The archaic practice of removing blood from the body to treat a wide range of illnesses lives on today as a standard treatment for certain blood disorders. The modern version of this approach, called therapeutic phlebotomy, can manage these conditions but still comes with limitations and complication risks. A drug from partners Protagonist Therapeutics and Takeda Pharmaceutical offers the promise of a therapeutic intervention for one of these rare blood diseases, polycythemia vera.
One-year data for the drug, rusfertide, were presented Saturday during the annual meeting of the American Society of Hematology in Orlando, Florida. Beyond showing the vast majority of study participants reached a point where they no longer needed phlebotomy, results also showed improvements on quality of life measures, such as the persistent fatigue that is the most common complaint of polycythemia vera patients, said Dr. Andrew Kuykendall, associate member in the department of hematology at Moffit Cancer Center and lead investigator in rusfertide’s pivotal study.
“There is this need to move beyond, move out of the dark ages to some extent, and replace therapeutic phlebotomy with something else that can reliably maintain and control blood cell counts in the safe range without really exacerbating iron deficiency and [also] promoting symptom improvement,” Kuykendall said in an interview.
Polycythemia vera is a rare blood cancer that leads to overproduction of red blood cells. Consequently, blood becomes thicker and clots more easily, putting patients at risk for cardiovascular events such as heart attack or stroke. Therapeutic phlebotomy brings red blood cell counts closer to normal levels but requires regular clinical visits for the procedure. Adverse effects include fluid shifts in the body that leave patients feeling dizzy, Kuykendall said. Therapeutic phlebotomy also exacerbates the iron deficiency that these patients already have because the body is using iron to make red blood cells.
In an interview earlier this year, Takeda President of Research & Development Andrew Plump described therapeutic phlebotomy as “very medieval.” Furthermore, while it’s can be effective, over time, many patients who routinely undergo this procedure develop iron deficiency. Rusfertide is a peptide that Protagonist designed to stand in for hepcidin, a hormone that regulates how iron is absorbed, stored, and distributed in the body.
“Basically what it’s doing is it’s trapping iron in its natural stores and making it less available to the bone marrow,” Plump said. “So it’s reducing production of red blood cells. It’s a very physiologically relevant pathway, and what we’ve seen in Phase 2b [clinical testing] is essentially functionally curing [of] these patients.”
The placebo-controlled Phase 3 test of rusfertide evaluated 293 patients with polycythemia vera over the course of 156 weeks. Data from the first 32 weeks, which showed 76.9% of patients achieved a clinical response, were presented earlier this year during the annual meeting of the American Society of Clinical Oncology.
The latest data presented at the ASH meeting are from patients who have received the once-weekly injectable drug for 52 weeks. These results show 61.9% of patients treated with rusfertide continued to not need phlebotomy. The study drug was safe and well tolerated. The most common adverse effects were injection site reactions, anemia, and fatigue.
Few drugs are available for polycythemia vera. Medications used to reduce blood counts are one option for those who can’t tolerate phlebotomies. Incyte’s oral small molecule Jakafi, which was initially approved in 2011 for myelofibrosis, expanded its FDA approval to polycythemia vera in 2014. In this indication, the Incyte drug is approved as second-line option for a narrow segment of patients, Kuykendall said. PharmaEssentia’s Besremi, approved by the FDA in 2021, offers a first-line treatment choice. This drug is an engineered version of interferon alfa, a protein that activates and regulates the immune response.
Interferon drugs aren’t used for patients with a history of mood disorders or those with a history of autoimmune conditions, Kuykendall said. It also takes time for interferon drugs to work, and even when they work in polycythemia vera, patients may still need phlebotomies to maintain disease control. That leaves an unmet need for patients who can’t tolerate existing drugs or need better disease control, he said.
Last year, Takeda paid $300 million to begin a partnership with Protagonist. Newark, California-based Protagonist is still responsible for the Phase 3 study and an FDA submission; the two companies will share in U.S. commercialization of the drug. The deal gave Takeda the rights to commercialize rusfertide in the rest of the world. With the positive Phase 3 results now available, Protagonist and Takeda said they are preparing a regulatory submission for the drug.
Photo: virusowy, Getty Images
