Effect of Teriflunomide on Substantial Disability Worsening in Patients with Relapsing Forms of MS in the Phase 3 Tower Study

Background: Teriflunomide is approved for the treatment of relapsing forms of MS (RMS). In 2 phase 3 clinical trials (TEMSO, NCT00134563; TOWER, NCT00751881), teriflunomide 14 mg significantly reduced the risk of 12-week confirmed disability worsening (12wCDW) in patients with RMS.

Objectives: To assess the effect of teriflunomide 14 mg on more substantial disability worsening events using 3 exploratory definitions of 12wCDW in a post hoc analysis of the phase 3 TOWER study.

Methods: In TOWER, patients with RMS were randomized 1:1:1 to placebo, teriflunomide 7 mg, or 14 mg. The study ended 48 weeks after the last patient was randomized. 12wCDW (defined as a ≥1.0-point increase in EDSS from a baseline score of ≤5.5, or a ≥0.5-point increase from a baseline score of >5.5, that persisted for ≥12 weeks) was the key secondary endpoint. In this post hoc analysis of patients treated with teriflunomide 14 mg (intent-to-treat population), risk of 12wCDW was evaluated according to the following thresholds of EDSS increase: definition 1, ≥1.5 points (baseline score ≤5.5) or ≥0.5 points (baseline score >5.5); definition 2, ≥2.0 points (baseline score ≤5.5) or ≥0.5 points (baseline score >5.5); definition 3, ≥2.0 points (baseline score ≤5.5) or ≥1.0 point (baseline score >5.5). Risk of 12wCDW was assessed using a Cox proportional hazards model.

Results: In the primary TOWER analysis, risk of 12wCDW was significantly reduced in patients receiving teriflunomide 14 mg (n=370) vs placebo (n=388): hazard ratio (HR) 0.685, 95% confidence interval (CI) 0.467, 1.004, P=0.0440. This was maintained using the stricter criterion of EDSS increase in definition 1: HR 0.508, 95% CI 0.280, 0.924, P=0.0239. Non-significant reductions in the risk of 12wCDW with teriflunomide 14 mg were also observed using definitions 2 and 3 (HR 0.627 [95% CI 0.287, 1.371], P=0.2416; HRs were identical due to the occurrence of the same number of 12wCDW events).

Conclusions: Teriflunomide 14 mg significantly reduced the risk of more substantial disability worsening in both the primary analysis and using an exploratory definition of 12wCDW. A non-significant reduction in risk of 12wCDW was observed using even higher thresholds of EDSS increase, although the lower number of overall events reduced the power to detect significant differences between groups. These observations are consistent with primary analyses of 12wCDW in both TOWER and TEMSO, and provide further insight into the significant impact of teriflunomide on disability worsening in patients with MS.