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New JAK Inhibitors in Development

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Published on July 25, 2014

JAK inhibitors, such as ruxolitinib (Jakafi®), are changing the landscape of treatment for myeloproliferative neoplasms (MPNs).  Dr. Bart Scott from Seattle Cancer Care Alliance discusses how JAK inhibitors work to treat MPNs, new JAK inhibitors currently in trial, and why it’s an exciting time for research in the MPN field. 

This event was produced in association with City of Hope and sponsored by Patient Empowerment Network through educational grants from Incyte Corporation and Geron Corporation.

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Transcript | New JAK Inhibitors 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. Scott:

Okay. So there are several different JAK2 inhibitors that are in clinical trial development. Ruxolitinib, also known as Jakafi, is the only FDA-approved JAK STAT pathway inhibitor at this point in time. There are drugs that are coming along.

One of them is momelotinib, and right now there is the Phase III randomized trial comparing momelotinib to ruxolitinib. What’s the difference between these? The difference has to do with side effects primarily, and the differences in the side effects is likely due to their binding affinity for these JAK receptors.

And there’s many different JAK receptors. There’s primarily two that are important in MPN. That’s the JAK1 receptor and the JAK2 receptor. JAK1 receptor primarily initiates cytokines, and JAK2 primarily initiates stem cell activity, productivity, increased numbers.

So depending on what kind of symptoms a patient has, what kind of problems a patient has, you could see why it might be more beneficial to inhibit more of the JAK1 receptor versus the JAK2 receptor. So, that’s some of the differences.

Andrew Schorr:

All right. Just a question here. So I’ve benefitted from ruxolitinib but not everybody does.

Dr. Scott:

Not everyone does.

Andrew Schorr:

So you need others that operate differently.

Dr. Scott:

That’s right. And these JAK STAT pathway inhibitors, it depends where they kind of inhibit the JAK STAT pathway as to whether or not you would benefit. And even among people with this JAK2 V617F mutation, there are differences within those individuals.

And some of them have mutations in the receptor that presents binding of ruxolitinib, for instance.

Andrew Schorr:

Okay. I just want to, we’ve talked about a lot of sites, so I want to make sure you understand.

Dr. Scott:

I know.

Andrew Schorr:

Okay. Pathways.

Dr. Scott:

Right.

Andrew Schorr:

So what is the path? Like a highway, what is it?

Dr. Scott:

Okay. If you’ve got a cell, on the surface of this cell there’s a receptor and there’s different kinds of hormones and proteins that are circulating in your blood that comes along and binds to these different receptors. And once that binding happens, it stimulates a pathway.

It stimulates a pathway in that cell, and one of these pathways in a cell is called the JAK STAT pathway. And the JAK STAT pathway activates a series of signals along this pathway that ultimately goes to the nucleus of the cell, and the nucleus of the cell is what tells the cell how to function and what to do.

And it’s this pathway, JAK STAT pathway, is activated, and these signals get to this nucleus. It sends a certain message to this cell and that message may be, okay, you need to make more of yourself because I don’t have enough red blood cells, or I don’t have enough platelets, so start making those. The problem is that occasionally these pathways are altered, and one of the issues in MPNs is that the JAK STAT pathway is constitutively active, meaning that it’s always turned on.

Whether that receptor has bound or not and, so, since this nucleus is always getting these signals, okay, make more red blood cells or make more platelets, or perhaps make more cytokines, which increases inflammation, you will always have these responses.

These pathways exist for a reason. Let’s say you’re in a car accident, and you’re bleeding. You need to make more red blood cells, you need to increase inflammation. So there’s a natural reason to have this pathway. But, as I said, in the MPNs, that pathway is constitutively active.

Andrew Schorr:

Okay.

Dr. Scott:

It’s always turned on.

Andrew Schorr:

So I take one of these pills. So there may be others developed?

Dr. Scott:

Yes.

Andrew Schorr:

Take that pathway and dial it down.

Dr. Scott:

That’s right. So you can imagine that there are side effects associated with that, because that pathway exists for a reason. So I mentioned to you that in essence the ruxolitinib (Jakafi) and general to JAK2 inhibitors are immune suppressants because they suppress this cytokine production that you have, and then one of the major side effects of ruxolitinib is low platelet counts.

So frequently we have to dose reduce patients, because their platelet count goes low. Well, that’s because you’re inhibiting the pathway that is in some parts responsible for production of platelets.

Andrew Schorr:

Okay. One other question about these JAK2 inhibitors or however we want to describe them.

Dr. Scott:

Right.

Andrew Schorr:

Are you encouraged with what’s going on in the lab that you’ll have more than ruxolitinib, and there was one drug in this area that was pulled out of trial?

Dr. Scott:

Yeah. Fedratinib.  

Andrew Schorr:

Fedratinib, maybe some people were in a trial. It was pulled out, but there are others. You mentioned one, momelotinib…

Dr. Scott:

Momelotinib.

Andrew Schorr:

…and there are others. Are you encouraged?

Dr. Scott: 

Yes. I think it’s a very exciting time in the field of MPN in general, because there’s new therapies that are becoming available. And this is a disease that didn’t have a lot of interest, you know, five or six years ago, but now it’s really taken off. So I think it’s a very encouraging time.

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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