Tag Archive for: telomerase inhibitor

Expert Outlook | New Myelofibrosis Therapies Showing Promise

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What myelofibrosis therapies in development show promise? Dr. John Mascarenhas, a myelofibrosis researcher, reviews innovative treatments that are being combined with JAK inhibitors as well as single agent therapies that are making headway for patients with myelofibrosis. 

Dr. John Mascarenhas is Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai. Learn more about Dr. Mascarenhas.

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Transcript:

Katherine Banwell:

The JAK inhibitor class of therapies has been around for over a decade now. What new therapies are showing promise when being studied in combination with these therapies? 

Dr. John Mascarenhas:

So, I think the ones that are really exciting, and there are a number. We don’t know which one is the best, but I’ll tell you the ones that I think really have potential would be drugs like pelabresib, the pan-BET inhibitor, and the MANIFEST-2 study. Even a drug called navitoclax, that isn’t going to move forward, taught us a lot. We know that pathway is important, we just have to improve upon how we’re doing this.

Drugs like selinexor (Xpovio), the XPO1 inhibitor, is ongoing in the SENTRY study. A drug called navtemadlin is a very active drug, and that’s been shown as a single agent after ruxolitinib (Jakafi) failure. But now, it’s going after those patients who are not having an optimal response with ruxolitinib, adding it on on the backend.  

So, what I really love about the way we’re doing this is, I think it’s a very thoughtful approach trying to use these really active drugs that exploit non-redundant pathways in the disease, both either up front, to really get the biggest bang for your buck, to really try to reduce the diseased burden earlier on, or to try to add on as a strategy if patients aren’t enjoying the maximum benefit from ruxolitinib. So, we are really trying to tackle it from different angles and some of these drugs really look promising. 

Katherine Banwell:

Yeah, yeah. Are there other single agent therapies that are being studied for myelofibrosis?  

Dr. John Mascarenhas:

There are. So, I’ll name two that I also think really deserve some attention. One is called TP-3654, and it’s a drug by Sumitomo that’s a PIM 1 kinase inhibitor. So, this also goes after a very specific pathway – inflammatory pathway – a signaling pathway – that is known to be an important driver of disease and has very nice data, particularly from a symptom-burden perspective. But also, again, this concept of disease modulation and reduction in cytokines in patients who’ve previously been on ruxolitinib.  

So, there’s data there where they’re going to add it on to ruxolitinib that really looks like an interesting approach forward. And then the drug I think many of us are very anxious to see results in which is ongoing, is the IMpactMF study.   

This is the randomized phase three study of imetelstat (Rytelo), which is a telomerase inhibitor and infusional agent that goes after a very important enzyme that keeps malignant cells alive and really is one of the drugs that I think has the true potential to go after the stem cell, the origin of the disease, and improve survival. It’s the only study we have had, and currently have, where the endpoint for the registration phase we’ve studied is survival. It’s patients who have failed ruxolitinib and are getting this drug as a single agent, versus best available therapy.  

A very exciting trial and really important. Whether you’re on the trial or you’re a candidate for it, it really helps us move the field forward, because it gives us essential insights into the disease and how to do better. 

Katherine Banwell:

Yeah. When it comes to the latest research and treatment, what question should patients ask their health care team about new or developing treatment options? 

 Dr. John Mascarenhas:

Well, I think every patient is different, and truly different since their biology is different, the way they present is different, their course is different. So, really, the treatment options, including the trial options, really need to be tailored to the patient. It has to make sense for that patient. It has to meet their expectations, be aligned with their goals of therapy, and balance. Balance risk with potential benefit. Patients have to understand. The physicians have to present very clearly that some trials are randomized studies, and you could get a placebo. 

And it’s often blinded, so the patient doesn’t know, the physician doesn’t know. But importantly, in some of these studies, there’s crossovers, so even if you don’t get the drug up front, you can get it in the backend. All of these things really have to be disclosed very carefully and thoughtfully, so the patient’s really making an informed decision that makes sense for them and is meeting their expectations. 

Emerging Treatments in Myelofibrosis Care

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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. 

Notable New MPN Treatments

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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.