BTKi Safety Data

EP: 1.BTK Inhibitor Overview

EP: 2.BTK Inhibitor Clinical Development

EP: 3.Phase II Clinical Trial: Evobrutinib

EP: 4.Phase II Clinical Trial: Fenebrutinib

EP: 5.Phase II Clinical Trial: Tolebrutinib

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EP: 6.BTKi Safety Data

EP: 7.BTKi Safety Concerns

EP: 8.BTKi Mechanism of Action

EP: 9.BTKi Effect on Chronic Active Lesions

EP: 10.BTKi Treatment: Clinical Measures

EP: 11.BTKi Treatment Paradigm

Jiwon Oh, MD, PhD, FRCPC: Speaking of safety, Christoph, can I ask you what available safety data we have for the BTK inhibitors that are currently under evaluation?

Krzysztof Selmaj, MD, PhD: Safety is very important, of course, for such a prolonged disease like multiple sclerosis, and we have data from the earlier studies, which are coming from the oncology field. These studies mostly used first-generation BTK inhibitors, and with these initial studies with this type of inhibitors, there were some clear safety issues, like cardiovascular events, including arrhythmias, which have been observed, like hypertension, and hemorrhages.

In addition to that, there were also symptoms of gastrointestinal intolerance. There was diarrhea and abdominal pain. These inhibitors show some rash in patients treated with them and also arthralgia. Of course, I will come to the case of liver enzymes in a moment.

This was the original findings. Now when we use the second generation of Bruton's tyrosine kinase inhibitors in our studies, which was described before, so this safety profile is much better. Several of the symptoms were not observed. For example, cardiovascular events are almost not present. There's no arrhythmias, and there are no hemorrhages. Then we might have some minor proportion of thrombocytopenia, so we should be aware about that. Usually this is transient, and this does not, you know, evoke an important decision on continuation of treatment.

There's also a percentage of patients that have these gastrointestinal symptoms. The problem with safety is related to liver enzymes. It was found that patients treated with BTK inhibitors have increased levels of transaminases, mostly ALT. Usually it's asymptomatic, and usually it's transient. Because of that, there was a special attention paid to this liver enzyme increase.

Specifically because, for example, in the evobrutinib study, 16 patients discontinued because of the high levels of ALT, and in the tolebrutinib studies, there were fewer patients showing this increase in aminotransferases, there was at least one case with the serious symptoms. After stopping treatment, it disappeared.

Because of all these observations, there was some activity taken by the FDA, and the FDA put some transient halt on developing one of these drugs. It was put quite late because when the phase 3 studies were already completed recruitment. Because initially they advised not to treat patients with BTK inhibitors early after treatment initiation up to 60 days. But when they did it, when they make this announcement, most of the patients were already behind the time point.

Evobrutinib phase 3 programs and tolebrutinib phase 3 program, they are going on. And we'll have this data as you have heard quite soon. But these are symptoms which need to be carefully evaluated. And we think that we can handle it. This is, as I said, most asymptomatic and transient.

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: Well, coming to the hepatotoxicity signal, do you think it's a class effect or do you think it's agent-specific?

Krzysztof Selmaj, MD, PhD: Because it was seen with evobrutinib, it was seen with fenebrutinib, and it was seen with tolebrutinib. Actually one study, orelabrutinib, was completely discontinued because of that increase of transaminases. I think this is class effect.

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: The reason why I ask is I think the FDA is treating it like a class effect. It's clear some of the patients must have hypersensitivity reactions, which is like an immune response to, and I'm just wondering if the covalent ones that change, create a hapten effect are different to the non-covalent ones. I'm wondering if fenebrutinib will get through this without having a significant hypersensitivity reaction.

Amit Bar-Or, MD, FRCPC: We'll wait and see with what happens with fenebrutinib. I tend to agree with Christoph that this is certainly not unique to a BTK inhibitor. It's happening with several BTK inhibitors, but to your point Gavin, it doesn't happen to everybody, right? So it is actually something that happens in a significant minority of individuals. As one pointed out, if it happens, it happens within the first few months. And so there's something interesting about susceptibility of a particular group of individuals, and as usual, if we could figure out risk mitigation strategies, and part of the effort now is to monitor people very closely with frequent blood tests to assess early on in the exposure to try to get a better sense of the mechanisms that underlies. Is there anything that we can capture and understand about the profile of those individuals who get it versus those to be able to risk mitigate in them and free others from that risk?

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: I think when you look at the oncology products, there was almost certainly a signal in oncology, which was missed in a way. I suspect it was missed because oncology patients are quite ill systemically, and they get a bit of abnormal liver tests. You can't really blame the BTK inhibitor, but I'm almost certain that the signal exists before these drugs went to people with MS.

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