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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

PDF: https://link.springer.com/content/pdf/10...026-13675-7.pdf

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 period; rate ratio 0.779 (95% CL: 0.629-0.965)
  • 44.3% (P20/P20) vs 49.5% (T14/P20) of participants experienced a relapse over the combined analysis period (KM estimate)
  • 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; NEDA-4 5.2% vs 2.3%
  • 12-week CDA 23.1% vs 30.5%; 24-week CDA 21.3% vs 26.0% (numerically favoring 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%), ALT increased (19.5%), nasopharyngitis (17.8%), 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 (56.21 mo P20/P20; 56.20 mo T14/P20)

Countries: Ukraine

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
  • Sufficient compliance with the accelerated teriflunomide elimination procedure (assessed at follow-up visit 1 or abbreviated follow-up visit 2 of the core study)
  • Note: baseline characteristics such as age 18-55 years, diagnosis of relapsing MS (RRMS or SPMS with relapses per 2010 McDonald criteria), EDSS 0-5.5, and evidence of recent clinical or MRI activity applied to enrollment in the core study, not the LTE

Baseline Characteristics

CharacteristicP20mg/P20mgT14mg/P20mgTotal
N439438877
Female n (%)286 (65.1)290 (66.2)576 (65.7)
Mean Age (SD)38.8 (8.77)39.4 (8.78)39.1 (8.77)
White n (%)429 (97.7)430 (98.2)859 (97.9)
BMI Mean (SD)24.7 (5.1)24.4 (4.8)24.6 (5.0)
BMI Median (Min, Max)23.6 (15.6, 45.1)23.6 (14.8, 46.3)

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
All efficacy endpoints in the LTE were exploratory (ARR, time to first confirmed relapse, CDA, MRI endpoints); safety endpoints included TEAEs, serious TEAEs, TEAEs of special interest, and AE-related discontinuationsPrimaryT14mg/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%0.779 (ARR rate ratio, P20/P20 vs T14/P20)Not reported (descriptive analyses only)
SecondaryName: Annualized Relapse Rate (ARR) — combined analysis period · P20mg/P20mg: 0.143 (95% CL: 0.123-0.167) · T14mg/P20mg: 0.184 (95% CL: 0.158-0.213)
SecondaryName: ARR rate ratio (P20/P20 vs T14/P20) · P20mg/P20mg: 0.779 (95% CL: 0.629-0.965) · T14mg/P20mg: Reference
SecondaryName: Participants experiencing confirmed relapse by week 384 (KM estimate) · P20mg/P20mg: 44.3% (95% CL: 39.7-49.3) · T14mg/P20mg: 49.5% (95% CL: 44.8-54.4)
SecondaryName: Remained relapse-free from core baseline to end of LTE · P20mg/P20mg: 56.7% · T14mg/P20mg: 51.6%
SecondaryName: 12-week Confirmed Disability Accumulation (CDA) by week 396 · P20mg/P20mg: 23.1% (95% CL: 19.3-27.5) · T14mg/P20mg: 30.5% (95% CL: 26.2-35.3)
SecondaryName: 24-week CDA by week 384 · P20mg/P20mg: 21.3% (95% CL: 17.7-25.6) · T14mg/P20mg: 26.0% (95% CL: 21.9-30.6)
SecondaryName: Mean absolute change from core baseline in EDSS at EOS · P20mg/P20mg: 0.16 (SD 1.008) · T14mg/P20mg: 0.34 (SD 1.105)
SecondaryName: NEDA-3 at end of LTE · P20mg/P20mg: 77 (17.5%) · T14mg/P20mg: 33 (7.5%)
SecondaryName: NEDA-4 at end of LTE · P20mg/P20mg: 23 (5.2%) · T14mg/P20mg: 10 (2.3%)
SecondaryName: Cumulative new/enlarging T2 lesions (combined analysis) · P20mg/P20mg: 1.352 (95% CL: 1.152-1.586) · T14mg/P20mg: 1.951 (95% CL: 1.664-2.287)
SecondaryName: Mean cumulative CUALs per year · P20mg/P20mg: 1.352 (95% CL: 1.153-1.586) · T14mg/P20mg: 1.954 (95% CL: 1.667-2.291)
SecondaryName: No CUALs through combined analysis period · P20mg/P20mg: 34.7% · T14mg/P20mg: 23.2%
SecondaryName: No new Gd+T1 lesions (core baseline to extension EOT) · P20mg/P20mg: 66.7% · T14mg/P20mg: 54.3%
SecondaryName: Mean change in brain volume from core baseline to LTE EOT · P20mg/P20mg: -2.52% (SD 2.179) · T14mg/P20mg: -2.72% (SD 2.024)
SecondaryName: Mean change from core baseline in MSFC Z-score at extension EOT · P20mg/P20mg: -0.001 (SD 0.6457) · T14mg/P20mg: -0.210 (SD 0.8443)
SecondaryName: Mean change from core baseline in SDMT at extension EOT · P20mg/P20mg: 0.0 (SD 16.30) · T14mg/P20mg: -0.6 (SD 15.97)
SafetyName: ≥1 TEAE · P20mg/P20mg: 411 (93.6%) · T14mg/P20mg: 410 (93.6%) · Total: 821 (93.6%)
SafetyName: Serious TEAE · P20mg/P20mg: 56 (12.8%) · T14mg/P20mg: 57 (13.0%) · Total: 113 (12.9%)
SafetyName: TEAE leading to discontinuation · P20mg/P20mg: 34 (7.7%) · T14mg/P20mg: 41 (9.4%) · Total: 75 (8.6%)
SafetyName: Fatal TEAE · P20mg/P20mg: 1 (0.2%) · T14mg/P20mg: 0 (0%) · Total: 1 (0.1%)
SafetyName: Premature treatment discontinuation (LTE) · P20mg/P20mg: 106 (24.1%) · T14mg/P20mg: 117 (26.7%) · Total: 223 (25.4%)
COVID-19AdverseP20mg/P20mg: 116 (26.4%) · T14mg/P20mg: 108 (24.7%) · Total: 224 (25.5%)
NasopharyngitisAdverseP20mg/P20mg: 82 (18.7%) · T14mg/P20mg: 74 (16.9%) · Total: 156 (17.8%)
ALT increasedAdverseP20mg/P20mg: 73 (16.6%) · T14mg/P20mg: 98 (22.4%) · Total: 171 (19.5%)
LymphopeniaAdverseP20mg/P20mg: 66 (15.0%) · T14mg/P20mg: 64 (14.6%) · Total: 130 (14.8%)
HeadacheAdverseP20mg/P20mg: 57 (13.0%) · T14mg/P20mg: 64 (14.6%) · Total: 121 (13.8%)
Upper respiratory tract infectionAdverseP20mg/P20mg: 47 (10.7%) · T14mg/P20mg: 51 (11.6%) · Total: 98 (11.2%)
Most common SOC - Infections and infestationsAdverseP20mg/P20mg: 66.3% · T14mg/P20mg: 62.3%
Most common SOC - InvestigationsAdverseP20mg/P20mg: 36% · T14mg/P20mg: 40%
Most common SOC - Nervous system disordersAdverseP20mg/P20mg: 28.9% · T14mg/P20mg: 31.1%
AEs leading to discontinuation (most common)AdverseUnintended pregnancy (1.5%), ALT increased (0.8%), dyspnea (0.6%), macular edema (0.6%); all protocol-mandated criteria for discontinuation
DILI casesAdverseNone identified despite ALT elevations

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
  • Only a self-selected subset of core participants entered LTE, limiting NEDA-4 interpretation

Funding

The study was supported by funding from Johnson & Johnson. Medical writing support was provided by Shweta Pitre, MPH, CMPP (SIRO Clinpharm UK Ltd). Additional editorial support was provided by Lori Kornberg and Doyel Mitra, PhD (both Johnson & Johnson).

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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