Progressive Multiple Sclerosis and BTK Inhibitors

Hesham Abboud, MD, provides insight into the impact of the differnet biochemical compositions of the currently investigated BTKis and highlights on-going clinical trials.

Ahmed Obeidat, MD, PhD: Dr Abboud, from perspective, thinking about the differences and similarities maybe between these molecules, what would be something that you would be looking forward to learn more about these molecules? I know you mentioned the CNS [central nervous system] penetration and things like this, and you mentioned something about the progressive MS versus the relapsing MS. Can you elaborate more on the progressive versus relapsing and BTK inhibitors?

Hesham Abboud, MD: We have 3 molecules now that are in phase 3 clinical trials and we are part of the deliberate clinical trial for secondary progressive MS. It is also being trialed in primary progressive MS. These 2 clinical trials are against placebo and then 2 parallel clinical trials against active comparator are also taking place in relapsing remitting MS. There is also a fenebrutinib clinical trial in primary aggressive and also relapsing remitting. I guess the most important thing that we're waiting to see is the differential, not just efficacy but also safety, based on the different molecular structure and mechanism of action of each of these molecules. The general thinking currently, is that the more potent the medication the higher the probability of adverse effects compared to medications that are more selective and ones that are reversible, for example, might be less potent but safer in terms of adverse effects.

Ahmed Obeidat, MD, PhD: This brings us to first and second generation BTK inhibitors right. Then, what my understanding is and ones we're testing in MS are more of the second generation, and that's more less off-target effects. That's the idea, right, Dr Greenberg?

Benjamin Greenberg, MD: It is. The history of this dates to the Bruton's Tyrosine Kinase was originally described in children with X linked A gamma globulin anemia, children with immunodeficiency. And then over time, the first group to understand the biology or the potential for a druggable target were our colleagues in oncology. They recognized the Brutons' Tyrosine Kinase played a role in certain leukemias and lymphomas. And the first FDA approved BTK inhibitor was for an oncology indication and it was referred to as a first-generation BTK inhibitor. What differentiated it from the second generation? It was selectivity. And what we found with the first generation that was less selective for Bruton's Tyrosine Kinase, and it would lead to off-target effects and other cells being affected other kinases being affected, there were risks. Those patients have cardiac arrhythmias there was a risk of bleeding disorder. But as the world of pharmacology made the molecules more selective for Bruton's Tyrosine Kinase, hence the second generation, we started to see less off-target effects and a better safety profile. And you're right, the drugs that we're testing in multiple sclerosis all fall into this class of second generation. But they still are quite diverse as you mention Hesham, the CNS penetration, the potency, where they bind and how the binds are different. And as your listing the tolebrutinib trials, the fenebrutinib trials across a diversity of MS subtypes, elapse remitting, secondary progressive, primary progressive. It's worth noting there are other BTK inhibitors that are being studies, evobrutinib is an example, remibrutinib is an example, in relapsing remitting disease. And it's going to set us up for a fascinating situation in a few years where we have very different sets of data for the different drugs relative to in which patient population do they work or not, and obviously the safety profiles. And one of the things we're starting to ask ourselves is how will we compare or absorb this data across such a diversity of drugs.

Ahmed Obeidat, MD, PhD: To follow up on this point, we mentioned that they are tested in various disease states like primary progressive, secondary progressive, and relapsing remitting. And then once they get approved for their indication, if they make it to the primary endpoint of the trail, now can wesay, "OK this molecule will work in relapsing MS, but this is a BTK inhibitor. It should work in primary progressive if the other molecule worked in primary progressive." Is this something that we're going to be able to say or maybe not?

Benjamin Greenberg, MD: Another way to ask that question, and I'm going to put you on the spot as well, is will either of us do off-label prescribing if a separate drug in the class reaches an end point. Now, I prescribe off-label in my practice all the time in different ways, symptomatic medications, even disease modifying medications. It falls within our purview with a medical license to do off-label prescribing, and that's the art of medicine. This is an area where I'll actively suggest to colleagues not to do off-label prescribing and it's because there is such a diversity. And to your point around potency and CNS penetration, I can imagine a world where a less potent but highly CNS penetrant molecule may be better than a more potent less penetrant molecule for progressive disease or not. I can make an argument both ways. And to take data from one drug that reaches an endpoint in progressive disease, I don't think I can apply it any of the other drugs.

Transcript Edited for Clarity

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