ECTRIMS 2023: Tolebrutinib found to show benefits for up to 3 years

Therapy being tested with aim to prevent smoldering neuroinflammation

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with tolebrutinib for up to nearly three years was tied to low relapse rates, stable disability, and few new brain lesions among people with relapsing forms of multiple sclerosis (MS), according to new data from the long-term safety (LTS) extension of a Phase 2b trial.

The data were presented in two posters at the 9th joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), held last week in Milan.

The research was funded by Sanofi, tolebrutinib’s developer. The company believes the experimental treatment has the potential to target smoldering neuroinflammation, a type of chronic inflammation that’s been linked to MS progression.

“Addressing the smoldering neuroinflammation activity … represents a great unmet need in MS and offers significant potential for limiting the destructive, disabling nature of this disease,” Erik Wallstroem, MD, PhD, global head of neurology development at Sanofi, said in a company press release.

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According to Jiwon Oh, MD, a scientist from Canada, the medical community’s understanding of MS biology “has changed dramatically in the last couple years.”

“We now know that most people with MS experience disability accumulation from ‘smoldering inflammation,’ despite being free of acute inflammation activity,” Oh, a staff neurologist at St. Michael’s Hospital, in Toronto, said in an email to Multiple Sclerosis News Today.

“To support people with MS we must treat both the acute and the smoldering process of MS,” Oh said.

Tolebrutinib is one of a number of investigational MS therapies designed to inhibit a protein called Bruton’s tyrosine kinase, or BTK. This protein is important for the activity of immune cells thought to drive inflammation in MS.

The Phase 2b trial (NCT03889639) enrolled 130 people with relapsing forms of MS at study sites in North America and Europe. Each was randomly assigned to receive one of four oral tolebrutinib doses — 5, 15, 30, or 60 mg — daily for 12 weeks, or about three months. All participants also received a placebo for one month, either before or after tolebrutinib treatment.

The results, initially shared in 2020, indicated that tolebrutinib at its highest dose (60 mg) led to significant reductions, by at least 85%, in new or enlarging brain lesions, as well as active inflammatory brain lesions, compared with the placebo period.

After the main trial, all but five patients — 125 participants in total — opted to enter an ongoing LTS or long-term extension study (NCT03996291), in which all are receiving daily tolebrutinib. Participants received the dose that had been assigned to them in the main study for about six months, after which everyone switched to the 60 mg dose.

Data presented earlier this year, covering up to 120 weeks, or about 2.5 years of treatment in the LTS, indicated that the therapy remained well tolerated, with low relapse rates and stable disability levels.

We now know that most people with MS experience disability accumulation from ‘smoldering inflammation,’ despite being free of acute inflammation activity. To support people with MS we must treat both the acute and the smoldering process of MS.

In the new presentations, scientists now discussed trial findings as of a cut-off date of Feb. 14, covering up to 144 weeks, or nearly three years, of treatment. At that time, 103 of the people who entered the extension — more than 80% — remained on treatment.

Oh, also the medical director of the Barlo Multiple Sclerosis (MS) Program at St. Michael’s, discussed tolebrutinib’s safety and clinical efficacy in a poster, titled “Safety and Clinical Efficacy Outcomes from the Long-term Extension Study of Tolebrutinib in Participants with Relapsing Multiple Sclerosis: 3-Year Results.

As in the previous analysis, disability levels remained stable with up to the 144-week mark.

Annualized relapse rates also remained low, with patients who had received tolebrutinib 60 mg for at least eight weeks (about two months) experiencing an average of 0.23 relapses yearly compared with 1.23 in the prior to entering the main trial. About two-thirds (68.5%) of patients remained relapse-free at week 144.

The therapy’s long-term safety profile remained consistent with earlier findings. Common side effects included COVID-19 infection (34.4%), cold-like symptoms (16%), headache (13.6%), upper respiratory tract infection (11.2%), and back pain (9.6%).

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3 of 20 participants show signs of smoldering inflammation

In another poster, this one titled “MRI Outcomes from the Long-term Extension Study of Tolebrutinib in Participants with Relapsing Multiple Sclerosis: 3-Year Results,” additional details were presented on the 144-week findings related to MRI outcomes. This talk was given by Daniel Reich, MD, PhD, a neurologist and neuroradiologist at the U.S. National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH).

Since the last scan at week 96, which was about one year earlier, the mean number of new active (inflammatory) lesions remained low, at or below 0.5 new lesions for all treatment arms. Most participants, ranging from 72%-87% per the original treatment arm, had no new active lesions during that time.

Likewise, new or enlarging lesions remained low and also were stable up to week 144. Among those who had always been on the 60 mg dose of tolebrutinib, mean total lesion volume from the start of the main trial increased by less than 7%.

Among 20 people with available data, a paramagnetic rim lesion (PRL) — reflecting smoldering inflammation — was observed in one person prior to the main trial. It had disappeared by week 144. Three other participants developed new PRLs during the study.

“MRI findings from the ongoing LTS extension … support the efficacy of tolebrutinib in reducing acute inflammation in people with relapsing MS,” the researchers wrote.

According to Wallstroem, key in the research is targeting damage that occurs without relapses.

“We are exploring multiple treatment approaches with unique mechanisms of action that have the potential to slow or halt disability – one of greatest unmet needs for people with disease,” Wallstroem wrote to Multiple Sclerosis News Today.

“The data presented at MS Milan 2023 strengthen the growing body of scientific and clinical evidence supporting the potential of brain-penetrant and bioactive tolebrutinib to address the smoldering inflammation within the brain that is causing disease worsening even in the absence of relapses,” Wallstroem said.

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Extension trial to continue for 1 more year

The extension trial is expected to finish in November 2024. Meanwhile, the 60 mg dose of tolebrutinib is being evaluated in four Sanofi-sponsored Phase 3 studies.

All four trials were put on a partial hold by the U.S. Food and Drug Administration (FDA) in July 2022 due to reports of reversible liver damage, and enrollment was paused at all U.S. sites.

The twin GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials, for people with relapsing forms of MS, have both completed enrollment, as has HERCULES (NCT04411641), which recruited people with non-relapsing secondary progressive MS.

PERSEUS (NCT04458051), involving adults, ages 18-55, with primary progressive MS (PPMS), is the only trial still enrolling. It is seeking up to 990 participants at sites outside the U.S.

“The efficacy and safety data I’ve seen so far from tolebrutinib are promising, and there are emerging preclinical data supporting a possible effect on key components of smoldering inflammation,” Oh said.

“The field is awaiting the Phase III trial results of tolebrutinib with eager anticipation, which we hope will lead to a change in the standard of care for people with MS across the spectrum of the disease,” she said.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the 9th joint ECTRIMS-ACTRIMS meeting Oct. 11-13. Go here to see the latest stories from the conference.