Tolebrutinib particularly beneficial in patients with MS who have more MRI lesions

Key takeaways:

• MRI paramagnetic rim lesions are associated with disability accumulation in multiple sclerosis.
• Tolebrutinib best mitigated disability risk in those with more paramagnetic rim lesions at baseline.

WEST PALM BEACH, Fla. — Tolebrutinib had the most protective effect against disability worsening at 6 months in patients with multiple sclerosis who had a greater number of MRI paramagnetic rim lesions at baseline, data show.

The findings are from a post-hoc analysis of phase 3 studies presented at ACTRIMS.

“A number of these [Bruton’s tyrosine kinase] inhibitors have the ability to easily cross the blood-brain barrier and reach bioactive concentrations within the central nervous system,” Jiwon Oh, MD, PhD, associate professor of neurology at the University of Toronto, said during her presentation. “They do have the potential to play a major role as a therapeutic agent in multiple sclerosis.”

Paramagnetic rim lesions (PRLs) found on MRI scans are associated with signs of MS disease worsening and have shown resistance to current therapies, Oh said.

Since Bruton’s tyrosine kinase inhibitors like tolebrutinib can modulate the effects of neuroinflammation, Oh and colleagues sought to evaluate whether PRLs at baseline can serve as a viable biomarker for disability accumulation and response to tolebrutinib in three phase 3, randomized, double-blind clinical trials: HERCULES, GEMINI 1 and GEMINI 2.

In HERCULES, researchers randomly assigned 1,131 participants in a 2:1 ratio to receive tolebrutinib or placebo. In the GEMINI trials, 1,873 participants were randomly assigned 1:1 to tolebrutinib or teriflunomide, each with matching placebo.

The current post-hoc analysis was limited to 39% of HERCULES participants and 34% of GEMINI participants who had adequate PRL imaging and evaluation.

Oh and colleagues assessed the impact of tolebrutinib from the time of 6-month confirmed disability worsening (CDW) in participants with zero, one to three, or four or more PRLs at baseline.

Across the trials, 61% of participants had PRLs. In HERCULES, 40%, 36% and 25% of participants had zero, one to three, or four or more PRLs at baseline, respectively. In GEMINI, 38%, 35% and 27% had zero, one to three, or four or more PRLs.

In both trials, the risk for 6-month CDW increased as the number of baseline PRLs increased in patients who received placebo or teriflunomide.

The researchers reported that tolebrutinib appeared to mitigate the risk for 6-month CDW, with a more demonstrable effect in those with one or more baseline PRLs. For example, in HERCULES, the risk was 54% lower in participants with four or more PRLs vs. the comparator group. In GEMINI, there was 46% and 49% lower risk in participants with one to three and four or more PRLs, respectively.

Oh noted that the risk for 6-month CDW among participants across the trials who received tolebrutinib was “numerically similar” to the risk of those without PRLs.

"This post-hoc analysis suggests that the impact of tolebrutinib treatment on disability accumulation may be greater for people with PRLs at baseline," Oh said.