Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial | Demyelinating Disorders | JN Learning | AMA Ed Hub [Skip to Content]
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Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM StudyA Randomized Clinical Trial

Educational Objective
To compare the efficacy of ponesimod vs teriflunomide in a phase 3, multicenter, randomized, double-blind, active-comparator superiority study of patients with relapsing multiple sclerosis.
1 Credit CME
Key Points

Question  How does the efficacy of ponesimod compare with that of teriflunomide in a phase 3, multicenter, randomized, double-blind, active-comparator superiority study based on relapse rate, fatigue, magnetic resonance imaging–defined disease activity, tissue loss, and disability accumulation in patients with relapsing multiple sclerosis, over 108 weeks?

Findings  In this randomized clinical trial, ponesimod was significantly superior to teriflunomide in reducing the annualized relapse rate (−30.5%), Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis symptom score (−3.57), and combined unique active lesions on magnetic resonance imaging (−56%).

Meaning  In this study, efficacy of ponesimod was superior to teriflunomide, and ponesimod had a safety profile consistent with sphingosine-1-phosphate modulators without any new safety signals.

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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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: January 28, 2021.

Published Online: March 29, 2021. doi:10.1001/jamaneurol.2021.0405

Corresponding Author: Ludwig Kappos, MD, Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Spitalstrasse 2, CH-4031 Basel, Switzerland (ludwig.kappos@usb.ch).

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Kappos L et al. JAMA Neurology.

Author Contributions: Dr Kappos had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kappos, Burcklen, Hennessy, Pozzilli, D'Ambrosio, Linscheid, Vaclavkova, Sprenger.

Acquisition, analysis, or interpretation of data: Kappos, Fox, Burcklen, Freedman, Havrdová, Hennessy, Hohlfeld, Lublin, Montalban, Pozzilli, Scherz, Linscheid, Vaclavkova, Pirozek-Lawniczek, Kracker, Sprenger.

Drafting of the manuscript: Kappos, Burcklen, Hennessy, Pozzilli, Scherz, Linscheid, Vaclavkova, Pirozek-Lawniczek.

Critical revision of the manuscript for important intellectual content: Kappos, Fox, Burcklen, Freedman, Havrdová, Hennessy, Hohlfeld, Lublin, Montalban, Pozzilli, Scherz, D'Ambrosio, Vaclavkova, Pirozek-Lawniczek, Kracker, Sprenger.

Statistical analysis: Burcklen, Hennessy, Scherz, Vaclavkova, Kracker.

Administrative, technical, or material support: Burcklen, Hennessy, D'Ambrosio, Pirozek-Lawniczek.

Supervision: Kappos, Burcklen, Hennessy, Pozzilli, Scherz, D'Ambrosio, Vaclavkova, Sprenger.

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.

Funding/Support: Funding was provided by Janssen Research & Development LLC, and the OPTIMUM study was supported by Actelion Pharmaceuticals, part of Janssen Pharmaceutical Companies.

Role of the Funder/Sponsor: Janssen Research & Development LLC and Actelion Pharmaceuticals, part of Janssen Pharmaceutical Companies, in collaboration with study investigators and the contracted clinical research organizations, were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Parts of the results of this study were presented as abstracts at the American Academy of Neurology Annual Meeting; April 25 to May 1, 2020; virtual; e-posters and e-presentations at the Sixth Congress of the European Academy of Neurology; May 23 to 26, 2020; virtual; and as an oral presentation at the European Committee for Treatment and Research in Multiple Sclerosis; September 11 to 13, 2019; Stockholm, Sweden.

Data Sharing Statement: See Supplement 3.

Additional Contributions: The authors thank the study participants without whom this study would not have been accomplished. The authors thank Lisa Ford, MD, a paid employee of Janssen Research & Development LLC, for her critical scientific and medical review and editorial contributions. Writing assistance was provided by Anupama Singh, CMPP, and Shweta Pitre, CMPP, SIRO Clinpharm Pvt Ltd, funded by Janssen Global Services. Additional editorial support was provided by Bradford Challis, PhD, and Robert Achenbach, Janssen Global Services LLC. These individuals were compensated.

Additional Information: See eAppendix 2, eTable 5, and eTable 6 in Supplement 1 for details on the independent data monitoring committee, ophthalmology safety board, major adverse cardiovascular event adjudication committee, MRI reading center, and investigators. In addition, the data-sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access Project site at https://yoda.yale.edu/.

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