SUMMARY: Polycythemia vera (PV) is a clonal myeloproliferative neoplasm characterized by excessive Red Blood Cell (RBC) production, most often driven by JAK2 mutations. A hallmark of PV is sustained erythrocytosis, which contributes to increased blood viscosity and significantly elevates the risk of thrombotic events. Standard management strategies include phlebotomy, low-dose Aspirin, and cytoreductive agents such as Hydroxyurea, Interferons, and Ruxolitinib. While phlebotomy remains a key tool for hematocrit (Hct) control, frequent procedures are burdensome for many patients, can worsen iron deficiency, and often fail to alleviate constitutional symptoms like fatigue. In this context, Rusfertide, a novel, self-injectable hepcidin mimetic, has emerged as a promising therapeutic strategy targeting iron metabolism to modulate erythropoiesis more precisely.
A Hepcidin-Based Therapeutic Approach
Hepcidin is a hormone produced by the liver that regulates iron absorption in the intestine and iron release from storage sites like macrophages and the liver. It does this by binding to ferroportin, an iron transport protein responsible for transporting iron out of intestinal cells and from storage sites (like macrophages) into the bloodstream. Following its binding to ferroportin, hepcidin causes its degradation, which in turn reduces iron export from cells and lowers iron levels in the blood. Hepcidin levels are generally low in iron deficiency anemia facilitating increased intestinal iron absorption and release of iron from storage sites and promoting iron availability for erythropoiesis. Hepcidin therefore is the master regulator that controls iron homeostasis in the bone marrow for RBC production.
Rusfertide is a first-in-class synthetic peptide the mimics hepcidin and reduces iron availability for erythropoiesis in the bone marrow, thereby mitigating RBC overproduction, characteristic of PV, potentially reducing or eliminating the need for phlebotomies. The unique, subcutaneously administered formulation of Rusfertide allows for convenient weekly self-injection, potentially decreasing reliance on phlebotomy and improving patient quality of life.
VERIFY Trial Design and Objectives
The VERIFY study (NCT05210790) is an ongoing, multinational, randomized, double-blind, placebo-controlled Phase 3 trial, designed to assess the safety and efficacy of Rusfertide in patients with phlebotomy-dependent PV receiving standard-of-care therapy. Enrolled patients were required to have frequent phlebotomies to maintain hematocrit control, with or without concurrent cytoreductive therapy. In Part 1a of the study (Weeks 0–32), patients (N=293) were randomized 1:1 to receive once-weekly Rusfertide (N=147) or placebo (N=146) and patients were stratified by concurrent cytoreductive therapy. The median patient age was 57 years. The Primary endpoint was the proportion of patients achieving clinical response, defined as the absence of phlebotomy eligibility, and no phlebotomies between weeks 20–32. Key Secondary endpoints included number of phlebotomies, proportion of patients with Hct <45%, and changes in patient-reported outcomes (PROMIS Fatigue Short Form-8a and MFSAF Total Symptom Score). Following the 32-week blinded phase (Part 1a), patients could enter an open-label extension (Part 1b, weeks 32–52), with a planned long-term follow-up (Part 2) for up to 3 years.
Clinical Outcomes: Efficacy Highlights
The trial met its Primary endpoint, demonstrating that 76.9% of patients treated with Rusfertide achieved a clinical response compared with 32.9% in the placebo group (P< 0.0001).
Key efficacy findings included:
- Phlebotomy reduction: Mean number of phlebotomies from weeks 0–32 was o.5 with Rusfertide versus 1.8 with placebo (P< 0.0001).
- Hematocrit control: 62.6% of Rusfertide-treated patients maintained Hct <45%, compared with 14.4% in the placebo group (P< 0.0001).
- Symptom improvement: Statistically significant improvements were seen in fatigue (PROMIS Fatigue SF-8a) and PV-related symptom burden (MFSAF TSS), highlighting a benefit on patient quality of life (P<0.03).
Patients at baseline averaged over four phlebotomies in the preceding 28 weeks, yet the majority receiving Rusfertide required none during the first 32 weeks of the study. Notably, 72.8% of patients on Rusfertide required no phlebotomy at all during this period, compared to 21.9% on placebo.
Safety Profile and Tolerability
Rusfertide was generally well tolerated and injection site reactions were the most common adverse event (55.9% in Rusfertide vs. 32.9% in placebo). Anemia was more frequent with Rusfertide (15.9% vs. 4.1%), reflecting its mechanism of reducing iron availability. Interestingly, fewer new malignancies were reported in the Rusfertide arm (N=1) versus placebo (N=7), though the significance of this observation requires longer follow-up.
Implications for Practice
The VERIFY trial supports Rusfertide as a potential paradigm shift in the management of PV, particularly for patients who are phlebotomy-dependent. By addressing erythrocytosis through iron restriction rather than marrow suppression, Rusfertide introduces a novel mechanism that complements existing therapies.
If approved, rusfertide would:
- Offer an effective alternative to repeated phlebotomies.
- Provide symptom relief, particularly in domains like fatigue and cognitive impairment, which are often unaddressed by standard treatments.
- Be suitable as an adjunct to cytoreductive therapy or as a standalone intervention for those who decline or are ineligible for such agents.
- Improve patient autonomy and quality of life through self-administration and reduced healthcare interactions.
Ongoing Evaluation and Regulatory Outlook
VERIFY continues in its open-label and long-term follow-up phases to evaluate the durability of response, long-term safety, and thrombotic outcomes over 3 years. Regulatory submissions are in preparation across the U.S., Europe, and Japan. Should Rusfertide gain regulatory approval, it is anticipated to become a valuable component of the standard treatment landscape for PV—potentially freeing patients from the physical, logistical, and emotional burdens of recurrent phlebotomy.
Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). Kuykendall A, Pemmaraju N, Pettit K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA3)
