Mayzent Approved in Europe as First Oral Treatment for Active Secondary Progressive MS

The experimental BTK inhibitor SAR442168 showed an acceptable safety profile and met its primary endpoint — a significant reduction in the number of new lesions visible on a brain imaging scan — in a Phase 2 trial in people with multiple sclerosis (MS), study results show.

SAR442168, formerly known as PRN2246, is an oral, small molecule being co-developed by Principia Biopharma and Sanofi Genzyme. It works by inhibiting Bruton’s tyrosine kinase (BTK), a protein important for the proliferation of immune cells, particularly B-cells. By blocking BTK, it is expected that SAR442168 can reduce inflammation that damages the nervous system in MS.

In a previous Phase 1 study (ACTRN12617001457336) conducted in healthy volunteers, SAR442168 showed a good safety profile, with no serious treatment-related adverse events reported. Importantly, data from this study also demonstrated that SAR442168 can cross the blood-brain barrier, which very selectively controls what compounds can and cannot enter the brain from the bloodstream.

“We believe our BTK inhibitor has the potential to transform how MS is treated,” John Reed, MD, PhD, global head of research and development at Sanofi, said in a press release. “This molecule may be the first B-cell-targeted MS therapy that not only inhibits the peripheral immune system, but also crosses the blood-brain barrier to suppress immune cells that have migrated into the brain.”

The Phase 2 trial (NCT03889639), funded by Sanofi, enrolled 120 people with relapsing MS, between the ages of 18 and 55.

The trial had a “cross-over” design. Participants were divided into two groups of 60. One group received one of four doses of SAR442168 for the first 12 weeks of the trial, then “crossed over” to receive a placebo for an additional four weeks. The other group received the same treatment, but in the opposite order — first, four weeks of placebo, then 12 weeks of SAR442168 at one of four doses. This design allows participants to serve as their own controls, and it minimizes the amount of placebo treatment needed to attain meaningful results.

According to Sanofi, treatment with SAR442168 achieved the trial’s primary endpoint, significantly reducing the number of new, active gadolinium (Gd)-enhancing T1-hyperintense brain lesions in a dose-dependent manner after 12 weeks of treatment. These lesions, visible on magnetic resonance imaging (MRI) scans of the brain, indicate areas with damage to the nervous system.

Safety results in the Phase 2 study were comparable with those of the previous Phase 1 trial. More detailed results from the new trial are planned to be presented at upcoming medical meetings.

“We are encouraged by these clinical results and look forward to rapidly advancing our brain-penetrant BTK inhibitor into pivotal clinical trials,” Reed said.

Phase 3 clinical trials testing SAR442168 in both relapsing and progressive forms of MS are anticipated to begin in mid-2020. Data from the Phase 2 study will be used to determine the treatment dose given in these upcoming trials.

Additionally, participants who completed the 16 weeks of the Phase 2 trial have the option to enroll in an extension study (NCT03996291).