Slowing of Cortical Gray Matter Atrophy with Teriflunomide is Associated with Delayed Conversion to Clinically Definite MS

Abstract

Background: In this post hoc analysis, we explored the effect of teriflunomide on cortical gray matter (CGM) atrophy in patients with a first clinical episode suggestive of multiple sclerosis (FCEMS) and assessed the relationship between CGM atrophy and risk of conversion to clinically definite MS (CDMS) in the phase 3 TOPIC study. Methods: Patients were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ≤108 weeks (core study). In the extension, teriflunomide-treated patients received their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. CGM volume changes were assessed during the core study at predefined time points. Findings: The analysis population comprised 485 patients (placebo, n=159; teriflunomide 7mg, n=156; teriflunomide 14 mg, n=170). When grouped based on the interquartile range of CGM atrophy in placebo-treated patients, more patients receiving teriflunomide 14 mg were in the group with the least (Group 1) vs most (Group 3) CGM atrophy (28.2% vs 16.5%). Teriflunomide 14 mg significantly reduced median percentage CGM change vs placebo (P=0.0185, P=0.0359, P=0.0027, and P=0.0416 at Months 6, 12, 18, and 24, respectively). Effects of teriflunomide 7 mg were similar. For every 1% decrease in CGM volume during years 1-2, risk of CDMS conversion increased by 14.5% during years 1-2 (P=0.0004) and by 6.6% during years 1-5 (P=0.0570). Patients with less CGM atrophy were less likely to convert to CDMS during years 1-2 (Group 1 vs 3, 59% risk reduction, P=0.0007) and years 1-5 (Group 1 vs 3, 42% risk reduction, P=0.0138). In a Cox proportional hazard model, CGM atrophy and MRI lesions combined were significant predictors of CDMS conversion (C-statistic, 0.6831). Interpretation: These findings support the clinical relevance of CGM atrophy and importance of early intervention in patients with FCEMS. Funding Statement: This study and development of the manuscript were supported by Sanofi. Declaration of Interests: Robert Zivadinov: Speaking and consultant fees (Celgene, EMD Serono, Genzyme, Novartis); editorial board (BioMed Res Int, BMC Med, BMC Neurol, Clinical CNS Drugs, J Alzh Dis, Vein and Lymphatics, World J Surg Proc); financial support for research activities (Mapi Pharma, Genzyme, Novartis, Protembis, Celgene). Michael G Dwyer: Study consulting (Claret Medical); scientific advisory board (EMD Serono); institutional grant support (Novartis). Ellen Carl: Nothing to disclose. Elizabeth M Poole and Steve Cavalier: Employees of Sanofi, with ownership interest. Niels Bergsland: Editorial board (PLOS ONE and J Neuroimaging).