Rusfertide Improves Hematocrit Control and Decreases Use of Phlebotomy Among Patients With PV

Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, discusses results from the REVIVE trial, which determined that among patients with polycythemia vera (PV), rusfertide—an injectable peptide mimetic of the master iron regulatory hormone hepcidin—demonstrated improved hematocrit control and decreased the use of phlebotomy.

Transcript:

My name is Marina Kremyanskaya. I'm an associate professor of medicine at Icahn School of Medicine at Mount Sinai. I'm going to speak today about a recent study that was published in the New England Journal of Medicine about the effect of rusfertide, which is a hepcidin mimetic treatment of polycythemia vera (PV). This is the first study that is utilizing the hepcidin iron pathway as a potential treatment for hematologic malignancy polycythemia vera.

What's interesting about polycythemia vera is that it's a chronic myeloid malignancy, which is mostly characterized by overproduction of red blood cells, with the major complication of this disease [being] increased risk of thrombosis, specifically things like heart attacks and strokes, as well as other venous thrombosis. What was done in this study is that patients with polycythemia vera who have high phlebotomy requirements were treated with a hepcidin mimetic rusfertide. I'm just going to spend a couple of minutes explaining why that makes sense.

Polycythemia vera in our patients are typically divided into 2 major risk groups, low risk and high risk. It's based on the risk of thrombosis and the prognostication itself is [mostly] based on [the] patient's age. If they're over 60, they're considered high risk and their previous history of thrombosis. So, if they've had thrombosis before, they're also considered high risk.

Low risk patients are treated with low dose aspirin, as well as therapeutic phlebotomies to keep hematocrit at less than 45%, which has been shown to decrease their risk of thrombotic events and cardiovascular events. High-risk patients are treated the same, except they're also treated with cytoreductive therapies, which [have] been shown to decrease their risks of thrombotic events. And the side of reductive therapy that's typically used is hydroxyurea, various forms of interference, and a Janus kinase (JAK) inhibitor, ruxolitinib. What is known is that [patients with] PV tend to be very iron deficient because of the high use of iron for red blood cell production, but also for those patients that require a lot of phlebotomies.

Hepcidin is a negative regulator of iron metabolism. When hepcidin levels are low, hepcidin binds to its receptor on the cells called ferroportin, and that results in retention of iron in the form of ferritin inside these cells. Therefore, there's basically less iron available for red blood cell production. This is the concept that was used to devise this treatment strategy. It has been shown that in [patients with] polycythemia vera, due to iron deficiency and due to high erythropoiesis in the bone marrow, the hepcidin levels tend to be low, at least lower than what would be expected in the setting. This study is a phase 2 study in patients with polycythemia vera, who are in frequent need of phlebotomies. They had to have at least 3 phlebotomies in 6 months prior to enrollment. The study consisted of 3 different parts. The first part was where these patients were started on the hepcidin mimetic called rusfertide.

The dose for each individual patient was titrated [3:59] to get them to the goal hematocrit [of] less than 45%. And then even in this first part of the study, it was apparent quickly that once patients start treatment with this agent, they really don't need phlebotomies anymore. So, [for] those people that were requiring 3 or more phlebotomies in 6 months and some of them required as many as 5, basically the requirements for phlebotomies were eliminated.

The second part of the study was called randomized withdrawal. Patients were randomized to either go on placebo or continue their last effective dose of rusfertide. That was the primary endpoint for the study, and that was really, I think, the most important point for this article. What was shown is [that in] this second part of the study, comparing patients that received rusfertide versus those that received placebo, a role response of not requiring the phlebotomy, not getting a phlebotomy, and finishing the whole 12-week period, the difference was 60% of responders in rusfertide arm versus 70% of responders in the placebo arm, which is highly statistically significant.

The third part of the study is basically [an] open-label extension, where everybody continues the drug, whatever is effective for them. The important findings here [are], like I said, in [the] randomized withdrawal part, there was a statistically significant difference between those patients that received rusfertide versus placebo.

What was also shown is that this effect was sustained and that [for] those patients that were on rusfertide, their hematocrit levels remained steadily controlled as opposed to those patients that went on placebo, their hematocrit levels rose. Since this drug affects the hepcidin iron pathway, the other things that were important to look at is, how does it affect the iron parameters? These patients, like I mentioned before, are typically iron deficient in the beginning. When we look at ferritin level as a marker of iron stores, the levels were very low, definitely in the iron deficiency range, and as they were treated the ferritin level increased to normal range.

So, patients with PV tend to have a lot of systemic symptoms to various degrees. Some of these symptoms are fatigue, difficulties concentrating—patients will call it brain fog—and as well as pruritus or itching, and other symptoms as well. For those patients that had moderate to severe symptoms, specifically in some of these categories such as fatigue and difficulty concentrating, as well as pruritus, treatment with rusfertide in part 1 of the study showed improvement in symptoms using the validated MBN [7:10] symptom assessment score with patient reported outcomes.

Another important finding is that potentially this treatment, not only decrease[s] or basically eliminate[s] patient need for phlebotomies, but also improves patient symptoms and improves their quality of life. One of the important reasons is that there are different parameters in polycythemia vera patients that we look at to assess the disease control. I think most people would agree that the most important parameter is hematocrit, hemoglobin control. This strategy allows [for] steady control of hematocrit as opposed to our current approach where we're using therapeutic phlebotomies where it's more reactive. So once the numbers get high, patients get therapeutic phlebotomies. And so there is this up and down in their levels. And this allows for more steady treatment and steady control of hematocrit.

In addition, I think most patients find this inconvenient at best, potentially life-altering to [keep] having to get phlebotomies. So, this ability [allows them] to not be tied to an institution where they can get a phlebotomy [and] remov[es] the anxiety of whether they're going to need a phlebotomy. Some patients really don't physically tolerate getting phlebotomies, [so] again, this potentially would remove all these factors from being part of their treatment plan.

Rusfertide is a subcutaneous injection. It's administered once a week. Patients were self-administering the medication after they were educated on the proper way to do it. One of the more common side effects that was seen was injection side reactions, and it was typically low grade. As patient[s] remained on [the] study, the degree of the injection site reactions and the frequency went down, so [the] vast majority of patients did not have any issues tolerating that.

I think the study shows that this drug could potentially be effective in treating polycythemia vera. Currently, there's an ongoing phase 3 study where patients are randomized to placebo versus rusfertide from the beginning with a larger number of patients enrolled. This will allow us to get more information not only on [the] effectiveness of the drug, but also more information on symptom control. I think we're all excited to see the results of the VERIFY trial.

Source:

Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med 2024;390:723-735. doi: 10.1056/NEJMoa2308809