Tag Archive for: navitoclax

Emerging Treatments in Myelofibrosis Care

Dr. Naveen Pemmaraju from MD Anderson Cancer Center discusses emerging myelofibrosis therapies currently in Phase II and III trials, including novel agents and combination treatments that show promise for patients. 

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program and Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.

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Transcript:

Katherine Banwell:

There are a couple of new and emerging treatments as well, right? What are those?  

Dr. Naveen Pemmaraju:

Yeah, so right. So, I’m proud to report to the viewers that just now in real time, just in the last year, really we have had several major developments. Now these are not yet FDA-approved agents. They’re experimental investigational agents, but they’ve reached what’s called Phase II or Phase III testing which are the later stages of testing. I’d like to highlight four or five of those.  

These are mostly in the combination space. So, this is a JAK inhibitor plus the new agent. One is called navitoclax. That’s a BCLXL inhibitor, not yet FDA-approved for any indication. However, this has been shown to have activity in the Phase I and II trials, either as a single agent or in combination.  

Now that’s reached Phase III testing. The second one is the pelabresib agent, which is a bromodomain or BET inhibitor. A third, if you can believe it, it’s selinexor (Xpovio), which is an XPO1 inhibitor. Also, a fourth really now entering into Phase III trials is the MDM2 inhibitor navtemadlin. You have these four drugs, which are either completing or starting Phase III, which is the most advanced testing.  

That means they’re randomized trials, usually international trials, many hundreds of patients. It’s an amazing effort that’s unprecedented. By the way, these are being tested in the frontline setting before patients have ever had a JAK inhibitor in combination with.

Beyond that, Katherine, there’s many, many trials with novel agents by themselves. So, imetelstat (Rytelo) comes to mind, which is a telomerase inhibitor, for example, which is also in Phase III testing in the relapse setting. So, you’ve already had a JAK inhibitor, it didn’t work out for you. Interestingly in that trial, the overall survival is the primary endpoint rather than spleen and symptoms, which marks the first time we’ve ever seen that. 

It also marks the understanding that these chronic diseases, chronic myelofibrosis can then turn into a more advanced acute in the relapse setting. So, that’s just a sample of some of the ones that are now entering the late stages of trials, many more in Phase I and II. In a good way, there’s a new trial opening once a week. 

Which Emerging Myelofibrosis Therapies Are Showing Promise?

Which Emerging Myelofibrosis Therapies Are Showing Promise? from Patient Empowerment Network on Vimeo.

What are the latest advances in myelofibrosis therapy? Expert Dr. Gabriela Hobbs discusses various inhibitor therapies, including BET inhibitors, that are currently being studied in clinical trials for patients with myelofibrosis.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Gaby Hobbs.

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Transcript:

Katherine:

Can you share with the audience how the field of myelofibrosis has changed over the course of your career? 

Dr. Hobbs:

Yeah, so it really has been a very exciting journey. So, when I was in medical school, I think that we basically had just discovered the JAK2 mutation.  

So, in the course of my own training and then my professional career, we’ve gone from myeloproliferative diseases being conditions where we really didn’t necessarily have a reason why people would get these conditions. Now not only do we know about the JAK2 mutation, but we know about many other mutations that patients can have. Then in 2011, the first JAK inhibitor was approved, ruxolitinib (Jakafi), and since then, three additional JAK inhibitors have now been approved, including pacritinib (Vonjo), fedratinib (Inrebic), and most recently, momelotinib (Ojjaara).  

So, the field has definitely advanced concretely in that regard. But we also just have much more information about how to diagnose these conditions and also how to treat them. Outside of the JAK inhibitors, we’re better at recognizing when patients need to go to get a bone marrow transplant. For example, and our outcomes with bone marrow transplantation have improved significantly. We also have many other treatment approaches that wouldn’t have existed before, and we also recognize that patients with MPNs live with a lot of symptoms. So, I think that we’re better at just the doctoring part of taking care of patients with MPN. So, definitely, the field has just really, really changed significantly in the last two decades.  

Katherine:

What are new and emerging therapies that are showing promise?  

Dr. Hobbs:

Yeah, so the list is long and it’s getting longer. So, in addition to the fact that we now have four JAK inhibitors approved, which is worth just remembering that, because not that long ago we only had one, and one of them was just approved less than six months ago.   

There are many new agents that are being studied in combination with the JAK inhibitors. This past year at the American Society of Hematology meeting, which is the annual meeting where we go to share our research and learn from our colleagues, there were two Phase III studies that were presented at the same time.  

I can’t remember, or I don’t think, but that has really ever happened before for myelofibrosis. One of them was with an agent called pelabresib, which is a type of molecule called a BET Inhibitor. And the other one was with an agent called navitoclax, which is an agent called a BCLXL-BCL2 inhibitor, which is a molecule that helps cells to undergo apoptosis or programmed cell death.   

So, these molecules were both combined with ruxolitinib. And we saw the results of the Phase III studies for each of these agents, and they were really quite exciting. The punchline for both of these studies is that they demonstrated that when you give two drugs as opposed to just one, the amount of patients that have a significant reduction in their spleen is doubled than when you give ruxolitinib in it by itself. So, for some of our patients that is a really meaningful number. You know, if you’re a patient that suffers from a big spleen, knowing that there’s a possibility of having two drugs that you can take to really shrink that spleen in a significant way, I think is very, very promising. On the symptom front, taking two medicines versus one medicine really didn’t seem to make a huge difference. I think we can analyze this in two different ways.  

We can see the negative or the positive side of this. So, on the negative side, well, it’s too bad that, you know, added medication didn’t help patients feel better. But on the upside, it’s also good that taking two medicines didn’t make people feel worse. Sometimes you can think of, you know, if you’re taking more medication, maybe you will feel worse. So, the jury is kind of still add on the significance of those results.

But regardless, without getting into too much detail about these studies, I think it’s really exciting for myelofibrosis patients to know that there are two agents that are in Phase III testing. That means that the next step is really consideration of FDA approval. So, when medications go through clinical trials, they go through earlier phase studies, Phase I, Phase II, and then finally they get to Phase III. A lot of work and effort has gone into these two compounds to try to get them to FDA approval. So, we’ll wait and see if in the next year or so we have new agents for the treatment of MF. 

In addition to these two, which of course are the most advanced, there really are a variety of other agents that are being tested. Those, for the most part, are still in Phase II testing. And similarly to the ones I mentioned before, most of the compounds, the way that they go into trials is first they start out showing that they’re safe by themselves, and then they get added to a JAK inhibitor.

So, far, because ruxolitinib has been the one that we’ve had around for the longest, most of these studies are being tested in combination with ruxolitinib. But we start to hear rumblings from clinical trials that perhaps some of the newer trials will consider using other JAK inhibitors as combination partners, which is a natural evolution. So, to name a few other agents, we have drugs like selinexor (Xpovio), and navtemadlin we have a PIM kinase inhibitor, a lysyl oxidase inhibitor, an LSD1 inhibitor, the list is long of all these different agents.  

Preliminarily, at least from the data we’ve seen from all of these compounds, I think there’s a lot of room for excitement. We see that combining these drugs together, the new agent plus the ruxolitinib, leads to a significant reduction in the spleen. And in some of these agents, we’re starting to see other endpoints. So, in addition to just looking at can we make patients feel better and can we shrink their spleens?

We’re starting to look at other things such as when we add these medications, do we see a reduction in the scarring or the fibrosis in the bone marrow? Do we see a decrease in the cells that have the mutation? Do we see the patients live longer? All of those things are endpoints in our studies that we really haven’t tested before. So, I think the field really will produce a lot of exciting data in the next couple of years.  

Katherine:

You mentioned clinical trials, and we will talk about those in a few moments, but are there innovations in technology that are accelerating myelofibrosis research?  

Dr. Hobbs:

So, the most obvious way to answer that question is simply that it’s much easier to diagnose myelofibrosis now, thanks to the ability to do genetic testing now much more easily than before. So, I think that previously, you know, getting JAK2 testing or testing for the other mutations was not as simple or would take a long time for the results to come back.  

Now, you know, I see even in the smallest of practices, ordering not just the JAK2 gene, but ordering what many of us do, which is like a panel of genes, where you test for a lot of the genes at the same time, has become almost commonplace. So, that’s really a meaningful advance in that it’s a technology that’s available and it’s no longer as prohibitively expensive as it was before.  

That doesn’t mean that some patients don’t end up getting charged in ways that doesn’t make any sense anymore, but that’s a conversation for another time. But I think just having the ability to make those diagnoses because of how easy it is now to test for these mutations is really very meaningful. Outside of that, I mean, I would say that along with the improvement in the knowledge of what mutations patients have with myelofibrosis, we definitely have deeper ways of analyzing what genes are being expressed and in what cells they’re being expressed to really understand, you know, when do patients first get those mutations and how do those mutations change over time.

So, we’re really diving deep into the actual biology of the bone marrow and there’s some studies that have demonstrated that patients may even have the JAK-2 mutation in utero, which is really, really fascinating. So, definitely a lot more understanding of the actual biology of how these diseases happen.   

Advances in Myelofibrosis Research

Advances in Myelofibrosis Research from Patient Empowerment Network on Vimeo.

What are the recent developments in the study and advancement of myelofibrosis treatment? MPN researcher Dr. Gabriela Hobbs discusses ongoing clinical trials for new JAK inhibitors, BET inhibitors, and anemia therapies, among others.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia, and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Hobbs.

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Transcript:

Katherine:

What about myelofibrosis, Dr. Hobbs? What advances are being made in the care of patients with this more advanced MPN? 

Dr. Hobbs:

Yeah. So, in myelofibrosis, I would say it is almost difficult to keep track of how many clinical trials are currently open. So, in 2011, we had ruxolitinib approved, or Jakafi. That was the first JAK inhibitor. Since then, we’ve had two more JAK inhibitors approved, fedratinib (Inrebic) and most recently pacritinib (Vonjo). And we’re currently awaiting the fourth JAK inhibitor to be approved, and that’s called momelotinib.   

And in addition to the JAK inhibitors, there are lots of other clinical trials underway right now that are either alone – a drug by itself or a drug in combination with ruxolitinib.  

So, there are several Phase III studies. And the reason why that’s important is that after Phase III we usually see a drug approval. So, we can expect, hopefully in the next couple of years, to see many more drugs available on the market to treat patients with myelofibrosis. Some of those include agents that block different pathways within a cell. And that includes a drug called parsaclisib. There’s a drug called pelabresib (CPI-0610), which is a BET inhibitor.  

There’s another drug called navitoclax (ABT-263), which is a cousin of venetoclax (Venclexta), which is a drug that we’ve been using a lot in leukemia. So, there’s lots of different drugs that are being used in combination with ruxolitinib. There’s also a drug called luspatercept (Reblozyl) that’s also been approved for myelodysplastic syndromes. And I suspect that that’ll be approved as well to help patients with anemia. So, really, there’s lots of drugs that are being studied right now. And I think the question that we’re all asking is, well, how are we going to use all of these different drugs? So, I look forward to seeing the results of those studies.  

Katherine:

Mm-hmm. Will some drugs work better for some patients and others not? 

Dr. Hobbs:

That is such a good question. And so, what I’m hoping to see is exactly that. I’m hoping to see that for patients, for example, with anemia, perhaps we’re going to be using luspatercept and momelotinib. Perhaps we’re going to see that patients with certain mutations may respond better to certain medications like the BET inhibitors or navitoclax or the PI3 kinase inhibitor, parsaclisib. But as of now, we don’t have enough information.  

We haven’t seen enough results of these studies to start to be able to know, you know, what is the patient that’s going to do better with two drugs versus one drug? And so, I think that over the next couple of years we’re going to start to have answers to those questions.  

Advice for Hesitant MPN Clinical Trial Participants

Advice for Hesitant MPN Clinical Trial Participants from Patient Empowerment Network on Vimeo.

What should MPN patients know about clinical trials? Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London shares information about the varying degrees of clinical trials and advice to those who are hesitant about clinical trials.

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Transcript:

Dr. Nicole Rochester: 

It’s said that clinical trials are tomorrow’s medicine today, and you’ve already kind of alluded to the importance of clinical trials as it relates to MPN. What would you say to an MPN patient who is on the fence or may be concerned or afraid of participating in a clinical trial?

Dr. Claire Harrison: 

It’s right to be cautious and, you know, careful because ultimately it’s a huge privilege as a clinician that involves patients in clinical trials that my patients trust me and trust my team to look after them with something that is experimental, but remember there are varying degrees of experimental. Most clinical trials are not first in man, you’re not a complete guinea pig, it may be a drug, for example, navitoclax is in clinical trials mainly for myelofibrosis also ET and PV but that is a drug that has been used for thousands of patients, for another indication so talk to your healthcare team, if you don’t find the answer from the primary person that you’re used to dealing with, find someone else, be linked to somebody you trust and that you have a good relationship with, take someone with you to the consultation, write down the questions I’m so sure you say this all the time, don’t you Nicole to the people that you talk to, but write down your questions, don’t be afraid to ask them again, there is no stupid question in this context, you will be given a 30-plus page booklet to read, and I lost count of the number of times, my patients go, yeah, I’ve got this, or I trust you.

Actually, you know, you need to read it…we are experimenting on you, and you need to read that and understand. And you need to understand, what happens if I go on the control arm, will I be able to cross over? How many visits will I have, will I have to pay for those visits, etcetera. It’s all really important. But ultimately the relationship with your healthcare provider is important, and using an advocate is really important too.

Dr. Nicole Rochester: 

I agree 100 percent. So important, these are things that I talk about all the time, so I really appreciate that you highlighted that, and just the importance of patients taking an active role in their medical care and also the trust that is required between the patient and their treating providers. So I really appreciate that. Do you have any examples, Dr. Harrison, in your own practice of successes with MPN patients who have participated in clinical trials? 

Dr. Claire Harrison: 

Oh yes, I think I started doing clinical trials, well golly, a long time ago. I think my first clinical trial, probably the records were written parchment to be honest, but we’ve still learned a lot from that, so that was an ET study. It was from that study we understood about the JAK2 mutation, and we understood how patients behave differently. I think probably the most gratifying thing for me was being involved in the JAK inhibitor studies in myelofibrosis and being involved in delivering ruxolitinib and Jakafi to patients and seeing the benefits for those patients. 

Big things, you know, there are patients who are alive because they took part in that trial today, I think, but there are also patients for whom small things were also really important, so as a patient, that’s important to define what is the benefit you want to get. So one of my first patients, you haven’t been able to have a bath or a shower for years, because he had terrible what we call aquagenic pruritus, itching induced by contact with water, we called him two days after he started ruxolitinib (Jakafi), and he was in tears, he could take…or you can take it out.

These things are really important. Like myself, I can imagine not being able to dig it out, I would either be very tough for another patient, it was, well, I looked really skinny because I’d lost loads of weight and I put weight on, and body image was really important as well, but then the small things like being able to be…participate more in family activities is really, really important too. 

Notable New MPN Treatments

Notable New MPN Treatments from Patient Empowerment Network on Vimeo

What’s the latest in myeloproliferative neoplasm (MPN) treatments? Dr. Kristen Pettit from Rogel Cancer Center gives updates about treatment developments for myelofibrosis, polycythemia vera (PV), and essential thrombocythemia (ET) care including JAK inhibitors, BCL-2 inhibitors, BCL-XL inhibitors, BET inhibitors, and others.

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Transcript:

Dr. Kristen Pettit:

There are so many new treatments in MPNs that I’m excited about, so one that is investigational that has been moving through the pipeline is momelotonib, which is a newer JAK inhibitor for patients with myelofibrosis. The mechanism of action is slightly different than the other JAK inhibitors, ruxolitinib (Jakafi), baricitinib (Olumiant), and pacritinib that’s improved as well.

The hope with momelotonib is that it will do some of the good things that the other JAK inhibitors do reduce symptoms and reduce spleen size, but also potentially improve anemia for patients who struggle with anemia, which is such a high proportion of our patients with myelofibrosis. I think that’s one exciting thing, another exciting avenue are new potential up-front treatment strategies that are being studied, so there are a number of different clinical trials going on right now, testing the strategy of either standard ruxolitinib or Jakafi by itself compared head-to-head versus a combination of Jakafi plus another medication.

Those other medications that are being tested in trials include the BET inhibitor called parsaclisib, also BCL-2, BCL-XL inhibitor called navitoclax, and a Pi3 Kinase inhibitor called parsaclisib. These upfront head-to-head treatment strategies are going to be very important to keep an eye out for over the next couple of years. The hope is that these combination strategies could deepen responses and potentially prolong responses when a new drug is combined with the JAK inhibitor as the first treatment option for patients with myelofibrosis. In the later line setting, one thing that’s exciting is Imetelstat, which is a telomerase inhibitor.

This is the first study in my myelofibrosis that is trying to specifically prove whether or not it is linked in survival for patients with myelofibrosis. So, I think that’s very exciting and something to keep an eye out for.

In polycythemia vera, one newer treatment option that’s getting a lot of excitement is the Hepcidin mimetic called rusfertide, this medication will hopefully harness the body’s iron metabolism pathway and act as sort of a chemical phlebotomy as opposed to an actual therapeutic phlebotomy in order to control the hemoglobin and hematocrit for patients with PV as well as improve symptoms.

In ET the newer agents that are being investigated include the BET inhibitor parsaclisib, is also being studied for myelofibrosis as well as an LSD-1 inhibitor called bomedemstat. Both of these look exciting so far, as far as their ability to both control platelet count and improve symptoms for patients with ET.

Promising ET, PV & Myelofibrosis Therapies in Development

Promising ET, PV & Myelofibrosis Therapies in Development from Patient Empowerment Network on Vimeo

MPN specialist, Dr. Srdan Verstovsek discusses the latest research and progress for the treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF).

Dr. Srdan Verstovsek is Chief of the Section for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Verstovsek, here.

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Transcript:

Dr. Srdan Verstovsek

When we talk about the new therapies in development, there are many in myelofibrosis in particular, and a few are in essential thrombocythemia and polycythemia vera. Let’s start with ET and PV. Here we are expecting either studies, or possibly even approval, of a long-acting interferon called Ropeginterferon that was approved a year ago in Europe for PV patients.

We gonna have, hopefully here in the United States, that drug for our patients in a year or perhaps studies in PV, or perhaps most definitely, I would say, studies in ET with this drug. That would be enhancement of what we done off-label using interferons that are approved for some other conditions. We know that interferons are biological agents active in these conditions to control the bone marrow, and perhaps even decrease the number of malignant cells in the bone marrow of patients with ET and PV, which may be beneficial down the road.

In myelofibrosis, the picture is completely different. In this setting, the life expectancy, unfortunately, is affected as we discussed, and we need therapy that would be perhaps improving that life longevity. As we know, the ruxolitinib JAK inhibitor that has been around for nine years can extend the life a few years, but not cure people.

So, helping JAK inhibitors by combinations with other active agents that would be biologically modifying that bone marrow, decrease the tumor burden, improving the quality of life or anemia, are at forefront of what is happening right now. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug.

These are phase three studies that are planned to start soon for possible approval for combinations over JAK inhibitor alone for different problems that people face.

Or, later on in the course of the disease, JAK inhibitor may fail. What do you do then? So, we have studies announced that will be done in what we call a second line, after-JAK inhibitor. And the MDM2 inhibitor was announced. Imetelstat inhibitor in the second line. Momelotinib JAK inhibitor in the second line. Fedratinib is being studied, another JAK inhibitor. Pacritinib for patients with low platelets

These are all phase three studies. That’s means for approval of this drug, so that will be three and four, seven different phase three for myelofibrosis patients with different clinical scenarios, different clinical problems are being done, or about to be done, in very near future. So, my prospect is here. My view on that is that we will have, hopefully, at least some of these seven studies leading to approval of some new drugs for our patients with myelofibrosis.