17%) of 29 in the placebo group (P = .002). Criteria for phlebotomy eligibility were met by 3 patients (10%) in the rusfertide group vs 15 patients (52%) in the placebo group.
Between baseline and the end of part 1 of the trial, rusfertide treatment was associated with a decrease in individual symptom scores on the modified Myeloproliferative Neoplasm Symptom Assessment Form among patients with moderate or severe baseline symptoms.
During parts 1 and 2 of the trial, grade 3 adverse events occurred in 13% of patients receiving rusfertide; no grade 4 or 5 events were observed. Injection-site reactions—all grade 1 or 2—occurred in 60% of patients.
The investigators concluded, “In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo.”
Dr. Kremyanskaya, of the Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Protagonist Therapeutics. For full disclosures of the study authors, visit nejm.org.
