Tolebrutinib Slows Disability in Non-Relapsing Secondary Progressive MS

Investigational tolebrutinib slowed disability progression in people with non-relapsing secondary progressive multiple sclerosis (SPMS), the phase III HERCULES trial showed.

The Bruton’s tyrosine kinase (BTK) inhibitor met the study’s primary endpoint of delaying time to onset of 6-month confirmed disability progression (CDP), reported Robert Fox, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio.

Six-month CDP was 26.9% in the tolebrutinib group and 37.2% in the placebo group (HR 0.69, 95% CI 0.55-0.88, P=0.0026), Fox said in a late-breaking presentation at the annual European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen.

“Importantly, the curves started separating early and continued to separate over the follow-up period,” Fox said in an interview with MedPage Today. “This shows a rather constant and consistent treatment effect over the course of the study.”

Most secondary endpoints showed similar trends: 3-month CDP was 32.6% in the tolebrutinib group and 41.5% with placebo (HR 0.76, 95% CI 0.61-0.94, P=0.013). Six-month confirmed disability improvement was 10% in the tolebrutinib group and 5% with placebo (HR 1.88, 95% CI 1.10-3.21, P=0.021).

Tolebrutinib also significantly lowered the annualized rate of new or enlarging T2 lesions compared with placebo (adjusted rate ratio 0.62, 95% 0.43-0.90, P=0.011). No significant difference was seen in brain volume changes between the treatment and placebo groups.

The GEMINI 1 and 2 studies of tolebrutinib in relapsing MS, which also were presented at ECTRIMS, did not reach their primary endpoint of reduced annualized relapse rates compared with teriflunomide (Aubagio), Fox noted. Pooled 6-month CDW data in the GEMINI studies, however, showed a delay in time to onset of 29%, supporting the outcome in HERCULES.

“HERCULES is the first trial to show slowing progression of disability in non-relapsing, secondary progressive MS,” Fox said.

“Paired with GEMINI 1 and 2, which found a decrease in the sustained progression of disability despite having no benefit on focal inflammation compared to teriflunomide … this points to the conclusion that we are impacting the insidious progression of non-relapsing, secondary progressive MS.”

Disability accumulation starts early in MS and is thought to be driven by chronic neuroinflammation, overlapping at times with relapses, Fox observed.

“We have over 20 approved MS therapies,” he said. “They’re all focused on the relapsing component. We don’t have any therapies with demonstrated efficacy in non-relapsing, secondary progressive MS.”

Tolebrutinib is thought to work on both B cells and microglial activation, he pointed out. “Importantly, it has blood-brain barrier penetration,” Fox said. “It can get into the brain at concentrations high enough to be biologically active.”

HERCULES randomized 1,131 people with non-relapsing SPMS to either 60 mg oral tolebrutinib (754 people) or placebo (377 people). “This was an event-driven trial,” Fox said. The treatment period was 24 to 48 months, and all participants continued in the study until 288 6-month CDP events were observed.

Before screening, participants had no clinical relapses within 24 months and documented evidence of disability progression within 12 months. Expanded Disability Status Scale (EDSS) scores were at least 3 but no higher than 6.5.

Mean baseline age was about 49. “Median EDSS was 6 — needing to walk with a cane — so this was a pretty typical secondary progressive MS patient population,” Fox said.

Six-month CDP was defined as an increase of at least 1 point from baseline EDSS score when the baseline score was 5 or less, or an increase of at least 0.5 points when baseline EDSS was greater than 5, confirmed over 6 or more months.

A preliminary analysis showed an increase in some adverse events, including respiratory infections, with tolebrutinib compared with placebo. In the tolebrutinib arm, 15% had serious treatment-emergent adverse events. Two patients in the tolebrutinib group died: one due to post-operative complications of a liver transplant which was assessed as treatment-related, and one by assisted suicide.

Liver enzyme elevations more than three times the upper limit of normal emerged in 4.1% of patients taking tolebrutinib. Overall, 0.5% of participants in the tolebrutinib group had severe elevation of alanine aminotransferase (ALT), with increases more than 20 times the upper limit of normal. All were within the first 3 months of treatment and most resolved.

In 2022, the FDA placed tolebrutinib studies in MS and myasthenia gravis on partial clinical hold based on reports of drug-induced liver injury.

The death of the liver transplant patient in HERCULES occurred before a revised protocol with more stringent monitoring was implemented, Fox noted. “It appears that the most serious risks are in the first 90 days, and that’s when there is weekly liver monitoring,” he said.

The HERCULES results will form the basis for discussions with global regulatory authorities later this year, drugmaker Sanofi said. The phase III PERSEUS trial is evaluating tolebrutinib in primary progressive MS, with results expected in 2025.

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