Trial Outcomes & Findings for Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis (NCT NCT03232073)

NCT ID: NCT03232073

Last Updated: 2025-06-22

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

877 participants

Primary outcome timeframe

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

Results posted on

2025-06-22

Participant Flow

Total of 877 participants entered this extension study from the core study (NCT02425644) and all received at least one dose of ponesimod 20 milligrams (mg) treatment.

Efficacy data: presented for extension set (ES; who consented and had 1 dose of ponesimod in extension study) in combined analysis period (included all available data from randomization in core study up to extension end of study \[EOS\] for those who entered ES). Safety data: presented for ES in extension analysis period (included all available data collected on or after date of 1st intake of ponesimod in extension study, through last treatment date in extension study+15 days).

Participant milestones

Participant milestones
Measure	Ponesimod 20 mg (Core and Extension Study) Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Overall Study STARTED	439	438
Overall Study COMPLETED	352	371
Overall Study NOT COMPLETED	87	67

Reasons for withdrawal

Reasons for withdrawal
Measure	Ponesimod 20 mg (Core and Extension Study) Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Overall Study Death	1	0
Overall Study Adverse Event	7	12
Overall Study Lost to Follow-up	6	6
Overall Study Lack of Efficacy	10	8
Overall Study Physician Decision	9	2
Overall Study Withdrawal by Subject	54	39

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Total n=877 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	439 Participants n=93 Participants	438 Participants n=4 Participants	877 Participants n=27 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Continuous	36.5 years STANDARD_DEVIATION 8.75 • n=93 Participants	37.2 years STANDARD_DEVIATION 8.75 • n=4 Participants	36.8 years STANDARD_DEVIATION 8.75 • n=27 Participants
Sex: Female, Male Female	286 Participants n=93 Participants	290 Participants n=4 Participants	576 Participants n=27 Participants
Sex: Female, Male Male	153 Participants n=93 Participants	148 Participants n=4 Participants	301 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants n=93 Participants	17 Participants n=4 Participants	39 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	409 Participants n=93 Participants	411 Participants n=4 Participants	820 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=93 Participants	10 Participants n=4 Participants	18 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants
Race (NIH/OMB) White	429 Participants n=93 Participants	430 Participants n=4 Participants	859 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=93 Participants	6 Participants n=4 Participants	14 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Annualized Confirmed Relapse Rate (ARR)	0.143 relapses per patient-year Interval 0.123 to 0.167	0.184 relapses per patient-year Interval 0.158 to 0.213

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Time From Core Study Randomization to First Confirmed Relapse	402.71 Weeks Interval 82.29 to NA refers to data for inter-quartile upper limit which was not estimable to due to low number of events.	NA Weeks Interval 53.57 to NA refers to data for median and inter-quartile upper limit which were not estimable to due to low number of events.

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Time to First 12-week Confirmed Disability Accumulation (CDA)	NA Weeks NA refers to data for median, inter-quartile lower and upper limit which were not estimable to due to low number of events.	NA Weeks Interval 254.86 to NA refers to data for median and inter-quartile upper limit which were not estimable to due to low number of events.

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Time to First 24-week Confirmed Disability Accumulation (CDA)	NA Weeks NA refers to data for median, inter-quartile lower and upper limit which were not estimable to due to low number of events.	NA Weeks Interval 313.29 to NA refers to data for median and inter-quartile upper limit which were not estimable to due to low number of events.

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percentage of Participants With Absence of Relapses	56.7 Percentage of Participants	51.6 Percentage of Participants

PRIMARY outcome

Timeframe: 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

Population: The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=346 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=364 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change From Baseline in Expanded Disability Status Scale (EDSS)	0.16 Score on a scale Standard Deviation 1.008	0.34 Score on a scale Standard Deviation 1.105

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=436 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study	17.5 Percentage of Participants	7.5 Percentage of Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=437 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=435 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study	5.2 Percentage of Participants	2.3 Percentage of Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=196 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=193 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)	-2.52 Percent Change Standard Deviation 2.179	-2.72 Percent Change Standard Deviation 2.024

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=438 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=435 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI	1.352 CUAL per patient-year Interval 1.153 to 1.586	1.954 CUAL per patient-year Interval 1.667 to 2.291

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=350 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=347 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI	0.211 Gd+ T1 lesions Interval 0.131 to 0.341	0.395 Gd+ T1 lesions Interval 0.25 to 0.622

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=438 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=435 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Cumulative Number of New or Enlarging T2 Lesions Measured by MRI	1.352 Lesions per year Interval 1.152 to 1.586	1.951 Lesions per year Interval 1.664 to 2.287

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=347 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=348 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions) T2 Lesions	-435.7 cubic millimeters (mm^3) Standard Deviation 2822.71	91.5 cubic millimeters (mm^3) Standard Deviation 3647.08
Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions) T1 Hypointense Lesions	165.6 cubic millimeters (mm^3) Standard Deviation 1427.30	309.4 cubic millimeters (mm^3) Standard Deviation 1712.36

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=435 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions) T2 lesions	152 Participants	101 Participants
Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions) Gd+ T1 lesions	293 Participants	236 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=350 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=346 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)	22.3 Percentage of lesions	25.1 Percentage of lesions

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	411 Participants	410 Participants

PRIMARY outcome

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities	153 Participants	140 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=361 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=361 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate	67.4 Beats per minute (bpm) Standard Deviation 9.64	67.6 Beats per minute (bpm) Standard Deviation 9.33

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=361 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=361 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF PR Interval	150.0 millisecond (ms) Standard Deviation 20.41	153.3 millisecond (ms) Standard Deviation 20.27
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF QRS Duration	92.1 millisecond (ms) Standard Deviation 9.22	93.3 millisecond (ms) Standard Deviation 10.63
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF QT Interval	392.5 millisecond (ms) Standard Deviation 27.26	391.0 millisecond (ms) Standard Deviation 25.67
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF QTcB Interval	414.8 millisecond (ms) Standard Deviation 19.20	413.8 millisecond (ms) Standard Deviation 19.66
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF QTcF Interval	406.9 millisecond (ms) Standard Deviation 17.78	405.7 millisecond (ms) Standard Deviation 17.78

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=361 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=361 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in Heart Rate (HR) From Baseline up to End of Study Treatment	-1.7 beats per minute (bpm) Standard Deviation 10.00	-1.5 beats per minute (bpm) Standard Deviation 9.17

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=361 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=361 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment PR Interval	0.5 millisecond (ms) Standard Deviation 14.09	2.0 millisecond (ms) Standard Deviation 14.37
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment QRS Duration	-0.4 millisecond (ms) Standard Deviation 6.79	2.9 millisecond (ms) Standard Deviation 6.88
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment QT Interval	7.8 millisecond (ms) Standard Deviation 25.68	8.9 millisecond (ms) Standard Deviation 21.66
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment QTcB Interval	2.9 millisecond (ms) Standard Deviation 16.75	5.2 millisecond (ms) Standard Deviation 17.07
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment QTcF Interval	4.6 millisecond (ms) Standard Deviation 15.28	6.5 millisecond (ms) Standard Deviation 14.18

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=315 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=327 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values FEV1	3.01 Liters (L) Standard Deviation 0.768	3.08 Liters (L) Standard Deviation 0.797
Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values FVC	-3.96 Liters (L) Standard Deviation 0.965	4.04 Liters (L) Standard Deviation 1.031

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=315 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=327 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%) FEV1	-7.96 Percent change Standard Deviation 13.356	-6.75 Percent change Standard Deviation 12.323
Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%) FVC	-5.09 Percent change Standard Deviation 11.793	-3.93 Percent change Standard Deviation 12.141

PRIMARY outcome

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	56 Participants Interval 0.442 to	57 Participants Interval 0.38 to

PRIMARY outcome

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Non-skin malignancy	4 Participants	3 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Bradyarrhythmia occurring post-first dose	11 Participants	13 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Severe liver injury	5 Participants	5 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Bronchoconstriction	31 Participants	25 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Macular edema	4 Participants	6 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Serious opportunistic infections including PML	2 Participants	1 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Skin cancer	4 Participants	3 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Unexpected neurological or psychiatric symptoms / signs (PRES, ADEM, atypical MS relapses)	1 Participants	2 Participants
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs) Convulsions	2 Participants	3 Participants

PRIMARY outcome

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=439 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With AE Leading to Premature Discontinuation of Study Treatment	34 Participants	41 Participants

PRIMARY outcome

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).

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=424 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=423 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC FEV1: >20 %	80 Participants	82 Participants
Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC FEV1: >30 %	18 Participants	21 Participants
Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC FVC: >20 %	54 Participants	60 Participants
Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC FVC: >30 %	19 Participants	15 Participants

PRIMARY outcome

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).

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=423 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=423 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline FEV1: >20 %	70 Participants	68 Participants
Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline FVC: >20 %	59 Participants	57 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=315 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=327 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT) FEV1	-7.14 Percentage predicted change Standard Deviation 13.315	-5.43 Percentage predicted change Standard Deviation 11.839
Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT) FVC	-4.70 Percentage predicted change Standard Deviation 13.129	-3.19 Percentage predicted change Standard Deviation 13.081

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=288 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=299 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS) FEV1	-5.95 Percentage predicted change Standard Deviation 12.854	-4.08 Percentage predicted change Standard Deviation 14.365
Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS) FVC	-4.48 Percentage predicted change Standard Deviation 13.727	-1.98 Percentage predicted change Standard Deviation 15.747

PRIMARY outcome

Timeframe: 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

Population: The DL\[CO\] sub-study extension set included all participants in the extension set who have consented to participate in the DL\[CO\] sub-study during the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=65 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=53 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline	0.7 Millimoles/minute/kilopascal Standard Deviation 3.44	0.1 Millimoles/minute/kilopascal Standard Deviation 4.17

PRIMARY outcome

Timeframe: 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

Population: The DL\[CO\] sub-study extension set includes all participants in the extension set who have consented to participate in the DL\[CO\] sub-study during the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=50 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=41 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in DL[CO] (% Predicted) From Baseline to EOT	5.7 Percentage predicted DL[CO] Standard Deviation 32.20	-9.4 Percentage predicted DL[CO] Standard Deviation 7.82

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=39 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=35 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Change in DL[CO] (% Predicted) From Baseline to EOS	9.3 Percentage predicted DL[CO] Standard Deviation 39.38	2.2 Percentage predicted DL[CO] Standard Deviation 49.50

OTHER_PRE_SPECIFIED outcome

Timeframe: 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])

Population: Population analysis included numbers of participants based on sub-set of extension set who had a re-initiation. Here, 'n' (number analyzed) is defined as participants analyzed at specified timepoints.

Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: heart rate were reported.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=30 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=40 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate 3 hours Post-dose	64.6 beats per minute (bpm) Standard Deviation 9.33	67.8 beats per minute (bpm) Standard Deviation 10.71
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate 4 hours Post-dose	66.0 beats per minute (bpm) Standard Deviation 9.73	67.6 beats per minute (bpm) Standard Deviation 10.01
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate Predose	68.1 beats per minute (bpm) Standard Deviation 8.73	71.0 beats per minute (bpm) Standard Deviation 9.21
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate 1 hour Post-dose	66.5 beats per minute (bpm) Standard Deviation 10.53	69.0 beats per minute (bpm) Standard Deviation 10.13
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate 2 hours Post-dose	64.3 beats per minute (bpm) Standard Deviation 9.91	65.1 beats per minute (bpm) Standard Deviation 8.68

OTHER_PRE_SPECIFIED outcome

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.

Outcome measures

Outcome measures
Measure	Ponesimod 20 mg (Core and Extension Study) n=30 Participants Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=40 Participants Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcF Interval: 4 hours Post-dose	411.5 millisecond (ms) Standard Deviation 18.36	398.5 millisecond (ms) Standard Deviation 18.27
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF PR Interval: Predose	152.8 millisecond (ms) Standard Deviation 17.66	149.8 millisecond (ms) Standard Deviation 19.13
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF PR Interval: 1 hour Post-dose	150.5 millisecond (ms) Standard Deviation 17.25	152.6 millisecond (ms) Standard Deviation 22.66
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF PR Interval: 2 hours Post-dose	150.1 millisecond (ms) Standard Deviation 16.60	153.6 millisecond (ms) Standard Deviation 23.51
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF PR Interval: 3 hours Post-dose	152.3 millisecond (ms) Standard Deviation 17.73	154.5 millisecond (ms) Standard Deviation 21.91
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF PR Interval: 4 hours Post-dose	150.7 millisecond (ms) Standard Deviation 17.82	151.8 millisecond (ms) Standard Deviation 19.68
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QRS Duration: Predose	94.6 millisecond (ms) Standard Deviation 11.06	91.5 millisecond (ms) Standard Deviation 7.03
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QRS Duration: 1 hour Post-dose	95.2 millisecond (ms) Standard Deviation 11.42	93.2 millisecond (ms) Standard Deviation 8.72
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QRS Duration: 2 hours Post-dose	93.9 millisecond (ms) Standard Deviation 11.71	92.7 millisecond (ms) Standard Deviation 7.57
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QRS Duration: 3 hours Post-dose	94.5 millisecond (ms) Standard Deviation 11.60	94.5 millisecond (ms) Standard Deviation 7.80
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QRS Duration: 4 hours Post-dose	94.7 millisecond (ms) Standard Deviation 10.48	92.5 millisecond (ms) Standard Deviation 7.35
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QT Interval: Predose	391.5 millisecond (ms) Standard Deviation 24.80	378.8 millisecond (ms) Standard Deviation 23.61
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QT Interval: 1 hour Post-dose	396.7 millisecond (ms) Standard Deviation 28.76	380.9 millisecond (ms) Standard Deviation 21.78
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QT Interval: 2 hours Post-dose	402.0 millisecond (ms) Standard Deviation 29.00	386.0 millisecond (ms) Standard Deviation 19.62
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QT Interval: 3 hours Post-dose	400.2 millisecond (ms) Standard Deviation 27.78	386.9 millisecond (ms) Standard Deviation 21.38
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QT Interval: 4 hours Post-dose	400.0 millisecond (ms) Standard Deviation 27.49	383.9 millisecond (ms) Standard Deviation 23.14
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcB Interval: Predose	416.2 millisecond (ms) Standard Deviation 19.05	411.4 millisecond (ms) Standard Deviation 20.85
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcB Interval: 1 hour Post-dose	416.0 millisecond (ms) Standard Deviation 24.11	407.6 millisecond (ms) Standard Deviation 22.96
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcB Interval: 2 hours Post-dose	414.8 millisecond (ms) Standard Deviation 22.83	401.7 millisecond (ms) Standard Deviation 20.88
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcB Interval: 3 hours Post-dose	414.2 millisecond (ms) Standard Deviation 23.30	410.1 millisecond (ms) Standard Deviation 22.33
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcB Interval: 4 hours Post-dose	418.0 millisecond (ms) Standard Deviation 20.30	406.6 millisecond (ms) Standard Deviation 22.33
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcF Interval: Predose	407.4 millisecond (ms) Standard Deviation 17.09	400.0 millisecond (ms) Standard Deviation 18.69
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcF Interval: 1 hour Post-dose	409.2 millisecond (ms) Standard Deviation 20.58	398.1 millisecond (ms) Standard Deviation 18.22
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcF Interval: 2 hours Post-dose	410.1 millisecond (ms) Standard Deviation 20.41	396.2 millisecond (ms) Standard Deviation 16.61
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF QTcF Interval: 3 hours Post-dose	409.0 millisecond (ms) Standard Deviation 20.97	402.0 millisecond (ms) Standard Deviation 16.82

Adverse Events

Ponesimod 20 mg (Core and Extension Study)

Serious events: 56 serious events

Other events: 339 other events

Deaths: 1 deaths

Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Serious events: 57 serious events

Other events: 328 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Associate Director Clinical Sciences Neuro

Actelion Pharmaceuticals Ltd

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days to allow for filing of a patent application.
Publication restrictions are in place

Restriction type: OTHER

Measure	Ponesimod 20 mg (Core and Extension Study) n=439 participants at risk Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) n=438 participants at risk Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.
Investigations Aspartate Aminotransferase Increased	3.9% 17/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	5.9% 26/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Blood and lymphatic system disorders Leukopenia	4.1% 18/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	5.3% 23/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Blood and lymphatic system disorders Lymphopenia	15.0% 66/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	14.6% 64/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Gastrointestinal disorders Diarrhoea	5.0% 22/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	3.4% 15/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
General disorders Fatigue	5.5% 24/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	6.8% 30/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Infections and infestations Covid-19	26.2% 115/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	24.7% 108/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Infections and infestations Nasopharyngitis	18.7% 82/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	16.9% 74/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Infections and infestations Respiratory Tract Infection	5.2% 23/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	3.4% 15/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Infections and infestations Upper Respiratory Tract Infection	10.7% 47/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	11.6% 51/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Infections and infestations Urinary Tract Infection	8.2% 36/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	7.5% 33/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Investigations Alanine Aminotransferase Increased	16.6% 73/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	22.4% 98/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Investigations Lymphocyte Count Decreased	6.8% 30/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	6.8% 30/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Musculoskeletal and connective tissue disorders Arthralgia	7.1% 31/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	8.7% 38/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Musculoskeletal and connective tissue disorders Back Pain	10.3% 45/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	6.8% 30/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Nervous system disorders Dizziness	5.0% 22/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	3.9% 17/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Nervous system disorders Headache	13.0% 57/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	14.6% 64/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.
Vascular disorders Hypertension	8.4% 37/439 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.	10.0% 44/438 • 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 The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.