Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis

Abstract

Background: In this pooled, post hoc analysis of a phase 2 trial and the phase 3 TEMSO, TOWER, and TENERE clinical trials, long-term efficacy and safety of teriflunomide were assessed in subgroups of patients with relapsing multiple sclerosis (MS) defined by prior treatment status.

Methods: Patients were classified according to their prior treatment status in the core and core plus extension periods. In the core period, patients were grouped according to treatment status at the start of the study: treatment naive (no prior disease-modifying therapy [DMT] or DMT > 2 years prior to randomization), previously treated with another DMT (DMT > 6 to ≤24 months prior to randomization), and recently treated with another DMT (DMT ≤6 months prior to randomization). In the core plus extension period, patients were re-baselined to the time of starting teriflunomide 14 mg and grouped according to prior treatment status at that time point. Efficacy endpoints included annualized relapse rate (ARR), probability of confirmed disability worsening (CDW) over 12 weeks, and Expanded Disability Status Scale (EDSS) score. The incidence of adverse events was also assessed.

Results: Most frequently received prior DMTs at baseline were glatiramer acetate and interferon beta-1a across treatment groups. Teriflunomide 14 mg significantly reduced ARR versus placebo in the core period, regardless of prior treatment status. In the core and extension periods, adjusted ARRs were low (0.193-0.284) in patients treated with teriflunomide 14 mg across all subgroups. Probability of CDW by Year 4 was similar across subgroups; by Year 5, the percentage of patients with 12-week CDW was similar in treatment-naive patients and patients recently treated with another DMT (33.9 and 33.7%, respectively). EDSS scores were stable over time in all prior-treatment subgroups. There were no new or unexpected safety signals. Limitations include selective bias due to patient attrition, variability in subgroup size, and lack of magnetic resonance imaging outcomes.

Conclusions: The efficacy and safety of teriflunomide 14 mg was similar in all patients with relapsing MS, regardless of prior treatment history.

Trial registration: Phase 2 trial core: NCT01487096 ; Phase 2 trial extension: NCT00228163 ; TEMSO core: NCT00134563 ; TEMSO extension: NCT00803049 ; TOWER: NCT00751881 ; TENERE: NCT00883337 .

Keywords: Disease-modifying therapy; Multiple sclerosis; Relapse rate; Teriflunomide; Treatment history.

Conflict of interest statement

Giancarlo Comi: Compensation for consulting services and/or speaking activities (Almirall, Biogen, Celgene, Excemed, Forward Pharma, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi, Teva); fees for non-CME services (Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Sanofi, SSIF, Teva). Mark S Freedman: Research/educational grant support (Genzyme); honoraria/consulting fees (Actelion [J&J], Bayer HealthCare, Biogen, Chugai, EMD Canada, Genzyme, Merck, Novartis, Roche, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen, Chugai, Genzyme, Merck Serono, Novartis, Roche, Sanofi, Teva Canada Innovation). José E Meca-Lallana: Grants or speaking and consultation honoraria (Almirall, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Teva). Patrick Vermersch: Honoraria, consulting fees (Almirall, Bayer, Biogen, Celgene, Genzyme, GSK, Merck Serono, Novartis, Sanofi, Servier, Teva); research support (Bayer, Biogen, Genzyme, Merck Serono, Sanofi). Byoung Joon Kim: Honoraria, consulting fees (Astellas, Bayer, Celltrion, Corestem, Genuv, Genzyme). Alexander Parajeles: Nothing to disclose. Keith R Edwards: Consulting fees (EMD Serono); research support (Biogen, Genentech, Novartis, Sanofi). Ralf Gold: Consulting fees (Bayer Schering, Biogen, Elan, Genzyme, Roche, Teva); grant/research support (Bayer Schering, Biogen, Genzyme, Teva). Houari Korideck and Elizabeth M Poole: Employees of Sanofi at the time the study was conducted. Jeffrey Chavin: Employee of Sanofi. Patricia K Coyle: Consulting fees (Accordant, Biogen, Genentech/Roche, Genzyme/Sanofi, Novartis, Serono, TG Therapeutics); research support (Actelion, Alkermes, Corrona LLD, Genentech/Roche, MedDay, NINDS, Novartis).

Figures

Fig. 1

Adjusted ARR with teriflunomide 14 mg or placebo, stratified by prior treatment history (core period) in the modified intent-to-treat population. The core period for the recently-treated-with-another-DMT group included patients who received IFNB-1a in the core TENERE study who entered the extension and were treated with teriflunomide 14 mg; their first 108 weeks on teriflunomide in the extension study were included. The modified intent-to-treat population included patients who received one or more study doses and were analyzed according to the treatment group to which they were randomized. ARR annualized relapse rate, CI confidence interval, DMT disease-modifying therapy, IFNB interferon beta

Fig. 2

Overall adjusted ARR in patients treated with teriflunomide 14 mg (core and extension period). ARR annualized relapse rate, CI confidence interval, DMT disease-modifying therapy

Fig. 3

Percentage of teriflunomide 14 mg-treated patients with 12-week CDW (core and extension period). CDW confirmed disability worsening, DMT disease-modifying therapy