Rusfertide reduces hematocrit without phlebotomy in polycythemia vera
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Induction therapy with twice-weekly rusfertide helped patients with polycythemia vera achieve target hematocrit below 45% without phlebotomy, according to a study presented at ASH Annual Meeting and Exposition.
The twice-weekly injections appeared safe and well-tolerated, results of the PTG-300-08 trial showed.
After induction, all patients successfully maintained target hematocrit levels with subsequent weekly treatment with rusfertide (PTG-300, Protagonist Therapeutics).
“The results of [a prior phase 2 trial] as well as this trial provide strong evidence that rusfertide, and possibly other hepcidin-mimetic agents, is active both in well-controlled and newly diagnosed patients,” Yelena Ginzburg, MD, associate professor of medicine (hematology and medical oncology) at The Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, told Healio. “[This] opens the door for a paradigm shift in standard-of-care management of [patients with polycythemia vera who require phlebotomy].”
Patients with polycythemia vera who have hematocrit levels above 45% are at elevated risk for thrombotic complications. They typically undergo phlebotomy and/or cytoreductive therapy to help them reach a hematocrit target below 45%.
Results of a phase 2 trial showed rusfertide — a peptide mimetic of hepcidin — maintained hematocrit below 45% for patients with polycythemia vera. Researchers observed this benefit among high-risk and low-risk patients, those who concurrently received cytoreductive therapy (eg, hydroxyurea, interferon or ruxolitinib [Jakafi, Incyte]) and those who were treated with phlebotomy alone.
In the PTG-300-08 trial, Ginzburg and colleagues assessed the potential of rusfertide to normalize hematocrit to below 45% for patients with polycythemia vera who were not able to or not willing to receive sufficient phlebotomy or cytoreductive treatment to control hematocrit.
“The results of the phase 2 trial PTG-300-04, presented at ASH in the same session, showed that rusfertide for [patients with polycythemia vera] with hematocrit less than 45% — well-controlled patients — essentially eliminates the need for maintenance therapeutic phlebotomy,” Ginzburg said. “The current trial evaluated what happens when patients are not well-controlled, enabling us to ask whether rusfertide alone in the absence of phlebotomy enables rapid hematocrit control in erythrocytotic [patients with polycythemia vera].”
Researchers enrolled 20 patients (mean age, 56.1 years; 75% men) with polycythemia vera. Mean time since diagnosis was 3.74 years.
All patients had baseline hematocrit above 48% and history of three or more hematocrit values above that level in the year preceding enrollment.
Thirteen patients had low-risk disease, 16 were receiving concurrent hydroxyurea and four were treated with phlebotomy alone.
Patients received rusfertide in addition to their current therapy. Initially, they received 40-mg doses administered subcutaneously twice weekly. When hematocrit reached below 45%, they received weekly rusfertide at adjusted doses to maintain their hematocrit levels.
Researchers reported the following baseline values in the cohort: hematocrit (mean, 51%; minimum-maximum, 47.4-59), white blood cell count (mean, 12,338 µL; minimum-maximum, 7,000-24,600), red blood cell count (mean, 5.9 x 106/ µL; minimum-maximum, 4.3-7.6) and platelets (mean, 486,500/ µL; minimum-maximum, 242,000-904,000).
All patients achieved rapid decreases in hematocrit to below 45% without use of phlebotomy. When investigators reduced the rusfertide regimen to once-weekly maintenance doses, hematocrit levels remained well-controlled.
Researchers reported a rapid decline in hemoglobin, as well as a rapid decrease in erythrocyte counts. The latter finding indicates decreased hematocrit is due to decreased erythrocytosis, researchers wrote.
Among 11 patients with adequate follow-up, researchers reported a mean rate of absolute hematocrit decrease of 1.76% per week (median, 1.81% per week; minimum-maximum, 0.65-2.69) and a mean time to reach target hematocrit below 45% of 4.79 weeks (median, 4.14 weeks; minimum-maximum, 3.57-8.14).
“The results are consistent with the physiological effect of hepcidin,” Ginzburg said. “The speed of the suppressive effect on erythropoiesis is impressive.”
Eight patients reported adverse events. Seven experienced mild or moderate injection site reactions, the most common of which were erythema (n = 7), induration (n = 5) and pruritus (n = 2). Two patients each developed hypertension, pyrexia and thrombocytosis.
Two patients experienced serious adverse events — one case each of pleuritic chest pain and worsening migraine — but researchers characterized both as unrelated to rusfertide.
“The main thrust of the results is the reliable control of the hematocrit below 45% without phlebotomy,” Ginzburg said. “While we know that patients with high phlebotomy requirements have an increased risk for thrombosis relative to those with lower phlebotomy requirements, it remains incompletely understood what drives that risk.
“One possible hypothesis is that [patients with polycythemia vera] with high phlebotomy requirements spend substantial amounts of time between phlebotomies with hematocrit above 45%,” Ginzburg added. “Rusfertide would remove this risk factor and possibly enable us to understand better the underlying cause of thrombotic risk among these patients.”
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Ginzburg Y, et al. Abstract 390. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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