Why Gene Silencing Could Change Polycythemia Vera Treatment

Therapeutic phlebotomy has been the cornerstone of treatment for polycythemia vera for decades. Patients with the blood cancer produce too many red blood cells, which raises the risk of blood clots, and drawing blood brings those counts back down. The trade-offs come with the routine of unpredictable office visits, a large needle and iron levels that fall low enough to cause symptoms of their own.

Divesiran reaches the same goal of keeping hematocrit, the share of blood made up of red blood cells, in a safe range, but it gets there by raising levels of hepcidin, a hormone that limits how much iron reaches the bone marrow, so the marrow has less to work with and slows production.

In the phase 2 SANRECO trial, 88% of patients treated with divesiran maintained a hematocrit below 45% between weeks 18 and 36 without a phlebotomy, compared with 19% of patients who received placebo.

CURE spoke with Dr. Marina Kremyanskaya, lead investigator of the SANRECO trial and associate professor of medicine, hematology and medical oncology, at the Icahn School of Medicine at Mount Sinai in New York, about what the results may mean for patients who are living on a phlebotomy schedule now.

CURE: Why is phlebotomy dependence an issue in polycythemia vera?

Kremyanskaya: Therapeutic phlebotomy is a mainstream treatment for patients with polycythemia vera that we have been using forever. It is literally taking out blood, so it is like a blood donation except that it is done for therapeutic purposes. Patients with polycythemia vera make too much blood, which puts them at risk for blood clots.

It is also a pretty big burden. They have to come in. They do not know whether they are going to need a phlebotomy, or whether it is going to be a short visit or a long visit. Some patients have a hard time tolerating it. It is a pretty big needle that needs to be used to collect the blood, and some patients get a lot of anxiety from knowing that they may need to have this procedure.

Because patients need so many phlebotomies, we are also making them really iron deficient. Part of that is what we are trying to do, but as a result, patients can get really symptomatic because their iron levels are so low. It works, but we think we could do a lot better. We should be able to offer more modern, more effective treatments for our patients.

How much time does phlebotomy take in polycythemia vera?

It is not unusual for patients to spend anywhere from an hour, which I think would be ideal, to three hours, potentially even longer, every time they need a phlebotomy in the office. I do not know the exact numbers, but I can give an estimate. A patient who gets phlebotomies on a frequent basis might come in every month, or every three months. They have to come to a place where that can be done, which is not any doctor's office. Typically, it is a hematology practice, and they get the labs, get the results and then have the procedure.

Patients with polycythemia vera are typically people who are working, who have families and who do all of the normal activities. So it takes a significant chunk of their life to do this.

How does divesiran work in polycythemia vera?

Normally, our bone marrow needs a lot of iron to make red blood cells. That is where the majority of iron in the body goes. Typically, if there is not a lot of iron in the body, people become anemic. Most people have heard about that, when someone says they are anemic because they do not have enough iron.

What happens with polycythemia vera is that the normal pathway is somewhat broken. Even though the body is iron deficient, the bone marrow still takes all the iron that is available and still makes the red blood cells. There is none of that stoppage that you would normally see when you do not have polycythemia vera. The body becomes really low on iron, because all of the iron is being funneled into the bone marrow.

What we are doing is turning off that flow of iron into the bone marrow. That gives a little bit of iron back to the rest of the body, which does not need that much for normal cell function, and the total iron in the body is somewhat increased. People potentially feel better, because there is iron available for other functions of their body.

What did the phase 2 SANRECO trial show in polycythemia vera?

These patients no longer need as many phlebotomies as they have in the past. I cannot speak to the experience of individual patients beyond what has been publicly disclosed. But in general, they are happier because they do not need to get phlebotomies as much, and it keeps their hematocrit levels steady. What we see is that patients are feeling better, and they are reporting that their polycythemia vera-related symptoms are improving.

What are the side effects of divesiran?

In general, the drug is well tolerated. We always worry about safety with any drug, and specifically with new drugs.

This is an injection that is given subcutaneously, right under the skin, and sometimes people can have a local reaction, even a little bit of redness or itchiness. What was seen in phase 1 is that it is very self-limited. Patients do not need any other interventions.

Grade 1 anemia is very mild anemia. With the mechanism of action of the drug, where we are limiting the amount of red blood cells being produced, this is not unexpected. As long as it is grade 1 anemia that is tolerated by patients, and they are not symptomatic from it, I think that is a pretty good safety result.

What does the 88% response rate with divesiran mean for patients?

What it suggests is that with a drug like divesiran, we can potentially keep hematocrit under control without the need for therapeutic phlebotomies in the majority of patients. That is a pretty exciting response rate. It is important to keep in mind that this is a phase 2 study, and we are looking forward to seeing what happens with phase 3.

What is next for divesiran and the planned phase 3 trial?

It was nice to see that dosing the drug every 12 weeks, as opposed to every six weeks, is potentially similarly effective.

The phase 3 trial is still being planned. Treatment every 12 weeks will be more convenient for patients compared with every six weeks, or something more frequent. But it is still a clinical trial, so there will be close monitoring no matter what. Even with less frequent doses, patients will still be under very close monitoring.

This is an exciting field right now for polycythemia vera, where we are using a new mechanism of action that we would not have thought about a number of years ago. We took knowledge from what was really a separate field, iron biology, and are using it as innovation to treat patients with polycythemia vera. There is a lot of excitement going on in the field.

Transcript has been edited for clarity and conciseness.

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