Rusfertide May Eliminate Need for Frequent Phlebotomies in Polycythemia Vera

Srdan Verstovsek, MD, PhD

Treatment with rusfertide (PTG-300), a hepcidin mimetic, can aid in decreasing the need for phlebotomies in patients with polycythemia vera, according to Srdan Verstovsek, MD, PhD. He emphasized that this agent can help patients avoid adverse effects (AEs) associated with their disease and phlebotomy.

“We are talking about polycythemia vera and new drugs in polycythemia vera, which is exciting. That has not been the norm over the past 20 years,” Verstovsek said.

In an interview with OncLive^®, Verstovsek, the United Energy Resources, Inc., Professor of Medicine and a hematologist-oncologist in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the benefits of rusfertide, an agent currently under evaluation in patients with polycythemia vera. In addition, he laid out the distinctions between low-risk and high-risk polycythemia vera and explained the benefits of this drug in both populations.

OncLive^®: What is the current treatment landscape for patients with polycythemia vera who require routine phlebotomy?

Verstovsek: Polycythemia vera, as the name implies, comes with a high blood cell count. The number 1 blood cell count that we worry about is the red blood cell [RBC] count. We phlebotomize all our patients with polycythemia vera, which means bloodletting. With that, we decrease the number of RBCs.

We look specifically at hematocrit levels. That’s the percentage of blood that is made up of RBCs. We want to maintain this level below 45%.

In many patients, we use different pills or injections, which are cytoreductive therapies, to minimize the need for phlebotomy and possibly control the high white blood cell [WBC] and platelet levels to make patients feel better. However, the goal of controlling the hematocrit levels below 45% is not readily achieved in the community setting, and that is a problem.

How commonly do patients with polycythemia vera require consistent phlebotomy?

We traditionally divide patients into 2 groups. First, we make a diagnosis. Then, we prognosticate with the question: What’s the risk of blood clotting? That’s the major [cause of death in this population].

About a third of patients with polycythemia are at low risk for blood clotting. They are only phlebotomized, and we don’t worry about their WBC or platelet levels. We give them baby aspirin to decrease the thickness [of their blood].

Phlebotomy makes patients iron deficient. Iron is food for RBCs, so no iron, no phlebotomy. However, that is not so useful as a therapeutic strategy. Many patients still need frequent phlebotomies, such as 3, 4, or 5 a year [and] some patients develop iron deficiency–related symptoms, like brittle nails, memory impairment, and restless legs syndrome.

There is an unmet need in patients with low-risk disease who depend on [multiple phlebotomies a year], or who have AEs from iron deficiency or even from the phlebotomies themselves. We need to give them something to eliminate the need for phlebotomy.

In high-risk patients, two-thirds of the patients with polycythemia vera, we typically give hydroxyurea chemotherapy by mouth to eliminate the need for phlebotomy and normalize the WBC and platelet levels, if necessary.

What we learned from a retrospective chart review analysis in the United States and Europe is that most patients do not eliminate the need for phlebotomy. This is critical because the studies show that when patients are on hydroxyurea and require 3 or more phlebotomies a year, they have a higher risk than necessary of blood clots and a higher risk of dying. We are not doing a good job, for several reasons, such as toxicity and misunderstanding what needs to be done. Around 20% to 40% of the patients on hydroxyurea are not optimally receiving the therapy and still need something to eliminate their need for phlebotomy, even when they’re on chemotherapy.

What is the unique mechanism of action of the hepcidin mimetic rusfertide, and how is this agent designed to work in patients with polycythemia vera to help control their hematocrit levels?

Because RBCs use iron, patients with polycythemia vera normally become iron deficient. Giving iron to supplement this [deficiency] would make the cells grow, which would be counterproductive.

[The way in which] iron metabolism is controlled in the body is connected to the topic of hepcidin mimetics. Hepcidin is an important protein that regulates where the iron is. Hepcidin mimetics keep the iron stored inside the liver, gut, or spleen, [which make up] the reticuloendothelial system, meaning there is less iron available for blood making, which is quite an interesting concept.

Rusfertide eliminates phlebotomy needs, [because there is] no iron for blood making, and it also harmonizes the iron in the body, so that the ferritin levels, a common measure of iron in the body, become normal in many patients. [In addition to these benefits,] iron deficiency–related symptoms often go away.

Rusfertide will be investigated vs placebo in the upcoming phase 3 VERIFY trial (NCT05210790) in patients with polycythemia vera. What is the rationale of this trial?

Many patients are low risk and can be managed only with phlebotomy. Many other patients are high risk and managed with a cytoreductive therapy, but still have too many phlebotomies, for example, 3 in 6 months or 5 in a year. That means these patients spend too much time with hematocrit levels above 45% and are exposed to the risks of blood clots and death. That’s the bottom line.

In the open-label, phase 2 [REVIVE trial (NCT04057040)], rusfertide eliminated the need for phlebotomy in 84% of patients within 28 weeks.

An agent like rusfertide is a welcome development in the field. It’s injectable under the skin, and patients administer it themselves once a week. It’s effective, it appears to be safe, and it can be used in patients who are low risk and have too many phlebotomies or patients who are high risk and on cytoreductive therapy. It’s broadly applicable and it’s needed.

What is the protocol for this trial?

This phase 3 study is built on the experience of the phase 2 study, and it includes patients from a variety of backgrounds. Patients don’t need to be on any therapy at all, [and are eligible] as long as they fulfill the requirement for needing too many phlebotomies, which is harmful for them.

In the beginning, patients will be evaluated to make sure that they are managed optimally with rusfertide, receiving an optimal dose without AEs, which requires a few months of adjustments. Then, they will be followed for efficacy over a period. There is a placebo control arm, which would prove the point that the therapy is effective and not a fluke.

Then, there will be long-term follow up of a year or more. Because polycythemia vera is a lifelong condition, we are not eliminating the disease. Instead, [our goal is to control] it well with rusfertide and other therapies. We want to prove that rusfertide is effective, safe, simple, and long lasting. Studies like this that cover a year or more are the norm for polycythemia vera.

We are looking forward to this study opening across the globe over the next couple of years, enrolling many patients to prove the value of eliminating the need for phlebotomy, improving patient quality of life, and [putting rusfertide] on the market for our patients in everyday practice.

If data from VERIFY prove positive, how could rusfertide potentially affect the quality of life of patients with polycythemia vera?

I envision [this trial] will be successful in improving the value in eliminating phlebotomy and improving quality of life. [Rusfertide might become] a natural choice for patients who are otherwise low risk and can manage with phlebotomy but have problems with it, such as too many phlebotomy and iron deficiency AEs. For these patients, we would typically struggle [with determining the best therapeutic option]. Should we give them chemotherapy? Should we give them medication that is perhaps too toxic [and administer it indefinitely]?

Rusfertide appears to fulfill a need in these patients. And, in patients who are suboptimal responders on some other cytoreductive therapy, such as hydroxyurea, adding rusfertide to optimize the care and eliminate the need for phlebotomy is a natural next step. There is the possibility of multiple clinical scenarios where the drug may become valuable, ranging from low-risk to high-risk patients.

What other developments in polycythemia vera are you intrigued by?

VERIFY is the latest of the rusfertide trials in the rebirth of interest for polycythemia vera. In November 2021, following prior approval in Europe, [the FDA approved ropeginterferon alfa-2b-njft (Besremi)], so we have that as a choice as well after hydroxyurea. Now, for use after hydroxyurea, we have ropegintergeron-alfa-2b, and hopefully rusfertide as well, on top of the 2014 [FDA approval] of ruxolitinib [Jakafi] as a valuable JAK inhibitor. We are broadening the scope of choices here, all to make treatment better for our patients.

What is the main message for colleagues regarding rusfertide and the VERIFY trial, which will soon begin enrollment?

[We rarely] talk about studies in polycythemia vera, because too many times we consider it a benign condition. However, when you dig in and analyze the results, that’s not so. Patients are unnecessarily exposed to uncontrolled blood cell counts, which lead to untimely deaths from thrombotic events.

To optimize care in the community setting for our patients with polycythemia vera, we should all engage in developing new drugs. Rusfertide is 1 that is effective, safe, and self-administered. It is therefore simple and appears to be durable. Let’s all engage together and give it the chance to be approved. Let’s prove that it’s valuable in all these aspects. In a few years, if it gets approved, our patients will benefit from it.