Behind the FDA Approval: Rusfertide Redefines the Polycythemia Vera Paradigm

Rusfertide was approved by the FDA¹ for adults with polycythemia who require phlebotomy, based on results from the phase 3 VERIFY trial (NCT05210790).² In an interview with Targeted Oncology, Andrew T. Kuykendall, MD, discussed the mechanism of rusfertide, key VERIFY findings, and where the agent may fit within the evolving polycythemia vera treatment paradigm. Kuykendall is the lead investigator on the VERIFY trial and an associate member in the Department of Hematology at Moffitt Cancer Center.

Targeted Oncology: What is the mechanism of rusfertide and how does itwork in treating patients with polycythemia vera.

Andrew T. Kuykendall, MD: Rusfertide is a hepcidin mimetic, so it mimics a hormone called hepcidin, which is our master regulator of iron homeostasis. Hepcidin is interesting in the sense that, patients who have iron deficiency are anemic; they don't have enough red blood cells, and so, in that setting, you kind of downregulate hepcidin, and you free up iron delivery to the bone marrow to make more red blood cells and compensate for that anemia. However, polycythemia vera is unique in the sense that most of these patients are using up all their iron to make red blood cells, and so they are systemically iron deficient, but they have too many red blood cells, and so you have downregulation of hepcidin, and that frees up iron to be delivered to the bone marrow, and then you make more red blood cells, but you already have too many. And then we treat that a lot of times with phlebotomy, and that further makes patients iron deficient. So then, patients are even more so downregulating hepcidin. Rusfertide mimics hepcidin; it simulates a high hepcidin state, kind of withholding the iron delivery to the bone marrow, and thereby restricting hematocrit elevations and controlling hematocrit levels without the need for a phlebotomy.

Please discuss the VERIFY trial that supported the FDA approval of rusfertide for polycythemia vera.

The VERIFY trial is a phase 3 study that was largely designed to confirm the results we saw in the phase 2 REVIVE study (NCT04057040).³ REVIVE was more of a study focused on rusfertide itself. One unique aspect of the study was the blinded withdrawal period, in which patients were switched to placebo without knowing whether they were still receiving rusfertide. But ultimately, what we saw with REVIVE is that rusfertide could really eliminate the need for phlebotomy and control hematocrit in a sustained fashion, and so VERIFY was designed to confirm those results.

VERIFY enrolled patients with polycythemia vera who were requiring phlebotomy; they had to have had at least 3 phlebotomies in the 24 weeks prior to screening, or 5 phlebotomies in the past year. These patients were reliant upon phlebotomy to control hematocrit. They could be on cytoreductive therapy or not; they could be on hydroxyurea, interferon, or ruxolitinib, or they could be managed with phlebotomy alone. Patients were randomized to receive rusfertide in addition to their current standard of care, or they were received placebo.

There’s a 20-week dose-titration period where patients kind of increase their dose of rusfertide to the goal dose. Then, the primary endpoint, at least in the US, was assessed from weeks 20 to 32, and it was looking at the absence of phlebotomy eligibility, so not needing phlebotomies. During this period of time, what we saw in the primary analysis was that patients who were randomized to rusfertide met this criterion of absence of phlebotomy eligibility much more often than patients who were randomized to placebo.

Other end points were looked at as well. Some of these were looking at hematocrit control in slightly different ways, such as the mean number of phlebotomies over the first 32 weeks of the study, or the absence of consistent hematocrit levels less than 45% without a phlebotomy throughout the entirety of those first 32 weeks. And again, drastically more patients on rusfertide achieved those endpoints than patients on placebo.

The last 2 key secondary end points were interesting because they were patient-reported outcomes that were looking at both fatigue, as this is something that’s quite commonly seen in polycythemia vera and often associated with a poor quality of life, as well as the Myelofibrosis Symptom Assessment Form, or MFSAF, which has been validated in prior myeloproliferative neoplasm studies.

And again, impressively, rusfertide showed improvements in fatigue and improvements in disease-related symptoms, with statistically significantly greater improvements than those seen in patients who were in the placebo group. Again, confirming not only that rusfertide was able to control hematocrit, but it also improved patient-reported outcomes, which obviously is extremely meaningful to patients. After that, patients who were on placebo did roll over to rusfertide, and so there was an additional part of the study, part 1b, where patients who had been receiving placebo received rusfertide. And again, there we saw the drastic ability of those patients to then achieve hematocrit control and decrease their need for phlebotomy as well.

Where does rusfertide fit into the treatment paradigm for polycythemia vera?

Rusfertide is unique in that it doesn’t necessarily slot into one specific place within the treatment paradigm. I think it’s causing us to kind of rethink the treatment paradigm a little bit, and I think it’s something that allows us to be a little bit more individual with how we create treatment plans for patients.

I think the easiest thing to say is that rusfertide can probably replace phlebotomy altogether in patients who are struggling with it or have challenges with phlebotomy. I think this is certainly a godsend for folks who want to move beyond this archaic method of controlling their disease. But certainly, there are folks who have challenges with just coming in and getting phlebotomies, keeping up with them, and getting them appropriately.

Rusfertide shows the ability to be independently self-administered to get consistent control of hematocrit. I think this is something that could be looked at early in the disease, when patients are getting a lot more phlebotomies. It can also be looked at in patients who are on cytoreductive therapy who are still needing phlebotomies and may have to be on higher doses of their cytoreductive therapy to control that need, but may not tolerate those higher doses well.

I’m particularly intrigued by patients who are suffering from this profound fatigue. We have these patients who, regardless of whatever we treat them with, even though they’re considered “at goal” or we’re hitting our marks, they feel terrible, and they feel like they can’t live the life that they used to live or want to live. So I’m particularly interested in how that might be able to kind of move the needle for some of these patients who really struggle on a day-to-day basis.

So really, rusfertide is something that I think can be thought about in a lot of different patients at different points during their disease course to see if this something that we can add to their current standard of care and maybe accomplish something we haven’t been able to with the other therapies that we have.

What are some unanswered questions and next steps with rusfertide?

Yeah, I think there are a few areas where I’m very intrigued by where rusfertide fits, particularly in patients with different profiles than those enrolled in VERIFY. Specifically, patients who maybe aren’t needing a ton of phlebotomies but struggle with this profound fatigue—I think there are maybe some interesting pathways there that we could still pursue, even in patients who might not be needing consistent phlebotomies.

I’m intrigued by using it early on, soon after diagnosis, as maybe a better way to achieve that first hematocrit control. Patients in VERIFY had to have hematocrit levels less than 45% when they started on the study. But given the kind of results we’ve seen from this, as well as some smaller studies with rusfertide, I’d be intrigued to be able to use this early on when patients are presenting with really high hematocrit levels. Is this a safer, more effective way to get these blood counts under control without patients getting, you know, like 6 phlebotomies in 6 weeks or something like that?

I’m also intrigued by how this works in relation to other therapies. With ropeginterferon, which we’re increasingly using in polycythemia vera, it takes a while to get its effect as far as controlling all these blood counts. Interferons are notoriously slow to gain that effect, but they’re a long-term play. Can rusfertide be something that we combine early on with ropeginterferon to allow for more optimized control of the disease, to allow that ropeginterferon really some time to benefit?

So, yeah, I think there are a few different areas where I’d be looking for some more information and where I think additional focused trials could really provide some guidance on how best to leverage this in the real world now.

What are the next steps needed to advance the polycythemia treatment paradigm as a whole?

When we think about what comes next, we have to consider what we’ve accomplished so far. We’re pretty good at identifying high-risk features and reducing thrombotic risk in these patients to a level that may be comparable to that associated with hypertension or hyperlipidemia. Interferons have shown the potential to lower allele burdens over time and potentially impact disease progression. Ruxolitinib has shown similar findings in the MAJIC-PV study.⁴

We can continue to build on those successes. There’s a lot of interest right now in developing mutation-specific JAK inhibitors. That’s still very early, and it may be more challenging than we initially anticipated. But if we had a therapy that could specifically eliminate the mutated cells harboring the JAK2 mutation that drives this disease, that would be disruptive to the treatment paradigm.

Building on rusfertide, the hepcidin pathway is clearly amenable to therapeutic intervention. There’s significant interest in other agents targeting this pathway, including potentially longer-acting therapies that could be given less frequently or that have different mechanisms of action.

It will be interesting to see how these agents develop and whether they can reproduce the efficacy and symptomatic benefits we’ve seen so far with rusfertide.

REFERENCES

1. FDA approves first drug of its kind for polycythemia vera, a rare blood disorder. News release. FDA. August 28, 2026. Accessed August 30, 2026. https://tinyurl.com/c56mh86y

2. Kuykendall AT, Pemmaraju N, Pettit KM, et al. Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). J Clin Oncol. 2025;43(17 suppl):LBA3. doi:10.1200/JCO.2025.43.17_suppl.LBA3

3. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al; REVIVE Trial Investigators. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 2024;390(8):723-735. doi:10.1056/NEJMoa2308809.

4. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. 2023;41(20):3534-3546. doi:10.1200/JCO.22.01935