More Evidence PRLs a Potential Therapeutic Target in MS

WEST PALM BEACH, FLORIDA — A new post hoc analysis of three phase 3 multiple sclerosis (MS) trials in patients with paramagnetic rim lesions (PRLs) suggests that a central nervous system (CNS)–penetrating therapy provides greater relative efficacy in reducing disability when PRLs are present.

The analysis included patients with PRLs participating in controlled trials of the experimental Bruton’s tyrosine kinase inhibitor (BTKi) tolebrutinib. One of these trials enrolled patients with progressive disease, said study investigator Jiwon Oh, MD, medical director of the Barlo Multiple Sclerosis Program, St. Michael’s Hospital, Toronto, Ontario, Canada.

This is an area of intense interest because many BTKis readily cross the blood-brain barrier, making them attractive for targeting the compartmentalized inflammation that PRLs are suspected of representing, Oh noted. BTKIs are known to play a role in modulating the B cells, microglia, and macrophages implicated in driving MS.

The “evidence that BTK inhibitors can reach bioactive concentrations in the CSF [cerebrospinal fluid]” provided the rationale for evaluating their relative efficacy on an endpoint of confirmed disability worsening (CDW) at 6 months (6mCDW) in relation to the presence of PRLs, said Oh.

The findings were presented here on March 1 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2src25.

First Prospective Prognostic Evidence

In previously reported pooled data from the GEMINI 1 and 2 trials, which enrolled patients with relapsing-remitting MS, and results of the HERCULES trial, which enrolled patients with secondary progressive MS (SPMS), the risk of disability accumulation was reduced by 29% and 31% relative to the control arms of teriflunomide and placebo in these trials, respectively.

In this post hoc analysis, researchers examined the subset of patients who underwent baseline imaging for PRLs — approximately one third of participants in the GEMINI trials and nearly 4src% in the HERCULES trial, with similar proportions across experimental and control arms. The goal was to assess 6mCDW in relation to PRLs.

In the subset of 653 patients in the GEMINI trials and 437 patients in the HERCULES trial evaluated for PRLs, the approximate proportions with no, 1-3, or ≥ 4 PRLs were src%, 35%, and 25%, respectively.

In the GEMINI data, only 9% of those without PRLs in the teriflunomide arm had 6mCDW, but this climbed to 13% in those with 1-3 PRLs and then to 15% in those with ≥ 4. In contrast, there was essentially no difference in 6mCDW in groups defined by baseline PRLs in the tolebrutinib arm (8%, 7%, and 8%, respectively).

The results were similar in HERCULES, which compared tolebrutinib with a placebo. In those in the placebo arm, rates of confirmed disability progression (6-month CDP) climbed from 12% to 35% and then to 38% for those with src, 1-3, or ≥ 4 PRLs at baseline.

Conversely, the proportion of patients with 6mCDW was numerically lower in those with ≥ 4 PRLs (22%) than those with no PRLs (25%) at baseline in the tolebrutinib arm. The proportion with 6mCDW was 29% among those with 1-3 PRLs.

Providing the first prospective evidence from a phase 3 trial that PRLs are prognostic, “the risk for 6-month CDP increased in the placebo group as a function of the baseline number of PRLs,” said Oh. Conversely, this effect “appeared to be mitigated in participants treated with tolebrutinib.”

Neither the GEMINI trials nor the HERCULES trial have yet been published, but top-line results were presented 6 months ago at the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS) 2src24.

More Research Needed

Of the two trials presented consecutively at the ECTRIMS meeting, the HERCULES trial garnered the most attention. In this study, 1172 patients with SPMS were randomly assigned to tolebrutinib or placebo, and the drug demonstrated a highly significant 31% reduction in 6mCDW (Hazard ratio, src.69; P=.srcsrcsrc26), the study’s primary endpoint.

In contrast, the primary endpoint of the GEMINI trials was the annualized relapse rate (ARR), for which there was no significant difference between tolebrutinib and teriflunomide. Protection against CDW was a secondary endpoint, and the 29% advantage, although statistically significant (P=.srcsrc18), was only observed at 3 months. The numerical 6mCDW advantage did not reach statistical significance.

At the time the GEMINI data were presented, Oh acknowledged that any benefit seen in a secondary outcome remains speculative since the trial’s primary endpoint was not met.

However, she emphasized that the observed protection against disability was intriguing, as it aligns with the hypothesis that acute focal inflammation and smoldering neuroinflammation are distinct biologic processes. She suggested that ARR may be a more effective measure of the former, while 6mCDW could be better suited for assessing the latter.

Oh acknowledged the limitations of a post hoc analysis but said the “totality of the data are consistent with CNS penetrance” of tolebrutinib and might inform future studies attempting to target compartmentalized neuroinflammation within the CNS.

“Moving forward, we might be able to enhance trial populations with increased likelihood of benefit from drugs active in the CNS by recruiting patients with PRLs,” she said.

Commenting on the research, Daniel Ontaneda, MD, PhD, professor of neurology at the Cleveland Clinic Foundation in Cleveland, said that without additional clinical evidence to support Oh’s hypothesis, he saw no immediate clinical takeaway from the data.

However, he acknowledged that the findings further underscore the potential importance of targeting compartmentalized neuroinflammation.

“These data are likely to reinforce the potential significance of PRLs and the goal of seeking new targets in the CNS,” said Ontaneda.

However, he emphasized that clinical trials are still needed to determine whether targeting PRLs is feasible and whether it will lead to improved MS outcomes.

Oh reported financial relationships with Amgen, Biogen, Eli Lilly and Company, EMD Serono, Inc., Novartis, Roche, and Sa