The emerging role of hepcidin modulation in polycythemia vera

Polycythemia vera (PV) is a chronic Philadelphia chromosome–negative myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis, most commonly driven by activating mutations in JAK2 (notably V617F, present in >95% of cases) that cause constitutive JAK–STAT signaling.¹ Key hallmarks of the disease include elevated hematocrit and increased risk of thrombotic complications (stroke, myocardial infarction, deep vein thrombosis).² Alongside this, patients also bear the burden of systemic symptoms, including fatigue, difficulty concentrating, pruritus, and night sweats.³

The current primary goal of PV management, in both low- and high-risk patients, is thrombosis prevention, with secondary goals including symptom control, quality of life (QoL) improvement, and limiting progression to post-PV myelofibrosis (PPV-MF) or acute myeloid leukemia (AML).³ To achieve this, four steps are recommended in all patient groups: management of cardiovascular risk factors, use of low-dose aspirin, maintaining optimal hematocrit levels (below 45%) through frequent therapeutic phlebotomy and cytoreductive therapy, and ensuring leukocyte count is kept below 11 × 109/L.³

In a number of observational real-world studies, hematocrit control has been found to be suboptimal in a significant proportion of patients with PV.^4,5 For example, the multicenter, noninterventional, nonrandomized, prospective observational REVEAL study (NCT02252159) found that 48.5% of patients had a hematocrit of greater than 45% at the time of enrollment.⁵ This underscores the need for novel therapeutic agents to effectively control hematocrit, reducing the risk of thrombotic complications and decreasing symptom burden.

Rationale for hepcidin modulation

Iron homeostasis and erythropoiesis are tightly linked via the hepcidin–ferroportin axis. Hepcidin, a liver-derived peptide hormone, is the master regulator of systemic iron trafficking: it limits intestinal iron absorption and iron release from macrophages by inducing degradation of the iron exporter ferroportin.⁶ In addition to this, hepcidin also affects iron recycling by macrophages.⁶ In patients with PV, hepcidin is low due to decreased circulating iron levels and increased erythroferrone as a consequence of erythroid hyperplasia.⁷ This suppression of hepcidin enables increased iron absorption and recycling, thereby supporting the excessive red blood cell production that is the hallmark of this disease.⁷

Hepcidin modulation presents a promising therapeutic opportunity to address the underlying dysregulation of iron metabolism central to PV biology and to control hematocrit without the need for therapeutic phlebotomies. The hepcidin modulator furthest along in development is rusfertide, a direct synthetic hepcidin mimetic; however, other investigational agents targeting the hepcidin-ferroportin axis are also being explored. These function as hepcidin stimulators to increase endogenous hepcidin levels or as ferroportin inhibitors to reduce iron availability for erythropoiesis.

Agents being explored

Rusfertide

Rusfertide is a first-in-class synthetic hepcidin mimetic administered subcutaneously to directly replicate endogenous hepcidin activity, with data from several clinical trials indicating its promising safety and efficacy.³ These include the Phase II REVIVE study (NCT04057040), the open-label THRIVE extension study (NCT06033586), and the ongoing Phase III VERIFY (NCT05210790) trial. In VERIFY, 293 phlebotomy-dependent patients with PV on standard-of-care therapy were randomized to receive rusfertide (n=147) or placebo (n=146) as a once-weekly self-administered injection. The primary endpoint of the study was met, with a significantly greater proportion of patients in the rusfertide arm achieving a clinical response (defined as the absence of phlebotomy eligibility) during weeks 20-32 (76.9% for rusfertide versus 32.9% for placebo; p<0.0001).⁸ Additionally, treatment with rusfertide resulted in a significant decrease in the mean number of phlebotomies, superior hematocrit control, and an improvement in patient-reported outcomes captured by the PROMIS Fatigue SF-8a and Myeloproliferative Neoplasm Symptom Assessment Form (MFSAF) symptom scores.⁸

Based on the existing body of encouraging data, the U.S. Food and Drug Administration (FDA) accepted a New Drug Application (NDA) and granted Priority Review for rusfertide on March 2, 2026, with approval anticipated in the third quarter of the year based on the Prescription Drug User Fee Act (PDUFA) goal date.⁹ Additionally, the agent received Breakthrough Therapy, Orphan Drug, and Fast Track designations.

These developments have positioned rusfertide as a potential first-in-class, non-cytoreductive therapy, and its approval could represent a paradigm shift, moving from reactive hematocrit control via phlebotomy to proactive modulation of iron availability. In a recent interview, Andrew Kuykendall, MD, from Moffitt Cancer Center, Tampa, FL, comments on where rusfertide may fit into the treatment algorithm for PV if it is approved. He highlights that “it could be a part of everyone’s journey with polycythemia vera…it certainly fits in a lot of different potential buckets and fits a lot of different patients, but it may be different for different patients where exactly it fits into that treatment paradigm.”

Divesiran

Another hepcidin-modulating agent showing promise in PV is divesiran, a liver-targeted GalNAc-conjugated small interfering RNA (siRNA) that targets and silences transmembrane serine protease 6 (TMPRSS6) mRNA in the liver. TMPRSS6 is a negative regulator of hepcidin production; its silencing results in an upregulation of hepcidin synthesis and reduced iron availability for erythropoiesis. ¹⁰

Diversiran is being explored in phlebotomy-dependent PV in the ongoing Phase I/II SANRECO study (NCT05499013), with early Phase I results presented last year at the 30th Congress of the European Hematology Association (EHA) by Marina Kremyanskaya, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, NY.¹⁰ In the trial, divesiran was administered by subcutaneous injection every 6 weeks at various dose levels, and Dr Kremyanskaya highlights that “in patients treated at all dose levels, the number of phlebotomies significantly decreased …the level of hepcidin went up in all dose cohorts… and ferritin went up to normal levels, suggesting that, overall, there’s a redistribution of iron. So while iron is overall restricted for erythropoiesis, it is presumably available for other cellular processes, which is why we are hoping that, similar to the other drugs in this field, we will see an improvement in symptoms.”

Sapablursen

Another agent that targets and degrades TMPRSS6 mRNA is sapablursen, a liver-directed, ligand-conjugated antisense oligonucleotide. The Phase II IMPRSSION study (NCT05143957) is an ongoing global, open-label trial evaluating sapablursen for hematocrit control and reduction of phlebotomy requirements in phlebotomy-dependent patients.¹¹ The top-line results of this trial were presented at the 67th ASH Annual Meeting and Exposition, and indicated that treatment with sapablursen increases serum hepcidin, controls hematocrit, reduces phlebotomy needs, and improves quality of life in a dose-dependent manner.¹¹ This agent is administered subcutaneously with a convenient once-monthly dosing schedule, and Ruben Mesa, MD, Levine Cancer Institute, from the Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston Salem, NC, suggests that it is “a very important addition to the growing pantheon of hepcidin mimetics that may have important disease therapy implications for patients with polycythemia vera”.

Other hepcidin pathway targets

In addition to the previously mentioned agents, other approaches targeting the hepcidin-ferroportin axis are in development or being investigated in preclinical models, including vamifeport, DISC-3405, and AG-236. Vamifeport is a first-in-class oral small-molecule ferroportin inhibitor that directly binds to the cellular iron exporter ferroportin, inhibiting its function and promoting its internalization and degradation. This results in intracellular iron sequestration, including within splenic macrophages.¹² Although this agent is primarily being studied in sickle cell disease and β-thalassemia, it has shown efficacy in preclinical JAK2-mutant PV mouse models, reducing serum iron levels, and could provide an oral alternative to other hepcidin modulators. ^13,14 DISC-3405, a humanized immunoglobulin (Ig)G1 monoclonal antibody targeting TMPRSS6, has shown promising early results and is now being evaluated in a 52-week Phase II study in the United States (NCT06985147).¹⁵ Finally, AG-236, an siRNA targeting TMPRSS6, is also under investigation, with topline results from a Phase I healthy volunteer trial expected in 2026.¹⁶

Implications and unanswered questions

Hepcidin modulation introduces a fundamentally different therapeutic axis in PV that may offer several advantages, including reduced or eliminated phlebotomy burden and improved symptom control, particularly those related to iron deficiency induced by repeated venesection. Accumulating clinical data suggest that hepcidin-targeted therapies may soon become an integral component of the PV treatment paradigm. At the same time, important questions remain. The long-term safety of chronic iron restriction, optimal combinations with cytoreductive therapies such as JAK inhibitors or interferons, and the potential effects on the natural history of the disease require further study. Long-term extension studies, such as THRIVE, are essential to determine whether consistently controlling hematocrit through chronic hepcidin modulation will yield the hypothesized reduction in thrombotic risk.¹³ It is important to note that hepcidin mimetics will likely act as a complementary therapy to standard cytoreductive agents, rather than a replacement, as these treatments reduce thrombotic risk through alternative mechanisms and address underlying disease drivers to modify the disease (e.g., reducing the JAK2 V617F mutation allele burden).¹³

Conclusion

The convergence of dysregulated erythropoiesis and iron metabolism in PV provides a strong biological rationale for hepcidin modulation. With late-stage clinical success and impending regulatory decisions, agents such as rusfertide and the broader pipeline, including divesiran, sapablursen, and vamifeport, signal a shift toward more targeted, physiology-driven management of PV.