ECTRIMS 2024: Tolebrutinib may target smoldering inflammation

Sanofi’s tolebrutinib significantly delayed disability progression, by 31%, and increased the rates of disability improvement compared with a placebo in people with nonrelapsing secondary progressive multiple sclerosis (SPMS), according to new data from the HERCULES Phase 3 clinical trial.

The investigational BTK inhibitor also was found to significantly reduce the risk of disability progression in people with relapsing forms of multiple sclerosis (MS) who took part in the GEMINI trials. However, tolebrutinib failed to meet the main GEMINI goal of lowering relapse rates compared with the approved oral therapy Aubagio (teriflunomide).

The findings were presented in a pair of Sanofi-sponsored late-breaking presentations at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, which was held Sept. 18-20, online and in-person in Copenhagen.

Sanofi believes the totality of the data indicates that tolebrutinib can target smoldering inflammation — a type of chronic and persistent inflammation that’s thought to contribute to MS progression even in the absence of the active inflammatory attacks that drive relapses — according to the company.

“Targeting this underlying, smoldering neuroinflammation process, that we believe drives this disease progression, is key to closing the gaps in MS treatment today,” Erik Wallstroen, MD, PhD, global head, neurology development at Sanofi, said in an emailed statement to Multiple Sclerosis News Today.

“We’re incredibly pleased with what we’ve seen from tolebrutinib in these pivotal phase 3 trials,” Wallstroen added. “Tolebrutinib is charting a new pathway for treating the disability that impacts so many people living with MS, likely by targeting smoldering disease directly in the brain.”

The company indicated in a press release that these trial data will be used for discussions with regulatory authorities worldwide, with plans to begin submitting applications for tolebrutinib’s approval in the second half of next year.

Sanofi testing tolebrutinib in 4 Phase 3 clinical trials

Tolebrutinib belongs to a class of therapies called BTK inhibitors, which block the activity of a protein called Bruton’s tyrosine kinase that’s important for the survival and activation of immune cell populations implicated in MS.

Sanofi’s Phase 3 clinical development program for tolebrutinib includes four clinical trials — dubbed GEMINI 1, GEMINI 2, HERCULES, and PERSEUS — involving distinct MS populations.

The identical GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) clinical trials collectively enrolled more than 1,800 people with relapsing forms of MS, including relapsing-remitting MS and active SPMS. Each was randomly assigned to receive a 60 mg dose of tolebrutinib or Aubagio, daily for up to three years.

Jiwon Oh, MD, a neurologist at St. Michael’s Hospital and the University of Toronto in Canada, presented top-line data from the GEMINI studies in a talk at the meeting. Oh’s presentation was titled “Efficacy and Safety of Tolebrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis: Results From the Phase 3 GEMINI 1 and 2 Trials.”

The results showed that annualized relapse rates were similar for patients given tolebrutinib or Aubagio — 0.12 relapses per year in both groups. These rates were generally low, but the lack of significant difference between the two groups meant the trials failed to meet their main goal.

Still, a significantly lower proportion of patients given tolebrutinib experienced six-month confirmed disability worsening (CDW), or an increase in Expanded Disability Status Scale (EDSS) scores that is sustained for at least six months, relative to those on Aubagio — 9.9% versus 13.2%. That amounts to a 29% lower risk of progression with tolebrutinib, according to the researchers.

Moreover, more individuals on tolebrutinib experienced a six-month confirmed disability improvement (CDI), or a sustained reduction in disability scores, compared with the Aubagio group (13.8% versus 12%), although the difference was not statistically significant.

The rate of new or enlarging lesions was comparable between the groups, but participants who received the investigational therapy had significantly more new inflammatory brain lesions than those on Aubagio in both trials.

Oh indicated that the findings overall suggest tolebrutinib has a benefit on disease progression “that is independent of relapse activity,” an effect likely related to its ability to suppress smoldering neuroinflammation.

HERCULES data show a 31% lower risk of disability progression for patients

In another talk, titled “Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results From the Phase 3 HERCULES Trial,” Robert Fox, MD, a neurologist at the Cleveland Clinic’s Mellen Center and chair of the HERCULES global steering committee, discussed findings from that Phase 3 trial (NCT04411641).

HERCULES enrolled 1,131 adults, ages 18-60, with nonrelapsing SPMS, who were randomly assigned to receive daily oral tolebrutinib (60 mg) or a placebo for up to four years.

The trial’s main goal was to determine if tolebrutinib could delay disability progression, and this goal was met. Significantly fewer people on tolebrutinib experienced a six-month CDW event relative to those in the placebo group (26.9% vs. 37.2%). This amounted to a 31% lower risk of disability progression with the experimental treatment.

In terms of six-month CDI, there was an 88% benefit from tolebrutinib, according to Fox, with 10% of those on treatment experiencing such a disability reduction compared with 5% on the placebo.

Tolebrutinib also was associated with a significant, 38% reduction in new or enlarging brain lesions, but there was no significant slowing of brain tissue loss. Fox said that the “surprising discordance between the disability rates and the brain volume loss rates” was “a little bit of a head scratching.”

I have many patients with gradual progression of their MS despite no relapses, and I’ve had very little to offer for treatment. … Now it looks like we have identified a treatment that slows the insidious decline with which so many patients struggle.

According to Fox, chair of the HERCULES steering committee and a paid advisor to Sanofi for the trial, these findings offer, “for the first time, a Phase 3 trial showing a treatment benefit in non-relapsing secondary progressive MS.”

Fox said the findings are promising.

“I have many patients with gradual progression of their MS despite no relapses, and I’ve had very little to offer for treatment,” Fox told Multiple Sclerosis News Today. “Now it looks like we have identified a treatment that slows the insidious decline with which so many patients struggle.”

In both studies, tolebrutinib was generally safe and well tolerated, although a small percentage of patients in both trials experienced significant increases in liver enzymes, and a single patient in HERCULES required a liver transplant and later died from complications of that transplant.

These elevations in liver enzymes all occurred in the first three months of dosing, but Fox indicated that liver monitoring was increased in frequency about halfway through the trial, with the goal of identifying at-risk patients sooner.

“There are safety issues that will need careful discussion with our patients, but this finally appears to be a treatment for [a] manifestation of MS that we have not been able to treat,” Fox said.

Sanofi is still running the PERSEUS Phase 3 trial (NCT04458051), which is investigating tolebrutinib against a placebo in people with primary progressive MS. Top-line data from that trial is expected in the second half of 2025.