OPTIMUM Phase 3 Extension Further Highlights Sustained Efficacy, Safety of Ponesimod

Newly reported data from the phase 3 OPTIMUM-LT open-label extension trial (NCT03232073) showed that treatment with ponesimod (Ponvory; Vanda Pharmaceuticals) was safe and led to sustained reduction in relapses, MRI lesions, and low disability accumulation among patients with relapsing multiple sclerosis over a long-term period. At time points of up to 8.2 years, more than half of the patients included were still relapse-free.¹

The extension trial featured 877 patients from the original OPTIMUM phase 3 study, the trial that led to ponesimod’s FDA approval in 2021. Of the 439 patients receiving ponesimod in both the core and extension trial, 352 completed. Within this group, results showed an annualized relapse rate of 0.143 (95% CI, 0.123-0.167), with 56.7% of patients relapse-free over the combined analysis period, which lasted up to 8.2 years. Overall, the median time to relapse for the approved sphingosine-1-phosphate receptor (S1P) modulator was 402.71 weeks.

These data were presented at the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31, in Phoenix, Arizona, by Mallery G. Mayo, senior director of Medical Affairs at Vanda Pharmaceuticals. In the extension trial, Mayo et al tested the effect of ponesimod on ARR, time to confirmed relapse, confirmed disability progression (CDP), and new/enlarging T2- and gadolinium-enhancing T1 lesions. In addition, safety and tolerability were assessed from the start of the extension study and included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs.

While the study authors were unable to estimate the 3- and 6-month CDP due to low number of events, they did find that the mean number of new/enlarging T2 lesions per year was 1.352 (95% CI, 1.152-1.586) for those on ponesimod. In addition, the number of Gd+ T1 lesions at the end-of-treatment visit was 0.211 (95% CI, 0.131-0.341).

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In terms of safety, ponesimod maintained its typical profile, with the most common TEAEs being COVID-19 infection (25.4%), alanine aminotransferase increase (19.5%), nasopharyngitis (17.8%), lymphopenia (14.8%), and headache (13.8%). Of the 877 patients in the long-term extension, 821 (93.6%) had any TEAE, 113 (12.9%) had a serious AE, and 75 (8.5%) discontinued because of a TEAE.

By binding selectively to S1P, ponesimod prevents lymphocytes from exiting lymph nodes, reducing their infiltration into the central nervous system. With a half-life around 33 hours, ponesimod differs from other approved S1P modulators on market. Ponesimod’s selectivity for S1P reduces off-target effects that are more common with fingolimod, another approved treatment, and its short half-life and rapid reversibility make it easier to manage in cases of infection, surgery, or pregnancy planning.

OPTIMUM, the trial that led to ponesimod’s approval in 2021, was a head-to-head study that tested the safety and efficacy of 20-mg ponesimod against 14-mg teriflunomide (Aubagio; Sanofi) in adults with relapsing MS. Data from the study showed that treatment with ponesimod led to a 30.5% greater reduction in ARR at week 108 relative to teriflunomide (P = .003). In addition, ponesimod-treated patients demonstrated statistically significant effects on symptoms of fatigue compared with teriflunomide, with a mean difference of –3.57 (P = .0019) on Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis.²

Additional data from the original trial showed that treatment with ponesimod was associated with a 56% reduction in the cumulative number of combined active lesions (P <.001). Previously reported cardiac data showed no major cardiovascular events–defined as CV death, non-fatal myocardial infarction, and non-fatal stroke–were identified in patients treated with ponesimod. Hazard risks and rhythm TEAEs of special interest were reported in 29 patients (5.1%) on ponesimod compared with 24 patients (4.2%) in the teriflunomide group.³

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REFERENCES
1. Mayo MG, Polymeropoulos CM, Birznieks G, Polymeropoulos MH. LBA17 - Ponesimod in Relapsing Forms of Multiple Sclerosis - Long-Term Safety and Efficacy Results from the Optimum Open-Label Extension Study (OPTIMUM-LT). Presented at: 2025 CMSC Annual Meeting; May 28-31. Phoenix, Arizona. LBA17
2. Janssen Submits Ponesimod New Drug Application to the U.S. FDA for Treatment of Adults with Relapsing Multiple Sclerosis. News release. March 18, 2020. Accessed March 18, 2021. prnewswire.com/news-releases/janssen-submits-ponesimod-new-drug-application-to-the-us-fda-for-treatment-of-adults-with-relapsing-multiple-sclerosis-301026319.html
3. Vaclavkova A, Burcklen M, Freedman M, et al. Cardiac safety of ponesimod in relapsing multiple sclerosis in the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0194