Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus

The CLASI is a clinician rated scale designed to assess the disease activity and damage in CLE in adults. It is composed of 56 items covering 2 dimensions: the disease activity (CLASI-A) and the disease damage (CLASI-D). CLASI-A disease activity covers the domains: erythema, scale/hypertrophy, recent hair loss/alopecia, and mucous membrane lesions. CLASI-A sub-score ranges for 0 to 70, where 0-9 indicates mild disease, 10-20 indicates moderate disease, and 21-70 indicates severe disease. Higher score indicates a more severe skin disease. Baseline was defined as the Day 1 assessment value.

Time frame: Baseline (Day 1) and Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Week 12 are reported.

Blood samples were collected at the specified timepoints. AUC0-12 was assessed by a Bayesian analysis using the population PK model.

Time frame: 2-5 hours post first morning dose on Days 1, 57, and 85; 1 hour before morning dose on Days 57 and 85; 7-10 hours after morning dose on Day 57

Population: PK population included all randomized and treated participants for whom the PK data are considered interpretable. Participants with data collected at Day 1, 57, and 85 are reported.

The CLASI is a clinician rated scale designed to assess the disease activity and damage in CLE in adults. It is composed of 56 items covering two dimensions: the disease activity (CLASI-A) and the disease damage (CLASI-D). CLASI-A disease activity covers the domains: erythema, scale/hypertrophy, recent hair loss/alopecia, and mucous membrane lesions. CLASI-A sub-score ranges 0 to 70, where 0-9 indicates mild disease, 10-20 indicates moderate disease, and 21-70 indicates severe disease. CLASI-D disease damage covers the domains: dyspigmentation, scarring/atrophy/panniculitis, and clinically judged scarring of the scalp (including scarring alopecia). Scale ranges 0 (absence of disease damage) to 56 (severe disease damage) using the parameters of dyspigmentation and scarring. For CLASI-A and CLASI-D, higher score indicates a more severe skin disease. Change from baseline in CLASI components' score are reported. Baseline was defined as the Day 1 assessment value.

Time frame: Baseline (Day 1) and Weeks 4, 8, 12, and 16

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Weeks 4, 8, 12, and 16 for each specified category are reported.

The Peak Pruritus NRS (itch-NRS) is a single item patient reported outcomes (PRO) tool that participants used to report the intensity of their pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 (no itch) to 10 (worst itch imaginable) NRS by answering the following question: On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?. The total score on scale ranges from 0 (no itch) to 10 (worst itch imaginable). Higher score indicates a more severe skin disease. Baseline was defined as the average of daily non-missing scores obtained during the week prior to Day 1.

Time frame: Baseline (Day 1) and Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Week 12 are reported.

The Peak Pain NRS (Pain-NRS) is a single item PRO tool that participants used to report the intensity of their CLE-related pain (skin, oral, genital) during a daily recall period. Participants were asked to rate their worst pain on a 0 (no pain) to 10 (worst pain imaginable) NRS by answering the following question: On a scale of 0 to 10, with 0 being 'no pain' and 10 being the 'worst pain imaginable', how would you rate your pain at the worst moment due to your lupus during the previous 24 hours?. The total score on scale ranges from 0 (no pain) to 10 (worst pain imaginable). Higher score indicates a more severe skin disease. Baseline was defined as the average of daily non-missing scores obtained during the week prior to Day 1.

Time frame: Baseline (Day 1) and Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Week 12 are reported.

Skindex 29+3 is a PRO measure designed to assess the effects of skin disease on participants' health-related quality of life in adults. It contains the following domains: emotions (10 items), symptoms (7 items), functioning (12 items), lupus-specific issues (3 questions), and 1 item about treatment that is not part of the total score. Recall period is during the past week. Each item is rated on a 5-point Likert scale (never, rarely, sometimes, often, all the time). These responses are then transformed to a linear scale ranging from 0 to 100 in 25-point increments, with 100 representing maximal disability. The total score is the average of participants' responses to items in a given domain, ranging from 0 to 100, where higher scores indicate a greater impact on the health-related quality of life. Baseline was defined as the Day 1 assessment value.

Time frame: Baseline (Day 1) and Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement.

The OHIP-14 is a PRO questionnaire that is composed of 14 items that assess 7 different dimensions, considering the perception of the individual in relation to the impact of oral conditions in the physical, psychological and social well-being in the last month. Each of the 14 items has a set of possible answers distributed in a Likert scale (0 = never, 1 = hardly ever. 2 = occasionally 3 = fairly often, 4 = very often), which represents the frequency that the individual perceives the impact of oral health on 7 dimensions: functional limitation (2 items), physical pain (2 items), psychological discomfort (2 items), physical disability (2 items), psychological disability (2 items), social disability (2 items) and handicap (2 items). The OHIP-14 scores range from 0 to 56 and are calculated by summing the ordinal values for 14 items. Domain scores range from 0 to 8. Higher OHIP-14 scores indicate worse oral-health-related quality of life. Baseline was defined as Day 1 assessment value.

Time frame: Baseline (Day 1) and Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Week 12 are reported.

Blood samples were collected at the specified timepoints. Cmax was assessed by a Bayesian analysis using the population PK model.

Time frame: 2-5 hours post first morning dose on Days 1, 57, and 85; 1 hour before morning dose on Days 57 and 85; 7-10 hours after morning dose on Day 57

Population: PK population included all randomized and treated participants for whom the PK data are considered interpretable. Participants with data collected at Day 1, 57, and 85 are reported.

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: Glucose ≤ 3.9 millimoles per liter (mmol/L) and \< lower limit of normal range (LLN) or ≥ 11.1 mmol/L (unfasted); ≥ 7 mmol/L (fasted); Creatine Kinase \> 3 ULN; Sodium ≤ 129 mmol/L or ≥ 160 mmol/L; Potassium \< 3 mmol/L or ≥ 5.5 mmol/L; Creatinine ≥ 150 micromoles per liter (μmol/L) (Adults) or ≥ 30% change from baseline or ≥ 100% change from baseline; Creatinine Clearance ≥ 60 - \< 90 milliliters per minute (mL/min) (mild decrease in glomerular filtration rate \[GFR\]) or ≥ 30 - \< 60 mL/min (moderate decrease in GFR) or ≥ 15 - \< 30 mL/min (severe decrease in GFR) or \< 15 mL/min (end stage renal disease); Alanine Aminotransferase \> 3 ULN or \> 5 ULN; Aspartate Aminotransferase \> 3 ULN or \> 5 ULN; Alkaline Phosphatase \> 1.5 ULN; Total Bilirubin \> 1.5 ULN.

Time frame: From first dose of study treatment (Day 1) up to end of study (Week 16)

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: Heart Rate (HR) \< 50 beats/min (bpm) or \< 50 bpm and decrease from baseline ≥ 20 bpm or \< 40 bpm or \> 90 bpm; PR Interval \> 200 milliseconds (msec) or \> 200 msec and increase from baseline ≥ 25% or \> 220 msec; QRS Interval \> 110 msec or 110 msec and increase from baseline ≥ 25% or \> 120 msec; QT Interval \> 500 msec; corrected QT (QTc) Interval \> 450 msec or \> 480 msec or increase from baseline \[30-60\] msec or increase from baseline \> 60 msec.

Time frame: From first dose of study treatment (Day 1) up to end of study (Week 16)

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered). Only participants with data collected for each specified category at Week 16 are reported.

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: pH ≤ 4.6 or ≥ 8.

Time frame: From first dose of study treatment (Day 1) up to end of study (Week 16)

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered). Only participants with data collected for each specified category at Week 16 are reported.

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: Diastolic Blood Pressure (DBP) ≤ 45 millimeters of mercury (mmHg) and decrease from baseline ≥ 10 mmHg or ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; Pulse Rate (PR) ≤ 50 bpm and decrease from baseline ≥ 20 bpm or ≥ 120 bpm and increase from baseline ≥ 20 bpm; Systolic Blood Pressure (SBP) ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg or ≥ 160 mmHg and increase from baseline ≥ 20 mmHg; Weight ≥ 5% decrease from baseline or ≥ 5% increase from baseline.

Time frame: From first dose of study treatment (Day 1) up to end of study (Week 16)

Population: Safety population included all randomized participants exposed to the IMP (regardless of the amount of treatment administered). Only participants with data collected for each specified category at Week 16 are reported.

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; Platelets \<100 x 10\^9 per liter (/L) or ≥ 700 x 10\^9/L; Erythrocytes ≥ 6 x 10\^12/L; Leukocytes \< 3 x 10\^9/L (Non-Black \[NB\]); \< 2 x 10\^9/L (Black\[B\]); or ≥ 16 x 10\^9/L; Neutrophils \< 1.5 x 10\^9/L (NB); \< 1 x 10\^9/L (B); Lymphocytes \> 4 x 10\^9/L; 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 range (ULN) (if ULN ≥ 0.5 x 10\^9/L).

Time frame: From first dose of study treatment (Day 1) up to end of study (Week 16)

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 study treatment, whether or not considered related to the study treatment. TEAEs were defined as the adverse events that occurred from the time of the first IMP administration up to the end of study visit. Serious adverse events (SAE): Any AE 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. 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 study treatment (Day 1) up to end of study (Week 16)

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

The CLASI is a clinician rated scale designed to assess the disease activity and damage in CLE in adults. It is composed of 56 items covering 2 dimensions: the disease activity (CLASI-A) and the disease damage (CLASI-D). CLASI-A disease activity covers the domains: erythema, scale/hypertrophy, recent hair loss/alopecia, and mucous membrane lesions. CLASI-A sub-score ranges for 0 to 70, where 0-9 indicates mild disease, 10-20 indicates moderate disease, and 21-70 indicates severe disease. Higher score indicates a more severe skin disease. The CLASI-A50/75 responder was defined as a participant who achieved a decrease by at least 50%/75% of CLASI-A sub-score from baseline.

Time frame: Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement.

The IGA-CLE is a clinician reported outcome (ClinRO) that allows for clinicians to assess the overall disease activity of CLE using a 5-point scale: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). The severity of CLE is determined by descriptions of a combination of 3 plaque characteristics: erythema, scale, elevation. Erythema is the primary characteristic that influenced the rating, with other characteristics considered secondarily. Telangiectatic change is not considered in the rating. The assessment did not require the presence of all 4 characteristics, the severity was averaged over the observed characteristics. The total score on scale ranges from 0 to 4. Higher score indicates a more severe skin disease.

Time frame: Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement. Only participants with data collected at Week 12 are reported.

The PhysGA- disease activity is a 5 point-Lickert scale instrument designed to assess physician-reported disease activity. The investigators were asked the following question How active would you say your patient's cutaneous lupus erythematosus is currently? The total score on scale ranges from 0 (not active at all) to 4 (extremely active). Higher score indicates a more severe skin disease.

Time frame: Week 12

Population: Efficacy population included all randomized participants exposed to the IMP, with available Baseline assessment of the CLASI-A who actually received at least 1 complete dose of IMP and with at least 1 post IMP administration measurement.

Blood samples were collected at the specified timepoints. t1/2z was assessed by a Bayesian analysis using the population PK model.

Time frame: 1 hour before morning dose and 2-5 hours post first morning dose on Day 85

Population: PK population included all randomized and treated participants for whom the PK data are considered interpretable. Participants with data collected at Day 85 are reported.

Blood samples were collected at the specified timepoints. tmax was assessed by a Bayesian analysis using the population PK model.

Time frame: 2-5 hours post first morning dose on Days 1, 57, and 85; 1 hour before morning dose on Days 57 and 85; 7-10 hours after morning dose on Day 57

Population: PK population included all randomized and treated participants for whom the PK data are considered interpretable. Participants with data collected at Day 1, 57, and 85 are reported.