OPTIMUM-LTE
(2026)Objective
To assess the long-term safety and efficacy of ponesimod 20 mg during extended treatment in participants with relapsing multiple sclerosis (RMS), and to evaluate outcomes after switching from teriflunomide 14 mg to ponesimod 20 mg, in the open-label extension of the phase 3 OPTIMUM study.
Study Summary
• Relapse occurred in 44.3% of P20/P20 vs 49.5% of T14/P20 participants
• NEDA-3 at end of extension was achieved by more continuous-ponesimod participants: 17.5% (P20/P20) vs 7.5% (T14/P20)
• Serious TEAEs occurred in 12.9% overall (P20/P20 12.8%; T14/P20 13.0%); TEAEs leading to treatment discontinuation in 8.6% (P20/P20 7.7%; T14/P20 9.4%); no new safety signals emerged
Intervention
Ponesimod 20 mg once daily (selective S1P1 receptor modulator), with prior teriflunomide-treated participants switched to ponesimod 20 mg at extension entry.
Inclusion Criteria
Completion of the 108-week treatment period of the phase 3 OPTIMUM core study (core eligibility: age 18–55, relapsing MS [RRMS or SPMS with relapses per 2010 McDonald criteria], EDSS 0–5.5, recent clinical or MRI activity).
Study Design
Arms: Ponesimod 20mg → Ponesimod 20mg (P20/P20, n=439) vs Teriflunomide 14mg → Ponesimod 20mg (T14/P20, n=438)
Patients per Arm: 439 vs 438
Outcome
• Higher NEDA-3 with continuous ponesimod: 17.5% vs 7.5%
• 93.6% of both groups had ≥1 TEAE; serious TEAEs 12.9% overall; no new safety signals
• Disease control achieved in OPTIMUM core was maintained on extended ponesimod treatment
Bottom Line
In the open-label OPTIMUM long-term extension, ponesimod 20 mg maintained low relapse rates and sustained disease control over 5 years in relapsing MS with no new safety signals; participants who switched from teriflunomide to ponesimod also had low relapse activity, though continuous ponesimod achieved higher NEDA-3 (17.5% vs 7.5%).
Major Points
- Of 1133 participants who completed the OPTIMUM core study, 877 enrolled in the 240-week (5-year) open-label extension (P20/P20: 439; T14/P20: 438).
- Mean ARR over the combined analysis period was 0.143 (95% CL 0.123–0.167) for continuous ponesimod and 0.184 (95% CL 0.158–0.213) for the teriflunomide-to-ponesimod switch group.
- Relapse occurred in 44.3% of P20/P20 vs 49.5% of T14/P20 participants over the extension.
- NEDA-3 at end of the extension was achieved by 17.5% of continuous-ponesimod vs 7.5% of switch-group participants.
- Safety was consistent with the known ponesimod profile: 93.6% of both groups had ≥1 TEAE, serious TEAEs in 12.9% overall, treatment-discontinuation TEAEs in 8.6% overall, and no new safety signals.
- All efficacy analyses were descriptive (open-label, non-comparative), as baseline characteristics may not be comparable between groups at extension entry.
Study Design
- Study Type
- Prospective, multicenter, open-label, non-comparative long-term extension of the phase 3 OPTIMUM study
- Randomization
- No
- Blinding
- Open-label (the parent OPTIMUM core study was double-blind, randomized 1:1)
- Sample Size
- 877
- Follow-up
- Treatment period up to 240 weeks (~5 years); up to 288 weeks in Ukraine; combined analysis period from core randomization onward
Primary Outcome
Definition: Annualized relapse rate (ARR), defined as the number of confirmed relapses per patient-year, over the combined analysis period (exploratory)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| T14/P20: 0.184 (95% CL 0.158–0.213) | P20/P20: 0.143 (95% CL 0.123–0.167) | - (P20/P20 0.123–0.167; T14/P20 0.158–0.213) | Not applicable (descriptive, non-comparative analysis) |
Limitations & Criticisms
- Open-label, non-comparative extension; all efficacy analyses were descriptive and exploratory with no formal statistical testing.
- Baseline characteristics may not be comparable between groups at extension entry, and the switch group had a treatment change confounding direct comparison.
- Selection/survivorship bias: only core-study completers (877 of 1133) entered the extension.
- Variable treatment exposure, since the treatment period could be shortened in some countries once ponesimod became commercially available (or extended to 288 weeks in Ukraine).
Citation
Montalban X, et al. Long-term safety and efficacy of ponesimod in participants with relapsing multiple sclerosis: results from the phase 3 OPTIMUM 5-year long term extension study. J Neurol. 2026;273(4):234.