Rusfertide Significantly Reduces Therapeutic Phlebotomy Necessity in Polycythemia Vera

Andrew Kuykendall, MD

The hepcidin mimetic rusfertide demonstrated a significant reduction in the need for therapeutic phlebotomies and improved hematocrit in patients with polycythemia vera (PV), according to Andrew Kuykendall, MD.

The phase 3 VERIFY trial (NCT05210790), which was presented at the 2025 ASCO Annual Meeting, evaluated rusfertide as a potential new treatment option for patients with PV. Of note, data from part 1a of the trial revealed that rusfertide also showed a statistically significant improvement in symptoms, including fatigue and other symptoms related to myeloproliferative neoplasms, based on patient-reported outcomes (PROs).

During part 1a, between weeks 20 to 32, the study met its primary end point of clinical response to rusfertide without therapeutic phlebotomies, with confirmed hematocrit of 45% or greater, and 3% or higher than baseline hematocrit, or hematocrit of 48% or greater. Specifically, at weeks 20 to 32, 32.9% (n = 48/146) and 76.9% (n = 113/147) of patients in the placebo and rusfertide arms, respectively, had an absence of phlebotomy eligibility (P < .0001).

“Rusfertide mimics hepcidin, and thereby withholds iron from the bone marrow, so you can control hematocrit without becoming more iron deficient,” Kuykendall explained during an interview with OncLive® at the meeting. “We evaluated [rusfertide] in the phase 2 REVIVE trial [NCT04057040], and then this led to VERIFY.”

During the interview, Kuykendall discussed the rationale for targeting the hepcidin pathway with rusfertide in patients with PV, rusfertide’s effect on the necessary number of therapeutic phlebotomies, how rusfertide helps improve patient quality of life (QOL), and future research directions for rusfertide in PV. Kuykendall is an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

OncLive: What was the rationale for targeting the hepcidin pathway with rusfertide?

Kuykendall: Patients [with PV] are in a unique situation where they produce too many red blood cells. This is a chronic leukemia driven by JAK2 mutations that require them to overproduce blood cells. These patients are at risk for cardiovascular events, as well as symptoms related to iron deficiency that can reduce their QOL. Unfortunately, a lot of times, to control their blood counts, we perform therapeutic phlebotomies, which drain them of their iron, making them more iron deficient. Oftentimes, we consider that a victory, because the blood counts aren't too high, but often patients feel terrible with zero iron. Rusfertide is a hepcidin mimetic, and hepcidin is the master regulator of iron homeostasis in the body. Rusfertide mimics hepcidin, and thereby actually withholds iron from the bone marrow, so you can control hematocrit without becoming more iron deficient. We evaluated [rusfertide] in REVIVE, and then this led to VERIFY.

We saw [in VERIFY] that rusfertide can control hemoglobin and hematocrit, and reduce the need for phlebotomies in patients with PV. Very importantly, we also saw that patients had improvement in their QOL and symptoms with PROs, looking at fatigue as well as more general myeloproliferative neoplasm–related symptoms. This is an exciting study, and it has the potential to add to the standard of care for patients with PV and bring an additional therapeutic option to the table.

What is rusfertide’s effect on the number of therapeutic phlebotomies patients need, and how does this translate in clinical practice?

In patients with PV, as a part of their treatment plan to reduce their thrombotic risk, we perform these therapeutic phlebotomies to target a hematocrit that's consistently less than 45%. Many times, patients with PV have to get a phlebotomy every month, every 2 months, or every 3 months. In this trial, we identified patients who required a significant number of phlebotomies. This was defined as at least 3 phlebotomies over the course of the 6 months prior to going on the study, or 5 phlebotomies within a year. What we saw with rusfertide is that the mean number of phlebotomies over the 32 weeks on the study went down to 0.5, drastically reducing the phlebotomy requirements of these patients who had previously been receiving consistent phlebotomies before going on the study.

How does the use of rusfertide—and less therapeutic phlebotomies—help improve quality of life?

We know our patients with PV fortunately have a relatively good prognosis. For the most part, if we can avoid major cardiovascular events, the median [overall] survival in PV is approximately 15 to 20 years. Patients are often living with this disease for a long time. That can be a good and a bad thing, because in many cases, patients have to deal with chronic, problematic, and vague symptoms such as fatigue, brain fog, decreased attentiveness, and [other similar symptoms]. We were hoping that through this mechanism of action, by targeting this iron pathway [and by potentially] alleviating some of that iron deficiency, we could also improve patients' QOL. This is something that we need to focus on in these more chronic diseases, instead of just modifying or getting rid of the disease, [although] we all want to do that. We also need to improve patients’ experience with their disease and think about disease experience modification. It’s important that we build in these PROs to make sure that we're improving QOL for patients as well. We looked at the PROMIS fatigue score, which is a validated score that assesses the [effect] fatigue has on patients’ lives. We showed that patients who were treated with rusfertide had a more drastic improvement in their fatigue compared with placebo. Additionally, we looked at the Myelofibrosis Symptom Assessment Form, which is a validated symptom assessment tool that's used in patients with myeloproliferative neoplasms. Again, we saw that patients had improvement in their total symptom score from 0 to 32 compared with placebo. We believe that rusfertide has the ability not just to control hematocrit, decrease the need for phlebotomy, but also improve patients' quality of life.

What was the safety profile of rusfertide?

Anytime we're thinking about treatments for PV, we're very thoughtful about the [adverse] effect [AE] profile. Patients have to live with this disease for a long time. We're not tolerant of any significant AEs. Fortunately, with rusfertide as the main AE that we saw was injection site reactions, which are common with any kind of subcutaneous injectable. These were usually mild and self-resolved, but we did see those in over half of the patients. Additionally, we saw that anemia in a subset of patients. However, this is consistent with the mechanism of action; we're trying to bring down hemoglobin, and therefore, seeing some mild anemia would be expected with this agent.

There was some concern in the phase 2 trial about skin cancers. We know skin cancers are quite common in our patients with PV. We know they are exacerbated by current treatments such as hydroxyurea and ruxolitinib [Jakafi]. We monitored patients with screening tests, looking at skin dermatologic screening exams prior to going on study, and then throughout the study as well. Interestingly, we found 10 skin malignancies in patients during the screening portion before they were [randomly assigned, which] speaks to the fact that this is a common occurrence in [patients with] PV. During the trial, in the first 32 weeks, we found 8 non-PV secondary malignancies. Interestingly, of those 8 patients, 7 occurred in the placebo arm, and only 1 occurred in the rusfertide arm, again, alleviating any concern we have that this could be exacerbating or leading to other ordinances.

What were the overall implications of the study?

With this study, and with REVIVE, what we’ve seen is rusfertide can control hematocrit, decrease phlebotomy eligibility in patients, and improve disease-specific quality of life symptoms. This is important and focuses on several different unmet needs that we see in this population. I see this [agent] adding to the current standard of care in patients with PV. For patients who are struggling with phlebotomies, this is certainly an optimal agent to consider whether or not they're on cytoreductive therapy, or not on cytoreductive therapy, and patients who are struggling with fatigue related to systemic iron deficiency. Again, this becomes a therapeutic option for these patients, and therefore, having another agent that we can leverage for multiple different reasons in this patient population is certainly exciting.

Are there plans to investigate rusfertide further in PV?

What was so great about REVIVE is that it enrolled this heterogeneous patient population. We enrolled [patients with] low- and high-risk disease, those who were not on cytoreductive therapy, and those who were on cytoreductive therapy. Of the patients who were on cytoreductive therapy, which comprised more than 50% of patients, most of those patients were on hydroxyurea, which is consistent with general practice. However, we did have patients who were on interferon formulations. We did have some patients who were on ruxolitinib, as well. Without intending to, we almost performed a half-combination study, as many of these patients were on other therapies. The question is, can we optimize that care going forward? Is this a great partner for [an agent such as] ropeginterferon alfa-2b [Besremi], which maybe takes a little bit longer to control hematocrit? Can we use this earlier in the disease state? Most of the patients on the REVIVE study had controlled hematocrit [at enrollment]. They had to achieve a controlled hematocrit before they started, even though they had been receiving phlebotomies. What about using this in newly diagnosed patients who have higher hematocrit who need help reducing them in a safer way? I believe these are questions we need to answer going forward.

Reference

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(suppl 17):LBA3. doi:10.1200/JCO.2025.43.17_suppl.LBA3