Sanofi disclosed data from a failed Phase 3 trial of the BTK inhibitor tolebrutinib in primary progressive multiple sclerosis (PPMS), an outcome that prompted the company to step back from the indication. Investigators and Sanofi reviewed subgroup and biomarker findings to understand drivers of the negative readout. The company’s presentation at ACTRIMS26 unpacked potential explanations—trial design, patient selection, or insufficient target engagement in PPMS—and highlighted the difficulty of translating BTK biology into progressive MS outcomes. Sanofi’s withdrawal underscores the high technical and clinical risk in neuroinflammation and progressive neurodegenerative endpoints. For BTK developers and investors, the episode emphasizes the importance of indication‑specific biology and robust biomarker strategies; companies will likely revisit dosing, CNS exposure metrics, and adaptive designs before pursuing progressive MS programs.