Rusfertide is a synthetic peptide that mimics hepcidin, the hormone that controls how much iron reaches the bloodstream. By restricting the iron supply to the bone marrow, it limits red blood cell production and lowers hematocrit (the share of blood made up of red cells). It was developed by Protagonist Therapeutics under the code name PTG-300 and is marketed by Takeda as Mimrylo.
The most important fact: the FDA approved Mimrylo on August 28, 2026, for the treatment of erythrocytosis (too many red blood cells) in adults with polycythemia vera (PV), a bone marrow cancer (Drugs@FDA, NDA 220605; Takeda, August 28, 2026). That is its only approved use. It has not been tested in people whose high hematocrit comes from testosterone.
This page summarizes what the FDA label, the clinical trials and the companies’ regulatory announcements report, with status checked as of October 13, 2026. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Hepcidin mimetic; synthetic cyclic peptide |
| Brand / approval | Mimrylo (Takeda), NDA 220605; FDA approval August 28, 2026 (priority review, orphan, new molecular entity) |
| Approved indication | Erythrocytosis in adults with polycythemia vera |
| Route | Subcutaneous injection, once weekly (higher doses split into 2 injections) |
| Strengths | 9.5, 19, 28, 41 and 54 mg single-dose vials |
| Labeled dose | Start 19 mg weekly; range 9.5–108 mg weekly, adjusted to keep hematocrit under 45% |
| Half-life (label) | 28.6 ± 11.3 h after a 19 mg dose in healthy participants |
| Mechanism | Blocks the iron exporter ferroportin, reducing iron available for red cell production |
| US status | Prescription only; the label lists no DEA schedule |
| WADA | Not named on the 2026 Prohibited List |
What it is
Hepcidin is the body’s master iron-regulatory hormone (Kremyanskaya et al., NEJM 2024). It works by binding ferroportin, an iron exporter on the surface of cells that release iron into the blood. In cell-culture work, hepcidin binding caused ferroportin to be pulled inside the cell and degraded, which cut off iron export (Nemeth et al., Science 2004). High hepcidin therefore means less iron in circulation and less iron for making hemoglobin.
Rusfertide copies this action. The label describes it as “a mimetic of the endogenous hormone hepcidin that blocks the iron transporter ferroportin,” which “reduces availability of iron for production of red blood cells resulting in lower hematocrit levels” (FDA label).
Structurally, it is a short synthetic peptide closed into a ring by a disulfide bond, with a palmitoyl (fatty-acid) side chain attached to one lysine. The free base has the formula C₁₁₄H₁₈₁N₂₇O₂₈S₂ and an average molecular weight of 2,442.0. It is supplied as the acetate salt in a freeze-dried powder that is mixed with a supplied diluent before injection (FDA label).
Why an iron blocker for polycythemia vera
PV is a myeloproliferative neoplasm caused by a JAK2 mutation, which drives uncontrolled red blood cell production (Gendrot et al., Blood Cancer J 2026). Keeping hematocrit under 45% is the main treatment goal (Takeda, August 28, 2026). In VERIFY, standard care meant phlebotomy (removing blood) alone or combined with cytoreductive drugs such as hydroxyurea, ruxolitinib or interferon (FDA label). Many PV patients are iron deficient, from repeated phlebotomy and other causes, yet keep overproducing red cells. That functional iron deficiency is linked to fatigue and other symptoms (Gendrot et al., Blood Cancer J 2026).
Rusfertide takes a different route. Instead of removing red cells after they are made, it limits the iron the marrow can use to make them. In VERIFY, mean ferritin (a marker of stored iron) rose from 21 mcg/L at baseline to 124 mcg/L at week 32 and 174 mcg/L at week 52 in patients randomized to rusfertide (FDA label). This is consistent with iron being held in storage rather than used for red cells.
Pharmacokinetics
| Parameter | Value (label) |
|---|---|
| Time to peak (19 mg, healthy) | Median 24 h (range 4–48 h) |
| Absolute bioavailability (subcutaneous) | ≈51% |
| Plasma protein binding | Over 99% |
| Apparent volume of distribution | 38.4 ± 19.1 L |
| Elimination half-life (19 mg, healthy) | 28.6 ± 11.3 h |
| Time to steady state (weekly dosing) | About 3 doses |
| Accumulation at 54 mg weekly | 1.6× for AUC, 1.3× for Cmax |
| Urinary excretion | Below detection limit |
Exposure rises less than proportionally with dose over 9.5–54 mg. Rusfertide is broken down into smaller peptides by proteases and by hydroxylation. Two metabolites, M4 and M9, keep some activity (about 65% and 14% of the parent’s potency). Age, sex, body weight and mild-to-moderate kidney impairment did not change exposure in a clinically meaningful way. Severe kidney impairment and moderate liver impairment also did not change exposure after a 19 mg dose. Severe liver impairment has not been studied (FDA label).
The drug effect lasts beyond a single day. In healthy participants, serum iron fell most 24–48 hours after a single dose, and the 41 mg and 54 mg doses kept it lower for up to 96 hours (FDA label). The first-in-human study, in healthy men, found dose-dependent falls in serum iron and transferrin saturation after single doses of 1–80 mg (Modi et al., Eur J Haematol 2024).
Approved medical use
Indication and labeled dosing
Mimrylo is indicated “for the treatment of erythrocytosis in adults with polycythemia vera” (FDA label). Key points from the label:
- The starting dose is 19 mg by subcutaneous injection once a week.
- The weekly dose range is 9.5–108 mg. Doses above 54 mg need two injections, and doses above 82 mg are split across day 1 and day 4 or 5.
- The dose can be raised one step after at least 2 weeks at the current dose, to reach or hold a hematocrit under 45%.
- The dose is lowered one step for grade 2 or higher anemia or for drug-related grade 3 or higher toxicity. At 9.5 mg weekly, the next step is stopping.
- A complete blood count (CBC) is checked every 2–4 weeks, or as clinically indicated, after starting and during dose changes.
- The label lists no contraindications.
Regulatory history
| Date | Event | Source |
|---|---|---|
| March 2, 2026 | FDA accepted the NDA and granted Priority Review; rusfertide already held Breakthrough Therapy, Orphan Drug and Fast Track designations | Takeda, March 2, 2026 |
| August 28, 2026 | FDA approval of NDA 220605 (Type 1 new molecular entity; priority review; orphan) | Drugs@FDA |
| September 3, 2026 | Current label version published on DailyMed | DailyMed |
Outside the US, Takeda’s approval announcement says only that the company is “working with regulators outside of the U.S.” It names no other approvals (Takeda, August 28, 2026).
What the research shows
All controlled efficacy data come from patients with PV. The published trials below were funded by Protagonist Therapeutics or co-authored by its employees.
VERIFY: the phase 3 trial behind approval
VERIFY was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial in 293 adults with PV (NCT05210790). Patients qualified if they still needed frequent phlebotomy (at least 3 in the prior 28 weeks or 5 in the prior year) despite standard care, which was phlebotomy alone or with cytoreductive drugs. Mean age was 57 years, and 73% were men. Patients received rusfertide or placebo on top of standard care for 32 weeks, starting at 19 mg weekly and titrated to keep hematocrit under 45% (FDA label).
A “response” meant no phlebotomy eligibility between weeks 20 and 32. Phlebotomy eligibility was a confirmed hematocrit of at least 45% that was also at least 3 points above baseline, or any hematocrit of at least 48%.
| Endpoint | Placebo (n = 146) | Rusfertide (n = 147) | Difference (95% CI) |
|---|---|---|---|
| Response, weeks 20–32 | 32.9% | 76.9% | 43.8% (33.5–54.2); p under 0.0001 |
| Mean phlebotomies, weeks 0–32 | 1.82 | 0.53 | −1.29 (−1.59 to −1.00); p under 0.0001 |
| Hematocrit kept under 45%, weeks 0–32 | 14.4% | 62.6% | 48.2% (38.4–57.9); p under 0.0001 |
| Change in PROMIS fatigue score, week 32 | +0.19 | −1.79 | −1.98 (−3.71 to −0.25); p = 0.0252 |
Source: FDA label, Table 5.
Mean hematocrit rose over 32 weeks on placebo but stayed at or below baseline on rusfertide. When placebo patients switched to rusfertide after week 32, their hematocrit fell quickly. The label does not report rates of thrombosis or other hard clinical outcomes.
REVIVE: phase 2
REVIVE enrolled 70 phlebotomy-dependent PV patients in a 28-week open-label dose-finding phase. It was followed by a 12-week double-blind randomized withdrawal phase in 59 of them (Kremyanskaya et al., NEJM 2024).
| Measure | Before rusfertide (28 weeks) | On rusfertide (part 1) |
|---|---|---|
| Estimated phlebotomies per year | 8.7 ± 2.9 | 0.6 ± 1.0 |
| Mean maximum hematocrit | 50.0 ± 5.8% | 44.5 ± 2.2% |
In the randomized withdrawal phase, 60% of patients who stayed on rusfertide responded, compared with 17% switched to placebo (p = 0.002). Grade 3 adverse events occurred in 13% of patients, with no grade 4 or 5 events. Mild-to-moderate injection-site reactions were common.
Patients starting with uncontrolled hematocrit
A separate open-label phase 2 study treated 20 PV patients whose baseline hematocrit was above 48% (mean 51.6%). They received 40 mg twice weekly until hematocrit fell under 45%, then weekly dosing (Chew et al., Leuk Res 2025). By week 8, 85% had a hematocrit under 45%. The median time to first reaching that level was 4.9 weeks, and no patient needed phlebotomy during treatment. This study had no control group, and 7 of 20 patients stopped treatment.
Hereditary hemochromatosis (not an approved use)
Because hepcidin is deficient in HFE-related hemochromatosis, rusfertide was also tested in an open-label phase 2 study of 16 patients on maintenance phlebotomy (Kowdley et al., Lancet Gastroenterol Hepatol 2023). Mean phlebotomies over 24 weeks fell from 2.31 before the study to 0.06 on treatment, and 15 of 16 patients were phlebotomy-free. The study had no primary endpoint and no control group, and rusfertide is not approved for this condition.
Relevance to high hematocrit on testosterone
Readers on testosterone therapy often ask about rusfertide because it lowers hematocrit. What the evidence supports is narrow.
How testosterone raises hematocrit
Erythrocytosis is a well-documented effect of testosterone. The Endocrine Society guideline describes erythrocytosis on testosterone as hematocrit above 54%. It advises withholding testosterone until hematocrit returns to normal and then resuming at a lower dose, and it notes that therapeutic phlebotomy is also effective (Bhasin et al., JCEM 2018). The testosterone cypionate page covers how the size of the rise differs by formulation.
Suppressing hepcidin is one of the ways testosterone raises red cell production, and this is the part that connects to rusfertide:
- Older men, testosterone gel. In a 6-month randomized trial, hemoglobin and hematocrit rose by 7–10%. The rise came with higher erythropoietin and lower ferritin and hepcidin at 1 and 3 months. By 6 months, hepcidin and erythropoietin had drifted back toward baseline while hematocrit stayed raised (Bachman et al., J Gerontol A 2014).
- Young men, testosterone enanthate. In a randomized trial of 50 men given 200 mg/week or placebo during a 28-day severe energy deficit, hepcidin fell by 41% with testosterone compared with placebo (Hennigar et al., JCEM 2020).
- In mice, hepcidin over-expression blunted the effect. Mice engineered to over-express hepcidin in the liver did not show the expected hemoglobin rise with testosterone (Guo et al., Aging Cell 2013).
- In mice, hepcidin was not essential. Testosterone still raised hematocrit in mice lacking hepcidin altogether. The authors concluded that hepcidin suppression “is not essential” for testosterone’s effect on red cell production in healthy mice (Guo et al., Andrology 2020).
So hepcidin suppression is part of the mechanism, alongside a higher erythropoietin set point, but it is not the whole story.
What is not known
- No trials in testosterone users. As of October 13, 2026, every rusfertide study registered on ClinicalTrials.gov is in polycythemia vera or hereditary hemochromatosis. None studies testosterone-related erythrocytosis (ClinicalTrials.gov).
- The approved use is PV only. The label’s dosing, its 45% hematocrit target, and its safety data all come from PV patients (FDA label). PV is a JAK2-driven marrow neoplasm. A 2026 review notes that iron balance in secondary (non-PV) forms of erythrocytosis “has been less often investigated” (Gendrot et al., Blood Cancer J 2026).
- Healthy-volunteer data show only the mechanism. In healthy subjects given 60 mg weekly for 5 weeks, serum iron, transferrin saturation, hemoglobin and hematocrit fell as expected (Modi et al., Clin Pharmacol Drug Dev 2025). That study was not designed to test any clinical benefit.
- The evidence on standard approaches is also thin. A 2024 review argued that evidence on the efficacy and safety of therapeutic phlebotomy for testosterone-induced erythrocytosis is lacking, and that repeated phlebotomy eventually depletes iron stores (Bond et al., Endocr Connect 2024).
Using rusfertide for testosterone-related high hematocrit would be off-label and untested. Whether it is effective or safe in that setting has not been studied.
Side effects and risks
The label has no boxed warning. In the 32-week randomized part of VERIFY, these adverse reactions occurred at least 5 points more often than with placebo (FDA label):
| Adverse reaction | Rusfertide (n = 145) | Placebo (n = 146) |
|---|---|---|
| Injection-site reactions | 56% | 33% |
| Anemia | 16% | 4.1% |
| Thrombocytosis (high platelets) | 8% | 0.7% |
| Dyspnea (shortness of breath) | 8% | 1.4% |
Across 285 patients exposed to rusfertide (median 61 weeks), 11% needed a dose reduction for an adverse reaction, mostly anemia (10%). Permanent discontinuation for injection-site reactions, thrombocytosis or anemia was uncommon, at 0.4–0.7% each.
Rising platelet counts
This is a labeled warning. Within 4 weeks of starting, platelet counts rose by an average of 31%. In 36% of patients they exceeded 600 × 10⁹/L, and in 6% they exceeded 1,000 × 10⁹/L. Counts generally plateaued by week 8. The label advises CBC monitoring every 2–4 weeks after starting and during dose changes, and notes that platelet rises may need changes to cytoreductive therapy or to the rusfertide dose (FDA label).
Injection-site reactions
Injection-site reactions occurred in 47% of rusfertide-treated patients in VERIFY. The most common were redness (27%), itching (17%), pain (15%) and swelling (8%). Two patients had grade 3 reactions, and two (0.7%) stopped treatment because of them (FDA label).
Anemia
Anemia follows from how the drug works. Restricting iron for red cells can push hemoglobin too low. The label handles this through dose reduction at grade 2 or higher anemia (FDA label).
Pregnancy and breastfeeding
In animal studies, rusfertide caused malformations in rats and fetal death in rabbits at exposures below those of the maximum human dose. The label recommends pregnancy testing and effective contraception during treatment and for at least 30 days after the last dose. It advises against breastfeeding for the same period, citing possible impaired iron absorption in the infant (FDA label). In rats, rusfertide had no effect on male or female fertility or sperm parameters.
Antibodies, heart rhythm and interactions
- Anti-drug antibodies. These developed in 34% of VERIFY patients. About a third of those were neutralizing, and 12% cross-reacted with natural hepcidin. Antibodies showed no apparent link to drug levels, efficacy or safety.
- Heart rhythm. No clinically significant QTc prolongation was seen at 1.3 times the peak concentration of the maximum dose.
- Interactions. In laboratory tests, rusfertide did not inhibit or induce the major CYP450 enzymes and was not a substrate or inhibitor of common drug transporters.
Source for all three: FDA label.
Legal status and use outside medicine
In the US, Mimrylo is a prescription drug, and its label lists no DEA controlled-substance schedule (FDA label). Rusfertide is not named on the WADA 2026 Prohibited List.
Key takeaways
- FDA-approved in 2026, for PV only. Mimrylo was approved on August 28, 2026, for erythrocytosis in adults with polycythemia vera, after a priority review.
- It works by restricting iron. As a hepcidin mimetic, rusfertide blocks ferroportin so the marrow has less iron for making red cells.
- Strong phase 3 effect in PV. In VERIFY, 76.9% of patients responded compared with 32.9% on placebo, and phlebotomies fell from 1.82 to 0.53 over 32 weeks.
- Main risks are platelets, anemia and injection sites. Platelets rose about 31% early on, and CBC checks every 2–4 weeks are part of the label.
- Not studied for testosterone-related high hematocrit. Testosterone does suppress hepcidin, but no trial has tested rusfertide in testosterone users. That use would be off-label and of unknown benefit and safety.
Sources
- Takeda Pharmaceuticals America. Mimrylo (rusfertide) for injection, for subcutaneous use, prescribing information. DailyMed.
- US Food and Drug Administration. Drugs@FDA: NDA 220605, Mimrylo (rusfertide acetate). FDA.
- Takeda. Takeda receives U.S. FDA approval of MIMRYLO (rusfertide), marking a potential shift in the treatment paradigm for polycythemia vera. News release, August 28, 2026. Takeda.
- Takeda. Takeda and Protagonist announce U.S. Food and Drug Administration accepts New Drug Application and grants Priority Review for rusfertide as a potential first-in-class therapy for polycythemia vera. News release, March 2, 2026. Takeda.
- Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 2024;390(8):723–735. PubMed.
- Chew LP, Ginzburg YZ, Kirubamoorthy K, et al. Rusfertide rapidly decreases hematocrit in patients with suboptimally controlled polycythemia vera. Leuk Res. 2025;159:108132. PubMed.
- Modi NB, Shames R, Lickliter JD, Gupta S. 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. Eur J Haematol. 2024;113(3):340–350. PubMed.
- Modi NB, Dinh P, Ajari I. Multiple-dose pharmacokinetics, pharmacodynamics, safety, and tolerability of subcutaneous rusfertide, a hepcidin mimetic, in healthy subjects. Clin Pharmacol Drug Dev. 2025;14(4):311–323. PubMed.
- Kowdley KV, Modi NB, Peltekian K, et al. Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8(12):1118–1128. PubMed.
- Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093. PubMed.
- Gendrot B, Peyssonnaux C, Plo I, Vaulont S, Fouquet G. Impaired iron balance and erythrocytosis: a complex relationship. Blood Cancer J. 2026;16(1):111. PubMed.
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744. PubMed.
- Bachman E, Travison TG, Basaria S, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci. 2014;69(6):725–735. PubMed.
- Hennigar SR, Berryman CE, Harris MN, et al. Testosterone administration during energy deficit suppresses hepcidin and increases iron availability for erythropoiesis. J Clin Endocrinol Metab. 2020;105(4):dgz316. PubMed.
- Guo W, Bachman E, Li M, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell. 2013;12(2):280–291. PubMed.
- Guo W, Schmidt PJ, Fleming MD, Bhasin S. Hepcidin is not essential for mediating testosterone’s effects on erythropoiesis. Andrology. 2020;8(1):82–90. PubMed.
- Bond P, Verdegaal T, Smit DL. Testosterone therapy-induced erythrocytosis: can phlebotomy be justified? Endocr Connect. 2024;13(10):e240283. PubMed.
- ClinicalTrials.gov. Search results for intervention “rusfertide” (accessed October 13, 2026). ClinicalTrials.gov.
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA 2026 Prohibited List.