Hepcidin Mimetic Eliminates Need for Phlebotomy in Polycythemia Vera

PTG-300, a hepcidin mimetic, eliminated the need for phlebotomy and the resultant iron deficiency in patients with high- and low-risk polycythemia vera (PV), according to data presented at the virtual 62nd ASH Annual Meeting and Exposition by Marina Kremyanskaya, MD, PhD, of Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

“Hepcidin is a negative regulator of iron metabolism, and like phlebotomy, where a volume of blood is physically removed from a patient to achieve the goal hematocrit of <45%, PTG-300 eliminates the flow of iron into the plasma so that it becomes unavailable for erythropoiesis in the bone marrow,” Dr. Kremyanskaya told ASH Clinical News. “Therefore, production of red cells decreases and hematocrit is controlled that way.”

The mainstay of PV treatment is phlebotomy, but repeated phlebotomy results in iron deficiency which can lead to symptoms including fatigue, weakness, and pica.

This phase II trial was conducted in three parts. Part 1 was a 28-week dose-finding phase. From week 4 to 16, PTG-300 was given weekly, with doses titrated up every month, at 10, 20, 40, 60, and 80 mg adjusted to maintain hematocrit <45%. Once the effective dose was found, patients remained on that dose until week 29.

Part 2 is a 12-week blinded randomized withdrawal of PTG-300 compared with placebo. During this phase, if participants required phlebotomy, they resumed their last known effective dose and entered part 3, a 52-week open-label extension phase.

To be eligible patients had PV and at least three phlebotomies with or without concurrent cytoreductive therapy to maintain a hematocrit level of ≤45% in the 24 weeks prior to enrollment. The primary endpoint was the proportion of patients whose hematocrit is maintained without the need for phlebotomy.

Dr. Kremyanskaya reported results from 18 patients who had received PTG-300, with a treatment duration ranging from 5 to 54 weeks. Enrollment on the trial is ongoing. Prior to study enrollment, approximately half of patients were treated with phlebotomies alone (most required 3-5 phlebotomies in the 6 months before study initiation) and the other half were treated with phlebotomies plus hydroxyurea or interferon.

In the dose-finding portion of the study, the investigators observed that PTG-300 quickly eliminated the need for phlebotomy, even among this group of patients who were heavily dependent on phlebotomy. Hematocrit levels decreased with dosing and were maintained at <45% throughout the treatment period; red blood cell count also decreased, becoming significant at 8 weeks of follow-up.

All patients were iron-deficient at baseline, but, looking at iron parameters, the researchers found that PTG-300 normalized iron stores as soon as 4 weeks of treatment. Ferritin levels that were consistent with significant iron-deficiency at baseline rapidly increased during treatment, Dr. Kremyanskaya noted.

The researchers also assessed PV-related symptoms by using the Myeloproliferative Neoplasm Total Symptom Score (MPN-TSS). By 28 weeks, TSS had dropped from an average of 16.5 to 10. Notably, there was a decrease in problems with concentration, fatigue, and pruritis.

More than 90% of drug-related adverse events were grade 1. There were no grade 3 or 4 adverse events, no serious adverse events, and no patient stopped treatment due to adverse events, the authors reported.

“As more patients are enrolled and as duration on study continues, we will have more robust data on safety and efficacy of this drug,” Dr. Kremyanskaya concluded. “We are also very interested in examining the effect of PTG-300 on symptoms of PV. Long term, it would be good to know if this treatment has any affect on the thrombotic risk of these patients.”

Study authors report relationships with Protagonist Therapeutics, which sponsored this trial.


Kremyanskaya M, Ginzburg Y, Kuykendall AT, et al. PTG-300 eliminates the need for therapeutic phlebotomy in both low and high-risk polycythemia vera patients. Abstract#482. Presented at the 2020 American Society of Hematology Annual Meeting, December 6, 2020.