Rusfertide, the First Hepcidin Mimetic for the treatment of Polycythemia Vera (PV) is Approved by the U.S. FDA

On August 28, 2026, Protagonist Therapeutics, Inc. (NASDAQ: PTGX) announced that its partner Takeda had received U.S. Food and Drug Administration approval for rusfertide (MIMRYLO™; Takeda Pharmaceutical Company Limited), a subcutaneously injected, first-in-class hepcidin mimetic peptide, for the treatment of erythrocytosis in adults with polycythemia vera (PV). It is the first hepcidin mimetic approved for any indication, and the first drug approved for PV that works by directly correcting the iron-availability defect that drives the disease’s hallmark overproduction of red blood cells, rather than by suppressing the bone marrow non-specifically or mechanically removing blood.

PV is a chronic blood cancer, one of the myeloproliferative neoplasms, in which the bone marrow makes far more red blood cells than the body needs. The excess cells thicken the blood, raising the risk of stroke, deep vein thrombosis, and pulmonary embolism, and driving a set of symptoms- severe fatigue, itching, difficulty concentrating, night sweats- that many patients live with for years. For most of the modern treatment era, managing PV has meant keeping hematocrit, the proportion of blood volume occupied by red cells, below 45% through some combination of therapeutic phlebotomy (periodic blood removal, functionally similar to donating blood but done for treatment rather than donation) and cytoreductive drugs such as hydroxyurea, interferon, or the JAK inhibitor ruxolitinib. Neither approach touches the underlying biology of why PV patients overproduce red cells in the first place.

According to figures cited in the approval announcement, an estimated 78% of PV patients still have uncontrolled hematocrit despite standard care, and those with uncontrolled hematocrit face a fourfold higher risk of cardiovascular death or major cardiovascular events compared with patients who stay below the 45% threshold. Separately, a SEER-based epidemiological analysis presented at the 2026 ASCO Annual Meeting estimated that roughly 88,943 Americans were living with PV in 2025, a prevalence of 25.6 per 100,000, projected to reach as many as 97,011 by 2030 as the population ages; the researchers attributed the rising case count to demographic aging and improved survival rather than to any increase in new diagnoses.

A Mimetic of the Body’s Own Iron Regulator
Rusfertide’s mechanism distinguishes it from all prior PV treatments. Hepcidin is a peptide hormone made by the liver that serves as the body’s master regulator of iron availability: when hepcidin levels rise, the hormone binds to and degrades ferroportin, the channel that exports iron out of cells and into the bloodstream, which in turn limits how much iron is available to the bone marrow for making new red blood cells. In PV, hepcidin levels are paradoxically low relative to the degree of erythrocytosis, leaving iron more available than it should be and allowing the JAK2-driven malignant clone to continue manufacturing red cells largely unchecked. Rusfertide is a synthetic peptide designed to mimic hepcidin’s action, binding ferroportin directly and restricting iron delivery to erythroid progenitor cells in the marrow, thereby throttling red blood cell production at its source. Dinesh V. Patel, PhD, President and Chief Executive Officer of Protagonist, described the drug as addressing “the underlying biology of erythrocytosis in PV” and noted that the program began 14 years ago on that hypothesis. The drug is self-administered as a once-weekly subcutaneous injection.

The idea of targeting the hepcidin-ferroportin axis in PV is not unique to Protagonist. A review published in Blood in March 2026 by Kremyanskaya, Ginzburg, and Hoffman surveyed a broader class of hepcidin-pathway modulators now in development, including two additional hepcidin agonists, divesiran and sapablursen, alongside rusfertide, and noted that the reverse strategy, lowering hepcidin to free up iron, is being pursued for the anemia associated with myelofibrosis using JAK2 inhibitors such as pacritinib and momelotinib and the anti-hemojuvelin antibody DISC-0974, an investigational monoclonal antibody developed by Disc Medicine to treat anemia caused by chronic inflammation. A separate review in Blood Reviews, published online in late August 2026 by Costa, Pilo, and Breccia, framed hepcidin-directed therapy as “a complementary approach to clone-directed therapies” in PV, pointing out that erythrocytosis, although driven by constitutive JAK2 signaling, remains dependent on iron availability, and that current evidence for rusfertide rests largely on hematologic surrogate endpoints rather than on demonstrated reductions in thrombotic risk or disease modification, questions the authors describe as still open.

The VERIFY Trial
The approval of rusfertide rests on the Phase 3 VERIFY study (NCT05210790), a randomized, double-blind, placebo-controlled trial that enrolled 293 patients with PV and randomized them to receive rusfertide or placebo as an add-on to standard of care, which in the trial included hydroxyurea, interferon, and/or ruxolitinib. Patients qualified for phlebotomy in the trial if they had a confirmed hematocrit of 45% or higher that was at least 3 percentage points above their individual baseline, or a hematocrit of 48% or higher regardless of baseline.

According to results presented at the 2025 ASCO Annual Meeting, 76.9% of patients receiving rusfertide achieved a clinical response, defined as absence of phlebotomy eligibility, during Weeks 20 through 32 of the study, compared with 32.9% of patients on placebo. Patients on rusfertide required a mean of roughly 0.5 phlebotomies across the first 32 weeks, versus 1.8 for placebo. The trial met its primary endpoint and all four prespecified key secondary endpoints, including the proportion of patients maintaining a hematocrit below 45% and the mean change from baseline in total fatigue score on the PROMIS Fatigue Short Form 8a at Week 32. That last endpoint is notable because fatigue in PV has historically been difficult to manage with existing treatments, and the improvement was substantial enough to be reflected directly in the approved product label. The most common adverse reactions, occurring in more than 15% of patients, were injection site reactions (56%) and anemia (16%).

Those Phase 3 results build on earlier, smaller studies. A Phase 2 open-label trial, the PACIFIC study (NCT04767802), reported in Leukemia Research in December 2025, treated 20 patients with elevated baseline hematocrit (mean 51.6%) with rusfertide 40 mg subcutaneously twice weekly until hematocrit fell below 45%, then weekly thereafter; 85% of patients reached that threshold by Week 8, median time to first response was 4.9 weeks, and no patient required phlebotomy while on treatment. A separate, thorough QT study published in Clinical Therapeutics in November 2025 evaluated rusfertide’s effect on cardiac repolarization in 60 healthy volunteers and found no clinically relevant effects on heart rate, cardiac conduction, or the QTc interval, addressing a standard cardiac safety question ahead of the drug’s broader use. And a review in Experimental Hematology & Oncology summarizing updates from the ASH 2025 Annual Meeting grouped rusfertide alongside clone-directed agents such as INCA033989 and the epigenetic drug pelabresib as part of a wider set of investigational strategies now being tested across myeloproliferative neoplasms, specifically describing rusfertide as a “phlebotomy-sparing physiologic therapy.”

From Protagonist’s Bench to Takeda’s Label
Rusfertide was discovered by Protagonist Therapeutics, which led its development through Phase 3. The two companies entered into a worldwide license and collaboration agreement in January 2024, under which Takeda paid Protagonist a $300 million upfront payment and gained responsibility for the drug’s regulatory submission and commercialization, while Protagonist retained an option to co-promote in the U.S. and split profits there evenly with Takeda. That original agreement also gave Protagonist a window after the regulatory filing to opt out of the U.S. profit-sharing arrangement in exchange for a larger package of one-time payments and royalties.

In April 2026, Protagonist exercised that opt-out right. According to the company’s own announcement of the FDA approval, the decision triggers $275 million in near-term payments, a $200 million opt-out fee together with a separate $75 million approval milestone, and leaves Protagonist eligible for up to an additional $875 million in future milestones tied to regulatory and commercial progress, plus tiered royalties on worldwide net sales ranging from 14% to 29%, which the company estimates would average out to approximately 21% at $1.5 billion in annual sales. Patel described the decision as reflecting “full confidence in Takeda as the ideal partner to bring Rusfertide to patients who need it most.”

Rusfertide is Protagonist’s second FDA approval within the same year. In March 2026, the FDA approved icotrokinra (ICOTYDE™, Janssen Biotech, Inc., a Johnson & Johnson company), an orally administered targeted peptide that blocks the interleukin-23 receptor, for moderate-to-severe plaque psoriasis, a molecule Protagonist discovered jointly with Johnson & Johnson scientists and advanced through Phase 1 before handing off later development and commercialization. Between the two approvals, Patel said, Protagonist now has “two approved products validating our peptide-centric drug discovery and development acumen,” and the company says it intends to apply that same discovery platform to a set of wholly owned programs still in its own pipeline, including an oral IL-17 antagonist peptide, obesity-focused dual and triple agonists, an oral hepcidin functional mimetic, and newly announced discovery programs in IL-4 and amylin biology.

Safety Considerations
Rusfertide’s U.S. prescribing information includes warnings for new or worsening thrombocytosis; platelet counts can rise on treatment, generally plateauing by around Week 8, and the label calls for complete blood counts every two to four weeks after starting therapy and during dose adjustments, since platelet elevation may require initiating or modifying cytoreductive therapy or adjusting the Rusfertide dose. Injection-site reactions, including erythema, itching, pain, and swelling, and in some cases Grade 3 reactions, have been reported; the label recommends ice, topical corticosteroid creams, antihistamines, or analgesics as needed. Based on findings in animal reproduction studies, Rusfertide may cause fetal harm, and patients are advised to stop the drug if they become pregnant; pregnancy testing is recommended before starting treatment, and effective contraception is advised during treatment and for at least 30 days afterward for patients of reproductive potential. Breastfeeding is not recommended during treatment or for 30 days after the final dose, given the potential for impaired iron absorption in a breastfed child.

What Remains Open
Several questions sit outside what the VERIFY trial and its approval can answer on their own. The trial’s endpoints, hematocrit control and phlebotomy avoidance, are surrogate and functional measures; as the Blood Reviews analysis by Costa and colleagues points out, whether hepcidin-directed iron restriction actually lowers the rate of thrombotic events or changes the long-term trajectory of PV, as opposed to controlling its most visible hematologic marker, has not yet been established and would require longer follow-up than a registration trial typically provides. Long-term platelet effects also merit continued observation, since new or worsening thrombocytosis is called out as a specific warning on the label rather than a rare finding. And rusfertide’s approval covers PV specifically; the broader hepcidin-ferroportin axis is being explored in other directions as well, including targeting hepcidin to lower it rather than raise it in the anemia of myelofibrosis, an application that involves an entirely different set of drugs and is not affected by this approval.

Related Onco’Zine Coverage

• New Drug Application Approved for Rusfertide for Adults with Polycythemia Vera [Article]
• ASH 2025: Positive Topline Results from Phase 2a Study of Sapablursen in Polycythemia Vera [Article]

References
[1] Protagonist Therapeutics, Inc. Protagonist Therapeutics Announces U.S. FDA Approval of Hepcidin Mimetic Peptide MIMRYLO™ (rusfertide) for Polycythemia Vera. Press release via ACCESS Newswire, August 28, 2026.
[2] Takeda Pharmaceutical Company Limited. Takeda and Protagonist Announce ASCO Plenary Presentation Highlighting Full 32-Week Results from Phase 3 VERIFY Study of Rusfertide. Press release, 2025.
[3] Takeda Pharmaceutical Company Limited. Rusfertide Demonstrates Promising Results in Phase 3 VERIFY Trial in Polycythemia Vera. Press release, 2025.
[4] Takeda and Protagonist Therapeutics, Inc. Enter into Worldwide License and Collaboration Agreement for Rusfertide, a Late-Stage Rare Hematology Asset. Press release, January 2024.
[5] BioPharma Dive. Takeda pays $300M to license Protagonist drug for blood disorder. 2024.
[6] Protagonist Therapeutics, Inc. Protagonist Exercises Rusfertide U.S. Opt-Out Right Under Takeda Collaboration. Press release, April 28, 2026.
[7] Zhang T, Jiang H, Liu D. Emerging agents and regimens for myeloproliferative neoplasms: updates from ASH 2025 Annual Meeting. Exp Hematol Oncol. 2026 Aug 3;15(1):69. doi: 10.1186/s40164-026-00813-0. PMID: 42547880; PMCID: PMC13430699.
[8] Costa A, Pilo F, Breccia M. Targeting the hepcidin-ferroportin axis in polycythemia vera: a complementary approach to clone-directed therapies. Blood Rev. 2026 Aug 26:101420. doi: 10.1016/j.blre.2026.101420. PMID: 42660705.
[9] Kremyanskaya M, Ginzburg YZ, Hoffman R. Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis. Blood. 2026 Mar 19;147(12):1278-1288. doi: 10.1182/blood.2025028643. PMID: 41100735.
[10] Chew LP, Ginzburg YZ, Kirubamoorthy K, Lee SE, Lee JH, Modi NB, Khanna S, Dinh P, Valone F, Molina A, Gupta S. Rusfertide rapidly decreases hematocrit in patients with suboptimally controlled polycythemia vera. Leuk Res. 2025 Dec;159:108132. doi: 10.1016/j.leukres.2025.108132. PMID: 41175501.
[11] Modi NB, Dinh P, Xue H, Darpo B. Evaluation of Rusfertide, a Hepcidin Mimetic, on Cardiac Repolarization: A Randomized, Placebo- and Positive-Controlled Crossover Thorough QT Study in Healthy Participants. Clin Ther. 2025 Nov;47(11):1043-1052. doi: 10.1016/j.clinthera.2025.09.002. PMID: 41033871.
[12] ASCO 2026 Abstract. Estimated prevalence of polycythemia vera in the United States (2025-2030): SEER analysis with modeled reporting delay. J Clin Oncol. 2026;44(16_suppl):e18589.
[13] AJMC. Polycythemia Vera Prevalence to Near 100K by 2030 as Symptom Burden Grows. 2026.
[14] Protagonist Therapeutics, Inc. Protagonist Therapeutics Announces U.S. FDA Approval of ICOTYDE™ (icotrokinra) for the Treatment of Moderate to Severe Plaque Psoriasis. Press release, March 2026.
[15] U.S. Food and Drug Administration. MIMRYLO (rusfertide) Prescribing Information. Takeda Pharmaceuticals, 2026.

This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. Prescribing information referenced here is not a complete summary of safety data; consult the full FDA-approved label before making treatment decisions.

Featured image © 2026 CH/JCO Used with permission.

DOI