Estimating the Onset of Efficacy With Teriflunomide in Patients With Relapsing Forms of Multiple Sclerosis (P7.214)

OBJECTIVE: To estimate the onset of efficacy of teriflunomide in patients with relapsing forms of multiple sclerosis (RMS) by evaluating treatment effects on relapse and magnetic resonance imaging (MRI) lesions during the first few months of clinical trials. BACKGROUND: Teriflunomide is an oral, once-daily immunomodulator for relapsing-remitting MS. In the extensive clinical development program, teriflunomide has demonstrated efficacy in key clinical measures, and shown a well-characterized and consistent safety profile. As plasma accumulation occurs slowly, steady-state concentrations are not reached until 3-3.5 months after treatment initiation. Analyses of efficacy at early timepoints were investigated to assess the level of protection against disease activity prior to reaching steady state. DESIGN/METHODS: An integrated analysis of the TEMSO (NCT00134563) and TOWER (NCT00751881) studies was used to assess relapse, and to model pharmacokinetic/pharmacodynamic (PK/PD) data to explore the relationship between plasma concentration and efficacy. The phase 2 study (NCT01487096) evaluated MRI early after treatment initiation (number of combined unique active lesions [UALs] per scan, every 6 weeks), while the phase 3 TOPIC study (NCT00622700) included an early MRI scan at 12 weeks. RESULTS: Nelson-Aalen relapse rate estimates (TEMSO/TOWER) showed start of treatment effect with teriflunomide 14 mg or 7 mg vs placebo within 6 weeks. In the phase 2 study, combined UALs decreased at 6 weeks with teriflunomide 14 mg or 7 mg vs placebo, and reached significance by 12 weeks. In the TOPIC study, total lesion volume and UALs were reduced at 12 weeks with teriflunomide 14 mg vs placebo. PK/PD modeling demonstrated a relationship between plasma steady state concentration and efficacy. Laboratory assessments showed that neutrophil and lymphocyte counts decreased within 6 weeks, consistent with the hypothesized teriflunomide mechanism of action. CONCLUSIONS: Data on relapses, MRI activity and laboratory assessments demonstrate that the effects of teriflunomide are evident shortly after initiating treatment, before steady-state concentrations are reached. Study Supported by: Genzyme, a Sanofi company. Disclosure: Dr. Wolinsky has received personal compensation for activities with Teva Neuroscience, Sanofi-Aventis Pharmaceuticals Inc., Roche Diagnostics Corp., Novartis, XenoPort, RND, Genzyme Corp., and Athersys. Dr. Wolinsky has received royalty payments from the University of Texas. Dr. Wolinsky has received research support from National Institutes of Health, Sanofi-Aventis Pharmaceuticals Inc., and Genzyme Corp. Dr. Dukovic has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. Dr. Truffinet has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc. as an employee. Dr. Kappos has received personal compensation for activities with the University Hospital Basel. Dr. Kappos has received research support from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, Novartis, and Roche Diagnostics Corp.