Targeting Syk in Adult Immune Thrombocytopenic Purpura

Transcript: Ivy Altomare, MD: Amit, you very eloquently went through the Syk [spleen tyrosine kinase] pathway earlier, and so I’d like to start with you to discuss the data for fostamatinib, the Syk inhibitor. Before we get to the data, can you describe what this drug is, how it is taken? You talked about how it works, if you want to give a brief synopsis again of how Syk inhibition works in ITP [immune thrombocytopenic purpura], and then we will move on to the phase III FIT trials.

Amit Mehta, MD: Sure. The only Syk inhibitor we have currently is fostamatinib, the generic name of the drug, and that got approved in 2018 for patients with chronic immune thrombocytopenia who failed at least 1 prior therapy or more. In a nutshell, how it functions is it’s a small molecule, oral tyrosine kinase inhibitor [TKI] that competitively inhibits the phosphorylating binding site on the Syk molecule inside the macrophage.

Basically, the macrophage phagocytosis that would have been stimulated by the platelet antibody complex, but by giving a small molecule inhibitor, a TKI essentially, you’re able to prevent that phosphorylation of the Syk molecule and therefore shut down the downstream signaling intracellularly, preventing phagocytosis. That’s indeed what has panned out in the clinic, and now an FDA approved product. So that’s how it works.

Again, oral medication, small molecule tyrosine kinase inhibitor, inhibiting the Syk pathway in macrophage cells. The dosing that’s approved is that it’s 100 mg orally, bid twice a day, and what the label says by the FDA is that if they are not having a sufficient response in the estimation of the clinician, it doesn’t give a specific definition or anything of that nature, then you can up the dose to 150 mg bid. That’s an important point for hematologists in practice to know that remember that you can increase the dose because there is a dose response relationship because of the competitive inhibition of that particular site on the Syk molecule. That’s in a nutshell the dosing and the mechanism.

The main adverse effects that we’ve seen, based on the clinical trials, the most prominent ones on the study in terms of frequency—diarrhea, hypertension, rash, elevated levels of AST [aspartate aminotransferase] and ALT [alanine aminotransferase], no severe cases, which is an important point. There were no severe hepatotoxic cases, nor is there any kind of boxed warning for hepatotoxicity. But mild to moderate AST/ALT elevations were seen, so it has to be monitored. Overall, it seemed to be a relatively well tolerated medication, always a crucial point for a chronic disease therapy because they need to stay on these type of medicines, including fostamatinib, indefinitely, as far as we understand, until we have data to suggest otherwise. Those are the main adverse effects.

It seems to have checked a lot of the key boxes that we were hoping for in development, to say it’s an oral medication, small molecule tyrosine kinase inhibitor, seems to not have a significant liver toxicity profile, and overall a well tolerable toxicity profile in general. So hopefully it’s easy enough for patients to take, plus no food timing requirements as well.

Ivy Altomare, MD: Right. And if there is a dose escalation then, of course, there is a dose reduction if a patient is having diarrhea. You can dose reduce, and often if an antimotility agent doesn’t work, that will take care of the problem, as I understand.

Amit Mehta, MD: Correct. What’s recommended, and what’s been seen in the trials as well as in practice now that it’s been on the market, is that typically, we can use our standard anti-diarrheal strategies—Imodium and Lomotil and so forth, and whatever we may prefer individually. And it can be dose reduced, as you said, if necessary. The lowest approved dose is 100 mg once a day. And they say that if the patient has not tolerated that dose, then you should discontinue the medication.

Transcript Edited for Clarity