Role of Oral BTKi in MS Management


Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC, provides an overview of the different types of Bruton tyrosine kinase inhibitors (BTKi) in management of MS.

Ahmed Zayed Obeidat, MD, PhD: Let’s touch on the future. We talked about how we have a great landscape and great medications to use. Many drugs are very effective, and people are doing well, but there’s something on the horizon. The pipeline in MS [multiple sclerosis] is also really nice. The pipeline is crowded, but in a good way.

There’s this class of oral medications that’s hopefully coming soon. They’re in advanced testing. Most are phase 3 studies. They’re called BTK [Bruton tyrosine kinase] inhibitors. [Americas Committee for Treatment and Research in Multiple Sclerosis Forum is] 1 of the conferences where we see a lot of talks about them, and there are some publications out from phase 2 studies. How do you feel about this class of medication? What is this class going to carry for us? It’s an oral class—that’s the thing about it that’s important.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: The only other B-cell therapies today are injected or infused, so you don’t have an opportunity to have that effect without this new class of drug. It’s reminiscent of when we first had therapies. They were the interferons, and we had interferon wars. Who’s better on the interferons? Then the S1P receptor agonists had just come out. Now we have 4 or 5 S1Ps, so we have the S1P receptor wars.

Here’s a whole other class of drugs where everybody seems to have their BTK du jure, and they have several we know of. What makes them interesting as a class is that this takes us beyond something we talked about at the beginning: the cells that are being generated are in the periphery, and they’ve got to get into the brain. We’re trying to prevent them from getting into the brain by blocking them, modulating them, or depleting them.

The immune system isn’t there just to kill or cause problems. It’s there to heal. Part of the healing process of the immune system can occur intra–CNS [central nervous system]. This is where this class of drug has the potential, at least from the animal models that have been used to bring them to bear. The drugs not only can they control the inflammation from outside, depleting those cells from getting in, but they will get into the brain and act on the immune system that’s present. The effect they tend to have, especially on the brain microglia, is to promote the repair side of the immune system. Which offers the possibility of treating even more progressive cases. We have studies going on in relapsing/remitting, primary progressive, and secondary progressive with all these agents. I can’t say 1 is better than the other; we don’t have the ability yet.

Ahmed Zayed Obeidat, MD, PhD: Like head-to-head comparisons.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: There are pharmacological differences slightly between these drugs. Some are tightly bound, and when they bind to their target, they won’t let go. Others are reversible. That leads to [asking], if you stop the drug, how quickly do things come back? Those are differences. Whether that pans out in terms of benefit to the patient with MS is going to be the result of the phase 3 trials.

We know that only a couple of them have been showing to get into the brain, because individuals have measured it; others haven’t done those studies to measure it. That may be coming. Those are some of the features that are important.

This is a rate-limiting step, and it will also be a class effect, because it’s an oral medication. Every oral drug goes first to the liver and usually goes to the liver on the way out of the body as well. The liver is going to see it twice, and I don’t think there’s an oral drug on the planet that doesn’t have the potential for causing liver toxicity. We’ve seen some of that emerge with a couple of the products. Whether that’s going to be a game changer and knock the class out is unclear at this point. Whether it’s something that will occur if you stay on them long term, we don’t know. But I’m being cautious about the results at this stage.

Ahmed Zayed Obeidat, MD, PhD: Because we don’t know.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: We don’t. Even the stuff that’s been published isn’t based on the repair side of this equation. It’s based on the control of the inflammation, like we do in most phase 2 studies, which is to look at gadolinium-enhancing lesions as an outcome. So they work; we know that.

Ahmed Zayed Obeidat, MD, PhD: And we know that from phase 2 studies…

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Tolebrutinib and evobrutinib have both been shown to reduce gadolinium-enhancing lesions. With some of them we saw relapse rate reductions, but those studies aren’t powered on relapse or progression.

Ahmed Zayed Obeidat, MD, PhD: This is why we’re eagerly waiting for the phase 3 results.

Mark S. Freedman: It’s going to be a couple of years, I’m afraid. We’re not going to get the answers tomorrow.

Ahmed Zayed Obeidat, MD, PhD: It’s a class we talk about all the time in many of the conferences. Even patients ask us about it all the time because the information is available online. When you think about that, you mentioned the gadolinium enhancement in the phase 2 studies. From a safety perspective, you mentioned the liver. What else? Because they’re the enhanced second generation, they have fewer off-target effects. What else do you worry about in these agents?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: You worry about PML [progressive multifocal leukoencephalopathy], and you worry about opportunistic infections. The side effect profiles of the drugs are different because of the pharmacological trait that tyrosine kinases are everywhere in the body and different organ systems.

Ahmed Zayed Obeidat, MD, PhD: Yes, exactly.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Some are more specific to the Bruton tyrosine kinase; others spill over. Whether that will pan out as a problem is unclear because we don’t have a lot of information on these products. We have 1 that’s been used for years to treat lymphoma, and it’s hard to extrapolate the data to patients with MS because lymphoma folks are very sick, and they’ve had other problems with chemotherapy. But the idea is that these drugs are taking care of the inflammation from without and have potential for promoting repair from within.That puts them in this a new class of drug.

Ahmed Zayed Obeidat, MD, PhD: Maybe you’re hitting both processes.

Mark S. Freedman: Simultaneously.

Ahmed Zayed Obeidat, MD, PhD: That may help with relapsing disease, with the progressive aspects of MS, inflammation, and whatever is going on with repair and neuro-repair. So you’re optimistic?

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: I’ve been in this field long enough to know that we’ve had a lot of failed trials over the years. I’m hopeful that with so much emphasis on the different drugs—there’s at least 5 out there—maybe we’ll hit a home run on this 1. Then you’ve got an oral therapy, and adherence is high. Being able to accomplish 2 things at once may go against what people are talking about for the future, which is combination therapy. What combination would we use? Obviously, we’d have something that would control the inflammation, but maybe we’ll find something that can promote repair. That would be the combination.

Ahmed Zayed Obeidat, MD, PhD: The sequencing might also be interesting.

Mark S. Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC: Or you take it for a little while with 1 and then try something with the other. But we don’t have these drugs yet to talk about that in any detail.

Transcript edited for clarity

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