Rusfertide

Rusfertide is a synthetic peptide mimetic of hepcidin, the body's principal hormonal regulator of systemic iron availability. It binds ferroportin, the sole known cellular iron exporter, and induces its internalization and degradation. By blocking ferroportin-mediated iron export from enterocytes, macrophages, and hepatocytes, rusfertide reduces the iron supply available for erythropoiesis, thereby limiting red blood cell production and lowering hematocrit in polycythemia vera, a myeloproliferative neoplasm characterized by JAK2-driven red blood cell overproduction. This iron-restriction mechanism is distinct from cytoreductive therapies (hydroxyurea, interferon) and from therapeutic phlebotomy, which removes red cells directly rather than limiting their production.

FDA approval rests on the Phase 3 VERIFY trial (NCT05210790, "A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients With Polycythemia Vera," 293 participants), a randomized, placebo-controlled study in adults with polycythemia vera who required frequent phlebotomy to maintain hematocrit control. Participants continued their existing standard of care and were randomized to add once-weekly subcutaneous rusfertide or placebo for 32 weeks (both arms then received open-label rusfertide). During weeks 20-32, 76.9% of patients receiving rusfertide plus standard of care achieved a clinical response (hematocrit control without phlebotomy), compared with 32.9% of patients receiving placebo plus standard of care. Rusfertide was studied as an add-on to standard of care, not as monotherapy; VERIFY did not test whether it can substitute for phlebotomy or cytoreductive therapy alone. No pediatric or animal-model efficacy data were identified for this indication.

Typical dosage: 19-108 mg (once weekly, subcutaneous).

Per the FDA-approved prescribing information, MIMRYLO (rusfertide) is dosed by subcutaneous injection once weekly. The recommended starting dose is 19 mg weekly, titrated based on hematocrit response and tolerability up to a maximum of 108 mg weekly. Dosing is individualized and requires regular hematocrit and complete blood count monitoring. This is a description of the approved label and educational information only; it is not medical advice, and dosing for polycythemia vera should be directed by a hematologist.

Rusfertide's approval is specifically as an addition to existing standard-of-care therapy for polycythemia vera, therapeutic phlebotomy and/or cytoreductive agents such as hydroxyurea or interferon, not as a monotherapy replacement for either. The VERIFY trial evaluated rusfertide added to whatever standard-of-care regimen a participant was already on; no data support using rusfertide as a substitute for cytoreductive therapy in patients whose disease requires it. No anecdotal combination protocols outside this studied add-on use were identified.

Rusfertide is approved by the U.S. Food and Drug Administration for one or more labeled indications. Approval covers only the labeled indication, population and dosing. Refer to the prescribing information for full safety and dosing details.

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Reported side effects: Injection-site reactions (56%) and anemia (16%) were the most common adverse events in clinical trials; labeled warnings include thrombocytosis and embryo-fetal toxicity.

The FDA label carries no boxed warning and lists no contraindications. The most common adverse reactions in the VERIFY trial were injection-site reactions (56% of patients), managed with ice, topical steroids, antihistamines, or analgesics, and anemia (16%). Labeled warnings include thrombocytosis (rusfertide may increase platelet counts; complete blood counts are monitored every 2-4 weeks) and embryo-fetal toxicity, for which the label recommends pregnancy testing and contraception during treatment. Long-term safety data beyond the VERIFY trial's reporting window have not been described in the sources reviewed here.