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Rusfertide

A synthetic peptide that mimics hepcidin, the liver hormone that controls iron. Discovered by Protagonist Therapeutics and sold by Takeda as Mimrylo, it was FDA-approved on August 28, 2026 to treat erythrocytosis (too many red blood cells) in adults with polycythemia vera. Given as a once-weekly injection, it limits the iron available to make red cells, so most patients no longer need regular phlebotomies.

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TL;DR

Rusfertide (brand name Mimrylo) is a weekly injection for polycythemia vera, a blood cancer that makes too many red blood cells. It copies hepcidin, the body's iron-control hormone, and cuts off the iron the bone marrow needs to make red cells. In its main trial most patients no longer needed blood removed (phlebotomy) to keep their blood counts safe. Common side effects are injection-site reactions, low red-cell counts and rising platelet counts.

What is Rusfertide?

Rusfertide (development code PTG-300; brand name Mimrylo) is a 17-amino-acid synthetic peptide built to act like hepcidin, the hormone the liver uses to switch off iron supply to the blood. The FDA approved it on August 28, 2026, to Takeda Pharmaceuticals America, for the treatment of erythrocytosis in adults with polycythemia vera (PV). It is the first approved PV treatment that mimics hepcidin. PV is a chronic blood cancer, a myeloproliferative neoplasm, in which JAK2-driven bone marrow makes too many red blood cells. Uncontrolled hematocrit (the share of blood volume that is red cells) raises the risk of stroke, deep-vein thrombosis, pulmonary embolism and cardiovascular death, and the standard goal is to keep it below 45%. The main tool has long been phlebotomy, removing blood by needle, often every few weeks, sometimes combined with drugs that suppress the marrow such as hydroxyurea, interferon or ruxolitinib. Phlebotomy works by draining the body's iron, which commonly leaves patients iron-deficient; VERIFY patients started with a mean ferritin of just 21 mcg/L. Rusfertide takes a different route to the same goal. Like hepcidin, it shuts down ferroportin, the channel that releases iron from gut cells and recycling macrophages into the blood, so the marrow gets less iron and makes fewer red cells. Researchers have called it a 'chemical phlebotomy'. In the Phase 3 VERIFY trial (293 adults who still needed frequent phlebotomies despite standard care), 76.9% of patients on rusfertide had no phlebotomy eligibility during weeks 20–32, against 32.9% on placebo. The label's starting dose is 19 mg injected under the skin once a week, adjusted between 9.5 mg and 108 mg to keep hematocrit below 45%. Protagonist Therapeutics discovered and developed it through Phase 3, and Takeda now holds worldwide rights. It does not treat the underlying cancer clone, and it has not been shown to reduce clots or slow disease progression. 'Rusfertide' sold online as a research peptide is not Mimrylo.

What Rusfertide Is Investigated For

Rusfertide has one approved use: controlling erythrocytosis in adults with polycythemia vera. The evidence for that use is strong. In the Phase 2 REVIVE trial (NEJM 2024), phlebotomies fell from an estimated 8.7 a year before treatment to 0.6 a year on rusfertide. In its randomized withdrawal phase, 60% of patients kept on rusfertide still responded, against 17% switched to placebo. The Phase 3 VERIFY trial randomized 293 phlebotomy-dependent adults to rusfertide or placebo on top of their usual care, which included phlebotomy alone or with hydroxyurea, interferon or ruxolitinib. It met its primary endpoint: 76.9% vs 32.9% had no phlebotomy eligibility during weeks 20–32. It also met its key secondary endpoints, including fewer phlebotomies (0.53 vs 1.82 on average through week 32), more patients keeping hematocrit below 45% (62.6% vs 14.4%) and a modest improvement in fatigue. The caveats matter. Hematocrit control is a surrogate. The CYTO-PV trial showed that keeping hematocrit below 45% cuts cardiovascular death and major clots, but rusfertide itself has not yet been shown to reduce clots, prolong life or slow progression to myelofibrosis or leukemia. It is not cytoreductive and does not target the JAK2-mutant clone, and platelet counts commonly rise on treatment. Use outside PV, such as in hereditary hemochromatosis, rests on a 16-patient open-label study and is not approved.

Erythrocytosis in adults with polycythemia vera (FDA-approved August 28, 2026)
Strong90%
Fewer phlebotomies: 0.53 vs 1.82 on average over 32 weeks in VERIFY
Strong90%
First approved hepcidin mimetic — a non-cytoreductive way to control hematocrit
Strong90%
PV-related fatigue (improved vs placebo on PROMIS Fatigue in VERIFY)
Moderate70%
Hereditary hemochromatosis (small open-label Phase 2 only; not approved)
Preliminary30%

History & Discovery

The idea behind rusfertide comes from two decades of hepcidin biology. Hepcidin was identified in 2000–2001, and in 2004 Elizabeta Nemeth, Tomas Ganz, Jerry Kaplan and colleagues showed it controls iron by binding ferroportin and triggering its destruction. Native hepcidin is a 25-amino-acid peptide with four disulfide bonds, and it is hard to make and has poor drug-like properties. In 2011 Ganz and Nemeth's UCLA group showed that hepcidin's 7–9 N-terminal amino acids were enough to keep its activity, and designed 'minihepcidins' that lowered iron in mice (Preza et al., JCI). In 2016 a minihepcidin normalized hematocrit in mice carrying the JAK2 mutation that causes PV (Casu et al., Blood), which made the case for hepcidin agonists in polycythemia vera. Protagonist Therapeutics, a peptide company in Newark, California, developed its own hepcidin mimetic, PTG-300, later named rusfertide, and selected it for development in PV in 2017. It also ran Phase 2 studies in β-thalassemia (TRANSCEND) and hereditary hemochromatosis. The Phase 2 REVIVE trial in PV began in October 2019. In September 2021 the FDA placed all rusfertide trials on clinical hold after a 26-week transgenic (rasH2) mouse study showed benign and malignant skin tumors. Protagonist re-examined the four cancer cases seen among more than 160 trial patients, found no new signals, added safety rules, and the hold was lifted on October 11, 2021. The Phase 3 VERIFY trial started in 2022. REVIVE was published in NEJM in February 2024, the same period in which Takeda partnered on the drug. VERIFY met its primary endpoint and all four key secondary endpoints in March 2025 and was presented as a plenary at ASCO 2025. The NDA was submitted in December 2025 and accepted with Priority Review. The drug also held Breakthrough Therapy, Orphan Drug and Fast Track designations. In April 2026 Protagonist exercised its opt-out, which gave Takeda exclusive worldwide development and commercialization rights and triggered a $200 million payment; a further $200 million opt-out payment and a $75 million milestone were tied to FDA approval. The FDA approved Mimrylo on August 28, 2026, to Takeda Pharmaceuticals America, for the treatment of erythrocytosis in adults with PV. It was the first approved PV treatment that mimics hepcidin. Takeda has said it is working with regulators outside the US, and Phase 2 rusfertide studies are listed for Japan and China. Protagonist is now developing an oral small-molecule hepcidin functional mimetic, PN-8047, with Phase 1 planned for early 2027.

How It Works

Red blood cells need iron. Your body controls how much iron reaches the bone marrow with a liver hormone called hepcidin, which closes the 'iron doors' (a protein called ferroportin) on gut cells and on the cells that recycle iron from old red blood cells. In polycythemia vera, a mutation makes the marrow pump out too many red cells, and hepcidin is too low to slow it down. Rusfertide is a lab-made copy of hepcidin's action. It closes those iron doors, so less iron reaches the marrow and fewer red cells are made. The result is like a phlebotomy done with chemistry instead of a needle, and the iron stays in storage instead of being thrown away.

Hepcidin regulates iron by binding ferroportin, the cellular iron exporter, and triggering its internalization and degradation (Nemeth et al., Science 2004). With ferroportin gone, gut cells cannot pass dietary iron into the blood and liver and spleen macrophages cannot release the iron they recycle, so plasma iron falls and less iron reaches the developing red cells. In polycythemia vera, JAK2-driven erythropoiesis carries on despite low systemic iron, and hepcidin levels are relatively low (Kremyanskaya et al., Blood 2026). Phlebotomy then leaves many patients iron-deficient. Handa and colleagues called this the 'irony' of PV: patients are iron-deficient and erythrocytotic at the same time. The approach rests on the fact that erythrocytosis in PV, although driven by constitutive JAK2 signaling, still depends on iron availability (Costa et al., Blood Rev 2026). Rusfertide is a disulfide-cyclized 17-residue peptide amide (S6,S16-cyclo[N-isovaleryl-Asp-Thr-His-Phe-Pro-Cys-Ile-Lys(Nε-palmitoyl-γ-Glu)-Phe-Glu-Pro-Arg-Ser-Lys-Gly-Cys-Lys-NH2], molecular weight about 2,442). Its first five residues (Asp-Thr-His-Phe-Pro) match the start of human hepcidin-25. Academic work on 'minihepcidins' showed that hepcidin's 7–9 N-terminal amino acids are the minimal structure that retains ferroportin-degrading activity (Preza et al., JCI 2011). Rusfertide adds a palmitoyl-γ-glutamyl fatty-acid side chain on lysine 8, and the drug is more than 99% bound to plasma proteins. The label describes the mechanism simply: rusfertide mimics hepcidin and blocks ferroportin, reducing the iron available for red-cell production. Pharmacology from the label: after a subcutaneous dose, absorption is slow, with peak levels at a median of 24 hours and about 51% bioavailability. The half-life is about 29 hours, and steady state comes after about three weekly doses. Serum iron reaches its lowest point 24–48 hours after a dose, with longer suppression at higher doses. Rusfertide is broken down by trypsin-like proteases and hydroxylation into smaller peptides, two of which (M4 and M9) keep partial activity. It does not inhibit or induce CYP enzymes and is not a substrate or inhibitor of the major drug transporters. Kidney function (including eGFR below 30) and moderate liver impairment did not meaningfully change exposure, and a thorough QT study found no clinically significant QTc prolongation. Because rusfertide works on iron supply rather than on the malignant clone, it is not cytoreductive. It lowers red-cell output, but platelets tend to rise, which the label lists as a warning.

Evidence Snapshot

Overall Confidence80%

Human Clinical Evidence

Strong for hematocrit control in polycythemia vera. REVIVE (Phase 2, NEJM 2024; 70 patients in the dose-finding phase, 59 in a randomized withdrawal) showed phlebotomies falling from about 8.7 a year to 0.6 a year, with 60% vs 17% response in the withdrawal phase. PACIFIC (Phase 2, 20 patients starting with hematocrit above 48%) brought 85% below 45% by week 8 without phlebotomy. VERIFY (Phase 3, 293 patients, double-blind, placebo-controlled) met its primary endpoint (76.9% vs 32.9% response, weeks 20–32) and its key secondary endpoints. Evidence is limited to surrogate endpoints. No outcomes trial has measured clots, survival or progression.

Animal / Preclinical

Supportive. Rationally designed minihepcidins lowered serum iron and liver iron in mice (Preza et al., JCI 2011). In mice carrying the orthologous JAK2 mutation that causes human PV, a minihepcidin normalized hematocrit and reduced spleen enlargement (Casu et al., Blood 2016). Rusfertide's own nonclinical package found embryo-fetal toxicity in rats and rabbits and no carcinogenicity in the final 6-month transgenic mouse and 2-year rat studies.

Mechanistic Rationale

Very strong. The hepcidin-ferroportin axis is one of the best-defined hormone–receptor systems in physiology, and red-cell production depends on iron supply even when it is driven by a JAK2 mutation. Restricting iron, which phlebotomy does crudely, is already the backbone of PV care; rusfertide does it pharmacologically without removing iron from the body.

Research Gaps & Open Questions

What the current literature has not yet settled about Rusfertide:

  • 01Clinical outcomes. Rusfertide controls hematocrit, and CYTO-PV links hematocrit below 45% to fewer cardiovascular deaths and clots, but no trial has shown that rusfertide itself reduces thrombosis, improves survival or changes progression to myelofibrosis or leukemia.
  • 02Platelets. About a third of patients go above 600 × 10⁹/L. Whether the sustained rise matters for clotting or bleeding risk in PV, and how best to manage it alongside cytoreductive drugs, needs long-term data.
  • 03Long-term safety beyond the roughly 61-week median exposure in VERIFY, including malignancy surveillance after the 2021 mouse-study hold, is being followed in the extension and the THRIVE long-term study.
  • 04Immunogenicity. 34% developed anti-drug antibodies and 12% of those cross-reacted with natural hepcidin. Whether this has any effect on the body's own iron regulation after years of treatment, or after stopping, is unknown.
  • 05Where it fits. Head-to-head or sequencing data against or alongside interferon, hydroxyurea and ruxolitinib, and its value in low-risk patients currently managed with phlebotomy alone, have not been tested in dedicated trials.
  • 06Competing hepcidin-pathway approaches. Two other hepcidin-pathway agonists, divesiran and sapablursen, are in clinical development for PV, and Protagonist's oral small-molecule hepcidin functional mimetic PN-8047 is heading to Phase 1. How these will compare with weekly rusfertide injections is unknown.
  • 07Other iron disorders. Hereditary hemochromatosis (one 16-patient open-label study) and β-thalassemia (Phase 2 TRANSCEND) remain unproven indications.

Forms & Administration

Mimrylo is a sterile, preservative-free lyophilized powder in single-dose vials (9.5, 19, 28, 41 and 54 mg), each packed with a prefilled diluent syringe and vial adapter. The powder is reconstituted by injecting the diluent into the vial and swirling gently (not shaking), then used within 4 hours. It is injected subcutaneously into the abdomen (at least 2 inches from the navel) or the front of the thigh. The outer upper arm can be used only when a caregiver gives the injection. Sites should be rotated, and no more than two injections should be given in one day. Vials are stored at room temperature (20–25°C) in the carton to protect them from light, and must not be frozen. Patients or caregivers are trained by the healthcare team before injecting at home. It is a prescription medicine started by a hematologist. Research-chemical 'rusfertide' is not this product.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

Typical Range

Label starting dose: 19 mg by subcutaneous injection once a week. The labeled range is 9.5 mg to 108 mg a week, adjusted in fixed steps (9.5 → 19 → 28 → 41 → 54 → 69 → 82 → 95 → 108 mg) to bring or keep hematocrit below 45%.

Frequency

Once weekly. Weekly doses above 54 mg are given as two injections (on the same day up to 82 mg). Doses above 82 mg are split, with the first injection on day 1 and the second on day 4 or 5. No more than two injections a day.

Timing Considerations

No specific timing requirements: can be administered at any time of day, with or without food, and is not tied to exercise timing. Consistency matters more than the specific clock — dose at roughly the same time each day (or same day each week, for weekly protocols) to keep exposure steady.

Cycle Length

Continuous, indefinite therapy; rusfertide is not cycled. In VERIFY the randomized phase ran 32 weeks, followed by open-label treatment to week 52 and an extension to week 156. In the earlier REVIVE trial, patients switched to placebo mostly lost hematocrit control within the 12-week withdrawal period (17% still responding vs 60% on rusfertide).

Protocol Notes

What follows is the FDA label's dosing, used under the supervision of a hematologist. It is not a self-dosing protocol. Dose increases are considered only after at least 2 weeks at the current dose, with at least 2 weeks between increases. A complete blood count is checked every 2–4 weeks, or as clinically indicated, after starting and during dose changes, because the dose has two failure modes: too little leaves hematocrit high, and too much causes anemia. For grade 2 or worse anemia, or for drug-related grade 3 or worse side effects, the dose drops one step. A patient who needs a reduction while already at 9.5 mg stops treatment. Missed doses on weekly dosing: if 1–4 days late, inject right away and keep the usual schedule; if more than 4 days late, inject right away, take the next dose 3 days later, then resume the usual schedule. Twice-weekly dosing has its own shorter rules in the label. Each vial is reconstituted with its prefilled diluent and must be used within 4 hours. Platelet counts often rise in the first 8 weeks, so the prescriber may need to adjust other PV medicines. In VERIFY, rusfertide was given on top of phlebotomy-based care and, for many patients, hydroxyurea, interferon or ruxolitinib.

Mimrylo is approved only for erythrocytosis in adults with polycythemia vera, with hematocrit-guided titration and regular blood counts. It has no approved use in healthy people, athletes, children or hemochromatosis, and in anyone without PV its expected effect is iron-restricted anemia. Pregnancy should be excluded before starting, and effective contraception used during treatment and for 30 days afterward.

Timeline of Effects

Onset

Serum iron drops within 24–48 hours of a dose. Hematocrit falls over weeks rather than days, because only new red-cell production is restricted. In the PACIFIC study, patients starting with hematocrit above 48% on a higher twice-weekly starting regimen (40 mg) reached hematocrit below 45% after a median of 4.9 weeks, and 85% got there by week 8. Under the label's 19 mg weekly start with gradual titration, VERIFY allowed 20 weeks for dose-finding before the response window began.

Peak Effect

VERIFY measured response during weeks 20–32, once doses had been titrated: 76.9% of rusfertide patients had no phlebotomy eligibility in that window, against 32.9% on placebo. Mean hematocrit change stayed at or below zero on rusfertide through week 32 while it rose on placebo. When the placebo group switched to rusfertide after week 32, their hematocrit fell rapidly. Iron stores keep rebuilding over the first year (mean ferritin 124 mcg/L at week 32 and 174 mcg/L at week 52), and platelet increases usually level off by week 8.

After Discontinuation

Rusfertide does not change the disease; it only holds back iron supply while it is being taken. Its half-life is about 29 hours, so iron restriction fades within days to weeks of the last dose. In REVIVE's randomized withdrawal, only 17% of patients switched to placebo kept their response over 12 weeks, against 60% who stayed on rusfertide. Because iron stores rebuild during treatment, it is reasonable to expect red-cell production to recover once the drug stops. Anyone stopping should be monitored by their hematologist and may need phlebotomy again.

Monitoring & Measurement

Bloodwork & Labs

  • •Complete blood count — hematocrit and hemoglobin (efficacy and anemia), platelet count (thrombocytosis warning) and white cells; every 2–4 weeks after starting and during dose changes, per the label
  • •Ferritin and iron studies, which typically rise from iron-deficient baselines as iron stores rebuild
  • •Pregnancy test before starting in anyone who could become pregnant

Functional & Performance Tests

  • •Count of phlebotomies needed, the outcome VERIFY was built around
  • •Fatigue and symptom scores (VERIFY used PROMIS Fatigue Short Form 8a and the MFSAF symptom form)
  • •Injection-site check at each injection, rotating sites

When to Test

CBC every 2–4 weeks, or as clinically indicated, from the start of treatment and through each dose change; dose increases at least 2 weeks apart. Platelets usually plateau by week 8. Once the dose is stable, monitoring follows the hematologist's routine PV schedule.

Interpretation & Notes

Success is a hematocrit kept below 45% without phlebotomy, and VERIFY's definition of phlebotomy eligibility is a useful benchmark. Patients counted as needing phlebotomy if hematocrit was confirmed at 45% or higher and at least 3 percentage points above baseline, or was 48% or higher. Watch the platelet count as closely as the hematocrit, because platelet rises are the label's main warning and may change the rest of the treatment plan. A falling hemoglobin with symptoms such as breathlessness or fatigue suggests the dose is too high. Breathlessness (dyspnea) was also reported more often than on placebo.

Common Questions

What is Mimrylo (rusfertide) used for?

Mimrylo is FDA-approved, as of August 28, 2026, to treat erythrocytosis (too many red blood cells) in adults with polycythemia vera. In the trial that supported approval, patients were already on standard care and still needed frequent phlebotomies (at least 3 in the previous 28 weeks or 5 in a year). Rusfertide was added to whatever they were already taking, phlebotomy alone or phlebotomy plus hydroxyurea, interferon or ruxolitinib. It is not approved for children or for any other condition.

How does rusfertide work? (Mimrylo mechanism of action)

Rusfertide is a hepcidin mimetic. Hepcidin is the liver hormone that turns down iron supply. It binds ferroportin, the channel that lets iron out of gut cells and out of the macrophages that recycle iron from old red cells, and makes the cell pull ferroportin in and destroy it. In polycythemia vera, hepcidin levels are relatively low and the JAK2-driven marrow keeps making red cells as long as iron is available. Rusfertide does hepcidin's job at a higher, steady level. Serum iron falls within 24–48 hours of a dose, the marrow gets less iron, red-cell production slows and hematocrit comes down. Meanwhile iron that would have gone to the marrow builds up in storage, so ferritin rises. In VERIFY, mean ferritin rose from 21 mcg/L at baseline to 174 mcg/L at week 52.

What are the side effects of rusfertide?

In VERIFY's 32-week placebo-controlled phase, the most common side effects were injection-site reactions (56% vs 33% on placebo), mostly redness, itching, pain and swelling, and almost all mild to moderate. Anemia occurred in 16% vs 4.1%, because the drug can restrict red-cell production too much, and it was the most common reason for lowering the dose. Thrombocytosis (high platelets) occurred in 8% vs 0.7%, and shortness of breath in 8% vs 1.4%. The label has three warnings. Platelets rise by an average of 31% within 4 weeks; 36% of patients went above 600 × 10⁹/L and 6% above 1,000 × 10⁹/L. Injection-site reactions occurred, including two grade 3 cases. And animal studies point to possible harm to a fetus. There is no boxed warning and no listed contraindication.

What is the dose of Mimrylo?

Under the FDA label, treatment starts at 19 mg by subcutaneous injection once a week. A hematologist then adjusts the dose in steps (9.5, 19, 28, 41, 54, 69, 82, 95 or 108 mg a week) to keep hematocrit below 45%, waiting at least 2 weeks between increases and checking a complete blood count every 2–4 weeks while adjusting. Weekly doses above 54 mg are given as two injections, and doses above 82 mg are split between day 1 and day 4 or 5. The dose is lowered for grade 2 or worse anemia or grade 3 or worse drug-related side effects. This is label dosing that a prescriber individualizes; it is not something to self-manage.

Does rusfertide replace phlebotomy, hydroxyurea or interferon?

It replaces most phlebotomies for most patients, but in the trial it was added to existing therapy, not used instead of it. In VERIFY, patients averaged 0.53 phlebotomies over 32 weeks on rusfertide against 1.82 on placebo, and 76.9% had no phlebotomy eligibility during weeks 20–32. Rusfertide is not a cytoreductive drug. It controls red cells by restricting iron and does not target the JAK2-mutant clone. Platelets often rise on it, so some patients may need their cytoreductive therapy started or adjusted. Decisions about hydroxyurea, interferon or ruxolitinib still depend on each patient's thrombosis risk and blood counts.

Can I buy rusfertide online as a research peptide?

Not legitimately, and online products are not Mimrylo. Mimrylo is a prescription drug supplied by Takeda as a sterile powder in single-dose vials with a matching diluent. Rusfertide is a 17-amino-acid ring-shaped peptide with a palmitic-acid side chain. Research-chemical sellers' certificates cannot show that a vial holds that exact molecule at the stated dose, sterile and free of harmful by-products. The drug is also only safe with close blood monitoring. It routinely causes anemia when the dose is too high and raises platelet counts, which is why the label calls for a complete blood count every 2–4 weeks while the dose is being adjusted. In someone without polycythemia vera, it would simply starve the marrow of iron. If you have PV, talk to a hematologist about whether Mimrylo fits your treatment plan.

Does rusfertide cause iron deficiency?

Not in the usual sense. Phlebotomy treats PV by draining the body's iron, so many patients start out iron-deficient: VERIFY patients began with a mean ferritin of 21 mcg/L. Rusfertide restricts iron delivery to the marrow instead of removing iron from the body, so iron stores refill (mean ferritin reached 124 mcg/L at week 32 and 174 mcg/L at week 52) while red-cell production stays controlled. The trade-off is that too much effect causes anemia (low hemoglobin). That happened in 16% of patients in the controlled phase and is managed by lowering the dose.

Can rusfertide treat hemochromatosis?

It is not approved for it. Hereditary hemochromatosis is a hepcidin-deficiency disease, so a hepcidin mimetic is a logical idea. In a 16-patient open-label Phase 2 study (Lancet Gastroenterology & Hepatology 2023), patients on weekly rusfertide needed an average of 0.06 phlebotomies over 24 weeks, against 2.31 in the 24 weeks before, and 15 of 16 were phlebotomy-free. That is a proof-of-concept result with no control group, not grounds for treating hemochromatosis outside a trial.

Who Rusfertide Is NOT For

Contraindications
  • •Pregnancy — the label lists no formal contraindications, but animal studies showed malformations and fetal loss at exposures below the human maximum dose. Pregnancy should be excluded before starting, contraception used during treatment and for 30 days after, and treatment stopped if pregnancy occurs.
  • •Breastfeeding — not recommended during treatment and for 30 days after the final dose.
  • •Children and adolescents — safety and effectiveness have not been established.
  • •People without polycythemia vera, including athletes and healthy people — restricting iron supply in a normal marrow produces anemia, with no approved benefit.
  • •Marked existing thrombocytosis — not a formal contraindication, but because rusfertide raises platelets (36% of patients exceeded 600 × 10⁹/L), it needs close CBC monitoring and possibly cytoreductive therapy.
  • •Severe (Child-Pugh C) liver impairment — not studied.

Drug & Supplement Interactions

The label reports no pharmacokinetic drug interactions. In laboratory testing rusfertide does not inhibit the major CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A) or induce CYP1A2, 2B6 or 3A, and it is neither a substrate nor an inhibitor of the common drug transporters (including P-gp, BCRP, OATP1B1/1B3, OAT1/3 and OCT1/2). It is cleared by peptide breakdown, so classic metabolic interactions are not expected. The relevant interactions are with the rest of PV treatment. In VERIFY, rusfertide was added to phlebotomy alone or phlebotomy plus hydroxyurea, interferon or ruxolitinib. Because it raises platelets, the label notes that cytoreductive therapy may need to be started or adjusted. Iron supplements work against the treatment goal. With ferroportin blocked, oral iron absorption is also expected to fall, although this has not been formally studied. Any plan to give iron, oral or intravenous, during rusfertide treatment should be a hematologist's decision. Patients should give their prescriber a full list of medicines and supplements.

Safety Profile

Safety Information

Common Side Effects

Injection-site reactions — 56% vs 33% on placebo (redness 27%, itching 17%, pain 15%, swelling 8%); two grade 3 reactions and two discontinuationsAnemia (low hemoglobin from too much iron restriction) — 16% vs 4.1% on placebo; the main reason for dose reductions (10% of patients)Thrombocytosis / rising platelet count — 8% vs 0.7% reported as an adverse reaction; average platelet rise of 31% within 4 weeksShortness of breath (dyspnea) — 8% vs 1.4% on placebo

Cautions

  • • New or worsening thrombocytosis: 36% of patients exceeded 600 × 10⁹/L and 6% exceeded 1,000 × 10⁹/L. Counts usually plateau by week 8, but the label calls for a CBC every 2–4 weeks during initiation and dose changes, and some patients need cytoreductive therapy started or adjusted
  • • Embryo-fetal toxicity: rat and rabbit studies showed malformations and fetal loss at exposures below the human maximum dose. Pregnancy testing before starting and effective contraception during treatment and for 30 days after are recommended
  • • Breastfeeding is not recommended during treatment and for 30 days after the last dose, partly because of possible impaired iron absorption in the infant
  • • Anti-drug antibodies developed in 34% of VERIFY patients. About a third of those were neutralizing and 12% cross-reacted with natural hepcidin; titers were low and had no apparent effect on efficacy or safety, but long-term meaning is unknown
  • • Not studied in severe (Child-Pugh C) liver impairment; safety and efficacy in children are not established
  • • In September 2021 the FDA briefly placed rusfertide trials on hold after skin tumors appeared in a 26-week transgenic (rasH2) mouse study. The hold was lifted on October 11, 2021, and the final label reports no carcinogenicity in a 6-month transgenic mouse study or a 2-year rat study

What We Don't Know

VERIFY's median exposure was about 61 weeks, so multi-year safety is still being collected in the open-label extension and the THRIVE long-term safety study. The clinical significance of sustained higher platelet counts in a disease already prone to clots is not yet known. Whether rusfertide lowers thrombotic events, changes survival, or affects progression to myelofibrosis or leukemia has not been studied in an outcomes trial. The meaning of cross-reactive antibodies against natural hepcidin over many years of treatment is uncertain.

Myths & Misconceptions

Myth

Rusfertide treats the cancer in polycythemia vera.

Reality

It does not target the JAK2-mutant clone, and it has not been shown to slow the disease. It controls one major consequence of PV, red-cell overproduction, by restricting iron supply. Researchers describe it as a 'chemical phlebotomy' that complements clone-directed therapy rather than replacing it.

Myth

Because it blocks iron, rusfertide makes iron deficiency worse.

Reality

It does the reverse for iron stores. Phlebotomy removes iron from the body; rusfertide keeps iron in storage and away from the marrow. In VERIFY, mean ferritin rose from 21 to 174 mcg/L over a year while hematocrit stayed controlled. The real risk is anemia (low hemoglobin) if the dose is too high, which is why the label requires regular blood counts.

Myth

With rusfertide, nobody with PV needs phlebotomy anymore.

Reality

Most do not, but not all. In VERIFY, 76.9% had no phlebotomy eligibility during weeks 20–32, meaning nearly a quarter still did. Average phlebotomies over 32 weeks fell to 0.53, not zero, and some patients remain better served by other strategies.

Myth

Research-chemical rusfertide sold online is the same as Mimrylo.

Reality

It is not. Mimrylo is a sterile, regulated product with a matched diluent, used with blood counts every 2–4 weeks during dose adjustment. An unverified vial of a cyclized, lipidated 17-residue peptide could be the wrong molecule, the wrong amount or contaminated. In someone without PV, even the real drug would only cause iron-restricted anemia.

Myth

Rusfertide is approved for hemochromatosis because it controls iron.

Reality

Its only approval is for erythrocytosis in adults with polycythemia vera. Hemochromatosis data come from one 16-patient open-label Phase 2 study, which was promising but uncontrolled and is not a basis for routine use.

Published Research

16 studies

Targeting the hepcidin-ferroportin axis in polycythemia vera: a complementary approach to clone-directed therapies (Costa et al., Blood Rev 2026)

A 2026 review that keeps the evidence in proportion. Rusfertide has shown durable hematocrit control and large reductions in phlebotomy across Phase 2 and Phase 3, but the evidence rests largely on surrogate hematologic endpoints. Whether iron-directed treatment reduces thrombotic risk or changes the course of the disease is still undefined, and the authors frame it as complementary to clone-directed therapy.

ReviewPMID: 42660705

Rusfertide rapidly decreases hematocrit in patients with suboptimally controlled polycythemia vera (Chew et al., Leuk Res 2025 — PACIFIC Phase 2)

Clinical TrialPMID: 41175501

Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis (Kremyanskaya et al., Blood 2026)

ReviewPMID: 41100735

Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: A double-blind first-in-human study (Modi et al., Eur J Haematol 2024)

Clinical TrialPMID: 38785334

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera (Kremyanskaya et al., NEJM 2024 — REVIVE Phase 2)

The trial that established hepcidin mimicry as a PV treatment. In 70 phlebotomy-dependent patients, the estimated phlebotomy rate fell from 8.7 a year before treatment to 0.6 a year during the 28-week dose-finding phase, and mean maximum hematocrit fell from 50.0% to 44.5%. In the 12-week randomized withdrawal (59 patients), 60% kept on rusfertide responded, against 17% switched to placebo (P=0.002). No grade 4–5 events occurred, and grade 1–2 injection-site reactions were common.

Randomized Controlled TrialPMID: 38381675

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial (Kowdley et al., Lancet Gastroenterol Hepatol 2023)

Single-arm Phase 2 in 16 adults with HFE hemochromatosis on maintenance phlebotomy. On weekly rusfertide, mean phlebotomies over 24 weeks fell to 0.06, from 2.31 in the 24 weeks before, and 15 of 16 patients were phlebotomy-free. Adverse events were mild or moderate apart from a pre-existing pancreatic cancer judged unrelated. Proof of concept only, with no control arm.

Clinical TrialPMID: 37863080

Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis (Handa et al., Curr Opin Hematol 2023)

ReviewPMID: 36728649

Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera (Casu et al., Blood 2016)

PreclinicalPMID: 27154187

Cardiovascular events and intensity of treatment in polycythemia vera (Marchioli et al., NEJM 2013 — CYTO-PV)

The evidence behind the hematocrit-below-45% target that rusfertide is dosed to. In 365 patients with JAK2-positive PV, a hematocrit target below 45% cut cardiovascular death and major thrombosis to 2.7%, from 9.8% with a 45–50% target (hazard ratio 3.91 for the higher target). Rusfertide trials measure hematocrit control, not these outcomes directly.

Randomized Controlled TrialPMID: 23216616

Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload (Preza et al., JCI 2011)

PreclinicalPMID: 22045566

Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (Nemeth et al., Science 2004)

Landmark MechanismPMID: 15514116

VERIFY: A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera (NCT05210790, ClinicalTrials.gov)

Clinical Trial

MIMRYLO (rusfertide) for injection — US Prescribing Information (DailyMed)

Label

FDA Approves First Drug of Its Kind for Polycythemia Vera, a Rare Blood Disorder (FDA, August 28, 2026)

Regulatory

Protagonist Therapeutics announces removal of FDA clinical hold on the rusfertide clinical development program (October 11, 2021)

Press Release

Protagonist Reports Second Quarter 2026 Financial Results and Provides Corporate Update (SEC Form 8-K Exhibit 99.1, August 5, 2026)

Regulatory Filing

Quick Facts

Class
Hepcidin Mimetic
Tier
B
Evidence
Strong
Safety
Moderate Data
Updated
Oct 2026
Citations
16PubMed

Also known as

MimryloPTG-300Hepcidin mimetic

Tags

FDA-ApprovedHepcidin MimeticPolycythemia VeraHematologyRare DiseaseIron Regulation

Evidence Score

Overall Confidence80%

Clinical Trials

View Clinical Trials

Links to ClinicalTrials.gov for reference. Listing does not imply endorsement.