The WILLOW Study With M5049 in SLE and CLE (SCLE and/or DLE) (WILLOW)

The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) was a validated instrument used to assess disease activity (CLASI-A) and damage in lupus erythematosus. The activity scale included erythema, scale/hypertrophy, active alopecia, recent hair loss, and mucous membrane disease, while the damage scale measured dyspigmentation, atrophy, and scarring. CLASI-A scores ranged from 0 to 70, with mild, moderate, and severe disease corresponding to scores of 0-9, 10-20, and 21-70, respectively. Erythema and scale/hypertrophy sub-scores were computed across 13 body areas, with maximum scores of 39 and 26, respectively. The remaining 5 points reflected contributions from active alopecia (0-3), recent hair loss (0-1), and mucous membrane involvement (0-1), completing the total CLASI-A activity score. Directionality reflected worsening with higher scores and improvement with lower scores.

Time frame: Baseline, week 16

Population: The Full Analysis Set (FAS) included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS. Overall number of participants analyzed refers to those evaluable for the outcome measure,

BILAG-based BICLA response is defined as participants meeting all of the following criteria: 1. Improvement in baseline BILAG scores in all organ systems with moderate or severe disease activity-i.e., all grade A scores (severe disease requiring high-dose therapy) must improve to B (moderate), C (mild), or D (no activity); all grade B scores (moderate disease requiring moderate therapy) must improve to C or D; 2. No new BILAG A scores and no more than one new BILAG B score; 3. No worsening in total SLEDAI-2K score from baseline; 4. No significant deterioration (≤10%) in physician's global assessment; and 5. No treatment failure, defined as initiation of non-protocol therapy. Directionality is toward clinical improvement and disease stabilization.

Time frame: At Week 24

Population: The Full Analysis Set (FAS) included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) is a 13-item, self-reported questionnaire designed to assess fatigue and its impact on daily activities and functioning in individuals with chronic illness, including systemic lupus erythematosus. Each item is rated on a 5-point Likert-type scale ranging from 0 = not at all to 4 = very much. Items are scored to ensure that 0 represents the worst and 4 the best possible outcome. The score ranges from 0 to 52, with higher scores indicating less fatigue and better functioning.

Time frame: Baseline and at Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible.Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

The Skindex 29+3 is a self-reported measure of skin-specific symptoms and functioning for CLE populations, and includes items from the Skindex-29, designed for use across dermatologic conditions, and 3 additional items specific for lupus. Subscale scores are generated for each of the 3 original domains of the Skindex-29 i.e., symptoms, functioning, and emotional well-being. For all subscale scores, higher scores indicate lower functioning/worse symptoms. The symptoms domain includes items measuring physical sensations such as itching, burning, stinging, and pain. Each item is rated on a 5-point Likert scale from 1 (never) to 5 (all the time), and scores are transformed to a 0-100 scale, with higher scores indicating more severe symptoms.

Time frame: Baseline and at week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible.Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

The Skindex 29+3 is a self-reported measure of skin-specific symptoms and functioning for CLE populations, and includes items from the Skindex-29, designed for use across dermatologic conditions, and 3 additional items specific for lupus. Subscale scores are generated for each of the 3 original domains of the Skindex-29 i.e., symptoms, functioning, and emotional well-being. For all subscale scores, higher scores indicate lower functioning/worse symptoms. The emotion domain of the Skindex-29+3 assesses the psychological impact of skin disease in individuals with cutaneous lupus erythematosus. It includes items that measure feelings such as embarrassment, frustration, anger, sadness, and worry related to skin symptoms. Each item is rated on a 5-point Likert scale from 1 (never) to 5 (all the time), and scores are transformed to a 0-100 scale, with higher scores indicating greater emotional distress.

Time frame: Baseline and at Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible.Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

The Skindex 29+3 is a self-reported measure of skin-specific symptoms and functioning for CLE populations, and includes items from the Skindex-29, designed for use across dermatologic conditions, and 3 additional items specific for lupus. Subscale scores are generated for each of the 3 original domains of the Skindex-29 i.e., symptoms, functioning, and emotional well-being. For all subscale scores, higher scores indicate lower functioning/worse symptoms. The functioning domain assesses the impact of skin disease on daily activities, social interactions, and work. Items are rated on a 5-point Likert scale (1 = never to 5 = all the time) and transformed to a 0-100 scale, where higher scores reflect greater impairment in functioning.

Time frame: Baseline and at Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible.Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

The Skindex-29+3 is a self-reported measure of skin-specific symptoms and functioning for CLE populations. It includes items from the Skindex-29, designed for use across dermatologic conditions, and 3 additional items specific to lupus. Subscale scores are generated for the 3 original domains: symptoms, functioning, and emotional well-being. For all subscales, higher scores indicate worse symptoms or lower functioning. The lupus-specific domain captures symptoms and concerns unique to cutaneous lupus, including sensitivity to sunlight, flares from environmental exposure, and emotional impact of lupus-related skin changes. Each item is rated on a 5-point Likert scale from 1 (never) to 5 (all the time), and scores are transformed to a 0-100 scale. Higher scores reflect greater symptom burden and disease impact.

Time frame: Baseline and at Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible.Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

Laboratory parameters included hematology, biochemistry, Urinalysis, Renal Toxicity and Hepatotoxicity. Number of Participants with Abnormal laboratory parameters (severity of grade greater or equal to 3) were reported. Severity of grade 3 or higher TEAEs were graded using National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death.

Time frame: From screening upto safety follow up period (up to approximately 33 weeks)

Population: The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.

12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical importance was determined by the investigator. The number of participants with clinically important increases in QTCF findings were reported.

Time frame: From screening upto safety follow up period (up to approximately 33 weeks)

Population: The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.

CS reduction is defined as the reduction of daily prednisone-equivalent dose from \>= 10 mg at Day 1 to \<= 5 mg by the Week 12 visit and sustained through Week 24. The number of participants with Clinically Meaningful CS Reduction were reported.

Time frame: Day 1 up to Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS. Overall number of participants analyzed refers to those evaluable for the outcome measure.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and were closely followed.

Time frame: From screening upto safety follow up period (up to approximately 33 weeks)

Population: The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.

The Cutaneous Lupus Activity Investigator's Global Assessment (CLA-IGA) is a validated clinician-reported outcome measure used to assess disease severity in participants with cutaneous lupus erythematosus. It is based on a 5-point ordinal scale that evaluates overall lesion characteristics, where 0 indicates clear skin and 4 represents severe disease. The scale includes the following categories: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe).

Time frame: Baseline and at Week 16 and Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Overall number of participants analyzed refers to those evaluable for the outcome measure, while number analyzed refers to those evaluable at specific timepoints. Participants who were randomized in error were excluded from FAS.

The Physician's Global Assessment of Disease Activity was recorded using the 100 millimeter horizontal Visual Analog Scale (VAS). The score reflects the clinician's integrated judgment based on clinical signs, symptoms, laboratory findings, and patient-reported outcomes. PGA is used to quantify disease severity and monitor treatment response over time. Physician rated participant's disease activity on a scale ranged from 0-100 millimeter (mm), where 0 indicated no disease activity and 100 represented maximum disease activity.

Time frame: Baseline and at Week 16 and Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Overall number of participants analyzed refers to those evaluable for the outcome measure, while number analyzed refers to those evaluable at specific timepoints. Participants who were randomized in error were excluded from FAS.

The Cutaneous Lupus Activity Investigator's Global Assessment (CLA-IGA) is a validated clinician-reported outcome measure used to assess disease severity in participants with cutaneous lupus erythematosus. It is based on a 5-point ordinal scale that evaluates overall lesion characteristics, where 0 indicates clear skin and 4 represents severe disease. The scale includes the following categories: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). The number of participants with CLA-IGA score 0 or 1 at Week 16 and Week 24 were reported.

Time frame: At Week 16 and Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

BICLA (BILAG-Based Composite Lupus Assessment) defines response as improvement in all baseline BILAG A scores to B, C, or D and all B scores to C or D, with no new A scores and no more than one new B score. Responders must also show no worsening in SLEDAI-2K or Physician's Global Assessment (defined as ≥0.3-point increase). Corticosteroid (CS) reduction is defined as a decrease in daily prednisone-equivalent dose from ≥10 mg at Day 1 to ≤5 mg by Week 12, sustained through Week 24. BILAG grades reflect disease severity: A = severe disease requiring high-dose therapy; B = moderate disease requiring moderate therapy; C = mild stable disease; D = no current activity.

Time frame: At week 24 (BICLA Response) and Day 1 upto Week 24 (CS Reductions)

Population: The FAS included all participants randomized in the cohort to which they were eligible. Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

Lupus Low Disease Activity State (LLDAS) Attainment at Week 24 is defined as meeting all of the following criteria at the specified time point: SLE Disease Activity Index 2000 (SLEDAI-2K) ≤4 with no activity in major organ systems, no new disease activity compared to the previous assessment, Physician's Global Assessment (PGA) ≤1, current prednisone dose ≤7.5 mg/day, and standard maintenance dosing of immunosuppressive therapies. The number of participants with LLDAS Attainment at Week 24 were reported.

Time frame: At Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

Remission attainment was defined as a Clinical Hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index score of 0, Physician's Global Assessment of Systemic Lupus Erythematosus \<0.5 (0-3 scale), daily prednisolone-equivalent dose ≤5 mg, and stable use of immunosuppressive therapies including biologics. Number of participants who attained remission was reported.

Time frame: At Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

SRI-4 response was defined as \>= 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score, no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score, no worsening (less than 10 percent increase) from baseline in Physician's Global Assessment of Disease Activity (PGA) and no treatment failure. SLEDAI-2K assessment consists of 24 items with total score of 0(no symptoms) to 105 (presence of all defined symptoms) with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to Systemic Lupus Erythematosus (SLE), divided into 9 organ systems. For each organ system A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale =from 0(very well) to 100(very poor).

Time frame: At Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

The 28-joint count questionnaire assesses 14 joints on each side (28 joints overall) for both tenderness and swelling. The outcome for the assessment of each joint can be absent, present, replaced or unable to evaluate.Tender 28-joint count will be derived as the count of joints which are tender. Swollen 28-joint count will be derived as the count of joints which are swollen. The number of tender and swollen joints will be calculated as the count of joints which are both tender and swollen. Percentage of Participants with 50% Reduction in Baseline Tender and Swollen Count at Week 24 was reported.

Time frame: At Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Overall number of participants analyzed refers to those evaluable for the outcome measure. Participants who were randomized in error were excluded from FAS.

Time to First Moderate/Severe British Isles Lupus Assessment Group (BILAG) Flare is defined as the time from baseline to the first occurrence of moderate or severe disease activity, as measured by the BILAG Index. The BILAG Index assesses clinical signs, symptoms, and laboratory parameters related to systemic lupus erythematosus (SLE) across 9 organ systems. Each organ system is scored alphabetically: A (severe disease), B (moderate disease), C (mild stable disease), D (inactive but previously active), and E (inactive and never affected). A moderate/severe flare is defined as the presence of at least one new or worsening BILAG A score (severe disease activity) or two or more new or worsening BILAG B scores (moderate disease activity) in any organ system, compared to the previous visit. Time to First Moderate/Severe British Isles Lupus Assessment Group (BILAG) Flare was estimated via Kaplan-Meier method.

Time frame: Baseline (Day 1) through Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.

Time to First Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI) Severe Flare is defined as the time from baseline to the first occurrence of a severe flare, as measured by the SLEDAI Flare Index (SFI). A severe flare is characterized by a ≥12-point increase in the SLEDAI score from the previous visit, accompanied by a ≥2.5-point increase in the physician's global assessment (on a 0-3 visual analogue scale), and a change in treatment such as initiation of corticosteroids at a dose \>0.5 mg/kg/day and/or the addition of a new immunosuppressive agent. Time to First Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index (SFI) Severe Flare was estimated via Kaplan-Meier method.

Time frame: Baseline (Day 1) through Week 24

Population: The FAS included all participants randomized in the cohort to which they were eligible. Participants who were randomized in error were excluded from FAS.