Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis

The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study (core study). The core study has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with RMS. The subjects are treated with either ponesimod or the active comparator, teriflunomide in the core study. The purpose of this long term extension of the core study is to characterize the long-term safety and control of disease of ponesimod in subjects with RMS. In particular, the study will allow to observe potential adverse events which may only occur after long term treatment with ponesimod. The study will also investigate the effect of re-initiation of ponesimod after a brief interruption in a relatively large population (all subjects treated with ponesimod in the core study and eligible for the extension study) on disease activity in terms of relapses and MS-related MRI lesions. There is currently limited guidance on when a new MS treatment should be started after discontinuation of teriflunomide and the study will contribute with data on safety and efficacy of switching from teriflunomide to ponesimod after an interruption as mandated by the protocol. The study will also allow confirmation of sustained efficacy of ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during long-term treatment. In addition, combined data from the core study together with the results of the current extension study will allow comparison of MS activity in subjects who were switched from teriflunomide to ponesimod versus those who were treated with ponesimod in both studies.

• Ponesimod (Drug): Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15

Primary outcomes

• Annualized Confirmed Relapse Rate (ARR) [From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: ARR: number of confirmed relapses per patient-year. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours, in the absence of fever or infection. A confirmed relapse is identified when a patient's symptoms worsen as indicated by an increase in their Expanded Disability Status Scale (EDSS) or Functional Systems (FS) scores, consistent with previous clinically stable assessments. Specific criteria for a confirmed relapse include: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0 (normal)-10 (death due to MS).
• Time From Core Study Randomization to First Confirmed Relapse [From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: Time to first confirmed relapse: date of first confirmed relapse (in either core or extension study) minus date of randomization in core study+1 day. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse are: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS).
• Time to First 12-week Confirmed Disability Accumulation (CDA) [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of randomization in the core study + 1 day. A 12-week CDA is defined as a 12-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 12-weeks. CDA is defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score >=5.5, confirmed after 12 weeks. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
• Time to First 24-week Confirmed Disability Accumulation (CDA) [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: Time to first 24-week CDA was defined as start date of the first 24-week CDA minus date of randomization in the core study + 1 day. A 24-week CDA was defined as a 24-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 24-weeks. CDA was defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score >=5.5, confirmed after 24 weeks. EDSS was an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
• Percentage of Participants With Absence of Relapses [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
• Change From Baseline in Expanded Disability Status Scale (EDSS) [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: EDSS is ordinal clinical rating scale based on standard neurological examination for assessing neurological disability and impairment in MS. Seven FS scores were rated on a scale ranged from 0 to 5 or 6 to assess visual, brain, stem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral functions while ambulation was scored on scale ranged from 0 to 12 to assess walking distance and assistance. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS) in 0.5 unit increments that represented higher levels of disability. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
• Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: NEDA-3 up to extension EOS is defined by the absence of confirmed relapse, gadolinium-enhancing (Gd+ T1) lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-3. Confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
• Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: NEDA-4 up to EOS is defined by the absence of confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA until EOS, and absence of annual brain volume decrease >=0.4% from core baseline up to extension EOS. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-4. Confirmed relapse: when patient's symptoms worsen by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in core study for each outcome measure and each participant individually.
• Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI) [From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months]: Percent change from baseline in brain volume (PCBV) measured by MRI were reported. Normalized Brain Volume at core baseline was measured in cubic centimeter (cm\^3). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
• Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: CUALs was calculated as sum of new T1 Gadolinium-enhanced (Gd+) lesions and new or enlarging T2 lesions (without double-counting of lesions) from baseline up to extension EOS based on the Magnetic resonance imaging (MRI). Average number of lesions per patient-year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
• Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI [From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months]: Number of Gd+ T1 lesions measured by MRI were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. For this outcome measure, results presented here are for the Extension end-of-treatment visit.
• Cumulative Number of New or Enlarging T2 Lesions Measured by MRI [From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months]: Cumulative number of new or enlarging T2 lesions measured by MRI were reported. Average number of lesions per year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
• Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions) [From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months]: Change from baseline in volume of MRI lesions (T2 lesions, T1 hypointense lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
• Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions) [From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months]: Number of participants with absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
• Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs) [From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months]: Percentage of Gd+ lesions at baseline evolving to PBHs were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with TEAEs were reported. An AE is any untoward medical event that occurs in a participants being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.
• Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with treatment-emergent new morphological ECG abnormalities were reported. Treatment-emergent new morphological ECG abnormalities are defined as those ECG abnormalities occurring from start of treatment up to treatment end date + 15 days.
• Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate [From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Actual values of 12-lead ECG measurements up to end of study treatment: heart rate were reported. In this outcome measure, results were presented for extension end of treatment visit.
• Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF [From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Actual values of 12-lead ECG measurements up to end of study treatment: PR, QRS, QT, QTcB, QTcF were reported. In this outcome measure, results were presented for extension end of treatment visit.
• Change in Heart Rate (HR) From Baseline up to End of Study Treatment [From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Change in heart rate (HR) from baseline up to end of study treatment were reported.
• Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment [From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Change in PR, QRS, QT, QTcB, QTcF from baseline up to end of study treatment were reported.
• Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values [From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Absolute values in FEV1 and FVC values were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Results are presented for extension end of treatment visit.
• Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%) [From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Percent change in FEV1 and FVC from baseline (%) were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. In this outcome measure, results were presented for extension end of treatment visit.
• Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with treatment-emergent SAEs were reported. A SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, or was an important medical event. Treatment-emergent SAEs are defined as SAEs occurring from start of treatment up to treatment end date + 15 days.
• Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with treatment-emergent AESIs were reported. AESIs included bradyarrhythmia occurred post-first dose, macular edema, bronchoconstriction, severe liver injury, serious opportunistic infections including progressive multifocal leukoencephalopathy (PML), skin cancer, non-skin malignancy, convulsions, unexpected neurological or psychiatric symptoms/signs (posterior reversible encephalopathy syndrome \[PRES\], acute disseminated encephalomyelitis \[ADEM\], and atypical MS relapses). Treatment-emergent AESIs are defined as AESIs occurring from start of treatment up to treatment end date + 15 days.
• Number of Participants With AE Leading to Premature Discontinuation of Study Treatment [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with AE leading to premature discontinuation of study treatment were reported. An AE is any untoward medical event that occurs in a participant being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.
• Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with treatment-emergent decrease from baseline >20% and >30% in FEV1 or FVC were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).
• Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline [From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days]: Number of participants with treatment-emergent decrease of >20% points in percent predicted FEV1 and FVC from baseline were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).
• Number of Participants With a Decrease of >=200 mL or >=12% in FEV1 or FVC From Baseline to EOT [From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Number of participants with a decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT were planned to be reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. This endpoint is not relevant as a substantial proportion of patients continued onto post-treatment disease-modifying therapy (DMT), hence it cannot provide an assessment of reversibility.
• Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT) [From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Change in FEV1 and FVC (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
• Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS) [From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months]: Change in FEV1 and FVC (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
• Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline [From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months]: Absolute change in lung diffusion capacity as assessed by DL\[CO\] from baseline were reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
• Change in DL[CO] (% Predicted) From Baseline to EOT [From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months]: Change in DL\[CO\] (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
• Change in DL[CO] (% Predicted) From Baseline to EOS [From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months]: Change in DL\[CO\] (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Other outcomes

• Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate [Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])]: Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: heart rate were reported.
• Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF [Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])]: Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: PR, QRS, QT, QTcB, QTcF were reported.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Signed informed consent
2. Subjects with MS having completed the double-blind treatment in the core study as scheduled
3. Compliance with teriflunomide elimination procedure
4. Women of childbearing potential (WOCBP) must have a negative pre-treatment urine pregnancy test, must agree to undertake 4-weekly urine pregnancy tests, and must have been using reliable methods of contraception. Fertile male subjects participating in the study must agree to use a condom.

Exclusion Criteria:

1. Any of the following cardiovascular conditions on Day 1 pre-dose:

   1. Resting heart rate (HR) < 50 bpm;
   2. Presence of second degree atrioventricular (AV) block or third degree AV block or a QTcF interval > 470 ms (females), > 450 ms (males);
2. Any of the following alerts from central laboratory at Visit 14 of the core study (EOT) which was confirmed as an alert at repeated testing or not repeated prior to FU1 of the core study:

   1. Lymphocyte count: < 0.2 x 109/L;
   2. Neutrophil count <1.0 × 109/L;
   3. Platelet count < 50 × 109/L;
   4. Creatinine clearance < 30 mL/min
3. At Visit 14 of the core study (EOT) >30% decrease from core study baseline FEV1 and/or FVC;
4. Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior to first dosing in the extension study.
5. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of the extension study.
6. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or abbreviated visit FU2, or on Day 1 of the extension study pre-dose:

   1. Suspected opportunistic infection of the CNS or any other infection which, in the opinion of the investigator, contraindicates re-start of the study drug;
   2. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms.
7. Need for and intention to administer forbidden study treatment-concomitant therapy
8. Women who are pregnant or lactating.
9. Male subjects wishing to parent a child;
10. Treatment with any MS Disease Modifying Therapies;
11. Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the subject at risk by participating in the study;
12. Subjects unlikely to comply with the extension study protocol based on investigator best judgment

Participant flow

Outcome results

• Annualized Confirmed Relapse Rate (ARR) (Primary), Mean, relapses per patient-year: Ponesimod 20 mg (Core and Extension Study) 0.143 (0.123 to 0.167); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 0.184 (0.158 to 0.213)
• Time From Core Study Randomization to First Confirmed Relapse (Primary), Median, Weeks: Ponesimod 20 mg (Core and Extension Study) 402.71 (82.29 to NA); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) NA (53.57 to NA)
• Time to First 12-week Confirmed Disability Accumulation (CDA) (Primary), Median, Weeks: Ponesimod 20 mg (Core and Extension Study) NA (NA to NA); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) NA (254.86 to NA)
• Time to First 24-week Confirmed Disability Accumulation (CDA) (Primary), Median, Weeks: Ponesimod 20 mg (Core and Extension Study) NA (NA to NA); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) NA (313.29 to NA)
• Percentage of Participants With Absence of Relapses (Primary), Number, Percentage of Participants: Ponesimod 20 mg (Core and Extension Study) 56.7; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 51.6
• Change From Baseline in Expanded Disability Status Scale (EDSS) (Primary), Mean, Score on a scale: Ponesimod 20 mg (Core and Extension Study) 0.16 +/- 1.008; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 0.34 +/- 1.105
• Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study (Primary), Number, Percentage of Participants: Ponesimod 20 mg (Core and Extension Study) 17.5; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 7.5
• Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study (Primary), Number, Percentage of Participants: Ponesimod 20 mg (Core and Extension Study) 5.2; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 2.3
• Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI) (Primary), Mean, Percent Change: Ponesimod 20 mg (Core and Extension Study) -2.52 +/- 2.179; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) -2.72 +/- 2.024
• Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI (Primary), Mean, CUAL per patient-year: Ponesimod 20 mg (Core and Extension Study) 1.352 (1.153 to 1.586); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 1.954 (1.667 to 2.291)
• Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI (Primary), Mean, Gd+ T1 lesions: Ponesimod 20 mg (Core and Extension Study) 0.211 (0.131 to 0.341); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 0.395 (0.250 to 0.622)
• Cumulative Number of New or Enlarging T2 Lesions Measured by MRI (Primary), Mean, Lesions per year: Ponesimod 20 mg (Core and Extension Study) 1.352 (1.152 to 1.586); Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 1.951 (1.664 to 2.287)
• Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions) (Primary), Mean, cubic millimeters (mm^3): Ponesimod 20 mg (Core and Extension Study) -435.7 +/- 2822.71; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 91.5 +/- 3647.08
• Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions) (Primary), Count of participants, Participants: Ponesimod 20 mg (Core and Extension Study) 293; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 236
• Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs) (Primary), Number, Percentage of lesions: Ponesimod 20 mg (Core and Extension Study) 22.3; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 25.1
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Ponesimod 20 mg (Core and Extension Study) 411; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 410
• Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities (Primary), Count of participants, Participants: Ponesimod 20 mg (Core and Extension Study) 153; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 140
• Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate (Primary), Mean, Beats per minute (bpm): Ponesimod 20 mg (Core and Extension Study) 67.4 +/- 9.64; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 67.6 +/- 9.33
• Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF (Primary), Mean, millisecond (ms): Ponesimod 20 mg (Core and Extension Study) 150.0 +/- 20.41; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) 153.3 +/- 20.27
• Change in Heart Rate (HR) From Baseline up to End of Study Treatment (Primary), Mean, beats per minute (bpm): Ponesimod 20 mg (Core and Extension Study) -1.7 +/- 10.00; Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) -1.5 +/- 9.17
• 16 more outcome measures not shown.

Adverse events

Time frame: Serious and Other AEs:From treatment start in extension study to EOT+15 days in extension study. Actual time varied till 71.8 months+15 days; All-cause mortality:From extension study baseline to EOS in extension study. Actual time varied till 73.2 months

Serious adverse events by term

71 more terms not shown.

Other adverse events by term

Limitations and caveats: Due to limited availability of COVID-19 vaccine-naïve MS patients, the COVID-19 vaccination sub-study was cancelled and removed from the protocol after implementation of amendment 5.

48 more sites not listed.

• Study Protocol (PDF, 2022-03-15)
• Statistical Analysis Plan (PDF, 2024-03-04)

• Tatiana Sidorenko, MD, PhD, Study director, Actelion

NIH grants: 2016