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Improving a Breakthrough: Combination Therapies with JAK Inhibitors

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Published on May 21, 2013

JAK2 inhibitor therapies have been one of the most exciting recent breakthroughs for myelofibrosis. Researchers are now looking for ways to improve them further. Dr. Claire Harrison explains what is currently known about JAK inhibitors and how they can be used with other medications for greater effectiveness in the future. Watch now!

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Transcript | Improving a Breakthrough: Combination Therapies with JAK Inhibitors

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.

Andrew Schorr:

Hello.  I'm Andrew Schorr for Patient Power. 

Ruxolitinib (Jakafi or Jakavi) is the first of what promises to be a whole group of JAK2 inhibitor medicines to be used for myeloproliferative conditions.  How well are they working, and what questions need to be answered so they can work better?  We want to get the perspective of a leading expert, and so joining us now is Dr. Claire Harrison.  Dr. Harrison is an MPN specialist at Guy's and St. Thomas' Hospital in London.  She's with us as she attends a medical conference, the European Focus on Myeloproliferative Neoplasms.  Dr. Harrison, thank you for joining us. 

Dr. Harrison:

My great pleasure. 

Andrew Schorr:

Dr. Harrison, so the buzz now is combination therapy, as we use in so many other cancers.  Where are we now with this for MPNs, and in particular myelofibrosis? 

Dr. Harrison:

I think, to put this quite simply, JAK inhibitors offer the most exciting therapeutic prospect for patients with myelofibrosis of any therapeutic advance in these diseases, to date.  They are not, however, suitable for all patients with these diseases.  We're becoming more and more familiar with the benefit for patients in terms of shrinking the spleen, improving constitutional symptoms, but we're trying to understand a little bit better how can we balance side effects, which we have to expect with every medication, against those benefits.  What should our target be?  Should we be targeting a 50 percent reduction in spleen size?  Should we be pushing for complete reduction, if we get there, but should we be doing that at the expense, for example, with ruxolitinib, Jakafi or Jakavi, as it's now known, or perhaps anemia or a low platelet count for patients? 

As we look across the spectrum of other JAK inhibitors which, of course, are at various stages of development, we see some potentially very exciting, maybe differentiating abilities with these agents.  So, for example, just to pick a few, the Sanofi agent, SAR302503 has completed a Phase III study.  We expect the results of this at ASH this year.  This agent, potentially, is of great interest, as it appears to be as efficacious in reducing splenar symptoms for patients with a lower platelet count as ruxolitinib (Jakafi or Jakavi).  It may also reduce the JAK allele burden, although there's conflicting data with regard to that.  We don't know how important that reduction might be.  And it may also reduce the hallmark of the disease, fiber in the bone marrow.  

Another good example is, perhaps, where these agents might be slightly different, perhaps, because of their different targets in the body, is the CYT387 agent, which we've seen now several presentations, so we can be even more confident of the data coming from this molecule that, despite its activity as a JAK 1/2 inhibitor, it appears to paradoxically increase hemoglobin in a sustained fashion in some patients.  That is very important, because anemia is very common for patients, and can cause big problems in terms of management, energy levels, quality of life.  If that's sustained without significant other stings in the tail, so to speak, side effects, then that could be really important and exciting. 

There are other JAK inhibitors, of course, including some that might more specifically target the mutation, and we wait with great excitement for the benefits of these drugs, as we've seen in other fields that different drugs may have different targets, different benefits for patients. 

You asked me, also, a question about combination therapy.  So, in my view there are several different rationales for using combination therapy for patients with myelofibrosis.  One might be, to be able to maintain an adequate dose of a JAK inhibitor without having too much anemia or low platelet counts from the cytopenia.  A simple example of combination, but not one I had in mind, was to use blood transfusion therapy to allow the patient to continue at an effective dose, but a more rational combination, might be, to use erythropoietin or ESA-like agent.  We've been studying this across the COMFORTII study using danazol (Danocrine), for example, an androgen agent to stimulate and increase hemoglobin while allowing an adequate dose. 

But, perhaps, of more trial interest, is to try to improve and drive forward the benefit of these agents, to try to strive towards cure.  Because of the complexity of the disease, which may be viewed as a disadvantage, we also have many different other targets we can address.  We could then, for example, utilize JAK inhibition in combination with agents that modify the genetic machinery, such as histone deacetylase inhibitors.  We could, perhaps, think about other targets in the JAK/STAT pathway such as PI-3 kinase inhibitors. 

We can look at other pathways in the cells, such as the smoothened pathway, and there are three studies, at least, ongoing with this combination, looking, can we, first of all, combine these drugs safely, first question.  Second question, what is the effective dose?  Third question, is this better than any of these agents on their own? 

The last thought that occurs to many of us, in terms of combination therapy, is that, because of the effects of the disease in making the spleen so big, and general fitness of the patients being so impaired—many patients, if they want to and if they have a donor, cannot proceed to transplantation, which at present is the only cure for this disease.  It might be possible to combine the benefits of JAK inhibitors in shrinking the spleen, improving fitness and then moving to transplantation and, perhaps, even using these agents through transplant to balance cytokines and the risks of graft-versus-host disease. 

All of these studies are ongoing.  It's an explosion of great clinical activity and interest in this field at the present time and very, very exciting. 

Andrew Schorr:

Dr. Claire Harrison from Guy's and St. Thomas' Hospital in London, thank you for joining us and your devotion to patients. 

Dr. Harrison:

Thank you. 

Andrew Schorr:

We'll have a lot more with Dr. Harrison, including a discussion of intolerance of medicines and resistance to them when a patient might have to be switched from one medicine to another, in a coming interview. 

Thank you for joining us now.  I'm Andrew Schorr.  Remember, knowledge can be the best medicine of all. 

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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