Ryan Haumschild, PharmD, MS, MBA: How could BTKis [Bruton tyrosine kinase inhibitors] potentially address unmet needs in multiple sclerosis [MS]? A brand new class, including non-relapsing secondary, progressive MS, or primary progressive multiple sclerosis. I know there is a few trials like the HERCULES trial [NCT04411641], but if you could, probably characterize it for us.

Mitzi Joi Williams, MD, FAAN: So this is very exciting. The thought of therapies that penetrate the CNS [central nervous system] is exciting because many things are going on in CNS. As we’re learning more about the pathophysiology of MS, we’re learning more about things like smoldering inflammation that can be happening over time, which may be leading to progression. So there’s a lot of potential for drugs that can really affect those lesions inside the CNS. And I think that the exciting thing is that there are definitely some therapeutic unmet needs. We spoke about some of those in one of our earlier programs. Primary progressive MS, there’s only 1 treatment approved for that. And then non-relapsing, secondary progressive MS, or inactive progressive MS, there’s nothing. So the thought that there are several trials going on, several with tolebrutinib, and 1 with fenebrutinib, looking at non-relapsing, secondary progressive disease as well as primary progressive disease, it’s very exciting because those are patients who really need other therapy options.

Ryan Haumschild, PharmD, MS, MBA: Those new therapy options are going to bring new end points. What are the different ways that we’re looking at? If we’re doing cross-trial comparisons and there are 5 BTKis coming forward, how do we really apply that information? Dr Hickman, someone that always is looking at the clinical evidence to give recommendations, what are some of the differences between the primary outcomes, studying the trials for relapsing forms of multiple sclerosis vs maybe the progressive forms? And if you could, maybe this might deal with the annual relapse rate or the time of onset to disability progression. Characterize those for us, and how we can start to look to those end points moving forward between the 2.

Amanda Hickman, PharmD, MPH, MSCS: Absolutely. They are. It basically goes back to what form of MS does the patient have? So those that are relapsing, have periods of activity, periods of remission. We definitely want our medications to manage them not having those relapses. We want to keep them in that remission. But when you look at the progressive types of MS, they don’t have those remissions or very clear remissions. They just have a steady decline in disability. At that point, we’re looking at quality of life and the burden of disabilities. So it could be touching back kind of to our oncology peers, where, for those cancers that we can’t really stop but we want to keep them as steady as possible, make sure we delay that onset of disability and keep them as fully living as possible.

Mitzi Joi Williams, MD, FAAN: And if I could add something. I think the difficulty with measuring progression is that it’s something that we see over the long term, and can be very difficult to capture in a 1- or 2-year clinical trial. Even if we look at measures of disability and our trials are successful in affecting those, it doesn’t necessarily translate to how someone would do over 10 years when we’re just looking at them over 18 months or over 2 years. And so I think that it also raises the importance of the need for better scales to measure disability. Traditionally, we’ve used our EDSS [Expanded Disability Status Scale] scale, which is very heavily weighted on walking, but we know that there’s a lot more disability than just walking; cognitive function, other things that cause people to leave the workforce and not be able to function. I think that the fact that we’re now looking at this will probably spur our neurology community, and inspire us to make sure that we are looking for better and newer measures to really capture some of that progression that we can’t measure in our traditional disability scales.

Amanda Hickman, PharmD, MPH, MSCS: One of the goals of treatment is to delay the progression of disability, but so many of our trials do just look at relapse because they’re closely associated with disability. But you don’t see disability as the main primary outcome that we’re looking at there, so I think that’s spot on. And I think we’re getting tools in there to focus on the studies, rather than those items that are beyond mobility, but total disability.

Mitzi Joi Williams, MD, FAAN: Absolutely.

Transcript edited for clarity.