Where Tolebrutinib Fits: Weighing the EU Approval, FDA Divergence, and the Road Ahead in nrSPMS

On June 23, 2026, the European Commission approved tolebrutinib (Cenrifki; Sanofi) for the treatment of nonrelapsing secondary progressive multiple sclerosis, making it the first therapy specifically designed to target disability progression in this population. The decision was based primarily on results from the phase 3 HERCULES trial, in which tolebrutinib reduced the risk of 6-month confirmed disability progression by 31% compared with placebo and nearly doubled the rate of confirmed disability improvement.

The approval marked a meaningful milestone for a patient population that has historically had very few therapeutic options, though it arrives amid ongoing uncertainty in the US, where Sanofi's new drug application remains pending without a confirmed PDUFA date.

Tom Fuchs, MD, PhD, is a postdoctoral researcher at the MS Center at Amsterdam University Medical Center whose work sits at the intersection of progressive MS, biomarker development, and clinical monitoring. Following the EU approval, NeurologyLive reached out to Dr. Fuchs for immediate expert reaction on what the decision means for the field, how to contextualize the divergence between European and US regulators, and what gaps remain even as a new therapy enters the market.

In this Q&A, Fuchs shared his initial reaction to the approval and how he interprets the differing conclusions reached by European and US regulators. He addressed where tolebrutinib could fit within the current treatment landscape for nrSPMS, what the regulatory divergence signals about the future of progression-targeting therapies, and why he believes the field must now build more sophisticated systems for detecting and monitoring progressive disease.

NeurologyLive: What was your initial reaction to the European Commission's decision to approve tolebrutinib for nonrelapsing secondary progressive MS, particularly in light of the FDA's earlier decision?

Tom Fuchs, MD, PhD: My initial reaction was cautious optimism. For many years, one of the greatest unmet needs in multiple sclerosis has been finding therapies that meaningfully impact progressive disease biology, particularly for patients with nonrelapsing secondary progressive MS, a population that has historically had very few therapeutic options. I think many clinicians and researchers saw this approval as genuinely exciting.

There is a growing sense that we may finally be entering an era where we can begin affecting the slower, more progressive disease processes that drive long-term disability accumulation, rather than focusing exclusively on relapse-associated inflammation. However, I think the medical community is approaching this with understandable hesitation. The liver toxicity concerns that emerged during development are real, and they deserve continued close scrutiny. As with all MS therapies, benefit must always be weighed against risk.

But overall, I think what many of us are feeling is hope. Progressive MS has long been one of the most frustrating areas of neurology because patients reaching this stage of disease often had relatively little reason to feel optimistic about new treatment advances. If therapies like tolebrutinib ultimately prove successful, that could meaningfully change the lives of many patients who previously had far fewer options.

How do you interpret the differing conclusions reached by European and US regulators? Do you think they reflect different views of the available evidence, differences in risk-benefit assessment, or something else?

I suspect this primarily reflects differences in how regulators weigh unmet clinical need against treatment-associated risk. The evidence itself is the same, but regulatory agencies can reasonably differ in how much uncertainty they are willing to tolerate when evaluating therapies for conditions where treatment options remain limited. In Europe, I think there was recognition of the tremendous unmet need that exists for patients with progressive MS, particularly those without active inflammatory disease.

At the same time, this situation is not entirely unique to tolebrutinib. Across multiple sclerosis treatment more broadly, efficacy has almost always come alongside meaningful risks. Whether we are talking about infection risk, malignancy concerns, autoimmune complications, or in this case liver toxicity, physicians routinely help patients navigate these trade-offs. The most important principle is transparency.

Clinicians need to have honest conversations with patients about both the potential benefits and known risks, and together make decisions that reflect each individual's priorities and risk tolerance. If patients do choose therapies with known risks, then our responsibility is to monitor carefully and mitigate those risks as effectively as possible. In my view, that shared decision-making process remains central regardless of what individual regulatory agencies decide.

If tolebrutinib ultimately becomes available in the US, where do you envision it fitting within the treatment landscape for nonrelapsing secondary progressive MS?

If approved in the United States, I think tolebrutinib could fill a very important gap in our current treatment landscape. Much of our therapeutic arsenal remains highly effective at controlling relapse-associated inflammation, but far less effective at addressing the slower progressive disease processes that often continue even when conventional inflammatory activity has quieted down.

But I think the introduction of therapies like this also creates a new challenge for the MS community. If we are entering an era of CNS-penetrant therapies specifically designed to target progressive disease biology, then we as a field now need to become substantially better at identifying which patients are accumulating progressive pathology and which patients are at highest risk of worsening.

Historically, our monitoring systems have been heavily centered around relapses and MRI lesion activity. That framework may no longer be sufficient. We will increasingly need better biomarker-based approaches that combine fluid and imaging markers, including measures such as neurofilament light chain, GFAP, cortical and deep gray matter neurodegeneration, chronic active lesions, and other indicators of ongoing tissue injury, to better understand who needs these therapies most urgently. The therapeutic era is evolving, and our monitoring systems now need to evolve alongside it.

Looking beyond this specific decision, what does this regulatory divergence tell us about the future development and evaluation of therapies targeting progression independent of relapse activity and progressive forms of MS?

I think this decision highlights something much bigger than a single therapy. It reflects a broader shift occurring throughout the multiple sclerosis field. For decades, treatment success in MS has been defined largely by controlling relapses and reducing MRI-visible inflammatory activity. Increasingly, however, we recognize that disability accumulation frequently continues independently of these traditional markers through processes often described as progression independent of relapse activity, or PIRA.

If we are serious about targeting these progressive mechanisms therapeutically, then we must also become much better at measuring them clinically. From my own perspective, I believe cognitive monitoring deserves particular attention in this conversation. In our own work, we have shown that cognitive decline in MS often occurs independently of relapse activity, and in many cases independently of physical disability worsening as well.

We have also shown that it is closely associated with known markers of progressive pathology and strongly linked to real-world outcomes that matter to patients, including employment, social participation, independence, and overall quality of life. The encouraging part is that many of these tools are already within reach. Cognitive testing has been developed and refined internationally over the past 40 years, and instruments such as the BICAMS testing battery are already well established in terms of clinical value, usability, reliability, and interpretability.

More broadly, we also need better prognostic and risk stratification tools to help clinicians identify which patients are most vulnerable to progressive disease worsening. These tools need to be transparent, accurate, well-calibrated, easy to interpret, and realistic for busy clinical environments. Our team recently developed the DAAE Score prognostic tool, which has undergone rigorous validation and is nearing real-world clinical implementation for predicting increased likelihood of transitions toward progressive MS. The broader lesson here is that developing therapies for progressive MS is only the first step. As a field, we must now build equally sophisticated systems for detecting progressive pathology early, monitoring it effectively, and identifying the patients who stand to benefit most.