The Promise of Frexalimab in MS: Part 2

In part 1 of this interview, Patrick Vermersch, MD, PhD, University of Lille, France, introduced the mechanisms at work in frexalimab, a second-generation investigational anti-CD40L antibody, in the treatment of multiple sclerosis (MS), and the implications of its approval.

In part 2 of this 3-part interview, Vermersch walks through the next steps in the investigation into the medication’s efficacy in MS treatment, whether it could be considered in the treatment of other conditions outside of MS, and the most surprising takeaways from the phase 2 trial, which is currently published in The New England Journal of Medicine.

This transcript has been lightly edited for clarity and length.

Transcript

The American Journal of Managed Care^® (AJMC^®): Do you foresee frexalimab benefiting other subsets of MS or diseases outside of MS?

Vermersch: The phase 2 focus on relapsing MS and the vast majority of the patients are relapsing-remitting MS—almost 94%. The primary end point of the phase 2 is related to focal inflammation, and mainly, MRI activity, but what is important in MS is not only target relapses and MRI activity but also to decrease the risk of confirmed disability progression. And so, we need to have robust data in phase 3, not only in relapsing-remitting MS, but also in the progressive phase of the disease.

The plan with Sanofi is now to have phase 3 studies, not only in relapsing-remitting MS, but also secondary progressive MS and non-active non-relapsing secondary progressive MS, because we would like to know the impact of frexalimab outside of inflammation. So, we will recruit patients with this non-relapsing secondary progressive MS (SPMS), patients with no relapse, and most of them will not have MRI activity also, to know a little bit more about the impact of frexalimab in purely progressive MS without superimposed activity, both clinically but also a vast majority, not a radiologically, also. It will be interesting to have both studies at the same time, and the plan is that: to have 2 studies, one focusing on relapsing-remitting, and another one on non-relapsing SPMS.

Outside MS could be interesting because, as you know, in the spectrum of autoimmune diseases, B cells, T cells, dendritic cells, microglia, macrophages—macrophages may play a role in many autoimmune diseases. For example, in lupus these kinds of drugs could be very interesting also to test because with the data we have today, it looks safe. But we need to wait, of course.

AJMC: Were there any surprising findings in your phase 2 study?

Vermersch: The first surprise for me is the magnitude of the results concerning the MRI data gathered on enhancing lesions but also new T2 [lesions]. In fact, you know, the activity occurs very early, which is good, because we need to control the inflammation as soon as possible. And as you know, the primary end point was only after week 12. ... And we have such robust data that we know there’s almost a 90% decrease of the risk to have new gadolinium [gad]-enhancing lesions versus placebo, which is extremely good, in fact. And as you know, we have already presented last year at the ECTRIMS-ACTRIMS meeting, data after 24 weeks. And maybe the effect is sustained in and even more amplified in patients on frexalimab from the onset. So maybe at 6 months of treatment, we have almost a complete suppression of inflammation, no gad-positive lesions and almost no new T2 [lesions]. Together less than 4% of the patients had new gad-positive lesions during the extension phase from week 12 to week 24, which is impressive, of course.

I would like also to note, a very surprising finding for me is the impact on patient-reported outcomes [PROs]. As you know in MS, this field of PROs is more and more important, even for the authorities, and it was surprising to observe an early impact only after week 12, on 2 scales. The MSIS, the Multiple Sclerosis Impact Scale, the physical component had a significant difference between frexalimab and placebo in favor of frexalimab, and also concerning fatigue. Fatigue is a very important symptom probably for most of the patients, the most disabling symptom in MS is [fatigue]. And we have an impact—early impact—on fatigue, with validated scales of PROMISE [Patient-Reported Outcomes Measurement Information System] MS—Fatigue.

Fatigue is very interesting, because after week 12 maybe we have no significant impact on relapses or no significant impact on disability, it's too short a period. But, even considering no impact on relapse, no impact on disability progression, we have an impact on fatigue on the MS Impact Scale physical component. That means, probably, we have an indeed indirect action of the drug into the [central nervous system] to have such impact on fatigue, which is extremely important for us because of the importance of fatigue MS.