Brain volume loss in relapsing multiple sclerosis: indirect treatment comparisons of available disease-modifying therapies

Background: Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials. Methods: In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA). Results: In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 – 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 – 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 – 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 – 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 – 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA. Conclusions: Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL.