Ozanimod Demonstrates Greater Efficacy, Safety Than Ponesimod in Matching-Adjusted Indirect Comparison

Elyse Swallow, MA

In the first matching-adjusted indirect comparison (MAIC) between ozanimod (Zeposia; BMS) and ponesimod (Ponvory; Janssen), 2 FDA-approved sphingosine 1-phosphate (S1P) receptor modulators for multiple sclerosis (MS), results suggest that ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial (NCT02047734), while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial (NCT02425644). Participants from both trials were matched for age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale (EDSS) score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe.

Owing to the lack of head-to-head randomized controlled trials comparing MS DMTs, lead investigator Elyse Swallow, MA, vice president, Analysis Group, and colleagues performed a MAIC to compare efficacy and safety outcomes between ozanimod and ponesimod. RADIANCE-B compared ozanimod to interferon ß-1a, while OPTIMUM compared ponesimod with teriflunomide. Duration of treatment was 24 months in the RADIANCE-B trial and 108 weeks in the OPTIMUM trial.

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There were no 1-year outcomes reported in the OPTIMUM trial, so investigators conducted only a 2-year comparison between the 2 studies. In the adjusted analysis, compared with ponesimod, treatment with ozanimod was associated with a 19% and 20% decrease in annualized relapse rate (ARR) at 2 years before and after matching, respectively; however, these differences were not significant. Ozanimod was associated with significantly greater reductions in brain volume loss before (rate ratio [RR], 0.20; 95% CI, 0.05-0.35; P <.01)) and after (RR, 0.20; 95% CI, 0.05-0.36; P <.01) matching.

"Some differences were noted with respect to the methodologies used to estimate the selected outcomes (ARR and BVL), but the main differences identified in the trials were in the patient characteristics measured, specifically the percentage of patients receiving DMTs within 2 years before randomization and patients’ geographic representation," Swallow et al wrote. "The latter differences were accounted for by the MAIC methodology, by weighting patients in the ozanimod arm to match the average baseline characteristics in the ponesimod arm."

After adjustment, there were statistically significant differences in safety outcomes, including a lower risk of adverse events (AEs) leading to discontinuation (risk differences [RD], –6.1%; 95% CI, –8.9% to –3.4%), lower risk of any treatment-emergent AE (RD, –11.9%; 95% CI, –16.8% to –7.0%), and lower risk of absolute lymphocyte count less than 0.2 K/μL (RD, –2.3%; 95% CI, –4.2% to –0.5%). Prior to matching, herpesvirus infections were less common in the ozanimod group, but the difference became insignificant after matching. Incidence of basal carcinoma, another safety outcome, had a change before and after adjustment, but neither value was statistically significant between the therapies.

There were some limitations to the MAIC, including the fact that cross-trial differences such as exclusion criteria in trial design could not be fully controlled. Additionally, despite adjusting for baseline differences, multiple unobserved differences may have confounded the analysis, investigators noted. The MAIC was also based on a non-anchored coparison because of the lack of common comparator across trials, which lessoned the opportunity to assess the presence of confounding bias and limited the ability to address possible confounding bias via an anchor-based comparison.

REFERENCE
1. Swallow E, Pham T, Patterson-Lomba O, et al. Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: a matching-adjusted indirect comparison. Mult Scler & Relat Disord. 2023;71:104551. doi:10.1016/j.msard.2023.104551