COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).