ACTRIMS 2025: Tolebrutinib impact greater in MS patients with PRLs
Treatment candidate found effective in reducing disability progression risk
Sanofi’s experimental BTK inhibitor tolebrutinib is more effective at reducing the risk of disability progression in people with multiple sclerosis (MS) who have evidence of paramagnetic rim lesions (PRL), according to a new analysis of three Phase 3 clinical trials.
PRLs are a type of chronic inflammatory lesions that have been associated with faster disability progression in MS. These lesions are characterized by an outer rim of iron-containing inflammatory immune cells and a core region with extensive demyelination — myelin loss — and nerve cell damage.
In people without PRLs, the risk of progression was very similar for those given tolebrutinib or a control treatment. But if patients had these lesions at the time treatment was started, tolebrutinib reduced that risk by as much as 54%, the data showed.
“When you actually look at the impact of tolebrutinib on six-month confirmed disability worsening, it seemed to be more evident in participants who did have PRLs at baseline,” or the trials’ start, Jiwon Oh, MD, PhD, the lead researcher and a professor at the University of Toronto in Canada said in a presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2025, held Feb. 27 to March 1, in Florida and virtually.
The greatest difference, of more than 15%, was seen in patients with four or more PRLs at baseline, Oh noted.
Oh’s talk was titled “Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes.”
Tolebrutinib tested in patients in GEMINI 1, 2, and HERCULES
MS is a neurological disorder in which the immune system mistakenly attacks the myelin sheath, a protective coating around nerve fibers. This leads to progressive nerve cell degeneration and a range of MS symptoms.
Most people with MS are initially diagnosed with relapsing-remitting MS, known as RRMS. This form of the disease is marked by periods of worsening neurological symptoms, or relapses, followed by periods of recovery. Without treatment, the vast majority of people with RRMS eventually transition to another disease form called secondary progressive MS (SPMS), in which symptoms steadily worsen even in the absence of relapses.
Tolebrutinib, now being developed by Sanofi, is a small molecule inhibitor of the Bruton tyrosine kinase (BTK), an enzyme that’s critical for the survival and activation of B-cells and microglia. These two immune cell types are known to drive MS inflammation and disease progression.
The drug can cross the blood-brain barrier, a semipermeable cellular barrier that regulates which substances can pass from the blood to the brain. A key limitation of many drugs is that they cannot cross this barrier, and are therefore not able to limit localized inflammation in the brain and spinal cord.
To date, tolebrutinib has been evaluated in three completed Phase 3 clinical trials: GEMINI 1 (NCT04410978), GEMINI 2 (NCT04410991), and HERCULES (NCT04411641). The GEMINI studies tested the therapy candidate against the approved drug Aubagio (teriflunomide) in people with relapsing forms of MS. The HERCULES trial, meanwhile, compared tolebrutinib with a placebo in people with nonrelapsing SPMS. A fourth trial, dubbed PERSEUS (NCT04458051), is now underway to assess the therapy’s effects in primary progressive MS patients.
Top-line data from the GEMINI and HERCULES trials, presented last year, showed that tolebrutinib significantly reduced the risk of six-month disability progression — by 29% in people with relapsing forms of MS and by 31% in those with nonrelapsing SPMS. These effects were independent of relapse activity, suggesting that the drug may work by suppressing smoldering, or chronic, inflammation.
To examine this further, the team of researchers now conducted a post-hoc analysis of these trials to determine if the presence of PRLs — an indicator of chronic inflammation — impacted tolebrutinib’s effects.
“PRLs, or paramagnetic rim lesions, are known to be associated with increased risk of disability accumulation, specifically smoldering-associated worsening, and nearly 50% of people living with MS present at least one PRL at diagnosis,” Oh wrote in an email to Multiple Sclerosis News Today.
In the presentation, Oh noted that “the objective of this study was to evaluate baseline PRLs as a prognostic and predictive biomarker for disability accumulation, as well as treatment response in the GEMINI 1 and 2 and HERCULES clinical trials.”
Risk of disability progression about 50% less in patients with 4 or more PRLs
About a third of the trial sites overall had MRI machines that could capture appropriate images to visualize PRLs. Thus, about 34% of GEMINI 1 and 2 participants, and 39% of those enrolled in HERCULES had available PRL data at the start of the trials.
The proportion of patients with PRL imaging was similar between treatment groups in each trial, the team noted. Also, the characteristics of patients with PRL data were generally similar to the overall population in each study, according to Oh, who also serves as the medical director of the Barlo MS Program at St. Michael’s Hospital in Toronto.
In the GEMINI trials, 38% of patients had no PRLs, while 35% had 1-3 such lesions and 27% had four or more. The proportions were similar in HERCULES. In that trial, 40% of participants with PRL imaging had no PRLs, while 36% had 1-3 and 24% had four or more lesions.
Among individuals given Aubagio in the GEMINI trials or the placebo in HERCULES, the risk of disability worsening increased with an increasing number of PRLs at baseline. This “clearly shows that higher PRL lesion burden is associated with a higher risk of disability accumulation,” Oh said.
However, treatment with tolebrutinib was found to reduce the risk of progression in people with PRLs, with greater benefits observed in those with a higher number of such lesions at baseline.
These data suggest that impact of tolebrutinib may be greater in patients with a higher number of PRLs. … These results … are further evidence supporting the impact of tolebrutinib on the … processes driving disability.
In the GEMINI trials, for example, people with no PRLs had an 18% lower risk of progression when given tolebrutinib compared with those on Aubagio. But this risk was further decreased, by 46%, in patients with 1-3 PRLs, and by 49% in those with four or more PRLs at baseline.
Similar results were seen in the HERCULES trial, in which people with no PRLs had a slightly greater risk of disability progression with tolebrutinib — a 17% difference from the placebo. That risk, however, was 15% lower with tolebrutinib in people with 1-3 PRLs, and 54% lower in those with at least four PRLs.
“These data suggest that [the] impact of tolebrutinib may be greater in patients with a higher number of PRLs at baseline,” Oh wrote in the email, adding that “these results are consistent with the belief that PRLs are an indicator of diffuse smoldering neuroinflammation and are further evidence supporting the impact of tolebrutinib on the … processes driving disability.”
Oh said the findings are “noteworthy” because these results are from a prospective clinical trial and not from retrospective studies.
“Overall, when you take into account the findings that were recently reported with the totality of the data in HERCULES and GEMINI, as well as the results that I’m reporting today, these findings are consistent with the … bioactive mechanism of action of tolebrutinib,” she concluded.
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