Tolebrutinib for nonrelapsing SPMS delays disability progression in trial
Treatment also found to reduce rate of new or enlarging lesions on MRI scans
Sanofi‘s oral BTK inhibitor tolebrutinib significantly delayed the onset of six-month confirmed disability progression compared with a placebo, by 31%, in people with nonrelapsing secondary progressive multiple sclerosis (SPMS).
That’s according to recently published data from the HERCULES Phase 3 trial (NCT04411641), where the experimental therapy also increased the odds of six-month confirmed disability improvement by 88%, and reduced the rate of new or enlarging lesions on MRI scans by 38%.
Results from the trial were published in The New England Journal of Medicine, in the paper “Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis.” The work was funded by Sanofi.
“In this large phase 3 study, tolebrutinib was found to slow the progression of disability in a subset of multiple sclerosis for which we have no approved therapies,” Robert Fox, MD, chair of the HERCULES global steering committee, vice chair of research at Cleveland Clinic’s Neurological Institute, and a paid advisor to Sanofi, said in a press release from the company. “The results of this study signal a new chapter in multiple sclerosis because we finally found a potential way to treat non-relapsing secondary progressive forms.”
FDA decision on tolebrutinib expected by Sept. 28
Based on HERCULES data, Sanofi recently asked the U.S. Food and Drug Administration (FDA) to approve tolebrutinib for nonrelapsing SPMS. The company also filed for the approval of tolebrutinib to slow disability accumulation independent of relapse activity in adults with MS. A decision from the FDA is expected by Sept. 28.
Most people with MS initially develop relapsing-remitting MS (RRMS), which is marked by relapses in which symptoms suddenly worsen and periods of remission when symptoms ease or disappear entirely. Over time, people with RRMS may progress to another disease form called SPMS, which is marked by symptoms that worsen over time, independent of relapse activity.
Some people with SPMS continue to experience relapses, but some do not, and these patients are much harder to treat. Currently, no treatments are approved for nonrelapsing SPMS in the U.S.
The HERCULES trial enrolled 1,131 adults with nonrelapsing SPMS, who had experienced no relapses in the past two years but had evidence of disability progression, as measured by the Expanded Disability Status Scale (EDSS). Participants were randomly assigned to receive tolebrutinib (60 mg taken daily with a meal) or a placebo, and were followed for a median of about 2.5 years.
Over the course of the trial, 22.6% of patients given tolebrutinib and 30.7% of those on the placebo experienced six-month confirmed disability progression, defined as an increase in EDSS scores that is sustained for at least six months. That represented a 31% lower risk of disability progression with tolebrutinib.
Other measures of disability, such as three-month confirmed disability progression, six-month confirmed disability improvement, also were significantly different between tolebrutinib and the placebo, favoring the experimental therapy.
Finally, MRI scans showed the annual rate of new or enlarging lesions on MRI scans was significantly lower with tolebrutinib.
“These results support the role of tolebrutinib in slowing disability accrual in persons with nonrelapsing secondary progressive multiple sclerosis, a population with an unmet need for treatments that delay disability,” the researchers concluded.
Phase 3 trials testing tolebrutinib vs. Aubagio for relapsing MS
Data from two other tolebrutinib Phase 3 trials, called GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991), were published in the same journal in a separate article, titled “Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis.”
These studies collectively enrolled 1,873 adults with relapsing forms of MS, and randomly assigned them to receive tolebrutinib or Aubagio (teriflunomide).
The trial’s main goal was to determine if tolebrutinib could outperform Aubagio at reducing relapse rates — but this goal was not met. In both studies, relapse rates were fairly similar among tolebrutinib- and Aubagio-treated patients.
However, the rate of six-month confirmed disability worsening was significantly lower with tolebrutinib than Aubagio (8.3% vs. 11.3%), reflecting a 29% reduced risk of disability worsening with tolebrutinib.
Still, because the study was designed primarily to assess the effect of treatment on relapses, not disability worsening, more studies will be needed to confirm this effect, the researchers wrote.
Safety findings were overall consistent in the HERCULES and GEMINI studies. Across the studies, about 5% of patients experienced an increase in liver enzymes (indicative of liver damage).
One patient in HERCULES needed a liver transplant and died due to complications after the procedure, though Sanofi noted the death occurred before more stringent liver-monitoring protocols were implemented. No patients in the GEMINI studies died of treatment-related issues.
About the Author
