Mechanisms of Action of Eltrombopag

Transcript:

Phillip Scheinberg, MD: The mechanism of action of eltrombopag is actually quite intriguing, to be honest. The drug was developed to treat a condition called ITP, which is immune thrombocytopenia purpura, and it was approved in the United States in 2008 alongside romiplostim, which is the other agent in this class of drugs called the thrombopoietin receptor agonists. So eltrombopag and romiplostim at the time were approved for ITP. Now, we wanted to improve platelet counts in aplastic anemia because that’s a very limiting transfusion dependency. Patients usually have to get platelets twice a week.

So we wanted to stimulate platelet production but potentially stem cells, as well, given the fact that thrombopoietin can stimulate stem cells in vitro. And thrombopoietin is an important cytokine to actually stimulate hematopoietic stem cells, which are deficient in thrombopoietin; they do have a reduced number of stem cells. That formed the rationale to target that very primitive stem cell compartment by giving higher doses of eltrombopag. So the doses that are used in IPT, which are 50 and 75 mg, are not the doses that were developed in aplastic anemia, which went up to 150 mg. That was part of the reason to try to do that, given the fact that the endogenous thrombopoietin level, if you were to measure thrombopoietin in a patient with aplastic anemia, is really high. So the enthusiasm and the concern of not being effective were actually pretty real. That’s why the higher doses were chosen, in order to try to overcome that internal high endogenous thrombopoietin.

Having said that, we’re not sure whether that’s all that’s happening. Now, there are correlative laboratory studies to show an increase in CD34 cells with an eltrombopag-containing regimen, so that gives you more reassurance that you’re actually stimulating these cells, that they’re appearing more in the bone marrow. But in the ITP literature, there are other effects that have been shown to be associated with eltrombopag, like increasing regulatory T cells, promoting tolerance, decreasing interferon gamma and TNF [tumor necrosis factor]-alpha, all cytokines that we know are important inhibitors in aplastic anemia. So those data haven’t been shown in aplastic anemia, but they have been shown in ITP. So it’s reasonable to think that similar things might be happening.

And also don’t forget that eltrombopag is also a chelator. It’s an iron chelator, so you see that ferritin levels actually go down in patients, not only in ITP, which have been shown in pediatric patients, but also in aplastic anemia. There’s a paper this year. Now, we think that excess iron might not be good for the bone marrow, but we don’t know whether getting rid of that iron is actually a cause of improving hematopoiesis. I mean, there are some data, retrospective, to suggest that, but getting rid of iron can’t hurt in a population that’s very transfusion overload.

So we’re looking now at this in a multifaceted way. And more important, at ASH [American Society of Hematology Annual Meeting & Exposition] last year, there was another mechanism that was presented by Andre Larochelle, MD, at the NIH [National Institutes of Health] that shows that eltrombopag might actually bypass the inhibitory effect of interferon gamma. So interferon gamma inhibits hematopoiesis.

Thrombopoietin cannot overcome that, but eltrombopag can overcome that inhibition binding in an intramembrane domain, so that interferon gamma is trying to inhibit, but eltrombopag is able to stimulate in the presence of interferon, an important cytokine, an important inhibitory cytokine. So that might be another way by which eltrombopag is actually stimulating a very primitive stem cell population, alongside the other immunomodulatory effects and chelation.

Transcript Edited for Clarity