Rusfertide
Rusfertide (PTG-300), synthetic cyclic peptide hepcidin mimetic
Written by Aaron CuhaReviewed Sep 2026
Also known as: PTG-300, Rusfertide acetate, Mimrylo
An 18 residue cyclic peptide that mimics the iron hormone hepcidin, approved by the FDA on 28 August 2026 for erythrocytosis in adults with polycythaemia vera. In the 293 person VERIFY trial, 76.9 percent on rusfertide against 32.9 percent on placebo avoided qualifying for a phlebotomy between weeks 20 and 32.
Overview
Rusfertide is a synthetic, lipidated, disulfide-bridged 18 amino acid peptide that copies the action of hepcidin, the liver hormone that controls how much iron reaches the bloodstream. In polycythaemia vera the bone marrow makes too many red cells; the standard control is repeated phlebotomy, which leaves patients iron deficient. Rusfertide restricts the iron available for red cell production, so the haematocrit falls without bleeding the patient. It was discovered by Protagonist Therapeutics and is sold in the United States by Takeda as Mimrylo, a once-weekly subcutaneous injection.
The pivotal evidence is VERIFY (NCT05210790), a randomised, double-blind, placebo-controlled phase 3 in 293 adults with polycythaemia vera who still needed frequent phlebotomies despite standard care. The peer-reviewed publication of VERIFY could not be located in PubMed on 11 September 2026, so the numbers below come from section 14 of the FDA label. Between weeks 20 and 32, 113 of 147 (76.9 percent) on rusfertide were free of phlebotomy eligibility against 48 of 146 (32.9 percent) on placebo, a risk difference of 43.8 percentage points (95 percent CI 33.5 to 54.2). Mean phlebotomies over 32 weeks were 0.53 against 1.82. Haematocrit stayed below 45 percent throughout in 62.6 percent against 14.4 percent. The one patient-reported outcome, PROMIS fatigue, improved by 1.98 points more than placebo (95 percent CI 0.25 to 3.71, P equals 0.0252), a statistically significant but numerically small change on a T-score scale. Earlier, the 70 person REVIVE phase 2 (New England Journal of Medicine, 2024) showed the same pattern: phlebotomies fell from 8.7 per year to 0.6 during 28 weeks of open-label dosing, and in a 12 week randomised withdrawal 60 percent on rusfertide against 17 percent on placebo kept a response.
Adverse reactions from the label, weeks 0 to 32: injection site reactions in 56 percent against 33 percent on placebo, anaemia in 16 percent against 4.1 percent, thrombocytosis in 8 percent against 0.7 percent, dyspnoea in 8 percent against 1.4 percent. Dose reductions for adverse reactions in 11 percent, mostly for anaemia. The label carries warnings for new or worsening thrombocytosis and for injection site reactions. Across the study 285 people were exposed for a median 61 weeks.
Regulatory position: FDA approved 28 August 2026, NDA 220605, as a new molecular entity, for the treatment of erythrocytosis in adults with polycythaemia vera. Drugs@FDA lists the marketing status as Prescription. No MHRA, TGA or Health Canada record was located.
Mechanism of action
Hepcidin binds ferroportin, the only known cellular iron exporter, and causes it to be internalised and degraded. That traps iron inside gut cells and macrophages and lowers serum iron, so the marrow has less iron to build haemoglobin. Rusfertide mimics hepcidin at ferroportin; the FDA label describes the mechanism as inhibition of ferroportin that reduces iron availability for red blood cell production, lowering haematocrit. In VERIFY, mean ferritin rose from 21 mcg per litre at baseline to 124 at week 32 and 174 at week 52 in treated patients, which is the iron that would otherwise have gone into red cells. What it does not do: rusfertide has no action on the JAK2 mutant clone that drives polycythaemia vera. It manages the red cell consequence of the disease. The 2026 Blood Reviews review of the hepcidin-ferroportin axis makes the same point, describing the evidence as based on surrogate haematological endpoints with the effect on thrombosis and disease trajectory undefined. Human pharmacokinetics from the label: absolute subcutaneous bioavailability about 51 percent, median peak at 24 hours, mean elimination half-life 28.6 hours (plus or minus 11.3), protein binding above 99 percent, catabolised to smaller peptides. Steady state after about 3 weekly doses. A thorough QT study in 60 healthy volunteers found no clinically relevant effect on the QTc interval.
Human evidence
One randomised, double-blind, placebo-controlled phase 3 of 293 people (VERIFY, 32 week blinded period, reported so far only on the FDA label), one randomised-withdrawal phase 2 of 70 people published in the New England Journal of Medicine, an open-label phase 2 of 20, a haemochromatosis phase 2 of 16, and phase 1 pharmacology in healthy volunteers. All sponsor funded. Total exposure in the pivotal trial was 285 people for a median 61 weeks.
- VERIFY (label data): 293 adults, mean age 57, 73 percent male, 89 percent White, all still phlebotomy dependent despite standard care (45 percent on phlebotomy alone, 39 percent also on hydroxyurea, 13 percent also on interferon). Response weeks 20 to 32: 76.9 against 32.9 percent. 91.2 percent completed week 32.
- VERIFY secondary endpoints: 0.53 against 1.82 phlebotomies over 32 weeks; haematocrit maintained below 45 percent in 62.6 against 14.4 percent; PROMIS fatigue T-score difference 1.98 points in favour of rusfertide, statistically significant and small.
- VERIFY safety, weeks 0 to 32, 145 against 146: injection site reactions 56 against 33 percent (grade 3 in 0.7 percent), anaemia 16 against 4.1 percent, thrombocytosis 8 against 0.7 percent, dyspnoea 8 against 1.4 percent. Permanent discontinuations for injection site reactions 2, thrombocytosis 2, anaemia 1.
- REVIVE phase 2: 70 enrolled, phlebotomies fell from 8.7 to 0.6 per year in the open-label part; randomised withdrawal in 59, response 60 against 17 percent. Symptom scores fell in people with moderate or severe baseline symptoms, an uncontrolled within-group observation.
- Open-label phase 2 in 20 people with haematocrit above 48 percent: 85 percent below 45 percent by week 8; 7 of 20 discontinued over 52 weeks.
- Haemochromatosis phase 2 in 16: phlebotomy-free in 15 of 16 over 24 weeks; liver iron did not fall significantly. Not the approved indication.
- Thorough QT study in 60 healthy volunteers: no clinically relevant QTc effect.
What this does not tell you: The primary endpoint is avoidance of phlebotomy eligibility, a management surrogate. VERIFY was not designed to, and did not, show any reduction in thrombosis, progression to myelofibrosis or acute leukaemia, or death, which are the outcomes that matter most in polycythaemia vera. The blinded comparison is 32 weeks. The trial population was 89 percent White and 73 percent male. The fatigue result is real but about 2 points on a T-score scale. The phase 3 has not yet appeared in a peer-reviewed journal, so the label is the only detailed source and it was written by the sponsor and reviewed by the FDA rather than by independent referees. Anaemia in 16 percent shows that a drug which restricts iron can overshoot.
Reading the research record
Rusfertide reached approval on a clean and conventional path: a venture-backed originator (Protagonist) ran the phase 1 and phase 2 work and the phase 3, and a large company (Takeda) holds the US application. Every study on this page was paid for by one of them and the Leukemia Research and Clinical Therapeutics papers have Protagonist employees as authors, all of which is disclosed in the papers. That is how new drugs are made and it is not a criticism, but it means there is no independent trial of rusfertide anywhere.
The more important thing to hold in mind is what kind of drug this is. Polycythaemia vera is a clonal blood cancer driven almost always by a JAK2 mutation. Interferon and ruxolitinib act on the clone; phlebotomy and rusfertide act on the red cell count. Rusfertide is, in the phrase used by a 2023 review, a chemical phlebotomy: it does what the needle does without the needle and without the iron deficiency. The 2026 Blood Reviews assessment states the limit precisely, that the evidence rests on surrogate haematological endpoints and the effect on thrombosis and disease course is undefined. A profile that implied disease modification would be wrong. The label's warning about new or worsening thrombocytosis is the other side of the same coin: suppressing red cells does not suppress the clone's platelet output, and 8 percent of treated patients developed thrombocytosis against 0.7 percent on placebo.
The evidence, charted
Fig. 1 · evidence composition
7of 9 citations (78%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2023 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 3 of 4, prescription route in 0, not approved in 1. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Review2026
MIMRYLO (rusfertide) for injection, prescribing information, section 14 Clinical Studies
VERIFY: 293 adults randomised 1:1. Response (no phlebotomy eligibility, weeks 20 to 32) in 113 of 147 (76.9 percent) against 48 of 146 (32.9 percent), risk difference 43.8 percentage points (95 percent CI 33.5 to 54.2), P below 0.0001. Mean phlebotomies 0.53 against 1.82. Haematocrit kept below 45 percent in 62.6 against 14.4 percent. PROMIS fatigue difference minus 1.98 (95 percent CI minus 3.71 to minus 0.25). Injection site reactions 56 against 33 percent, anaemia 16 against 4.1 percent, thrombocytosis 8 against 0.7 percent. The peer-reviewed VERIFY paper was not locatable in PubMed on 11 September 2026.
U.S. Food and Drug Administration, Drugs@FDA label, NDA 220605 - Human2025
A Phase 3 Study of Rusfertide in Patients With Polycythemia Vera (VERIFY)
Phase 3, 293 participants, sponsor Protagonist Therapeutics. Primary completion 21 February 2025; status active, not recruiting, with open-label treatment continuing to week 156. No results posted on the registry as of 11 September 2026.
ClinicalTrials.gov - Human2024
Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera
REVIVE phase 2: 70 enrolled in a 28 week open-label dose-finding part, then 59 randomised 1:1 to rusfertide (30) or placebo (29) for a 12 week withdrawal period. Estimated phlebotomies fell from 8.7 per year before treatment to 0.6 during part 1; response in the withdrawal period 60 percent against 17 percent (P equals 0.002). Grade 3 adverse events in 13 percent, no grade 4 or 5; grade 1 to 2 injection site reactions common. Funded by Protagonist Therapeutics.
New England Journal of Medicine - Human2025
Rusfertide rapidly decreases hematocrit in patients with suboptimally controlled polycythemia vera
Open-label phase 2 in 20 patients with baseline haematocrit above 48 percent, dosed 40 mg twice weekly then weekly. By week 8, 17 (85 percent) reached haematocrit below 45 percent, median time 4.9 weeks; no phlebotomies during treatment. 7 of 20 discontinued; 85 percent had treatment-emergent adverse events, mostly grade 1 to 2. Several authors are Protagonist employees and the investigators received Protagonist funding.
Leukemia Research - Human2023
Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial
16 adults with hereditary haemochromatosis on maintenance phlebotomy received 24 weeks of rusfertide; 12 completed. Phlebotomies fell from 2.31 in the 24 weeks before to 0.06 during treatment (P below 0.0001), 15 of 16 were phlebotomy-free. Liver iron concentration did not change significantly (1.4 to 1.1 mg per g, P equals 0.068). No primary endpoint was prespecified. Sponsor funded; a different disease from the approved indication.
Lancet Gastroenterology and Hepatology - Human2025
Evaluation of Rusfertide, a Hepcidin Mimetic, on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled Crossover Thorough QT Study in Healthy Participants
60 healthy adults, 90 mg rusfertide against placebo and moxifloxacin. Placebo-corrected QTc change ranged minus 2.0 to 1.8 ms and an effect above 10 ms was excluded up to about 2,130 ng per mL. 40 percent had mild treatment-emergent adverse events. Sponsored and funded by Protagonist.
Clinical Therapeutics - Human2024
Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers
Randomised open-label crossover in healthy adults, 10 to 60 mg. Median time to peak 24 hours at 10 to 30 mg and 2 to 4 hours at 45 to 60 mg; mean terminal half-life 19.6 to 57.1 hours; dose-related falls in serum iron and transferrin saturation. Injection site erythema and pruritus were the treatment-related adverse events in 10 percent or more.
Drugs in R and D - Review2026
Targeting the hepcidin-ferroportin axis in polycythemia vera: a complementary approach to clone-directed therapies
States that current evidence for rusfertide is largely based on surrogate haematological endpoints and that whether iron-directed strategies reduce thrombotic risk or modify disease trajectory remains undefined.
Blood Reviews - Human2026
Study to Evaluate the Long-term Safety of Rusfertide (PTG-300) in Subjects With Polycythemia Vera
Open-label phase 3 extension for 46 people rolling over from phase 2 studies; active, not recruiting; primary completion April 2026; no results posted. Further phase 2 trials in Japan (NCT07648030, 9 participants, recruiting) and China (NCT07765602, 24, not yet recruiting) are registered.
ClinicalTrials.gov
Frequently asked questions
What is rusfertide and what is it approved for?
A synthetic 18 amino acid cyclic peptide that mimics hepcidin, the hormone that controls iron release into the blood. The FDA approved it on 28 August 2026 as Mimrylo for erythrocytosis (excess red cells) in adults with polycythaemia vera. It is a once-weekly subcutaneous injection.
How well did it work in the phase 3 trial?
In VERIFY, 293 people who still needed frequent phlebotomies despite standard care were randomised to rusfertide or placebo. Between weeks 20 and 32, 76.9 percent on rusfertide avoided qualifying for a phlebotomy against 32.9 percent on placebo. Mean phlebotomies over 32 weeks were 0.53 against 1.82. The trial was funded by the manufacturer and the results so far are published only on the FDA label.
Does it reduce blood clots or change the course of the disease?
That has not been shown. VERIFY measured haematocrit control and phlebotomy need, not thrombosis, progression to myelofibrosis or survival, and it was not designed to. Rusfertide does not act on the JAK2 mutant clone that drives polycythaemia vera; it controls the red cell count.
What are the side effects?
Injection site reactions in 56 percent against 33 percent on placebo, anaemia in 16 percent against 4 percent, raised platelets in 8 percent against under 1 percent, and breathlessness in 8 percent against 1.4 percent, over 32 weeks. About 11 percent needed a dose reduction, mostly for anaemia. The label warns about new or worsening thrombocytosis.
Can it treat iron overload or haemochromatosis?
A 16 person open-label phase 2 in hereditary haemochromatosis found that 15 of 16 went without phlebotomy for 24 weeks, but liver iron did not fall significantly and there was no control group. It is not approved for that use anywhere.