Comparative Efficacy and Safety of Ozanimod and Dimethyl Fumarate for Relapsing-Remitting Multiple Sclerosis Using Matching-Adjusted Indirect Comparison

Background Patients with multiple sclerosis (MS) experience relapses and sustained disability progression. Since 2004, the number of disease-modifying therapies (DMTs) for MS has grown substantially. As a result, patients, healthcare providers, and insurers are increasingly interested in comparative efficacy and safety evaluations to distinguish between treatment options, but head-to-head studies between DMTs are limited. Objective The aim of the current study was to compare efficacy and safety outcomes with the DMTs ozanimod and dimethyl fumarate (DMF) using a matching-adjusted indirect comparison (MAIC) to adjust for cross-trial differences in study design and population. Methods A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod compared with DMF. Individual patient-level data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate-level patient data (APD) for DMF were obtained from CONFIRM and DEFINE. A MAIC is used to weight IPD to APD based on important baseline patient characteristics considered to be effect modifiers or prognostic factors in order to balance the covariate distribution to establish more homogenous trial populations. Once trial populations are determined to be sufficiently homogenous, outcomes of interest are estimated and used to generate treatment effects between the weighted IPD and APD. We used MAIC methodology to compare efficacy and safety outcomes of interest between ozanimod 1.0 mg once daily (OD) and DMF 240 mg twice daily (BID), including confirmed disability progression (CDP) at 3 and 6 months, annualized relapse rate (ARR), proportion of patients relapsed, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. Results After matching patient data, baseline patient characteristics were balanced between patients receiving ozanimod and those receiving DMF. Compared with DMF, ozanimod demonstrated significantly improved CDP at 3 months (hazard ratio 0.67; 95% confidence interval [CI] 0.53-0.86), ARR (rate ratio [RR] 0.80; 95% CI 0.67-0.97), proportion of patients relapsed (odds ratio [OR] 0.66; 95% CI 0.52-0.83), overall AEs (OR 0.11; 95% CI 0.08-0.16), SAEs (OR 0.27; 95% CI 0.19-0.39), and discontinuations (OR 0.11; 95% CI 0.07-0.17). CDP at 6 months did not differ significantly between the two agents (RR 0.89; 95% CI 0.62-1.26). Conclusions After adjustment of baseline patient characteristics, the MAIC demonstrated that the efficacy and safety of ozanimod 1.0 mg OD was superior to that of DMF 240 mg BID. Although a MAIC is less likely to produce biased estimates than a naive or a standard indirect treatment comparison via a common comparator, limitations include potential confounding due to unobserved and thus unaccounted for baseline differences. Plain Language Summary Ozanimod and dimethyl fumarate (DMF) are disease-modifying therapies used to treat relapsing-remitting multiple sclerosis (MS). Comparative efficacy and safety evaluation is important to key patients, healthcare providers, and health insurers; however, head-to-head studies between MS therapies are limited. In this analysis, we used an indirect treatment comparison method, specifically a matching-adjusted indirect comparison (MAIC), to compare results of clinical trials of ozanimod and DMF. In this MAIC, findings suggested that ozanimod was associated with greater reductions of relapses, a lowered risk of disability progression at 3 months, and improved safety outcomes compared with DMF. Although MAICs were conducted while adjusting for important treatment-effect modifiers and/or prognostic factors, the possibility of confounding as a result of unobserved baseline differences remains. Such an issue can be resolved only by conducting a head-to-head treatment comparison in a randomized clinical trial.

Automated summary

This study compared the efficacy and safety of ozanimod and dimethyl fumarate (DMF) for multiple sclerosis using a matching-adjusted indirect comparison method. The results suggested that ozanimod showed greater reduction in relapses, lower risk of disability progression at 3 months, and improved safety outcomes compared to DMF. However, limitations include potential confounding due to unobserved baseline differences, highlighting the need for head-to-head treatment comparisons in randomized clinical trials.