Rusfertide Treatment For Elevated Red Blood Cell Production
Overview
Polycythemia vera is a chronic myeloproliferative disorder marked by elevated red blood cell production. Rusfertide, a peptide mimetic of the iron-regulating hormone hepcidin, has been developed to limit iron availability for erythropoiesis. However, its safety and efficacy in patients with polycythemia vera who require regular phlebotomies have not been established.
The international, phase 2 REVIVE trial aimed to assess the safety and efficacy of rusfertide in this patient population. The trial consisted of two parts: Part 1 involved a 28-week dose-finding phase, where patients received rusfertide. Part 2 was a 12-week double-blind, randomized withdrawal period, where participants were assigned to either continue rusfertide or switch to a placebo. The primary efficacy measure was defined as achieving hematocrit control, avoiding the need for phlebotomy, and completing the treatment regimen during Part 2. Patient-reported outcomes were also evaluated using the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), with scores ranging from 0 to 10, indicating the severity of symptoms.
In Part 1, 70 patients were enrolled, with 59 advancing to Part 2—30 receiving rusfertide and 29 receiving a placebo. Prior to rusfertide treatment, the average number of annual phlebotomies was 8.7±2.9, which reduced significantly to 0.6±1.0 during Part 1, marking an estimated reduction of 8.1 phlebotomies per year. Additionally, the average maximum hematocrit level during Part 1 was 44.5±2.2%, a marked improvement from the 50.0±5.8% observed before treatment. In Part 2, 60% of patients treated with rusfertide met the primary efficacy endpoint compared to just 17% in the placebo group (P=0.002). Furthermore, patients reported a decrease in the severity of symptoms on the MPN-SAF, particularly those with moderate or severe baseline symptoms.
Adverse events of grade 3 severity were observed in 13% of patients during both parts of the trial, but no grade 4 or 5 events were reported. Mild to moderate injection-site reactions were also common.
In summary, rusfertide effectively maintained a mean hematocrit below 45% during the 28-week dose-finding period, and a higher percentage of patients achieved treatment response during the randomized withdrawal phase compared to placebo. These findings suggest rusfertide is a promising treatment option for managing polycythemia vera, especially for patients dependent on regular phlebotomies.
Introduction
Polycythemia vera is a type of myeloproliferative neoplasm marked by an increase in red blood cell production, often accompanied by elevated white blood cell and platelet counts. The majority of patients with this condition harbor a somatic mutation in the JAK2 gene, which drives the excessive production of mature hematopoietic cells. This condition is associated with a heightened risk of thromboembolic events, a risk traditionally linked to erythrocytosis, though recent studies suggest that elevated white blood cell or platelet counts may also contribute to this risk. Patients with polycythemia vera often experience systemic symptoms such as pruritus, night sweats, difficulty concentrating, and fatigue.
The primary treatment goal in polycythemia vera is to mitigate the risk of thromboembolic events by maintaining a hematocrit level below 45%. Treatment strategies are tailored based on the patient’s thrombosis risk, with low-risk patients typically receiving aspirin and undergoing phlebotomy, while high-risk patients—those aged 60 or older, with a history of thrombosis, or both—may require additional cytoreductive therapies such as hydroxyurea, ruxolitinib, or interferon alfa. However, real-world evidence indicates that current treatments often fail to maintain the target hematocrit in a significant number of patients, leaving them vulnerable to complications.
Hepcidin, a peptide hormone produced by the liver, plays a crucial role in regulating iron metabolism. It is upregulated by circulating iron levels and inflammatory cytokines and downregulated by bone marrow erythroid activity. Hepcidin binds to the iron transporter ferroportin, inhibiting iron release into the bloodstream and reducing serum iron levels and transferrin saturation. This mechanism leads to functional iron deficiency and decreased red blood cell production. Preclinical research suggests that enhancing hepcidin activity in polycythemia vera patients could help control erythrocytosis and potentially alleviate symptoms.
Rusfertide, an injectable peptide that mimics the action of endogenous hepcidin, has shown promise in reducing serum iron levels in healthy volunteers in a dose-dependent manner, indicating its potential to decrease red blood cell production in polycythemia vera patients. The phase 2 REVIVE trial was conducted to assess the safety and efficacy of rusfertide in patients with polycythemia vera who require regular phlebotomy.
Method
The trial consists of three parts, with the primary focus on assessing the efficacy and safety of rusfertide in patients with polycythemia vera. Part 1 of the trial involved a 28-week, open-label period where rusfertide was added to the patient’s current therapy, with doses adjusted to maintain a hematocrit level below 45%. Part 2, which was unblinded in March 2023, is a 12-week, double-blind, randomized withdrawal phase where patients either continued rusfertide or switched to a placebo. Part 3 is an ongoing open-label extension in which all participants are receiving rusfertide.
The trial includes strict monitoring of adverse events, which are assessed using the National Cancer Institute’s criteria. An independent safety committee regularly reviews the data. Notably, the study experienced a temporary clinical hold imposed by the FDA after a potential tumorigenicity signal was detected in animal models. The hold was lifted after updating the trial documents and obtaining institutional approvals.
Eligible participants are adults with polycythemia vera who require frequent phlebotomies, defined as at least three in the 28 weeks prior to the start of the trial. Patients on stable doses of cytoreductive therapies such as hydroxyurea, interferon alfa, or ruxolitinib were allowed to continue these treatments while participating in the trial.
The primary endpoint of the study was hematocrit control without the need for phlebotomy during the randomized withdrawal period. Secondary endpoints included changes in phlebotomy rates and symptom scores from baseline to specific time points, as measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).
Efficacy analyses were conducted on an intention-to-treat basis in Part 1, while the primary endpoint in Part 2 was assessed in a randomized population excluding those who discontinued due to the clinical hold. The study was designed to have sufficient power to detect significant differences between the rusfertide and placebo groups. Time-to-event analyses were performed to estimate outcomes such as loss of response and phlebotomy eligibility.
Overall, the trial is designed to rigorously evaluate the efficacy of rusfertide in managing polycythemia vera while carefully monitoring safety, particularly concerning potential long-term risks identified during the study.
Result
Between October 2019 and March 2022, a total of 82 patients were screened for the trial, with 70 enrolled in the initial phase (intention-to-treat population) and 59 randomized to receive either rusfertide or a placebo in the subsequent phase (randomized population). Eleven patients did not proceed to randomization; three withdrew due to adverse events, while eight left for other reasons. The primary endpoint analysis focused on the randomized group. Treatment was halted for six patients in this group due to a clinical hold.
Baseline demographics and disease characteristics of the intention-to-treat population are detailed in Table 1. Among the patients, 37 (53%) received phlebotomy alone, and 33 (47%) received cytoreductive therapy with supplemental phlebotomy. Forty patients (57%) had high-risk disease, and over 30% had polycythemia vera for over five years. The mean number of phlebotomies in the 28 weeks before starting rusfertide was high (4.7 ± 1.6). By the time of unblinding, 74% of patients had been on rusfertide for at least a year. Phlebotomy use significantly decreased or stopped in all patients following the initiation of rusfertide, with a notable reduction in the mean phlebotomy rate from 8.7 ± 2.9 to 0.6 ± 1.0 per year.
In Part 2 of the trial, involving 59 patients (30 on rusfertide and 29 on placebo), 60% of the rusfertide group and 17% of the placebo group showed a response (P=0.002). A sensitivity analysis confirmed the robustness of these findings. The rusfertide group had fewer patients (10%) meeting the criteria for phlebotomy compared to 52% in the placebo group. By the end of Part 2, 93% of the rusfertide group and 48% of the placebo group had not undergone phlebotomy. The mean absolute change in hematocrit from baseline was minimal in the rusfertide group (0.3 ± 3.1 percentage points) compared to the placebo group (2.0 ± 2.6 percentage points).
During rusfertide treatment, the mean hematocrit and erythrocyte count remained below baseline levels, while these measures increased in the placebo group. The mean serum ferritin level, indicative of systemic iron deficiency at baseline, rose during rusfertide treatment. Patient-reported outcomes showed reduced severity of disease-related symptoms in Part 1, particularly among those with moderate to severe symptoms at baseline.
Safety analysis revealed that all patients experienced at least one adverse event, with ten grade 3 events reported but no grade 4 or 5 events. Injection-site reactions were the most frequent adverse events, generally mild and decreasing over time. Serious adverse events aligned with the underlying conditions of polycythemia vera. Notably, no thromboembolic events occurred during the trial, despite a history of such events in some patients prior to starting rusfertide.
In summary, the trial demonstrated that rusfertide effectively reduces the need for phlebotomy in patients with polycythemia vera and results in significant clinical improvements compared to placebo. Adverse events were consistent with the patients’ pre-existing conditions, with no new severe safety concerns related to rusfertide therapy.
Conclusion
This trial demonstrates that rusfertide therapy effectively managed erythrocytosis in patients with polycythemia vera, maintaining hematocrit levels below 45% and reducing or eliminating the need for phlebotomy. Some patients sustained these outcomes for over 2.5 years without phlebotomy. While controlling hematocrit levels can lower thrombotic risk, further studies with extended follow-up are necessary to determine if rusfertide influences the incidence of thromboembolic events.
Unlike its impact on erythrocytosis, rusfertide led to a modest increase in platelet counts but did not affect leukocyte counts. Preclinical studies and evidence from the trial suggest that rusfertide mimics the action of hepcidin, increasing serum ferritin levels without causing tissue iron depletion. This indicates a redistribution of systemic iron, with normal ferritin levels and persistently low transferrin saturation and serum iron, suggesting no iron overload.
Phlebotomy, often burdensome and associated with worsening iron deficiency, remains a common necessity in patients with poorly controlled hematocrit. Rusfertide appears to improve hematocrit control and reduce phlebotomy needs. However, current therapies have not conclusively altered the progression of polycythemia vera, and the impact of hematocrit control versus other factors on thromboembolic risk remains unclear. Previous studies, such as those involving ruxolitinib, have shown benefits related to hematocrit control but varying results in thrombotic event occurrence.
The trial’s limitations include a small patient cohort and short follow-up duration, which restrict assessments of rusfertide’s effects on polycythemia vera complications and disease progression. Open-label design might also influence symptom reporting, and potential risks such as skin cancer, necessitating frequent dermatologic exams, remain uncertain.
Rusfertide represents a promising advancement in polycythemia vera treatment, offering a novel mechanism for achieving and maintaining hematocrit control and reducing phlebotomy needs and related symptoms. The ongoing phase 3 VERIFY trial (ClinicalTrials.gov number, NCT05210790) will further evaluate its efficacy.
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