BTKi Safety Concerns

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

EP: 6.BTKi Safety Data

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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

Krzysztof Selmaj, MD, PhD: Of course, several of these patients with liver toxicity, they have some additional conditions which predispose them for the high liver enzymes, but you know, still the numbers were not huge numbers, but still enough to make some awareness about this.

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: I don't think this is going to change our practice because when you think about other therapies we use, you know, teriflunomide and the S1Ps, even ocrelizumab, there is an incidence of transaminase elevations with all our therapies. So, you know, we used to monitoring liver function, abnormalities, and even with anti-convulsants, we see this problem. My gut feeling is I don't think it's going to be a major problem if these drugs get through the pipeline. Do you think it's going to be a major problem?

Jiwon Oh, MD, PhD, FRCPC: I think it might be a bit of an inconvenience, but as long as the frequent lab monitoring is only required early on, I think it's something that will be relatively easily dealt with. I agree with you Gavin. Elevated liver enzymes is something that we as multiple sclerosis neurologists and neurologists in general are pretty familiar with.

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: There's some nice technology coming, so I might as well talk about it, but we are going to be able to get home. I think we're going to be able to get home liver function test monitoring using lateral flow technology. There's a technology that's being tested right now, so we may be able to allow patients to monitor their own liver function tests in the home environment. That'll make a big difference actually. This is like a finger prick. A finger prick. And then what happens is it's an enzyme reaction. You get a lateral flow test and depending on the intensity; it tells you how bad your liver function tests are. It's not like the Theranos test though. No. This is a real innovation.

Jiwon Oh, MD, PhD, FRCPC: Speaking of which, I think we touched on some of these points, but Patrick, based on our experience in the MS world with other drugs as well that may have potential drug induced liver injury, what do you speculate will happen with some of these BTK inhibitors should they become approved for use in MS? What are things we can do to mitigate the risk of liver injury?

Patrick Vermersch, MD, PhD: Of course, we need to have a good strategy to minimize this risk indeed. When we pull all the data we have today with the different drugs, probably a class effect indeed. Indeed, almost 50%, we have also an additional risk factor, hepatic steatosis, alcohol consumption, other drugs, maybe susceptibility also of drug toxicity of the liver. Probably before treating a patient with a BTK inhibitor, screening for hepatitis, for example, probably also screening to test for nonalcoholic steatohepatitis, ferritin level, for example, also to discuss about the alcohol consumption, maybe also a risk factor and also a screening for other drugs with a potential combination with BTK inhibitors for liver toxicity. I think maybe it will be partially successful, but indeed we don't know exactly the mechanism of action of this drug toxicity. So maybe some suggest it will be secondary inflammation, related to the drug, some think the direct toxicity to the hepatocyte. To the best of my knowledge, there is no consensus concerning this mechanism of action, but I think it's manageable, of course, as you just said, you are quite familiar to have a close monitoring. It's different across countries. We have, of course, amendments in these ongoing studies. Sometimes it's once a week during the first 3 months, for example, for others, it's every 2 weeks during the first 6 months. We will see when we will have the full picture with all the BTK inhibitors how to best monitor this patient. But I think it's manageable.

Jiwon Oh, MD, PhD, FRCPC: Thank you, and as you said, Patrick, I think hopefully over time we'll have a better understanding of what the mechanism of injury is in the few patients that did show drug-induced liver injury in the clinical development program. And so that will further help to guide our management of people that are initiating and continuing on BTK inhibitors.

Getting back to the safety piece, just wanted to clarify. Patrick, I know Christoph talked about a number of cases of concerning liver enzyme elevation in both the tolebrutinib and evobrutinib clinical trials, but in the phase 2 evobrutinib trial, were there any concerning cases of liver enzyme elevation?

Patrick Vermersch, MD, PhD: Yes, maybe as Christoph said before, 2 cases with transient ALT, AST increase, transient and fully reversible, so maybe a reassuring, it's small population. It's something like 125 patients, so maybe it's relatively rare even if we consider the number of patients we have. Maybe by chance we have only 2 significant cases in the evobrutinib phase 2.

Jiwon Oh, MD, PhD, FRCPC: In the phase 2 program there were no cases that met Hy's Law criteria, okay. I also wanted to clarify, in the tolebrutinib phase 2 clinical trial there were about 5% of patients that had liver enzyme elevation, but none of these met Hy's Law criteria and were not of significant concern, and once therapy was discontinued, the liver enzymes normalized rapidly, but the concerning cases, the handful of cases that were identified were in the tolebrutinib phase 3 clinical development program.

Patrick Vermersch, MD, PhD: This could also be a class effect; some patients increase of lipase, and we don't know exactly the mechanism of reaction for lipase, transient and fully reversible, but I think we need to mention it.

Jiwon Oh, MD, PhD, FRCPC: You know, I think with all of these small signals that are emerging, it is important to continue to be vigilant and monitor throughout the phase 3 clinical development program for all of the phase 3 clinical development programs, because as we said, many of these adverse events are likely a class effect rather than a specific BTK inhibitor effect.

Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath: I think with the monitoring requirements these may affect the way we use these drugs. Ideally, when they come to market, we want to use them early, but if they've got a major burden and we probably won't use them early, we'll probably use them as backups, unless the efficacy is so profound and I'm predicting there's going to be a disconnect between its impact on relapses and more activity and hopefully we're going to get a much bigger impact on disability progression based on the CNS effects. If that happens, then we will probably use them earlier, it's going to be an interesting anticipation for these results to see how effective these drugs are as a class.

Jiwon Oh, MD, PhD, FRCPC: As you say, Gavin, I think we're fortunate in the MS field that there are so many different treatment options and even little things can determine what agent is used because if the monitoring burden is too heavy, it may not be convenient enough for some patients. We've seen in the field, even with once a day vs twice a day oral dosing, there's a difference in what people are willing to do chronically because this is something that needs to continue to happen over time. It will be interesting to see how this plays out.

TRANSCRIPT EDITED FOR CLARITY