New Agents Advance Treatment Options for Polycythemia Vera

Patients with polycythemia vera (PV) are often affected by thromboembolic events, and though risk of progression remains a concerns for treating hematologists, 2 recent advancements in the field may have a positive effect on the disease and overall treatment.

The first is ropeginterferon alfa-2b (Besremi), a biological agent which targets the malignant clone associated with PV. It is given under the skin as injection every 2 weeks. However, if less frequent delivery is needed, studies have shown ropeginterferon to be tolerated and effective long term.

The second agent is rusfertide, another injectable, once a week, under the skin agent. This synthetic medication has demonstrated hematocrit control in patients with PV. While it does not need to be combined with any other drug to be effective in patients with PV, it is complementary with other agents.

In an interview with Targeted OncologyTM following the 36th Annual International Congress: Hematologic Malignancies (ICHM), Srdan Verstovsek, MD, PhD, the United Energy Resources, Inc., professor of Medicine, chief of the Section for Myeloproliferative Neoplasms and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center in Houston, discussed the ways in which ropeginterferon and rusfertide can reduce thromboembolic events in PV.

Can you provide a brief summary of your presentation given at ICHM on the progress of PV?

Polycythemia vera is one of what you usually consider benign conditions of the bone marrow. It is in the milder proliferative neoplasm group. The patients usually live about 15 to 20 years, which is close to normal because a typical patient is 65 years of age. But there are patients that are younger than that, and you wonder what their overall outcome is. The standard therapies do not address those issues of long-term survival. They are always focused on controlling the blood cell count to control the thrombotic risk, because the thrombotic risk is typically a complication that may lead to untimely death.

The development of interferon, which is the first approved drug of that class, ropeginterferon alfa-2b, also known as besremi in November of last year, in the United States, changed the outcome of the patients beyond just controlling the blood cell count. The drug was approved in November based on about 75% complete hematological response in prior studies in PV patients. Complete hematological response is usually defined as elimination of phlebotomy and maintenance of hematocrit below 45%. That is the percent of blood that is made of red blood, control of the white blood cells and control of the platelets, so 3 lines control.

We know that interferon works. This is not the first interferon ever used, but it is the first approved. I would say 5-10% of patients in community settings are usually exposed to interferon, usually younger ones, because the issue is tolerance. This 1 is given under the skin every 2 weeks and appears to be tolerated very well. That means that you can give it for much longer. Usually, in clinical studies with prior versions of interferon is only about 3-5 years on average duration. If people have it for 15 to 20 years on average, you need a long term therapy. That's why hydroxyurea chemotherapy by mouth is a typical choice and 9 out of 10 patients would be given hydroxyurea. Now with this interferon tolerance improved, your abilities improve, response is excellent, and there is a potential for more.

I highlighted in my presentation a molecular response. Molecular response is where you are decreasing the JAK2allele burden. That's the percent of cells in a sample of the patients that have mutations, and it goes down over time steadily. By 5 years, about 14% of patients have undetectable JAK2 mutations. People say, what does this mean? I can't tell you yet, but response prospects are that if we continue like this, and you can with this drug, then more patients will have molecular response and you may have a potential for disease modification. Fewer patients will have not just a blood clot risk, but also less of a transformation to myelofibrosis or acute myeloid leukemia, which are long term complications not too many people talk about.

This is quite the development. First, interferon approved for PV is safer and appears to be able to be delivered for much longer, maintaining that response and having potential for that biological modification down the road if we continue to treat patients long term. Now, there are other drugs in development, this one was just approved not too long ago. We have a drug called rusfertide in a phase 3 randomized study for patients with PV that have a need for too many phlebotomies. What I'm talking about is that the standard practice for all polycythemia vera patients is to have bloodletting done, phlebotomy, to decrease the hematocrit below 45%. A majority are also given hydroxyurea to normalize the white blood cells or platelets and eliminate the need for phlebotomy.

Many times that phlebotomy need is too high, even in people who are on hydroxyurea or perhaps on interferon as we discussed earlier on. Then, you can add a new medication. Rusfertide in this case is added hydroxyurea or if nothing is in use, you just use it alone to eliminate the need for phlebotomy. Rusfertide is the hepcidin mimetic, the master iron metabolism regulator. It would decrease the availability of iron for blood making, achieve the iron in the reticle interior system of the body, keeping it in the liver lining, the gastrointestinal tract, in the spleen. And immediately in a great majority of the patients, 84% of the patients within two weeks, eliminate the need for phlebotomy in the phase 2 study.

We are excited about having a prospect to the open phase 3 randomized, placebo controlled, blinded study for possible approval of yet another drug for PV patients in those that need to manage phlebotomies. Whether there are any therapies not, that need for phlebotomy is important to control, eliminate basically, because you still have too high of a risk of blood clotting if the numbers go up and down and you keep phlebotomizing. It should be eliminated and that's the goal of this setup.

Can you discuss the comparisons between ropeginterferon alfa-2b and rusfertide?

Ropeginterferon is a biological agent in the sense that we have interferon in our own body. It goes up when we have inflammation or an infection and that causes some flu type symptoms that people usually recognize easily when we talk about side effects of interferon. Ropeginterferon in preparation has this pegylated part to it, allowing it to be slowly released. That is why it's given under the skin as an injection every 2 weeks. Earlier on all their preparations were given either every day or 3 times a week or once a week. We did an injection and you may have some side effects, flu type symptoms. Less frequent delivery is then desirable, and then like we know now from the studies of ropeginterferon, it can be tolerated and it can be effective long term.

What it does is it modifies the bone marrow. It is an immune booster, it changes the proliferation of the cells in the bone marrow, it may normalize it in some patients, it can decrease the JAK2 allele burden, that means the number of cells affected by disease, as we said before. It has a not a lot of different possibilities as to how it works and what it does. The bottom line is it's effective, it's tolerable, it's biological. I would use it particularly in younger people, but if the tolerance is good as we see it, it can be used in older people as well without much of a problem.

Rusfertide, another injectable under the skin once a week, is a synthetic medication that mimics a protein in the blood which is called hepcidin, which is important for one to regulate where the iron is. The higher the hepcidin, and this is hepcidin mimetic, the less of the iron would be getting out of the GI tract and there will be less of the iron available for the blood making. This balance of the iron in the body is outweighed by the hepcidin mimetic by having a higher hepcidin, as that is what the rusfertide would be doing. In that sense, these are completely different modes of action. They may even complement each other. In the phase 2 open label of rusfertide, there are some patients that are on interferon and still require too many phlebotomies, you add rusfertide to it and eliminate the need for phlebotomies.

Rusfertide is complementary to other medications which we have, particularly hydroxyurea. We have experienced the combination of interferon, combination with ruxolitinib as well in the PV setting. It is a nice addition to what we would otherwise use. It does not necessarily need to be compared to anything as it's a combination partner as well as a single agent.

What are some of the side effects of these newer PV treatments? When should patients contact their healthcare team about the symptoms?

For ropeginterferon, the side effects are classic interferon related but less common. That would be occasional injection site irritation, usually not the big deal. For flu type symptoms, we would usually prevent or control by giving patients before injection, some Benadryl or some Tylenol, perhaps even after injection. The long term, perhaps the suppression of bone marrow too much, you decrease the dose. Autoimmune problems and depression are known usual problems with interferon and may be present occasionally with ropeginterferon as well. These are usually discovered because they're slowly evolving by the treating doctor upon visit with the patients and asking questions such as how are you feeling and testing for thyroid problems because autoimmune thyroid problems can evolve on interferon.

With rusfertide, we never had any cited mimetics ever. The knowledge about the side effect is relatively limited compared to interferon, but in the phase 2 open label study, there was not much talk about. There were some injection site irritations as well, but not much of anything else of significance. For a long-term use, because that will be my goal, to have any new medications used for a very long time, years and years, decades, we still don't have that information. We'll see if there are any possible side effects long term with rusfertife, but I will hope not.

How has the field of PV treatment changed in the last 20 years? What work still needs to be done?

20 years is a very long period of time, even for benign conditions like polycythemia vera. Were. From understanding the diagnostic process of what needs to be done to make proper diagnosis, what needs to be done to recognize the patients that need to be tested, that was some 10-15 years ago, to understanding how to optimally assess the therapy benefits. Not only looking at the red blood cell count, but also looking at the control of the white and platelets seen in symptoms in addition to red blood cell count. And developing the criteria for failure of a therapy so that you can have a first line and the second line therapies.

Not everybody responds to a first line. You need to know how to assess the benefit and develop drugs for the second line, which was Ruxolitinib some years ago. Now with the approval of ropeginterferon as a full-fledged first line choice in addition to hydroxyurea, you see how the field evolved from an obscure, benign condition that nobody cared about to having more options than one approved therapies and a new one, rusfertide in the phase three study for possible approval. The field is evolving, perhaps not extraordinarily fast, but for the benign condition like polycythemia vera, which is not benign in everybody, we are talking about a huge development in the field over the last 10 years.