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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
Open accessAbstract
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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Highly Effective Therapy Versus Escalation Approaches in Early Multiple Sclerosis
Rjeily, N. B., Mowry, E. M., Ontaneda, D., & Carlson, A. K. (2023) · Neurologic Clinics · doi:10.1016/j.ncl.2023.06.004 · Cited by 22
Quesada-Simó, A., Garrido-Marín, A., Nos, P., & Gil-Perotín, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1186016 · Cited by 19
“These agents have shown their effectiveness in MS in different clinical trials compared to placebo, IFNγ or TFM (Calabresi et al., 2014; Kappos et al., 2018; Comi et al., 2019; Kappos et al., 2021).”
BackgroundLesion location across diagnostic regions in multiple sclerosis
Pongratz, V., Bussas, M., Schmidt, P. J., Grahl, S., Gasperi, C., Husseini, M. E., Harabacz, L., Pineker, V., Sepp, D., Grundl, L., et al. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103311 · Cited by 24
Kihara, Y., Jonnalagadda, D., Zhu, Y., Ray, M., Ngo, T., Palmer, C. R., Rivera, R., & Chun, J. (2022) · The FASEB Journal · doi:10.1096/fj.202101531r · Cited by 18
Fatigue: a common but poorly understood symptom in neurological and non-neurological diseases
Penner, I., Grothe, M., & Chan, A. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01153-z · Cited by 20
Morgan, A., Tallantyre, E. C., & Ontaneda, D. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2208347 · Cited by 18
“5% (compared to teriflunomide) [32] Fumarates: Oral Dimethyl fumarate 44-53% [35,36] 26% at 2 years [37] -0.”
Kohle, F., Dalakas, M. C., & Lehmann, H. C. (2023) · Therapeutic Advances in Neurological Disorders · doi:10.1177/17562864221137129 · Cited by 17
Brieva, L., Calles, C., Landete, L., & Oreja-Guevara, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1543649 · Cited by 16
Cagol, A., Schädelin, S., Pretzsch, R., Kappos, L., Sormani, M. P., & Granziera, C. (2025) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2025.101476 · Cited by 14
Self-citationPersonality Traits and Fatigue in Multiple Sclerosis: A Narrative Review
Ciancio, A., Moretti, M. C., Natale, A., Rodolico, A., Signorelli, M., Petralia, A., Altamura, M., Bellomo, A., Zanghì, A., D'Amico, E., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12134518 · Cited by 16
Lehto, J., Nylund, M., Matilainen, M., Sucksdorff, M., Vuorimaa, A., Rajander, J., Wahlroos, S., Hariri, P., & Airas, L. M. (2023) · European Journal of Neurology · doi:10.1111/ene.15834 · Cited by 18
“This shift has happened at the expense of recent phase III trials [36, 37], where relatively less active cohorts of patients were enrolled compared with past trials [18, 19].”
ResultRuotolo, I., Sellitto, G., Ianniello, A., Petsas, N., Castelli, L., Galeoto, G., Berardi, A., Barletta, V. T., Conte, A., & Pozzilli, C. (2022) · Neurological Sciences · doi:10.1007/s10072-022-06080-1 · Cited by 16
Self-citationSellitto, G., Ruotolo, I., Ianniello, A., Felicetti, F., D'Ambrosi, G., Berardi, A., Galeoto, G., Conte, A., & Pozzilli, C. (2024) · BMC Neurology · doi:10.1186/s12883-024-03643-x · Cited by 15
“Its responsiveness and meaningful change of FSIQ-RMS have been analyzed in one international phase III trial, the Optimum Trial, which represents the first study to implement a validated disease-specific fatigue measure (PRO) as a prespecified endpoint [13].”
MethodSelf-citationWillems, E., Schepers, M., Piccart, E., Wolfs, E., Hellings, N., Ait-Tihyaty, M., & Vanmierlo, T. (2024) · The FASEB Journal · doi:10.1096/fj.202301557rr · Cited by 11
Kandjani, O. J., Yaqoubi, S., Vahdati, S. S., Borhannejad, B., Dastmalchi, S., & Alizadeh, A. A. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115182 · Cited by 17
An overview on disease modifying and symptomatic drug treatments for multiple sclerosis
Costa, G. D., Leocani, L., Rodegher, M., Chiveri, L. R., Gradassi, A., & Comi, G. (2024) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2024.2410393 · Cited by 15
Constantinescu, V. A., Akgün, K., & Ziemssen, T. (2022) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2022.2138330 · Cited by 15
Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society
Collongues, N., Durand‐Dubief, F., Lebrun‐Frénay, C., Audoin, B., Ayrignac, X., Bensa, C., Bigaut, K., Bourre, B., Dalliere, C. C., Ciron, J., et al. (2024) · Multiple Sclerosis Journal · doi:10.1177/13524585231223880 · Cited by 14
Impact of Disease-Modifying Therapies on Gut–Brain Axis in Multiple Sclerosis
Negro, I. D., Pez, S., Versace, S., Marziali, A., Gigli, G. L., Tereshko, Y., & Valente, M. (2023) · Medicina · doi:10.3390/medicina60010006 · Cited by 9
“These drugs showed a reduced relapsing rate compared to placebos or moderate-efficacy DMTs [62–64].”
BackgroundGlasmacher, S. A., Kearns, P. K. A., Hassan, Z., Connick, P., Tauber, S. C., Reetz, K., Foley, P., & Chandran, S. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103837 · Cited by 12
Ashwani, Sharma, A., Choudhary, M. K., Gugulothu, D. B., Pandita, D., Verma, S., Vora, L. K., Khatri, D. K., & Garabadu, D. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04868-8 · Cited by 17
The effect of disease modifying therapies on fatigue in multiple sclerosis.
Rivera, S. C., Aiyegbusi, O., Meier, D. P., Dunne, A., Harlow, D., Henke, C., Kamudoni, P., & Calvert, M. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.105065 · Cited by 12
Aharoni, R., Milo, R., & Arnon, R. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.124.000927 · Cited by 12
Yang, X.-P., Yan, Y., Liu, S., Wang, Z.-Q., & Feng, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1376494 · Cited by 11
Disease-modifying therapy initiation patterns in multiple sclerosis in three large MS populations
Stahmann, A., Craig, E. M., Ellenberger, D., Fneish, F., Frahm, N., Marrie, R. A., Middleton, R., Nicholas, R. S., Rodgers, J., Warnke, C., et al. (2024) · Therapeutic Advances in Neurological Disorders · doi:10.1177/17562864241233044 · Cited by 9
Tervonen, T., Fox, R., Brooks, A., Sidorenko, T., Boyanova, N., Levitan, B., Hennessy, B., & Phillips-Beyer, A. (2023) · Multiple Sclerosis Journal - Experimental, Translational and Clinical · doi:10.1177/20552173221150370 · Cited by 11
Self-citationGonzález‐Lorenzo, M., Ridley, B., Minozzi, S., Giovane, C. D., Peryer, G., Piggott, T., Foschi, M., Filippini, G., Tramacere, I., Baldin, E., et al. (2024) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011381.pub3 · Cited by 51
Disease‐modifying therapies in multiple sclerosis: A focused review of rituximab
Alping, P. (2023) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13932 · Cited by 10
“The study also found a reduction in relapses and lesions found on (magnetic resonance imaging) MRI from week 4 to week 72, compared with the year before treatment start.”
BackgroundSwallow, E., Pham, T., Patterson-Lomba, O., Yin, L., Gomez-Lievano, A., Liu, J., Tencer, T., & Gupte-Singh, K. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.104551 · Cited by 10
Hennessy, B., Zierhut, M., Kracker, H., Keenan, A., & Sidorenko, T. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103908 · Cited by 10
Self-citationDisease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?
Bellanca, C. M., Augello, E., Mariottini, A., Bonaventura, G., Cognata, V. L., Benedetto, G. D., Cantone, A. F., Attaguile, G. A., Mauro, R. D., Cantarella, G., et al. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240124114126 · Cited by 9
“Regarding the primary endpoint which was the ARR, ponesimod was superior to teriflunomide in reducing the incidence of relapses by 30.5% [168].”
BackgroundInfluentialImpact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review
Elkhooly, M., Bao, F., & Bernitsas, E. (2023) · Brain Science · doi:10.3390/brainsci14010004 · Cited by 9
“Ponesimod was compared with teriflunomide in phase three OPTIMUM study, which included 1133 patients with RRMS. Ponesimod was significantly superior to teriflunomide in reducing fatigue using FSIQ-RRM with a mean score of − 3.57 ( − 0.01 vs. 3.56; p < 0.001) in the ponesimod group [31].”
BackgroundResultInfluentialCha, E., Kim, J., Gotina, L., Kim, J., Kim, H. J., Seo, S. H., Park, J., Joo, J., Kang, M.-S., Lee, J., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00498 · Cited by 10
Hach, T., Shakeri-Nejad, K., Bigaud, M., Dahlke, F., de Micco, M., Pétricoul, O., Graham, G., Piani-Meier, D., Turrini, R., Brinkmann, V., et al. (2022) · Journal of Interferon and Cytokine Research · doi:10.1089/jir.2022.0078 · Cited by 9
Cagol, A., Schaedelin, S. A., Ocampo‐Pineda, M., Benkert, P., Melie‐García, L., Luchetti, L., Yaldizli, Ö., Oechtering, J., D’Souza, M., Fischer‐Barnicol, B., et al. (2025) · Journal of Neurology · doi:10.1007/s00415-025-13221-x · Cited by 10
Self-citationConstantinescu, V., Haase, R., Akgün, K., & Ziemssen, T. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1431380 · Cited by 8
Gakis, G., Angelopoulos, I., Panagoulias, I., & Mouzaki, Α. (2023) · Autoimmunity Reviews · doi:10.1016/j.autrev.2023.103480 · Cited by 10
Ublituximab-xiiy as a treatment option for relapsing multiple sclerosis
Jakimovski, D., Weinstock-Guttman, B., & Zivadinov, R. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2268842 · Cited by 8
“%) and particularly in the OPTIMUM ponesimod trial where the teriflunomide arm had 1.25% volume loss from baseline to week 108 [42].”
BackgroundInfluentialBazzurri, V., Fiore, A., Curti, E., Tsantes, E., Franceschini, A., & Granella, F. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.105015 · Cited by 8
Alnaif, A., Oiler, I. G., & D’Souza, M. (2022) · The Annals of Pharmacotherapy · doi:10.1177/10600280221140480 · Cited by 8
Treatment of relapsing multiple sclerosis – recommendations of the Croatian Neurological Society
Habek, M., Adamec, I., Barun, B., Kes, V. B., Raspopović, A. B., Glavor, K. D., Gabelić, T., Gržinčić, T., Jukić, M., Jurašić, M., et al. (2022) · Croatian Medical Journal · doi:10.3325/cmj.2022.63.379 · Cited by 11
Lickliter, J., Yang, X., Guo, J., Pan, W.-B., & Wei, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1380975 · Cited by 7
Kruger, T. M., Valenzuela, B., Thompson, C., Ouwerkerk-Mahadevan, S., & Ruixo, J. P. (2023) · Clinical Pharmacokinetics · doi:10.1007/s40262-023-01308-5 · Cited by 7
“The secondary efficacy endpoints included cumulative number of combined unique active lesions (CUAL; defined as new T1 Gd+ at baseline [T1B] MRI lesions plus new or enlarging T2 lesions [without double-counting of lesions]) from baseline to Week 108 [20].”
BackgroundRole of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury
Sun, G., Wang, B., Zhu, H.-Q., Ye, J.-M., & Liu, X. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1265398 · Cited by 7
Treatment of Multiple Sclerosis
Cross, A., & Riley, C. (2022) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001170 · Cited by 37
Effect of Ponesimod Exposure on Total Lymphocyte Dynamics in Patients with Multiple Sclerosis
Valenzuela, B., Ruixo, J. J. P., Leirens, Q., Ouwerkerk‐Mahadevan, S., & Poggesi, I. (2021) · Clinical Pharmacokinetics · doi:10.1007/s40262-021-01019-9 · Cited by 5
“AC-058B301 (NCT02425644) [14] Ponesimod 20 mg qd, following an initial gradual uptitration (2, 2, 3, 3, 4, 4, 5, 6, 7, 8, 9, 10, 10, 10, 20 mg) Teriflunomide 14 mg Predose at Weeks 12, 60, and 108 3 h postdose at Day 1 and Week 12 Visit 1 (screening), Visit 2 (baseline), Visits 4–13 (Weeks 2, 4, 12, and every 12 weeks…”
MethodResultInfluentialNeurovascular dysfunction in the development and progression of neuroinflammatory diseases
Gowdy, J., Ahn, J. J., Miller, R. H., & Islam, Y. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1741928 · Cited by 8
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)
- 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
- hybrid
- doi.org
- 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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