FDA Grants Approval to First-in-Class Mimrylo for Treating Polycythemia Vera

Polycythemia vera, a rare blood disease linked to cardiovascular complications, now has a new FDA-approved treatment. Takeda Pharmaceutical’s Mimrylo, developed using a first-in-class approach, is positioned to become a new first-line therapy for the condition.

Patients with polycythemia vera experience excessively high levels of red blood cells, a condition known as erythrocytosis. The FDA approval, announced after Friday’s market close, covers the treatment of erythrocytosis in adults with polycythemia vera. The once-weekly injection, known in development as rusfertide, will be marketed under the brand name Mimrylo.

As a myeloproliferative neoplasm, polycythemia vera is a rare blood cancer stemming from acquired mutations that cause the bone marrow to overproduce blood cells. Symptoms include headache, dizziness, and persistent fatigue. The disorder also thickens the blood, elevating the risk of severe complications like heart attacks and strokes.

The standard treatment for polycythemia vera has been therapeutic phlebotomy, a procedure involving the removal of some blood to normalize red blood cell counts. Mimrylo, initially developed by Protagonist Therapeutics, mimics the body’s natural management of erythrocytosis. This peptide drug is an engineered version of hepcidin, a hormone that regulates iron. By limiting the iron available to the bone marrow, hepcidin decreases the iron utilized for red blood cell production.

Naturally occurring hepcidin is unsuitable as a drug due to its instability, poor solubility, and low potency, Protagonist CEO Dinesh Patel noted in an interview prior to the regulatory decision. Mimrylo originated from Protagonist’s platform technology, which engineers peptides with superior drug properties.

In 2024, while Protagonist was conducting Phase 3 testing of Mimrylo, Takeda paid $300 million upfront to collaborate on the drug, with Protagonist remaining responsible for completing the pivotal trial. Phase 3 results demonstrated that 76.9% of patients receiving once-weekly injections of the study drug did not require therapeutic phlebotomies at 32 weeks, compared to 32.9% of patients in the placebo group. The most common adverse reactions were injection site reactions and anemia.

One-year results were presented last December at the American Society of Hematology annual meeting. During an interview at the conference, Dr. Andrew Kuykendall, the study’s lead investigator and associate member in the department of hematology at Moffitt Cancer Center, stated the drug could transform how physicians treat polycythemia vera. “It is replacing therapeutic phlebotomy, which is archaic,” he said. “Given that therapeutic phlebotomy is truly the mainstay of treatment for everyone at some point during their polycythemia vera course, I believe it is certainly practice-changing.”

Currently, only a limited number of drugs are available for polycythemia vera. Incyte’s JAK inhibitor Jakafi, initially approved for myelofibrosis in 2011, added polycythemia vera to its label in 2014. However, this approval designates it as a second-line treatment for patients who do not respond to first-line treatment with hydroxyurea, a drug used to treat certain cancers, including blood cancers. The first-line setting also includes PharmaEssentia’s Besremi, an engineered version of interferon alpha, a signaling protein that regulates and activates the immune response.

Dr. Kuykendall noted that Besremi is not appropriate for all polycythemia vera patients. Interferon therapies cannot be used by individuals with mood disorders, as they exacerbate depression symptoms. Additionally, Besremi is unsuitable for patients with autoimmune conditions because interferon therapies can overstimulate the immune system. These risks are highlighted in a black box warning on the drug’s label, leaving an unmet need for patients who cannot take existing therapies or require better disease control, according to Kuykendall.

The label for Mimrylo is broad, with no restrictions to a particular line of therapy. Although the Phase 3 study enrolled patients with uncontrolled high red blood cell levels who relied on therapeutic phlebotomy, the FDA approval does not mandate that patients be phlebotomy dependent.

Takeda’s initial agreement with Protagonist included sharing U.S. profits from sales of an approved drug, but it also allowed Protagonist to opt out of this arrangement for cash. In April, Protagonist chose the cash option, receiving an immediate $200 million payment, with another $200 million due upon approval. The approval also triggered a $75 million milestone payment. Protagonist remains eligible for up to $975 million in additional milestone payments, plus royalties from Takeda’s sales of the product.

Patel stated that although Protagonist intended to retain Mimrylo and commercialize it, the financial terms offered by Takeda were too attractive. The additional financial upside ultimately led the company to opt out of sharing in the commercialization of its former lead drug asset, securing capital to deploy toward other drug candidates. “It takes us on a path of financial independence, funding our R&D pipeline in a confident manner and creating value for shareholders without diluting them,” Patel said regarding Protagonist’s exercise of the opt-out provision.

Takeda now holds exclusive global commercialization rights to Mimrylo. The drug joins a hematology portfolio that includes Takeda products for rare blood disorders, such as several treatments for hemophilia. Takeda has projected that Mimrylo could reach up to $2 billion in peak revenue, providing another prospective blockbuster to offset declining revenue as its current top seller, the inflammatory bowel disease drug Entyvio, faces patent expirations. Prior to Mimrylo’s approval, Leerink Partners had modeled the drug reaching $2 billion in sales by 2035, which would translate to approximately $470 million in royalty payments to Protagonist.

A Takeda spokesperson stated that Mimrylo’s list price is $4,200 per vial; assuming a single vial for each weekly dose, that equates to $218,400 annually. The drug is now available. An open-label extension of Mimrylo’s pivotal study is ongoing, and Takeda plans to share additional data at upcoming medical conferences. The pharmaceutical company is also working to bring Mimrylo to other global markets.

In related news, PharmaEssentia’s Besremi is expanding its indications beyond polycythemia vera, having received an additional FDA approval for essential thrombocythemia. Similar to polycythemia vera, essential thrombocythemia is a type of myeloproliferative neoplasm characterized by excessively high levels of platelets in the blood, which increases the risks of blood clots, abnormal bleeding, and enlarged spleens. Hydroxyureas, a class of cancer drugs, are a standard first-line treatment for this condition, with anagrelide typically serving as the second-line treatment to reduce platelet counts.

Besremi is an engineered version of interferon alpha, a signaling protein involved in the immune response to viruses and cancers. While the exact mechanism is not fully understood, its binding to the interferon alpha receptor initiates a signaling cascade believed to modulate the excessive production of blood components, including platelets. The drug is administered as a subcutaneous injection every two weeks. The Phase 3 study supporting the regulatory submission demonstrated durable responses and reduced blood clot events compared with anagrelide over 12 months of treatment.

“The approval of Besremi provides an important new treatment option supported by strong clinical evidence that also works at the source of the disease rather than solely managing symptoms,” Dr. Ruben Mesa, principal investigator in the study and president of Advocate Health’s Cancer National Service Line, stated in PharmaEssentia’s Monday announcement.

Photo by Takeda Pharmaceutical

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