Tolebrutinib: A New Hope in Multiple Sclerosis Treatment

 

Introduction

Multiple sclerosis (MS) is a chronic neurological condition that affects millions worldwide. Despite the availability of several therapies, there remains a significant unmet need, especially for people living with progressive forms of MS. Tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor currently in late-stage clinical trials, is generating attention for its potential to change the treatment landscape.

What is Tolebrutinib?

Tolebrutinib, also known as SAR442168, is an experimental oral medication designed to inhibit BTK, an enzyme that plays a key role in the activation of immune cells such as B cells and microglia. By reducing the overactivity of these cells, the drug aims to decrease inflammation and slow the progression of disability in MS.

How Does It Work?

Unlike many current therapies that primarily reduce relapses, tolebrutinib targets both inflammatory and degenerative processes within the central nervous system. Its ability to cross the blood-brain barrier means it can act directly on microglia in the brain and spinal cord. This dual mechanism makes it particularly promising for progressive forms of MS where relapse activity is less common.

How is It Taken?

Tolebrutinib is taken as a once-daily oral tablet, offering patients a convenient alternative to injectable or infusion-based therapies.

Clinical Trial Insights

Phase 2:
In relapsing MS, tolebrutinib demonstrated significant reductions in MRI-detected brain lesions compared to placebo.

Phase 3 GEMINI (Relapsing MS):
The drug did not outperform teriflunomide in reducing relapses but did show a 29% reduction in disability progression, highlighting its potential in long-term disease management.

Phase 3 HERCULES (Secondary Progressive MS):
Tolebrutinib delayed confirmed disability progression by 31% compared with placebo. It also nearly doubled the proportion of patients experiencing disability improvement and reduced the number of new MRI lesions. These results are especially significant as few therapies have demonstrated such effects in progressive MS.

Phase 3 PERSEUS (Primary Progressive MS):
This ongoing study is evaluating tolebrutinib in primary progressive MS, with results expected in 2025.

Safety and Side Effects

While results are encouraging, safety remains a major focus. The most notable concern is liver toxicity. Some patients in trials developed significant elevations in liver enzymes, with rare cases leading to serious outcomes. For this reason, close liver function monitoring is essential, particularly in the first few months of treatment.

Other commonly reported side effects include respiratory infections, headaches, back pain, urinary tract infections, and swelling in the legs or hands.

Regulatory Status

Tolebrutinib is not yet approved by regulatory authorities. It is currently under priority review by the U.S. Food and Drug Administration, with a decision expected in late 2025. The drug has also been granted Breakthrough Therapy designation, reflecting its potential to meet critical unmet needs in progressive MS.

Conclusion

Tolebrutinib represents one of the most exciting developments in multiple sclerosis research. By slowing disability progression—particularly in progressive forms of the disease—it could become the first oral therapy to address this unmet need. However, careful monitoring for liver safety issues will be crucial. If approved, tolebrutinib may provide patients and clinicians with a valuable new tool in the fight against MS.