Multiple sclerosis (MS) is an inflammatory autoimmune disorder and causes progressive neurological disability in young adults. Ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator, is under development for treatment of relapsing multiple sclerosis (RMS).
To assess the effect of ponesimod on confirmed disability accumulation (CDA) relative to placebo and other disease-modifying therapies (DMTs) in treating RMS.
A literature review was performed and a database of 154 unique trials with 58 MS treatments was developed. The database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Results for CDA were reported with Kaplan-Meier plots; thus, extensive data were available to develop a longitudinal model for probability of a 12-week CDA event. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time. Arm-level variables explored as effect modifiers included: percent of patients with remitting RMS, trial start year, mean duration of disease, percent of patients who received DMT within past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.
This model utilized longitudinal data from 26 RCTs in RMS (18 unique treatments [including placebo], 69 treatment arms, and 417 timepoints in 31,160 patients). HRs were estimated for 12-week CDA for 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (6 treatments). Relative treatment effect was found to be significantly smaller in trials with higher pDMT. Results favored ponesimod in comparison to placebo (HR: 0.61; 95% CI: 0.44–0.83), glatiramer acetate (0.65; 0.44–0.94), and interferon β-1b (0.51; 0.33–0.77) in delaying 12-week CDA. Ponesimod was estimated to have numerical improvement to S1P receptor modulators fingolimod, ozanimod, laquinimod, as well as teriflunomide, interferon β-1a (intramuscular and subcutaneous), peginterferon β-1a, cladribine, daclizumab, and dimethyl fumarate (HR range: 0.77–0.94).
Ponesimod was statistically superior compared to placebo and a range of other DMTs suggesting robust efficacy in the treatment of MS.