Dr Erik Wallstroem and Tom Snow Highlight New MS Treatments Aimed at Smoldering Inflammation


Three new novel treatments have shown promise in the treatment of multiple sclerosis (MS), including the potential to target neuroinflammation at its source.

Erik Wallstroem, MD, Phd, Global Head of Development, Neurology and Ophthalmology, and Tom Snow, Global Franchise Head, Neurology and Rare Blood Disorders, of Sanofi, sat to discuss 3 new treatments in multiple sclerosis (MS). Findings presented at ECTRIMS-ACTRIMS 2023 demonstrated the efficacy of these treatment in reaching the central nervous system (CNS) and impact smoldering neuroinflammation accompanying MS.

Here, Wallstroem and Snow detail the working mechanisms of these treatments and place them in context of the current MS treatment paradigm.


This transcript has been lightly edited for clarity.

What has necessitated new interventions like tolebrutinab, frexalimab, and SAR443820 (RIPK1i) in the treatment of MS?

Wallstroem: Even though we are getting better and better at tackling the relapses and the new MRI lesions, that doesn't explain all of the symptoms that the MS patients have. It's the most obvious perhaps in progressive patients, but also in relapsing patients, and there are many patients that are reporting to the neurologist that they are getting worse, without perhaps much activity on the MRI. And we know we have to go to traditional mechanisms. And one aspect of that is that we also know that we need to control this classical measure.

So, there is a trend towards more use of high efficacy therapies. And we think that it's very appropriate; there's not that many of them. So, we think that that's where the new therapies will need to come in: high-efficacy therapies, not medium- or low-efficacy therapies—really high-efficacy therapies, and therapies that add new mechanisms.

Many in the field now talk about smoldering disease, this low-level inflammation in the nervous system, and there may be different ways to tackle that type of inflammation. And that is very much coupled to the progression and the aspect of MS that is still not well treated.

Snow: We see from published data that unmet need that still exists even in patients who are on a so-called high-efficacy therapy, those patients still experienced disease progression. So, even though we're shutting down the relapses and to a great extent shutting down MRI lesions, those patients are still getting worse. They're still progressing. In terms of, you know, the standard disability scales that we see, they still experience issues with fatigue and cognition. And when you speak to neurologists, and speak to patients, this is a very real phenomenon where they feel like they're somehow getting worse even though they might not have had a relapse in several years.

What underlying mechanisms at play set these interventions apart from previous treatments?

Wallstroem: So actually now, in the pipeline of MS, we're looking at three different mechanisms. And perhaps the most well-known is BTK [Bruton tyrosine kinase] inhibition, and with this agent we're investigating tolebrutinab. So that's one we're actually investigating through the whole spectrum of MS both in relapsing disease, primary progressive and secondary progressive disease, and it's a BTK inhibitor. And so it targets a molecule that is expressed on B cells, but also on cells in the central nervous system, such as microglia cells.

And we think that this is an agent that may have an effect on classical lesions that we have seen in phase 2 and having additional effects in the central nervous system and targeting aspects of what we can call smoldering inflammation. So that's kind of one treatment principle. And we are looking forward to getting the first readouts of tolebrutinab next year. So, that will be very interesting to see where it can fit into treatment paradigm.

There is one agent called frexalimab, which is an anti-CD40 ligand inhibitor, which is earlier in development—but we recently got the phase 2 data—and that is a monoclonal antibody that tackles MS and in a very, very different way. So it goes upstream in the immune system. It inhibits co-stimulatory molecules, which interferes with interaction of T and B cells. So it's both T and B cells and also innate immune cells in the periphery. And we have shown a very pronounced effect on the development of new lesions.

But I think the takeaway for that compound is that it's very upstream in the immune system. And it's not only B cells, it's B and T cells and innate immune cells. So very different mechanism as compared to BTK inhibitors like tolebrutinab and we will have to watch the data play out and see which of these will be most effective and which patients will benefit most from the different types of intervention.

Then I just briefly want to mention a third one. We have an ongoing phase 2 trial with an agent called a centrally acting RIPK1 inhibitor. So that's also an agent—a small molecule—that can go into the central nervous system. It goes to a different type of pathology, a mechanism we call necroptosis, that actually is active in MS, in progressive MS, and potentially other neurodegenerative conditions. So three very, very different mechanisms. But I do think that it speaks to the heterogeneity in MS and the need to sort of test different mechanisms to really find what can help patients most.

Snow: Right now, the dominant mechanism in treating MS is B-cell depletion with anti-CD20 monoclonal antibodies, which we think could be improved upon for a number of reasons. One, when you deplete B cells over a long term, there are questions that are raised around safety. And we saw this during COVID-19, in terms of vaccination response and other infection risks.

The other is, and I think Eric laid this out nicely, is that I think our understanding of MS has evolved. While B cells are important, they're not the only cells that are important. That interaction between B and T cells, and also cells like microglia cells of the innate immune system, those are playing a role. And if we can address them, we can hopefully tackle both the kind of acute inflammation, relapses and MRI lesions, as well as this smoldering neuroinflammation that takes place causing long-term disability.

Related Videos
A panel of 3 experts on multiple sclerosis
A panel of 3 experts on multiple sclerosis
Kelly Harris, APRN
Jessica K. Paulus, ScD, Ontada
Rachel Dalthorp, MD
A panel of 3 experts on multiple sclerosis
A panel of 3 experts on multiple sclerosis
Jessica K. Paulus, ScD, Ontada
Michael Thorpy, MD
Sindhuja Kadambi, MD, MS
Related Content
CH LogoCenter for Biosimilars Logo