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OPTIMUM 5 YEARS

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

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Year of Publication: 2026

Authors: Montalban X, Hohlfeld R, Pozzilli C, ..., Kappos L

Journal: Journal of Neurology

Citation: Journal of Neurology (2026) 273:234

Link: https://doi.org/10.1007/s00415-026-13675-7

Clinical Question

Does ponesimod 20 mg maintain its safety and efficacy in relapsing MS over 5 years of extended treatment?

Bottom Line

Ponesimod 20 mg demonstrated sustained efficacy and acceptable safety over 5 years in relapsing MS, with no new safety signals. Participants who switched from teriflunomide to ponesimod also benefited, though NEDA-3 rates were notably higher in those on continuous ponesimod.

Major Points

  • Of 1133 core OPTIMUM participants, 877 (77.4% from each arm) enrolled in the 240-week LTE
  • Mean ARR was 0.143 (95% CL: 0.123-0.167) for P20mg/P20mg vs 0.184 (95% CL: 0.158-0.213) for T14mg/P20mg in combined analysis
  • 44.3% (P20/P20) vs 49.5% (T14/P20) of participants experienced a relapse over the extended period
  • NEDA-3 at end of LTE: 17.5% in P20/P20 vs 7.5% in T14/P20 — more than double the rate with continuous ponesimod
  • TEAEs occurred in 93.6% of both groups; serious TEAEs in 12.8% (P20/P20) vs 13.0% (T14/P20)
  • TEAE-related discontinuations: 7.7% (P20/P20) vs 9.4% (T14/P20)
  • Most common TEAEs: COVID-19 (25.5%), nasopharyngitis (17.8%), ALT increased (19.5%), lymphopenia (14.8%), headache (13.8%)
  • One death (pulmonary embolism, venous thrombosis) in P20/P20 group, considered unrelated to study drug
  • No DILI cases identified despite ALT elevations; no new safety signals emerged over 5 years

Design

Study Type: Prospective, multicenter, open-label, non-comparative, long-term extension of phase 3 OPTIMUM study

Randomization:

Blinding: Open-label

Allocation: Non-randomized; participants continued on prior treatment assignment from core study (P20mg/P20mg) or switched from teriflunomide to ponesimod (T14mg/P20mg)

Follow-up Duration: Up to 240 weeks (up to 288 weeks in Ukraine due to regional crisis); median ~56 months

Centers: 0

Countries:

Sample Size: 877

Analyzed: 877

Analysis: Descriptive analyses only; no formal statistical comparisons between groups due to non-randomized design, treatment switching, and baseline differences at LTE entry. Negative binomial model used for ARR estimation with core study treatment as factor and log time on study as offset.

Power Calculation: Sample size determined by number of participants completing core OPTIMUM and consenting to LTE; no formal power calculation

Registration: NCT02425644

Inclusion Criteria

  • Completion of the 108-week treatment period in the phase 3 OPTIMUM core study
  • Age 18-55 years (at core study enrollment)
  • Diagnosis of relapsing MS (RRMS or SPMS with relapses per 2010 McDonald criteria)
  • EDSS score of 0-5.5 (at core study enrollment)
  • Evidence of recent clinical or MRI activity (at core study enrollment)
  • Sufficient compliance with accelerated teriflunomide elimination procedure

Arms

FieldP20 mg/P20 mgT14 mg/P20 mg
N439438
InterventionPonesimod 20 mg once daily in core study, continued at 20 mg once daily in LTE (with up-titration from 2 to 10 mg over days 1-14)Teriflunomide 14 mg once daily in core study, switched to ponesimod 20 mg once daily in LTE after accelerated elimination procedure
DurationUp to 240 weeks (up to 288 weeks in Ukraine)Up to 240 weeks (up to 288 weeks in Ukraine)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Safety (TEAEs, serious TEAEs, TEAEs of special interest, AE-related discontinuations) and efficacy (ARR, time to first confirmed relapse, CDA, MRI endpoints) over the long-term extension periodPrimaryT14mg/P20mg: ARR 0.184 (95% CL: 0.158-0.213); 49.5% experienced relapse; NEDA-3 at end of LTE 7.5%P20mg/P20mg: ARR 0.143 (95% CL: 0.123-0.167); 44.3% experienced relapse; NEDA-3 at end of LTE 17.5%Not reported (descriptive analyses only)
Secondary
Secondary
Secondary
Safety
Safety
Safety
Safety
Safety
COVID-19Adverse
NasopharyngitisAdverse
ALT increasedAdverse
LymphopeniaAdverse
HeadacheAdverse
Upper respiratory tract infectionAdverse
Most common SOC - Infections and infestationsAdverse
Most common SOC - InvestigationsAdverse
Most common SOC - Nervous system disordersAdverse
Unintended pregnancy (1.5%), ALT increased (0.8%), dyspnea (0.6%), macular edema (0.6%); all protocol-mandated criteria for discontinuationAdverse
None identified despite ALT elevationsAdverse

Criticisms

  • Open-label, non-comparative design with no formal statistical comparisons between groups
  • Baseline characteristics at LTE entry may not be comparable between groups due to treatment switching
  • 25.4% of participants prematurely discontinued treatment during the LTE, which may bias long-term efficacy estimates
  • T14mg/P20mg group had only ~108 weeks of teriflunomide before switching, limiting ability to assess pure switch effect
  • Sample size driven by core completers rather than formal power calculation

Based on: OPTIMUM 5 YEARS (Journal of Neurology, 2026)

Authors: Montalban X, Hohlfeld R, Pozzilli C, ..., Kappos L

Citation: Journal of Neurology (2026) 273:234

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