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Two large clinical studies on relapsing and chronic progressive MS published / Hope for effect independent of acute inflammation

The drug tolebrutinib raises high hopes for the treatment of multiple sclerosis (MS): on April 8, 2025, the results of two large-scale, international Phase III trials were published in the New England Journal of Medicine. One publication under the last authorship of the University Medical Center Freiburg deals with the effects in relapsing-remitting MS (Gemini 1 and 2). Another (HERCULES) deals with MS that slowly worsens after initial relapses, which is referred to as non-relapsing secondary progressive MS. Both studies find positive effects or trends for the course of MS. This brings a drug within reach that not only reduces relapses, but also possibly slows the progression of disability - regardless of visible inflammation.

The GEMINI-1 and 2 studies were conducted under the last authorship of Prof. Dr. Heinz Wiendl, Medical Director of the Department of Neurology with Neurophysiology at the Freiburg University Medical Center. They show that tolebrutinib reduces acute relapses in relapsing forms of MS at least as well as the standard drug teriflunomide. However, the primary endpoint of superiority over teriflunomide was not achieved. In addition, there were clear indications that the disease progressed more slowly - even independently of relapses, a phenomenon known as PIRA (progression independent of relapse activity). The GEMINI studies were randomized, placebo-controlled and conducted across several countries. Both provide strong evidence of a disease-modifying effect of tolebrutinib beyond the known inflammatory processes. However, a final evaluation of the long-term effect is still pending.

At the same time, the HERCULES study demonstrated significant positive effects in secondary progressive MS for the first time. The primary endpoint of the study, namely that the progression of disability was delayed, was achieved. This makes tolebrutinib one of the few drugs with an effect in this difficult-to-treat form of the disease.

"Our results show that tolebrutinib works in MS patients in whom active inflammation is no longer detectable - and that is an absolutely crucial point of innovation," says Wiendl. This is a significant advance over previous therapies, which are primarily aimed at controlling acute inflammatory processes.

"One of the most important findings of these studies is that tolebrutinib can slow down the disease even if no acute inflammation is visible," Wiendl emphasizes. This is because previous drugs have been able to slow down acute inflammation to some extent, but not slow deterioration without measurable signs of inflammation.

"The results are an important step in MS therapy. There is an urgent need for drugs that slow down the progression of the disability," says Wiendl. "The results of the two studies show that this is exactly where tolebrutinib comes in."

Tolebrutinib is part of a Sanofi study program that covers both relapsing and progressive forms of MS. The studies were supported by Sanofi. Based on the data now published, the company has already applied for approval from the US Food and Drug Administration (FDA).

Original title of the study (Gemini1+2): Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis
DOI: 10.1056/NEJMoa2415985
Link to the study:www.nejm.org/doi/full/10.1056/NEJMoa2415985

Original title of the study (Hercules): Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis
DOI: 10.1056/NEJMoa2415988
Link to the study: www.nejm.org/doi/full/10.1056/NEJMoa2415988