FDA Grants Breakthrough Therapy Designation to Rusfertide for Polycythemia Vera


The FDA has granted breakthrough therapy designation to rusfertide as a potential therapeutic option for patients with polycythemia vera to reduce erythrocytosis in those who do not require further treatment for thrombocytosis and/or leukocytosis.

The FDA has granted breakthrough therapy designation to rusfertide (PTG-300) as a potential therapeutic option for patients with polycythemia vera to reduce erythrocytosis in those who do not require further treatment for thrombocytosis and/or leukocytosis.1

The designation is based, in part, by data from the phase 2 PTG-300-04 trial (NCT04057040), which showed that the injectable hepcidin mimetic allowed for the majority of patients to eliminate therapeutic phlebotomies, maintain a target hematocrit level of less than 45%, reverse iron deficiency, and experience improvements with regard to their symptoms.2

“We are thrilled to receive the breakthrough therapy designation for rusfertide in polycythemia vera, a serious disease where the need for different and better treatment options is clear and pressing,” Suneel Gupta, PhD, chief development officer at Protagonist Therapeutics, stated in a press release. “Rusfertide is a natural hormone mimetic and may stand out as the first non-cytoreductive therapeutic drug for polycythemia vera. We look forward to working closely with FDA regulators to advance and complete all relevant clinical studies, both ongoing and planned, as quickly as possible.”

The novel injectable synthetic mimetic of hepcidin was developed to provide stronger potency, solubility, and stability, according to Protagonist Therapeutics; this could potentially result in better in vivo pharmacokinetic and pharmacodynamic characteristics vs the natural hormone.3

The 3-part phase 2 PTG-300-04 trial includes: a 28-week dose-finding portion; a 12-week blinded randomized withdrawal portion, where rusfertide is compared with placebo; and a 52-week open-label extension phase.

To be eligible for participation, patients needed to have been diagnosed with polycythemia vera using the 2016 World Health Organization criteria and have had 3 or more phlebotomies with or without concurrent cytoreductive therapy to maintain a hematocrit level of 45% or higher in the 24 weeks before enrollment. The agent was delivered subcutaneously on a weekly basis, in the following doses: 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg. Notably, doses were adjusted to maintain a hematocrit level of less than 45%.

Data from the trial were presented during the 2020 ASH Annual Meeting & Exposition. At the time, 13 patients had been enrolled; 7 of these patients were considered to be low risk, and the mean age was 57.4 years (range, 31-74). Six patients received periodic therapeutic phlebotomy alone, 6 concurrently received hydroxyurea (Hydrea), and 1 had concurrent interferon. A total of 3 patients underwent randomization.

During the open-label, dose-finding portion of the trial, all patients, except for 1, were phlebotomy free. A total of 3 patients completed part 1 of the research and did not undergo therapeutic phlebotomy vs the 3 to 5 phlebotomies that had been needed in a similar period before the study began.

During the dose-finding period, hematocrit levels of under 45% continued to be controlled for the 28 weeks in all patients, with the exception of 2. Two patients had hematocrit levels of greater than 45%; however, this level was below 45% following phlebotomy in 1 patient and increased dosing in both patients. Additionally, investigators noted a decrease in erythrocyte numbers and an increase in mean corpuscular volume in all patients but 2. Moreover, before treatment, the mean iron-related parameters proved to be consistent with systemic iron deficiency while serum ferritin progressively increased toward a normal range.

Regarding safety, the most common adverse effect was injection site reaction, and this was experienced by 3 patients. However, the majority of the reactions were grade 1 or 2 in severity and proved to be transient in nature. Notably, no patients discontinued treatment.

Updated data from the trial will be shared at the upcoming 2021 EHA Annual Congress.

Previously, the FDA granted orphan drug and fast track designations to rusfertide for use in patients with polycythemia vera.


  1. Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed June 4, 2021. https://bit.ly/3vRx6Gd
  2. Product candidates: rusfertide (PTG-300). Protagonist Therapeutics website. Accessed June 4, 2021. https://bit.ly/3ihxucZ
  3. 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. Blood. 2020;136(suppl 1):33-35. doi:10.1182/blood-2020-137285
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