Sanofi (SAN) Status Update summary

Key clinical trial results and efficacy

• Tolebrutinib delayed 6-month confirmed disability progression by 31% in non-relapsing secondary progressive MS (nrSPMS) compared to placebo (HR 0.69; p=0.0026), with nearly double the proportion achieving confirmed disability improvement.

• In relapsing MS (RMS), tolebrutinib did not significantly reduce annualized relapse rates versus teriflunomide/Aubagio, but delayed 6-month confirmed disability worsening by 29% (HR 0.71; p=0.023), though this was nominal as the primary endpoint was not met.

• Both trials reported low relapse rates, well-balanced baseline characteristics, and high study completion rates.

• Significant reduction in annualized rate of new/enlarging T2 lesions was observed in nrSPMS.

• The impact on disability progression in RMS aligns with the benefit seen in nrSPMS, suggesting efficacy against progression independent of relapses.

Safety and monitoring

• Liver enzyme elevations (>3x ULN) occurred in 4–5.6% of tolebrutinib-treated patients, with rare serious cases; one fatal case occurred before enhanced monitoring was implemented.

• Enhanced liver monitoring (weekly for 12 weeks) was implemented and is considered manageable given the unmet need.

• Adverse events were generally balanced between arms, with slightly higher rates of respiratory infections, hypertension, COVID-19, urinary tract infections, nasopharyngitis, and headache in the tolebrutinib group.

• Deaths were balanced across treatment and control arms and assessed as unrelated to treatment.

• Liver safety signals are consistent with other BTK inhibitors, and frequent monitoring in the first 90 days is now standard.

Clinical significance, unmet need, and patient impact

• Tolebrutinib is the first agent to show a delay in disability progression in non-relapsing SPMS, addressing a major unmet need.

• Physicians expect high patient willingness to accept liver monitoring and risk due to the lack of alternatives and meaningful reduction in disability progression.

• The results are considered more meaningful due to the low activity of the patient population and the absence of effective treatments for non-relapsing SPMS.

• SPMS is underdiagnosed and undertreated, and approval of tolebrutinib could catalyze reclassification and increased diagnosis.

• Current MS therapies mainly target peripheral immune cells and do not address CNS-driven progression.