AAN 2023: Tolebrutinib safely lowers relapse rates over 2.5 years

Phase 2b extension trial now has 125 MS patients on 60 mg daily dose

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration for the AAN science conference of a human brain.

About 2.5 years of treatment with tolebrutinib was associated with low relapse rates and stable disability levels among people with relapsing forms of multiple sclerosis (MS), according to data in an ongoing, open-label extension of a Phase 2b trial.

The oral treatment also continued to show a “favorable” safety profile in the extension study.

Findings were presented by Jiwon Oh, MD, a neurologist at St. Michael’s Hospital in Toronto, at the American Academy of Neurology (AAN) 2023 Annual Meeting, running April 22-27 in Boston and virtually.

Her presentation was titled, “Safety and Clinical Efficacy Outcomes From the Long-term Extension Study of Tolebrutinib in Participants With Relapsing Multiple Sclerosis: 2.5-Year Results.” Four of this study’s six researchers are employees of Sanofi, tolebrutinib’s developer.

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Tolebrutinib, a BTK inhibitor, aims to lower inflammation in MS patients

Tolebrutinib is designed to inhibit a protein called Bruton’s tyrosine kinase (BTK) that’s important for the activity of B-cells and other immune cells thought to drive inflammation in MS. The experimental therapy is one of a number of BTK inhibitors being developed to potentially treat this neurodegenerative disease.

Given their ability to target key cells implicated in MS, “the field is very excited about these molecules,” Oh said.

The main Phase 2b trial (NCT03889639), which opened in March 2019 and finished in January 2020, tested multiple ascending doses of tolebrutinib in people with relapsing types of MS.

A total of 130 patients were randomly assigned to one of four tolebrutinib doses — 5, 15, 30 or 60 mg — given daily for 12 weeks (about three months). All participants also received a placebo for four weeks, given either before or after tolebrutinib treatment.

Results showed that the higher dose (60 mg) led to a significant, 89% reduction in new or enlarging brain lesions compared with the placebo period, as well as an 85% reduction in new active brain lesions.

Those who completed the main trial then were invited to enter the ongoing long-term safety extension study (NCT03996291). Most — 125 people — opted to continue with daily tolebrutinib treatment in this extension, after a gap period of about seven weeks.

Participants received the dose assigned to them in the main study for about six months, before switching to the 60 mg dose.

Data covering about 1.5 years of treatment, presented at last year’s AAN meeting, indicated that tolebrutinib continued to keep the number of inflammatory brain lesions low.

Annual mean relapse rate of 0.2 seen in ongoing extension study

In this year’s presentation, Oh discussed safety and efficacy findings in extension study patients treated for up to 120 weeks, or about 2.5 years. Its data cutoff date was July 7, 2022; this long-term trial is due to end in late November 2024.

Findings show annualized relapse rates remained low, at a mean of 0.2 relapses per year, compared with a mean relapse rate of 1.23 in the year prior to entering the main trial.

Notably, 73.4% of participants treated with tolebrutinib at 60 mg for at least eight weeks experienced no relapses in the extension study. Among those who did, one relapse over the follow-up period typically was reported.

Disability levels, as assessed with the Expanded Disability Status Scale (EDSS), also have remained stable over these 2.5 years.

As observed in the main trial, tolebrutinib was generally well tolerated, with no new safety signals identified in patients who switched to the 60 mg dose in the extension study. The most common adverse event across the study was COVID-19 infection, occurring in 31 people.

“The vast majority [of COVID-19 cases] were mild to moderate,” Oh noted. “Three were considered to be serious, and two [patients] had to be hospitalized, but it’s noteworthy that all of the cases resolved and all of the participants remained in the study.”

Other common side effects seen with tolebrutinib, such as headache, cold-like symptoms, and upper respiratory tract infections, also are common to other disease-modifying MS treatments, Oh said.

A total of 18 people discontinued treatment, three because of side effects that included headache, temporary increases in the levels of liver enzymes, and brittle hair.

Phase 3 trials of tolebrutinib underway in relapsing and progressive MS forms

Sanofi’s experimental oral therapy also is being assessed in four Phase 3 trials.

The twin GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials are testing tolebrutinib against Aubagio (teriflunomide), an approved therapy, in people with relapsing forms of MS, including relapsing-remitting MS and active secondary progressive MS (SPMS).

The HERCULES (NCT04411641) and PERSEUS (NCT04458051) trials are examining tolebrutinib against a placebo in people with progressive forms of MS. HERCULES is testing the therapy in patients with non-relapsing SPMS; PERSEUS is for people with primary progressive MS (PPMS).

Of note, all four Phase 3 studies were put on a partial hold by the U.S. Food and Drug Administration (FDA) in July 2022 due to reports of liver damage, which were said to be limited and reversible. Under the hold, all U.S. sites have been paused, and trial participants of less than 60 days have discontinued treatment.

Three trials report completed enrollment. PERSEUS is still is recruiting people with PPMS, ages 18-55, at various sites outside the U.S.

“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 development program to better understand the safety and efficacy profile of tolebrutinib for people living with MS,” Oh concluded.

In a separate AAN presentation, “Comparative CNS Pharmacology of Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating MS,” researchers at Sanofi examined the pharmacological properties of tolebrutinib in cells and nonhuman primates.

They also compared those properties with two other BTK inhibitors currently in Phase 3 trials for MS — Merck KGaA’s evobrutinib and Genentech’s fenebrutinib. Ongoing trials of evobrutinib also are on a partial FDA hold due to signs of liver damage in some patients.

Findings overall indicated that tolebrutinib was much more potent that the other two candidates at inhibiting their target enzyme, and faster acting than the other BTK inhibitors.

Tolebrutinib also was the only BTK inhibitor that reached the brain and spinal cord at concentrations expected to stop the activity of microglia. These immune cells are involved in smoldering neuroinflammation, a type of chronic inflammation that drives brain tissue loss and MS progression.

Note: The Multiple Sclerosis News Today team is providing coverage of the American Academy of Neurology (AAN) 2023 Annual Meeting April 22-27. Go here to see the latest stories from the conference.

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