RMS Study of BTK Inhibitor SAR442168

Inclusion Criteria:

• Participants are eligible to be included in the study only if all of the followingcriteria apply: Age I 01. The participant must be 18 to 55 years of age, inclusive, atthe time of signing the informed consent. Type of participant and diseasecharacteristics I 02. The participant must have been diagnosed with RMS according tothe 2017 revision of the McDonald diagnostic criteria. I 03. The participant has anEDSS score ≤5.5 at the first Screening Visit I 04. The participant must have at least 1 of the following prior to screening: ≥1 documented relapse within the previous yearOR ≥2 documented relapses within the previous 2 years, OR ≥1 documented Gd-enhancingbrain lesion on an MRI scan within the previous year. Note: The initial clinicaldemyelinating episode of MS should be counted as a relapse for the first 2 criteria.Weight I 05. Not applicable. Sex I 06. Male or Female Contraceptive use by men orwomen should be consistent with local regulations regarding the methods ofcontraception for those participating in clinical studies. Male participants wishingto conceive a child and female participants becoming pregnant or wishing to becomepregnant must permanently discontinue the study intervention and follow the localteriflunomide label recommendation. A) Male participants Male participants areeligible to participate if they agree to the following during the intervention periodand until the accelerated elimination procedure is performed. • Refrain from donatingsperm Plus either: • Be abstinent from heterosexual intercourse as their preferred andusual lifestyle (abstinent on a long-term and persistent basis) and agree to remainabstinent OR • Must agree to use contraception/barrier method as detailed below -Agree to use a male condom and should also be advised of the benefit for a femalepartner to use a highly effective method of contraception as a condom may break orleak when having sexual intercourse with a woman of childbearing potential (WOCBP) whois not currently pregnant B) Female participants • A female participant is eligible toparticipate if she is not pregnant or breastfeeding, and at least one of the followingconditions apply: - Is not a WOCBP OR - Is a WOCBP and agrees to use a contraceptivemethod that is highly effective (with a failure rate of <1% per year), with low userdependency, as described in Appendix 4 during the intervention period and until theaccelerated elimination procedure is completed after the last dose of studyintervention. - A WOCBP must have a negative highly sensitive pregnancy test (urine orserum, as required by local regulations) within 24 hours before the first dose ofstudy intervention. - If a urine test cannot be confirmed as negative (eg, anambiguous result), a serum pregnancy test is required. In such cases, the participantmust be excluded from participation if the serum pregnancy result is positive. •Additional requirements for pregnancy testing during the study and after studyintervention are located in the schedule of activities (SoA). • The Investigator isresponsible for review of medical history, menstrual history, and recent sexualactivity to decrease the risk for inclusion of a woman with an early undetectedpregnancy, if allowed by local regulations. Informed Consent I 07. The participantmust have given written informed consent prior to undertaking any study-relatedprocedure. This includes consent to comply with the requirements and restrictionslisted in the informed consent form (ICF) and in this protocol. In countries where thelegal age of maturity is greater than 18 years, a specific ICF for such legally minorparticipants must also be signed by the participant's legally authorizedrepresentative.

Exclusion Criteria:

• Participants are excluded from the study if any of the following criteria apply:Medical conditions E 01. The participant has been diagnosed with PPMS according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing SPMS. E 02. Theparticipant has a history of infection or may be at risk for infection: • A history ofT-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solidorgan, stem cell, and bone marrow transplantation) and/or antirejection therapy. • Theparticipant has received any live (attenuated) vaccine (including but not limited tovaricella zoster, oral polio, and nasal influenza) within 2 months before the firsttreatment visit. • The participant has a lymphocyte count less than the lower limit ofnormal (LLN) at the Screening Visit. • A history of diagnosis of progressivemultifocal leukoencephalopathy (PML) or evidence of findings suggestive of PML on thescreening MRI. • A history of infection with human immunodeficiency virus (HIV). • Ahistory of active or latent tuberculosis (TB) (unless the participant has completed afull course of anti-tuberculosis therapy or it is documented by a specialist that theparticipant has been adequately treated and can begin treatment with animmunosuppressive agent); screening tuberculosis testing should be performed atscreening and again during the study, if clinically indicated. Blood testing (eg,QuantiFERON TB Gold test) is preferred; skin testing (eg, tuberculin skin test) willbe allowed if blood testing is not available or the blood test result isindeterminate. • Persistent chronic or active recurring infection requiring treatmentwith antibiotics, antivirals, or antifungals. • Fever within 4 weeks of the ScreeningVisit (≥38°C; however, if due to brief and mild ear, nose, throat viral infectionparticipant may be included based on the Investigator's judgment). • At screening, theparticipant is positive for hepatitis B surface antigen and/or hepatitis B coreantibody and/or is positive for hepatitis C antibody. Serologies consistent withresolved infection or vaccination may not exclude potential participants from thetrial. • Any other active infections that would adversely affect participation or IMPadministration in this study, as judged by the Investigator. E 03. The presence ofpsychiatric disturbance or substance abuse as evidenced by: • A history of anypsychiatric disease, behavioral condition, or depression requiring hospitalizationwithin 2 years prior to the Screening Visit. • A documented history of attemptedsuicide over the 6 months prior to the Screening Visit, presents with suicidalideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS)during the study, OR if in the Investigator's judgment, the participant is at risk fora suicide attempt. • A history of alcohol or drug abuse within 1 year prior to theScreening Visit. E 04. The following findings obtained during the screening visitconsidered in the Investigator's judgment to be clinically significant: • Anyscreening laboratory values outside normal limits • Abnormal ECG E 05. Conditions thatmay predispose the participant to excessive bleeding: • A bleeding disorder or knownplatelet dysfunction at any time prior to the Screening Visit • A platelet count <150 000/μL at the Screening Visit • The participant has had major surgery within 4 weeksprior to the Screening Visit, which could affect the participant's safety or affectimmune response (as judged by the Investigator) or has planned any elective majorsurgery during the study. E 06. Conditions that would adversely affect participationin the study or make the primary efficacy endpoint non-evaluable: • Sensitivity to anyof the study interventions, or components thereof, or has a drug or other allergythat, in the opinion of the Investigator, contraindicates participation in the study. • A short life expectancy due to pre-existing health condition(s) as determined bytheir treating neurologist. • A history or presence of significant other concomitantillness according to the Investigator's judgment such as, but not limited tocardiovascular (including Stage III or IV cardiac failure according to New York HeartAssociation [NYHA] classification), or renal (ie, undergoing dialysis), neurological,endocrine, gastrointestinal, hepatic (ie, underlying hepatobiliary disease, screeningALT >3 X upper limit of normal (ULN), or albumin ≤2.5 g/dL [25 g/L]), metabolic,pulmonary, or lymphatic disease that would adversely affect participation in thisstudy. • Any malignancy within 5 years prior to the Screening visit (except foreffectively treated carcinoma in situ of the cervix or adequately treatednon-metastatic squamous or basal cell carcinoma of the skin) will also beexclusionary. • Any other medical condition(s) or concomitant disease(s) making themnonevaluable for the primary efficacy endpoint or that would adversely affectparticipation in this study, as judged by the Investigator. Prior/concomitant therapyE 07. The participant has received any of the following medications/treatments withinthe specified time frame before any baseline assessment (no washout is required forinterferon beta or glatiramer acetate treatments): Systemic corticosteroids,adrenocorticotropic hormone : 1 month prior to screening MRI scan. Dimethyl fumarate (DMF), siponimod :1 month prior to randomization. Intravenous immunoglobulin,fingolimod: 2 months prior to randomization. Teriflunomide (<3 months treatment),mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprineand methotrexate, mycophenolate: 3 months prior to randomization (no time restrictionif accelerated elimination procedure is done). Teriflunomide (≥3 months treatment),lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence ofcardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), otherstrongly immunosuppressive treatments with very long-lasting effects: any time.Natalizumab: 6 months prior to randomization. B-cell-depleting therapies such asocrelizumab and rituximab: 6 months prior to randomization or until return of B-cellcounts to normal levels, whichever is longer. Highlyimmunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 bodysurface area, cyclophosphamide, cladribine: 2 years prior to randomization.Alemtuzumab: 4 years prior to randomization. Other MS-disease modifying treatments: 5half-lives or until end of pharmacodynamics activity, whichever is longer. E 08. Theparticipant is receiving strong inducers or inhibitors of cytochrome P450 (CYP) 3A orCYP2C8 hepatic enzymes as listed in Appendix 8A. E 09. The participant is receivinganticoagulant/antiplatelet therapies, including: • Acetylsalicylic acid (aspirin) •Antiplatelet drugs (eg, clopidogrel) • Warfarin (vitamin K antagonist) • Heparin,including low molecular weight heparin (antithrombin agents) • Dabigatran (directthrombin inhibitor) • Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors)Note: All above drugs need to be stopped at least 5 half-lives before study drugadministration except for aspirin, which needs to be stopped at least 8 days before. E

10. A history of a hypersensitivity reaction to teriflunomide, leflunomide, or to anyof the inactive ingredients in Aubagio (this includes anaphylaxis, angioedema, andserious skin reactions) Prior/concurrent clinical study experience E 11. Theparticipant was previously exposed to any BTK inhibitor, including SAR442168. E 12.The participant has taken other investigational drugs within 3 months or 5 half-lives,whichever is longer, before the Screening Visit. Diagnostic assessments E 13. Theparticipant has had a relapse in the 30 days prior to randomization. E 14. Theparticipant has contraindication for MRI, ie, presence of pacemaker, metallic implantsin high-risk areas (ie, artificial heart valves, aneurysm/vessel clips), presence ofmetallic material (eg, shrapnel) in high risk areas, known history of allergy to anycontrast medium, or history of claustrophobia that would prevent completion of allprotocol-scheduled MRI scans Note: People with a contraindication to Gd can beenrolled into the study but cannot receive Gd contrast dyes during their MRI scans.Other exclusions E 15. Individuals accommodated in an institution because ofregulatory or legal order; prisoners or participants who are legallyinstitutionalized. E 16. Any country-related specific regulation that would preventthe participant from entering the study. E 17. Participant not suitable forparticipation, whatever the reason, as judged by the Investigator, including medicalor clinical conditions, or participants potentially at risk of noncompliance to studyprocedures or not able to follow the schedule of protocol assessments due to otherreasons (exception: participants who are not able to complete electronic clinicaloutcome assessments may be given paper clinical outcome assessments to complete). E
11. Participants are dependent on the Sponsor or Investigator (in conjunction withSection 1.61 of the International Council for Harmonisation (ICH) Good ClinicalPractice (GCP) Ordinance E6). E 19. Participants are employees of the clinical studysite or other individuals directly involved in the conduct of the study, or immediatefamily members of such individuals. E 20. Any other situation during studyimplementation/course that may raise ethics considerations. Note: a one-time retest atscreening may be performed if an abnormal laboratory test value is consideredtemporary. 5.3 LIFESTYLE CONSIDERATIONS 5.3.1 Meals and dietary restrictions SAR442168shall be taken with a meal. When possible, the meal (eg, breakfast, lunch, or dinner)should be consistent in terms of time of day throughout the study. The typical time ofday at which IMP is administered will be collected at each visit. The participant mustrefrain from consumption of grapefruit or grapefruit juice from 5 days prior tointervention administration and throughout the treatment phase. 5.3.2 Caffeine,alcohol, and tobacco For each visit with PK/PD assessment, participants will abstainfrom ingesting caffeine- or xanthine-containing products (eg, coffee, tea, coladrinks, and chocolate) for 2 hours before the start of treatment until aftercollection of the final PK and/or PD sample later that day. For each visit with PK/PDassessment, participants will abstain from alcohol for 24 hours before the start oftreatment until after collection of the final PK and/or PD sample later that day.During the entire study, the IMP should be used with caution in participants whoconsume substantial quantities of alcohol. 5.3.3 Activity No special restrictions. 5.4SCREEN FAILURES Screen failures are defined as participants who consent to participatein the clinical study but are not subsequently randomly assigned to the studyintervention. A minimal set of screen failure information is required to ensuretransparent reporting of screen failure participants to meet the ConsolidatedStandards of Reporting Trials (CONSORT) publishing requirements and to respond toqueries from regulatory authorities. Minimal information includes demography, screenfailure details, eligibility criteria, and any SAE. Individuals who do not meet thecriteria for participation in this study (screen failure) may be rescreened up to 2times. Rescreened individuals should be assigned a different participant number.