Rusfertide
High EvidenceA first-in-class synthetic hepcidin-mimetic (mini-hepcidin) peptide given as a weekly subcutaneous injection to control red-blood-cell overproduction in polycythemia vera (PV). By mimicking the iron-regulating hormone hepcidin, rusfertide binds the iron exporter ferroportin and restricts iron availability, reducing the need for therapeutic phlebotomy. Developed by Protagonist Therapeutics and partnered with Takeda, it met its primary endpoint in the Phase 3 VERIFY trial and, in March 2026, received FDA acceptance of its New Drug Application with Priority Review, with a decision expected in the third quarter of 2026.
What It Is
Rusfertide (development code PTG-300; Protagonist Therapeutics, in partnership with Takeda) is a synthetic peptide mimetic of hepcidin - the liver-made 25-amino-acid hormone that is the body's master regulator of iron. It belongs to the 'mini-hepcidin' class: engineered analogs built around the first nine amino acids of hepcidin's N-terminus (the DTHFPICIF sequence sufficient for activity), chemically modified to resist enzymatic breakdown and to bind ferroportin more durably than the natural hormone. Ferroportin is the only known cellular iron exporter; hepcidin (and rusfertide) bind it, trigger its internalization and degradation, and thereby trap iron inside enterocytes, macrophages and hepatocytes. The net effect is lower plasma iron and restricted iron supply to the bone marrow. In polycythemia vera - a chronic myeloproliferative neoplasm, usually driven by a JAK2 mutation, in which the marrow overproduces red cells and thickens the blood - limiting iron availability curbs erythrocytosis. Standard care relies on repeated therapeutic phlebotomy (blood-letting) to keep hematocrit below 45%, which is burdensome and paradoxically worsens iron deficiency and its symptoms. Rusfertide is designed to provide steady hematocrit control and reduce or eliminate the need for phlebotomy. It is given as a weekly subcutaneous self-injection. The clinical program includes the Phase 2 REVIVE study (NCT04057040), the pivotal Phase 3 VERIFY trial (NCT05210790, 293 patients), and the long-term extension THRIVE study (NCT06033586). In VERIFY, 76.9% of rusfertide-treated patients achieved a clinical response versus 32.9% on standard of care alone (p<0.0001), and the trial met all four key secondary endpoints, including hematocrit control and patient-reported fatigue and symptom-burden measures. The FDA had already granted rusfertide Breakthrough Therapy, Orphan Drug and Fast Track designations; on March 2, 2026 the agency accepted the New Drug Application and granted Priority Review, setting a decision (PDUFA) date in the third quarter of 2026. As of this writing (July 2026) rusfertide is investigational and not yet FDA-approved. It is a physician-prescribed injectable biologic-class peptide studied under clinical protocols - not a self-sourced 'research peptide,' and any vendor selling 'rusfertide' or 'PTG-300' powder is illegitimate.
Regulatory Status
Rusfertide is an investigational, prescription-track injectable peptide; it is not yet FDA-approved. It holds FDA Breakthrough Therapy, Orphan Drug and Fast Track designations for polycythemia vera. On March 2, 2026, Takeda and Protagonist announced that the FDA accepted the New Drug Application and granted Priority Review, with a target action (PDUFA) date in the third quarter of 2026. The NDA is supported by the Phase 3 VERIFY trial (NCT05210790), the Phase 2 REVIVE study (NCT04057040) and the long-term THRIVE extension (NCT06033586). It is administered under medical supervision as a weekly subcutaneous injection and is not a legitimate self-sourced 'research chemical.'
Effective: July 2026
View FDA SourceWhy Researchers Study It
Rusfertide is studied as the proof-of-concept that pharmacologically mimicking hepcidin can safely and durably control iron-driven blood disorders. In polycythemia vera, it addresses two problems at once: it offers steady hematocrit control without the peaks-and-troughs of episodic phlebotomy, and it may relieve the iron-deficiency symptoms (fatigue, brain fog, restless legs) that chronic blood-letting causes. Beyond PV, hepcidin mimetics are of broad interest for any condition of iron overload or dysregulated iron export - including hereditary hemochromatosis and certain anemias/thalassemias - making rusfertide a flagship example of the emerging 'iron-modulating peptide' field. For peptide scientists specifically, it is a case study in miniaturizing a native peptide hormone (hepcidin) down to a stabilized nine-residue-based analog that resists proteolysis, binds its target (ferroportin) with nanomolar potency, and achieves once-weekly dosing - the kind of engineering that turns a fragile endogenous hormone into a practical medicine.
Proposed Mechanisms
- Synthetic mini-hepcidin peptide modeled on the active N-terminal 9 amino acids of human hepcidin (DTHFPICIF), chemically modified for protease resistance and durable target binding
- Binds ferroportin - the body's only cellular iron exporter - with high potency (reported EC50 ~5 nM), triggering its internalization and lysosomal degradation
- Blocks iron efflux from enterocytes (dietary absorption), macrophages (recycled iron) and hepatocytes (stored iron), lowering plasma iron and transferrin saturation
- Restricts iron supply to the bone marrow, curbing the excess red-cell production (erythrocytosis) that defines polycythemia vera
- Provides steady hematocrit control as a weekly subcutaneous injection, reducing or eliminating the need for therapeutic phlebotomy
- Iron redistribution/sequestration rather than iron removal - aims to correct the functional iron-deficiency symptoms caused by repeated phlebotomy
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| RCT (human, Phase 3 - VERIFY) | Polycythemia vera - 293 phlebotomy-dependent patients, rusfertide added to standard of care vs standard of care alone (NCT05210790) | Met primary endpoint: 76.9% clinical response (hematocrit control without phlebotomy, weeks 20-32) vs 32.9% with standard of care alone (p<0.0001); all four key secondary endpoints met, including hematocrit control and improvements in PROMIS Fatigue and MFSAF total symptom score. Presented 2025; supports the 2026 NDA | Source |
| RCT (human, Phase 2 - REVIVE) | Polycythemia vera - dose-finding and blinded randomized-withdrawal design (NCT04057040) | Rusfertide reduced the frequency of phlebotomy and maintained hematocrit control below 45%; established durable responses and informed Phase 3 dosing | Source |
| Regulatory milestone | Polycythemia vera (Takeda / Protagonist) | FDA accepted the New Drug Application and granted Priority Review on March 2, 2026; target decision (PDUFA) in Q3 2026. Rusfertide also holds Breakthrough Therapy, Orphan Drug and Fast Track designations | Source |
| Safety (pooled clinical experience) | Polycythemia vera - REVIVE, VERIFY and THRIVE (NCT06033586) participants | Generally well tolerated; most adverse events were grade 1/2 injection-site reactions, with no new safety signals reported and serious adverse events judged unrelated to rusfertide. Long-term monitoring is ongoing | Source |
Commonly Discussed Benefits
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Safety & Cautions
- Investigational: not yet FDA-approved. Efficacy and safety conclusions rest on trial data; a regulatory decision is pending (expected Q3 2026)
- A physician-prescribed injectable peptide studied under clinical protocols - not a self-administered 'research peptide.' Any vendor selling 'rusfertide' or 'PTG-300' powder is illegitimate and unsafe
- Most common adverse events in trials were injection-site reactions (redness, pain, swelling); these were generally mild to moderate (grade 1/2)
- Because it manipulates systemic iron handling, rusfertide requires monitoring of blood counts and iron parameters and is intended for use only in diagnosed disease under specialist care
- An earlier FDA partial clinical hold (2021) related to a nonclinical rodent finding was subsequently resolved and the program continued; long-term human safety data are still accumulating
- Studied specifically in polycythemia vera; use in other iron-overload conditions (e.g., hereditary hemochromatosis, thalassemia) remains investigational
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Citations
- [1] Takeda and Protagonist: FDA Accepts New Drug Application and Grants Priority Review for Rusfertide (March 2026) PubMed
- [2] VERIFY: A randomized controlled Phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in polycythemia vera - ASCO 2025 PubMed
- [3] A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera (VERIFY) - ClinicalTrials.gov NCT05210790 PubMed
- [4] Adding the Hepcidin Mimetic Rusfertide to the Standard of Care Yields Benefits in Polycythemia Vera - The ASCO Post (Sept 2025) PubMed
- [5] Structural basis of ferroportin inhibition by minihepcidin - PMC (mechanism of mini-hepcidins) PubMed
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