Efficacy and Safety of Tolebrutinib (SAR442168) Tablets in Adult Participants With Generalized Myasthenia Gravis

The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.

The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. The QMG total score at Week 12 is reported in this outcome measure. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.

MGII: measure of MG severity, with demonstrated fatigability, reliability and construct validity. It consists of 22-item patient-reported questionnaire and 6 clinician-assessment items. MGII can be divided into 2 sub-scale-scores: ocular (8 items) \& generalized (20 items) impairments. Ocular sub-score: calculated by summing 1 to 6 items from patient questionnaire and items 1 \& 2 of clinician-assessment. Generalized score: calculated by adding items 7 to 22 from patient questionnaire \& items 3 to 6 from the clinician-assessment. Each item is scored on 4-point scale: from 0 (none) to 3 (severe), where higher score=more disease severity. MGII total score: sum of each item of patient questionnaire (total score:0 [normal] to 23 [severe]) \& clinician assessment items (total score:0 [normal] to 61 [severe]); ranged from 0 (normal) to 84 (severe). Higher scores=greater disease severity. DB period Baseline: defined as last available value prior to 1st dose of study medication in the DB period.

The MG-QOL15 is a 15-item, participant self-reported QoL instrument for participants with MG. The instrument is developed and validated to evaluate general QoL of participants with MG by a clinician in the practice setting. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items). Each item is scored on a scale of 0 (not at all) to 4 (very much), where higher score indicates severe QoL impairment. The MG-QOL15 total score is the sum of each individual item score and ranged from 0 (none) to 60 (severe). Higher scores indicates greater extent and dissatisfaction with MG-related dysfunction. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.

The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG.

The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG.

An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. A SAEs was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. AESI was defined as one of scientific \& medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was considered appropriate. Relatedness to study vaccine was based on Investigator's discretion.

Hematological parameters assessed were: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cell, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Only those categories in which at least 1 participant had data were reported.

Clinical chemistry parameters assessed were blood urea nitrogen, creatinine, glucose, total and direct bilirubin, potassium, sodium, chloride, bicarbonate, calcium, albumin, creatine phosphokinase, alkaline phosphatase, aspartate aminotransferase/serum glutamic-oxaloacetic transaminase, alanine aminotransferase/serum glutamic-pyruvic transaminase, lipase, and total protein. Only those categories in which at least 1 participant had data were reported.

ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QTcF.

Vital signs assessed were heart rate, systolic blood pressure, diastolic blood pressure, weight and temperature. Only those category (Weight >=5% increase from Baseline) in which at least 1 participant had data were reported.

The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.

The QMG is a clinician-reported outcome to assess muscle weakness in participants with MG. The QMG test consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is scored on 3-point scale ranged from 0 (none) to 3 (severe), where higher score represents most severe muscle weakness. The QMG total score is the sum of each individual item score which ranged from 0 (normal) to 39 (severe). Higher score represents greater disease activity. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.

MGII: measure of MG severity, with demonstrated fatigability, reliability and construct validity. It consists of 22-item patient-reported questionnaire \& 6 clinician-assessment items. MGII can be divided into 2 sub-scale-scores: ocular (8 items) \& generalized (20 items) impairments. Ocular sub-score: calculated by summing 1 to 6 items from patient questionnaire and items 1 \& 2 of clinician-assessment. Generalized score: calculated by adding items 7 to 22 from patient questionnaire \& items 3 to 6 from the clinician-assessment. Each item is scored on 4-point scale: from 0 (none) to 3 (severe), where higher score=more disease severity. MGII total score: sum of each item of patient questionnaire (total score:0 [normal] to 23 [severe]) \& clinician assessment items (total score:0 [normal] to 61 [severe]); ranged from 0 (normal) to 84 (severe). Higher scores=greater disease severity. OLE period Baseline:defined as last available value prior to 1st dose of study medication in the OLE period.

The MG-QOL15 is a 15-item, participant self-reported QoL instrument for participants with MG. The instrument is developed and validated to evaluate general QoL of participants with MG by a clinician in the practice setting. The domains covered by the questionnaire are mobility (9 items), symptoms (3 items), general contentment (1 item) and emotional well-being (2 items). Each item is scored on a scale of 0 (not at all) to 4 (very much), where higher score indicates severe QoL impairment. The MG-QOL15 total score is the sum of each individual item score and ranged from 0 (none) to 60 (severe). Higher scores indicate greater extent and dissatisfaction with MG-related dysfunction.

The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.

The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life, including talking, chewing, swallowing, breathing, brushing their teeth or combing their hair, getting up from a chair, double vision and eyelid droop. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 to 24, where a higher score represents severe disability due to MG. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.

The use of rescue therapy for generalized MG worsening is allowed at any time during both the DB and OLE parts of the study at discretion of the Investigator in case of at least a 2-point increase of individual non-ocular MG-ADL items compared to the Day 1 MG-ADL value or new or worsening of respiratory/ bulbar symptoms. Rescue therapy includes intravenous immunoglobulin, plasma exchange, change in the standard of care OCS dose or any use of new CS. OLE period Baseline value was defined as last available value prior to the first dose of the study medication in the OLE period.