Rusfertide Lowers Hematocrit in Patients With Polcythemia Vera


With rusfertide, clinical trial investigators are poised to fill a clinical gap by addressing iron deficiency in patients with polycythemia vera.

Iron metabolism normalization is key mechanism of action of the synthetic mimetic of hepcidin, rusfertide (PTG-300), which has been shown to help achieve hematocrit control in patients with polycythemia vera (PV) without the need for periodic therapeutic phlebotomy.1

During the 63rd American Society of Hematology Annual Meeting & Exposition (ASH), 2 presentations highlighted the promise and the need for further exploration of rusfertide in PV treatment.

According to earlier research, rusfertide regulates iron absorption, distribution, and storage, thereby controlling the body’s production of red blood cells. Rusfertide is meant to be more potent and offer greater stability and solubility compared with the natural hormone.1 When explored in a phase 2 study as induction therapy administered twice weekly, rusfertide was found to be effective in achieving the target hematocrit of < 45% quickly and without phlebotomy.

Phase 2 Study of Rusfertide in PV

A recent phase 2 trial presented during ASH found that rusfertide was safe and tolerable in the PV patient population and did improve hematocrit levels.

“PV is a chronic myeloproliferative disease, one of several, it is associated often given its chronicity with a long period of survival, including sometimes up to 20 years post diagnosis. There are groups of patients both better categorized into low risk versus high risk. The low-risk patients are younger and do not have a history of thromboembolic events. The higher risk population is older and or has a history of a thromboembolic event. Patients are often treated with therapeutic phlebotomy, that's the mainstay of treatment, especially in the low-risk population,” said lead study author Yelena Ginzburg, MD, an associate professor of Medicine, Hematology, and Medical Oncology at Mount Sinai Hospital in an interview with Targeted Oncology™.

PV is often associated with fatigue, which can be severe, due to the increase in iron utilization by the disease. Iron deficiency worsens after repeated therapeutic phlebotomy. Thus, the management and treatment of symptomatic iron deficiency remains an unaddressed clinical need in PV patients. 

Rusfertide is being investigated in over 160 patients. It was placed on clinical hold after both benign and malignant subcutaneous skin tumors were observed in a mouse model. The hold was removed in October 2021 after a review.

The first study evaluating rusfertide in this patient population is a phase 2 study with an estimated enrollment of 20 participants and an estimated completion date of April 2023. The primary end point of the study is efficacy, measured as the proportion of patients with hematocrit < 45%. The secondary end point is safety.2

The study is composed of a single arm, and all patients received the study drug. Dosing and schedule were adjusted every 2 to 4 weeks and treatment continued for up to 52 weeks.

At the time of data cutoff, 16 patients were enrolled. The mean age of the patients (12 male and 4 female) was 56.1, with the median time from diagnosis being 3.74 years. With the agent, a rapid decrease in hematocrit to below 45% without the use of phlebotomy was seen and continued to be well controlled after rusfertide was reduced.1

Fifty percent of patients experienced adverse events. Injection site reactions were seen in 7 patients and were mild to medium in severity. Common injection site reactions included erythema (n = 7), induration (n = 5) and pruritis (n = 2). Hypertension, pyrexia, and thrombocytes were also observed. Two serious adverse events, which included worsening migraine and pleuritic chest pain, were considered unrelated to rusfertide.1

“The adverse events were adjudicated to be related to the agent were all grade 1 and 2, there was one patient with asymptomatic thrombocytosis, that did not require any intervention. And the majority of the adverse events were injection site reactions, none of which led to the patients experiencing that side effect to come off of the study. And we're all relatively transient,” said Ginzburg.

Further analysis is needed in order to validate these phase 2 findings.

"The main point that we are hoping to see with the trial as it continues is both prolonged continuous, either phlebotomy free or phlebotomy reducing effect of using rusfertide in the chronic setting that can also ultimately allow us to evaluate a potential reduction in the thrombotic events in this patient population,” said Ginzburg

Phase 3 Study of Rusfertide in PV

A phase 3 trial is currently underway to potentially confirm the previous phase 2 results. The global, multicenter, randomized trial aims to enroll approximately 250 participants to assess the primary end points of a confirmed HCT of 45% or less or a HCT of 48% or less.3

“We borrow the experience from the phase 2 study. The phase 2 study was open to any patients, whether they are low risk and would usually receive only phlebotomy or is it for high-risk patients... as long as there are too many phlebotomies, these patients were eligible for the phase two open label study. And what we have seen is that almost everybody benefits right away by elimination of the phlebotomy and people feel better. Based on this information. The phase three study is similar in the design,” said Srdan Verstovsek, MD, PhD, the United Energy Resources, Inc. Professor of Medicine and hematologist-oncologist at MD Anderson Cancer Center in an interview with Targeted Oncology™.

The phase 3 study will include 3 parts. Part 1a will be a randomized, double-blind, placebo-controlled, add-on group period lasting 32 weeks. Patients will be stratified by ongoing PV treatment and randomized 1:1 to receive either rusfertide or placebo added-on to their ongoing PV treatment. Part 1b will be composed of subjects who completed part 1a successfully. They will receive rusfertide for 20 weeks. Part 2 will be a long-term extension phase, where all patients who complete part 1b will receive rusfertide for an additional 32 weeks.

“The key point would be to eliminate need for phlebotomy. That is, the value that we understand is the number 1 goal in PV patients. But along the way, because other issues may arise in life of the PV patients, we want to know and make sure that the therapy has other benefits. And you may understand where we are, the quality of life is the paramount, you want to have a therapy that not only normalize the blood numbers, but with that improve the quality of life,” said Verstovsek.

1.Ginzburg Y, Kirubamoorthy K, Salleh S, et al. Rusfertide (PTG-300) induction therapy rapidly achieves hematocrit control in polycythemia vera patients without the need for therapeutic phlebotomy. Blood. 2021; 138(1): 390. doi: 10.1182/blood-2021-149205
2. 4.PTG-300 in patients with polycythemia vera and elevated hematocrit. Accessed January 5, 2022.
3.Verstovsek S, Kuykendall A, Hoffman R, et al. A Phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2021; 138(1): 1504. doi: 10.1182/blood-2021-149219

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