The FDA has approved the first drug in a new class to treat polycythemia vera.

The U.S. Food and Drug Administration has approved Mimrylo (rusfertide), the first drug that mimics the hormone hepcidin and thus limits the availability of iron for the formation of new red blood cells. The drug is intended for the treatment of erythrocytosis in adults with polycythemia vera, a chronic myeloproliferative blood disorder. The FDA approval was made on August 28, 2026. [1]

The approval is based primarily on the results of the international Phase III VERIFY study, which enrolled 293 patients. Many of these patients, even with standard therapy, continued to require regular therapeutic phlebotomy to control hematocrit levels. The addition of rusfertide significantly reduced this need: during the key study period, 76.9% of patients achieved a clinical response, compared to 32.9% in the placebo group. [2]

The fundamental difference of the new drug is that it doesn't simply remove excess red blood cells from the bloodstream, as bloodletting does, but rather interferes with their formation. Rusfertide mimics the effect of the natural iron metabolism regulator hepcidin, reducing the amount of iron available to the bone marrow for the synthesis of hemoglobin and new red blood cells. [3]

However, ruxfertide cannot be considered a drug that will automatically replace all existing treatments for polycythemia vera. In the VERIFY study, it was used in addition to standard therapy, which in different patients could include phlebotomy, hydroxyurea, interferon, or ruxolitinib. Rather, the approval creates a new opportunity to control one of the central mechanisms of the disease—the chronic overproduction of red blood cells. [4]

Key fact	Data
Preparation	Mimrylo
International name	rusfertide
Developer	Protagonist Therapeutics
Right to develop and commercialize	Takeda
FDA approval date	August 28, 2026
FDA indication	Treatment of erythrocytosis in adults with polycythemia vera
Class	hepcidin mimetic
Route of administration	subcutaneously
Initial dose	19 mg once a week
Key research	VERIFY, Phase III, NCT05210790
Number of participants	293

Why is it important to monitor hematocrit in polycythemia vera?

Polycythemia vera is a chronic myeloproliferative neoplasm. In this condition, the bone marrow produces too many blood cells, especially red blood cells. In most cases, the disease is associated with acquired mutations in the JAK2 gene, leading to persistent activation of signaling mechanisms regulating blood cell production. The increased red blood cell mass increases the hematocrit and blood viscosity. [5]

The primary clinical concern is not the elevated red blood cell count itself, but the associated vascular complications. Higher blood viscosity and other changes in the hemostatic system increase the risk of thrombosis, including deep vein thrombosis, pulmonary embolism, heart attack, and stroke. Therefore, maintaining a stable hematocrit below 45% is considered one of the primary treatment goals. [6]

One of the oldest and most effective methods for achieving this goal remains therapeutic phlebotomy—the controlled removal of a certain volume of blood. Essentially, the procedure rapidly reduces the total mass of circulating red blood cells. However, it must be repeated, sometimes quite frequently. In addition to requiring medical visits, regular blood removal can exacerbate iron deficiency, which some patients associate with fatigue, impaired concentration, and other symptoms. The developers of rusfertide sought to address this problem of phlebotomy with a different approach—not by removing existing cells, but by limiting the resources needed to produce them. [7]

The disease is also not limited to changes in the general blood count. Patients may experience severe fatigue, itchy skin, night sweats, difficulty concentrating, and other systemic symptoms. Therefore, successful treatment is assessed not only by laboratory parameters: reducing the need for procedures, maintaining a stable hematocrit, and improving the patient's well-being are also important. [8]

The problem with polycythemia vera	Possible consequence
Excessive production of red blood cells	increased hematocrit
Increased blood viscosity	increased risk of thrombosis
Uncontrolled hematocrit	risk of stroke and other cardiovascular events
Frequent phlebotomies	patient burden and iron deficiency
Iron deficiency	may contribute to fatigue and other symptoms
Systemic disease activity	itching, night sweats, fatigue, problems with concentration

How Rusfertide Works: Iron Management Instead of Blood Removal

Rusfertide's mechanism is built around hepcidin, a peptide hormone that plays a central role in regulating iron metabolism. Hepcidin determines the amount of iron released into the bloodstream from the intestines and cellular stores. One of its main targets is the protein ferroportin, which releases iron from cells into the blood. [9]

Rusfertide is a peptide mimetic of hepcidin. The drug reduces the availability of available iron in plasma, and consequently, its delivery to the bone marrow. Since erythroid cells require large amounts of iron to form hemoglobin, limiting its availability slows the excessive production of red blood cells. [10]

This is an unusual approach for polycythemia vera. Cytoreductive drugs affect cell proliferation through various pathways, whereas phlebotomy removes already formed red blood cells. Rusfertide interferes with the physiological iron distribution system. This is why the FDA classifies it as first-in-class, meaning it is the first approved member of a fundamentally new class of drugs for this disease. [11]

It is important to note that controlled iron restriction differs from the simple development of random iron deficiency. The dosage is adjusted based on the hematocrit and tolerability. According to the approved US product information, the starting dose is 19 mg subcutaneously once weekly; subsequent dose adjustments are possible, and the acceptable weekly dosing range is 9.5 to 108 mg. [12]

Approach	The basic principle
Phlebotomy	physical removal of a portion of circulating red blood cells
Hydroxyurea	decrease in cell proliferation
Interferon	impact on pathological clone and hematopoiesis
Ruxolitinib	inhibition of the JAK signaling pathway
Rusfertid	mimicking hepcidin and limiting iron availability for erythropoiesis

What the VERIFY study showed

VERIFY is an international, randomized, double-blind, placebo-controlled phase III study (NCT05210790). The randomized arm included 293 adult patients with polycythemia vera: 147 received rusfertide and 146 received placebo. All participants required regular phlebotomies despite standard therapy. Approximately 56% of patients in each group were receiving concomitant cytoreductive therapy. [13]

Rusfertide was administered subcutaneously once weekly. Therapy was initiated at 19 mg, after which the dose was adjusted to maintain hematocrit below 45%. The primary endpoint was clinical response from weeks 20 to 32: the patient had to be ineligible for phlebotomy and had not received such a procedure during this period.[14]

The difference was significant. 76.9% of patients treated with rusfertide achieved a clinical response, compared to 32.9% of those receiving placebo—an absolute difference of 44 percentage points. The average number of phlebotomies over the first 32 weeks was only 0.5 procedures in the rusfertide group, compared to 1.8 procedures in the control group. Both differences were statistically highly significant—p<0.0001. [15]

An even more significant difference was observed when analyzing stable hematocrit control. Levels below 45% were maintained throughout the observation period by 62.6% of participants in the rusfertide group, compared with only 14.4% in the placebo group. Furthermore, the new drug group recorded a statistically significant improvement in fatigue and overall symptom burden. These results are particularly important, as chronic fatigue is one of the most common complaints in patients with polycythemia vera. [16]

VERIFY Result	Rusfertid	Placebo
Patients	147	146
Clinical response at 20-32 weeks	76.9%	32.9%
Absolute difference	+44.0 p.p.	-
Average number of phlebotomies for 0-32 weeks	0.5	1.8
Maintaining hematocrit <45%	62.6%	14.4%
Improved fatigue indicators	statistically significant	less
The significance of the main differences	p<0.0001	-

What is known about Mimrylo's safety?

The most common adverse event was injection site reactions. In the randomized portion of VERIFY, they were observed in 55.9% of patients receiving rusfertide versus 32.9% in the placebo group. This category includes redness, itching, soreness, and swelling at the subcutaneous injection site. Most of the reported reactions were mild. [17]

The second major adverse effect was anemia. It was reported in 15.9% of patients in the rusfertide group and 4.1% of patients in the placebo group. This effect is consistent with the drug's mechanism of action: excessive iron restriction can reduce red blood cell production to a greater extent than is required for simple hematocrit control. Therefore, the dose should be adjusted based on laboratory parameters. [18]

The FDA's official instructions also highlight the possibility of developing or worsening thrombocytosis—an increase in platelet count. Regular monitoring of complete blood counts is recommended after initiating treatment and when changing the dose. The registration information also includes warnings regarding injection site reactions and potential harm to the fetus when used during pregnancy. [19]

In the first 32 weeks, serious adverse events were reported in 3.4% of patients treated with rusfertide and 4.8% of patients in the control group, with the researchers not considering the reported serious events to be related to rusfertide. This is encouraging, but polycythemia vera is a chronic disease whose treatment can last for years, so longer-term follow-up data will be particularly important. The VERIFY study includes follow-up for up to 156 weeks, and the open-label portion of the program is ongoing. [20]

Adverse event in VERIFY	Rusfertid	Placebo
Injection site reactions	55.9%	32.9%
Anemia	15.9%	4.1%
Fatigue	15.2%	15.8%
Serious adverse events	3.4%	4.8%
Additional FDA warning	possible increase in platelets	-

Why Mimrylo's approval could change the way we treat patients

The primary practical benefit of rusfertide is its ability to reduce patient reliance on repeated phlebotomy. For someone who requires regular clinic visits for blood removal, switching to weekly subcutaneous therapy has the potential to significantly improve daily life. In the study, this benefit was supported not only by laboratory parameters: the number of phlebotomies was significantly reduced, and fatigue scores improved. [21]

At the same time, the new drug should not be perceived as a universal replacement for hydroxyurea, interferon, ruxolitinib, or other components of therapy. VERIFY was designed primarily as a study of the addition of ruxolitinib to the existing standard of care. More than half of the participants continued to receive cytoreductive therapy. Therefore, the results primarily demonstrate the potential for significantly improving erythrocytosis control while maintaining existing treatment. [22]

Another key question is the impact of therapy on the long-term risk of thrombosis, disease progression to myelofibrosis or acute leukemia, and overall survival. VERIFY convincingly demonstrated hematocrit control and a reduction in the need for phlebotomy, but the study was not powered to demonstrate a reduction in mortality or major cardiovascular events. Therefore, it would be premature to conclude that rusfertide has already proven its ability to prevent strokes or prolong survival. [23]

Nevertheless, the FDA's decision represents a significant shift in treatment strategy. For the first time, the regulatory agency has approved a drug that utilizes the body's own iron-control system to manage excessive erythropoiesis. If its efficacy and safety are confirmed with long-term use, the hepcidin pathway could become a standalone therapeutic approach for diseases characterized by abnormal red blood cell production. [24]

What has already been shown	What remains to be established
Significant reduction in the need for phlebotomies	impact on long-term risk of thrombosis
More stable hematocrit <45%	impact on overall life expectancy
Improved fatigue indicators	influence on transformation into myelofibrosis
Effectiveness over standard therapy	optimal place of the drug in the treatment sequence
Acceptable safety in the registration study	safety for long-term use

Sourceb news

Kuykendall AT et al. Results from VERIFY, a phase 3, double-blind, placebo-controlled study of rusfertide for treatment of polycythemia vera. Journal of Clinical Oncology. 2025;43(17_suppl):LBA3.
DOI: 10.1200/JCO.2025.43.17_suppl.LBA3. [25]

Data from the longer-term VERIFY follow-up to 52 weeks were also published in Blood:

Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study. Blood. 2025;146(Suppl 1):81. DOI: 10.1182/blood-2025-81. [26]

The proof-of-concept data for rusfertide treatment prior to phase III were published in the phase II REVIVE study in The New England Journal of Medicine:

Kremyanskaya M. et al. Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera. N Engl J Med. 2024;390:723-735. DOI: 10.1056/NEJMoa2308809. [27]