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Antifibrotic Medications in Development

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Published on July 8, 2014

From the 2014 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Dr. Srdan Verstovsek, Dr. Ross Levine and Dr. Olatoyosi Odenike, provide details about the latest developments in antifibrotic agents for the treatment of myelofibrosis (MF). The MPN experts speak in detail about the promising new medication, PRM-151, as well as others that have been in recent trials such as the Hedgehog Pathway Inhibitor IPI-926.

Sponsored by Incyte Corporation.



Transcript | Antifibrotic Medications in Development

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Dr. Verstovsek:

The other news on this meeting was the first presentation of a what we call antifibrotic medication called PRM-151. It’s a very early Phase II preliminary results of a medication that potentially can affect the fibrosis on its own, which we believe has significant and detrimental effect on the bone marrow function.

The results are very preliminary and only about 26, 27 patients, for a very short follow-up of three to six months, where we may not even see any benefit of antifibrotic medications because prognosis may require much long time to go away or to be diminished.

And certainly, one would like to see clinical benefits of the drug, not just a bone marrow change, but in change in a blood cell count, spleen, all these benefits that we talked about. What’s your take on the preliminary results so far with the PRM-151?

Dr. Levine:

I don’t know what Olatoyosi thinks—thought it was quite exciting. We’ve been talking for decades about the need for drugs, about the fibrotic process, other as part of what they do, or as a specific thing that they do. And the fact that we’re getting, as you say, preliminary evidence that an antifibrotic agent, that is different in mechanism than JAK inhibitors and other drugs we use, has some efficacy is quite encouraging.

There’s a lot we don’t know, how they work, why they work. Is there differences in patients that benefit, and patients that don’t? And probably most importantly, can we combine this antifibrotic, with all these other great new medicines, and some of the older medicines we’ve had? So I think for patients, the excitement is that it heads us in a new direction, and it’s early in the game, but I think it’s very exciting. And we want to build on this early success and take it a lot further.

And I think it’s up to all of us to explain to our patients over the next year or two, what this drug means, how to use it, and who ultimately will potentially benefit from it?

Dr. Verstovsek:

That’s great. Now, the PRM-151 is the biological agent actually. It’s a recombinant protein of a protein that we all make in the liver. It controls the fibrotic process in normal healthy conditions, but it’s very low in the patients with myelofibrosis in the blood. And we assume that it’s because it’s used in the bone marrow to fight the malignant fibrosis. So giving it as a IV medication monthly makes sense. But it may take a long time for this to work. What should we do with that?

That’s the, the ultimate question, because patients and the physicians want something that works right now. We are now accustomed to fast results with the JAK2 inhibitor. We see the benefits within a month, if not sooner. How should we go about that?

Dr. Odenike:    

I think fibrosis is a bit of a more challenging nut to crack. We know that bone marrow fibrosis probably doesn’t develop overnight. And that even with more definitive therapy, it’s like our generic stem cell transplants, which is the only known cure for the disease, that even in that setting, the fibrosis may take some time to receive a result.

So I would submit that early on, when we have drugs that have the potential, either based on laboratory studies, which are now being extended into humans, to reverse this process that we will need to be patient. The important thing I would say only on with those agents is to make sure that they’re safe, you know, and that they’re tolerable, that we find an appropriate dose. That we can then sort of, you know, build upon or expand for that.

It may also be possible that such agents will not be, you know, giving us, you know, pretty profound results as a single agent. But understanding how they work, or how they may work early on, may lend itself therefore to meaningful combinations, which will then so move the field forwards. But it, it’s great that we have, you know, potential access. Our patients have potential access to clinical trials with such exciting agents.

Dr. Levine:

I think the other really important thing for our patients and for all of us is that it is opening up a new window. And sometimes, it’s important to realize that if you had said to a doctor or a patient 10 years ago, that I have a drug that I’m going to give just to reverse the fibrosis process, people would of thought it was science fiction, or that it was never going to work.

And more importantly, that a company would’ve never wanted to study that, because they didn’t understand the disease. They didn’t understand the needs of our patients. They didn’t understand the patient population. But as we have new ideas, and they’re showing some evidence that things work. And I think we’ll see many more efforts with other agents as well.

And so I think this is actually going to open up a whole new area of drugs that are antifibrotic in nature and not just in patients with these diseases, but other diseases where there’s bone marrow fibrosis. So, I’m as excited about the generalities as any implications, and the enthusiasm that this will lead in general, as I am about, just about this drug which I’m very excited about.

Dr. Verstovsek:

I think that potential for the future is really good. This is appears to be a very safe drug. It’s a protein that we have, like I said. So there is no real toxicity. It may be given monthly as an IV infusion. It has already been combined with ruxolitinib (Jakafi), in some patients, in this Phase II study. It didn’t matter whether patients were on stable drugs or ruxolitinib or not.

And we have seen some biology collectivity. Some patients have slightly promising red blood cell count or platelets. Others may have a better spleen or better symptoms, nothing earthshaking. But I would say, cautiously optimistic about this drug producing something in these patients with advanced features, multiple treated and refractory, that may transfer clinical benefit over time. Or perhaps we should move more to earlier stage patients to see these benefits. It’s a good study.

The optimism is there for us to develop the drug more, find the best way, and develop it as a safer additional medication, in addition to the JAK2 inhibitors.

Now at this meeting, we had one other poster, which, unfortunately, did not bring good news. But it’s opening another area of research.

This is targeting other intracellular, meaning other protein cascades that signal inside the cells that may contribute to the disease myelofibrosis. And this was a study of a single agent Hedgehog inhibitor. Ross, what does Hedgehog inhibitor?

Dr. Levine:

So the Hedgehog Pathway, which is named, a scientist after the little mammals, for no reason, that has anything to do with hedgehogs, is a critical pathway of cells, that tells cells whether to be stem cells, that renew and sort of give rise to blood over the lifetime of a person—or to form the definitive blood cells that you need to do your day-to-day job, like red cells or white cells that fight infection or platelets that clot blood.

And Hedgehogs are a really important pathway to actually increase the number of stem cells. And so there’s a lot of data in very, very careful biologic systems to suggest that this is an important pathway in stem cells and, more importantly, in stem cells in different malignancies, including myeloproliferative neoplasms. However, this study really was a first sort of dip into the water, our toe into the water.

They tried a Hedgehog Inhibitor IPI-926, which is a relatively early Hedgehog inhibitor. It’s not probably the most advanced drug out there. It has certain liabilities due to its chemical scaffold, though it hits the target quite well. And probably more importantly, the preclinical studies at my lab presented it at the hematology meeting last year, suggested that these drugs really don’t work in mouse models by themselves. They only work when you combine them with a JAK inhibitor.

So, you’re right. The results from this study suggested that by itself, this drug wasn’t particularly efficacious and didn’t seem to offer a benefit. But that’s what the laboratory centers really predicted. So I think what this suggests is that you can get a Hedgehog inhibitor, that nothing bad happens, and that we need to get it on and move the combination studies.

I think we need to be realistic that this was an expected event and that hopefully, this agent and other Hedgehog inhibitors, will now be combined with JAK inhibitors, because that’s what the data suggests will work and that’s where we need to go. So I think we, as doctors, and our patients, need to be a little bit more realistic about the results of this study and not view it as a surprising disappointment, if you will.

Dr. Verstovsek:

That’s a, it’s a good learning point for us and to move on to combination studies. The combination studies appear to be the mainstream now of our clinical research in myelofibrosis. We build on a success of a JAK2 inhibitor, we can improve the quality of life of the patients, shrink the spleen, perhaps even prolong life in advanced patients for some time, but they need to do better.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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