Clinical Opinion: EU Approval of Tolebrutinib Signals New Direction for Nonrelapsing Secondary Progressive MS

The European Commission recently approved tolebrutinib (Cenrifki; Sanofi) for adults with secondary progressive multiple sclerosis (SPMS) without relapses in the previous 2 years, marking the first approval of a therapy specifically intended to target disability progression in this population. The decision followed a positive CHMP opinion and was supported primarily by findings from the phase 3 HERCULES trial, with additional supportive data from the GEMINI 1 and 2 studies in relapsing MS.^1,2

In HERCULES, treatment with tolebrutinib reduced the risk of 6-month confirmed disability progression by 31% compared with placebo in patients with nonrelapsing SPMS. The oral, brain-penetrant Bruton tyrosine kinase inhibitor (BTK) is designed to address smoldering neuroinflammation, including CNS-compartmentalized immune activity thought to contribute to disability accumulation independent of relapses. The approval also comes amid a more complex regulatory picture, as the therapy’s path in the United States remains unresolved.

To better understand the clinical implications of the decision, NeurologyLive® spoke with Jens Kuhle, MD, head of the Multiple Sclerosis Center and clinical neuroimmunology at University Hospital Basel. In this Q&A, Kuhle discusses the significance of the EU approval, the unmet need in nonrelapsing SPMS, the interpretation of HERCULES, and what differing regulatory outcomes may suggest about evaluating therapies that target progression independent of relapse activity.

NeurologyLive: What was your initial reaction to the European Commission’s approval of tolebrutinib for nonrelapsing SPMS?

Jens Kuhle, MD, PhD: My initial reaction was that the European Commission's decision was expected following the positive CHMP opinion in April, but that certainly does not diminish its importance. The CHMP opinion reflected the scientific conclusion that the overall benefit-risk profile was considered favorable, whereas the Commission's decision now translates that assessment into a treatment that can ultimately become available to patients across Europe.

From my perspective, the significance extends beyond tolebrutinib itself. Patients with nonrelapsing secondary progressive MS continue to accumulate disability despite the absence of relapses, yet therapeutic options have remained very limited. This approval recognizes that progression independent of relapses is not simply an inevitable phase of the disease but a therapeutic target that can be modified.

I think that is an important message for patients, clinicians, and for the future development of therapies targeting progressive MS.

What unmet need does this approval address, and how could it change the way clinicians approach this population?

The unmet need is not only the limited availability of therapies for nonrelapsing SPMS, but also the fact that this stage of the disease has traditionally been viewed as one in which disability progression is difficult to influence. Patients often continue to accumulate disability despite the absence of relapses, reflecting disease mechanisms that are at least partly distinct from the acute inflammatory activity targeted by most currently available therapies.

From my perspective, the approval reinforces an important conceptual shift: progression itself should be regarded as a therapeutic target rather than simply an inevitable consequence of longstanding disease. I do not think this will fundamentally change how we diagnose nonrelapsing SPMS, but it may encourage clinicians to identify progression earlier, monitor disability more systematically, and discuss treatment options before substantial irreversible disability has accumulated.

Importantly, this development also aligns with the increasing recognition that progression can be detected earlier and more objectively. Advances in clinical assessment, MRI, and fluid biomarkers are improving our ability to identify patients who are entering a progressive phase of the disease. As these tools become integrated into routine practice, therapies specifically targeting progression are likely to become increasingly relevant.

Ultimately, I think the greatest impact of this approval may be a more proactive approach to recognizing and treating progression rather than waiting until disability has become firmly established.

What aspects of the HERCULES data were most compelling, and how do you interpret the benefit-risk profile?

For me, the most compelling aspect of HERCULES was that the effect was demonstrated on confirmed disability progression in a population without recent relapses. Even more interesting, the observed benefit on disability progression was not accompanied by a clear effect on conventional measures of focal inflammatory disease activity, such as acute lesions or relapses.

This suggests that the therapeutic effect extends beyond simply suppressing acute focal inflammation and directly addresses the central clinical challenge in nonrelapsing SPMS. A relative reduction of around 31% in 6-month confirmed disability progression is clinically meaningful in this setting.

At the same time, I would interpret the results with appropriate caution. Clinical trials inform us about the average treatment effect in a population, but they do not tell us which individual patient will respond particularly well. I therefore see tolebrutinib as an important additional therapeutic option rather than a universal solution, with careful patient selection and appropriate liver monitoring remaining essential.

Looking ahead, I think this becomes even more relevant as our ability to monitor progression through clinical assessment, MRI, and fluid biomarkers continues to improve. Better tools to evaluate treatment response at the individual patient level, together with therapies with different mechanisms of action, will hopefully allow us to move toward a more personalized approach to treating progressive MS.

What do the differing regulatory outcomes in Europe and the United States suggest about evaluating progression-targeting therapies?

The differing outcomes highlight how difficult it remains to evaluate therapies aimed at slowing progression independent of relapses. In this setting, regulators have to judge a treatment effect on disability progression in a population with limited alternatives, while also weighing safety concerns and uncertainty around individual benefit. It is therefore not surprising that different agencies may place somewhat different emphasis on the same data.

From my perspective, the European decision suggests that the disability progression signal in HERCULES, together with the high unmet need in nonrelapsing SPMS, was considered sufficient to support a favorable benefit-risk assessment with appropriate monitoring. The FDA appears to have taken a more cautious view, particularly regarding the overall benefit-risk balance and safety profile.

Whether the FDA position evolves will likely depend on additional evidence, including longer-term safety data, further characterization of liver risk, and more information on which patients are most likely to benefit. I would not frame this as Europe and the United States disagreeing on the importance of progression independent of relapses. Rather, I think it reflects the fact that this is still a developing regulatory space, where the threshold for accepting disability progression endpoints, safety monitoring, and uncertainty around individual response is still being defined.