Thrombotic Risk Reduction and High Rate of Complete Molecular Response with the Long Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: Results from a Randomized Controlled Study, ASH 2019 interview with Dr. Kiladjian
by David Wallace
Dr. Jean Jacques Kiladjian, Professor of Clinical Hematology, Hopital Saint-Louis, Paris, France interviews with David Wallace, PV Reporter at ASH 2019. Discussing results from the ropeginterferon long term clinical trial in Polycythemia Vera. In the PROUD-PV / CONTINUATION PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi) was compared with the standard cytoreductive therapy regarding thrombotic and other adverse events as well as hematological and molecular parameters over a four-year period.
The key treatment goals for PV are to prevent thrombotic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. Long term treatment with ropeg is capable of inducing deep molecular responses. As a result, studies suggest that select patients could achieve “operational cure” with both complete hematological remission (CHR) and complete molecular response (CMR) with ropeg, opening the way for treatment discontinuation. This highly anticipated “long acting” interferon is expected to receive FDA approval in the United States in Q4 2020.
Transcription: Dr. J.J. Kiladjian ASH 2019 Ropeg interview with David Wallace PV Reporter
David Wallace: Hello, this David Wallace with PV Reporter and we are here for ASH 2019 in Orlando, Florida. And today, we are interviewing Dr. J. J. Kiladjian from Paris, France. We are very thankful to have you again this year, Dr. Kiladjian.
Dr. Kiladjian: Thank you, David.
David Wallace: So, the first thing I wanted to discuss was Ropeginterferon. So the thrombotic risk reduction and a high rate of complete molecular response with long term use of Ropeginterferon and PV. So tell us about your findings from this study.
Dr. Kiladjian: So during this meeting, we present the long-term results of the so-called ‘Proud-PV continuation studies.’ After four years of use in both parts of treatment. Do you remember this randomized study compared Hydroxurea to this new form of interferon Ropeginterferon alpha 2b. Which is a very long-acting interferon with an injection every two weeks and we show the other results after four years of treatment in both arms. And I would say that maybe like it is with French wine, it improves all the time. So what we show here, is that first – in terms of complete methodological response – 61% of patients in the Ropeg arm maintained the complete response after the fourth year of treatment, compared to only 43% in the hydroxyurea arm. In addition, they use up the drug very easy, because we noticed that more than 40% of patients during the fourth year require just one injection per month. For very easy treatment compared to every day at least or we then have weekly administration of the different forms of interferon. The second reassuring point was that we observed a very low rate of thrombotic events in both arms of treatment, in fact. And probably because we chose an early PV population. But still, we have around 3% thrombotic events in both arms of treatment. So it was very nice. The second important point, of course, is the molecular response, so the diminishing of the JAK2 units in allele burden. And at the fourth year of treatment, we had more than 65% in the interferon arm, we achieved some reduction in the JAK2 allele burden, compared to only 25% in the hydroxyurea arm. Importantly, the medium value of the JAK2…The quantity of JAK2 new patient that was once 30% in both groups at the beginning of the study, regularly decreased in the different arm down to less than 10% at the fourth year, while in the hydroxyurea arm, it remained mostly the same, slightly increased the ratio of 45% median allele burden at four years. So there is a huge difference between the two groups of treatment. In addition, we have now a proportion of patients who have achieved so-called complete molecular response, meaning that the JAK2 mutation is no longer detectable with the usual tests. And we have certain patients in the interferon arm, who achieved this complete molecular response, eleven of which also have complete hematological response and normal counts. JAK2 is no longer detectable and no patients in the Hydroxyurea arm unfortunately, to have these complete medical responses. So again, a big difference between the two drugs, in terms of potential disease modification on the long term. Because once you achieve complete hematological response with normal counts, complete molecular response, where JAK2 mutation is gone. So this totally opens the way to see if we can stop treatment with these patients and see what happens. We have this experience with the other forms of interferon. But here we have substantial proportions of patients, we may achieve this… Maybe not cure, but what we sometimes call an operational cure, meaning that it could be completely treatment-free, with normal counts, of course no symptoms and no JAK2 mutation.
David Wallace: Okay, that are impressive results and I remember that a couple of years ago, we talked about the early stage of Ropeg versus Hydroxyurea. In one year, there wasn’t a tremendous difference. But we know Ropeg is slow-acting. So this is great news for all patients, I think.
Dr. Kiladjian: Yes, exactly. I think you are right, the two drugs have different profiles. They are both useful I think, we do not throw away – of course – Hydroxyurea. The rapid interaction is important, you will quickly reach responses, you are protected from vascular events. So it’s also useful. But we have now this balance between the two drugs with different objectives on the long term, of course. And as you know, PV is not an acute disease, hopefully. So we have to deal with it for a long time, for many years. And if we can reduce the burden of treatment and sometimes stop treatment for patients, that would be great.
David Wallace: Alright, very good. If I were a patient just starting out on Ropeg, what would an initial dose be and what would be the incremental increases for dose adjustment? And then also, what would be the median dose that a patient on average might use?
Dr. Kiladjian: Well, this is an important question. That is not completely solved by the clinical trial because when we started the study, we were very cautious to avoid adverse events, so we started at a very low dose. So it took a while to increase progressively the dose, to achieve the efficient dose. That is probably somewhere around 250-400 micro-gram every two weeks. But what we noticed is that again, with the long-term use, we saw it decreased in the average dose every year. So going down from 600 micro-gram to less than 400 micro-gram at the fourth year. So showing again that you can probably stop maybe the high dose and after one or two years of treatment, start to decrease the dose, tackle the dose. And hopefully maybe stop one day.
David Wallace: Okay. That’s good to hear. So, do you foresee any combination studies with Ropeg? Are there any going on or is that a future possibility? Tell me your feelings about that.
Dr. Kiladjian: In Polycythemia Vera, I don’t think so. Because we have at least two efficient drugs that can be complimentary to a different one and switched together, etc. And we have nice results with both different, that’s quite interesting. So I don’t think a combination should be tested. Unless for a few patients who unfortunately are resistant to everything, who have a very aggressive disease, so maybe a small subset of patients. But this would be probably more important for patients with myelofibrosis, so advanced stage of PV, like the patients who were tested for example in the Ruxolitinib trial, the Response study, that had very advanced stage with a big spleen…a huge amount of phlebotomy and very ? diseases. So maybe yes, we have to find a partner for Ropeginterferon. As you probably know, we have an ongoing study in myelofibrosis combining Interferon and Ruxolitinib, that shows interesting results on the first part of the study. And we are expanding it for more patients. But we found nice molecular responses. And not only on JAK2, but also, you know that some patients have additional mutations, that sometimes have bad mutations that induce a poor prognosis. So we are pleased to see that we could reduce not only JAK2 mutation, but also these additional mutations that some patients combined with drugs. So yes, we still have to find partners.
David Wallace: Alright. And that leads me into my next question. So, with Pegasys we have seen good results, showing hematological and molecular remission. As a patient that’s on Pegasys and doing well, is there a benefit to switch into Ropeg? Or would you just keep the patient on the same medication?
Dr. Kiladjian: That is an important practical question, because a lot of patients on interferon, they currently are on Pegasys. Obviously, for Europe, the drug is now approved. The Ropeg has been approved for PV. So it would be natural to switch to this drug, because of regulatory reasons. Otherwise, I don’t know if the patient is well on Pegasys. Is there a benefit to switch? I think the only possibility probably would be to achieve better molecular response and stop treatment. So if the patient on Pegasys still has a high amount of JAK2 mutation, maybe it could be nice to try the other one. And also, the mode of administration is also easier. We have Ropeg pens that you can do for self-injection and doing one injection per month instead of weekly is also maybe an advantage for the patient.
David Wallace: Yes. And I can see that as a patient who takes Pegasys infrequently. But at one point, I was taking it every week. And to be able to push to once a month is a big deal, I think, for patients. Well, I’d like to thank you for talking with me again this year. And I look forward to your studies in the future. You’re always one of the world experts I like to keep an eye.
Dr. Kiladjian: Thank you very much, David.
David Wallace: Thank you.
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