FDA Lifts Hold on Rusfertide Clinical Development Program


The FDA has removed the full clinical hold that had previously been placed on trials evaluating rusfertide.

The FDA has removed the full clinical hold that had previously been placed on trials evaluating rusfertide (PTG-300), according to an announcement from Protagonist Therapeutics, Inc.1 With this decision, dosing on all studies evaluating the agent is permitted to resume.

The regulatory agency placed the hold on the trials in September 2021 following a notification from the pharmaceutical company detailing a non-clinical finding observed in a 26-week rasH2 transgenic mouse model study.2 The model had been designed to identify signals associated with tumorigenicity. Investigators had found benign and malignant subcutaneous skin tumors.

In response to the decision, the company collected all data requested from the FDA to serve as a basis for a complete response and removal of the clinical hold. To do this, individual patient clinical safety reports were provided, along with updated investigator brochure and patient informed consent forms. A comprehensive review of the most recent safety database was also conducted, which included the incorporation of new safety and stopping rules in the trial protocols.

Protagonist Therapeutics, Inc. shared that after patients have been reconsented, they will be working with study investigators and various sites to resume the dosing of the injectable synthetic mimetic of hepcidin in patients enrolled to ongoing clinical trials.

“We are extremely pleased that the FDA has acted so quickly in lifting the clinical hold on the rusfertide development program, allowing us to resume patient dosing in our clinical studies,” Dinesh Patel, PhD, president and chief executive officer of Protagonist Therapeutics, Inc., stated in a press release. “Patient safety continues to be our topmost priority. We believe that the cumulative evidence regarding safety and clinical risk-benefit of rusfertide is supportive of expedited clinical development.”

Previously, in June 2021, the FDA granted a 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.3

The decision was partially supported by findings from the phase 2 PTG-300-04 trial (NCT04057040), which demonstrated that rusfertide reversed iron deficiency, improved disease-related symptoms, and eliminated the need for therapeutic phlebotomy in patients with polycythemia vera.4

The trial enrolled patients who had polycythemia vera per 2016 World Health Organization criteria and at least 3 phlebotomies with or without concurrent cytoreductive therapy in the 6 months before the trial. The agent was administered subcutaneously at weekly doses of 10 mg to 80 mg in addition to prior standard therapy.

The primary end point of the trial was the proportion of patients in the randomized withdrawal period whose hematocrit was maintained without the need for a phlebotomy.

The trial consisted of 3 parts. In the dose-finding portion of the research, patients received a low dose of rusfertide; this was titrated every 4 weeks to control hematocrit at less than 45%. Once investigators established an effective dose, patients continued to receive the dose until 28 weeks.

Subsequently, patients began the blinded withdrawal phase of the trial. Here, they were randomized to continue their last effective dose of the agent, or they were given placebo. If the patient needed a phlebotomy at any point during this phase, they were withdrawn and entered the open-label extension phase of the trial. In the extension phase, they were restarted on their last effective dose of rusfertide.

Data from the trial were presented during the 2021 EHA Congress. At the time of the report, a total of 63 patients with polycythemia vera had received treatment with rusfertide. Duration of exposure to the agent ranged from 2 to 81 weeks, with a median exposure of 15 weeks.

The median age of these patients was 56 years (range, 27-76), 72.6% were male, and 48.4% were in the low-risk category. Moreover, 14.5% of patients previously had thrombotic events and 55% had a diagnosis of polycythemia vera for 3 years or less.

Additionally, 46.8% of patients received phlebotomy only and the rest of patients received phlebotomy with another cytoreductive agent, which could have included hydroxyurea (29%), interferon (14.5%), or ruxolitinib (Jakafi; 4.8%). Just under half of patients, or 46.8%, received 4 to 5 phlebotomies within the 6 months prior to the trial. Sixty-eight percent of patients had an allele burden of less than 60%.

Regarding patient global impression of change, 71% of participants had an improvement at 9 weeks of treatment and most patients were considered to be much improved and very much improved.

Rusfertide was determined to be well tolerated. Most of the treatment-related toxicities were grade 1 or 2 and only 2 grade 3 effects were experienced. The latter effects were not determined to be linked with rusfertide; 1 of these patients experienced vomiting and the other had distal popliteal artery aneurysm. Both patients continued the drug. Notably, no grade 4 adverse effects (AEs) were reported.

The most frequent AEs were injection site reactions and were associated with 28.1% of injections. Of these cases were noted to be transient and none of the patients who experienced them discontinued due to this toxicity. No serious AEs associated with the agent were observed. Only 1 patient discontinued treatment because of an AE, which was thrombocytosis.

“We are actively preparing to initiate the phase 3 registrational study for polycythemia vera in the first quarter of 2022,” Patel added. “Protagonist will continue to work closely with the FDA to ensure patient safety with amendments to current and planned future studies with rusfertide. We remain optimistic about the future potential of rusfertide to address unmet medical needs in excessive erythrocytosis and iron overload–related diseases like polycythemia vera and hereditary hemochromatosis, respectively.”


  1. Protagonist Therapeutics announces removal of FDA clinical hold on the rusfertide clinical development program. News release. Protagonist Therapeutics, Inc. October 11, 2021. Accessed October 12, 2021. https://bit.ly/3BzMBFx
  2. Protagonist Therapeutics reports FDA clinical hold on rusfertide clinical development program. News release. Protagonist Therapeutics, Inc. September 17, 2021. Accessed October 12, 2021. https://bit.ly/3oWFbsf
  3. Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed October 12, 2021. https://bit.ly/3vRx6Gd
  4. Kremyanskaya M, Ginzburg Y, Kuykendall A, et al. PTG-300 eliminates the need for therapeutic phlebotomy and reverses iron deficiency in both low and high-risk polycythemia vera patients. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S200.
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