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What We Know About MDM2 Inhibitors for Myelofibrosis

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Published on June 25, 2021

Why Are MDM2 Inhibitors Significant for People With MF?

In this MPN Ask the Expert program, Patient Power co-founder and two-time cancer survivor Andrew Schorr meets with Alessandro M. Vannucchi, MD, Associate Professor of Hematology and Director of the Specialty School in Hematology at the University of Florence, to take about Dr. Vannucchi's research into MPNs, and specifically myelofibrosis (MF). They discuss the ongoing Boreas Trial and how it could be significant for people with MF, including what we know so far about the effectiveness of navtemadlin (KRT-232), a new MDM2 inhibitor. How will this knowledge affect current patients with MF? Keep watching to find out.


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Transcript | What We Know About MDM2 Inhibitors for Myelofibrosis

Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr in San Diego, and as you can see, with me is someone in Florence, Italy in front of the famous cathedral there. And that is one of our renowned experts in MPNs and research, and that's Dr. Alessandro Vannucchi. He is the Director of Hematology at the University of Florence and a full professor there. Professor Vannucchi, welcome back to Patient Power.

Dr. Vannucchi: Hi, thank you. Thank you very much. I am very pleased to see you, and good morning and good afternoon in Florence time.

Andrew Schorr: Right, thank you for being with us, sir. So of course, you're well-known for your research in myeloproliferative neoplasms and even the molecular genetics of cancers and hematology, and that brings us to myelofibrosis. And you may recall, and some of our audience know, I've been living with myelofibrosis for about 10 years, and I've been fortunate that the first line of treatment, the JAK inhibitors, ruxolitinib (Jakafi), and now I take fedratinib (Inrebic), have worked pretty well for me. But my understanding is that is not the case, that a significant percentage of patients, that JAK inhibitors either don't work or don't continue to work. Is that correct?

Are the Current JAK Inhibitor Options Effective for all Myelofibrosis Patients?

Dr. Vannucchi: Yeah, that's correct. You are a good example of how much ruxolitinib and other JAK inhibitors, like fedratinib, may impact on the life and the quality of life of a subject with myelofibrosis. We know from studies, but I'd say right now from real life data, because now the number of patients that have received and are receiving ruxolitinib is really high. The drug is very active on targeting the main manifestations of the disease, they target the enlarged spleen causing splenomegaly reduction and improving the symptoms that are associated with the disease and overall improving the quality of life. And there are also some data that suggest that there might be a favorable impact also on prolongation of survival of this patient, but at the same time, we know that this is not a disease-modifying agent.

The majority of the patient have some kind of response to ruxolitinib, so the truly primary refractory patient is not common. But unfortunately, what happens is that after three to five years of treatment, more than 50% of the patients actually have lost the response to the drug. And so, these patients really represent an unmet need in terms of treatment because we know that losing a response to ruxolitinib is associated with a poor outcome. Median survival of these patients is around 13 to 15 months. And so, there is clearly the need of something after ruxolitinib for these patients.

Andrew Schorr: Okay. Well, let's talk about that. That's your area of research and there's a new phase three trial called the Boreas trial, which will be in Europe and in the US, and you're one of the investigators. And it's investigating whether if you inhibit a protein, I believe, known as MDM2, that that can give hope and successful treatment to these patients where the JAK inhibitor either didn't work or didn't keep working. So that brings us to the question, doctor, what is MDM2?

How Can We Address Treatment Resistance? What Is MDM2?

Dr. Vannucchi: So the study is not so simple at first sight because MDM2 is a key negative regulator of another protein that is a tumor suppressor gene, and this is P53. P53 is a key protein for maintaining cells in a normal state and when its function is lost, these cells may become tumor cells and may start to proliferate in an uncontrolled way. So, this happens because MDM2 binds to P53 and inhibits its activity through multiple mechanisms, overall resulting in behaving as a negative regulator, or P53.

So there are drugs that may target MDM2, and by inhibiting MDM2, they may restore the normal activity of P53 in the cells. And this has profound impact on a tumor cells, in terms of restoring its normal proliferation. So, there are – sorry.

Andrew Schorr: I just want to see if I get it right because it's a little complicated science. So, this TP53 is supposed to basically help kill cancer cells in your body, right, regulate things. And if through myelofibrosis, it is… can't do its job, you're trying to restore that equilibrium by inhibiting this MDM2, right? Did I get it right?

How Do MDM2 Inhibitors Work?

Dr. Vannucchi: Correct. That’s correct. The fact is that in the stem cells of myelofibrosis, the levels of MDM2 are increased, are increased by multiple mechanisms that are not completely clear, but these increased level of MDM2 results in inhibition of P53. And so, the rationale is that if you inhibit the increased levels of MDM2 in CD34-positive cells of patients with myelofibrosis, then you can have restoration of normal P53 function.

Andrew Schorr: Well, that would be great. And of course, for me on a JAK inhibitor, as you said, there's an unmet need. What do you do next, if the JAK inhibitor doesn't continue to work? So now we're going into a phase three trial. So that means there's been a phase two trial, there's been earlier trials. So now you have a pill. I think it's KRT232 [navtemadlin], which a patient would take as part of this trial. So how will the trial work, doctor? If I get it right, I understand that you take the pill for seven days and then you're off and then the next month you take it again, is that right?

Dr. Vannucchi: Yeah, that's correct. This is just a pill, once a day. And you take the pill for seven days and then stops for 28 days. So, these are cycles of treatment. Okay, so the Boreas trial is a phase three trial, that of course comes after proof of evidence of the activity of the drug KRT232 [navtemadlin]. And in the phase two trial, the optimal dose of the drug was established and there was preliminary evidence of activity, activity against the spleen, enlarged spleen, against splenomegaly. About 16% of patients who were refractory at the loss of response to ruxolitinib, were able to show benefits of the enlarged spleen and as many as 30% of the patients had improvement in symptoms. But there was also, an additional important observation, and this was that in patients receiving the drug, there was a dramatic decrease of the number of circulating CD34-positive cells.

This is an hallmark of myelofibrosis that distinguish myelofibrosis for other myeloproliferative neoplasms, the increased levels of circulating CD34-positive sets. So, the fact that one drug, and this is really unique until now to this drug, the fact that one drug can reduce the number of circulating CD34-positive cells in patients with myelofibrosis might suggest that these drug may have some kind of disease modifying activity. So, this is the knowledge on which the Boreas trial has been designed. And as you mentioned correctly, this is a phase three trial, a global trial. There are more than 130 clinical trials that will be open worldwide. And in this trial, patients who are refractory or resistant to ruxolitinib will be enrolled and they will be randomized to receive KRT232 [navtemadlin] or the best available treatment, that in fact, has not existed for patients who have lost a response to ruxolitinib.

And these patients will receive, therefore, best available therapy, whatever is available, or the drug, the active drug. And the endpoint is the reduction of the enlarged spleen at week 24. And the key secondary endpoint is improvement of symptoms, and there are several other secondary endpoints.

Andrew Schorr: Okay. So, 24 weeks taking the pills, seven days and then off, and then seven days again the next month. Now I understand, and it's so common with cancer drugs, these are powerful. There can be side effects, and I understand with KRT232 [navtemadlin], this can be nausea or gastrointestinal problems, but you hematologists have many medicines now to help people manage that, is that correct?

How Are Clinical Trial Researchers Addressing the Side Effects of This New Drug?

Dr. Vannucchi: Yeah, that's correct. We hematologists are well used to face with nausea and vomiting and also some diarrhea. And so, there are medications that help the patients to take the right drug and to continue to therapy, and this is very important. But the preliminary information from phase two study also indicated that this drug is, well, definitely better tolerated as compared to other similar molecules that have been tested in patients with polycythemia vera, for example. There is another drug that is called idasanutlin, and this drug was actually proved evidence of activity, but was stopped in more than 40% of the patients because of these gastrointestinal side effects. We hope that the KRT232 [navtemadlin] drug will be better tolerated, especially because we are used to manage these side effects.

Andrew Schorr: So I just want to emphasize this for our patients. So, we have the unmet need that Dr. Vannucchi mentioned, so that can give hope to people. Clinical trials can move things forward with scientists, such as Dr. Vannucchi, and others around the world, in trying to regulate myelofibrosis in a new way. And it can be a big deal if it works out, but we have to answer the question, now a large phase three trial.

I mentioned to our audience that there is a website that the company put up called Boreas, B-O-R-E-A-S, hyphen, trial.com, and that will have information for you, and also a map that explains where the trial is. And of course, sites get added and information is there. Dr. Vannucchi, are you hopeful that in this field where you've worked for a long time, this new approach can pay off and help more patients? 

How Does Someone With Myelofibrosis Know if a Clinical Trial Is Right for Them?

Dr. Vannucchi: Well, you know that there are several clinical trials that are ongoing in patients with myelofibrosis, with targets that are different from JAK2 and the JAK-STAT scenery. And we as a scientific community, we really put a lot of hopes in these trials, and I have to say that the P53 signaling and controlling the cells is one of the best-loved as new targets for patients with myelofibrosis. So of course, we need the data. This is why we are here, speaking of a controls phase three trial. And we really hope that patients will be enrolled very fast in order to have very fast answers to these important questions and unmet clinical needs.

Andrew Schorr: Okay. So for you, if you're living with myelofibrosis and the JAK inhibitors are not continuing to work, or maybe didn't work so well, even right at the outset, this is a discussion between you and your doctor, whether this trial, the Boreas trial, the phase three trial, would be right for you, give you benefit and give answers to the scientists and all of us around the world of maybe a new way of dealing with myelofibrosis. Dr. Alessandro Vannucchi, joining us from in front of the cathedral there in Florence. Thank you so much for being with us once again on Patient Power, and we wish you all the best with your research.

Dr. Vannucchi: Thank you and thank you for inviting me. It's a usual pleasure to speak with you, and I wish you the best, and to all the patients who are listening your site. Thank you very much.

Andrew Schorr: As I always say to you, Dr., chao.

Dr. Vannucchi: Chao.

Andrew Schorr: And I'm Andrew Schorr. Remember, knowledge can be the best medicine of all.

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