A ‘Head-scratcher’ 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,” Dr. 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 vs 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 because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. 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
Dr. 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 in 2024.
Commenting on the trial, 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.
Dr. 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 with 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” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.