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Cited by 228Multiple Sclerosis Research StudiesSphingolipid Metabolism and SignalingChronic Lymphocytic Leukemia Research

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Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial

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Kappos, Ludwig, Fox, Robert J., Burcklen, Michel, Freedman, Mark S., Havrdová, Eva K., Hennessy, Brian, Hohlfeld, Reinhard, Lublin, Fred, Montalban, Xavier, Pozzilli, Carlo, Scherz, Tatiana, D'Ambrosio, Daniele, Linscheid, Philippe, Vaclavkova, Andrea, Pirozek-Lawniczek, Magdalena, Kracker, Hilke, Sprenger, Till·2021·JAMA Neurology
DOI 10.1001/jamaneurol.2021.0405PMC PMC8008435
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Abstract

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. Design, Setting, and Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. Main Outcomes and Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Conclusions and Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.

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Figure 1. Patient Disposition In the ponesimod group, no patient discontinued treatment because of first-dose cardiac effect. Discontinuation in the ponesimod group was attributable to prespecified criteria: macular edema, pregnancy, lymphopenia, or a malignant condition.
Figure 1. Patient Disposition In the ponesimod group, no patient discontinued treatment because of first-dose cardiac effect. Discontinuation in the ponesimod group was attributable to prespecified criteria: macular edema, pregnancy, lymphopenia, or a malignant condition.CC BY-NC-ND · PubMed Central
Figure 2. Primary and Secondary End Points in the Full Analysis Set A, Confirmed relapses up to end of study, with annualized relapse rate from negative binomial regression for ponesimod (0.202) and teriflunomide (0.290); 30.5% indicates risk reduction. B, Symptoms domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS): change from baseline to week 108. C, Number of combined unique active lesions per year on magnetic resonance scans up to week 108; 56% indicates risk reduction. D, Time to 12-week confirmed disability accumulation. With regardt to nonsignificant results, the formal testing procedure stopped. The stratified log-rank test P value and stratified Cox regression risk reduction estimate are displayed. CL indicates confidence limits; LS, least squares.
Figure 2. Primary and Secondary End Points in the Full Analysis Set A, Confirmed relapses up to end of study, with annualized relapse rate from negative binomial regression for ponesimod (0.202) and teriflunomide (0.290); 30.5% indicates risk reduction. B, Symptoms domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS): change from baseline to week 108. C, Number of combined unique active lesions per year on magnetic resonance scans up to week 108; 56% indicates risk reduction. D, Time to 12-week confirmed disability accumulation. With regardt to nonsignificant results, the formal testing procedure stopped. The stratified log-rank test P value and stratified Cox regression risk reduction estimate are displayed. CL indicates confidence limits; LS, least squares.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Kappos, L., Fox, R. J., Burcklen, M., Freedman, M. S., Havrdová, E. K., Hennessy, B., Hohlfeld, R., Lublin, F., Montalban, X., Pozzilli, C., Scherz, T., D'Ambrosio, D., Linscheid, P., Vaclavkova, A., Pirozek-Lawniczek, M., Kracker, H., & Sprenger, T.
Affiliations
  • University of Basel (CH)
  • Cleveland Clinic (US)
  • Actelion (Switzerland) (CH)
  • University of Ottawa (CA)
  • Charles University (CZ)
  • Actelion Pharmaceuticals, Part of Janssen Pharmaceutical Companies, Allschwil, Switzerland
  • Munich Cluster for Systems Neurology (DE)
  • Icahn School of Medicine at Mount Sinai (US)
  • Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Vall d’Hebron University Hospital, Barcelona, Spain
  • Sapienza University of Rome (IT)
Corresponding author
Kappos, Ludwig
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2021-05-01
Volume
78
Issue
5
Pages
558
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2021.0405
PMC
PMC8008435
OpenAlex
W3149798718
Cited by
228
References
46
Citations by year
2026: 27 · 2025: 34 · 2024: 49 · 2023: 52 · 2022: 53 · 2021: 12
FWCI
27.66
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • JAMA Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc-nd)
Funders
Actelion Pharmaceuticals
Topics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Keywords
ponesimod, teriflunomide, relapsing multiple sclerosis, disease-modifying therapy, annualized relapse rate, disability progression, brain volume changes, no evidence of disease activity, fatigue, safety and tolerability
MeSH terms
Adolescent, Adult, Crotonates, Female, Humans, Hydroxybutyrates, Immunologic Factors, Magnetic Resonance Imaging, Male, Middle Aged, Neoplasm Recurrence, Local, Nitriles, Thiazoles, Toluidines, Disease Progression, Multiple Sclerosis, Relapsing-Remitting, Young Adult

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