The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies

Abstract

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Keywords: ARR and disability worsening; RRMS; TEMSO; TOWER; Teriflunomide; disease-modifying treatment.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.S.F. has received research/educational grant support from Bayer HealthCare and Genzyme; honoraria/consulting fees from Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi and Teva Canada Innovation; and is a member of company advisory boards/board of directors/or other similar group for Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi and Teva Canada Innovation. J.S.W. has received, within the last year, consulting fees from AbbVie, Alkermes, Bayer HealthCare, Forward Pharma, MedDay, Novartis, Roche Genentech, Sanofi Genzyme, Takeda and Teva. Royalties from the University of Texas Health Science Center at Houston for monoclonal antibodies out-licenced to Chemicon International. G.C. has received compensation in the past year for consulting services and/or speaking activities from Almirall, Biogen, Celgene, Excemed, Forward Pharma, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi and Teva. L.K.’s institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and XenoPort; speaker fees from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva; support of educational activities from Bayer HealthCare, Biogen Idec, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva; licence fees from Neurostatus Systems GmbH; and grants from Bayer HealthCare, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union and Roche Research Foundations. T.P.O. has received consulting fees and/or research support from Biogen Idec, Merck Serono and Sanofi and has participated in scientific advisory boards and/or speaking activities for Biogen Idec, Merck Serono and Sanofi. A.E.M. has received research support from Biogen Idec, Genentech, Novartis, Questcor, Roche and Sanofi and consulting fees from Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, Mallinckrodt Pharmaceuticals/Questcor, Novartis, Roche and Teva. K.T., M.B. and P.T. are employees of Sanofi Genzyme. P.W.O’C. has received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi, Teva and Warburg Pincus.

Figures

Figure 1.

(a) ARR by prior treatment. Overall p value for treatment-by-subgroup interaction for ARR: 14 mg, p = 0.4344. Percentages represent relative risk reductions (95% CI). ARR (95% CI) for teriflunomide 7 mg: ≥2 prior DMTs, 0.463 (0.231, 0.930), RR (95% CI) 0.584 (0.308, 1.104), difference versus placebo 41 .6%, p =0.0977; 1 prior DMT, 0.536 (0.423, 0.680), RR (95% CI) 0.836 (0.643, 1.087), difference versus placebo 16.4%, p =0.1804; no prior DMT, 0.329 (0.285, 0.380), RR (95% CI) 0.698 (0.583, 0.835), difference versus placebo 30.2%, p =0.0001. Overall p value for treatment-by-subgroup interaction for ARR, p =0.3947. In the placebo arms, ARR was significantly higher for patients with ≥2 DMTs (p =0.0183) or 1 prior DMT (p =0.0008) compared with treatment-naïve patients. (b) Disability worsening by prior treatment. aDerived from Kaplan–Meier estimates at week 132. bDerived using a Cox proportional hazard model with treatment, EDSS strata at baseline, region and study as covariates. cDerived from log-rank test, with EDSS strata at baseline, region, study and subgroup as covariates. Overall p value for treatment-by-subgroup interaction for disability worsening: 14 mg, p =0.0697. Percentages represent relative risk reductions (95% CI) on the hazard ratios. Probability of disability worseninga (95% CI) for teriflunomide 7 mg: ≥2 prior DMTs, 0.218 (0.061, 0.376), HR (95% CI) 0.666 (0.223, 1.992), difference versus placebo 33.4%, p =0.5707c; 1 prior DMT, 0.345 (0.259, 0.431), HR (95% CI) 0.950 (0.634, 1.422), difference versus placebo 5.0%, p =0.8505c; no prior DMT, 0.176 (0.139, 0.212), HR (95% CI) 0.792 (0.587, 1.068), difference versus placebo 20.8%, p =0.0948c. Overall p value for treatment-by-subgroup interaction for disability worsening: 7 mg, p =0.6921. In the placebo arms, there was a significantly greater risk of disability progression in patients with 1 prior DMT (p =0.0250) compared with treatment-naïve patients. The risk was also greater in patients with ≥2 prior DMTs, although significance was not reached (p = 0.4486). ARR: annualised relapse rate; CI: confidence interval; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; HR: hazard ratio; RR: relative risk.