Tolebrutinib Long-Term Data Continue to Show the BTK Inhibitor Is Safe, Clinically Effective in MS

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Safety and clinical efficacy data through 120 weeks from a long-term extension study of an ongoing phase 2b dose-finding study of tolebrutinib for relapsing multiple sclerosis (MS) were presented Monday at the American Academy of Neurology 2023 annual meeting by lead investigator by Jiwoh Oh, MD, PhD, neurologist and medical director, Barlo Multiple Sclerosis Program, St. Michael’s Hospital, University of Toronto.1-3

The investigational agent tolebrutinib (SAR442168) is an oral and selective small molecule Bruton tyrosine kinase (BTK) inhibitor that works to reduce the inflammation seen with relapsing and progressive forms of MS. At the heart of this inflammation is the survival and activation of B cells, which require the enzyme BTK to be activated and survive, and which also are responsible for much of the immune cell activity seen in MS progression.4With tolebrutinib, B-cell function is modulated rather than depleted and Fc gamma receptor activation of myeloid cells, including microglia, is also inhibited.

“Phase 2b trial findings showed brain-penetrant BTK inhibitor tolebrutinib was well tolerated and elicited dose-dependent reductions in new gadolinium-enhancing T1 and new/enlarging T2 lesions in participants with relapsing MS,” noted the study investigators. There was a more than 85% reduction in these lesions following a treatment course of 60-mg/d tolebrutinib over 12 weeks compared with placebo.

The primary end point of the long-term extension study, funded by Sanofi, was treatment-emergent adverse events (TEAEs). Secondary end points (indicating clinical efficacy) of note were annualized relapse rate (ARR)—measured among participants who received 8 or more weeks of tolebrutinib 60 mg through 120 weeks—and mean Expanded Disability Status Scale (EDSS) score.

“The phase 2b trial was not powered to look at clinical efficacy end points. Nonetheless, these are important to look at in these extension studies,” Oh underscored.

In the phase 2b dose-finding trial, there were 2 cohorts of patients, with 66 first having a 4-week placebo run-in period followed by 12 weeks of tolebrutinib at a dose of 5, 15, 30, or 60 mg/d and 64 patients first receiving 12 weeks of tolebrutinib at 1 of the 4 doses followed by a 4-week placebo run-out period. Participants who completed the phase 2b trial double-blind period were able to continue their tolebrutinib dose in a double-blind manner until phase 3 dose selection (60 mg/d).

“So over a period of 16 weeks, it was possible to evaluate the efficacy of 4 different doses of tolebrutinib,” Oh noted.

Most patients from the dose-finding study (n = 129) were eligible for the long-term extension study, and 125 participated. Of this group, 124 completed Part A (weeks 0-24) of the long-term extension study, receiving 1 of the 4 above mentioned doses and transitioned to Part B (weeks 24-120), where all were eligible to receive tolebrutinib 60 mg/d and transitionted to that dose.

As of July 7, 2022, 85.6% of the participants in the long-term extension were still receiving tolebrutinib.

For the primary outcome, no dose effects for TEAEs or serious adverse events were observed in Part A of the long-term extension and in Part B after everyone transitioned to the higher dose, no new safety signals were seen. Of the 18 patients who discontinued treatment, percentages were low for reasons why: 4% due to perceived lack of efficacy; 3%, progressive disease; 2%, participant decision; 2%, AEs (1 instance each of headache, transaminase elevation, and trichorrhexis); 2%, immigration; and 1%, planned pregnancy.

The most common TEAEs were COVID-19 in 25%; headache in 14%; nasopharyngitis in 13%; upper respiratory tract infection in 11%; bacterial cystitis, arthralgia, and back pain in 7% each; and pharyngitis in 6%.

“There are a number of TEAEs listed here that are pretty familiar,” Oh explained, “because this is a common list that we see with many different MS disease-modifying treatments.”

Promising findings were also seen for the ARR and EDSS score secondary end points. At week 120, the ARR was 0.20 (95% CI, 0.14-0.28) among patients who received at least 8 weeks of tolebrutinib 60 mg/d, and no relapses were seen in 73.4%; ARR was only measured after patients switched to the 60-mg dose. The rate of relapse was low overall, with 17.7% experiencing just 1 relapse, 6.5% having 2 relapses, and just 2.4% having 3 relapses. And in all of these treatment arms, the EDSS scores remained stable through week 120.

Able to penetrate the blood-brain barrier, findings from multiple animal studies suggest superiority of tolebrutinib over other BTK inhibitors in development,4and these newest data continue that trend.

“Through week 120, tolebrutinib 60 mg/d continues to demonstrate a favorable safety profile and favorable tolerability,” noted Oh at the end of the presentation. “And obviously it will be important to continue to follow people in this long-term extension, as well as to look to data from the phase 3 clinical development program to better understand the safety and efficacy profile of tolebrutinib for people living with MS.”

Four phase 3 trials are currently evaluating 60-mg/d tolebrutinib.


1. Long Term Safety and Efficacy Study of Tolebrutinib (SAR442168) in Participants With Relapsing Multiple Sclerosis. Updated April 24, 2023. Accessed April 24, 2023.

2. Dose-finding Study for SAR442168 in Relapsing Multiple Sclerosis. Updated March 8, 2023. Accessed April 24, 2023.

3. Safety and clinical efficacy outcomes from the long-term extension study of tolebrutinib in participants with relapsing multiple sclerosis: 2.5-year results. Presented at: AAN 2023; April 22-27, 2023; Boston, MA. Accessed April 24, 2023.

4. Wexler M. Tolebrutinib for multiple sclerosis. BioNews. Updated May 25, 2022. Accessed April 24, 2023.

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