#AAN2022 – Tolebrutinib Reduces Brain Damage Up to 1.5 Years in Trial

Long-term treatment with tolebrutinib significantly reduced signs of disease-related brain damage in people with relapsing multiple sclerosis (MS), according to new data from a Phase 2 clinical trial and its extension study.

Specifically, the investigational oral therapy was found to keep the number of inflamed brain lesions low over about 1.5 years.

The trial results were presented at the virtual 2022 American Academy of Neurology (AAN) Annual Meeting, in a poster titled “MRI Outcomes from the Long-term Extension Study of Tolebrutinib in Patients with Relapsing Multiple Sclerosis: 18-Month Results.”

Tolebrutinib is being developed by Sanofi as a treatment for all forms of MS. It is designed to block the inflammatory activity of immune cells that drive MS by inhibiting a protein called Bruton’s tyrosine kinase (BTK). Tolebrutinib is currently being tested in four Phase 3 clinical trials.

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GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) are testing tolebrutinib against the approved therapy Aubagio (teriflunomide) in people ages 18–55 with relapsing MS. Among the participants are individuals with active secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS).

Meanwhile, the HERCULES (NCT04411641) trial is evaluating tolebrutinib against a placebo in non-active SPMS patients, ages 18–60. The placebo-controlled PERSEUS study (NCT04458051) is testing the medication in adults up to age 55 with primary progressive MS (PPMS).

All four studies are currently enrolling new participants. Sanofi recently launched a website to facilitate participant recruitment based on a person’s MS diagnosis and disease severity, prior treatments, other diseases, and geographical location.

The developer had previously sponsored a Phase 2 dose-finding trial (NCT03889639) involving patients with relapsing MS. Participants were treated with daily tolebrutinib at one of four doses — 5, 15, 30, or 60 mg — for 12 weeks, or about three months. All patients also received a placebo for four weeks, either before or after their 12-week tolebrutinib treatment period.

That original study, which enrolled 130 participants, showed that the highest dose of tolebrutinib reduced the number of new or enlarging brain lesions by 89%, and the number of new active brain lesions by 85%, compared with the placebo. The therapy also was well-tolerated, with no new safety concerns being identified.

At the end of the initial study, 125 participants elected to continue receiving the treatment candidate in an open-label extension (NCT03996291).

For the first six months or so, participants in the extension continued treatment at whatever dose they had been on during the original trial. Then, all participants were switched to the highest dose of 60 mg/day, which is the dose that is currently being tested in Phase 3 studies.

As of Sept. 2021, imaging data up to 72 weeks — just shy of 1.5 years — was available for all 118 participants who remained in the study.

Results showed that the number of new gadolinium-enhancing lesions, which are lesions with active inflammation, was low — less than 0.5 per patient, on average — throughout the study in patients who were on the 60 mg/day dose the entire time.

For participants initially given lower doses, the number of new active lesions was somewhat higher at earlier time points. But once these participants transitioned to 60 mg/day, the numbers decreased to be comparable to those found in patients who started at the highest dose.

“New [gadolinium]-enhancing lesion counts remained low for tolebrutinib 60/60 mg [i.e., those who were on 60 mg/day the whole time] and were reduced in lower dose arms by [weeks 48 and 72] when all patients had switched to 60 mg,” the researchers wrote.

Total lesion volume was generally stable in patients who were on 60 mg/day of tolebrutinib: the total volume change from the study’s start to 72 weeks was an increase of 0.39 cubic centimeters. The numbers of paramagnetic rim lesions, a particular type of lesion associated with chronic inflammation, also were largely unchanged throughout the study period.

A separate poster, titled “Evaluating the Effect of BTK Inhibitor Tolebrutinib in Human Tri-culture,” reported the results of other ongoing tolebrutinib research. Scientists at Sanofi had conducted a series of tests of tolebrutinib using cells in laboratory petri dishes.

Specifically, the researchers used a “tri-culture” system that included three types of cells: neurons (nerve cells), astrocytes — star-shaped cells that are important for supporting neuronal function — and microglia, which are the resident inflammatory immune cells in the central nervous system (CNS).

In this system, treatment with tolebrutinib significantly reduced levels of several pro-inflammatory signaling molecules being produced by microglia, including tumor necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

“Tolebrutinib modulates inflammatory signaling in vitro [in the lab] in tri-cultures of neurons, astrocytes, and microglia, a culture designed to more closely mimic CNS signaling,” the researchers concluded.

Through separate analyses of autopsy data, they also showed that inflammatory microglia found in brain lesions of people with progressive MS express high levels of BTK, tolebrutinib’s target.

“Our work contributes to improved understanding of BTK signalling in neuroinflammation and how BTK inhibitors could target the neuroinflammation thought to contribute to MS disability progression,” the scientists wrote.

Note: The Multiple Sclerosis News Today team is providing coverage of the American Academy of Neurology (AAN) 2022 Annual Meeting. Go here to see the latest stories from the conference.