Rusfertide Reduces Phlebotomy Need, Improves Quality of Life in Polycythemia Vera

Rusfertide reduced phlebotomy need and improved quality of life in patients with polycythemia vera, according to phase 3 VERIFY trial results.

Treatment with the investigational therapeutic rusfertide has proven to be a potential treatment option for patients with polycythemia vera, a type of blood cancer, based on recent data from the phase 3 VERIFY trial, which were shared at the 2025 ASCO Annual Meeting.

Rusfertide has been shown to reduce or eliminate the need for phlebotomies, a procedure which removes extra blood cells from the body by using a needle to take blood from the vein, thus improving quality of life and improving symptom control, according to Dr. Aaron Gerds.

“[Rusfertide] is a new therapy that is alleviating the need for phlebotomies and improving patients' quality of life. This is incredibly important for patients. Having another tool in our arsenal to care for these patients is truly exciting,” Gerds explained in an interview with CURE.

In the interview, he highlighted what patients with polycythemia vera should know about the VERIFY trial, the significance of being able to forgo standard phlebotomy with rusfertide, and how individuals can access emerging treatments like this one.

Gerds is an assistant professor in the Department of Medicine at the Case Comprehensive Cancer Center School of Medicine, where he is also a member of the Developmental Therapeutics Program. He also serves as a physician in the Department of Hematology and Medical Oncology at the Cleveland Clinic, located in Ohio.

CURE: What should patients know about the VERIFY trial, presented at this year’s ASCO Annual Meeting?

The ASCO Annual Meeting is always a challenging conference for those of us in hematology. Hematologic neoplasms often represent a smaller portion of the larger ASCO meeting, and sometimes you really have to sift through numerous abstracts to find something truly impressive. However, this year, we had the fortunate event of a hematologic malignancy being featured as a plenary abstract. This is the prestigious session where they select the top few abstracts to present to a huge, enormous crowd, genuinely highlighting the importance of this research.

The fact that it concerns polycythemia vera is particularly significant for a somewhat rare blood cancer that often doesn't receive much attention. It's a disease we've known a great deal about for a long time but have relatively few approved therapies. As of today, there are only two FDA-approved drugs for polycythemia vera: Jakafi (ruxolitinib), approved in the second-line setting, and Besremi (ropeginterferon alfa-2b-njft), approved for all settings. Given this limited therapeutic landscape, a new, effective drug like rusfertide, which presents a completely different mechanism, is absolutely warranted for the field.

Can you walk us through the significance of the clinical trials evaluating rusfertide in polycythemia vera?

The trial presented at this year's ASCO meeting was a classic, definitive phase 3 registration study. It included patients who received the drug and those who did not, allowing for a thorough comparison with all the statistical power needed for regulatory approval. This was the trial in question.

This pivotal study was preceded by a phase 2 trial that convincingly showed that administering rusfertide could eliminate the need for phlebotomies. In the phase 2 trial, there was a blinded, randomized period where patients may or may not have received the drug. Once unblinded, it was clear that when the drug was used, the need for phlebotomy disappeared. When the drug was withdrawn, the need for phlebotomies returned, and once the drug was re-administered, the need for phlebotomies again resolved. This really proved the mechanism of action in a real-world setting, which was essential for moving forward with the phase 3 trial.

In the phase 3 study, again, it was a randomized, prospective trial where some patients received rusfertide and others did not. The top-line results indicated that between weeks 20 and 32 of the trial, 77% of patients taking rusfertide had a clinical response, compared with 33% in the control group. Clinical response, in this context, primarily refers to the control of blood counts, as that's the main factor we monitor in polycythemia vera: can we keep the hematocrit under 45%?

What I find truly interesting are some of the additional data presented. Patients' quality of life and symptom burden were better on rusfertide compared to the control group, which is important. While eliminating the need for phlebotomies is great, the ability to do something more — to genuinely improve patients' lives — is a significant advancement.

What do we currently know about how rusfertide affects symptoms like fatigue or concentration? Is there any evidence rusfertide improves quality of life compared with standard phlebotomy?

We certainly saw in the phase 2 trial that patients on rusfertide experienced a better quality of life on treatment compared to before they started. That was our first clue. In the ASCO presentation, we also observed improvements in symptoms and overall quality of life. Furthermore, when comparing patients on rusfertide to those in the control group, we saw additional improvements. This means there's not only intra-patient improvement (individuals feeling better while on the drug) but also inter-patient improvement (those receiving the medication feeling better than those who did not). I think this dual perspective is incredibly important.

Why do people feel better? That's another excellent question. Part of the reason is largely due to iron deficiency. We often treat polycythemia vera using phlebotomies, which lead to iron deficiency. This is how phlebotomies control red blood cell production. However, iron deficiency itself can cause many symptoms, such as fatigue, muscle, and joint aches and pains. There's also a very famous symptom called pica, where you have an urge to eat ice or dirt. So, many symptoms can accompany the iron deficiency induced by phlebotomies, which is the traditional mechanism for treating polycythemia vera.

Rusfertide works differently. It's a synthetic version that mimics hepcidin, our body's natural regulator of iron. Think of hepcidin like a cork in a bottle. If the "bottle" represents your iron stores, hepcidin effectively "corks" the opening, preventing iron from leaving. So, you can put iron into the stores, but rusfertide won't let it out. In this way, iron remains in storage, yet the bone marrow "thinks" it's iron-deficient and can't produce red blood cells as it normally would. It's essentially tricking the bone marrow into believing it's iron-deficient even when your body isn't. This allows for the control of red blood cell counts without necessarily experiencing all the symptoms associated with iron deficiency, which I find to be a clever approach.

We've known about hepcidin for a long time; it's something we learned about in medical school. This knowledge has been around for a while, but this is truly the first time we're harnessing its power in this specific way to treat polycythemia vera. Taking a step back, one even cooler part of this whole story is that we're actually targeting hepcidin in the opposite direction for another condition. We're trying to lower hepcidin levels in myelofibrosis and associated anemia.

Myelofibrosis is a closely related disease to polycythemia vera, part of the same family of diseases caused by similar mutations, but we often see anemia in these patients. So, in myelofibrosis-associated anemia, we're trying to lower hepcidin levels to improve, or increase, red blood cell counts. In polycythemia vera, we're doing the opposite: we're trying to raise hepcidin levels, or effectively raise them, to lower red blood cell counts. Thus, within the same field and effectively the same disease family, we're manipulating this pathway in two different ways to achieve two distinct effects.

If a patient’s hematocrit is already well-managed with phlebotomy, would they still benefit from rusfertide, or is this therapy better suited for those with more difficult-to-control disease?

Both the phase 2 and phase 3 trials tell us that it's effective for both groups. Patients who are only getting phlebotomies show all these benefits. Additionally, for patients who are on hydroxyurea, Jakafi, or an interferon but still require phlebotomies, adding rusfertide on top of their current treatment can improve both their blood count control and their symptoms and quality of life. So, I think in both situations, it can be beneficial.

What factors will determine whether rusfertide becomes a widely accessible option for patients, and how can individuals advocate for access to emerging treatments like this one?

That will certainly take more time. These are just the initial, top-line results — the week 32 data. The week 52 data is expected [this year (2025)], so you can mark that on your calendars. I believe the longer-term data will be helpful in answering those questions.

The company that makes the drug is certainly in conversations with regulatory authorities, asking, "What else is needed to have a good chance of approval to submit that new drug application?" That's going to be the next step: gathering all the data, the entire packet, and putting together a new drug application to submit to the regulatory authorities, or the U.S. Food and Drug Administration (FDA) in this case. Then, that packet or application, if you will, gets reviewed by the FDA. There's a number of reviews, hearings, and all kinds of processes that go along with that. At the back end of that, that's when we'll have a decision on regulatory approval.

Regulatory approval is just that next step. When you say, "access and widely available," the step after that is insurance coverage. Here in the United States, our healthcare system is often run by insurance companies. What will that regulatory approval look like? What will it include? What levels of disease and what parameters? Then there will be guidelines that come out, for example, from the NCCN, which will make guideline recommendations on the use of rusfertide. These two factors will be taken together, along with pricing and other factors. Then the insurance companies will decide what they will and won't cover, and that may actually impact access for a lot of patients.

What would you like patients to take away from today's conversation?

There are a couple of really important things to consider. First, we are continuously developing new therapies for polycythemia vera. Even though it's a rare disease and often not highlighted in the grand pantheon of diseases presented at ASCO, it remains a very important condition, especially for the patients who live with it. A dedicated group of us is very interested in this disease and working hard to develop new therapies. It's not just rusfertide in development; there are other drugs targeting the hepcidin pathway, as well as drugs outside that pathway. For instance, givinostat is in a randomized phase 3 registration-type study, also seeking approval. So, even though it's a rare disease, significant effort is being put into developing new and better therapies for our patients. I believe that's the most crucial take-home point.

Regarding rusfertide specifically, I think it's exciting. It's a new therapy that is alleviating the need for phlebotomies and improving patients' quality of life. This is incredibly important for patients. Having another tool in our arsenal to care for these patients is truly exciting and, I believe, can offer a lot for those living with polycythemia vera.

Transcript has been edited for clarity and conciseness.

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