Rusfertide More Than Triples Responses Vs Placebo in Phlebotomy-Dependent Polycythemia Vera

Marina Kremyanskaya, MD, PhD

Treatment with rusfertide led to a 60% response rate (n = 18/30) vs 17% (n = 5/29) with placebo in patients with phlebotomy-dependent polycythemia vera (P = .002), according to updated findings from part 2 of the phase 2 REVIVE trial (NCT04057040) which were published in the New England Journal of Medicine.¹

The international trial was designed with 3 parts: a 28-week, open-label, dose-finding portion in which rusfertide was added to a patient’s ongoing therapy of phlebotomy alone or cytoreductive therapy with optional phlebotomy; a double-blind, randomized withdrawal portion wherein patients were randomly assigned to receive rusfertide or placebo for 12 weeks (weeks 29 to 41); and an open-label extension period following patients on rusfertide therapy for up to 3 years.

Findings from part 1 showed that the estimated mean number of annual phlebotomies was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). Moreover, the mean maximum hematocrit level was 44.5±2.2% during part 1 vs 50.0±5.8% during the 28 weeks before the first dose of rusfertide. Patient quality of life was also improved on rusfertide, with a lower severity of disease-related symptoms.

“Rusfertide appears to represent a significant step forward in treating [patients with] polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” Marina Kremyanskaya, MD, PhD, an associate professor of medicine (hematology and medical oncology) at Icahn School of Medicine at Mount Sinai in New York, New York, and lead author of the study, stated in a news release.² “Pending further clinical studies, this injectable agent could become a valuable therapeutic tool for a disease which many patients and their physicians struggle to bring under control.”

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide is an injectable peptide mimetic of hepcidin that works by limiting iron access for erythropoiesis, representing a needed treatment for patients with phlebotomy dependence.¹

To qualify as phlebotomy dependent in the study, patients had to have undergone at least three phlebotomies during the 28 weeks before the first dose of rusfertide in part 1 of the trial, with the most recent phlebotomy having occurred within 12 weeks before screening.

Throughout the study, rusfertide was administered subcutaneously once a week with a dose ranging from 10 mg to 120 mg to ensure hematocrit levels remained below 45%.

The primary end point was response in part 2 defined by hematocrit control, lack of phlebotomy, and completion of the assigned treatment. Secondary end points in part 2 included the difference in hematocrit level from baseline to week 41.

Secondary end points in part 1 included the change in phlebotomy rate between the 28-week period before the first dose of rusfertide and part 1, the change in phlebotomy rate between weeks 17 and 29, and response, which was defined as the absence of phlebotomy eligibility.

Seventy patients were enrolled in part 1, and in part 2, 30 patients received rusfertide and 29 received placebo.

Previous findings from the trial were presented at the 2023 EHA Congress.³ Additional findings from part 2 demonstrated that the median time to loss of response, phlebotomy eligibility, and a first hematocrit of at least 45% were not reached with rusfertide vs 4.4 weeks with placebo. Additionally, fewer patients in the rusfertide arm (n = 28; 93%) vs the placebo arm (n = 14; 48%) did not undergo phlebotomy. The mean absolute change from baseline in the hematocrit level varied less in the rusfertide arm at 0.3±3.1 percentage points vs in the placebo arm at 2.0±2.6 percentage points.

Findings from part 3 were presented at the 2023 ASH Annual Meeting & Exposition. Of the 59 patients who were randomized in part 2, 58 continued on treatment in part 3. The median age of patients in part 3 was 57 years (range, 27-77); 70.7% were men, and 55.2% received phlebotomy, with 44.8% receiving concurrent cytoreductive therapy.⁴

Results from part 3 showed that rusfertide led to long-term hematocrit control without phlebotomy despite an initial increase in platelet counts within approximately 4 weeks of starting treatment. Moreover, rusfertide demonstrated sustained hematocrit levels below 45% and an overall reduction in erythrocyte counts. Prior to enrollment, patients’ ferritin levels were consistent with systemic iron deficiency (mean [±SE] ferritin 18.7 [±4.3] µg/L). By cycle 15 of rusfertide treatment, patients experienced an improvement in serum ferritin reaching normal levels (mean [±SE] ferritin 148.6 [±18.6] µg/L.⁴

Regarding safety in parts 1 and 2, low-grade (grade 1/2) injection-site reactions were common (86%). Grade 3 adverse effects occurred in 13% of patients in parts 1 and 2, including myocardial infarction, fatigue, increased platelet count, peripheral sensory neuropathy, syncope, squamous cell carcinoma, basal cell carcinoma, and hypertension; one patient had both acute myeloid leukemia and squamous cell carcinoma. None experienced a grade 4 or 5 event.¹

“Rusfertide shows great promise for achieving sustained hematocrit control in patients with PV. Just as importantly, it decreased the need for repeat phlebotomies, with some patients remaining virtually free of the procedure for more than two and a half years,” Kremyanskaya concluded.²

References

1. 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
2. A Mount Sinai-led study shows early success of a novel drug in treating a rare and chronic blood cancer. News release. Mount Sinai. February 21, 2024. Accessed February 27, 2024. https://www.mountsinai.org/about/newsroom/2024/mount-sinailed-study-shows-early-success-of-a-novel-drug-in-treating-a-rare-and-chronic-blood-cancer
3. Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: - blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.
4. Ritchie EK, Pettit KM, Kuykendall AT, et al. Durability of hematocrit control in polycythemia vera with the first-in-class hepcidin mimetic rusfertide: two-year follow up results from the Revive study. Blood. 2023;142(suppl 1):745. doi:10.1182/blood-2023-178253