Potential Rusfertide Approval May Offer More Control of Polycythemia Vera

The FDA granted priority review to rusfertide as a potential therapy for patients with polycythemia vera in March 2026.¹ If approved, the novel treatment may allow patients to “be more in control of their care,” according to Andrew Kuykendall, MD.

Following the agency’s regulatory decision, CancerNetwork^® spoke with Kuykendall, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, about what the potential approval of rusfertide would mean for patients with polycythemia vera. He highlighted how data from studies like the phase 3 VERIFY trial (NCT05210790) affirm rusfertide’s ability to control hematocrit in this population. Additionally, he detailed the potential next steps for determining the benefit of rusfertide in other polycythemia vera subgroups and described other hepcidin-targeting agents in the pipeline that may help improve patient outcomes.

Ultimately, Kuykendall noted that rusfertide may become part of the “armamentarium going forward for polycythemia vera.”

CancerNetwork: What would the potential FDA approval of rusfertide mean for patients with polycythemia vera?

Kuykendall: This would ultimately mean, in the simplest terms, that patients could live a life that would be free from phlebotomy. This is something that we have relied upon for the treatment of [patients with] polycythemia vera for the history of the disease. It's a bit archaic in the way that we do that, in terms of bloodletting these [patients]. Coming up with a better way to do that via a well-tolerated therapy that maintains consistent control of hematocrit is something that patients have repeatedly told us that they would seek.

[The approval would] allow patients to be more in control of their care, where they're not relying on coming into the hospital to get blood checks and phlebotomies. It [would] allow them to optimize their other cytoreductive therapies that they may be on while they can control this key metric in a better way.

As an investigator on the phase 3 VERIFY trial, how do efficacy findings from your investigation support the potential clinical utility of rusfertide in this population?

One of the interesting things about the VERIFY trial is that it was run in a clinically relevant way. I don't know if we can always say that with our clinical trials in oncology, but we took patients who had polycythemia vera who were requiring phlebotomies, and it didn't matter what other cytoreductive therapies they were on; they could continue those. Then, they were essentially randomly [assigned] to get the standard therapy, which would be lab checks and phlebotomies vs adding rusfertide to this. What we saw in the primary results was that if you are on rusfertide, you need far fewer phlebotomies. You have more consistent control of your hematocrit. We even saw some improvement in some of the patient-reported outcomes.

When we take that and say, "Okay, well, how would we use this in clinic," the easiest answer is the same way it was used for the trial. We look at those patients and say, "Hey, are you requiring phlebotomies? Are you struggling with phlebotomies? This is something we can add to whatever your existing therapy is and optimize things."

What do data show regarding the safety and tolerability of rusfertide in polycythemia vera?

I should probably never say something is well tolerated; that's for the patients to decide. But I would say that the [adverse] effect profile, the feedback we got from patients, and their ability to stay on these agents long term would suggest that there is a level of tolerability there. With polycythemia vera, we're often thinking about long-term goals in treating our patients. We don't accept [adverse] effects for those [patients] because we're thinking about being on agents indefinitely, or at least long term. Luckily, we saw that with rusfertide.

It's a subcutaneous injection. Any time you put a needle under the skin, there's going to be a risk for skin injection site reactions, which we did see. Fortunately, what we saw is after that first 32 weeks, the rates of those injection site reactions significantly went down. It seems to be something that happens more early on and then improves over time. Rarely did those lead to discontinuations or dose reductions. What we also saw is some of the other [adverse] effects that were commonly reported [with rusfertide] were just as commonly reported on the placebo arm and are often associated with the disease. These are probably not true drug-related [adverse] effects. Things like fatigue are inherently a part of polycythemia vera. When we think about the [adverse] effect profile, the injection site reactions were the one thing to keep an eye on, and it appears those are quite manageable and tend to decrease over time.

How do additional findings from the phase 2 REVIVE study (NCT04057040) and the long-term extension THRIVE study (NCT06033586) support the use of rusfertide?

VERIFY, as the phase 3 study, was confirming the findings of REVIVE. REVIVE was a phase 2 study; everyone was receiving the drug, but it had some interesting design features that allowed us to compare, for a short period of time, what would happen between placebo and the drug on that trial. VERIFY was confirming those initial findings of REVIVE, where we saw the ability to drastically reduce phlebotomy requirements, control hematocrits, and even [show] some symptomatic improvements that we saw in that study.

But at the same time, with polycythemia vera and a lot of our chronic malignancies, we're thinking about long-term goals. When we look at end points at 32 weeks that's always going to be limited. Our goal is not to do the best we can at 32 weeks. The goal is to do the best we can year after year. This is where we rely on these long-term follow-up and extension studies to get a sense for the prolonged durability of efficacy as well as the long-term safety profile.

What I'm most struck by from REVIVE to THRIVE is the percentage of patients who were made on study for that long. There have been multiple different clinical trials that have come out. There are multiple different opportunities for patients to seek alternative therapies, yet these patients are dedicated to staying on this trial, which speaks to the experience they've had where they're motivated to do that. What we've seen with REVIVE and THRIVE is this long-term experience, long-term safety profile, and durability of effect. That's important when we're thinking about bringing these things to patients because that's what patients care about: the long-term outcomes.

What are the next steps for researching rusfertide in polycythemia vera or other patient populations?

There are a couple interesting factors that I would be particularly interested in. One, we know that rusfertide works for patients who are requiring phlebotomies. Certainly, its mechanism is to control hematocrit in that way. Yet, I think these symptomatic improvements we've seen that may be tied to iron regulation—that's certainly deregulated in patients with polycythemia vera. The question is, can we achieve some of those symptomatic benefits in patients who are not requiring phlebotomies? Can we bring this to the table for patients who are maybe controlled on their cytoreductive therapy from a hematocrit standpoint, but still have fatigue and some disease-related [adverse] effects? Can we get benefit there? That's one key.

The second would be, is this something we can bring in earlier? When patients are first diagnosed, they have high hematocrits, they're uncontrolled, and they're starting cytoreductive therapy, but it's going to take some time for that to kick in to control things. Can we use this early in the disease to get that hematocrit quickly under control in a safe way and allow it to be onboarded with a cytoreductive therapy, such as an interferon formulation that may take longer to work? That's certainly a critical area where this could be leveraged. Then, does this work in other kind of mechanisms for erythrocytosis? What about rare conditions where you have EPO-secreting cysts, or other kinds of non-physiologic reasons for erythrocytosis? Can this function in a similar way there? There are a few different avenues where I'd be interested to see if rusfertide could have potential benefit.

Are there any other potential advancements in polycythemia vera or hematologic oncology that you are anticipating in the future? How might these developments impact the treatment paradigm?

[When] we look down the road at polycythemia vera, we've certainly had the approval of ropeginterferon alfa-2b [Besremi] a couple of years ago.² That gave us a newer interferon that can be used in this space. That built upon the pegylated interferon that we were already using, but we are certainly using ropeginterferon more than we use pegylated interferon. Now, we have the emergence of rusfertide. There are other hepcidin-targeting agents that are certainly in the pipeline that will be looking to build on the successes of rusfertide and potentially do so with longer-acting formulations or slightly different mechanisms of action. It is to be determined how those can improve on the successes that rusfertide has seen.

Then, the biggest view forward is whether we'll be able to get true JAK2 mutant-selective inhibitors that can hit this disease at the core. We have ruxolitinib [Jakafi], which is a JAK inhibitor that's approved in the second-line setting for patients with polycythemia vera.³ But there are some long-term complications with ruxolitinib that prevents its more widespread use when we think about non-melanoma skin cancers, weight gain, and shingles. Some of these newer selective JAK2 mutant inhibitors have the potential of being more disease modifying, maybe [without] some of those long-term risks. That could be an opportunity for patients in the future.

What do you hope others take away from this conversation?

Rusfertide is going to be part of our armamentarium going forward for polycythemia vera. This is an agent that is extremely well tolerated; that’s probably to be decided by the patients, but it certainly seems like that. It certainly [has a] very manageable safety profile, and it’s extremely effective across the board. It does seem like it’s able to get reliable control of hematocrit, and this is something that we’ve said for a long time as a core tenet of [treating patients with] polycythemia vera: to achieve stable and optimal control of hematocrit to reduce the risk for thrombotic events. This is something that could be a part of every patient with polycythemia vera’s treatment history, maybe not forever but at least at some point during their disease. It’s something that can be combined with other therapies that can be used for their disease too. It’s something that we’re going to be talking about a lot with patients.

References

1. Takeda and Protagonist announce U.S. Food and Drug Administration accepts new drug application and grants priority review for rusfertide as a potential first-in-class therapy for polycythemia vera. News release. Takeda. March 2, 2026. Accessed March 18, 2026. https://tinyurl.com/3njzamwp
2. U.S. FDA approves BESREMi (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia Corporation. November 12, 2021. Accessed March 18, 2026. https://bwnews.pr/2YHruCT
3. FDA Approves Jakafi® (ruxolitinib) for the treatment of patients with uncontrolled polycythemia vera. News release. Incyte Corporation. December 4, 2014. Accessed March 18, 2026. https://tinyurl.com/bdzxhyj5