Phase 3 VERIFY Trial Investigates Rusfertide’s Potential in Polycythemia Vera
In an interview, Aniket Bankar, MD, discussed the background, design, and goals of the phase 3 VERIFY trial of the hepcidin mimetic rusfertide for the treatment of patients with polycythemia vera.
a close-up of red blood cells flowing through a vein, displaying the characteristic sickle shape Generative AI: © catalin - stock.adobe.com
The phase 3 VERIFY trial (NCT05210790) is evaluating treatment with rusfertide (PTG-300), a hepcidin mimetic for the treatment of patients with polycythemia vera (PV) with the hope it may offer a useful option for this patient population.1
“Rusfertide could have its place in both low-risk and high-risk patients and both as first-line and second-line treatment,” said Aniket Bankar, MD, in an interview with Targeted OncologyTM. “When [other] treatments are not adequate to control the hematocrit, produce toxicities, or are contraindicated, rusfertide could be useful.”
In the multicenter, global, randomized trial, experts are comparing the efficacy and safety of rusfertide when given at a starting dose of 20 mg subcutaneously once a week to placebo plus ongoing therapy for patients with PV. The study will be done in 3 parts.
Enrollment is open to patients with PV who require frequent therapeutic phlebotomies with or without concurrent cytoreductive therapy to control hematocrit. The primary end point of the study is the amount of patients achieving a response in part 1a of the study from week 20 to week 32.
In the interview, Bankar, hematologist at Princess Margaret Cancer Center in Toronto, Canada, delved into the rationale behind studying rusfertide in the phase 3 VERIFY trial for the treatment of patients with PV.
Targeted Oncology: Can you briefly discuss the current challenges in managing patients with PV?
Bankar: Current challenges lie in making sure that their hematocrit is controlled [maintained ≤ 45%], irrespective of when they are visiting their phlebotomist, especially those low-risk patients who are managed with phlebotomies, or patients who are receiving cytoreductive treatment, including hydroxyurea and/or interferon. Many patients continue to need phlebotomies because of suboptimal hematocrit control. And when phlebotomies are frequently required, these patients lose iron and become iron-deficient, which can lead to worsening of symptoms. Some studies have also shown that when you have higher hematocrit levels, that can also increase the risk of developing symptoms and thrombosis.
Based on preclinical data and previous studies, why was rusfertide considered a promising therapeutic approach for PV?
Rusfertide is a hepcidin mimetic therapeutic peptide. The way it works is it blocks ferroportin, the channel that exports iron from its stores. A study had shown that in patients with PV, the hepcidin levels are low, leading to continuous export of iron from the iron stores to enable uncontrolled erythropoiesis, which is being driven primarily by the JAK2 V617F mutation. Based on this preclinical data, the phase 2 randomized study [REVIVE; NCT04057040] was conducted in patients with PV who required phlebotomies with or without cytoreductive treatment. In that phase 2 study, the investigators saw that about 60% of patients became phlebotomy-independent. To confirm the results from the phase 2 study, we are now conducting a global, phase 3, placebo-controlled, randomized trial.
Can you walk through the key elements of the VERIFY trial design, including the patient population, randomization, and primary end points?
This is a phase 3, placebo-controlled, blinded, randomized trial. Here, there are 3 parts to the trial. Part 1a is the double-blinded part where patients are randomized to either placebo or rusfertide in a 1:1 ratio. Part 1a has a duration of 32 weeks. After 32 weeks, the patients are unblinded. If they were not receiving rusfertide, then they will have the chance to cross over to receive rusfertide in the next part, which is part 1b [and] lasts 20 weeks, until week 52. In other words, patients who were not getting the drug in part 1a will have the option to receive rusfertide beginning in part 1b. Patients who were on rusfertide during part 1a are continued on rusfertide. Once parts 1a and 1b are completed after 52 weeks, patients will be rolled over on to the long-term extension phase [part 2], which is for an additional 2 years.
How does rusfertide compare with existing treatment options for patients with PV in terms of efficacy, safety, etc?
The phase 2 data [in REVIVE] showed about 60% response rates, and many of those patients are already receiving hydroxyurea, some of them are receiving interferon, and some of them are receiving ruxolitinib [Jakafi]. It has a place to address some of the unmet needs in patients with polycythemia vera who require phlebotomy, with or without cytoreductive therapy.
If the findings are positive from the phase 3 trial, how do you envision rusfertide impacting the future management of patients with PV?
Rusfertide could have its place in both low-risk and high-risk patients and both as first-line and second-line treatment. Right now, the standard of care for patients with PV who are low risk is either phlebotomy alone, or some patients may be on interferon or hydroxyurea. Most high-risk patients will be on some cytoreductive treatments. When these treatments are not adequate to control the hematocrit, produce toxicities, or are contraindicated, rusfertide could be useful.
What about the unmet needs?
If some patients have ongoing iron deficiency, rusfertide can control the problem of iron deficiency. In high-risk patients, despite patients being currently on the approved cytoreductive agents, if they are continuing to need phlebotomy, then this can work as an add on in those patients as was seen in the phase 2 REVIVE study. The population studied in the phase 2 study are PV patients who require phlebotomy, with or without cytoreductive therapy. However, there is no head-on, phase 3 comparison between the currently approved drugs, for example. This phase 3 trial is also enrolling both patients treated with or without cytoreductive agents. Additional studies comparing rusfertide to approved cytoreductive therapies or testing the use of rusfertide in combination regimens will shed additional light on the sequencing of rusfertide and its role in the treatment armamentarium for polycythemia vera.
