OPTIMUM-LTE post hoc data: There was no indication of relevant disease reactivation or rebound after ponesimod discontinuation in MS patients.In a post hoc analysis of the OPTIMUM* long-term extension (OPTIMUM-LTE) study, discontinuation of ponesimod did not lead to a clinically meaningful disease reactivation or rebound effect in patients with relapsing multiple sclerosis (MS).
“Considering the short half-life of ponesimod (approximately 33 hrs) and the rapid normalization of lymphocyte counts within 1–2 weeks following treatment discontinuation, any potential rebound would have been expected to occur relatively early,” said Dr Ludwig Kappos from the University of Basel, Switzerland, who presented the results at EAN 2026.
In this analysis, the annualized relapse rate (ARR) and relapse EDSS** did not suggest a clinically meaningful reactivation or rebound after ponesimod discontinuation, given the available follow-up, noted Kappos and colleagues.
Only seven relapses were reported among participants with at least 1 day of post-treatment follow-up. This is a far cry from the 58 relapses reported during the 6-month on-treatment reference period prior to discontinuation. [EAN 2026, abstract EPO-0139]
These corresponded to mean ARR estimates of 0.11 and 0.21 for the post- and on-treatment periods, respectively.
“Multiple sensitivity analyses consistently supported the main result, with no indication of relevant disease reactivation or rebound,” Kappos said. The mean ARR estimates among patients with 30 days of post-treatment follow-up were 0.11 and 0.20 for the respective post- and on-treatment periods.
The mean time to relapse after discontinuation was 15 days.
The results were similar in the subgroup analysis of participants who did not receive subsequent therapy within 30 days of discontinuation. The mean ARR estimate after treatment discontinuation was lower than that reported during the on-treatment period (0.12 vs 0.18).
Moreover, there were no post-treatment relapses associated with an EDSS increase of ≥2 points, nor were there any patients hospitalized during their relapse.
The OPTIMUM study
MS patients who do not adhere to treatment are unlikely to optimize its full benefit, and long-term treatment discontinuation entails a higher risk of severe relapse. [Neurology 2003;61:551-554; J Neurol 2008;255(Suppl 2):S79]
In the phase III OPTIMUM core study, 1,133 individuals with relapsing MS and baseline EDSS ≤5.5 were randomized 1:1 to either ponesimod 20 mg or teriflunomide 14 mg QD for 108 weeks. [JAMA Neurol 2021;78:558-567]
In the ensuing open-label LTE (n=877), participants initially randomized to ponesimod 20 mg continued with their regimen, while those receiving teriflunomide switched to ponesimod. They continued treatment for up to 5 additional years or until ponesimod became commercially available in their country. [J Neurol 2026;273:234]
This post hoc analysis included participants who permanently discontinued ponesimod in OPTIMUM-LTE (n=551; mean age at study entry 38.4 years, 65 percent women). Of these, 265 had received ponesimod 20 mg continuously since core study entry, and 286 had switched from teriflunomide 14 mg at LTE study entry. The median post-discontinuation follow-up period was 38 days.
Of note, participants who discontinued ponesimod did so prematurely or had to because the drug was not commercially available at the time of discontinuation.
One-third of the participants had at least one confirmed relapse during the core study period. The mean baseline EDSS score at LTE study entry was 2.6.
“Given the limited protocol-defined follow-up … these reassuring findings should be confirmed in real-world studies with longer treatment exposures and follow-up periods,” Kappos concluded.