Polycythemia Vera

Srdan Verstovsek, MD, PhD

March 2022

In segment 2 of our conversation with Srdan Vertsovsek, MD, PhD of MD Anderson, he shares the latest on research for polycythemia vera or PV treatments.

Rusfertide overview

The Patient Story: For PV, polycythemia vera, you pointed out two drugs in particular. So I’d like to talk about those. One is rusfertide, which helps to possibly eliminate phlebotomy, which would be huge news for a lot of patients.

It’s a Phase 2 study, can you talk more about what this means? The shot that would help replace the phlebotomies?

Dr. Srdan Verstovsek: Polycythemia vera is different than myelofibrosis. We caught it earlier in the life of the myeloproliferative neoplasms. There are abnormalities that lead to uncontrolled cell growth. Polycythemia patients come with a very high red blood cell count, and many have also high white cells and high platelets. That’s why it’s called polycythemia. All the cells grow.

Some patients may have enlarged spleen or have some symptoms. That’s fine, too, but not as bad as myelofibrosis. So the life expectancy is much, much longer. We don’t really worry about much of the expectancy, but we worry about what is the main cause of death, and that is the blood clot.

So it’s standard practice for many patients just to do phlebotomy occasionally to decrease the red blood cell number in the blood. And then you give them baby aspirin to decrease the stickiness. There is a plan for a Phase 3 randomized study next year in people with PV that have too many phlebotomies.

Now, some patients may have a problem with too many phlebotomies, With the phlebotomy, you eliminate iron from the body. The red color is in part of the item may have symptoms from the procedure. Symptoms from iron deficiency.

How rusfertide works

Rusfertide, in this case, may come as a choice because it cuts the iron supply to the bone marrow. That’s what it does. Very simple. It stores it in the liver or spleen and other parts of the organ of the body of the patients—no iron for the making of red blood cells.

Immediately, boom. And it’s safe. So that is being developed as a therapy in patients that are on phlebotomy regimens and have too many phlebotomies.

There are many other patients with PV that are already taking some medications. Hydroxyurea is the chemotherapy pill by mouth or an interferon is an injection under the skin. Or ruxolitinib that we talked about is also being used in PV. But maybe it doesn’t work.

Still, too many phlebotomies. Well, rusfertide works in this case, too, no matter whether you are on any pills or not, just phlebotomy, it works in the great majority of the patients. It’s quite amazing, actually, the new way of looking at the biology of the disease to cut the supply of the iron to the bone marrow biologically, physiologically, if you like in a body of the patients.

And there is a plan for a Phase 3 randomized study next year in people with PV that have too many phlebotomies. You can say, three or four are too many. We want patients not to have a need for phlebotomy at all, just to maintain the low number of red blood cells all the time decrease that blood clotting risk as much as you can. So these patients will be randomized between the placebo and the rusfertide for possible approval. Quite an exciting approach.

How often would PV patients get rusfertide (shot)?

The Patient Story: How often would someone have to get that shot just as many times as they would be instead of the phlebotomy would just be the shot instead?

Dr. Srdan Verstovsek: Once a week, people do it on their own at home, and they would occasionally come to check the blood and see whether there is any adjustments necessary in the dose, which is not usually a problem.

Rusfertide side effects

The Patient Story: I would be remiss not to ask about any notable side effects so far in terms of the shots?

Dr. Srdan Verstovsek: In fact, just a little bit at the site of injection in some patients, but nobody really stops because it goes away. You change the site in the belly or arm or a leg and not much anything else. It’s another biological principle of the disease that has been analyzed and discovered how to best approach it, and this is a very good example.

Ropeginterferon alfa 2b (BESREMi)

The Patient Story: There are different developments happening for PV, and I want to be able to shift now to another one that you talked about. What was the latest update with BESREMi or ropeg, with polycythemia vera patients responding better than to the hydroxyurea?

Dr. Srdan Verstovsek: We said that some patients with polycythemia vera are treated only with bloodletting, phlebotomy, and baby aspirin, but that’s actually a third of the patients.

Two-thirds of the patients are just to be at high risk for blood clotting, and phlebotomy alone is not good enough. So you give them chemotherapy by mouth. That’s hydroxyurea or injection under the skin, which is an interferon, a biological product. We all have interferon in our body, it’s an immune booster.

When you give it an extra injection, it can control the bone marrow growth of the cells, even normalize it sometimes, and affect the malignant clone. The number of cells with the mutations may decrease, and in some patients, you can give a ruxolitinib JAK inhibitor to decrease the growth and inflammation. But now interferon has been around for 50 years, actually different preparations of interferons.

On November 12, 2021, the first time ever in the United States, one of these interferons has been approved. And that’s the one that you are calling Besremi. It’s a commercial name. The real name is  ropeginterferon. We call it ropeg.

Ropeg (BESREMi) administration and dose schedule

It’s slow-release interferon that is given under the skin every two weeks. Many patients apparently can get it even once a month. Fewer injection means better tolerance.

Ropeg (BESREMi) side effects

Because of the injections, it causes flu-type symptoms. If you give it any other week or every four weeks, that doesn’t happen many times. The tolerance goes up. With the tolerance, you can then expect efficacy.

In three-quarters of the patients, we normalized the blood count – completely normal red blood cells, white cells and platelets, not just the red blood cells. All three. It was approved in Europe two years ago, and now it’s approved by the United States.

No answers today, but the potential exists, and it appears to be safe and appears to be effective for years.

Learning from ropeg studies in Europe

So at this meeting here earlier this month, the American Society of Hematology meeting, we learned about five years of therapy on a study that was done in Europe.

More than half the patients are still on therapy. It can be given as a first-line, which would be my preference is the biological agents. It can be given after hydroxyurea as a second line and it works the same way. It doesn’t really make any difference. That’s the potential that I’m talking about.

It can change possibly the number of cells affected by the disease over time to non-detectable. This is very something unusual to see so far with any other therapy. We call this the molecular response. You can measure the number of cells in the blood affected by the disease.

We don’t really know what to do out of it, but it’s very instructive that, yeah, there is a therapy that possibly can aim forward to what you ask for myelofibrosis. No answers today, but the potential exists, and it appears to be safe and appears to be effective for years.

Major questions now

• Can we eliminate disease?
• Can we prevent progression?
  • Because some patients with PV do go to myelofibrosis. Can you prevent that when they go to myelofibrosis, the outcome is worse?
  • Some patients go to acute leukemia from PV. Not too many, but some do. That’s really not very good at all.
  • So if you can minimize or eliminate detectable malignant cells, does this mean you’re preventing progression?
  • Are we talking about the cure? These are open questions.

They’re all big questions. No answers today, but the potential exists, and it appears to be safe and appears to be effective for the years. So that’s at least the background where we now want to build on it.

Like we said, build on what we know about, JAK inhibitors in MF (myelofibrosis) here. Let’s build on the interferon. It’s just approved. Let’s learn about it. Lets utilize it to the maximum to optimal efficacy over many years for our patients with polycythemia vera.

The differences with ropeginterferon

The Patient Story: All very promising, although we need more data. It was interesting what you said about what it’s being studied for. It could be the first line. You can start with ropeg, or you could use hydroxyurea and then use ropeg after.

There are different administrations. So there’s one that’s a pill, one that’s the shot. But also it may have the ability, as a biologic, to actually not just control but help with the disease, itself.

Dr. Srdan Verstovsek: Yeah, change in natural history, that’s the big potential which we strive to prove or disprove over time. And the key is that you can actually provide the therapy for many years because so far in the past, we were not able to do that. Usually, it was maybe three to five years maximum that you can provide the old-fashioned interferons that you have to give much more often that much more toxicities.

This one is different. And so it’s really what we need to do is embrace the new therapy now that it’s approved and try it in everyday practice in many more patients and see whether we can give it for five or 10 or 15 years, and whether we can really change the natural evolution of the disease.

Ropeg (BESREMi) side effects

The Patient Story: My last question is about what you just brought up, which is the side effects, the quality of life issue because you can have great efficacy. But if people cannot stay on it, then it’s not very effective. So what is it with ropeg that in terms of side effects so far that we’ve seen?

Dr. Srdan Verstovsek: They are not as prominent, but they are the same types as in the past. So less often. But we worry about:

• Depression
• We worry about autoimmune problems making people have a condition where the body attacks on its own parts like autoimmune problems.
• And we also want to make sure that there is no problem with too much suppression of the bone marrow causing anemia or thrombocytopenia.

But typically, it’s about this mental state, depression, autoimmune problems. You would actually exclude those patients from participation in such therapy because, you know, there is some small chance of a risk actually to cause some of these issues with depression and autoimmune problems.

How many people drop out of clinical trials from these side effects?

So these are known not as common. The dropout, meaning, how many people stop the therapy with peginterferon due to side effects, over five years of observation in this study that I described is very low – 10 percent, so it’s not very common.

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