ACTRIMS 2024: Tolebrutinib fails to eliminate iron rim lesions in Phase 2 trial

Scientists studying if higher dose needed, as treatment suggested some benefit

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Nearly one year of treatment with tolebrutinib, an oral small molecule being developed by Sanofi, failed to eliminate iron rim lesions in adults with multiple sclerosis (MS), according to data from a small Phase 2 clinical trial.

Researchers are continuing to examine study results to determine if a higher dose or other changes might better support tolebrutinib’s efficacy at reducing the number or volume of these smoldering lesions, also called paramagnetic rim lesions or PRLs.

María Inés Gaitán, MD, a neurologist with the National Institutes of Health (NIH), presented the findings at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, held Feb. 29-March 2 in Florida and virtually.

Gaitán’s late-breaking presentation was titled, “Primary Outcome of a Phase 2 Clinical Trial of Tolebrutinib, a Brain-Penetrant BTK Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in MS.” Four of this work’s 17 scientists are Sanofi employees.

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Seven patients given tolebrutinib entered study with paramagnetic rim lesions

MS results from immune system attacks on the myelin sheath, the fatty coating on nerve fibers that helps them send electrical signals. Resulting areas of damage can be seen as lesions on MRI scans.

Paramagnetic rim lesions are areas of damage where smoldering inflammation continues to cause myelin loss and nerve cell death over time. Such lesions are surrounded by a dark rim of iron-laden immune cells, which is visible with certain MRI techniques.

While the presence of PRLs is linked to a more severe disease course and greater cognitive decline, current disease-modifying therapies generally are unable to resolve iron rim lesions and prevent associated disability from accumulating.

Tolebrutinib is designed to inhibit an enzyme called Bruton’s tyrosine kinase or BTK, which is key for the development and function of certain immune cells thought to contribute to disease progression. These include B-cells, which are responsible for making antibodies, and microglia, the brain’s resident immune cells.

While anti-CD20 therapies such as Ocrevus (ocrelizumab) kill mature B-cells by targeting the CD20 protein on their surface, they have shown no effect on PRLs. But targeting “B-cells and innate immune cells in the edge of a chronic active lesion seems to be a good approach to treat chronic inflammation,” Gaitán said.

For this reason, the NIH’s National Institute of Neurological Disorders and Stroke launched a Phase 2 clinical trial (NCT04742400) to test tolebrutinib in people with at least one PRL evident on MRI scans. Eligible patients had been using an anti-CD20 therapy for at least six months, and they needed to be willing to stop that treatment for the duration of the trial.

Trial goal was disappearance of 1 or more PRLs in at least 2 treated patients

Seven adults (mean age, 47.7) without any inflammatory activity — no MS relapses, new lesions, or lesions with active inflammation — over the previous six months were enrolled. All were treated tolebrutinib at a 60 mg daily dose for 48 weeks (nearly one year). Four patients then moved to a 120 mg daily dose for the next 48 weeks, while the other three remained on the lower dose.

These patients, five men and two women, had a median of nine PRLs at the study’s start (baseline).

For comparison, researchers included a control group of five patients (mean age, 42), who stayed on treatment with a CD20 inhibitor. This group had a baseline median of 4.5 PRLs.

The trial’s main goal was to determine the proportion of PRLs whose iron rim was no longer evident after the initial 48 weeks. A positive result would be obtained if at least one PRL disappeared in at least two tolebrutinib-treated patients.

An analysis of 107 lesions, however, found that no PRL had disappeared despite nearly a year of treatment, suggesting that tolebrutinib had no effect on smoldering inflammation.

No MS relapses or new lesions seen in patients over two years of treatment

One possible explanation, Gaitán said, is that “PRL disappearance, maybe, is too high a bar.” To find out if a less rigid goal might produce better results, the researchers now are quantifying reductions in PRL size.

Another possibility is that the tolebrutinib dose given was too low. Data from the four patients who moved to the higher, 120 mg/day dose is now under analysis.

Gaitán, however, noted that results are likely to lack sufficient power, because the study intended for all seven patients to transition to the higher dose. It was not able to do so after a clinical hold on tolebrutinib trials was issued by the U.S. Food and Drug Administration upon reports of liver damage in other trials of this BTK inhibitor.

In this Phase 2 study, no serious side effects were reported with tolebrutinib, and no patient stopped treatment due to side effects. The most common adverse events reported in both the tolebrutinib and control groups were COVID-19, falls, and headache.

People on either tolebrutinib dose also did not experience any disease relapses or develop new lesions over the 96 weeks of treatment, consistent with data from an earlier tolebrutinib trial. Moreover, the number of B-cells remained below the reference range in all patients throughout that time window.

Prior treatment with CD20 inhibitors may slow B-cell repopulation, leading to prolonged efficacy against new lesions during treatment with tolebrutinib.

“Sequencing B-cell depletion followed by BTK inhibition may be a promising approach,” Gaitán concluded.

Note: The Multiple Sclerosis News Today team is providing coverage of the ACTRIMS Forum 2024 Feb. 29–March 2. Go here to read the latest stories from the conference.