A Novel Mechanism of Action in Treating Relapsing MS

MedPage Today brought together three expert leaders for a virtual roundtable discussion on the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). Moderator Daniel Ontaneda, MD, PhD, from the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, is joined by Enrique Alvarez, MD, PhD, from the University of Colorado Denver School of Medicine, and Gabrielle Macaron, MD, from the Université de Montréal in Quebec.

This final of four exclusive episodes on therapeutic advances in multiple sclerosis (MS) discusses the investigational CD40 ligand inhibitor frexalimab.

You can view other videos in this series here.

Following is a transcript of their remarks:

Ontaneda: Let’s move on to the next topic. And I think, whenever we go to large meetings like ECTRIMS-ACTRIMS, one of the things we always look for is, well, what were the therapeutic advances? And specifically, I think we’re kind of saturated with a lot of the disease-modifying treatments that work in very similar fashions.

But there was a couple of things that were very interesting at this meeting that were presented. So I’m not sure, Gabrielle, if you wanted to give us a little bit of a summary, a very interesting therapeutic agent that targets CD40, which I think was, it was interesting that this got … I was kind of surprised that it only got a poster presentation, but for me it was one of the few really novel therapeutic avenues at this meeting.

Macaron: Yeah, you’re talking about frexalimab, and I heard this from so many other colleagues, like why is it just a poster presentation? This was maybe the only, not only, but one of the main new, exciting things that was presented at ECTRIMS.

And it’s indeed an exciting mechanism of action. It’s really novel, a new soluble CD40 ligand. We already know that it’s higher in progressive MS form, in the plasma of patients who have a progressive MS form. So I think the idea here was to evaluate its efficacy specifically on progression. And if I recall, there was a paper published in Neurology a couple of years ago, and it’s on another molecule. I don’t remember the name of it [toralizumab], but that acts in a similar way. And the study, I think it was a phase I and showed that the drug was well tolerated and was safe.

So yes, I mean, in the study presented by Patrick Vermersch, it was a phase II study and they enrolled 129 patients either to receive high dose, low dose, or placebo. And the primary outcome was the number of new active MRI lesions at week 12. And I think what was presented at ECTRIMS was the open-label extension of this phase II study that was for 24 weeks.

And the results are really exciting, a significant reduction of above 90% of the number of new lesions, specifically in the high-dose arm, and good numbers as well in the low-dose arm at week 12. And this effect persisted in the open-label extension study. And I think in the open-label extension study, patients who were on the placebo arm switched after 12 weeks to frexalimab, and it really worked as well.

I think it’s an exciting study. It has generally a good safety profile. Most patients had minor upper respiratory tract infections and headaches, COVID-19 infections, and I don’t think there were any signs of worrisome of severe lymphopenia or hypogammaglobulinemia or something like that.

I think we still need to see the long-term results specifically on disability worsening. It’s a promise that we want to see … I think also for BTK [Bruton’s tyrosine kinase]. I think we’re not impressed anymore by a reduction of 90% of gadolinium-enhancing lesions. We need more than that. So if the promise with this and with BTK inhibitors is to act on mechanisms of tissue injury, that would be really exciting. But it’s going to take time, right?

Alvarez: I mean, when you talk about biomarkers, CD40-positive cells have been a biomarker of more active disease — particularly with progressive disease — and I think that that’s a little bit of the interesting part of the CD40 is that the phase II and the extension was on relapsing disease. You’re kind of like, well, what’s the interest, I guess, on it from a relapsing perspective? But clearly, I think from a progressive perspective, you could see it possibly having some effect. You get nervous about it being able to enter the CNS [central nervous system] being a molecule, like a monoclonal antibody. But I think it has that interest, again, to capture our attention and see where it comes out.

Ontaneda: Yeah, absolutely. So that’s the key thing that I think: finding a new mechanism of action is something that doesn’t happen frequently. And when we see results as positive as the ones we saw with this trial, it really gives us some hope that if we are targeting inflammation from a slightly different pathway — this means something different, for example, for patients who might have a more progressive disease course — could it be used in a different stage of disease?

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