BTK Inhibitors in Multiple Sclerosis

Benjamin Greenberg, MD, hypthothezies on where BTK inhibitors fit into the current treatment algorithim for the management of patients with multiple sclerosis.

Ahmed Obeidat, MD, PhD: That brings us now to the BTK inhibitor. That's the other major thing that we want to talk about today. And I want to start with you Dr Greenberg, you mentioned the classes. You said the immune modulator, immunosuppressant, and you mentioned I would say, immune reconstitution or the form that you said. What do you put BTK inhibitor on those and we talk about the mechanism for that?

Benjamin Greenberg, MD: They're a new class. They take bits and piece from the different classes. I think for the time being, the safest place to put them is closest in the immunosuppression category. And that's me being conservative and looking at risk of infections that we don't yet know about for certain. But there is some evidence to say that they may lead to immunomodulation, but if we do see certain infectious risks, we're going to have to categorize them as immunosuppressant, but they may not be as suppressive as say B-cell depleting agent or maybe some other drugs. There is a spectrum within immunosuppression where they can fit.

Ahmed Obeidat, MD, PhD: That's where they can fit. Dr Abboud, do you have additional thoughts on this?

Hesham Abboud, MD: One of the most attractive points about BTKis to me is their ability to go inside the central nervous system and act on cells like the microglia and how that will impact progressive forms of MS is very interesting. There is some suggestion that BTKi can help remyelination. And the fact that they are being trialed in both a secondary and primary progressive MS is interesting to me based on those proposed mechanisms of actions. And I'm looking forward to see how they will fare in controlling progressive disease.

Ahmed Obeidat, MD, PhD: This is a great kind of segue into the next points. Dr Greenberg, I'm going to ask you about BTK inhibitors in general, and now we hear about the race for BTK inhibitors that people can say or the several trials going on. It's exciting times. We hear about them in the news. We hear about the trials. We're part of these trials. I want to ask you to give an overview of those medication as a class, and kind of the general characteristics, and any differences between them.

Benjamin Greenberg, MD: It is a broad question because, as you're aware, there is extreme diversity in the world of Bruton's Tyrosine Kinase BTK inhibition. This is a complex enzyme with a lot of possible was to inhibit it, a lot of potential ways to bind to the enzyme. And what it leads to is a unique profile for every molecule that's being studied. We're used to, in our clinical practice, dealing with classes of drugs. I remember the days when we would have arguments about high-dose versus low-dose interferon, and we lumped the interferons together. It's pretty common for us to lump the B-cell depletors together as a category. But I'm going to caution all of us and those listening around lumping BTK inhibitors as a single class that data from one will transition to the other. And why is that? When inhibiting an enzyme, there are several things that are important that differentiate it from a monoclonal antibody or an immunomodulator. The first is selectivity. It's possible to have off-target effects. The inhibitor may not only bind to Bruton's Tyrosine Kinase, but it may bind to other Kinases in other cells leading to off-target effects or adverse effects. And for each molecule that's being studied, there's going to be different selectivity. I was very interested to hear about this notion of a broad impact, the microglia that you reference, and it creates this new class of drug. We do not have a drug yet that we know alter microglia function and so we don't know how to categorize it from an immunomodulation perspective. But each of these Bruton's Tyrosine Kinase inhibitors may have a different impact on microglia based on CNS penetration or how they bind the enzyme. And then, finally, amongst these different drugs, how they bind to the enzyme, whether it's reversible or irreversible, is going to be different. When you put that all together, you may have extreme difference both in efficacy and safety from drug to drug to drug and across different forms of MS, the relapse remitting, the secondary progressive, and the primary progressive. As you said, there's this race going on but what's interesting to me, at least, is in the past when you had a class of drugs and there was a race, everybody assumed whoever finished the race first was going to win relative to prescribing and everything else. I'm not sure that's the case here because each drug is going to be so unique.

Ahmed Obeidat, MD, PhD: They are very distinct- distinct enough that even they may still- even the ones still early in stages may have an added benefit.

Benjamin Greenberg, MD: We may discover this.

Ahmed Obeidat, MD, PhD: This is great.

Transcript Edited for Clarity

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