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Randomized Controlled Trial
. 2021 May 1;78(5):558-567.
doi: 10.1001/jamaneurol.2021.0405.

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

Ludwig Kappos  1 , Robert J Fox  2 , Michel Burcklen  3 , Mark S Freedman  4 , Eva K Havrdová  5 , Brian Hennessy  3 , Reinhard Hohlfeld  6   7 , Fred Lublin  8 , Xavier Montalban  9 , Carlo Pozzilli  10 , Tatiana Scherz  3 , Daniele D'Ambrosio  3   11 , Philippe Linscheid  3 , Andrea Vaclavkova  3 , Magdalena Pirozek-Lawniczek  3 , Hilke Kracker  3 , Till Sprenger  1   12
Affiliations
Randomized Controlled Trial

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

Ludwig Kappos et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: In the last 3 years, Dr Kappos’ institution (University Hospital Basel) received steering committee, advisory board, consultancy fees, and/or support for educational activities exclusively for research support at the Department from Actelion (step 2A), Allergan, Almirall, Baxalta, Bayer Healthcare, Biogen, Celgene/Receptos, CSL-Behring, Desitin, Excemed, Eisai, Genzyme, Japan Tobacco, Merck, Minoryx, Novartis, Pfizer, F. Hoffmann–La Roche Ltd, Roche, Sanofi Aventis, Santhera, and Teva and license fees for Neurostatus-UHB products. The research of the MS Center in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, Innosuisse, the European Union, and Roche Research Foundations. Drs Burcklen, Hennessy, Linscheid, Pirozek-Lawniczek, Vaclavkova, and Kracker are employees of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson. Dr Hennessy holds stock in Johnson & Johnson, Novo Nordisk, Arena Pharmaceuticals, and Galapagos and reported being a salaried employee of Actelion Pharmaceuticals Ltd during the conduct of the study. Drs Burcklen, Vaclavkova, and Kracker hold stock in Johnson & Johnson. Dr D'Ambrosio was an employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson, during the conduct of the study. Dr Scherz is an employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson, and a former employee of Novartis Pharma AG; she also holds stock in Johnson & Johnson. Dr Freedman reported having received personal fees from Bristol Myers Squibb/Celgene during the conduct of the study; honoraria from Actelion, Atara Biotherapeutics, Bayer Healthcare, Biogen Idec, Bristol Myers Squibb/Celgene, Chugai, Clene Nanomedicine, EMD Canada, Genzyme, Hoffman La–Roche Ltd, MedDay, Merck Serono, Novartis, Sanofi-Aventis/Sanofi Genzyme, and Teva Canada Innovation; and grants from Sanofi Genzyme and Roche outside the submitted work. Dr Fox reports having received personal consulting fees from AB Science, Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, Sanofi, Teva, and TG Therapeutics; served on advisory committees for Actelion, Biogen, Immunic, and Novartis; and received clinical trial contract and research grant funding from Biogen and Novartis outside the submitted work. Dr Hohlfeld received honoraria from Actelion, Biogen, Genzyme-Sanofi, Novartis, and Roche and research support from Biogen, Genzyme-Sanofi, Novartis, and Roche. Dr Hohlfeld also reported personal fees from Novartis, Sanofi, Merck, Biogen, Teva, Janssen/Johnson-Johnson, and Roche during the conduct of the study. Dr Lublin has received honoraria from Biogen, EMD Serono, Novartis, Teva, Actelion, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune, Receptos/Celgene, Forward Pharma, TG Therapeutics, Abbvie, Regeneron, Medday, Atara Biotherapeutics, Polpharma, Mapi Pharma, Innate Immunotherapeutics, Apitope, Orion Biotechnology, Brainstorm Cell Therapeutics, Jazz Pharmaceuticals, and GW Pharma. Dr Havrdová reported personal fees, advisory board membership, and/or speaker's honoraria from Biogen, Novartis, Roche, Sanofi, and Actelion and board membership for Celgene and Merck during the conduct of the study, as well as advisory board membership and speaker's honoraria from Biogen, Novartis, Roche, and Sanofi Genzyme; advisory board membership from Celgene and Sandoz; speaker’s honoraria and membership in a clinical trial advisory board membership from Merck Sernon; clinical trial advisory board membership with Actelion outside the submitted work, plus honoraria or research support from Teva and Merck Serono; and support from the Czech Ministry of Education (research project PROGRES Q27/LF1). Dr Montalban has received speaking honoraria and travel expenses for participation in scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck, Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society outside the submitted work. Dr Sprenger’s institution has received honoraria for speaking and consultation from Actelion, Biogen Idec, Desitin, Eli Lilly, Janssen, Johnson & Johnson, Novartis, Roche, Sanofi Genzyme, Electrocore, Merck, and Teva. Dr Pozzilli has served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, and Actelion; received funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion, and Novartis; and received research support from Biogen, Teva, Novartis, and Genzyme. Dr Lublin has received funding for research from Novartis, Actelion, Biogen, Sanofi, National Multiple Sclerosis Society, the National Institutes of Health, and Brainstorm Cell Therapeutics; has had consulting agreements or participated in advisory boards or data safety monitoring boards for Biogen, EMD Serono, Novartis, Teva, Actelion/Janssen, Sanofi/Genzyme, Acorda, Roche/Genentech, MedImmune/Viela Bio, Receptos/Celgene, Bristol Myers Squibb, TG Therapeutics, Medday, Atara Biotherapeutics, Polpharma, Mapi Pharma, Innate Immunotherapeutics, Apitope, Orion Biotechnology, Brainstorm Cell Therapeutics, Jazz Pharmaceuticals, GW Pharma, Mylan, Immunic, Population Council, and Avotres; and serving as a (nonpromotional) speaker for Sanofi, during which Dr Lublin may discuss unapproved agents that are in the multiple sclerosis developmental pipeline without any recommendation on their use. Finally, Dr Lublin reported consulting fees from Actelion/Janssen during the conduct of the study and grants from Brainstorm and stock options at Avotres outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
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 2.
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.
See this image and copyright information in PMC

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