Efficacy and safety of ponesimod compared to teriflunomide in patients with relapsing multiple sclerosis: results of the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study
ECTRIMS Online Library. Kappos L. 09/11/19; 279416; 93
Ludwig Kappos
Ludwig Kappos
Contributions
Abstract

Abstract: 93

Type: Scientific Session

Abstract Category: Therapy - Immunomodulation/Immunosuppression

L. Kappos1, M. Burcklen2, M. S Freedman3, R. Fox4, E.K. Havrdová5, B. Hennessy2, R. Hohlfeld6, F. Lublin7, X. Montalban8,9, C. Pozzilli10, T. Scherz2, P. Linscheid2, M. Pirozek-Lawniczek2, H. Kracker2, T. Sprenger11,12

1Departments of Medicine, Neurologic Clinical Research and Biomedical Engineering, University Hospital Basel, Basel, 2Actelion Pharmaceuticals, Allschwil, Switzerland, 3University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5Department of Neurology and Center for Clinical Neuroscience, Medical Faculty, Charles University, Prague, Czech Republic, 6Institute of Clinical Neuroimmunology, Munich, Germany, 7Icahn School of Medicine at Mount Sinai, New York, NY, United States, 8Division of Neurology, Toronto, BC, Canada, 9Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Barcelona, Spain, 10S. Andrea MS Centre, Rome, Italy, 11University Hospital Basel, Basel, Switzerland, 12DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany

Ponesimod is an orally active, selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1) that induces a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs thus reducing circulating lymphocyte counts. The OPTIMUM phase 3 study (NCT02425644) evaluates efficacy and safety of oral ponesimod vs. teriflunomide, an approved first-line oral medication, in adult patients with relapsing multiple sclerosis (RMS).The primary endpoint of the study is annualized relapse rate over 108 weeks. Secondary endpoints include effect on fatigue-related symptoms assessed with Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS), active lesions on MRI to Week 108, and time to 12- and 24-week disability accumulation to end-of-study. Safety and tolerability are assessed.
This multicenter, randomized, double-blind, parallel-group, active-controlled superiority study enrolled patients with established diagnosis of MS, as per 2010 McDonald criteria, with a relapsing course from onset and Expanded Disability Status Scale (EDSS) score of 0-5.5 inclusive and recent clinical or MRI disease activity. Patients were randomized (1:1) to receive either ponesimod 20 mg or teriflunomide 14 mg once-daily and the respective placebo for 108 weeks. The 14-day gradual up-titration regimen starting with 2 mg once-daily was implemented to mitigate potential effects on heart rate associated with S1P-receptor modulators.
In total, 1133 patients were randomized at 162 sites in 28 countries. Randomization was stratified by prior-disease modifying treatment in last two years (yes: 39.4%; no: 60.6%) and EDSS score at baseline (≤3.5: 83.4%; >3.5 16.6%). The mean age was 36.7 years and the majority (65%) were female. Most patients were recruited in Europe with 51% from EU countries. Mean baseline EDSS score was 2.6 and mean disease duration 7.6 years. Mean pre-study 12-month relapse rate was 1.3, and 483 (42.7%) patients had ≥1 gadolinium-enhancing T1 lesions on baseline MRI. The estimated study completion date is May 2019, and key efficacy and safety results will be available and presented at the meeting.
The results of this first large randomized controlled phase 3 study comparing two oral disease-modifying treatments across important clinical and MRI outcomes will help to determine the role of ponesimod, a selective S1P1 functional antagonist, as a potential treatment option in relapsing MS.
Disclosure: LK's Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, sanofi-aventis, Santhera, Teva, Vianex 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, the European Union and Roche Research Foundations.
MB, BH, PL, MPL and HK are employees of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson. BH holds stock in Johnson & Johnson, Novo Nordisk, Arena Pharmaceuticals and Galapagos. MB and HK hold stocks in Johnson & Johnson.
TSc is an employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson and a former employee of Novartis Pharma AG. TSc holds stock in Johnson & Johnson and Novartis.
MF has received honoraria from Actelion, Bayer Healthcare, Biogen Idec, Chugai, Clene Nanomedicine, EMD Canada, Genzyme, Hoffman La-Roche, MedDay, Merck Serono, Novartis, Sanofi-Aventis, Teva Canada Innovation, and research support from Genzyme.
RF has received honoraria from Actelion, Biogen, Genentech, Idec, Novartis, Teva, and research support from Biogen and Novartis.
EKH has received honoraria from Actelion, Biogen, Celgene, Merck, Novartis, Sanofi Genzyme and Teva.
RH has received honoraria from Actelion, Biogen, Genzyme-Sanofi, Novartis, Roche, and research support from Biogen, Genzyme-Sanofi, Novartis, Roche.
FL 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; GW Pharma.
XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, Excemed, MSIF i NMSS.
TSP's institution has received honoraria for speaking and consultation from Actelion, Biogen Idec, Desitin, Eli Lilly, Novartis, Sanofi Genzyme, Electrocore, Merck and Teva.
CP has served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, Actelion and funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion and Novartis, and research support from Biogen, Teva, Novartis and Genzyme.

Abstract: 93

Type: Scientific Session

Abstract Category: Therapy - Immunomodulation/Immunosuppression

L. Kappos1, M. Burcklen2, M. S Freedman3, R. Fox4, E.K. Havrdová5, B. Hennessy2, R. Hohlfeld6, F. Lublin7, X. Montalban8,9, C. Pozzilli10, T. Scherz2, P. Linscheid2, M. Pirozek-Lawniczek2, H. Kracker2, T. Sprenger11,12

1Departments of Medicine, Neurologic Clinical Research and Biomedical Engineering, University Hospital Basel, Basel, 2Actelion Pharmaceuticals, Allschwil, Switzerland, 3University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5Department of Neurology and Center for Clinical Neuroscience, Medical Faculty, Charles University, Prague, Czech Republic, 6Institute of Clinical Neuroimmunology, Munich, Germany, 7Icahn School of Medicine at Mount Sinai, New York, NY, United States, 8Division of Neurology, Toronto, BC, Canada, 9Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Barcelona, Spain, 10S. Andrea MS Centre, Rome, Italy, 11University Hospital Basel, Basel, Switzerland, 12DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany

Ponesimod is an orally active, selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1) that induces a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs thus reducing circulating lymphocyte counts. The OPTIMUM phase 3 study (NCT02425644) evaluates efficacy and safety of oral ponesimod vs. teriflunomide, an approved first-line oral medication, in adult patients with relapsing multiple sclerosis (RMS).The primary endpoint of the study is annualized relapse rate over 108 weeks. Secondary endpoints include effect on fatigue-related symptoms assessed with Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS), active lesions on MRI to Week 108, and time to 12- and 24-week disability accumulation to end-of-study. Safety and tolerability are assessed.
This multicenter, randomized, double-blind, parallel-group, active-controlled superiority study enrolled patients with established diagnosis of MS, as per 2010 McDonald criteria, with a relapsing course from onset and Expanded Disability Status Scale (EDSS) score of 0-5.5 inclusive and recent clinical or MRI disease activity. Patients were randomized (1:1) to receive either ponesimod 20 mg or teriflunomide 14 mg once-daily and the respective placebo for 108 weeks. The 14-day gradual up-titration regimen starting with 2 mg once-daily was implemented to mitigate potential effects on heart rate associated with S1P-receptor modulators.
In total, 1133 patients were randomized at 162 sites in 28 countries. Randomization was stratified by prior-disease modifying treatment in last two years (yes: 39.4%; no: 60.6%) and EDSS score at baseline (≤3.5: 83.4%; >3.5 16.6%). The mean age was 36.7 years and the majority (65%) were female. Most patients were recruited in Europe with 51% from EU countries. Mean baseline EDSS score was 2.6 and mean disease duration 7.6 years. Mean pre-study 12-month relapse rate was 1.3, and 483 (42.7%) patients had ≥1 gadolinium-enhancing T1 lesions on baseline MRI. The estimated study completion date is May 2019, and key efficacy and safety results will be available and presented at the meeting.
The results of this first large randomized controlled phase 3 study comparing two oral disease-modifying treatments across important clinical and MRI outcomes will help to determine the role of ponesimod, a selective S1P1 functional antagonist, as a potential treatment option in relapsing MS.
Disclosure: LK's Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, sanofi-aventis, Santhera, Teva, Vianex 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, the European Union and Roche Research Foundations.
MB, BH, PL, MPL and HK are employees of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson. BH holds stock in Johnson & Johnson, Novo Nordisk, Arena Pharmaceuticals and Galapagos. MB and HK hold stocks in Johnson & Johnson.
TSc is an employee of Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson & Johnson and a former employee of Novartis Pharma AG. TSc holds stock in Johnson & Johnson and Novartis.
MF has received honoraria from Actelion, Bayer Healthcare, Biogen Idec, Chugai, Clene Nanomedicine, EMD Canada, Genzyme, Hoffman La-Roche, MedDay, Merck Serono, Novartis, Sanofi-Aventis, Teva Canada Innovation, and research support from Genzyme.
RF has received honoraria from Actelion, Biogen, Genentech, Idec, Novartis, Teva, and research support from Biogen and Novartis.
EKH has received honoraria from Actelion, Biogen, Celgene, Merck, Novartis, Sanofi Genzyme and Teva.
RH has received honoraria from Actelion, Biogen, Genzyme-Sanofi, Novartis, Roche, and research support from Biogen, Genzyme-Sanofi, Novartis, Roche.
FL 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; GW Pharma.
XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, Excemed, MSIF i NMSS.
TSP's institution has received honoraria for speaking and consultation from Actelion, Biogen Idec, Desitin, Eli Lilly, Novartis, Sanofi Genzyme, Electrocore, Merck and Teva.
CP has served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, Actelion and funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion and Novartis, and research support from Biogen, Teva, Novartis and Genzyme.

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