Rusfertide Brings Future of Phlebotomies in Polycythemia Vera into Question

In effort to limit the number of phlebotimies needed for patients with polycythemia vera (PV), treatment with rusfertide (PTG-300) was investigated and helped improve the quality of life in patients with PV by achieving hematocrit (HCT) control through eliminating the need for therapeutic phlebotomy in patients with PV.

A phase 2 trial concluded rusfertide to be well tolerated and effective in achieving the target HCT of < 45% without phlebotomy in combination with induction therapy administered two times a week.

An ongoing phase 3 trial looks to confirm the findings of phase 2 as well as assess the primary end points of a confirmed HCT of 45% or less.

In an interview with Targeted Oncology^TM, Srdan Verstovsek, MD, PhD, a professor of Medicine and a hematologic oncologist at the University of Texas MD Anderson Cancer Center, discussed maintaining hematocrit levels in patients with PV as well as research on the use of rusfertide.

What is the importance of maintaining hematocrit levels? What do the guidelines currently recommend?

Verstovsek: Polycythemia Vera is one of the myeloproliferative neoplasms, which is defined by a very high blood cell count. The number 1 problem is too many red blood cells. We typically measure the red blood cells not just by the number, but by the percent of the blood that is a red blood cells, and that's called hematocrit. It has been shown that the hematocrit below 45% is valuable for patients with polycythemia vera. If it's below 45%, they have decreased risk of blood clotting, and blood clotting is the main problem and the main reason for dying from PV. Maintaining hematocrit below 45% in the prospective randomized study was proven to decrease the thrombotic risk and decrease the risk of dying, and that's why this is so critical for patients with polycythemia vera.

What would be your advice to community oncologists on preventing thrombosis?

The polycythemia vera patients will usually divided into groups. We assess the risk of thrombosis by looking at the age and the history of blood clotting. Patients that are younger than 60 and never had the blood clot would be low risk for blood clots. That's about a third of the patients. The two thirds of the patients that are either older than 60 or have a history of blood clot are called high risk polycythemia vera for blood clots. You want to in either case, minimize the time the patients spend at 45% hematocrit because that increases the risk of blood clotting and the risk of dying. In the low-risk patients, this is done by frequent phlebotomies. Phlebotomies means bloodletting, so in low-risk patients you phlebotomize, and bloodlet the patients and that would decrease the hematocrit. With phlebotomies, you also make people iron deficient. Iron is simply food for the red blood cells and as more phlebotomies happen, more iron deficiency happens, and that will decrease the rate of the phlebotomy. Still, there are patients that still require too many phlebotomies a year. The bottom line is that there are a number of patients that still spend a significant amount of time, about 45%, in their life. This is unnecessary.

In the high-risk group, we actually give patients medications on top of phlebotomy to eliminate the need for phlebotomies because they are at a higher risk for blood clotting. Nine out 10 times, we gave them hydroxyurea a chemotherapy by mouth. Sometimes we give interferon injections, or ruxolitinib [Jakafi] which is a JAK2 inhibitor that is approved as a second line therapy.

The goal here is to smooth the hematocrit percent below 45% all the time and eliminate need for phlebotomy. That is not the case in every practice. There are many retrospective chart review studies that show that this is not achievable. This is critical to maintain the patients below 45% all the time, particularly in the high-risk group. With the inability to control it, we need new agents that would help maintain the hematocrit below 45% in high-risk group all the time. Need is there in the low-risk group and in high-risk group to help achieve the goal of the therapy.

What is usually seen in terms of iron deficiency in these patients?

Phlebotomy is a regular way of managing the patients with polycythemia vera, and with it, you would eliminate iron from the body of the patients. Even on the cytoreductive therapy with hydroxyurea, you will have iron utilized by the uncontrolled global red blood cells because it's kind of a food for red blood cells. Most of the patients are iron deficient. It is counterproductive to give them iron supplementation because then they're able to start to grow and you need more phlebotomy. Then you need to modify cytoreductive therapy and give them more chemotherapy to counteract that growth of red blood cells.

Iron deficiency is a normal state of PV patients and that is in some cases the problem because iron deficiency causes symptoms memory loss, brittle nails, loss of here, restless leg syndrome, and that is a problematic issue because what do you do? You have iron deficiency as a normal state, it causes some issues. So you give iron, and then you need more phlebotomy. Normalizing the iron levels, which is possible with some of the new therapies, and not causing increased growth of the red blood cells would be beneficial for the patients at large.

Can you provide a brief overview of rusfertide and how it may help solve some problems that being seen in PV patients?

Rusfertide is the investigational agent which is given under the skin once a week. A patient basically can inject themselves. This drug really goes after the iron metabolism normalization. What it does is affect where the iron is distributed and how is it stored in the body of the person. Hepcidin is the protein in the blood that is a master iron metabolism regulator. When you have a higher hepcidin, the iron will be stored in the liver, in the spleen, in reticulo endothelial system of the body, in the gastrointestinal tract, and it will be less available for erythropoiesis for blood growth.

Rusfertide is a half sided, mimetic. There is a rare distribution of iron in the body, iron stays in the tissues and it's not available for blood making. What that does, immediately in almost all the patients in a phase 2 study which is underway, is eliminate the need for phlebotomy. Red blood cells go down and there is no iron in the bone marrow.

Not only do people feel better because you eliminate the need for phlebotomy, you don't feel well when the red blood cells are very high, but also because of the rare distribution of iron, it normalizes the iron measurements in the blood. Iron levels normalize, ferritin normalize, everything becomes normal. The symptoms related to the iron deficiency also go away. You have two sides of the benefit. One is primary goal elimination rate for phlebotomy and the second is improvements in the quality of life related to elimination of the higher red blood cell count that is causing some symptoms and improvements in the iron levels that are sometimes problematic. It is quite interesting, highly effective, and appears to be also very safe drug for development for therapy of polycythemia vera.

What will your phase 3 study assess and how will it be carried out?

We borrowed the experience from the phase 2 study. The phase 2 study was open to any patient whether it's a low risk that would usually receive only phlebotomy or is it for high risk patients that are typically on hydrea, interferon, or maybe on ruxolitinib. As long as there are too many phlebotomies a year, these patients were eligible for the rusfertide phase 2 open-label study. What we have seen is the that almost everybody benefits right away by elimination of the phlebotomy and people feel better.

Based on this information, the phase 3 study is similar in the design. The patients, either low risk or high risk, whether they are on any therapy or not, as long as they are on a stable dose and still need phlebotomies 3, 4, 5 times a year, would be eligible to enroll in the study. We want them to have no phlebotomies. The study will randomize the patients between placebo or rusfertide as an injection under the skin once a week to see whether we can eliminate phlebotomy.

The bottom line is that really doesn't matter whether the patient is low risk or high risk on therapy or off therapy. As long as the therapy they are on is not satisfactory in elimination of the phlebotomy, they're eligible. They will be randomized prospectively for a number of months to prove the point that in the randomized, placebo, controlled, blinded study, that rusfertide is very effective in normalizing hematocrit below 45% which is the primary goal in PV, and improve the quality of life at the same time.

What are the key end points? What do you hope to understand from this study?

The key point would be to eliminate the need for phlebotomy. That is the value that we understand is the number one goal in polycythemia vera patients. But along the way, because other issues may arise in the life of the policy team of our patients, we want to know and make sure that the therapy has other benefits. And you may understand that the quality of life is the paramount. You want to have a therapy that not only normalizes the blood numbers, but that improves the quality of life. So, we're going to look at the two particular aspects of the benefit: normalization and elimination of phlebotomy.

Normalization of the hematocrit below 45% and elimination of phlebotomy, durability of that benefit, making sure that there are no ups and downs, that this therapy works all the time, that the therapies given in a safe way, is given by the patients, so durability is another key secondary endpoint, but also improves the quality of life measured by different questionnaires. You want to objectivize that benefit on quality of life, by looking at specific issues that polycythemia vera patients suffer from. And finally, if these issues of quality of life are related to the iron levels, we're going to, of course, measure ferritin and make sure that these parameters correlate with improvements in quality of life and prove the point that normalization of iron elevation of iron deficiency is beneficial for the patients.

Are there any other relevant data that you have found interesting?

An abstract presented on the correlation between the risk of dying from myelofibrosis and the presence of the JAK2 mutation and specifically and how many cells in the body of the myelofibrosis patients are affected by the JAK2 mutation? What I'm talking about is assessment of the thrombotic risk. Now that we talked about the thrombotic risk in PV, we also need to realize that thrombotic risk exists in other myeloproliferative neoplasms, like myelofibrosis.

The summary of this presentation was from looking at European registry of myeloproliferative neoplasms that in all fibrosis, earlier stage patients they typically present with very high blood cell count, not red blood cell count, but usually white cells or platelets, when this is associated with a high level of the JAK2 mutation, that carries a significant thrombotic risk for these patients. We are basically extending from PV into the early-stage myelofibrosis. We need to have a better view and better understanding of who requires therapy for the thrombotic risk. We know a lot about PV, but we don't really know much about myelofibrosis. Early-stage myelofibrosis, with JAK2 mutations carries a very high thrombotic risk and we should probably do something about it by incorporating guidance in how to tackle myelofibrosis as well.