Hepcidin Mimetic PTG-300 Shows Early Promise in Polycythemia Vera


The first-in-class, synthetic hepcidin mimetic agent PTG-300 is being investigated in an ongoing phase 2 clinical trial, with the goal of introducing a novel therapeutic agent to the limited armamentarium in polycythemia vera.

Ronald Hoffman, MD

The first-in-class, synthetic hepcidin mimetic agent PTG-300 is being investigated in an ongoing phase 2 clinical trial (NCT04057040), with the goal of introducing a novel therapeutic agent to the limited armamentarium in polycythemia vera (PV).1

"PTG-300 is a big deal, and it is something different," said study investigator, Ronald Hoffman, MD, of The Icahn School of Medicine at Mount Sinai. "It was unanticipated that a regulator of iron metabolism could be used to treat patients with PV. This is the merging of 2 fields: science and hematology. The synergistic action that we have demonstrated is going to move the field forward and make a big difference for patients who have PV.”

Preliminary data from the trial showed that PTG-300 eliminated the need for phlebotomy due to persistent control of hematocrit levels of less than 45% in 6 evaluable patients who had at least 3 phlebotomies within a 24-week period prior to study enrollment, according to a press release from Protagonist Therapeutics.2

Additionally, the self-administered subcutaneous formulation was well tolerated. Injection site reactions and bruising were the only adverse effects (AEs) that have been reported to date.

The trial is expanding to include 50 patients to confirm the efficacy and safety of the non-cytoreductive agent in a larger patient population, explained Hoffman.

“It is early days, but the agent looks promising," said Hoffman. “[This research] represents a major and potentially paradigm shifting step forward in the way we treat patients with PV.”

In an interview with OncLive, Hoffman, professor of medicine, hematology, and medical oncology and director of the Myeloproliferative Diseases Program at The Icahn School of Medicine, Mount Sinai, discussed the preliminary findings from the phase 2 trial and the potential utility of PTG-300 in the treatment of patients with PV.

OncLive: Could you discuss the current treatment paradigm of PV? What is the role of phlebotomy in this space?

Hoffman: PV is a chronic myeloproliferative neoplasm (MPN) characterized by erythrocytosis, leukocytosis, and thrombocytosis. The major complications of PV are arterial and venous thrombosis or thrombotic events, and hemorrhagic events. PV can progress to myelofibrosis and acute myeloid leukemia (AML).

In 2020, therapy is risk stratified. Patients who are younger than 60 years of age or have not had a prior thrombotic event are usually treated exclusively with phlebotomy with the goal of maintaining hematocrit at a level of less than 45%.

Patients who are over 60 or have had a prior thrombotic event usually receive myelosuppressive therapy, such as hydroxyurea, which is the present standard of care, or pegylated interferon. If patients progress on those agents, they will receive the JAK1/2 inhibitor ruxolitinib (Jakafi). In addition, patients will frequently receive aspirin.

All of these therapeutic approaches are geared toward reducing the incidence of thrombosis. Though, the most important metric is maintaining hematocrit at a level of less than 45%.

None of the options that are presently available prevent disease progression to myelofibrosis or AML.

Could you provide some background on PTG-300? What is the drug’s mechanism of action?

This is an interesting and exciting area of research. PTG-300 is a hepcidin mimetic. Basically, hepcidin is a physiological regulator of iron metabolism. It essentially regulates the entrance of iron into the body from the intestine and the release of iron from the macrophage where it is stored throughout the body.

Through work with my colleague, Yelena Z. Ginzburg, MD, of Mount Sinai, who is an expert in iron metabolism, we realized that this class of drugs could be active in treating patients with PV. Even though patients with PV are iron deficient at diagnosis, phlebotomy [increases their] iron deficiency.

Our rationale was that if we can block the release of iron from the macrophages that serve as nursing cells [in the form of] red blood cells (RBCs), we could reduce the uncontrolled production of RBCs.

We've [moved forward with] PTG-300, which was administered subcutaneously to patients with PV.

What was the design of this trial, and what patients were included?

There are 3 components to this trial. One is a dose-finding component where we determined the optimal dose of subcutaneous PTG-300 that is required to maintain patients’ hematocrit levels below 45%. Then, patients were randomized to continue treatment with the agent or placebo. The goal is to see whether patients' erythrocytosis returns when they are on placebo. Then, there is a continuation phase of the trial where patients [on placebo receive] PTG-300.

Eligible patients had more than 3 phlebotomies over a period of 6 months prior to study entry. That allowed us to use the frequency of phlebotomy as a metric for the efficacy of PTG-300.

What have you found so far?

We've only treated a limited number of patients. Presently, 8 patients are enrolled on the trial, 7 of which have received the drug, and 6 of which are evaluable. I want to emphasize that these are patients who were heavily dependent on phlebotomy.

First, we found that the drug is completely safe. There were no AEs beyond those limited to the administration of a subcutaneous drug, such as local irritation. That occurred in several patients, but it was extremely manageable. There were no allergic reactions to the drug.

Most importantly, none of the patients experienced progression to myelofibrosis, AML, or MPN blast-phase, or experienced a thrombotic or hemorrhagic event during the administration period. Remarkably, in all but 1 of 6 patients who have gone through a significant administration period of PTG-300, the need for phlebotomy was eliminated.

All of the patients continue on trial at present, and we are continuing to accrue patients.

What advantage could the self-administration aspect of this regimen provide for patients?

That is the critical feature of this agent. Presently, we phlebotomize patients to [reach] a hematocrit below 45%, and then we see them intermittently after several weeks or months. When patients return after 2 or 3 months, we phlebotomize them again if their hematocrit is elevated.

Phlebotomies can be traumatic or frightening to some patients. Occasionally, elderly patients can become syncopal, or their congestive heart failure can be exacerbated with phlebotomy.

During that period of time between visits, it is highly likely that these patients have elevated hematocrit that isn’t [noticed] because we do not have continual testing.

With the administration of PTG-300, we've been able to provide sustained hematocrit control throughout the observation period. It has yet to be determined, but it is highly likely that this will lead to a significant reduction of long-term thrombotic events.

From the patient point of view, self-administration can be quite rewarding because they [don’t have to] come to the clinic [to be] sure that their hematocrit is well controlled. In addition, several patients on PTG-300 had systemic symptom relief, such as fatigue, itching, or aquagenic pruritus that are associated with PV.

It is a 3-pronged benefit: patients can independently treat themselves at home, they have relief of their systemic symptoms, and they have sustained hematocrit control without the need for repeated phlebotomy.

What are the next steps of the trial?

The phase 2 trial is going to include 50 patients, which was recently expanded from 30. The trial is also a multicenter study now.

We are going to get a better feel for the efficacy and utility of this drug. I am hopeful that the results that were demonstrated in this small sample size can be observed in a larger patient population. If so, the hope is that [we can launch] a randomized phase 3 trial [with PTG-300].


  1. Hoffman R. Polycythemia vera and PTG-300 study results. Presented at: Protagonist Therapeutics Corporate and R&D Update; May 7, 2020.
  2. Protagonist Therapeutics press release. Protagonist Therapeutics Announces Initial Phase 2 Results with Hepcidin Mimetic PTG-300 in the Treatment of Polycythemia Vera. Available from: Published May 7, 2020. Accessed May 15, 2020.
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