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SAN DIEGO -- A novel therapy for polycythemia vera (PCV) maintained stable hematocrit levels for as long as 2.5 years and significantly reduced use of phlebotomy, a small randomized trial showed.

The hepcidin mimetic rusfertide led to a response rate of 69.2%, defined as maintaining hematocrit <45% during 12 weeks of treatment without phlebotomy. Placebo-treated patients had a response rate of 18.5%. Additionally, 24 of 26 patients randomized to rusfertide did not receive phlebotomy as compared with 12 of 27 in the placebo arm.

During a randomized withdrawal, most patients treated with rusfertide remained phlebotomy free. Hemoglobin and erythrocyte counts increased only when rusfertide was held or discontinued, reported Ellen K. Ritchie, MD, of Weill Cornell Medical College in New York City, during the American Society of Hematology annual meeting.

"Mean hemoglobin levels generally remained stable and mean erythrocyte counts decreased through 2.5 years," Ritchie said. "Leukocyte counts also remained stable. Platelet count increased about 30% as patients started the drug but didn't increase further as they continued on rusfertide. Rusfertide resulted in normalization of serum ferritin levels over the 2.5 years."

Three-fourths of treatment-emergent adverse events (TEAEs) were grade 1/2, Ritchie noted. Eight patients developed second malignancies during the study. Prior malignancies, prior lesions, and/or the patient's medical history might have been contributing factors. Five patients, all at high risk, developed thromboembolic events.

During a discussion that followed the presentation, David Ross, MD, PhD, of the Royal Adelaide Hospital in Australia, pointed out that "one of the hopes with rusfertide was that superior hematocrit control would translate into a reduced risk of thrombosis. Did they occur despite hematocrit control or in people who were not well controlled?"

Acknowledging that the data were not yet available, Ritchie said, "Early on in this study, I suspect that there may have been difficulties in controlling hematocrit. The other thrombotic events were later, but after week 100, there were really no thrombotic events, which suggests to me that once we had adequate control, there was less thrombosis."

Bruce Raphael, MD, of NYU Langone Health in New York City, wondered whether cytoreductive chemotherapy had to be increased in some patients because of the rise in platelets.

"All I can tell you is that one patient discontinued at the physician's desire when the platelet count increased," said Ritchie. "I have no information that there were any other changes in cytoreductive therapy."

An unidentified physician asked whether the treatment interval could be increased in responding patients.

"There isn't any data for that," said Ritchie. "Physicians were at liberty to adjust the dose to keep the hematocrit less than 45%. I think as this study cohort continues to be studied, that will be an interesting question: whether we can decrease the frequency or whether we can decrease the dose in some of these patients."

Driven primarily by uncontrolled hematocrit levels, PCV causes uncontrolled erythrocytosis, systemic symptoms, and an increased risk of thromboembolic and cardiovascular complications. Rusfertide in PCV by limiting iron availability.

The three-part, phase II investigated the safety and efficacy of rusfertide in phlebotomy-dependent patients with PCV, treated with or without concurrent cytoreductive chemotherapy. The first part of the trial was a dose-finding and dose-evaluation component. Ritchie reported findings from the second part, a blinded, randomized withdrawal of treatment. Part three will be an open-label extension to evaluate dosing, safety, and efficacy for up to 3 years.

"The phase II randomized portion of the study was designed to look at efficacy," said Ritchie. "Half the patients were [randomly] enrolled on placebo and half continued on the drug, from weeks 29 to 41. At week 42, they were allowed to be enrolled in the open-label extension study."

The trial met the primary endpoint, as 18 of 26 (69.2%) patients achieved a stable hematocrit level of less than 45%. In the placebo arm of the withdrawal component, five of 27 (18.5%) patients achieved the primary endpoint (P=0.0003). Response to rusfertide was superior irrespective of whether patients received cytoreductive therapy, said Ritchie.

During the randomized withdrawal, 24 of 26 (92.3%) patients who continued rusfertide did not require phlebotomy as compared with 12 of 27 (44.4%) in the placebo arm. In the 28 weeks prior to starting rusfertide treatment in part one of the trial, the patients required an average of 4.7 phlebotomies, and more than 40% required five or more blood-removal procedures.

Ritchie said that 58 of the 70 patients enrolled in part one of the trial continued to part three. As of mid-October, 57 patients had been treated for at least a year, 51 for ≥1.5 years, and 37 for ≥2 years.

The only patients who did not achieve stable hematocrit levels with rusfertide were patients allocated to placebo during the randomized withdrawal.

Patient-reported outcomes improved during rusfertide treatment, including fatigue, early satiety, inactivity, concentration, night sweats, and itching.

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