Safety, Tolerability, Pharmacokinetics, and Therapeutic Efficacy of SAR441344 in Primary Sjögren's Syndrome (pSjS)

ESSDAI is validated and established outcome measurement for therapeutic efficacy in Sjögren's syndrome, evaluating disease activity mainly on extra-glandular manifestations. This score consists of 12 organ-specific domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral and central nervous system, hematological, biological), which are scored based on organ-specific items in 3 to 4 different severity grades (no, low, moderate, high; with 0=no and 3=high). These scores are summed up over all 12 domains in weighted way (severity grades are multiplied with weights ranging 1-6 depending on domain) to summarize into total score(0-123). Higher scores indicates worse outcome. Negative change from baseline indicates improvement. Baseline=Day 1 assessment value. Least squares (LS) mean is calculated using mixed models for repeated measures (MMRM). Observed values after occurrence of intercurrent events are excluded.

Time frame: Baseline (Day 1) to Week 12

Population: Efficacy population included all randomly assigned participants who actually received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement, with available Baseline assessment of the ESSDAI. Only participants with data collected for this outcome measure are reported.

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. AUC0-tau was assessed by a Bayesian approach using the population PK model.

Time frame: After the last SC dose on Week 10 up to 336 hours post-dose

Population: PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.

The ESSPRI is a validated and established outcome measurement, reported by participants, which rates the key disease manifestations: fatigue, dryness, and pain, based on a numeric scale ranging from 0 to 10, where 0 is defined as no symptoms and 10 as maximum imaginable complaints. The total score is the mean score of the 3 scales and ranges from 0 to 10. Higher scores indicates worse outcome. A negative change from baseline indicates improvement. Baseline is defined as Day 1 assessment value. LS mean is calculated using MMRM. Observed values after occurrence of intercurrent events are excluded.

Time frame: Baseline (Day 1) to Week 12

Population: Efficacy population included all randomly assigned participants who actually received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement, with available Baseline assessment of the ESSDAI. Only participants with data collected for this outcome measure are reported.

The MFI is a validated, 20 item self-report instrument to evaluate fatigue by investigating the following subscales: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. Each subscale consists of 4 items that are scored using a scale from 1 (yes, this is true) to 5 (no, this is not true) on which the participants indicate how the listed statements applied to their current fatigue situation. Item scores are summed to create individual subscale score ranging from 4 to 20. A higher score indicates a higher degree of fatigue. A negative change from baseline indicates improvement. Baseline is defined as Day 1 assessment value. LS mean is calculated using ANCOVA. Observed values after occurrence of intercurrent events are excluded.

Time frame: Baseline (Day 1) to Week 12

Population: Efficacy population included all randomly assigned participants who actually received at least 1 complete dose of IMP with at least 1 post-IMP administration measurement, with available Baseline assessment of the ESSDAI. Only participants with data collected for this outcome measure are reported.

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. Cmax was assessed by a Bayesian approach using the population PK model.

Time frame: After the last SC dose on Week 10 up to 336 hours post-dose

Population: PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344.

Time frame: At end of infusion and 4 hours post-infusion on Day 1; pre-dose at Weeks 2, 4, 6, 8, 10, and at Week 12

Population: Pharmacokinetic (PK) population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected at specified timepoints for each specified category are reported.

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344.

Time frame: At end of infusion and 4 hours post-infusion on Day 1; pre-dose at Weeks 2, 4, 6, 8, 10, and at Week 12

Population: PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected at specified timepoints for each specified category are reported.

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. Local tolerability at injection site was assessed following IMP injection and findings at the site of injection such as injection site erythema, injection site reaction, and injection site pain were recorded.

Time frame: Baseline (Day 1) to Week 10

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

Serum samples were collected at the specified timepoints for the assessment of ADAs to SAR441344. Number of participants with treatment-emergent ADA defined as at least 1 treatment-induced/boosted ADA during the treatment-emergent period, i.e. from the time of the IMP administration up to the end of study visit are reported. Number of participants with positive ADA are reported.

Time frame: Baseline, Week 4, Week 8, Week 12, and Week 24

Population: ADA population included all randomized participants treated with SAR441344 with at least 1 post-baseline ADA result (positive, negative or inconclusive). Only participants with data collected at specified timepoints are reported.

For the measurement of local tolerability, participants had a self-evaluation using a VDS before IMP administration, after completion of the IMP administration, and 2 hours post-administration. The participants were asked to report sensations at the injection site and rated the pain severity as following grading: 0= no pain; 1= mild pain; 2= moderate pain, 3= severe pain, 4= very severe. A positive change in VDS score indicated a higher pain severity compared to the pre-dose pain. The numerical change provides the number of grades the pain got worse (positive change) or improved (negative change). Total number of participants with pain intensity increase (change in VDS score of greater than or equal to 1) compared to pre-dose pain intensity are reported.

Time frame: Pre-dose (within 24 hours prior IMP dosing), post-dose (up to 15 minutes after dosing) and 2 hours post-dose at Weeks 2, 4, 6, 8 and 10

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered). Only participants with data collected at specified timepoints for each specified category are reported.

PCSA values:abnormal values considered medically important by Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by Sponsor.Criteria for PCSA:Sodium≤129 millimoles per liter(mmol/L),≥160 mmol/L;Potassium\<3 mmol/L,≥5.5 mmol/L;Glucose≤3.9 mmol/L and \<lower limit of normal(LLN),≥11.1 mmol/L(unfasted);≥7 mmol/L(fasted); Creatine kinase(CK)\>3 ULN,\>10 ULN;Creatinine≥150 micromoles/L(adults),≥30% change from baseline,≥100% change from baseline;Creatinine clearance(CG)≥60-\<90 milliliters per minute(mL/min)(mild decrease in glomerular filtration rate\[GFR\]),≥30-\<60 mL/min(moderate decrease in GFR),≥15-\<30 mL/min(severe decrease in GFR),\<15 mL/min(end stage renal disease),Urea nitrogen≥17 mmol/L;Alkaline phosphatase(ALP)\>1.5 ULN;Alanine aminotransferase(ALT)\>3 ULN; ALT\>3 ULN and bilirubin\>2 ULN;Aspartate aminotransferase(AST)\>3 ULN;Direct bilirubin\>35% bilirubin and bilirubin\>1.5 ULN;Total bilirubin\>1.5 ULN,\>2 ULN.

Time frame: Baseline (Day 1) to Week 24

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: HR \<50 bpm, \<40 bpm, \>90 bpm, \>90 bpm and increase from baseline ≥20 bpm, \>100 bpm; PR interval, aggregate \>200 milliseconds (msec), \>200 msec and increase from baseline ≥25%, \>220 msec, \>220 msec and increase from baseline ≥25%, \>240 msec, \>240 msec and increase from baseline ≥25%; QRS duration, aggregate \>110 msec, \>110 msec and increase from baseline ≥25%, \>120 msec, \>120 msec and increase from baseline ≥25%; QT interval, aggregate \>500 msec; corrected QT (QTc) correction method unspecified \>450 msec, \>480 msec, increase from baseline \[30-60\] msec, increase from baseline \>60 msec.

Time frame: Baseline (Day 1) to Week 24

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Hemoglobin (Hb) ≤115 grams per liter (g/L) (Male \[M\]) or ≤95 g/L (Female \[F\]), ≥185 g/L (M) or ≥165 g/L (F), decrease from baseline ≥20 g/L; Hematocrit ≤0.37 volume per volume (v/v) (M) or ≤0.32 v/v (F), ≥0.55 v/v (M) or ≥0.5 v/v (F); Erythrocytes (red blood cells \[RBC\]) ≥6 x 10\^12 per liter (/L); Platelets \<100 x 10\^9/L, ≥700 x 10\^9/L; Leukocytes (white blood cells \[WBC\]) \<3 x 10\^9/L (Non-Black\[NB\]) or \<2 x 10\^9/L (Black\[B\]), ≥16 x 10\^9/L; Neutrophils \<1.5 x 10\^9/L (NB) or \<1 x 10\^9/L (B); Lymphocytes \>4 x 10\^9/L, \<0.5 x 10\^9L; Monocytes \>0.7 x 10\^9/L; Basophils \>0.1 x 10\^9/L; Eosinophils \>0.5 x 10\^9/L or \>upper limit of normal(ULN) (if ULN ≥0.5 x 10\^9/L).

Time frame: Baseline (Day 1) to Week 24

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Potential of hydrogen (pH) ≤4.6 or ≥8.

Time frame: Baseline (Day 1) to Week 24

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Sitting systolic blood pressure (SSBP) less than or equal to (≤)95 millimeters of mercury (mmHg) and decrease from baseline ≥20 mmHg; ≥160 mmHg and increase from baseline ≥20 mmHg; Sitting diastolic blood pressure (SDBP) ≤45 mmHg and decrease from baseline ≥10 mmHg, ≥110 mmHg and increase from baseline ≥10 mmHg; Sitting heart rate (HR) ≤50 beats per minute (bpm) and decrease from baseline ≥20 bpm, ≥120 bpm and increase from baseline ≥20 bpm; Weight ≥5% decrease from baseline, ≥5% increase from baseline.

Time frame: Baseline (Day 1) to Week 24

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. TEAEs were AEs that occurred, worsened, or became serious during the TEAE period (time from the first IMP administration up to Week 24).

Time frame: From first dose of IMP (Day 1) up to end of follow-up period (Week 24)

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of IMP, whether or not considered related to the IMP. TEAEs: AEs that occurred, worsened, or became serious during the TEAE period (time from the first IMP administration up to Week 24). Serious adverse events (SAE): 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 disability/incapacity, or was a congenital anomaly/birth defect. An AESI: an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required.

Time frame: From first dose of IMP (Day 1) up to end of follow-up period (Week 24)

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered).

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. t1/2z was assessed by a Bayesian approach using the population PK model.

Time frame: Week 10 to Week 12

Population: PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population.

Blood samples were collected at the specified timepoints for the measurement of plasma concentrations of SAR441344. tmax was assessed by a Bayesian approach using the population PK model.

Time frame: After the last SC dose on Week 10 up to 336 hours post-dose

Population: PK population included all randomized and treated participants (safety population) with adequate PK results. Participants who received only placebo were not a part of the PK population. Only participants with data collected for this outcome measure are reported.