Novel Agent First to Slow Disability in nrSPMS

COPENHAGEN, Denmark — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
The Phase 3 HERCULES trial showed tolebrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, delayed the time to onset of 6-month confirmed disability progression by 31% compared with placebo. 
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 today by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute, Ohio, at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 (ECTRIMS). 
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said. 
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 MS patients at his clinic may fall into this category. 
A typical patient with nonrelapsing SPMS 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 to Medscape Medical News. 
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — downregulating 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 baseline.
Trial Results 
The HERCULES trial included 1131 patients with nonrelapsing SPMS, defined as having an expanded disability status scale (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% to 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,” 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).
A “Headscratcher” Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy. 
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Fox reported. 
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.” 
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group versus 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died due to post-operative complications, “a reminder that this can be a very serious complication of this drug,” said Fox. 
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment. 
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension. 
Weekly Liver Enzyme Testing 
Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later this year. 
Commenting on the trial for Medscape Medical News, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.””The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added. 
Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability 
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug to teriflunomide, a standard-of-care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates compared with teriflunomide. 
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial. 
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Fox said. 
The HERCULES trial was sponsored by Sanofi. Fox is a paid advisor to Sanofi. Kappos led the EXPAND trial of siponimod in secondary progressive MS. 
 
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