After some stumbles out of the starting gate, an experimental treatment that’s in a group hoping to be the next big thing for people with multiple sclerosis (MS) is a step closer to U.S. Food and Drug Administration (FDA) approval.
Tolebrutinib, developed by Sanofi, has been designated as a Breakthrough Therapy for the treatment of adults with non-relapsing secondary progressive MS (nrSPMS). The designation is intended to speed the development of drugs that are aimed at treating a serious condition, and that also may be significantly better than currently available treatments. It puts tolebrutinib on a fast track towards final FDA approval by making its researchers eligible for more frequent meetings with – and written guidance from – the drug agency. It also bring senior FDA managers into the development process.
According to a Sanofi news release, the Breakthrough Therapy designation followed positive results from the company’s HERCULES phase 3 study. It showed that tolebrutinib delayed the time to onset of 6-month confirmed MS disability progression (CDP), by 31% compared to placebo. In addition, 10% of the trial participants saw their disability improve – double the percent of participants who were treated with a placebo.
Ups and downs for BTKi treatments
Tolebrutinib is a Bruton’s tyrosine kinase inhibitor (BTKi). It’s designed to cross the blood-brain barrier and target immune cells that contribute to MS. According to an article in the April 2023 issue of Science, “preclinical studies show that BTK inhibition can suppress key pathological features of MS, including B cell activation, CNS lymphocyte infiltration, leptomeningeal inflammation, pro-inflammatory microglial activation and demyelination.”
But, over the past few years there have been problems reported with BTIs. In July of 2022 the FDA put Sanofi’s HERCULES study on a partial hold after tests suggested drug-induced liver enzyme elvations in just over 4% of study participants. The researchers report all except one of these elevations resolved without further medical intervention and they believe implementing more frequent patient monitoring has helped mitigate serious liver problems.
Other experimental BTKi treatments have also stumbled along the way to final government approval. In 2023 fenebrutinib trials were put on a partial hold, also due to liver concerns. Then, evobrutinib failed to beat its control drug, teriflunomide (Aubagio), in two phase 3 clinical trials.
Hoping tolebrutinib’s future is bright
So far, tolebrutinib is the only BTKi to have gained Breakthrough Therapy status. Hopefully, that status will also give a boost to Sanofi’s Phase 3 PERSEUS trial, which researchers hope to complete in the third quarter of 2025. PERSEUS is studying use of tolebrutinib to treat primary progressive MS (PPMS), a form of MS which can certainly use more therapeutic options.
As reported in a review article in the April 17, 2024 issue of Therapeutic Advances in Neurological Disorders, “So far, the benefit–risk profile of second-generation BTK inhibitors in the treatment of MS is encouraging….The introduction of BTK inhibition was perceived as a major breakthrough in oncology; it is hoped that these drugs will bring a similar incremental value to the therapeutic [tools available] in fighting MS.”
(This post first appeared as my column on the Rare Disease Advisor website.)
(Image by Roshan Rajopadhyaya from Pixabay.)
