Bruce Cree, MD, PhD, MAS, discusses new data presented at the 2023 European Academy of Neurology (EAN) congress on BTK inhibitors, such as Tolebrutinib, evobrutinib, renibrutinib, and fenibrutinib. Dr Cree also highlights important safety information and adverse events identified in these studies.
Bruce Cree, MD, PhD, MAS: So, at the EAN [European Academy of Neurology] meeting, there was some new data on the follow-up of the BTKIs [Bruton’s tyrosine kinase inhibitors] that are in development, and there are actually several BTKIs that are in development for relapsing MS [multiple sclerosis]. There is tolebrutinib, which is under development for relapsing MS, as well as nonrelapsing secondary progressive MS and primary progressive MS, evobrutinib, which is in development for relapsing MS, remibrutinib, which is in development for relapsing MS, and lastly, fenebrutinib, which is in development for relapsing MS and primary progressive MS. You can see there's a lot of interest in targeting Bruton's tyrosine kinase in multiple sclerosis. Now, what is Bruton's tyrosine kinase? Well, this is an important molecule involved in the signaling pathway on B lymphocytes, as well as on microglial cells. And so, the thought here is that one could influence B cell activity and obtain a degree of therapeutic benefit with these products that is similar to that of the B cell-defeating monoclonal antibody therapies. So, that is part of the hope with the Bruton's tyrosine kinases. The other part is this consideration that the products that are capable of crossing the blood-brain barrier may interact with microglial cells within the central nervous system and attenuate their activity. Microglial cells have been implicated in MS as cells that may prune synapses and may be involved in the neurodegenerative aspects of multiple sclerosis. The idea here is that perhaps by influencing microglial activity, one might have an impact on long-term MS-related disability. So, all 4 of these drugs are in development. None of them have been proven to engage with microglial cells in [patients with] MS. So, that is a hypothesis. They all attenuate B cell activity, but don't significantly deplete B cells in the same way that the anti-CD20 monoclonals do. And so, the thought there is that perhaps you can get a good balance between the modulation of disease activity by controlling B cell activity, and hypothetically, get an advantage over other products by this class of therapies' abilities to engage and interact with microglial cells. So, we saw several updates at the EAN on these products. We saw some phase 2 data presented on fenebrutinib, followed by phase 2 data for the other products, as well as the clinical trial designs that were presented, the ones that are ongoing right now. So, there's a lot of interest in this area. We don't have proof that these products are going to provide us with the relief of disability that we're hoping for. Unfortunately, for at least 2 of these products, we now know that they are associated with very serious drug-induced liver injury. And so, for tolebrutinib, and evobrutinib, both of those programs have had cases of patients who've had serious liver injury as a consequence of treatment. In my personal opinion, this is going to be a very important question for our patients. You know, it's going to be difficult to justify use of treatments that can cause serious drug-induced liver injury when we have so many other therapeutic options for relapsing MS. Now, granted for patients with secondary progressive MS and primary progressive MS, therapeutic options are rather limited. And so, there, patients might be willing to accept some risk of serious hepatic injury in order to reap a therapeutic benefit if these medications are proven to have robust effects on disability. So, it remains to be determined whether we will see serious cases of drug-induced liver injury with fenebrutinib and remibrutinib. There was data on remibrutinib in other disease states, other autoimmune disease states where this product seems to be quite safe. But we do know that fenebrutinib is associated with liver function abnormalities that can go quite high. So, although we haven't seen a case of drug-induced liver injury with fenebrutinib, it would not be surprising to me if eventually such a case did occur. This raises the question as to what regulators will do in considering these products. I suspect that if these drugs ultimately do get approval by regulators, that there will be a considerable discussion of the potential of drug-induced liver injury across the board as a therapeutic class effect, regardless of what the ultimate clinical trial data shows. So, these are some of the considerations that we have about this class of drugs. There is hope that these medications are going to deliver profound effects in terms of disability progression. Of course, we will have to wait until the phase 3 clinical trial programs for all of these products is complete in order to make that assessment.
Transcript edited for clarity.