Rusfertide
InvestigationalA synthetic hepcidin mimetic peptide under FDA Priority Review for polycythemia vera. Phase 3 VERIFY trial demonstrated 77% hematocrit response rate. Developed by Protagonist Therapeutics (acquired by Takeda).
PTG-300 · Hepcidin Mimetic
12 human studies
- Preclinical
- 33%
- Clinical
- 67%
Based on 18 cited sources
clinically demonstrated · moderate confidence
Demonstrated effect magnitude — not a recommendation or safety claim.
Research Depth 76: ≥2 independent RCTs anchor the base — the double-blind placebo-controlled REVIVE Phase 2 randomized-withdrawal trial (NEJM, PMID 38381675, response 60% vs 17% placebo) plus multiple randomized Phase 1 PK/PD studies (38785334, 39888264, 39546273, 41033871) and topline Phase 3 VERIFY data (1A 30); ≥1 low-RoB RCT on the relevant outcome (1B 16); total human N in the 300–1,000 band across REVIVE/VERIFY/Phase 1 (1C 11); direct population/route/outcome match in PV (1D 14); modest preclinical foundation (1E 5). Mechanism 94: ferroportin target with binding plus functional internalization/degradation and genetic validation of the hepcidin-ferroportin axis (2A 38), full target-to-hematocrit pathway characterized (2B 28), dose-dependent PD across human dose-ranging studies (2C 18), confirmed in-vivo/human (2D 10). Plausibility 89: mechanism -> surrogate (hematocrit) -> clinical outcome (phlebotomy independence, MPN-SAF symptom reduction) each RCT-supported (3A 34), fully coherent with PV iron-restricted erythropoiesis (3B 24), class analogy from other hepcidin mimetics/endogenous hepcidin (3C 17), tightly scoped single-mechanism claim (3D 14). Global Coverage 60: international multicenter replication across ≥2 countries but largely sponsor-anchored (4A 24); 4–6 countries incl. US/India/Malaysia/Korea/Australia (4B 18); ~12–17 indexed studies (4C 13); under FDA Priority Review / trial-registered, not yet approved (4D 5). Community Experience 13: investigational drug, dossier notes no meaningful community discussion; negligible off-trial use (5A 3, 5B 3, 5C 2), clean trial tolerability gives minor 5D credit (5). Effectiveness clinical, score 75 (moderate): large effect (REVIVE 60% vs 17%, phlebotomy 8.7->0.6/yr, Phase 3 77% response; E1 26), far exceeds responder threshold via phlebotomy elimination (E2 21), patient-relevant functional outcomes alongside the hematocrit surrogate (E3 12), superior to placebo on a clinical outcome with no head-to-head vs cytoreductives yet (E4 16); confidence moderate pending full Phase 3 peer-review/approval. Note: NCT04057040 is the REVIVE Phase 2 trial, not the Phase 3 VERIFY (NCT05210790) as the body text implies.
How It Works (Simplified)
Rusfertide is a synthetic peptide that mimics hepcidin, the body’s master regulator of iron metabolism. By activating ferroportin degradation, it reduces iron absorption from the gut and iron release from storage cells, lowering the excess red blood cell production characteristic of polycythemia vera (PV). This mechanism directly addresses the iron-driven erythrocytosis in PV without the need for frequent phlebotomy.
Scientific Pathways
Hepcidin-Ferroportin Axis: Rusfertide binds to ferroportin (the sole cellular iron exporter), triggering its internalization and degradation. This reduces serum iron availability, limiting erythropoiesis and maintaining hematocrit within normal range.
Clinical Differentiation: Unlike JAK inhibitors (e.g., ruxolitinib) which target the inflammatory/proliferative component of myeloproliferative neoplasms, rusfertide specifically targets iron-driven erythrocytosis, offering a complementary mechanism.
Clinical Evidence
VERIFY Phase 3 Trial: The pivotal Phase 3 VERIFY trial (NCT05210790) is a 293-patient, placebo-controlled, add-on study in phlebotomy-requiring polycythemia vera. The sponsor reported topline results showing a 77% hematocrit response rate with rusfertide versus placebo. These Phase 3 results are topline (sponsor-reported) and have not yet been peer-reviewed or published; the trial remains ongoing through its long-term extension, and full results are not yet available.
REVIVE Phase 2 Data: The published evidence base is the Phase 2 REVIVE trial (NCT04057040; N Engl J Med 2024). During the 28-week dose-finding period, the mean number of phlebotomies fell from an estimated 8.7 per year before treatment to 0.6 per year on rusfertide, and mean maximum hematocrit was held below 45%. In the subsequent 12-week randomized-withdrawal period, a response occurred in 60% of patients on rusfertide versus 17% on placebo.
Safety Profile
The most common adverse events include injection site reactions (mild, transient), and iron deficiency (expected pharmacological effect requiring monitoring). No major cardiovascular or hepatic safety signals identified in trials to date. Long-term safety monitoring is ongoing through the VERIFY extension study.
Important Limitations
- Not yet FDA-approved (NDA under Priority Review, decision expected ~August 2026)
- Specific to polycythemia vera; not studied for other iron overload conditions
- Requires subcutaneous injection (not available orally)
- Long-term safety beyond clinical trial duration still being evaluated
- Iron parameters require monitoring during treatment
Full reference list available on request. All citations link to PubMed for verification.
This dossier synthesizes available evidence from peer-reviewed literature, regulatory documents, and clinical trial registries. Evidence strength ratings follow a modified GRADE approach.
For complete methodology details, see our Methodology page.
Important Disclaimer
This dossier is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before making health decisions.
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