BTK Inhibitor Clinical Development

Opinion
Video

Patrick Vermersch, MD, PhD, and Krzysztof Selmaj, MD, PhD, provide an overview of the BTKi that are currently under investigation for MS, and Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, discusses what in vivo and in vitro preclinical work in models of MS have shown.

Jiwon Oh, MD, PhD, FRCPC: Dr Vermersch, I know there are many clinical trials happening, but can you give us an overview of the BTKis[Bruton's tyrosine kinase inhibitors] that are currently under investigation in MS [multiple sclerosis] and also talk about the patient population, as well as what phase of development they're in?

Patrick Vermersch, MD, PhD: We are lucky; we have many trials ongoing in MS with BTK inhibitors. Evobrutinib, we are now close to the results of the 2 pivotal trials in relapsing MS:EVOLUTION RMS 1 and EVOLUTION RMS 2, including relapsing MS. Maybe, we will have the results before the end of this year.

There is also a large program with tolebrutinib in GEMINI-1 and 2, including relapsing MS, but we have also nonclinically relapsing MS, which isSPMS [secondary progressive MS] without clinical relapse during the inclusion period. HERCULES and PERSEUS also including primary progressive MS, so, maybe a full picture of with tolebrutinib. We have also remibrutinib, included also in 2 trials, relapsing MS, and alsofenebrutinib, included also in 1 trial in relapsing MS and also a trial for PPMS with fenebrutinib compared to ocrelizumab. 

And interestingly, of course, the phase 3 trial with comparative arms for relapsing MS. It's teriflunomide as a comparator, so maybe that's great to have so many trials to have, maybe at the end, a global view of the impact and the potential of BTKis in MS.

Jiwon Oh, MD, PhD, FRCPC: Thank you, Dr Vermersch, and if I can now ask Dr Selmaj, Dr Vermersch gave us a very nice summary of all of the many different BTK inhibitors being investigated, and we know that all of these different drugs belong to the same family of molecule, but Dr Selmaj, can you outline some of the differences between the various BTKis that are being investigated right now? 

Krzysztof Selmaj, MD, PhD: OK, so as you have heard, we have several BTK inhibitors which are developing into MS therapy, and although they have similar basic mechanism of action, there are some differences. The first difference is about reversibility of blocking BTK. Most of our BTK inhibitors are irreversible molecules, so they block more or less BTK permanently. It doesn't mean they block it for good and forever, because after 5 or 7 days, because of natural protein degradation, after a single dose, you can still recover the activity. In general, these molecules really make a very deep effect and a strong effect on the BTK.

On the other hand, we have reversible inhibitor. Actually, right now, there's only one, fenebrutinib—the difference depends how these molecules target BTK itself. You know, they directly bind to the action site, the action spot which are involved with the activity of the enzymes, and they do it close to the active site to modulate the structure of the enzyme.

This is the first difference, I think, the major difference. Of course, as a consequence, there are also some differences in the pharmacokinetics. Some of the inhibitors have a longer half-life time, and they have a more prolonged effect comparing to others. And also, there is a difference in selectivity because we should remember that the BTK family of enzymes is not the one enzyme there are several enzymes we and sometimes we're not so closely related so the inhibitors we are actually using that we are not only target one enzyme but might go off target and target some other main enzymes kinases and we might have some side effects which we'll talk later about that so this is another difference.

Also a very important difference in CNS penetration as we've heard here it's critically important and this drug will get to the CNS and this is advantage of this therapy so of course the rate of penetration is very important and we know that for example tolebrotinib is the highest penetration, but on the other hand has the lowest selectivity so you know we have some things you know which we trade it off so so there are some differences you know how these differences will affect clinical outcomes you know we have to learn in future you know we have had several trials in the way and potentially might have some they might somehow affect our clinical outcomes but you know it will come with time.

Jiwon Oh, MD, PhD, FRCPC: Moving on, Dr Giovannoni, there's been quite a number of both in vitro and preclinical studies looking at the effects of BTKis on different aspects of MS pathophysiology, and can I ask you to summarize some of the key studies that you're aware of?

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: There's first the pharmacology and the pharmacology has been optimized. The first generation BTKi that was licensed was ibrutinib, and it was pretty dirty. The kinase family is very large, and from an evolutionary perspective, they all evolved from a single enzyme, and so there was a lot of off-target effects. The current crop that's in MS is quite specific in terms of their activity against Bruton's tyrosine kinase, and they have very little off-target effects. That's the first thing that's been done. The second has been optimized as CNS penetration, so there is animal data showing that these drugs do get into the CNS at concentrations that should inhibit B cells and microglia, and then there's been quite a few animal models showing that this class of therapy is effective at inhibiting CNS inflammation. The ones that have impressed me the most are the ones around microglia activation, and they are pretty good at dampening down activated microglia in animal models. I think from a basic science perspective, there's a compelling evidence base that these drugs do what they mean to do: CNS penetration and CNS microglia. In terms of B cell biology, there's also a whole lot of work done on the whole class while showing that they impact B cell biology in quite complex ways.

First of all, they obviously reduce the antigen presentation capacity of memory B cells because they inhibit the signaling. In the oncology space, over time, they change the repertoire because the memory B cell uses BTK as a pro-survival signal, so if you inhibit it, you actually reduce the pro-survival. Over time, the memory B cell probably drop off. The survival drops off, and in the ibrutinib data, you get a naïve repertoire emerging, which is probably going to happen in MS. I wouldn't be surprised in the MS population if we see, over time, the memory phenotype changing, and we get a naïve, which is probably a good thing because we think some of those memory B cells are pathogenic in terms of driving autoantigen presentation.

I think the basic science, animal models, as well as what we've learned from the oncology space, will apply to MS. I think it's low-hanging fruit, to be honest with you—we know that targeting B cells works in MS. In terms of efficacy, I have very little doubt that we are going to see an effective therapy. It's questions beyond effectiveness that are more important to answer.

Jiwon Oh, MD, PhD, FRCPC: Thanks, Dr Giovannoni. Clearly, there is a lot of evidence from in vitro studies, animal data, as well as studies from the oncology literature that makes us all very excited about the potential effects of BTK inhibitors in MS.

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