Rusfertide Approval Expands Options and Improves Burdens in Polycythemia Vera

The FDA approval of rusfertide (Mimrylo) offers a new way to control hematocrit in adults with polycythemia vera and reduce their reliance on repeated phlebotomies, according to Andrew Kuykendall, MD.¹

The approval was supported in part by findings from the phase 3 VERIFY trial (NCT05210790). Thirty two-week results from part 1a of VERIFY showed that patients treated with rusfertide (n = 147) achieved a clinical response of 76.9% vs 32.9% in those who received placebo (n = 146; P < .0001).^1,2

“Rusfertide is another tool in the toolbox, and it allows us to individualize our care a little bit better for the patients that we’re seeing,” Andrew Kuykendall, MD, said in an exclusive interview with OncLive®. “Having that flexibility is certainly a win [for polycythemia vera management.”

In the interview, Kuykendall discussed the rationale for targeting hepcidin, the design and findings from VERIFY, safety considerations, and where rusfertide may fit into clinical practice.

Kuykendall is an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

OncLive: What has been the development for hematocrit-controlling therapies in polycythemia vera? How does rusfertide work?

Kuykendall: We know that a big unmet need in polycythemia vera right now is maintaining consistent control of hematocrit. This is something that we’ve often done with phlebotomies, which is really challenging. [Maintaining hematocrit control with phlebotomies is] like you have a hole in your boat and you’re just dumping out water. It keeps the boat dry to some extent, but it’s a continuous process and it’s not super comfortable. When we listen to patients, we know that this is something that’s not acceptable. [Patients] desire something that could provide more consistent control and maybe unburden them from coming into the doctor’s office to get phlebotomy.

Rusfertide was first-in-class. It’s a hepcidin mimetic, and the idea was that patients with polycythemia vera are in a unique position where they’re iron deficient, which means that their hepcidin levels are low. When hepcidin levels are low, it frees up iron to be delivered to the bone marrow. What’s unique about that is that oftentimes when you’re iron low, you’re anemic. In polycythemia vera patients, their iron’s low, but they make too many red blood cells. [Therefore, patients with polycythemia vera] have this lower hepcidin, are delivering iron to the bone marrow, and are making more red blood cells in a state where they already have too many. Then we’re doing phlebotomy, making you more iron deficient and perpetuating that cycle.

Rusfertide is a mimetic of hepcidin and raises hepcidin levels, decreases iron delivery to the bone marrow, and allows for restriction of erythropoiesis. [This allows patients to achieve] a consistent red blood cell [level], or hematocrit, that could be at goal without these fluctuations. This is really important for patients because hematocrit control below 45% is a core tenet of treating these patients to reduce their cardiovascular risk and risk of thrombotic events. Rusfertide has shown the ability to do that in a better way than phlebotomies do. When we’ve looked in real-world settings, and phlebotomies fail to maintain that hematocrit, where over 70% of patients have hematocrit values that exceed [45%].

The VERIFY study showed [rusfertide’s] ability to [control hematocrit] in addition to improving disease-related symptoms, fatigue, and Myelofibrosis Symptom Assessment Form [MFSAF] scores.

On the heels of rusfertide, you have the exciting development of other agents that allow that upregulation of hepcidin, targeting the exact same pathway [as rusfertide] in a variety of different ways. We have antisense oligonucleotides with sapablursen, there’s also small interfering RNAs, and monoclonal antibodies. All of these are targeting that same pathway, hoping to upregulate hepcidin. The optimal way to do that, the frequency of therapy, and the adverse effect [AE] profile, are going to be important as these are developed.

What is the significance of the FDA approval of rusfertide for patients with polycythemia vera?

What this means to polycythemia vera patients is a couplefold. One, this allows for independence and autonomy. Patients desire not to be tied to the health care system. They want to be outside the office; they want to have control of their health. Rusfertied offers that, and is something that can be self-injected to maintain their hematocrit levels. They don’t have to rely on lab checks or phlebotomy, which is really good.

The ability to improve fatigue and disease-related symptoms [with rusfertide] is something that patients are actually desperate to achieve. This considerable fatigue that’s seen with polycythemia vera is something we hear consistently from patients, and we just don’t have things that help a ton with that fatigue, and it really is the biggest marker of impaired quality of life.

Patients don’t know that their thrombotic risk is reduced by being on cytoreductive therapy. We certainly love that as a goal, and we certainly want to reduce thrombotic events, but patients don’t feel that. What they feel is the inability to get out of bed, the inability to work, and having to take time off of work. If we can change that, that’s fulfilling that promise to patients that we’re listening to them and caring about what they care about.

[Finally, rusfertide] is a therapy really driven by patient feedback. This is something derived from what patients said to us during the phase 2 trials. It’s something patients really desire, and it’s a big win for the polycythemia vera community.

How was the VERIFY trial evaluating rusfertide in polycythemia vera designed?

The VERIFY trial is interesting in the sense that it was a very clinically relevant design. Patients had to have polycythemia vera and some degree of phlebotomy requirements which meant 3 phlebotomies in the past 6 months or 5 over the past year. [Although, regarding enrollment,] it didn’t matter what kind of cytoreductive therapy they were on, if they were high risk or low risk, and what their prior treatment history was. All of those [patients] were allowed on the study as long as they had polycythemia vera and had some phlebotomy requirements.

When patients were enrolled, they were randomized to either rusfertide or placebo, but they continued their current standard of care. If they were on hydroxyurea, it was continued. If they were on interferon, it was continued. If they were on ruxolitinib [Jakafi], it was continued. If they were on neither of those, that was continued. There was a brief dose-titration period from 0 to 20 weeks. The primary end point was looked at between weeks 20 and 32, and it was the absence of phlebotomy eligibility, meaning not meeting criteria to need a phlebotomy. That was seen in a much higher proportion of patients treated with rusfertide than placebo. Seventy-six percent of patients on rusfertide did not meet the criteria to get a phlebotomy, and these are patients who had consistently needed a phlebotomy before going on study.

After that, the design allowed patients on placebo to roll over and start rusfertide. That’s important as we’re enrolling patients on a trial, we don’t love the idea of a true placebo trial. Patients would like to receive the investigational therapy, and this allowed patients on placebo, after 32 weeks, to cross over onto rusfertide. Then we had a long-term extension program to assess the long-term safety profile of the agent.

The primary end point was met. Key secondary end points looked at the number of phlebotomies between weeks 0 and 32, as well as the ability [of patients] to stay completely phlebotomy-free over that time period. All of those [end points] favored rusfertide, in addition to the patient-reported outcomes. The Patient-Reported Outcomes Measurement Information System fatigue score as well as MFSAF showed a statistically consistent improvement in symptoms [with rusfertide] compared with placebo. Being able to show that in a blinded study is really important and vital for the community.

That was the critical nature of the design. Obviously, it’s a very positive study, but more importantly, it can be translated directly into practice. Most of these patients were on hydroxyurea and a lot of these patients were requiring a lot of phlebotomies. This is something that can be quickly incorporated into routine practice.

What adverse effects should be monitored for patients receiving rusfertide?

I would say there are two main things to watch out for. One is injection-site reactions. Anytime we put a needle in the skin, there is a risk of injection-site reactions. We actually saw it in about a third of the patients who were on placebo [in VERIFY], but a higher proportion of patients on rusfertide. Typically, they’re quite mild with some redness around the area. They can be managed supportively. Rarely, they could be more prominent, if ever, led to discontinuation of rusfertide and can be managed with various topical solutions, whether it’s a steroid cream or just aloe. These [AEs] are manageable.

The other [AE] to watch out for with any of these types of agents is that since we’re trying to bring hematocrit down, it’s expected that we’re going to see some degree of anemia. [Anemia] is something to watch out for as you’re titrating these medications. There was a 20-week dose-titration period on this study where patients got to their optimal dose. [This period] is going to be recommended [in practice] as well. When you start someone on rusfertide, checking the labs every 2 to 4 weeks until you find that stable dose is going to be important. Then I think [anemia] can be monitored less frequently.

[Rusfertide] is something designed to bring red blood cells down. Certainly, you could overshoot it if you went to too high of a dose or didn’t monitor patients for months at a time. Fortunately, on in VERIFY, we didn’t see any high-grade anemia. It was not something that was a major concern. But, if you run into other things that cause anemia like big surgeries, [high-grade anemia] might be something to keep an eye on while you’re going through those periods of time.

What additional data has been shown for rusfertide outside of VERIFY?

With VERIFY, we’ve seen nice efficacy and met the primary and key secondary end points. When you look at the phase 2 REVIVE trial (NCT04057040) and phase 3 THRIVE extension study (NCT06033586) that led into VERFIY, when we talk about polycythemia vera, we mentioned the primary endpoint at 32 weeks. A lot of people would say: “Polycythemia vera is something patients live with for 15 or 20 years. The end points that matter are going to be long term.” Completely agree, that’s why, we have REVIVE and THRIVE, this long-term extension where patients have been on [rusfertide] now for 4 or 5 years, and we can start to get some of the answer of long-term efficacy. Moreover, we’re not seeing any new safety concerns that linger or pop up over that timeframe.

Do you see rusfertide being implemented in clinical practice as a monotherapy or in combination with cytoreductive therapy?

Going back to the design of the VERIFY, rusfertide was used as a single agent, in combination with cytoreductive therapy, and in combination with various different cytoreductive therapies. [Rusfertide is] a treatment that can be employed in a variety of ways.

It’s hard to say that there’s going to be one bucket that rusfertide is an appropriate treatment for. The easiest bucket to think about is patients who are reliant on phlebotomy that don’t tolerate [phlebotomies well]. They struggle with coming in for the visits, don’t appreciate the fluid shifts, get lightheaded, need fluids afterward, and don’t have good venous access. Regardless of what it means to that patient not to tolerate phlebotomy as well, they’re a great candidate to receive rusfertide. It can be added if they’re on cytoreductive therapy or not.

You think about the relatively newly diagnosed patients who have high phlebotomy requirements early after diagnosis. Maybe they’re young, low risk, and hesitant to start cytoreductive therapy. [They are a] perfect patient to start and get good initial control, when we know that first period after diagnosis is maybe the riskiest period in terms of cardiovascular events.

In patients who are on cytoreductive therapy, [rusfertide] can be added to help optimize the dose. We have a lot of patients on high doses of hydroxyurea, they’re not that well tolerated, but we need to keep them there because it helps with their phlebotomy requirements. Maybe we drop the hydroxyurea down a little bit, supplement that with rusfertide, and allow for no phlebotomy and good, consistent control, but also a much more tolerable level of hydroxyurea. This could be applied to other cytoreductive therapies as well.

I’m particularly curious about what we do for patients with that profound fatigue, whether or not they’re requiring a ton of phlebotomies. That’s where we’ll have to get a little bit more information. Is this something that we can leverage in that extremely fatigued population as well?

How do you see the polycythemia vera space evolving in the coming years with the continued implementation of these hematocrit-controlling agents?

One thing that’s going to be nice is we’re going to get to move away from this archaic phlebotomy scenario. We’re not going to have to bleed patients as much, and that’ll be nice. It’ going to give this extra level of control. How exactly [rusfertide] is going to get utilized will be different based on patients, practice patterns, and things of that nature.

In reality, rusfertide is another tool in the toolbox, and it allows us to individualize our care a little bit better for the patients we’re seeing. We can say: “Hey, based upon your goals, your disease, what you require, how you tolerate the AE profiles, this is the right combination or this is the right agent for you.” Having that flexibility is certainly a win because, as much as we talk about individualizing care, we have a limited toolbox. When that’s the case, you can’t offer too many different things. [The FDA approval of rusfertide] is adding to that.

As we have more coming down the pipeline, you’re starting to get things that maybe are offered less frequently and have different mechanisms of action. We’ll have to learn more about what that means, but the more options we have that are safe and effective, the better. How that’ll play with other things for polycythemia vera coming down the pipeline like looking at mutation-specific JAK inhibitors, how this is going to play with interferon formulations such as ropeginterferon alfa-2b-njft [Besremi] that may take time to work, these are things that can play together in a nice way. Certainly, it’s an exciting time to bring more things to the table for these patients.

References

1. FDA approves first drug of its kind for polycythemia vera, a rare blood disorder. FDA. August 28, 2026. Accessed September 29, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-its-kind-polycythemia-vera-rare-blood-disorder
2. Kuykendall AT, Pemmaraju M, Pettit KM, et al. Results from VERIFY, a phase 3, double-blind, placebo-controlled study of rusfertide for treatment of polycythemia vera (PV). J Clin Oncol. 2025;43(suppl 17):LBA3. doi:10.1200/JCO.2025.43.17_suppl.LBA3