Rusfertide Could Represent New Therapeutic Option in Polycythemia Vera

Rusfertide (PTG-300) has shown promising efficacy in not only eliminating the need for phlebotomy in patients with polycythemia vera (PV), but also in improving their quality of life and symptom burden, according to Marina Kremyanskaya, MD, PhD.¹

What we are seeing is that not only can we use this drug to control the need for phlebotomy, which is significant because a lot of patients have a difficult time with phlebotomy, but also, patients are feeling better,” Kremyanskaya said. “It is an exciting new approach to the treatment of this disease.”

In an interview with OncLive, Kremyanskaya, an assistant professor of medicine, hematology, and medical oncology at Mount Sinai Hospital, discussed the results of the phase 2 PTG-300-04 trial (NCT04057040), which were presented at the European Hematology Association 2021 Virtual Congress, and the potential for rusfertide as a treatment option for patients with PV.

OncLive: Could you speak to the rationale for this study with PTG-300-04?

Kremyanskaya: PV is a clonal hematologic malignancy where patients experience an uncontrolled production of red blood cells, which can potentially increase the risk of thrombosis. The typical standard therapy for PV is therapeutic phlebotomy. This means that periodically, once their hematocrit gets above a certain level, which is approximately 45%, patients have a certain amount of blood removed. Patients with PV usually are iron deficient at diagnosis, and then the iron deficiency gets worse as we periodically perform therapeutic phlebotomies and remove blood.

The idea for the hepcidin therapy is it a negative regulator of iron metabolism, and typically in PV, hepcidin levels are low. As a result, iron is easily available for the production of red cells, or erythropoiesis, in the bone marrow. What is happening in this trial is that rusfertide is a hepcidin mimetic, providing hepcidin to the body. As a result, iron is being restricted so it is not easily available for erythropoiesis. By titrating to the right dose for each patient, they get to the point where they have just enough iron for normal bodily function., they are not anemic, but the controlled production of red blood cells is being controlled.

Could you speak to the design and methods that were utilized in this trial?

This is a phase 2 trial. Patients were enrolled if they had a diagnosis of PV, and the main requirement was that they had to have received 3 or more phlebotomies with 6 months of enrollment. We are choosing patients that are phlebotomy dependent. These patients could be high-risk or low-risk patients with PV, so they patients could also be on additional cytoreductive therapy for PV, but they were still required to have had those 3 or more phlebotomies before enrolling. Once enrolled each patient is given the subcutaneous injection of rusfertide that is self-administered once weekly. They start at a low dose, and then every month if needed, the dose is increased to get to the goal hematocrit level. There is some titration going on for each individual patient. We started at 10 mg, and then some patients need a higher dose. Basically, the dose is titrated up until the patients get to the right dose. The trial is set up into 3 parts. The first part is the dose-titration phase.

Patients then enter a randomized withdrawal phase. Each patient is randomized to either continue on the same dose of rusfertide that they were on, or they get placebo. They then continue on trial until either this portion is over, or if they required a phlebotomy during this phase of the trial, they come off, and they go back on their last effective dose. There is also an extension phase where patients just go back to their last effective dose and continue on the trial. The primary end point is to see the amount of phlebotomy a patient needs during the randomized withdrawal phase of the study.

Could you speak a little bit to the safety profile of rusfertide?

The drug is very well tolerated. Patients must learn how to do the injections. There were no grade 3 or 4 adverse effects [AEs] that were related to the drug. Of those patients [who did experience AEs], none of them had to stop [treatment]. For most of these patients, the AEs went away over time. Otherwise, there were no serious AEs that were related to the study drug.

What is the importance of this research overall for the practicing physician?

This is an exciting new drug for PV. We have a limited number of therapies that are available to these patients, and it could fulfill an unmet need for therapy, specifically for those who require a lot of phlebotomies and become very iron deficient. Many of these patients are symptomatic because of their iron deficiency, and unfortunately, it is not easy to correct. If you give them more iron, that could drive the production of red cells even further.

What is also being seen in patients on this study is that their ferritin levels go back up to normal levels. Additionally, we are looking at their symptom scores, which are still preliminary, but a lot of patients are feeling better. What we are seeing is that not only can we use this drug to control the need for phlebotomy, which is significant because a lot of patients have a difficult times with these, but also, they are feeling better. It is an exciting new approach to the treatment of this disease.

Reference

1. Kremyanskaya M, Ginzburg Y, Kuykendall A, et al. PTG-300 eliminates the need for therapeutic phlebotomy and reverses iron deficiency in both low and high-risk polycythemia vera patients. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S200.