METHODS OF TREATING MULTIPLE SCLEROSIS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/254,369, filed October 11, 2021, the disclosure of which is incorporated by reference herein. TECHNICAL FIELD [0002] The present disclosure relates to methods of treating multiple sclerosis. BACKGROUND [0003] Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system affecting approximately 2.5 million people worldwide. The disease is clinically perceived by relapses and progressive loss of neurological function, primarily attributed to demyelination, axonal loss, and gliosis culminating in long-term multifocal sclerotic plaques in the brain and spinal cord leading to neurological impairment and severe disability. The two main subtypes of MS are relapsing forms of MS (RMS) which represent 85% of MS patients and include relapsing-remitting disease (RRMS), clinically isolated syndrome, and active secondary progressive disease; and primary progressive MS (PPMS) which affects only 15% of MS patients. [0004] Relapses are defined as newly appearing neurological symptoms in the absence of fever or infections that last for more than 24 hours. Relapses may fully recover over days or weeks or lead to persistent residual deficits and accumulation of disability. [0005] The natural history of MS is usually divided into two partially overlapping phases, a predominantly inflammatory phase and a predominantly degenerative phase: after an initial phase of relapsing remitting MS, driven by inflammatory mechanism, patients experience a secondary progressive MS characterized by continuous worsening of symptoms independent of the occurrence of relapses, the degenerative phase of MS. Most currently available disease-modifying treatments (DMTs) address the inflammatory phase of MS and are less efficacious in the degenerative phase. [0006] Current medical practice encourages early intervention with disease-modifying treatments, with the intent of optimizing long-term clinical outcomes. [0007] Key objectives in the management of MS are reducing the rate of relapses and preventing or at least delaying disease progression. Most of the disease-modifying drugs approved for MS have to be administered by injection or infusion (subcutaneous [s.c.], intramuscular [i.m.], or intravenous [i.v.] route). Recently, new disease-modifying drugs administered orally have been approved for RMS. [0008] The following injectable drugs have been approved in at least one country for the treatment of MS: • Interferon (IFN) β-1a 30 mcg i.m. once weekly (Avonex®) • IFN β-1a 22 or 44 mcg s.c.3 times weekly (Rebif®) • IFN β-1b 250 mcg s.c. every other day (Betaferon®, Extavia®) • Pegylated IFN β-1a 125 mcg subcutaneously every 2 weeks (Plegridy®) • Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg subcutaneously 3 times weekly (Copaxone®) • Glatiramer acetate 20 mg s.c. o.d. (Glatopa®) • Natalizumab 300 mg i.v. every 4 weeks (Tysabri®) • Mitoxantrone i.v. every 3 months (Novantrone®) • Alemtuzumab concentrate for solution for infusion, 12 mg alemtuzumab in 1.2 mL (10 mg/mL) (Lemtrada®) [0009] Several oral drugs have also been approved for MS: • Fingolimod 0.5 mg orally o.d. (Gilenya®) • Teriflunomide 7 mg, 14 mg o.d. (Aubagio®) • Dimethyl fumarate (BG-12) gastro-resistant hard capsules 120/240 mg twice daily (Tecfidera®) • Cladribine 40 to 100 mg orally per treatment week (Mavenclad®) [0010] Sphingosine-1-phosphate (S1P) plays a central role in lymphocyte trafficking. S1P is synthesized and secreted by many cell types, including platelets, erythrocytes, and mast cells, and elicits a variety of physiological responses. Lymphocyte egress from primary and secondary lymphoid organs is dependent on the S1P1 receptor. S1P1 receptor modulators block lymphocyte migration out of lymphoid tissue into the lymphatic and vascular circulation, thereby reducing peripheral lymphocyte counts and preventing lymphocyte recruitment to sites of inflammation. Following withdrawal of an S1P1 receptor agonist, the functional lymphocytes return to the circulation from their sites of sequestration. Other functions that do not rely on homing mechanisms, such as antibody generation by B lymphocytes, first-line immunological protection by granulocytes and monocytes, and antigen-dependent T-cell activation and expansion, are not affected by this mechanism. [0011] S1P itself induces pleiotropic effects, which are mediated by a family of five G protein-coupled receptors, S1P1-S1P5, located on endothelial cells, vascular and cardiac smooth muscle cells, and cardiac myocytes. The first S1P receptor modulator, fingolimod (FTY720, Gilenya®), which has been approved by the FDA and the EMA for the treatment of MS, is not selective for the S1P1 receptor but interacts with S1P3, S1P4, and S1P5. [0012] Ponesimod, an iminothiazolidinone derivative, is an orally active, selective modulator of the S1P1 that induces a rapid, dose-dependent, and reversible reduction in peripheral blood lymphocyte count by blocking the egress of lymphocytes from lymphoid organs. T and B cells are most sensitive to ponesimod mediated sequestration. In contrast, monocyte, natural killer (NK) cell and neutrophil counts are not reduced by ponesimod. Ponesimod is commercially available as PONVORY™, a once-daily oral medication. In the United States the Food and Drug Administration (FDA) has approved PONVORY™ to treat adults with relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. [0013] In the pharmaceutical industry, the path from drug discovery to reaching an approved product is riddled with uncertainty. That path is one that since 2010 and out of more than 12,000 clinical studies, there is very low likelihood of regulatory approval of less than 10% (from Phase 1 to approval). The final path to approval is also not a certainty nor inevitable as failures continue as late as from Phase 3 to approval. This is not only due to the high unpredictability and uncertainty regarding how a pharmaceutical product will impact human biology, but often human behavior is unpredictable in how data is interpreted by regulatory agencies and whether the data warrants approving a study drug as an approved product for use in commerce. SUMMARY [0014] The disclosure relates to a pharmaceutical product comprising ponesimod, wherein the pharmaceutical product is packaged, and wherein the package includes a label that identifies ponesimod as an approved product for the treatment of multiple sclerosis. In some embodiments, the patient’s multiple sclerosis is relapsing multiple sclerosis. In other embodiments, the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease. [0015] The disclosure provides methods for treating multiple sclerosis in a patient in need thereof, comprising administering an approved product comprising ponesimod in an amount and manner that is described in a drug product label for the approved product and/or in a treatment regimen described herein. [0016] The disclosure also provides methods of selling an approved product comprising ponesimod, said method comprising selling such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating a patient with multiple sclerosis. [0017] The disclosure further provides methods of offering for sale a drug product comprising ponesimod, said method comprising offering for sale such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating a patient with multiple sclerosis. [0018] The disclosure further provides methods for reducing clinical management events and/or for easing use of drug treatment for treating multiple sclerosis in a patient in need thereof, comprising administering ponesimod in an amount and manner that is described in a drug product label for an approved product and/or in a treatment regimen described herein, namely administration of about 20 mg of ponesimod orally once daily, with or without utilization of the up-titration dosing procedure also described herein. [0019] The disclosure is also directed to an approved drug product as defined herein, wherein the pharmaceutical product comprises ponesimod in tablet form. [0020] The disclosure also provides methods for concomitant treatment of a beta-blocker and ponesimod in a patient in need thereof, wherein the patient is being treated with the beta- blocker and ponesimod treatment is to be initiated, and wherein the patient has a resting heart rate of greater than 55 beats per minute during treatment with the beta-block and prior to initiation of ponesimod, comprising administering ponesimod without interruption to the beta-blocker treatment. [0021] In other embodiments, the disclosure is directed to methods for concomitant treatment of a beta-blocker and ponesimod for a patient in need thereof, wherein the patient is being treated with the beta-blocker and ponesimod treatment is to be initiated, and wherein the patient has a resting heart rate of less than or equal to 55 beats per minute during treatment with the beta-block and prior to initiation of ponesimod, comprising interrupting the beta-blocker treatment until the patient’s heart rate is greater than 55 beats per minute and initiating ponesimod treatment in a titration regimen comprising administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14, followed by administering a 20 mg maintenance dose of ponesimod once daily thereafter, and reinitiating the beta-blocker after ponesimod has been up-titrated to the maintenance dosage. [0022] The disclosure also relates to methods of treating multiple sclerosis in a patient in need thereof, wherein the patient has sinus bradycardia, first or second degree AV block, or a history of myocardial infarction or heart failure occurring more than 6 months prior to the initiation of ponesimod treatment, comprising administering an effective regimen of ponesimod to the patient, wherein after a first dose of the ponesimod, the patient is monitored for a period of 4 hours for symptoms of bradycardia. In other embodiments, no first dose monitoring is needed wherein the patient has no sinus bradycardia, no first or second degree AV block, and no history of myocardial infarction or heart failure occurring more than 6 months prior to the initiation of ponesimod treatment. [0023] The disclosure further provides methods of reinitiating treatment with ponesimod following a missed dose in a patient in need thereof, wherein the patient is being treated with an oral, once daily 20 mg maintenance dose and fewer than four consecutive maintenance doses have been missed, comprising resuming treatment with the maintenance dose. [0024] In other embodiments, the disclosure is directed to methods of reinitiating ponesimod following a missed dose for a patient in need thereof, wherein the patient is being treated with an oral, once daily 20 mg maintenance dose or a 14-day titration regimen comprising administering orally once daily titration doses of 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14, and four or more consecutive maintenance doses or titration doses have been missed, comprising reinitiating ponesimod with the 14-day titration regimen. BRIEF DESCRIPTION OF THE DRAWINGS [0025] Fig.1 shows the testing strategy for the study described in Example 1. [0026] Fig.2A shows an overview of primary and main supplementary analyses of relapses (Forest plot with 99% CL). In Fig.2A, n(Pon) = No. of subjects in ponesimod arm; rate(Pon) = mean rate in ponesimod arm; n(Ter) = No. of subjects in teriflunomide arm; and rate(Ter) = mean rate in teriflunomide arm. * = Conducted on the Per Protocol Set; ** = Relapses with missing EDSS are imputed as confirmed relapses. Fig.2B shows the conceptual framework for the Fatigue Symptoms and Impact Questionnaire – Relapsed Multiple Sclerosis (FSIQ- RMS); * = items also present in physical impacts subdomain. [0027] Fig.3A shows change from baseline up to week 108 for the FSIQ-RMS weekly symptoms score by visit. MMRM (Main analysis) Analysis Set: Full Analysis Set. In Fig. 3A, subjects with available baseline and at least one post-baseline result are included in the analysis, whereby MMRM = mixed effects repeated measurements model with unstructured covariance, treatment, visit, treatment by visit interaction, baseline by visit interaction as fixed effects, baseline FSIQ score, EDSS strata (<=3.5,>3.5), DMT in last 2 years prior randomization strata (Y,N) as covariates. [0028] Fig.3B shows cumulative distribution function of change from baseline at week 108 for the FSIQ-RMS weekly symptoms score. [0029] Fig.4 is a Kaplan-Meier curve (main analysis) showing the time to first 12-week confirmed disability accumulation (CDA) up to end-of-study (EOS): Analysis Set: Full Analysis Set. In Fig.4, an event = 12 week CDA and subjects without event are censored at their last EDSS assessment without EDSS increase. Unstratified Kaplan-Meier estimates are presented. Bars on graph display pointwise 95% confidence intervals of the estimate. P- value is two-sided and based on the stratified log-rank test. Hazard ratio estimate obtained from stratified Cox regression with Wald confidence limits. Analysis is stratified by EDSS strata (≤ 3.5; > 3.5) and disease modifying therapy in last 2 years prior to randomization strata (Y,N). [0030] Fig.5 is a Kaplan-Meier curve (Main analysis) showing the time to first 24-week CDA up to EOS: Analysis Set: Full Analysis Set. In Fig.5, an event = 24 week CDA and subjects without event are censored at their last EDSS assessment without EDSS increase. Unstratified Kaplan-Meier estimates are presented. Bars on graph display pointwise 95% confidence intervals of the estimate. P-value is two-sided and based on the stratified log-rank test. Hazard ratio estimate obtained from stratified Cox regression with Wald confidence limits. Analysis is stratified by EDSS strata (≤ 3.5; > 3.5) and disease modifying therapy in last 2 years prior to randomization strata (Y,N). [0031] Fig.6 shows the 12-lead electrocardiogram (ECG) heart rate and absolute change from pre-dose at Day 1, by hour (Analysis Set: Safety Set). As per up-titration regimen, the dose of ponesimod on Day 1 is 2 mg. [0032] Fig.7 is a Forest plot (with 99% CL) showing an overview of primary and sensitivity analyses for confirmed relapses up to EOS (Analysis Set: Full Analysis Set). In Fig.7, n(Pon) = subjects in ponesimod group; rate(Pon) = annualized relapse rate in ponesimod group; n(Ter) = subjects in teriflunomide group and rate(Ter) = annualized relapse rate in teriflunomide group. The vertical solid line references the treatment effect from the main analysis. Negative binomial model is applied with Wald confidence limits, offset: log time (years) up to EOS. The main analysis is adjusted for the following covariates: EDSS strata (≤ 3.5; > 3.5); DMT in last 2 years prior to randomization strata (Y,N); and number of relapses in year prior to study entry (≤ 1; ≥ 2). [0033] Fig.8 is a Forest plot (with 99% CL) showing subgroup analyses of confirmed relapses up to EOS (Analysis Set: Full Analysis Set). In Fig.8, p* = interaction p-value; n(Pon) = no. of subjects in ponesimod group; rate(Pon) = mean rate in ponesimod group; n(Ter) = no. of subjects in teriflunomide group and rate(Ter) = mean rate in teriflunomide group. Negative binomial model is applied with Wald confidence limits, offset: log time (years) up to EOS, in each subgroup separately. Interaction p-value is from likelihood ratio test of interaction term in model with treatment, subgroup and treatment by subgroup interactions. The vertical solid line references the treatment effect from the main analysis. The main analysis is adjusted for the following covariates: EDSS strata (≤ 3.5; > 3.5); DMT in last 2 years prior to randomization strata (Y,N); and number of relapses in year prior to study entry (≤ 1; ≥ 2). Analyses in subgroups are not adjusted for covariates. [0034] Fig.9 shows change from baseline to week 108 in the FSIQ-RMS for the physical impact sub-domain. [0035] Fig.10 shows change from baseline to week 108 in the FSIQ-RMS for the cognitive/emotional impacts sub-domain. [0036] Fig.11 shows change from baseline to week 108 in the FSIQ-RMS for the coping impact sub-domain. [0037] Fig.12 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue below the median. [0038] Fig.13 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue below the median. [0039] Fig.14 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue above the median. [0040] Fig.15 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue above the median. [0041] Fig.16 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients without DMT treatment two years prior to randomization. [0042] Fig.17 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients without DMT treatment two years prior to randomization. [0043] Fig.18 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients without Gd+/T1 lesions at baseline. [0044] Fig.19 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients without Gd+/T1 lesions at baseline. [0045] Fig.20 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients with Gd+/T1 lesions at baseline. [0046] Fig.21 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients with Gd+/T1 lesions at baseline. [0047] Fig.22 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients with baseline EDSS ≤ 3.5. [0048] Fig.23 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients with baseline EDSS ≤ 3.5. [0049] Fig.24 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients having one or fewer relapses at baseline. [0050] Fig.25 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients having one or fewer relapses at baseline. [0051] Fig.26 shows change from baseline to week 108 in FSIQ-RMS weekly symptoms score for patients having two or more relapses at baseline. [0052] Fig.27 shows cumulative distribution function of change from baseline at week 108 in FSIQ-RMS weekly symptoms score for patients having two or more relapses at baseline. [0053] Fig.28 depicts a bar graph of the total number of differential events in each of the administrative claims databases for each S1P. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [0054] In the present disclosure the singular forms “a”, “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth. [0055] When a value is expressed as an approximation by use of the descriptor “about” or “substantially” it will be understood that the particular value forms another embodiment. In general, use of the term “about” or “substantially” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about” or “substantially”. In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” or “substantially” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range. [0056] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.” [0057] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiments and such a combination is considered to be another embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself. [0058] In some aspects, the present disclosure is directed to methods of avoiding worsening of fatigue-related symptoms in a human patient suffering from multiple sclerosis and fatigue, comprising, optionally, assessing the fatigue-related symptoms of the patient; and administering an effective regimen of ponesimod to the patient, wherein the regimen is sufficient to avoid worsening of the fatigue-related symptoms. As described herein, fatigue is fatigue associated with multiple sclerosis. [0059] In certain aspects, the methods are directed to patients that have had no prior disease modifying treatment (DMT) for multiple sclerosis within about two years prior to initiation of treatment with ponesimod. In some embodiments, the methods are directed to patients that have a baseline expanded disability status scale (EDSS) score of ≤ 3.5 prior to initiation of treatment with ponesimod. In other embodiments, the methods are directed to patients that have no Gd+/T1 lesions prior to initiation of treatment with ponesimod. Baseline refers to a time period prior to initiation of treatment with ponesimod and/or standard of care treatment. This time period is typically up to about 45 days prior to initiation of treatment, including, for example, up to about 40 days, up to about 35 days, up to about 30 days, up to about 25 days, up to about 20 days, up to about 15 days, or up to about 10 days prior to initiation of treatment with ponesimod and/or standard of care treatment. [0060] In other aspects, the present disclosure is directed to methods of reducing the number of combined unique active lesions (CUALs) in a patient suffering from multiple sclerosis, comprising administering an effective regimen of ponesimod to the patient, wherein the regimen is sufficient to reduce the number of CUALs by at least 40% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment that does not comprise ponesimod. [0061] In some aspects, the methods of the disclosure are performed on a human patient suffering from multiple sclerosis. In some embodiments, the patient’s multiple sclerosis is relapsing multiple sclerosis. In other embodiments, the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease. [0062] As used herein, the term “avoiding worsening of fatigue-related symptoms” refers to preventing the patient’s fatigue-related symptoms from becoming worse relative to the patient’s fatigue-related symptoms at baseline, wherein baseline refers to a time period prior to initiation of treatment with ponesimod. This time period is typically up to about 45 days prior to initiation of treatment with ponesimod, including, for example, up to about 40 days, up to about 35 days, up to about 30 days, up to about 25 days, up to about 20 days, up to about 15 days, or up to about 10 days prior to initiation of treatment with ponesimod. By avoiding worsening, the methods otherwise relate to stabilizing or improving fatigue-related symptoms. [0063] In some embodiments of the methods of the disclosure, the patient’s fatigue-related symptoms are assessed. In some embodiments of the methods of the disclosure, the patient’s fatigue-related symptoms are not assessed prior to initiation of treatment with ponesimod. As used herein, “fatigue-related symptoms” refer to symptoms of fatigue experienced by the patient. [0064] In some aspects, the fatigue-related symptoms are symptoms experienced by the patient while doing routine daily activities (e.g. housework, yard work, shopping, working). In some embodiments, the fatigue-related symptoms are those experienced by the patient while doing routine daily activities and include being physically tired, being mentally tired, being physically weak, lacking energy, feeling worn out, or feeling sleepy. [0065] In other embodiments, the fatigue-related symptoms are (1) being physically tired, (2) being mentally tired, (3) being physically weak, (4) lacking energy, (5) feeling worn out, (6) feeling sleepy while doing routine daily activities, and (7) feeling worn out while at rest. [0066] In some embodiments, the patient’s fatigue-related symptoms are assessed before initiation of ponesimod administration, for example, at baseline. In other embodiments, the patient’s fatigue-related symptoms are assessed after initiation of ponesimod administration to, for example monitor the fatigue-related symptoms during the treatment with ponesimod. In some embodiments, the patient’s fatigue-related symptoms are assessed both before initiation of ponesimod administration and after initiation of ponesimod therapy. [0067] The patient’s fatigue-related symptoms may be assessed by ascertaining from the patient the nature and severity of any symptoms of fatigue experienced by the patient. In some embodiments, the patient’s fatigue-related symptoms are assessed using a patient- reported outcome (PRO) questionnaire. [0068] In some embodiments, the patient-reported outcome questionnaire is the Fatigue Symptoms and Impact Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS) (available from Mapi Research Trust). The FSIQ-RMS is an MS specific 20-item PRO measure that comprises 2 domains: one measuring MS symptoms and one measuring MS-related impacts. See Hudgens S, et al., Development and Validation of the FSIQ-RMS: A New Patient- Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis. Value Health.2019 Apr;22(4):453-466. doi: 10.1016/j.jval.2018.11.007. Epub 2019 Feb 21. PubMed PMID: 30975397. With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping), the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients. Fig.2B depicts a conceptual framework for the FSIQ-RMS. [0069] In some embodiments, the patient-reported outcome questionnaire is the symptom domain of the FSIQ-RMS. The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms with a recall period of 24 hours measured on an 11-point numeric rating scale; the standardized symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain (i.e., section 1 of the questionnaire) is completed on 7 consecutive days. [0070] The FSIQ-RMS impact domain (FSIQ-RMS-I) consists of 13 items assessing impacts of fatigue-related symptoms with a recall period of 7 days measured on a 5-point verbal descriptor scale, the standardized impact domain score ranges from 0 to 100 with a higher score indicating greater impact. [0071] In some aspects of the methods of the present disclosure, the patient is administered an effective regimen of ponesimod. An effective regimen is one that elicits the biological or medicinal response in a human tissue system that is being sought by a researcher, medical doctor, or other clinician, which includes alleviation of one or more symptoms of the disease or disorder being treated. [0072] As used herein, the term “ponesimod” refers to the compound (R)-5-[3-chloro-4- (2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)- 3-o-tolyl-thiazolidin-4-one, which has the following structure: [0073] In some embodiments, “ponesimod” also refers to pharmaceutically acceptable salts of ponesimod. The term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example Handbook of Pharmaceutical Salts. Properties, Selection and Use, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012. [0074] It is to be understood that the present disclosure encompasses ponesimod in any form including amorphous as well as crystalline forms. It is further to be understood that crystalline forms of ponesimod encompasses all types of crystalline forms including polymorphs, solvates and hydrates, salts and co-crystals (when the same molecule can be co- crystallized with different co-crystal formers) provided they are suitable for pharmaceutical administration. In some embodiments, ponesimod is in crystalline form A or crystalline form C as described in WO 2010/046835, incorporated herein by reference. In some embodiments, ponesimod is in crystalline form C. [0075] It should be noted that the amounts of ponesimod described herein are set forth on a ponesimod free base basis. That is, the amounts indicate that amount of the ponesimod molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts). [0076] In some embodiments, the effective regimen comprises a daily dose of ponesimod. In some embodiments, the daily dose of ponesimod is administered orally. [0077] In some embodiments, the daily dose of ponesimod is administered once daily. [0078] In some embodiments, the daily dose of ponesimod is about 15 to about 25 mg. In further embodiments, the daily dose of ponesimod is about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg. In certain embodiments, the daily dose of ponesimod is about 20 mg. [0079] In some embodiments, about 20 mg of ponesimod is administered orally once daily. [0080] In other embodiments, the effective regimen comprises an up-titration, followed by a daily maintenance dose of ponesimod. An up-titration is a dosing procedure in which the daily dose of ponesimod is gradually increased over a period of days, culminating with administration of the maintenance dose. [0081] In some embodiments, the regimen comprises an up-titration at the initiation of the method of the disclosure. In other embodiments, the regimen comprises an up-titration upon re-initiation of the method after a discontinuation of the method of the disclosure. As used herein, “upon re-initiation of the method after a discontinuation” means an interruption of the administration of ponesimod of at least one, at least two or preferably at least 3 days before treatment is re-initiated. In some embodiments, the regimen comprises an up-titration step at initiation of the method or upon re-initiation of the method after a discontinuation. [0082] In some embodiments of the methods of the disclosure, the up-titration regimen one disclosed in U.S. Patent No.10,220,023, incorporated herein by reference. For example, in certain aspects, the up-titration comprises administering orally once daily about 2 mg of ponesimod on days 1 and 2; about 3 mg of ponesimod on days 3 and 4; about 4 mg of ponesimod on days 5 and 6; about 5 mg of ponesimod on day 7; about 6 mg of ponesimod on day 8; about 7 mg of ponesimod on day 9; about 8 mg of ponesimod on day 10; about 9 mg of ponesimod on day 11; and about 10 mg of ponesimod on days 12, 13, and 14. [0083] In other embodiments of the methods of the disclosure, the up-titration comprises administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14. [0084] In some embodiments, the maintenance dose is about 20 mg of ponesimod once daily. [0085] In some embodiments, the regimen comprises an up-titration step at initiation of the method or upon re-initiation of the method after a discontinuation, comprising administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; and 9 mg of ponesimod on day 11; 10 mg of ponesimod on days 12, 13, and 14, followed by the administering of the 20 mg of ponesimod once daily thereafter. [0086] In some aspects of the disclosed methods, the regimen is sufficient to avoid worsening of the fatigue-related symptoms. A regimen is sufficient to avoid worsening of the fatigue-related symptoms when the patient’s fatigue-related symptoms (assessed as described herein) after administration of the ponesimod regimen, are either improved or unchanged compared to the patient’s fatigue-related symptoms (assessed as described herein) prior to administration of the ponesimod regimen, for example, at baseline. [0087] In other embodiments, the methods of the disclosure are directed to reducing the number of combined unique active lesions (CUALs) in a patient. [0088] CUALs are new Gd+ T1 lesions plus new or enlarging T2 lesions (without double- counting of lesions). The cumulative number of CUAL is considered a reliable outcome measure of inflammatory MS disease activity. Radiological evidence of disease activity is routinely used to support disease diagnosis and to inform therapeutic decisions targeting no evidence of disease activity (NEDA), clinical (relapses or disability accumulation) or radiological (brain lesions on MRI) perspective. See Lublin FD. Disease activity free status in MS. Mult Scler Relat Disord.2012 Jan;1(1):6-7. doi: 10.1016/j.msard.2011.08.001. Epub 2011 Aug 27. PubMed PMID: 25876444. [0089] CUALs are detected using magnetic resonance imaging (MRI) techniques. [0090] In this aspect of the disclosed methods, the ponesimod regimen administered to the patient is sufficient to reduce the number of CUALs by at least 40% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment. That is, the patient administered the ponesimod regimen will have acquired at least 40% fewer CUALs as compared to a patient having substantially the same degree of MS progression who is receiving a standard of care treatment. [0091] In some embodiments, the ponesimod regimen administered to the patient is sufficient to reduce the number of CUALs by at least 20% to about 65% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment. In some embodiments, the ponesimod regimen administered to the patient is sufficient to reduce the number of CUALs by at least 30% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment. In some embodiments, the ponesimod regimen administered to the patient is sufficient to reduce the number of CUALs by at least 50% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment. In some embodiments, the ponesimod regimen administered to the patient is sufficient to reduce the number of CUALs by at least 55% relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment. [0092] As used herein, the term “standard of care treatment” refers to a physician- prescribed treatment of MS. In some embodiments, the standard of care comprises, consists of, or consists essentially of administering an MS treatment that has been approved by a regulatory authority. In some embodiments, the standard of care treatment is Interferon (IFN) β-1a 30 mcg i.m. once weekly (Avonex®), IFN β-1a 22 or 44 mcg s.c.3 times weekly (Rebif®), IFN β-1b 250 mcg s.c. every other day (Betaferon®, Extavia®), Pegylated IFN β- 1a 125 mcg subcutaneously every 2 weeks (Plegridy®), Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg subcutaneously 3 times weekly (Copaxone®), Glatiramer acetate 20 mg s.c. o.d. (Glatopa®), Natalizumab 300 mg i.v. every 4 weeks (Tysabri®), Mitoxantrone i.v. every 3 months (Novantrone®), Alemtuzumab concentrate for solution for infusion, 12 mg alemtuzumab in 1.2 mL (10 mg/mL) (Lemtrada®), Fingolimod 0.5 mg orally o.d. (Gilenya®), Teriflunomide 7 mg, 14 mg o.d. (Aubagio®), Dimethyl fumarate (BG-12) gastro-resistant hard capsules 120/240 mg twice daily (Tecfidera®), or Cladribine 40 to 100 mg orally per treatment week (Mavenclad®). [0093] In some embodiments, the standard of care treatment comprises a S1P receptor modulator that is not ponesimod. [0094] In other embodiments, the standard of care treatment comprises teriflunomide. In some embodiments, the standard of care treatment comprises administration of about 14 mg of teriflunomide orally once daily. [0095] In some embodiments, the patient has had no prior disease modifying treatment (DMT) for multiple sclerosis. In some embodiments, the patient has had no prior disease modifying treatment (DMT) for multiple sclerosis within about two years prior to initiation of treatment with ponesimod. In some embodiments, patients that have had no prior DMT for multiple sclerosis realize improved efficacy from use of ponesimod to address fatigue with respect to a standard of care treatment that does not comprise ponesimod, such as teriflunomide. Accordingly, with respect to these patients and others, the disclosed methods provide health care providers with options for improved outcomes compared to standard of care. [0096] In some embodiments, the methods are directed to patients having a baseline expanded disability status scale (EDSS) score of ≤ 3.5. In some embodiments, the methods are directed to patients having no Gd+/T1 lesions at baseline. [0097] The present disclosure also provides pharmaceutical products comprising ponesimod. Typically, the pharmaceutical product is a package or is packaged, for example, a bottle, a pouch, or a blister pack. [0098] In some embodiments, the package includes instructions. In certain embodiments, instructions are for administering ponesimod to a human patient suffering from multiple sclerosis and fatigue in a regimen that is effective to avoid worsening of fatigue-related symptoms. In other embodiments, the package provides instructions and/or fatigue-related symptom data directed to patients having had no prior disease modifying treatment (DMT) for multiple sclerosis for a period of about two years. In further embodiments, the package provides instructions and/or fatigue-related symptom data directed to patients having a baseline expanded disability status scale (EDSS) score of ≤ 3.5. In yet other embodiments, the package provides instructions and/or fatigue-related symptom data directed to patients having no Gd+/T1 lesions at baseline. [0099] As used herein, the term “group level” refers to a group level change or difference between groups of patients, e.g., group level differences in an outcome seen in clinical trials when comparing the treatment groups. For instance, FIG.3A shows the mean change from baseline for ponesimod 20 mg and teriflunomide 14 mg over time – and it visually shows the separation or difference in change from baseline in the treatment groups. [00100] As used herein, the term “patient level” refers to individual or within patient level of change. As used herein, “clinically meaningful” refers to the practical importance of a treatment effect and whether it has a real genuine, palpable, noticeable effect on symptoms and/or daily life. When interpreting data from a Patient Reported Outcome (PRO), for example, it is helpful to define a level of change on the PRO score over a predetermined time period that should be interpreted as a treatment benefit. Various terms are used for this level of change, including meaningful change threshold (MCT). This threshold can be used to conduct a responder analysis where an individual patient is a responder if the level of change on the PRO score for that patient exceeds the MCT. The proportion of responders between treatment groups can be compared to evaluate treatment effect. For example, in certain embodiments disclosed herein, there is an analysis of the percentage of responders in the ponesimod and teriflunomide treatment groups using an MCT of -6.3 on the FSIQ-RMS weekly symptom score. The percentage of subjects in the stable or improved category is also calculated. And the percentage of responders can also be visualized on a graph (a cumulative distribution function) which shows the cumulative percentage of patients showing all possible levels of change in the respective treatment groups. Accordingly, evaluation of within patient changes using MCT and associated responder analyses are used to provide additional interpretation to a p-value derived from a statistical test [00101] As used herein, the term “statistically significant” refers to the likelihood that a relationship between two or more variables is caused by something other than chance. A p- value less than 0.05 (typically ≤ 0.05) is a common metric for statistical significance and is indicative of strong evidence against the null hypothesis, as there is less than a 5% probability the null is correct (and the results are random). [00102] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound described herein to prevent the onset of the symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder. [00103] The disclosure further relates to a pharmaceutical product comprising ponesimod, wherein the pharmaceutical product is packaged, and wherein the package includes a label that identifies ponesimod as a an approved product for the treatment of multiple sclerosis. In some embodiments, the patient’s multiple sclerosis is relapsing multiple sclerosis. In other embodiments, the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease. [00104] The disclosure provides methods for treating multiple sclerosis in a patient in need thereof, comprising administering an approved product comprising ponesimod in an amount and manner that is described in a drug product label for the approved product and/or in a treatment regimen described herein. [00105] In certain aspects, methods of selling a drug product comprising ponesimod are also provided. The terms “sale” or “selling” as used herein refers to transferring a drug product, e.g., a pharmaceutical composition or a dosage form, from a seller to a buyer. In some embodiments, a drug product label for a reference listed drug for the drug product includes instructions for the treatment of multiple sclerosis. [00106] The term “offering for sale,” as used herein, refers to the proposal of a sale by a seller to a buyer for a drug product, e.g., a pharmaceutical composition or a dosage form. These methods comprise offering the drug product for sale. [00107] The term “drug product” is product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries. In the context of the present disclosure, and as reflected in Example 4, an “approved drug product” as used herein means: a pharmaceutical product that i) has been approved for introduction into commerce by a regulatory agency for use in treating adult humans with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease; ii) has an oral, once daily maintenance dosage of 20 mg of ponesimod and, optionally, a 14-day dose titration prior to the maintenance dosage of 20 mg, comprising administering orally, once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; 10 mg of ponesimod on days 12, 13, and 14, followed by the 20 mg maintenance dosage of ponesimod on Day 15 and thereafter; and (iii) demonstrated a statistically significant lower annualized relapse rate (ARR), and, optionally, a statistically significant lower number of Gd-enhancing T1 lesions and/or a statistically significant lower number of new or enlarging T2 lesions, without double counting of lesions, in a patient population with relapsing forms of MS, wherein the patients had an expanded disability status scale (EDSS) score of 0 to 5.5 at baseline, had experienced at least one relapse within the year prior, or two relapses within the prior 2 years, or who had at least one gadolinium- enhancing (Gd-enhancing) lesion on a brain MRI within the prior 6 months or at baseline, wherein patients with primary progressive MS were excluded, compared to the patients in the patient population that were administered a once daily 14 mg dosage of teriflunomide. Elements of the approved drug product are further defined in Example 4, Section 14, including Table 4 therein. [00108] In particular embodiments of the approved drug product, the patients in the patient population were treated for 108 weeks and ARR was reduced by 30.5% compared to teriflunomide 14 mg. [00109] Similarly, “label” or “drug product label” refers to information provided to a patient which provides relevant information regarding the drug product. Such information includes, without limitation, one or more of the description of the drug, clinical pharmacology, indications (uses for the drug product), contraindication (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how the drug is supplied, safety information for the patient, or any combination thereof. In certain embodiments, the label or drug product label provides an instruction for use in a patient requiring multiple sclerosis medication. In further embodiments, the label or drug product label identifies ponesimod and provides instructions for its use in a patient requiring multiple sclerosis medication. [00110] The term “reference listed drug” or “RLD” as used herein refers to a drug product to which new generic versions are compared to show that they are bioequivalent. It is also a medicinal product that has been granted marketing authorization by a member state of the European Union or by the Commission on the basis of a completed dossier, i.e., with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies. [00111] In the United States, a company seeking approval to market a generic equivalent must refer to the RLD in its Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on the FDA’s finding that a previously approved drug product, i.e., the RLD, is safe and effective, and must demonstrate, among other things, that the generic drug product is the same as the RLD in certain ways. Specifically, with limited exceptions, a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD. The RLD is the listed drug to which the ANDA applicant must show its ANDA drug product is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling and conditions of use, among other characteristics. In the electronic Orange Book, there is a column for RLDs and a column for reference standards. In the printed version of the Orange Book, the RLDs and reference standards are identified by specific symbol. [00112] A reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval. FDA generally selects a single reference standard that ANDA applicants must use in in vivo bioequivalence testing. Ordinarily, FDA will select the reference listed drug as the reference standard. However, in some instances (e.g., where the reference listed drug has been withdrawn from sale and FDA has determined it was not withdrawn for reasons of safety or effectiveness, and FDA selects an ANDA as the reference standard), the reference listed drug and the reference standard may be different. [00113] FDA identifies reference listed drugs in the Prescription Drug Product, OTC Drug Product, and Discontinued Drug Product Lists. Listed drugs identified as reference listed drugs represent drug products upon which an applicant can rely in seeking approval of an ANDA. FDA intends to update periodically the reference listed drugs identified in the Prescription Drug Product, OTC Drug Product, and Discontinued Drug Product Lists, as appropriate. [00114] FDA also identifies reference standards in the Prescription Drug Product and OTC Drug Product Lists. Listed drugs identified as reference standards represent the FDA’s best judgment at this time as to the appropriate comparator for purposes of conducting any in vivo bioequivalence studies required for approval. [00115] In some instances when FDA has not designated a listed drug as a reference listed drug, such listed drug may be shielded from generic competition. If FDA has not designated a reference listed drug for a drug product the applicant intends to duplicate, the potential applicant may ask FDA to designate a reference listed drug for that drug product. [00116] FDA may, on its own initiative, select a new reference standard when doing so will help to ensure that applications for generic drugs may be submitted and evaluated, e.g., in the event that the listed drug currently selected as the reference standard has been withdrawn from sale for other than safety and efficacy reasons. [00117] In Europe, Applicants identify in the application form for its generic/hybrid medicinal product, which is the same as an ANDA or supplemental NDA (sNDA) drug product, the reference medicinal product (product name, strength, pharmaceutical form, marketing authorization holder (MAH, first authorization, Member State/Community), which is synonymous with a RLD, as follows: [00118] 1. The medicinal product that is or has been authorized in the European Economic Area (EEA), used as the basis for demonstrating that the data protection period defined in the European pharmaceutical legislation has expired. This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the generic/hybrid medicinal product. [00119] 2. The medicinal product, the dossier of which is cross-referred to in the generic/hybrid application (product name, strength, pharmaceutical form, MAH, marketing authorization number). This reference medicinal product may have been authorized through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection. The product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the generic/hybrid medicinal product. [00120] 3. The medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable). [00121] The different abbreviated approval pathways for drug products under the Food, Drug, and Cosmetics (FD&C) Act are the abbreviated approval pathways described in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C.355(j) and 21 U.S.C.23355(b)(2), respectively). [00122] According to the FDA (“Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry,” U.S. Department of Health and Human Services, October 2017, pp.1-14, the contents of which is incorporated herein by reference), NDAs and ANDAs can be divided into the following four categories: [00123] (1) A “stand-alone NDA” is an application submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use. [00124] (2) A section 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. [00125] (3) An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on the FDA’s finding that the previously approved drug product, i.e., the reference listed drug (RLD), is safe and effective. An ANDA generally must contain information to show that the generic product (a) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the product. [00126] (4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which FDA has determined, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary to establish the safety and effectiveness of the drug product. [00127] A scientific premise underlying the Hatch-Waxman Act is that a drug product approved in an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling. In contrast to an ANDA, a section 505(b)(2) application allows greater flexibility as to the characteristics of the product. A section 505(b)(2) application will not necessarily be rated therapeutically equivalent to the listed drug it references upon approval. [00128] The term "therapeutically equivalent to a reference listed drug" means that the drug product is a generic equivalent, i.e., pharmaceutical equivalents, of the reference listed drug product and, as such, is rated an AB therapeutic equivalent to the reference listed drug product by the FDA whereby actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. [00129] “Pharmaceutical equivalents” means drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient as the reference listed drug. [00130] FDA classifies as therapeutically equivalent those products that meet the following general criteria: (1) they are approved as safe and effective; (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard; (4) they are adequately labeled; and (5) they are manufactured in compliance with Current Good Manufacturing Practice regulations [00131] The term "bioequivalent" or "bioequivalence" is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Section 505 (j)(8)(B) of the FD&C Act describes one set of conditions under which a test and reference listed drug shall be considered bioequivalent: [00132] the rate and extent of absorption of the [test] drug do not show a significant difference from the rate and extent of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or [00133] the extent of absorption of the [test] drug does not show a significant difference from the extent of absorption of the [reference] drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the [reference] drug in the rate of absorption of the drug is intentional, is reflected in its labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. [00134] Where these above methods are not applicable (e.g., for drug products that are not intended to be absorbed into the bloodstream), other scientifically valid in vivo or in vitro test methods to demonstrate bioequivalence may be appropriate. [00135] For example, bioequivalence may sometimes be demonstrated using an in vitro bioequivalence standard, especially when such an in vitro test has been correlated with human in vivo bioavailability data. In other situations, bioequivalence may sometimes be demonstrated through comparative clinical trials or pharmacodynamic studies. [00136] The methods may also comprise, consist of, or consist essentially of selling or offering to sell ponesimod into the stream of commerce. [00137] Clinical management events [00138] As noted herein, sphingosine-1-phosphate receptor modulators (S1Ps), a class of oral disease, modifying therapies (DMTs) for multiple sclerosis (MS), are cell-trafficking inhibitors that have been shown to have high efficacy. There are at least four S1Ps that are indicated for MS in the United States: fingolimod, siponimod, ozanimod, and ponesimod. Although these S1Ps share some similarities as a class, the individual S1Ps have differences in selectivity for receptor subtypes and phosphorylation requirements, half-lives, and safety profiles that result in different clinical requirements before and after treatment initiation. Some clinical management events are common across the S1Ps, such as complete blood count, electrocardiogram, and liver function tests before treatment initiation. However, each S1P also has unique recommendations for clinical management events described in their US Prescribing Information (USPI), which may impact their overall ease of use. S1Ps with fewer clinical management events may be easier to use than those that require more monitoring. [00139] As used herein, clinical management events refer to management of potential or actual events that may require medical intervention. As described herein, clinical management events prior to initiation of treatment include, for example, first-dose monitoring, genotyping, and/or an eye exam. After initiation, events include, for example, drug-drug interactions (DDI), eye exam, and/or liver function tests. [00140] The disclosure provides methods for reducing clinical management events before or during treatment of multiple sclerosis in a patient in need thereof, comprising administering ponesimod in an amount and manner that is described in a drug product label for an approved product and/or in a treatment regimen described herein, namely administration of about 20 mg of ponesimod orally once daily, with or without utilization of the up-titration dosing procedure also described herein. The reduction and ease of use are relative to a patient population at substantially the same level of disease progression receiving a standard of care treatment comprising an S1P receptor modulator other than ponesimod, including, for example, fingolimod, siponimod, and ozanimod (see Example 3). [00141] Other aspects of the disclosure [00142] Beta blockers, also known as beta-adrenergic blocking agents, are widely used medications to reduce blood pressure and may be co-administered in MS patients. Concomitant use of ponesimod and drugs that decrease heart rate may be result in bradycardia and heart block. As a result, caution should be applied when ponesimod is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate. In certain embodiments, for patients receiving a stable dose of a beta- blocker, the resting heart rate should be considered before introducing ponesimod treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If the resting heart rate is less than or equal to 55 bpm, beta- blocker treatment should be interrupted until the baseline heart rate is greater than 55 bpm. In this case, treatment with ponesimod can then be initiated and treatment with a beta-blocker can be reinitiated after ponesimod has been up-titrated (via the 14-day titration regimen) to the target maintenance dosage. [00143] For example, the negative chronotropic effect of coadministration of ponesimod and propranolol was evaluated in a dedicated pharmacodynamics safety study. In particular, the 14-day dose titration regimen of ponesimod was administered to subjects receiving propranolol (80 mg) once daily. As noted in Example 4, no significant changes in pharmacokinetics of ponesimod or propranolol were observed. [00144] In particular embodiments, where a patient is being treated with a beta-blocker and ponesimod treatment is to be initiated, and wherein the patient has a resting heart rate of greater than 55 beats per minute during treatment with the beta-block and prior to initiation of ponesimod, ponesimod is administered without interruption to the beta-blocker treatment. In other embodiments, where a patient is being treated with a beta-blocker and ponesimod treatment is to be initiated, and wherein the patient has a resting heart rate of less than or equal to 55 beats per minute during treatment with the beta-block and prior to initiation of ponesimod, beta-blocker treatment is interrupted until the patient’s heart rate is greater than 55 beats per minute and ponesmod treatment is initiated in a titration regimen comprising administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14, followed by administering a 20 mg maintenance dose of ponesimod once daily thereafter, and the beta- blocker is reinitiated after ponesimod has been up-titrated to the maintenance dosage. [00145] Because initiation of ponesimod treatment results in a decrease in heart rate (HR), first-dose 4-hour monitoring is also recommended for patients with sinus bradycardia (HR less than 55 beats per minute (bpm)), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction or heart failure occurring more than 6 months prior to treatment initiation and in stable condition. As part of the first dose 4-hour monitoring, a first dose of ponesimod (e.g. 2 mg of ponesimod as part of the titration regimen) is administered in a setting where resources to appropriately manage symptomatic bradycardia are available. Patients are to be monitored for 4 hours after the first dose for signs and symptoms of bradycardia with pulse and blood pressure measurements, preferably with a minimum of hourly measurements. Further, in additional embodiments, an electrocardiogram (ECG) is obtained for these patients prior to dosing and at the end of the 4-hour observation period. [00146] Accordingly, methods include treating multiple sclerosis in a patient in need thereof, wherein the patient has sinus bradycardia, first or second degree AV block, or a history of myocardial infarction or heart failure occurring more than 6 months prior to the initiation of ponesimod treatment, comprising administering an effective regimen of ponesimod to the patient, wherein after a first dose of the ponesimod, the patient is monitored for a period of 4 hours for symptoms of bradycardia. In other embodiments, no first dose monitoring is needed wherein the patient has no sinus bradycardia, no first or second degree AV block, and no history of myocardial infarction or heart failure occurring more than 6 months prior to the initiation of ponesimod treatment. [00147] If any abnormalities are present after four hours, even in the absence of symptoms, monitoring may be continued until the abnormality resolves. Abnormalities include, for example, a heart rate 4 hours post-dose that is less than 45 bpm; a heart rate 4 hours post-dose that is at the lowest value post-dose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; and/or an ECG 4 hours post-dose that shows new onset second-degree or higher AV block. [00148] If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 4 hours post-dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, appropriate management actions can be initiated. For example, the patient can begin continuous ECG monitoring, and can otherwise be monitored until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, the patient can be continued to be monitored, including overnight, and the 4-hour monitoring can be repeated after the second dose of ponesimod. [00149] In other embodiments, where patients have a preexisting heart and/or cerebrovascular condition; a prolonged QTc interval before dosing or during the 4-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drug with a known risk of torsades de pointes; and/or receiving concurrent therapy with drugs that slow heart rate or AV conduction, advice from a cardiologist should be sought to determine the most appropriate monitoring strategy, which can include, for example, overnight monitoring during treatment initiation. [00150] Although interruption during treatment is not preferred, this disclosure is also related to reinitiating ponesimod after treatment interruption. For example, if fewer than 4 consecutive doses are missed during titration, treatment is resumed with the first missed titration dose and the titration schedule is resumed as that dose and titration day. If fewer than 4 doses are missed during maintenance, treatment is resumed with the maintenance dose. If 4 our more consecutive doses are missed during titration or maintenance, treatment is reinitiated with Day 1 of the 14 day titration regimen, with first dose monitoring as described herein for those patients needing such monitoring. [00151] In other embodiments, use or concomitant use of certain drugs with ponesimod should be contraindicated, avoided, or discontinued. For example, methods include treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of alemtuzumab. Other methods include treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (such as, for example, verapamil or diltiazem), or other drugs that reduce heart rate (such as, for example, digoxin). Additional methods include treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of strong CYP3A4 and UGT1A1 inducers (such as, for example, rifampin, phenytoin, or carbamazepine) that decrease systemic exposure of the ponesimod. Aspects of the Disclosure - the present disclosure pertains to and includes at least the following additional aspects: [00152] 1. A method for treating multiple sclerosis in a patient in need thereof, comprising administering an approved drug product comprising ponesimod in an amount and manner that is described in a drug product label for the approved drug product. [00153] 2. The method of aspect 1, wherein about 20 mg of ponesimod is administered orally once daily [00154] 3. The method of aspect 1 or aspect 2, wherein the treatment comprises an up- titration step at initiation of the method or upon re-initiation of the method after a discontinuation, comprising administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; and 9 mg of ponesimod on day 11; 10 mg of ponesimod on days 12, 13, and 14, followed by administering 20 mg of ponesimod once daily thereafter. [00155] 4. The method of any one of aspects 1-3, wherein the multiple sclerosis is relapsing multiple sclerosis. [00156] 5. The method of aspect 4, wherein the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease. [00157] 6. A method of selling an approved drug product comprising ponesimod, said method comprising selling such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating a patient with multiple sclerosis. [00158] 7. A method of offering for sale a drug product comprising ponesimod, said method comprising offering for sale such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating a patient with multiple sclerosis. [00159] 8. The method of aspect 6 or aspect 7, wherein the drug product is an ANDA drug product, a supplemental New Drug Application drug product, or a 505(b)(2) drug product. [00160] 9. A pharmaceutical product comprising ponesimod, wherein the pharmaceutical product is packaged, and wherein the package includes a label that identifies ponesimod as an approved drug product for the treatment of multiple sclerosis. [00161] 10. A method for treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of alemtuzumab. [00162] 11. A method for treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (such as, for, example, verapamil or diltiazem), or other drugs that reduce heart rate (such as, for example, digoxin). [00163] 12. A method for treating multiple sclerosis in a patient in need thereof, comprising administering an effective regimen of ponesimod to the patient wherein the treatment further comprises avoiding, contradicting, or discontinuing concomitant use of strong CYP3A4 and UGT1A1 inducers (such as, for example, rifampin, phenytoin, or carbamazepine) that decrease systemic exposure of the ponesimod. [00164] The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein Example A: Fatigue Symptoms and Impact Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS) [00165] The patient-reported outcome questionnaire used for the below Examples is the Fatigue Symptoms and Impact Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS). The FSIQ-RMS is an MS specific 20-item PRO measure that comprises 2 domains: one measuring MS symptoms (7 items) and one measuring MS-related impacts (13 items). The 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping) are presented below. MS Symptoms Domain – 7 Items [00166] For the MS symptoms domain, the FSIQ-RMS asks about a patient’s fatigue- related symptoms of relapsing MS over the past 24 hours while doing routine daily activities (e.g., housework, yard work, shopping, working, etc.) for Items 1-6 or while at rest (e.g., reading a book, watching TV, etc.) for Item 7. Patients are asked to select a response on a scale of 0 to 10 that best describes their experience and are asked to not skip any questions, with no answers being right or wrong. [00167] Item 1 - In the past 24 hours, while doing routine daily activities, how physically tired did you feel? [00168] Item 2 - In the past 24 hours, while doing routine daily activities, how mentally tired did you feel? [00169] Item 3 - In the past 24 hours, while doing routine daily activities, how physical weak did you feel? [00170] Item 4 - In the past 24 hours, how would you rate your energy while doing routine daily activities? [00171] Item 5 - In the past 24 hours, while doing routine daily activities, how worn out did you feel? [00172] Item 6 - In the past 24 hours, while doing routine daily activities, how sleepy did you feel? [00173] Item 7 - In the past 24 hours, how worn out did you feel while at rest? MS-Related Impacts – 13 Items [00174] For the MS-related impacts domain, the FSIQ-RMS asks about how a patient’s life was affected by fatigue-related symptoms of relapsing MS in the past 7 days. Patients are asked to select a response on a scale of 0 to 4 that best describes their experience and are asked to not skip any questions, with no answers being right or wrong. [00175] Item 1 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have running errands (such as grocery shopping or going to the bank or ATM)? [00176] Item 2 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have communicating clearly? [00177] Item 3 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have thinking clearly? [00178] Item 4 - Thinking about your fatigue-related symptoms over the past 7 days, how difficult was it for you to motivate yourself to do routine daily activities? [00179] Item 5 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have doing indoor household chores? [00180] Item 6 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have walking? [00181] Item 7 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have maintaining relationships with people you are close to? [00182] Item 8 - Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty did you have taking part in social activities (such as going to the movies or going out to eat)? [00183] Item 9 - Thinking about your fatigue-related symptoms over the past 7 days, how frustrated were you? [00184] Item 10 - Thinking about your fatigue-related symptoms over the past 7 days, how often were you forgetful? [00185] Item 11 - Thinking about your fatigue-related symptoms over the past 7 days, how often did you have to take a nap? [00186] Item 12 - Thinking about your fatigue-related symptoms over the past 7 days, how often did you have to take a break? [00187] Item 13 - Thinking about your fatigue-related symptoms over the past 7 days, how often did you have to rearrange your plans?

Example 1. Study Design [00188] A prospective, multicenter, randomized, double-blind, active controlled, parallel- group, phase III, superiority study was conducted. The study was designed to compare the efficacy, safety, and tolerability of ponesimod 20 mg vs teriflunomide 14 mg in adult subjects with relapsing MS. [00189] Randomization: Subjects were randomized in a 1:1 ratio to ponesimod 20 mg or teriflunomide 14 mg, stratified by prior use of MS disease modifying treatment (DMT) in the last two years prior to randomization (yes, no) and by baseline expanded disability status scale (EDSS) score (EDSS ≤ 3.5, EDSS > 3.5). [00190] Inclusion Criteria [00191] This study enrolled adult male and female subjects aged 18 to 55 years with established diagnosis of MS, as defined by the 2010 revision of McDonald Diagnostic Criteria [Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol.2011;69(2):292–302], with relapsing course from onset (i.e., relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis [SPMS] with superimposed relapses). The trial included up to a maximum 15% of subjects with SPMS with superimposed relapses. [00192] Subjects had active disease evidenced by one or more MS attacks with onset within the period of 12 to 1 months prior to baseline EDSS assessment, or by two or more MS attacks with onset within the 24 to 1 months prior to baseline EDSS assessment, or with one or more gadolinium-enhancing (Gd+) lesion(s) of the brain on an MRI performed within 6 months prior to baseline EDSS assessment. Enrolled subjects were ambulatory with an EDSS score of up to 5.5 inclusive. The subjects were treatment-naïve (i.e., no MS disease- modifying therapy received at any time in the past) or previously treated with interferon (IFN) β-1a, IFN β-1b, glatiramer acetate, dimethyl fumarate, or natalizumab. [00193] Exclusion Criteria: [00194] Subjects with significant medical conditions or therapies for such conditions (e.g., cardiovascular, pulmonary, immunological, hepatic, ophthalmological, ocular) or lactating or pregnant women were not eligible to enter the study. [00195] Subjects with contraindications to MRI or with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study were not eligible to enter the study. [00196] Study/treatment duration: [00197] For an individual subject, the maximum duration of the study was approximately 118 weeks consisting of 6 weeks of screening, 108 weeks of treatment and 4 weeks of safety follow-up. Subjects discontinuing treatment prematurely had an option to stay in a post- treatment observation period (PTOP) for up to 108 weeks. [00198] The study consisted of the following periods: [00199] Pre-randomization period - Up to 45 days before randomization. [00200] Treatment period: The double-blind treatment period lasted for 108 weeks. It consisted of a randomization visit, visits at two, four, and 12 weeks after randomization, and 12-weekly visits thereafter. [00201] End-of-Treatment (EOT): [00202] The EOT visit took place at Week 108 (or earlier in case of premature discontinuation of study drug). In all cases, the EOT visit took place one day after the last dose of study drug but no later than 7 days after the last dose of study drug. [00203] Subjects who completed treatment until Week 108 were eligible to enroll in an extension study conducted under a separate protocol. Subjects who discontinued study drug prematurely for any reason were not eligible for the extension study. [00204] Subjects who prematurely discontinued study drug treatment were subsequently treated according to local standard of care at the investigator’s discretion and were followed in the post-treatment observation period. [00205] Post-treatment safety follow-up (FU) period: [00206] Teriflunomide is eliminated slowly from plasma. An accelerated elimination procedure was used by all subjects after the last dose of study drug. A safety FU after the last dose of study drug was mandated. [00207] All subjects entered the safety FU period: [00208] For subjects who entered the extension study, the FU period started after the last dose of study drug and ended with a safety FU visit (FU1) 14–22 days after the last dose of study drug or with an abbreviated FU223–37 days after the last dose of study drug (if compliance to the teriflunomide accelerated elimination procedure was assessed as not sufficient at FU1). [00209] For subjects who did not enter the extension study, the safety FU period lasted for 30 days after the last dose of study drug and included two safety FU visits (FU1, FU2) at 14– 22 and 30–37 days after the last dose of study drug, respectively. [00210] Post-treatment observation period (PTOP): [00211] Subjects who prematurely discontinued study treatment enter the PTOP which lasts until 108 weeks after randomization (i.e., planned EOT period). It consisted of an abbreviated schedule of assessments at the time of the originally scheduled 12-weekly visits. [00212] End-of-Study (EOS) [00213] EOS was reached when treatment, safety FU, and, if applicable, PTOP have been completed. [00214] For subjects who completed the 108-week treatment period and entered the extension study, the EOS visit corresponded to the FU visit (FU1) conducted 14–22 days after the last study drug dose or to the abbreviated FU2 visit conducted 23–37 days after the last study drug dose (if needed for compliance reasons with the teriflunomide accelerated elimination procedure). [00215] For all other subjects, the EOS visit corresponded to the 30-day FU visit (FU2) or to the last visit of PTOP (i.e., Week 108 Visit of the PTOP), whichever was last. [00216] Study Treatment: [00217] The treatment period consisted of an up-titration period (from Day 1 to 14) and a maintenance period (Day 15 until EOT). [00218] During an initial phase of the study, the study drugs in the up-titration period were administered in a double-dummy fashion. Ponesimod (or matching placebo) was presented as tablet, and teriflunomide 14 mg (or matching placebo) was presented as capsule (i.e., daily administration of one tablet and one capsule). At a later phase, the double-dummy material (tablet and capsule) was replaced by the daily administration of one capsule containing either ponesimod or teriflunomide. [00219] In the maintenance period, the study treatment consisted of the daily administration of one capsule containing ponesimod 20 mg or teriflunomide 14 mg. [00220] To reduce the first-dose effect of ponesimod, an up-titration scheme was implemented from Day 1 to Day 14: [00221] Days 1 and 2; 2 mg. [00222] Days 3 and 4; 3 mg. [00223] Days 5 and 6; 4 mg. [00224] Day 7; 5 mg. [00225] Day 8; 6 mg. [00226] Day 9; 7 mg. [00227] Day 10; 8 mg. [00228] Day 11; 9 mg. [00229] Days 12, 13, and 14; 10 mg. [00230] Day 15 until EOT; 20 mg. [00231] Primary analysis set for efficacy: The Full Analysis Set (FAS) included all randomized subjects. Subjects were evaluated according to the treatment they were randomized to. [00232] Primary efficacy variable/primary timepoint: The primary endpoint was annualized relapse rate (ARR) up to the end of study (EOS) defined as the number of confirmed relapses per subject-year. All available data up to EOS, regardless of treatment discontinuation was included (ITT approach). [00233] Secondary efficacy variables and testing strategy: Four secondary efficacy endpoints were analyzed as per the statistical testing strategy outlined in Figure 1. - Change from baseline to Week 108 in fatigue-related symptoms as measured by the symptoms domain of the FSIQ–RMS patient-reported outcome [Fatigue] - Cumulative number of combined unique active lesions from baseline to Week 108 on brain MRI [CUALs] - Time to first 12-week confirmed disability accumulation (CDA) from baseline to EOS on Expanded Disability Status Scale (EDSS) [12-week CDA] - Time to first 24-week CDA from baseline to EOS on EDSS [24-week CDA] [00234] See Figure 1 for a schematic representation of the testing strategy. [00235] The primary endpoint was powered with α = 0.01. The secondary endpoints tested with an overall α = 0.05. [00236] The sample size for the study was based on the primary endpoint and determined assuming a negative binomial distribution for number of confirmed relapses. A sample size of 1100 subjects (550 per treatment arm) would provide a power of approximately 90% for a significance level of 1%, under the assumption that ARR is 0.320 for teriflunomide 14 mg and 0.215 for ponesimod 20 mg (which corresponds to a rate ratio of 0.67) and using a dispersion = 0.9. An annual dropout rate of approximately 15% was assumed for the first year and 7.5% for the second year. [00237] Statistical Methods [00238] The Full Analysis Set (FAS) included all randomized subjects. In order to adhere to the intention-to-treat principle as much as possible, subjects were evaluated according to the treatment they have been randomized to. [00239] The Per-Protocol Set (PPS) comprises all subjects included in the FAS without any major protocol deviations, that impact the assessment of the primary/secondary endpoints, occurring prior to or at randomization. [00240] The Safety Set (SAF) included all randomized subjects who received at least one dose of study treatment. Subjects were analyzed based on actual treatment taken, not randomized treatment. [00241] A generalized linear model with negative binomial distribution was fitted for the primary efficacy endpoint ARR. Two-sided hypotheses were expressed in terms of the model parameters μP20mg and μT14mg. The primary null hypothesis was that the ARR (μ) does not differ between ponesimod 20 mg and teriflunomide 14 mg. [00242] The null hypothesis was tested by a two-sided Wald test within the negative binomial regression model with a two-sided significance level of 0.01 for conclusive evidence and 0.05 for a positive study. Two-sided 99% and 95% Wald confidence intervals were calculated for the relative reduction in mean ARR for ponesimod 20 mg compared to teriflunomide 14 mg. [00243] The primary statistical analysis of the ARR endpoint was performed on the FAS using a negative binomial model for confirmed relapses, with the stratification variables prior use of disease-modifying therapies (DMTs) and EDSS category as well as the number of relapses in the year prior to study entry, included in the model and time in the study as an offset variable. Sensitivity analyses was performed on the PPS and also based on different subgroups derived from baseline variables. [00244] The secondary efficacy endpoints were tested if the primary analysis on ARR leads to the rejection of the null hypothesis in favor of ponesimod 20 mg at an overall two-sided significance level of 0.05. A fallback method was used for testing the family of hypotheses related to the following three secondary endpoints: Absolute change of FSIQ-RMS from baseline to Week 108; Cumulative number of CUAL from baseline to Week 108; Time to 12- week CDA from baseline up to EOS. This was followed in a hierarchical manner by testing Time to 24-week CDA from baseline up to EOS; at the remaining alpha. [00245] The endpoints were analyzed using the FAS population. All secondary endpoints were also analyzed using the PPS population. Primary Objective [00246] To determine whether ponesimod is more efficacious than teriflunomide in terms of reducing relapses in subjects with RMS. Results [00247] Disposition and baseline characteristics: A total of 1133 subjects were randomized to the study, 567 to ponesimod 20 mg and 566 to teriflunomide 14 mg. Overall treatment and study discontinuation were balanced across both treatment arms, 83% of subjects completed treatment. The mean age was 36.7 years and 64.9% of subjects were female. Most subjects were recruited in Europe with 50.6% from EU countries. Mean baseline EDSS score was 2.6 and mean disease duration was 7.6 years. Mean pre-study 12- month relapse rate was 1.3, and 42.6% subjects had ≥ 1 gadolinium-enhancing (Gd+) T1 lesions. The treatment arms were generally balanced in terms of demographics and baseline disease characteristics. [00248] 1. Subject And Treatment Information [00249] A total of 1468 subjects were screened. Of those, 1133 subjects were randomized (567 to ponesimod 20 mg and 566 to teriflunomide 14 mg) across 162 sites in 28 countries, and 1131 subjects received at least one dose of study drug. The disposition of subjects is summarized in Table 1 and a summary of reasons (primary reason) for treatment discontinuation are shown in Table 2. Overall treatment and study discontinuation were balanced across both treatment arms. A total of 6.5% and 2.5% of the subjects discontinued due to AEs or tolerability related reasons in ponesimod 20 mg and teriflunomide 14 mg, respectively, while 1.9% and 4.3% discontinued due to efficacy related reasons. There were 2 deaths reported during the study - both on teriflunomide 14 mg. [00250] 1.1 Disposition and Treatment Discontinuation Information t t [00251] 1.2 Demographic and Baseline Characteristics [00252] Randomization was stratified by prior-DMT in the last two years prior to randomization (yes: 39.5%; no: 60.5%) and EDSS score at baseline (≤ 3.5: 83.3%; >3.5 16.7%). The mean age was 36.7 years and the majority of subjects (64.9%) were female. Most subjects were recruited in Europe with 50.6% from EU countries. Mean baseline EDSS score was 2.6, mean disease duration was 7.6 years and 97.4% were RRMS subjects. Mean pre-study 12-month relapse rate was 1.3, and 42.6% subjects had ≥ 1 Gd+ T1 lesions on brain MRI. The treatment arms were generally balanced in terms of demographics and baseline disease characteristics (Tables 3 and 4).

[00253] 1.3 Extent of Exposure [00254] The mean treatment exposure (irrespective of interruptions) was 96.7 weeks in the ponesimod 20 mg arm and 97.5 weeks in the teriflunomide 14 mg arm. The cumulative exposure to ponesimod 20 mg was 1045 subject-years and was 1057 subject-years for teriflunomide 14 mg arm. [00255] 2. Primary Endpoint Analysis [00256] Primary efficacy endpoint: Ponesimod 20 mg statistically significantly reduced ARR (confirmed relapses) up to EOS by 30.5% compared to teriflunomide 14 mg (ARR = 0.202 for ponesimod 20 mg vs.0.290 for teriflunomide 14 mg, rate ratio: 0.695 [99% CL: 0.536: 0.902], p = 0.0003). The primary endpoint results are robust, all sensitivity and supplementary analyses are in line with the primary analysis. [00257] A relapse is defined as new, worsening or recurrent neurological symptoms that occur at least 30 days after the onset of a preceding relapse, and that last at least 24 hours, in the absence of fever or infection. [00258] The new, worsening or recurrent neurological symptoms were evaluated by the treating neurologist and, if all the elements of the above definition were verified, and in the absence of another, better explanation of the subject’s symptoms, the event was considered as a relapse. The onset date of the relapse corresponded to the onset date of the symptoms. [00259] A relapse was confirmed by the treating neurologist only when the subjects’ symptoms were accompanied by an increase in EDSS/FS (functional system) scores, which were consistent with the subject’s symptoms, from a previous clinically stable EDSS/FS assessment (i.e., performed at least 30 days after the onset of any previous relapse), obtained by the efficacy assessor and consistent with the following: [00260] − An increase of at least half a step (0.5 points; unless EDSS = 0, then an increase of at least 1.0 points is required) or [00261] − An increase of at least 1.0 point in at least two FS scores, or [00262] − An increase of at least 2.0 points in at least one FS score (excluding bladder/bowel and cerebral). [00263] The primary statistical analysis was performed up to EOS on the FAS using a negative binomial regression model for confirmed relapses, with treatment as a factor and the binary stratification variables (EDSS ≤ 3.5 versus EDSS > 3.5; DMTs within last 2 years prior to randomization [Yes/No]) and the number of relapses in the year prior to study entry (categories ≤ 1 (or missing) and ≥ 2) included in the model. The model also included an offset variable defined as the log of time on study (in years) from randomization up to EOS. [00264] Ponesimod 20 mg statistically significantly reduced ARR (confirmed relapses) up to EOS by 30.5% compared to teriflunomide 14 mg (ARR = 0.202 for ponesimod 20 mg vs. 0.290 for teriflunomide 14 mg, rate ratio: 0.695 [99% CL: 0.536: 0.902], p = 0.0003). [00265] The primary endpoint results were robust; all sensitivity (see Fig.7) and supplementary analyses (see Fig.2A) are in line with the primary analysis. Subgroup analysis [see Fig.8], shows most notably that there appears to be a treatment-by-EDSS stratum interaction.

[00266] 3. Secondary Endpoint(S) Main Analyses [00267] 3.1 Fatigue - Change from Baseline to Week 108 in FSIQ-RMS Weekly Symptoms Score [00268] Change from baseline to Week 108 in the FSIQ-RMS weekly symptoms score, based on the full analysis set, was statistically significantly lower in the ponesimod 20 mg arm compared with teriflunomide 14 mg, based on an MMRM analysis (mean = -0.01 for ponesimod 20 mg vs.3.56 for teriflunomide 14 mg, mean difference: -3.57 [95% CL: -5.83: -1.32], p = 0.0019, an increase from baseline indicates worsening in fatigue symptoms). See Fig.3A. [00269] Cumulative distribution function of change is shown in FIG.3B. Results of the study are summarized below in Table 6A. In addition to the observation of statistical significance at the group level change from baseline favoring ponesimod, there is also observed a statistically significant difference in patients who were stable or improved on ponesimod compared to teriflunomide. This suggests a statistically significant and clinically meaningful difference for ponesimod at the patient level. Table 6A. Summary of Change from Baseline to Week 108 for FSIQ-RMS Weekly Symptoms Score Based on Full Analysis Set.

[00270] The FSIQ-RMS is an MS specific 20-item PRO measure that comprises 2 domains: one measuring MS symptoms and one measuring MS-related impacts. The symptoms domain of the scale was used in this study to compare the effect of ponesimod and teriflunomide on fatigue. This new tool has a number of advantages compared to the available fatigue tools for MS. See Hudgens S, et al., Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis. Value Health.2019 Apr;22(4):453-466. doi: 10.1016/j.jval.2018.11.007. Epub 2019 Feb 21. PubMed PMID: 30975397. With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping), the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients. [00271] The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms with a recall period of 24 hours measured on an 11-point numeric rating scale; the standardized symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain (i.e., section 1 of the questionnaire) is completed on 7 consecutive days. [00272] The FSIQ-RMS impact domain (FSIQ-RMS-I) consists of 13 items assessing impacts of fatigue-related symptoms with a recall period of 7 days measured on a 5-point verbal descriptor scale, ranging from no impact to extreme impact; the impact domain score ranges from 0 to 100 with a higher score indicating greater impact. As the impact domain of the FSIQ-RMS (i.e., section 2 of the questionnaire) has a 7-day recall period, it was completed on the last day (i.e., seventh day) of completion of section 1. [00273] FSIQ-RMS was completed during the pre-randomization period, at Visits 6, 7, 10, and 12 (Weeks 12, 24, 60, 84), 14 (EOT), and at unscheduled visits due to relapses (R1, R2, etc.) or other unscheduled visits (U1, U2, etc.) as described below. If applicable, FSIQ-RMS was performed at the corresponding visits in the PTOP. [00274] The completion of the FSIQ-RMS during the pre-randomization period was done as follows: At Visit 1 (Screening), subjects who appear eligible based on the assessments made during this visit (but prior to the results from the laboratory assessments are received) were provided with the electronic device containing the FSIQ-RMS. [00275] Once the results from the laboratory assessments confirmed the subject’s eligibility, and provided no other assessment performed in the meantime excluded the subject, the site coordinator contacted and asked the subject to start the completion of the FSIQ-RMS. At home, the subject completed the symptom domain of the FSIQ-RMS for 7 days (i.e., section 1 of the questionnaire). On the seventh day, the subject completed the impact domain of the FSIQ-RMS (i.e., section 2 of the questionnaire). The information captured from this assessment was used as the baseline data for the FSIQ-RMS. Ideally, the FSIQ-RMS was completed during the 7 consecutive days preceding the randomization. [00276] After randomization, the symptoms domain of the FSIQ-RMS (i.e., section 1 of the questionnaire) was completed by the subject at home on a daily basis, starting in the evening of the day of a visit when the FSIQ-RMS was administered (Day 1 of questionnaire administration cycle) and during the 6 subsequent days (i.e., over 7 days in total). Subjects returned the completed FSIQ-RMS diary at the next scheduled visit. On the seventh day, the subject completed the impact domain of the FSIQ-RMS (i.e., section 2 of the questionnaire). If applicable, at the end of the PTOP, the FSIQ-RMS was completed prior to Visit 14A (Week 108), ideally, during the 7 consecutive days preceding the visit. [00277] Results for the secondary endpoint of change from baseline to Week 108 in the symptoms domain of the FSIQ-RMS (assessed over a 7-day period) have shown the superiority of ponesimod 20 mg over teriflunomide 14 mg. [00278] 3.2 MRI - Combined Unique Active Lesions (CUAL) from Baseline to Week 108. [00279] CUAL are new Gd+ T1 lesions plus new or enlarging T2 lesions (without double- counting of lesions). [00280] The cumulative number of CUAL is considered a reliable outcome measure of inflammatory MS disease activity. Radiological evidence of disease activity is routinely used to support disease diagnosis and to inform therapeutic decisions targeting no evidence of disease activity (NEDA), clinical (relapses or disability accumulation) or radiological (brain lesions on MRI) perspective. See Lublin FD. Disease activity free status in MS. Mult Scler Relat Disord.2012 Jan;1(1):6-7. doi: 10.1016/j.msard.2011.08.001. Epub 2011 Aug 27. PubMed PMID: 25876444. [00281] MRI scans were performed at Visits 2 (Baseline), 10 (Week 60), and 14 (EOT) and at any unscheduled visit (U1, U2, etc.). If applicable, MRI scans also were performed at the corresponding visits in the PTOP (Visits 10A and 14A). Testing at all visits were performed up to 7 days prior to or after the visit date. In case of premature study treatment discontinuation, the MRI at EOT did not need to be performed if the EOT visit occurred within less than 4 weeks of the MRI assessment at Visit 10 (Week 60). [00282] MRI variables included the number and volume of new and total Gd+ lesions on T1-weighted MRI scans, number of new and enlarging lesions and lesion volume on T2- weighted MRI, and global measures of loss of brain tissue. [00283] Lesion count of MRI performed within 24 months prior to the study were recorded on the MS history page of the eCRF. These scans were not analyzed by the medical image analysis center (MIAC). [00284] T1-weighted imaging before and after i.v. administration of 0.1 mmol/kg body weight (= 0.2 mL/kg) of Gd as well as PD-T2-weighted imaging was performed. Gd may cause nausea and vomiting and in very rare cases allergic reactions that could require immediate anti-anaphylactic therapy (such as steroids, epinephrine/adrenaline, etc.). [00285] Ponesimod 20 mg statistically significantly reduced by 56% the number of CUALs between baseline and week 108 compared to teriflunomide 14 mg (mean CUALs per year = 1.405 for ponesimod 20 mg vs.3.164 for teriflunomide 14 mg, rate ratio: 0.44 [95% CL: 0.36: 0.54], p < 0.0001). A total of 4.9% and 4.9% of subjects had a baseline but no post- baseline MRI; sensitivity analyses using a range of methods (data not shown) for imputation of missing data supported the primary results (p < 0.0001 in all cases). [00286] Ponesimod 20 mg was clearly superior in reducing the number of CUALs vs teriflunomide 14 mg, fully supporting and complementing the results of the primary endpoint.

l [00287] 3.3 EDSS - Time to First 12-Week Confirmed Disability Accumulation (CDA) [00288] The 12-week confirmed disability accumulation, also sometimes referred to as disability progression (CDA/CDP) is a common endpoint in RMS studies, while 24-week CDA/CDP is regarded as the more robust and clinically relevant endpoint. See European Medicines Agency, Guideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis, 26 March 2015, EMA/CHMP/771815/2011, Rev.2, Committee for Medicinal Products for Human Use (CHMP). Teriflunomide 14 mg has shown a statistically significant reduction in the risk of 12-week CDP in the TEMSO and TOWER studies. See O'Connor P, et al. N Engl J Med.2011;365:1293-30; Confavreux C, et al.; TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247-56. doi: 10.1016/S1474-4422(13)70308-9. Epub 2014 Jan 23. PubMed PMID: 24461574. [00289] A 12-week CDA is an increase of at least 1.5 in EDSS for subjects with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with a baseline EDSS score ≥ 5.5 which is to be confirmed after 12 weeks. [00290] Baseline EDSS is defined as the last EDSS score recorded prior to randomization. The initial EDSS increase, meeting the above criteria, is defined as the onset of disability accumulation. [00291] All EDSS measurements (with or without relapse, at a scheduled or unscheduled visit) were used to determine the onset of disability accumulation. However, EDSS scores used for confirmation of disability accumulation were obtained at a scheduled visit (i.e., unscheduled visits cannot be used as confirmatory visits) outside any ongoing relapse. In this context, relapse duration is defined as period between start and end dates if available and limited to 90 days from onset if end date is not available or duration is longer than 90 days. [00292] In order to confirm that the EDSS increase is persistent, all EDSS measurements between the onset and the 12-week EDSS confirmation (minus 7-day visit time-window) need to show an increase in EDSS, meeting the criteria for accumulation of disability as defined above. [00293] A 12-week CDA was observed in 10.1%, and 12.4% of subjects up to EOS in the ponesimod 20 mg and teriflunomide 14 mg arms, respectively. The risk of 12-week CDA was not found to be statistically significantly different for ponesimod 20 mg as compared with teriflunomide 14 mg (hazard ratio: 0.83 [95% CL, 0.58 to 1.18]; log-rank p = 0.2939). Consequently, the formal testing procedure was stopped. See Table A3; see also Fig.4. [00294] 3.4 EDSS - Time to First 24-Week Confirmed Disability Accumulation (CDA) [00295] 24-week CDA was not formally tested and only evaluated in an exploratory manner. A 24-week CDA was observed in 8.1%, and 9.9% of subjects up to EOS in the ponesimod 20 mg and teriflunomide 14 mg arms, respectively. The risk of 24-week CDA for ponesimod 20 mg as compared with teriflunomide 14 mg was not found to be statistically significantly different at a nominal α = 0.05 (hazard ratio: 0.84 [95% CL, 0.57 to 1.24]; log- rank p = 0.3720). See Fig.5. [00296] A 24-week CDA is an increase of at least 1.5 in EDSS for subjects with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with a baseline EDSS score ≥ 5.5 which is to be confirmed after 24 weeks. [00297] Baseline EDSS is defined as the last EDSS score recorded prior to randomization. The initial EDSS increase, meeting the above criteria, is defined as the onset of disability accumulation. [00298] All EDSS measurements (with or without relapse, at a scheduled or unscheduled visit) were used to determine the onset of disability accumulation. However, EDSS scores used for confirmation of disability accumulation were obtained at a scheduled visit (i.e., unscheduled visits cannot be used as confirmatory visits) outside any ongoing relapse. In this context, relapse duration is defined as period between start and end dates if available and limited to 90 days from onset if end date is not available or duration is longer than 90 days. [00299] In order to confirm that the EDSS increase is persistent, all EDSS measurements between the onset and the 24-week EDSS confirmation (minus 7-day visit time-window) need to show an increase in EDSS, meeting the criteria for accumulation of disability as defined above. [00300] In this study, ponesimod 20 mg reduced by 17% and 16% the risk of 12- and 24- week CDA, respectively, compared to teriflunomide 14 mg, however the difference did not reach statistical significance. This study was not powered for 12- or 24-week CDA, so results were not bound to be statistically different. [00301] 4. Safety [00302] 4.1 Summary of All Adverse Events [00303] An overview of treatment emergent AEs (TEAEs) is presented in Table 8.

[00304] Overall, the proportion of subjects who experienced at least one TEAE was similar in both treatment arms (88.8% and 88.2% of subjects in the ponesimod 20 mg and the teriflunomide 14 mg arms, respectively). [00305] The most common TEAEs in the ponesimod 20 mg arm were ALT increased (19.5%), nasopharyngitis (19.3%), headache (11.5%) and upper respiratory tract infection (10.6%). The most common TEAEs in the ponesimod 20 mg arm were ALT increased (19.5% vs 9.4% in the teriflunomide arm), nasopharyngitis (19.3% vs 16.8%), headache (11.5% vs 12.7%) and upper respiratory tract infections (10.6% vs 10.4%). [00306] TEAEs leading to premature treatment discontinuation were reported in 8.7% of ponesimod 20 mg subjects compared to 6.0% of teriflunomide 14 mg subjects [see Table 9]. While the number of events was low, the difference in the type of AEs leading to treatment discontinuation was mainly driven by anticipated class effects on respiratory system and macular edema. No infections led to permanent study treatment discontinuation in the study.

[00307] There were two deaths reported in the study, one due to coronary artery insufficiency and one due to multiple sclerosis. Both deaths occurred in subjects receiving teriflunomide 14 mg. [00308] The proportion of subjects who experienced at least one SAE was similar in both treatment arms (8.7% and 8.1% of subjects in the ponesimod 20 mg and the teriflunomide 14 mg arms, respectively). [00309] An overview of AEs of special interest (AESIs) addressing anticipated risks of ponesimod is presented in Table 10. The most common AESIs were reported for category hepatobiliary disorders/liver enzyme abnormality (25.7% vs 14.5% in ponesimod 20 mg compared to teriflunomide 14 mg, respectively), followed by category hypertension (10.1% vs 9.0%), and pulmonary events (8.0% vs 2.7%).

[00310] The proportion of subjects who experienced ALT increase > 3xULN was higher in the ponesimod arm (17.3%) compared to teriflunomide (8.3%) whereas ALT increase > 8xULN was higher in the teriflunomide arm (2.1%) compared to ponesimod (0.7%). Based on the individual case review, most ALT/AST increases ≥ 3xULN occurred as a single transient asymptomatic episode, resolving with continued treatment or after protocol mandated treatment discontinuation. All but one case of bilirubin increase ≥ 2xULN occurred in subjects with pre- treatment bilirubin increases. One case of potential Hy’s law occurred in a subject with pre- existing transaminase elevation (ALT > 5xULN), and the event fully resolved within 2 weeks after treatment discontinuation. [00311] The incidence of treatment-emergent heart rate and rhythm (including hypotension) AESIs on Day 1 was higher in the ponesimod 20 mg arm (2.1%) than in the teriflunomide 14 mg arm (0.4%). See Table 10A. However, the overall incidence of first dose AESI on Day 1 was low (2.1%) in ponesimod. None of these events were serious nor led to permanent discontinuation of study treatment. Discharge criteria at 4 hours post-dose were met for ca.99% of subjects. No 2nd or higher degree AV block was observed. ECG HR effect: nadir at 2 hours post-dose (siponimod – 3-4 hours, fingolimod – around by 6 hours). Low incidence of low HR outliers (post-dose HR ≤ 40 bpm), all 3 of them with a pre-treatment HR of < 55 bpm, which is a known risk factor for post-dose bradycardia with S1P receptor modulators. [00312] The mean heart rate reduction compared to pre-dose reached a maximum for ponesimod 20 mg at 2-hours post dose, -8.7 bpm compared to -1.7 bpm for teriflunomide 14 mg (Figure 6). There were 3 subjects with asymptomatic post-dose HR ≤ 40 bpm in the ponesimod 20 mg arm (none on teriflunomide 14 mg); all of these subjects had a pre- treatment HR < 55 bpm, which would require post-dose monitoring according to regulatory precedence of siponimod [Mayzent® USPI]. Example 1A: FSIQ-RMS and Physical, Cognitive, and Coping Impact [00313] Change from baseline to Week 108 for the physical, cognitive/emotional and coping impacts sub-domains of FSIQ-RMS are shown in FIG.9, FIG.10 and FIG.11, respectively. [00314] Figures 9, 10 and 11 show the FSIQ-RMS physical, cognitive/emotional and coping impacts sub-domains at the group level, based on the full analysis set, for the ponesimod 20 mg treatment arm and the teriflunomide 14 mg treatment arm. Example 1B: Change From Baseline to Week 108 - Baseline Fatigue Below the Median [00315] Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue below the median is shown in FIG.12. Cumulative distribution function of change is shown in FIG.13. Results are summarized in Table 11A below. Baseline fatigue (i.e., weekly symptoms score at baseline) is provided in Table 11B and was used for the baseline fatigue below the median in this Example and the baseline fatigue above the median in Example 1C. [00316] Almost 65% of low baseline fatigue patients remained stable or improved over the 108 weeks on ponesimod, as compared to about 55% over the 108 weeks on teriflunomide. Table 11A. Change From Baseline to Week 108, Baseline Fatigue Below the Median for Ponesimod and Teriflunomide Table 11B. Baseline fatigue (symptoms score of FSIQ at baseline). Example 1C: Change From Baseline to Week 108 - Baseline Fatigue Above the Median [00317] Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms score for patients with baseline fatigue above the median is shown in FIG.14. Cumulative distribution function of change is shown in FIG.15. Example 1D: Change From Baseline to Week 108 – Patients with No Prior DMT Treatment [00318] Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms score for patients with no prior DMT treatment within about two years prior to initiation of treatment is shown in FIG.16. Cumulative distribution function of change is shown in FIG. 17. Results are summarized in Table 12 below. [00319] Patient improvement was clinically meaningful in 31.4% of patients on ponesimod (P=0.052), and about 75% of patients on ponesimod remained stable or improved by Week 108 (P=0.003). Table 12. Change From Baseline to Week 108 in Patients with no Prior DMT Treatment for Ponesimod and Teriflunomide Example 1E: Change From Baseline to Week 108 in Patients without Gd+ T1 Lesions at Baseline [00320] Mean change from baseline to Week 108 for change in FSIQ-RMS weekly symptoms score in patients without Gd+T1 lesions at baseline is shown in FIG.18. Cumulative distribution function of change is shown in FIG.19. Results are summarized in Table 13 below. [00321] Patients who had stable or improved symptoms of fatigue without baseline Gd+T1 lesions demonstrated a statistically significant difference for ponesimod compared to teriflunomide, about 68% for ponesimod vs. about 57% for teriflunomide (p=0.021). Table 13. Change From Baseline to Week 108 in Patients without Gd+ T1 Lesions at Baseline Example 1F: Change From Baseline to Week 108 in Patients with Gd+ T1 Lesions at Baseline [00322] Mean change from baseline to Week 108 for change in FSIQ-RMS weekly symptoms score in patients with Gd+T1 lesions at baseline is shown in FIG. 20. Cumulative distribution function of change is shown in FIG.21. Example 1G: Change From Baseline to Week 108 - Baseline EDSS ≤ 3.5 [00323] Mean change from baseline to Week 108 for change in FSIQ-RMS weekly symptoms score for patients with lower baseline EDSS is shown in FIG.22. Cumulative distribution function of change is shown in FIG.23. Results are summarized in Table 14 below. Table 14. Change From Baseline to Week 108 in Patients with Baseline EDSS ≤ 3.5 Example 1H: Change From Baseline to Week 108 - Patients with One or Fewer Prior Relapses at Baseline [00324] Mean change from baseline to Week 108 for change in FSIQ-RMS weekly symptoms score for patients with one or fewer prior relapses at baseline is shown in FIG.24. Cumulative distribution function of change is shown in FIG.25. Example 1I: Change From Baseline to Week 108 - Patients with Two or More Prior Relapses at Baseline [00325] Mean change from baseline to Week 108 for change in FSIQ-RMS weekly symptoms score for patients with two or more prior relapses at baseline is shown in FIG.26. Cumulative distribution function of change is shown in FIG.27. Example 2: Pre-Specified MRI Endpoints and No Evidence of Disease Activity (NEDA) status. [00326] In this study, prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status is evaluated. [00327] Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive ponesimod (PON) 20 mg or teriflunomide (TER) 14 mg for 108 weeks. MRI assessments were: volume of T2 lesions; mean number of new gadolinium- enhancing (Gd+) T1 lesions and new/enlarging T2 lesions; and absence of active MRI lesions at week 108. NEDA-3 status (absence of confirmed relapse, Gd+T1 lesions and new/enlarging T2 lesions on annual MRIs, and 12-week confirmed disability accumulation) was evaluated from baseline to week 108. [00328] A total of 985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean difference (PON−TER) in change from baseline in total volume of T2 lesions: −399.2 mm ³ (95% CLs:−651.5; −146.8, p=0.002); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (rate ratio [RR]:0.42, 95% CLs:0.31; 0.56, p<0.0001); mean numbers of new/enlarging T2 lesions per year: 1.40 vs 3.16 (RR:0.44, 95% CLs:0.36; 0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001) and absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, CL:1.27; 2.28, p=0.0004) achieved NEDA-3. The most frequent reason for not achieving NEDA-3 status at week 108 was presence of new/enlarging T2 lesions. [00329] Patients treated with ponesimod demonstrated a higher proportion of patients achieving NEDA-3 status compared to those treated with teriflunomide. Conclusions [00330] This study demonstrates the superior efficacy of ponesimod over the active control. This study is the first study showing a statistically significant effect on fatigue symptoms in a pre-defined secondary endpoint (disease specific validated PRO), targeting a key unmet need. [00331] This study also demonstrates that the safety profile of ponesimod appears to be consistent with previously observed safety findings with ponesimod, and the known safety profile of other S1P receptor modulators. The gradual up-titration appears to successfully mitigate first-dose effects of ponesimod and supports forgoing first dose monitoring for patients with no risk factors for symptomatic bradycardia. Example 3 – Clinical Management Introduction [00332] Sphingosine-1-phosphate receptor modulators (S1Ps), a class of oral disease modifying therapies (DMTs) for multiple sclerosis (MS), are cell-trafficking inhibitors that have been shown to have high efficacy. [00333] Four S1Ps are indicated for MS in the United States: fingolimod, siponimod, ozanimod, and ponesimod. Although these S1Ps share some similarities as a class, the individual S1Ps have differences in selectivity for receptor subtypes and phosphorylation requirements, half-lives, and safety profiles that result in different clinical requirements before and after treatment initiation. [00334] Some clinical management events are common across the S1Ps, such as complete blood count, electrocardiogram, and liver function tests before treatment initiation. However, each S1P also has unique recommendations for clinical management events described in their US Prescribing Information (USPI), which may impact their overall ease of use. S1Ps with fewer clinical management events may be easier to use than those that require more monitoring. Objective [00335] The objective of this study was to estimate the expected frequencies of differential clinical management events (eg, eye exam, first-dose cardiovascular monitoring, and drug- drug interactions [DDIs]) using real-world data sources of persons with MS; and to compare the use of SCS for the treatment of relapses between ponesimod (PON) and teriflunomide (TER) groups in the OPTIMUM trial (See Example 1). Methods Study Design [00336] Retrospective cohort study utilized the following three US administrative claims databases: 1) IBM® MarketScan® Commercial Claims and Encounters Database (IBM CCAE); 2) IBM® MarketScan® Medicare Supplemental and Coordination of Benefits Database (IBM MDCR); and 3) Optum® Clinformatics® Extended Data Mart – Socioeconomic Status (Optum SES). [00337] Analyses were performed on data converted to the Observational Medical Outcomes Partnership Common Data Model, version 5.3.1. [00338] Inclusion/exclusion criteria: claim for any MS DMT within the index period (1 January 2016-11 March 2019) and no other demyelinating disease diagnosis within 1 year before the index date. The index date was defined as follows: 1) For each patient, identify all DMT service dates within the index period; 2) Retain DMT service dates with prior MS diagnosis between the study period start date (1 January 2015) and the DMT service date; 3) Retain DMT service dates that fall within a continuous observation period spanning at least 1 year before and 1 year after the DMT service date; 4) Retain DMT service dates on which patient is aged ≥ 18 years; and 5) Of any remaining DMT service dates, select the earliest date per patient as the index date. [00339] Only differential events were quantified; common clinical management events that are applicable to all S1Ps were excluded from analysis, including complete blood count, Varicella zoster virus antibody testing, liver function tests (prior to S1P initiation), electrocardiogram, cancer screening, and pulmonary function tests. [00340] Differential clinical management events prior to initiation were first-dose monitoring, genotyping, and an eye exam; after initiation, events were DDIs, eye exam, and liver function tests. The results are summarized below in Table 15. Table 15. Differential Clinical Management Events Up to or After Treatment Initiation

S1P, sphingosine-1-phosphate receptor modulator; N/A, not available; DDI, drug-drug interaction; CYP, cytochrome 450; BCRP, breast cancer resistance protein; MAO, monoamine oxidase; UGT, UDP- glucuronosyltransferase. aAll S1Ps recommend an eye exam at any time if there is any change in vision while on therapy and regular follow-up exams for patients with a history of diabetes or uveitis. Fingolimod differs in additionally requiring an exam 3 to 4 months post initiation for all patients. Endpoints/Outcomes [00341] Total number of differential clinical management events (first-dose observation, eye exam, DDIs) before and during the first year of treatment for each S1P. [00342] Prevalence of comorbidities for which a first-dose observation is recommended prior to siponimod or ponesimod. [00343] Prevalence of comorbidities (uveitis, macular oedema, diabetes mellitus) for which an eye exam is recommended prior to ozanimod. [00344] Relative risk of DDIs among S1Ps (ie, number of drugs taken concomitantly with any DMT for MS that would result in a DDI when taken with an S1P [excluding DDIs common to all S1Ps]). [00345] Identified were DDI types, removing all DDI classes common to the 4 S1Ps (antineoplastic or immunosuppressive therapies, antiarrhythmic or QT-prolonging drugs, vaccines). Results are summarized below in Table 16. Table 16. USPI Drug Interactions Among S1Ps

USPI, US Prescribing Information; S1P, sphingosine-1-phosphate receptor modulator; FIN, fingolimod; SIP, siponimod; OZA, ozanimod; PON, ponesimod; SSRI, selective serotonin reuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; BCRP, breast cancer resistance protein; MAO, monoamine oxidase; CYP, cytochrome 450; UGT, UDP-glucuronosyltransferase; DDI, drug-drug interaction. aFor SIP: 1) Moderate or strong CYP3A4 inhibitors are specified as a DDI only when combined with moderate CYP2C9 inhibitors; here, it is sufficient to identify moderate CYP2C9 inhibitors (including moderate CYP2C9/CYP3A4 dual inhibitors); 2) Strong CYP3A4 inducers are specified as a DDI only when combined with moderate CYP2C9 inducers; here, it is sufficient to identify moderate CYP2C9 inducers (including moderate CYP2C9/strong CYP3A4 dual inducers). bOZA’s USPI lists CYP3A4 inhibitors and inducers as DDIs only when combined with other DDI types shown in this table (eg, dual inducers). Thus, for this study, it was not necessary to include these as separate DDI types. cPurple highlighting indicates drug interactions that are common to all S1Ps. dPharmacogenomic and laboratory test interactions are not in scope for this study, and interactions with foods and over-the-counter medications will not be detectable in the databases. Results [00346] The majority of patients in all databases were female. The results are summarized in Table 17. Table 17. Cohorts Demographics in Each Database IBM CCAE, IBM® MarketScan® Commercial Claims and Encounters Database; IBM MDCR, IBM® MarketScan® Medicare Supplemental and Coordination of Benefits Database; Optum SES, Optum® Clinformatics® Extended Data Mart – Socioeconomic Status; SD, standard deviation. [00347] In the IBM CCAE, ponesimod had the lowest number of differential clinical management events (1.11) compared with fingolimod (4.00), siponimod (2.19), and ozanimod (1.85). The results are summarized in Table 4. Similar results were obtained in the IBM MDCR and Optum SES databases, as shown in FIG.28. [00348] In FIG.28, the IBM CCAE, IBM® MarketScan® Commercial Claims and Insurance Database; IBM MDCR, IBM® MarketScan® Medicare Supplemental and Coordination of Benefits Database; Optum SES, Optum® Clinformatics® Extended Data Mart – Socioeconomic Status. The differential events are management events that have different recommendations for each S1P, such as first-dose monitoring and eye exam. Table 18. Estimated Number of Events of Differential Clinical Management Events per Patient in the IBM CCAE Study Cohort [00349] Per the USPI, first-dose monitoring is recommended for all patients before fingolimod initiation. The cardiovascular risks described in the USPIs for siponimod and ponesimod were observed in 9% of the IBM CCAE cohort. Thus, first-dose events were quantified as 1 per patient for fingolimod, 0.09 events per patient for siponimod and ponesimod, and 0 events for ozanimod, as shown in Table 18. [00350] An eye exam is recommended for all patients before fingolimod, siponimod, and ponesimod initiation. For ozanimod, 9% of the IBM CCAE cohort had conditions that trigger the recommendation for an eye exam, which translates into 0.09 events per patient for ozanimod and 1 event per patient for the other S1Ps, as shown in Table 4. [00351] In the IBM CCAE, the average number of DDI drugs used concomitantly with any MS DMTs within 1 year was 0.0005, 0.10, 1.76, and 0.02 for fingolimod, siponimod, ozanimod, and ponesimod, respectively, as shown in Table 4. [00352] Per the USPI, periodic liver function tests are recommended during fingolimod treatment, which was estimated as 1 event in the year following initiation, as shown in Table 4. Limitations [00353] The study design did not include exclusion criteria based on contraindications for each S1P. [00354] The study did not consider differences in recommended first-dose monitoring durations (6 hours for fingolimod and siponimod vs 4 hours for ponesimod) or other differences, such as reversibility of lymphocyte counts. [00355] Generalizability was limited because each database represents a specific population of patients (eg, the IBM CCAE consists of commercially insured individuals, whereas the IBM MDCR includes those who receive supplemental Medicare coverage). [00356] Administrative claims data lack clinical detail; a claim for a filled prescription does not indicate whether the medication was taken as prescribed and overlap of drug exposure dates (determined by overlap in drug supply by ≥ 1 day) may not reflect actual concomitant drug use. [00357] Because of low sample sizes for newer agents, this analysis assessed risk of DDIs (indicated as concomitant use with any MS DMT) rather than actual DDIs for each S1P. Conclusion [00358] The data were consistent across different databases and suggest ponesimod is expected to have the fewest clinical management events among S1Ps and may be easier to use overall than other S1Ps

Example 4: Approved Drug Product Label