Tolebrutinib is a brain-penetrant and bioactive Bruton’ s tyrosine kinase( BTK) inhibitor. Elevations in liver enzymes were observed in 4.1 % of participants taking tolebrutinib, similar to other BTK inhibitors being investigated for MS. Sometimes the elevations in liver enzymes can be extremely high, and one trial participant died from complications of liver injury.
“ Progression can be reduced. This opens up a new door to treatment in the progressive MS sphere,” says Professor Chataway.“ It’ s incredibly exciting. Effects on the liver need to be looked at, but this is delightful news for our patients with progressive MS.”
Based on the results of the HERCULES trial, the FDA granted breakthrough therapy designation for tolebrutinib as a treatment for non-relapsing SPMS. A breakthrough therapy designation speeds up the process of reviewing and approving drugs that aim to treat serious conditions and can show preliminary evidence of improvement over already available therapies. The target action date for a decision from the FDA is September 28, 2025. 6 A regulatory submission is also under review in the EU.
FUTURE DIRECTIONS IN RESEARCH
Professor Chataway is optimistic about tolebrutinib and other BTK inhibitors currently going through trial.“ I think the door is really opening now, and we can build on these treatments. It’ s very clear in my mind that progressive MS requires a multi-model approach. One drug will never be enough, so we’ re trying to get these pillars aligned.”
started recruiting in 2023. The first of its kind for MS, the OCTOPUS trial is designed to study multiple treatments at the same time. As the trial progresses, the research team will cut drugs that don’ t show potential and add in other drugs that look promising, thereby accelerating the trialing process. Trial sites continue to open up, and recruiting will go on through at least 2028 and possibly longer.
VOLUNTEERS NEEDED
Clinical trials need volunteers. Interested in joining a clinical trial for progressive MS? The database at clinicaltrials. gov includes information on clinical trials and observational studies around the world. Your neurologist may also be able to point you toward studies that match your diagnosis. And MS registries— such as NARCOMS and U. K. MS Register— allow you to take part in MS research by providing information from the comfort of your own home.
Participating in a clinical trial is not for everyone, says Professor Chataway, because it does require a commitment to stay the course.“ We’ re very sorry when there’ s no therapeutic result, but it can be physically and cognitively rewarding. Involvement in a clinical trial is a good thing, whatever the results. You gain frequent interaction with professionals who are highly knowledgeable about MS, particularly progressive MS. Instead of MS leading you, you lead MS. It’ s a really positive way to take back some control.”
He hopes to see multiple drugs approved to slow progressive MS and to ultimately move into the final frontier— regeneration.“ Remyelination drugs are starting to come into Phase 2 trials. It’ s very exciting, and there’ s a lot of work going on around the world,” says Professor Chataway.
He is also the lead researcher for the OCTOPUS trial, a multi-arm, multi-stage clinical trial for progressive MS that
1 Chataway J, Schuerer N, Alsanousi A, et al.“ Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis( MS-STAT): A randomised, placebo-controlled, phase 2 trial.” Lancet. 2014 Jun 28; 383( 9936): 2213-21.
2 Blackstone J, Williams T, Nicholas JM, et al.“ Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis( MS-STAT2): Protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.” BMJ Open. 2024 Sep 16; 14( 9): e086414.
3 Marrie RA, Rudick R, Horwitz R, et al.“ Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.” Neurology. 2010 Mar 30; 74( 13): 1041-7.
4 Feinstein A, Amato MP, Brichetto G, et al. CogEx Research Team.“ Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis( CogEx): A randomised, blinded, sham-controlled trial.” Lancet Neurol. 2023 Oct; 22( 10): 912-924.
5 Fox RJ, Bar-Or A, Traboulsee A, et al.“ Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis.” New England Journal of Medicine. 2025 Apr 8. doi: 10.1056 / NEJMoa2415988
6 Sanofi press release( https:// www. news. sanofi. us / 2025-03-25-Tolebrutinib-regulatory-submission-accepted-for-priority-review-in-the-US-for-patients-withmultiple-sclerosis)-accessed 5 / 5 / 2025.
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