Injectable Rusfertide Shows Promise for Erythrocytosis Control in Phlebotomy-Dependent PV

A team of clinical experts has analyzed data from the international phase 2 REVIVE trial, which investigated control of erythrocytosis in phlebotomy-dependent polycythemia vera using rusfertide, an injectable hepcidin mimetic. The team’s efficacy and safety findings were published in The New England Journal of Medicine.

“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,” wrote first author Marina Kremyanskaya, MD, PhD, of Icahn School of Medicine at Mount Sinai, New York, and colleagues.

Part 1 of the trial was a 28-week dose-finding assessment of rusfertide, which involved 70 patients with polycythemia vera. Fifty-nine of these patients were included in part 2 of the trial, a 12-week, double-blind, randomized withdrawal period during which 30 patients received rusfertide and 29 received placebo.

Regarding hematocrit control as a measure of rusfertide’s efficacy, the average maximum hematocrit among the patients was 50.0% during the 28 weeks before the first dose of rusfertide and fell to 44.5% during part 1. Regarding the number of phlebotomies per year, the estimated average number was 8.7 during the 28 weeks before the first rusfertide dose and fell to 0.6 during part 1.

“Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF [modified Myeloproliferative Neoplasm Symptom Assessment Form] in patients with moderate or severe symptoms at baseline,” Kremyanskaya and colleagues mentioned.

During part 2, the investigators observed that 60% of the patients who received rusfertide responded, compared with 17% of the patients who received placebo (P=0.002).

Regarding adverse events in parts 1 and 2, injection-site reactions of grade 1 or 2 severity were prevalent. Grade 3 adverse events affected 13% of the patients, and there were no grade 4 or 5 events.

Study coauthor Andrew Kuykendall, MD, of Moffitt Cancer Center, Tampa, Florida, in comments forwarded to Heme Today, conveyed his view that the REVIVE study “showed that there may be a preferred alternative to phlebotomy and hematocrit control in general in managing patients with polycythemia vera. The hepcidin mimetic, rusfertide, can effectively eliminate patients’ needs for phlebotomy and maintain consistent hematocrit control via a well-tolerated once weekly subcutaneous injection. The unique trial design that called for half of patients to be taken off of rusfertide and treated with placebo after 28 weeks provided a glimpse into the comparative benefit of rusfertide. Though brief, this period of comparison showed rapid loss of hematocrit control in patients who did not remain on rusfertide and showed that patients who remained on rusfertide had better control of disease-related symptoms that have long been difficult to manage. Ultimately, these findings led to the ongoing phase 3 VERIFY study which recently reported positive results.”

Dr. Kremyanskaya also explained, in remarks forwarded to Heme Today, that “[w]hat is especially exciting about the REVIVE study is that it utilized a completely novel approach as a potential treatment for polycythemia vera. It used a peptide hormone that is normally made by the liver to regulate iron homeostasis, to restrict iron availability for erythropoiesis, and thus controlled the hematocrit in patients with polycythemia vera. This phase 2 study showed in randomized fashion that this approach utilizing hepcidin mimetic rusfertide significantly decreased the need for therapeutic phlebotomies compared to placebo. It also indicated potential improvement in polycythemia vera related symptoms. Phase 3 VERIFY study is currently ongoing and is confirming these findings in a larger cohort of patients.”

The REVIVE trial is funded by Protagonist Therapeutics.

Reference

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