Rusfertide

A synthetic, lipidated hepcidin-mimetic peptide that blocks the iron exporter ferroportin, developed by Protagonist Therapeutics as PTG-300 and approved by the FDA in August 2026 as Mimrylo (Takeda) for erythrocytosis in adults with polycythemia vera.

Also referenced as: PTG-300, PTG300, TAK-121, Mimrylo, rusfertide acetate

Also appears in: Hormone

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What is Rusfertide?

Rusfertide is a synthetic peptide mimetic of hepcidin, the liver hormone that governs how much iron enters the bloodstream. It was discovered by Protagonist Therapeutics under the code PTG-300 by searching for compact peptide scaffolds that reproduce the ferroportin-binding pharmacophore of native hepcidin, a 25-residue hormone with four disulfide bonds that is difficult to synthesize and prone to aggregation. The prescribing information describes the drug substance as a cyclic peptide of about 2.4 kDa with a single disulfide bridge, an N-terminal isovaleryl cap, a C-terminal amide and one lysine side chain acylated with an N-palmitoyl-gamma-glutamyl group, supplied as the acetate salt; the lipid tail extends its half-life enough for weekly subcutaneous injection.

The molecule matters because it is the first hepcidin-pathway drug to reach approval. It is approved as Mimrylo, marketed by Takeda, for the treatment of erythrocytosis in adults with polycythemia vera, a JAK2-driven myeloproliferative neoplasm in which excess red cell production is otherwise controlled by repeated therapeutic phlebotomy. Rusfertide has not developed a meaningful presence in the research-peptide market.

How it works

• Hepcidin pharmacology at ferroportin. Hepcidin binds ferroportin, the only known cellular iron exporter, on duodenal enterocytes, macrophages and hepatocytes, triggering its internalization and degradation and so trapping iron inside those cells (Nemeth et al., Science, 2004;306(5704):2090–2093). Structure-function work later showed that hepcidin bound within ferroportin’s central cavity can also occlude iron transport directly, before any endocytosis occurs, which is the mechanism most relevant to short, drug-like hepcidin agonists (Aschemeyer et al., Blood, 2018;131(8):899–910). Cryo-electron microscopy of hepcidin bound to human ferroportin confirmed that the hormone plugs the outward-open transporter and that its binding is itself dependent on a metal ion at the site (Billesbølle et al., Nature, 2020;586(7831):807–811).
• Iron restriction in polycythemia vera. Nearly all patients with polycythemia vera are iron deficient, yet their hepcidin is not suppressed as far as the deficiency would predict; the disordered iron axis is considered part of the disease biology, and phlebotomy worsens the deficiency while controlling hematocrit (Ginzburg et al., Leukemia, 2018;32(10):2105–2116). A hepcidin mimetic sequesters iron in macrophage stores, limits the supply reaching erythroid precursors in the marrow and caps red cell production without directly targeting the JAK2 clone. In mice carrying the human JAK2 V617F mutation, minihepcidin peptides normalized hematocrit and reduced splenomegaly, the preclinical rationale for the program (Casu et al., Blood, 2016;128(2):265–276).
• Pharmacokinetics and pharmacodynamics. After subcutaneous injection in healthy volunteers, the lyophilized formulation reached peak plasma concentrations at a median of 24 hours for 10 to 30 mg doses and 2 to 4 hours for 45 and 60 mg doses, had a terminal half-life of roughly 20 to 57 hours, and produced dose-related falls in serum iron and transferrin saturation that support once- or twice-weekly administration (Modi et al., Drugs in R&D, 2024;24(4):539–552). A thorough QT study in 60 healthy adults found no clinically relevant effect on heart rate, conduction or the QTc interval at supratherapeutic exposure (Modi et al., Clinical Therapeutics, 2025;47(11):1043–1052).
• Consequence on other blood lineages. Because the drug acts on iron supply rather than on the neoplastic clone, it does not lower white cell or platelet counts, and the label documents that platelet counts rise by about 31% on average within the first four weeks before plateauing, a pharmacodynamic effect that distinguishes it from cytoreductive agents such as hydroxyurea and interferon (Mimrylo prescribing information, August 2026; Kuykendall et al., Journal of Clinical Oncology, 2026).

Research status

Early programs and a change of lead indication. Protagonist first took PTG-300 into beta-thalassemia, where iron restriction was expected to improve ineffective erythropoiesis, running two phase 2 studies (NCT03802201, 63 participants; NCT04054921, 34 participants). On May 7, 2020 the company discontinued development in beta-thalassemia and myelodysplastic syndromes and redirected the program to polycythemia vera while continuing to explore hereditary hemochromatosis.

REVIVE (NCT04057040), phase 2. REVIVE enrolled 70 patients with phlebotomy-dependent polycythemia vera beginning in October 2019. Part 1 was a 28-week open-label dose-finding period; part 2 randomized 59 patients 1:1 to continue rusfertide (30) or switch to placebo (29) for 12 weeks in a double-blind withdrawal design. The estimated phlebotomy rate fell from 8.7 per year in the 28 weeks before treatment to 0.6 per year during part 1, mean maximum hematocrit fell from 50.0% to 44.5%, and in part 2 a response, defined by hematocrit control, absence of phlebotomy and completion of the regimen, occurred in 60% of rusfertide patients versus 17% on placebo (P=0.002). Grade 3 adverse events occurred in 13% of patients across parts 1 and 2, with no grade 4 or 5 events, and grade 1 or 2 injection-site reactions were common (Kremyanskaya et al., New England Journal of Medicine, 2024;390(8):723–735). Part 3 was an open-label extension, and 46 patients continued into the THRIVE extension study (NCT06033586), which began on January 22, 2024 and supplied the four-year safety and efficacy data included in the regulatory submission.

PACIFIC (NCT04767802), phase 2. A 20-patient open-label study in polycythemia vera with hematocrit above 48% started in February 2021 and tested a more intensive induction period. By week 8, 17 patients (85%) had a hematocrit below 45%, median time to first hematocrit below 45% was 4.9 weeks, and no patient required phlebotomy during treatment; 85% had treatment-emergent adverse events, mostly grade 1 or 2 (Chew et al., Leukemia Research, 2025;159:108132).

The 2021 clinical hold. On September 17, 2021 Protagonist announced that the FDA had placed all rusfertide studies on full clinical hold after a 26-week study in rasH2 transgenic mice, a model used to detect tumorigenic signals, showed benign and malignant subcutaneous skin tumors. The FDA lifted the hold on October 11, 2021 after the company submitted individual patient safety reports, an updated investigator brochure and consent forms, a review of its safety database and new safety and stopping rules, and dosing resumed once participants were reconsented. The approved label’s nonclinical toxicology section states that rusfertide was not carcinogenic in a 6-month transgenic mouse study at subcutaneous doses up to 25 mg/kg per week or in a 2-year rat carcinogenicity study, and that it was not mutagenic in standard assays; the FDA’s review documents for NDA 220605 are the public record of how the 2021 finding was reconciled with that conclusion.

VERIFY (NCT05210790), phase 3. VERIFY began on April 11, 2022 and randomized 293 phlebotomy-dependent adults with polycythemia vera, with or without concurrent cytoreductive therapy, 1:1 to weekly subcutaneous rusfertide (147) or placebo (146) for a 32-week double-blind period (part 1a). The primary endpoint, absence of phlebotomy eligibility during weeks 20 to 32, was met by 77% of rusfertide patients (113) versus 33% on placebo (48; P<0.0001). All four key secondary endpoints were also met: mean phlebotomies from baseline to week 32 were 0.5 versus 1.8, hematocrit stayed below 45% throughout in 63% versus 14%, and both the PROMIS Fatigue SF-8a T-score (P=0.0252) and the MFSAF total symptom score (P=0.0240) improved relative to placebo. Injection-site reactions, anemia and fatigue were the most common adverse events. The results were presented at ASCO on June 1, 2025 and published online on October 13, 2026 (Kuykendall et al., Journal of Clinical Oncology, 2026). Week 52 data from part 1b, presented at ASH on December 6, 2025, showed that 61.9% of continuously treated patients had avoided phlebotomy eligibility from baseline through week 52, that 77.9% of placebo patients who crossed over at week 32 responded during weeks 40 to 52, and that 91% of participants remained on study at week 52, with injection-site reactions in 47.4%, anemia in 25.6% and fatigue in 19.6% over the year. Primary completion was recorded on February 21, 2025; the open-label continuation runs to 156 weeks, with study completion estimated for August 2028.

Regulatory path. Takeda holds worldwide rights, licensed from Protagonist in January 2024. Rusfertide held Orphan Drug and Fast Track designations, received Breakthrough Therapy designation on August 25, 2025, and the New Drug Application, submitted in December 2025, was accepted with Priority Review on March 2, 2026 with a target action date in August 2026. On August 28, 2026 the FDA approved NDA 220605 for Mimrylo (rusfertide acetate) for injection, a new molecular entity, for the treatment of erythrocytosis in adults with polycythemia vera. The indication carries no prior-therapy requirement. Takeda had announced no approval outside the United States as of November 2026; it has started a 9-participant phase 2 study in Japanese adults with polycythemia vera (NCT07648030, began July 14, 2026) and has registered a 24-participant phase 2 study in China (NCT07765602) planned to start in March 2027.

Hereditary hemochromatosis. An open-label, proof-of-concept phase 2 trial (NCT04202965) enrolled 16 adults with HFE-related hemochromatosis on maintenance phlebotomy for 24 weeks of treatment. Mean phlebotomies fell from 2.31 in the 24 weeks before the study to 0.06 during treatment (p<0.0001), 15 of 16 patients were phlebotomy-free, and transferrin saturation dropped within 24 hours of the first dose; the change in liver iron concentration by MRI was not statistically significant (p=0.068). One serious adverse event, a pancreatic adenocarcinoma diagnosed 21 days after the first dose, was judged pre-existing and unrelated (Kowdley et al., Lancet Gastroenterology & Hepatology, 2023;8(12):1118–1128). On November 8, 2022 Protagonist said that plans to start rusfertide studies in additional indications had been deferred in favor of polycythemia vera; no phase 3 trial in hemochromatosis was ever registered, and the company’s 2026 corporate updates no longer list the indication. There is no active clinical development of rusfertide outside polycythemia vera.

Independent assessment. Hematology groups have begun to weigh the approval against the existing cytoreductive options, with one commentary framing the VERIFY result as an incremental benefit assessment (Tefferi et al., American Journal of Hematology, 2026) and a review noting that effects on thrombosis, clonal evolution and disease progression remain to be characterized (Vannucchi et al., Expert Opinion on Pharmacotherapy, 2026).

Common dosage forms

• Mimrylo kit. A single-dose vial of sterile lyophilized powder in strengths of 9.5, 19, 28, 41 or 54 mg of rusfertide (as rusfertide acetate) together with a single-dose prefilled diluent syringe, for subcutaneous injection.
• Investigational presentations. An aqueous solution in a prefilled syringe and the lyophilized powder formulation that became the commercial product, supplied only to trial sites.

Key considerations

• Regulatory status. The FDA Approved status reflects the August 28, 2026 approval of Mimrylo (rusfertide acetate) for injection under NDA 220605 for the treatment of erythrocytosis in adults with polycythemia vera. No other regulator had announced an approval as of November 2026.
• Trial scope. VERIFY demonstrated hematocrit control, fewer phlebotomies and modest improvements in patient-reported fatigue and symptom scores over 32 weeks, with durability through 52 weeks; it was not powered for thrombosis, progression to myelofibrosis or leukemia, or survival. Rusfertide restricts iron supply rather than acting on the JAK2 clone, so it should not be assumed to modify the underlying disease, and no head-to-head comparison with ropeginterferon alfa-2b, ruxolitinib or hydroxyurea exists.
• Safety signals. The label warns of new or worsening thrombocytosis, with platelet counts rising about 31% on average within four weeks, of injection-site reactions in roughly half of treated patients, and of embryo-fetal toxicity based on animal data; anemia occurred in 16% versus 4.1%. The 2021 clinical hold was lifted within a month and the final label reports negative mouse and rat carcinogenicity studies, but multi-year exposure data come from a few dozen patients, so long-term surveillance for malignancy and thrombotic events remains open.
• Iron deficiency is the intended effect. Because the drug works by withholding iron from erythropoiesis, falling ferritin and mean corpuscular volume are expected pharmacology, and the symptoms sometimes attributed to iron deficiency in phlebotomized patients are not necessarily relieved by replacing phlebotomy with a hepcidin mimetic.
• Naming. PTG-300, TAK-121, rusfertide and Mimrylo all refer to the same peptide, and the approved product is the acetate salt. Rusfertide is unrelated to the earlier hepcidin analog LJPC-401 from La Jolla Pharmaceutical, which was tested in hemochromatosis and discontinued, and it is a hepcidin agonist, the opposite pharmacology to the anti-hepcidin agents developed for anemia of inflammation.