madman
Super Moderator
* “Polycythemia vera represents a unique situation, where you have overproduction of red blood cells in the setting of systemic iron deficiency,” Dr. Kuykendall said. Rusfertide was designed to address this particular issue.
* The endogenous hormone hepcidin is the principal regulator of systemic iron homeostasis, controlling iron through downregulation of ferroportin, a transmembrane protein responsible for delivering iron. In iron deficiency, and in polycythemia vera, hepcidin levels are low, and iron freely flows to the bone marrow at the expense of other iron-requiring tissues. Rusfertide, which is administered subcutaneously, is a first-in-class peptide mimetic of hepcidin. It binds to ferroportin, thereby triggering its degradation, restricting iron from the bone marrow, and controlling hematocrit, he explained.
* “Based on these data, we believe rusfertide represents a potential new treatment option in polycythemia vera,” said Dr. Kuykendall. The data will be used to file global marketing authorizations for the drug.
* The median treatment exposure in both groups was 32 weeks. The most common treatment-emergent adverse events in the rusfertide arm were localized injection-site reactions (55.9%) and anemia (15.9%), which were consistent with the drug’s administration route and mechanism of action. Serious adverse events were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm; none were considered to be related to rusfertide. An acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.
In patients with polycythemia vera requiring frequent phlebotomies, the investigational hepcidin mimetic rusfertide, given as a weekly subcutaneous injection, more than doubled the clinical response rate and significantly improved quality of life in the global phase III VERIFY study.1 These findings were presented during the Plenary Session of the 2025 ASCO Annual Meeting by Andrew Kuykendall, MD, Associate Member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.
Rusfertide significantly improved multiple endpoints: reducing the need for phlebotomy, improving hematocrit control, and reducing symptoms across two patient-reported outcome instruments. And it did so while maintaining a manageable safety profile that was consistent with prior studies, according to the investigators, thus meeting the primary endpoint and key secondary endpoints.
“Based on these data, we believe rusfertide represents a potential new treatment option in polycythemia vera,” said Dr. Kuykendall. The data will be used to file global marketing authorizations for the drug.
A Novel Approach to Iron Regulation
“Polycythemia vera represents a unique situation, where you have overproduction of red blood cells in the setting of systemic iron deficiency,” Dr. Kuykendall said. Rusfertide was designed to address this particular issue.
The endogenous hormone hepcidin is the principal regulator of systemic iron homeostasis, controlling iron through downregulation of ferroportin, a transmembrane protein responsible for delivering iron. In iron deficiency, and in polycythemia vera, hepcidin levels are low, and iron freely flows to the bone marrow at the expense of other iron-requiring tissues. Rusfertide, which is administered subcutaneously, is a first-in-class peptide mimetic of hepcidin. It binds to ferroportin, thereby triggering its degradation, restricting iron from the bone marrow, and controlling hematocrit, he explained.
About the VERIFY Trial
VERIFY is a global, ongoing phase III trial designed to confirm the benefit of adding rusfertide to the current standard of care for patients with polycythemia vera requiring frequent therapeutic phlebotomies. There were 293 patients in this three-part study:
The presentation at the ASCO meeting focused on the results from part 1A. Although the primary endpoint focused on weeks 20 to 32, the key secondary endpoints were assessed from weeks 0 to 32 and included the mean number of phlebotomies, the proportion of patients maintaining a hematocrit less than 45%, and patient-reported outcomes.
Among the 293 patients, baseline demographics and disease characteristics were well matched between the placebo and rusfertide groups, with the exception that the rusfertide arm had slightly more heavily phlebotomized patients (16 vs 7). More than half of patients in both arms received concurrent cytoreductive therapy, including hydroxyurea (39.2%), interferon (13.3%), and ruxolitinib (2.7%).
Multiple Endpoints Met
The VERIFY study met its primary endpoint of decreasing “phlebotomy eligibility,” which was a confirmed hematocrit level ≥ 45% and ≥ 3% higher than baseline hematocrit or hematocrit ≥ 48%. Double the proportion of patients given rusfertide achieved this response, 76.9% vs 32.9% in the placebo arm (P < .0001). Higher response rates were consistent across subgroups based on demographics, risk, or concurrent cytoreductive therapy, according to Dr. Kuykendall.
Compared with placebo, rusfertide was associated with a lower mean phlebotomy rate over weeks 0 to 32 (0.5 vs 1.8; P < .0001) and a significant improvement in hematocrit control < 45%, which is considered “a highly relevant clinical endpoint,” he said, as this has been shown to decrease the risk of cardiac events; the rate was 62.6% vs 14.4%, respectively (P < .0001). Patients receiving rusfertide also maintained more consistent hematocrit levels, whereas patients receiving the standard care alone experienced “sharp spikes” during treatment, he noted.
“Patients with polycythemia vera have a critically unmet need in terms of quality of life and symptoms. The major symptom that plagues these patients is fatigue, and although this is multifactorial, we understand that some of this is likely due to systemic iron deficiency,” Dr. Kuykendall continued. “Because of that, we thought a critical aspect of this study was to assess fatigue and how this could respond, given the mechanism of action of rusfertide on iron regulation.”
Using the PROMIS Fatigue Short Form, investigators observed that patients treated with rusfertide had improved fatigue scores from baseline to week 32, as compared with the placebo arm; the mean difference between the arms was almost two points (P = .0268). Rusfertide was also associated with a significant improvement in the Total Symptom Score (ie, 7, which suggests mild symptoms)—again, an almost two-point difference (P = .0239)—with fewer complaints of disease-related symptoms such as fatigue, night sweats, itching, abdominal symptoms, and bone pain.
Safety Profile
The median treatment exposure in both groups was 32 weeks. The most common treatment-emergent adverse events in the rusfertide arm were localized injection-site reactions (55.9%) and anemia (15.9%), which were consistent with the drug’s administration route and mechanism of action. Serious adverse events were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm; none were considered to be related to rusfertide. An acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.
Patients with polycythemia vera are at higher risk of nonhematologic secondary malignancies, particularly skin malignancies, which are often exacerbated with treatments such as hydroxyurea and ruxolitinib, Dr. Kuykendall noted. During part 1A, new cancers were reported in one patient (0.7%) in the rusfertide arm and in seven patients (4.8%) in the placebo arm.
The other parts of the VERIFY study will report longer-term treatment and safety outcomes for this chronic malignancy. Patients will be followed for up to 3 years.
* The endogenous hormone hepcidin is the principal regulator of systemic iron homeostasis, controlling iron through downregulation of ferroportin, a transmembrane protein responsible for delivering iron. In iron deficiency, and in polycythemia vera, hepcidin levels are low, and iron freely flows to the bone marrow at the expense of other iron-requiring tissues. Rusfertide, which is administered subcutaneously, is a first-in-class peptide mimetic of hepcidin. It binds to ferroportin, thereby triggering its degradation, restricting iron from the bone marrow, and controlling hematocrit, he explained.
* “Based on these data, we believe rusfertide represents a potential new treatment option in polycythemia vera,” said Dr. Kuykendall. The data will be used to file global marketing authorizations for the drug.
* The median treatment exposure in both groups was 32 weeks. The most common treatment-emergent adverse events in the rusfertide arm were localized injection-site reactions (55.9%) and anemia (15.9%), which were consistent with the drug’s administration route and mechanism of action. Serious adverse events were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm; none were considered to be related to rusfertide. An acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.
Adding the Hepcidin Mimetic Rusfertide to the Standard of Care Yields Benefits in Polycythemia Vera
In patients with polycythemia vera requiring frequent phlebotomies, the investigational hepcidin mimetic rusfertide, given as a weekly subcutaneous injection, more than doubled the clinical response r...
ascopost.com
In patients with polycythemia vera requiring frequent phlebotomies, the investigational hepcidin mimetic rusfertide, given as a weekly subcutaneous injection, more than doubled the clinical response rate and significantly improved quality of life in the global phase III VERIFY study.1 These findings were presented during the Plenary Session of the 2025 ASCO Annual Meeting by Andrew Kuykendall, MD, Associate Member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.
Rusfertide significantly improved multiple endpoints: reducing the need for phlebotomy, improving hematocrit control, and reducing symptoms across two patient-reported outcome instruments. And it did so while maintaining a manageable safety profile that was consistent with prior studies, according to the investigators, thus meeting the primary endpoint and key secondary endpoints.
“Based on these data, we believe rusfertide represents a potential new treatment option in polycythemia vera,” said Dr. Kuykendall. The data will be used to file global marketing authorizations for the drug.
A Novel Approach to Iron Regulation
“Polycythemia vera represents a unique situation, where you have overproduction of red blood cells in the setting of systemic iron deficiency,” Dr. Kuykendall said. Rusfertide was designed to address this particular issue.
The endogenous hormone hepcidin is the principal regulator of systemic iron homeostasis, controlling iron through downregulation of ferroportin, a transmembrane protein responsible for delivering iron. In iron deficiency, and in polycythemia vera, hepcidin levels are low, and iron freely flows to the bone marrow at the expense of other iron-requiring tissues. Rusfertide, which is administered subcutaneously, is a first-in-class peptide mimetic of hepcidin. It binds to ferroportin, thereby triggering its degradation, restricting iron from the bone marrow, and controlling hematocrit, he explained.
About the VERIFY Trial
VERIFY is a global, ongoing phase III trial designed to confirm the benefit of adding rusfertide to the current standard of care for patients with polycythemia vera requiring frequent therapeutic phlebotomies. There were 293 patients in this three-part study:
- Part 1A (weeks 0–32): Patients with polycythemia vera requiring frequent phlebotomies were randomly assigned in a 1:1 fashion to receive either rusfertide, self-injected weekly, or placebo—both of which were added to standard therapy (cytoreductive therapy could continue). Dosing was titrated over the first 20 weeks, with the primary endpoint assessed from weeks 20 to 32.
- Part 1B (weeks 32–52): Patients completing part 1A could roll over into an open-label part of the study wherein all patients received rusfertide.
- Part 2: The open-label, long-term safety-assessment phase.
The presentation at the ASCO meeting focused on the results from part 1A. Although the primary endpoint focused on weeks 20 to 32, the key secondary endpoints were assessed from weeks 0 to 32 and included the mean number of phlebotomies, the proportion of patients maintaining a hematocrit less than 45%, and patient-reported outcomes.
Among the 293 patients, baseline demographics and disease characteristics were well matched between the placebo and rusfertide groups, with the exception that the rusfertide arm had slightly more heavily phlebotomized patients (16 vs 7). More than half of patients in both arms received concurrent cytoreductive therapy, including hydroxyurea (39.2%), interferon (13.3%), and ruxolitinib (2.7%).
Multiple Endpoints Met
The VERIFY study met its primary endpoint of decreasing “phlebotomy eligibility,” which was a confirmed hematocrit level ≥ 45% and ≥ 3% higher than baseline hematocrit or hematocrit ≥ 48%. Double the proportion of patients given rusfertide achieved this response, 76.9% vs 32.9% in the placebo arm (P < .0001). Higher response rates were consistent across subgroups based on demographics, risk, or concurrent cytoreductive therapy, according to Dr. Kuykendall.
Compared with placebo, rusfertide was associated with a lower mean phlebotomy rate over weeks 0 to 32 (0.5 vs 1.8; P < .0001) and a significant improvement in hematocrit control < 45%, which is considered “a highly relevant clinical endpoint,” he said, as this has been shown to decrease the risk of cardiac events; the rate was 62.6% vs 14.4%, respectively (P < .0001). Patients receiving rusfertide also maintained more consistent hematocrit levels, whereas patients receiving the standard care alone experienced “sharp spikes” during treatment, he noted.
“Patients with polycythemia vera have a critically unmet need in terms of quality of life and symptoms. The major symptom that plagues these patients is fatigue, and although this is multifactorial, we understand that some of this is likely due to systemic iron deficiency,” Dr. Kuykendall continued. “Because of that, we thought a critical aspect of this study was to assess fatigue and how this could respond, given the mechanism of action of rusfertide on iron regulation.”
Using the PROMIS Fatigue Short Form, investigators observed that patients treated with rusfertide had improved fatigue scores from baseline to week 32, as compared with the placebo arm; the mean difference between the arms was almost two points (P = .0268). Rusfertide was also associated with a significant improvement in the Total Symptom Score (ie, 7, which suggests mild symptoms)—again, an almost two-point difference (P = .0239)—with fewer complaints of disease-related symptoms such as fatigue, night sweats, itching, abdominal symptoms, and bone pain.
Safety Profile
The median treatment exposure in both groups was 32 weeks. The most common treatment-emergent adverse events in the rusfertide arm were localized injection-site reactions (55.9%) and anemia (15.9%), which were consistent with the drug’s administration route and mechanism of action. Serious adverse events were reported in 3.4% of patients in the rusfertide arm vs 4.8% in the placebo arm; none were considered to be related to rusfertide. An acute myocardial infarction occurred during part 1A in the rusfertide group, 2 weeks after treatment initiation.
Patients with polycythemia vera are at higher risk of nonhematologic secondary malignancies, particularly skin malignancies, which are often exacerbated with treatments such as hydroxyurea and ruxolitinib, Dr. Kuykendall noted. During part 1A, new cancers were reported in one patient (0.7%) in the rusfertide arm and in seven patients (4.8%) in the placebo arm.
The other parts of the VERIFY study will report longer-term treatment and safety outcomes for this chronic malignancy. Patients will be followed for up to 3 years.
