Novel Hepcidin Mimetic Demonstrates Dose-Related Control of Hematocrit Levels in PV

Initial results from an ongoing phase 2 study demonstrate that individualized dosing of PTG-300, a novel hepcidin mimetic, provided dose-related control of hematocrit levels and eliminated the need for phlebotomy in 6 of 6 patients with polycythemia vera (PV) receiving therapy.

Srdan Verstovsek, MD, is a Professor of Medicine in the Leukemia Department at the University of Texas MD Anderson Cancer Center, Houston, where he specializes in myeloproliferative neoplasms (MPNs), chronic diseases of the bone marrow that lead to uncontrolled growth of the blood cells.

Dr Verstovsek spoke with Oncology Learning Network about the initial results of the phase 2 study, as well as next steps for research of this therapy in PV.

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What led you and your coinvestigators to evaluate PTG-300 in patients with PV?

In PV, the primary problem is uncontrolled growth of the red blood cells. Too many red blood cells as measured by hematocrit, a percent of blood that are red cells, leads to an increased risk of blood clotting.

The standard practice when we have a patient with diagnosed PV is to assess the risk of blood clotting and divide the patients with PV in so-called low-risk patients for blood clotting, which we treat with phlebotomy, bloodletting, and baby aspirin to decrease the stickiness between the cells.

For blood clotting in the high-risk PV patients we, in addition to phlebotomy and baby aspirin, implement a cytoreductive therapy, usually a chemotherapy, to normalize the blood cell count and perhaps eliminate need for phlebotomy and, with that, decrease the risk of blood clotting.

With phlebotomy, the patient with PV becomes iron-deficient. That would decrease the need for phlebotomy, perhaps not eliminate it completely because iron, in essence, is a food for red blood cells. With iron deficiency, some patients may have iron deficiency–related side effects. Phlebotomy itself may cause some problems in certain patients with PV.

With cytoreductive therapy, we may not be able to completely eliminate the need for phlebotomy. Therefore, the goal of further optimizing the therapy for PV, specifically focusing on control of the hematocrit as a measure of red blood cell count, is a valuable goal.

In this setting, therefore, understanding the biology or metabolism of iron is crucial. Here, the hepcidin mimetics, which would be affecting how the iron is stored and transported throughout the body, and particularly PV setting, is of value.

Therefore, we have the new medication, hepcidin mimetic PTG-300, in development as a new therapy for PV to control—in a completely different way (through, again, modifying the iron metabolism, hepcidin specifically)—the red blood cell count and improve our management of patients with PV.

Can you please briefly describe the study and its findings?

The study at hand is the open-label, phase 2 study where we enrolled patients with PV who may or may not be receiving a cytoreductive therapy. There are patients who are very low-risk but require phlebotomies quite often—they don't like that. They may have side effects from it or may have side effects from iron deficiency.

For patients receiving cytoreductive therapy, hydroxyurea is usually given to control the red blood cell count, but they may still require phlebotomy. This type of patient, either on or off cytoreductive therapy, who are requiring a certain number of phlebotomies, has been enrolled and is being enrolled in the on-going study of the hepcidin mimetic PTG-300.

It's injected once a week to eliminate the need for phlebotomy and improve metabolism of iron, and with that perhaps improve the symptoms of these patients, which would be a secondary benefit from the therapy itself. The primary goal would be elimination of the phlebotomy, and the secondary would be improvement in quality of life.

So far, we have exciting new data on a very small number of patients; however, it gives us a hint that PTG-300 is effective in eliminating the phlebotomy needs in these people that are requiring them quite often.

That gives us a possibility of developing in the near future this simple therapy that is given in a safe way, subcutaneously, to improve our management of these patients, and particularly to eliminate phlebotomy need and with that, ultimately, as a surrogate marker for decrease of thrombosis itself.

What are the next steps for research regarding PTG-300 in this patient population?

We are very early in development of this new therapy for our patients with PV, but we have a good signal that it does the job of eliminating the phlebotomy need.

Now, we are talking about the evidence based on <10 patients. So far, these 6 patients had a really good response and the medication has not provided any significant toxicity.

Now, there is much more work to be done. We need to expand our experience, obviously. We need to understand the management style.

What is the best starting dose? What is the frequency? Is it once a week, every other week, or twice a week? How often do we need to adjust the dose? Are there any long-term toxicities? Should this therapy be perhaps combined with cytoreductive therapy together? Is that possible in a safe way? There are many patient questions regarding where we go next.

We are excited about having evidence that, in a safe way, we can achieve the primary goal (one of many in PV), and that is control of red blood cells.

The ultimate goal after these questions have been answered is to find a group of patients in whom benefit would be the most obvious. Is this a group of low-risk patients who are managed typically with phlebotomy and aspirin? Is it a group of the patients in whom we should be looking for those that need too many phlebotomies or are bothered by frequency of phlebotomies or side effects?

Is it a subgroup of low-risk patients, or a group of patients who are receiving cytoreductive therapy and not deriving optimal benefits from it, in whom we should be adding PTG-300 to control their red blood cell count?

These are the questions that we will have to address along the way as we ultimately focus and find the best group of patients for further development of this drug so that it can ultimately be available to all our patients in community practice.

Is there anything else you would like to add?

I would like to encourage my colleagues in the field to join the effort and enroll patients in on-going studies—a multi-center, US-based study should help us identify these new therapies.

We don't have too many new therapies for PV, but here, we have evidence of a safe and effective therapy that, based on preliminary results, we should embrace together. 

Find additional details on this ongoing study here.