A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging, Parallel and Adaptive Study to Evaluate the Efficacy and Safety of Enpatoran in SLE and in CLE (SCLE and/or DLE) Participants Receiving Standard of Care (WILLOW)
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: EMD Serono Research & Development Institute, Inc.

Enpatoran (M5049)
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A 
Phase 
2, 
Randomized, 
Double-Blind, 
Placebo-Controlled Dose-Ranging, Parallel and 
Adaptive Study to Evaluate the Efficacy and Safety 
of Enpatoran in Systemic Lupus Erythematosus 
and in Cutaneous Lupus Erythematosus (Subacute 
Cutaneous Lupus Erythematosus and/or Discoid 
Lupus Erythematosus)
Participants Receiving 
Standard of Care
Study Number:
MS200569_0003
Protocol Version:
23 May 2024/Version 4.0
Merck Compound:
Enpatoran (M5049)
Merck Registered Compound Name in 
Japan:
Not applicable
Study Phase:
Phase 2
Short Title:
The WILLOW study with enpatoran in SLE and 
CLE (SCLE and/or DLE)
Acronym or Abbreviation:
WILLOW
Coordinating Investigator-1:
Coordinating Investigator-2:
 
 
 
 
 
 
 
 

Enpatoran (M5049)
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MS200569_0003
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Sponsor Name and Legal Registered 
Address:
Sponsor:
Affiliates of Merck KGaA, Darmstadt, Germany
For all countries, except the US and Canada:
Merck Healthcare KGaA, Darmstadt, Germany
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250
64293, Darmstadt, Germany
In the US and Canada:
EMD Serono Research & Development Institute, 
Inc.
an affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA, 01821, USA
Local Sponsor for Sites in Japan:
Merck Biopharma Co., Ltd. Japan
an affiliate of Merck KGaA, Darmstadt, Germany
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
Regulatory Agency Identifying 
Numbers:
IND: 145565
ClinicalTrials.gov identifier: NCT05162586
EUCT Number: 2024-510872-18-00
(Previously EudraCT: 2021-004648-27)
Keywords
TLR7, TLR8, WILLOW, adults, SLE, CLE, 
lupus, discoid lupus erythematosus, subacute 
cutaneous lupus erythematosus, M5049, and 
enpatoran

Enpatoran (M5049)
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
4.0
Global Amendment 3
23-May-2024
3.1
Local Amendment South Korea
12-Jun-2023
3.0
Global Amendment 2
17-Mar-2023
2.0
Global Amendment 1
12-Sep-2022
1.1-JPN
Local Protocol Amendment Japan
10-Dec-2021
1.0
Original Protocol
28-Sep-2021
Protocol Version 4.0 (23 May 2024)
Overall Rationale for the Amendment
The overall rationale for this protocol amendment is alignment with IB version 8.0 and to add 
language regarding potential BCRP-related DDIs.
Section # and Name
Description of Change
Brief Rationale
Section 8.2.3
Electrocardiograms
Addition of language regarding potential 
review of ECG tracings.
Allow flexibility.
Section 9.2 Sample Size 
Determination
Assumptions for sample size corrected.
Correction in the description of 
parameters (Emax), no change in 
actual sample size.
Section 9.4.4 Sequence of 
Analysis
Added clarification of involvement of Firewall 
Team in Cohort A Week 16 data review
To ensure data integrity 
throughout the study.
Addition of language regarding timing of final 
analysis for Cohort A and Cohort B.
Allow flexible timing for final 
analysis of Cohort A and 
Cohort B.
Appendix 2 Study 
Governance
Addition of language regarding the applicable 
EU legislation.
Preparation of CTIS transition.
Language added regarding involvement of 
Firewall Team in Cohort A Week 16 analysis
Completeness and consistency 
within document.
Appendix 5 Clinical 
Laboratory Tests
Addition of RBC count to hematological 
assessments.
Added for completeness.
Appendix 11 Country-
specific Requirements and 
Section 10 References
Added Appendix listing country-specific 
requirements for South Korea, to include 
further details of the changes added to
Protocol Version 2.0., additional citations have 
been added to List of References.
To align local protocol version 
with global protocol version.

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Section # and Name
Description of Change
Brief Rationale
Throughout
EUCT number added.
Minor editorial and document formatting 
revisions.
Table of Tables and Table of Figures has 
been added.
Preparation of CTIS transition.
Administrative and editorial 
updates.
For completeness and easy 
document navigation.
- Confidential 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not 
in full or part 
be passed on, reproduced, published, or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2024 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.

Enpatoran (M5049)
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Table of Contents
Title Page
..............................................................................................................1 
Table of Contents
..............................................................................................................5 
Table of Tables
..............................................................................................................9 
Table of Figures
..............................................................................................................9 
1 
Protocol Summary ..............................................................................10 
1.1 
Synopsis..............................................................................................10 
1.2 
Schema................................................................................................18 
1.3 
Schedule of Activities.........................................................................19 
2 
Introduction.........................................................................................31 
2.1 
Study Rationale...................................................................................31 
2.2 
Background.........................................................................................31 
2.3 
Benefit/Risk Assessment ....................................................................33 
2.3.1 
Risk Assessment.................................................................................35 
2.3.2 
Risk Assessment in the Context of SARS-CoV-2..............................38 
2.3.3 
COVID-19 Vaccination......................................................................38 
2.3.4 
Benefit Assessment.............................................................................39 
2.3.5 
Overall Benefit: Risk Conclusion.......................................................39 
3 
Objectives and Estimands...................................................................40 
4 
Study Design.......................................................................................46 
4.1 
Overall Design....................................................................................46 
4.2 
Scientific Rationale for Study Design ................................................48 
4.3 
Justification for Dose..........................................................................49 
4.4 
End of Study Definition......................................................................51 
5 
Study Population.................................................................................51 
5.1 
Inclusion Criteria ................................................................................52 
5.2 
Exclusion Criteria...............................................................................56 
5.3 
Lifestyle Considerations .....................................................................61 
5.3.1 
Meals and Dietary Restrictions...........................................................61 
5.3.2 
Activity ...............................................................................................61 
5.4 
Screen Failures....................................................................................61 
6 
Study Intervention and Concomitant Therapies .................................62 

Enpatoran (M5049)
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6.1 
Study Intervention Administration .....................................................62 
6.2 
Study Intervention Preparation, Handling, Storage, and 
Accountability.....................................................................................63 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................64 
6.3.1 
Study Intervention Assignment ..........................................................64 
6.3.2 
Blinding ..............................................................................................65 
6.3.3 
Emergency Unblinding.......................................................................66 
6.4 
Study Intervention Compliance ..........................................................67 
6.5 
Dose Selection and Modification........................................................67 
6.6 
Continued Access to Study Intervention After the End of the 
Study...................................................................................................67 
6.7 
Treatment of Overdose .......................................................................68 
6.8 
Concomitant Therapy .........................................................................68 
6.8.1 
Corticosteroids....................................................................................68 
6.8.2 
Corticosteroids Rescue Medication ....................................................69 
6.8.3 
Permitted Medicines ...........................................................................69 
6.8.4 
Prohibited Medicines..........................................................................71 
6.8.5 
Other Interventions .............................................................................73 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................73 
7.1 
Discontinuation of Study Intervention................................................73 
7.1.1 
Temporary Discontinuation................................................................73 
7.1.2 
Permanent Discontinuation.................................................................73 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................74 
7.3 
Lost to Follow-Up...............................................................................74 
8 
Study Assessments and Procedures....................................................75 
8.1 
Efficacy Assessments and Procedures................................................76 
8.2 
Safety Assessments and Procedures ...................................................76 
8.2.1 
Physical Examinations........................................................................77 
8.2.2 
Vital Signs ..........................................................................................77 
8.2.3 
Electrocardiograms.............................................................................77 
8.2.4 
Clinical Safety Laboratory Assessments ............................................78 

Enpatoran (M5049)
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8.2.5 
Disease and Disease Treatment History .............................................79 
8.2.6 
Suicidal Ideation and Behavior Risk Monitoring...............................80 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ............................................................................................80 
8.3.1 
Method of Detecting Adverse Events and Serious Adverse Events...81 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events ...............81 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse Events .....81 
8.3.4 
Pregnancy ...........................................................................................82 
8.3.5 
Cardiovascular and Death Events.......................................................83 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................83 
8.3.7 
Adverse Events of Special Interest (AESI) ........................................83 
8.3.8 
Management of Adverse Events (Including AESI)............................83 
 
 
 
 
 
 
8.7 
Immunogenicity Assessments ............................................................87 
8.8 
Health Economics...............................................................................87 
9 
Statistical Considerations....................................................................87 
9.1 
Statistical Hypotheses.........................................................................87 
9.2 
Sample Size Determination ................................................................88 
9.3 
Analyses Sets......................................................................................91 
9.4 
Statistical Analyses.............................................................................92 
9.4.1 
Efficacy Analyses ...............................................................................93 
9.4.1.1 
Primary Analysis of Percent Change in CLASI-A at Week 16..........95 
9.4.1.2 
Primary Analysis of the Response in BICLA at Week 24..................96 
9.4.2 
Safety Analyses ..................................................................................97 
9.4.2.1 
Adverse Events ...................................................................................97 
9.4.2.2 
Clinical Laboratory Test Values.........................................................97 
9.4.2.3 
Vital Signs ..........................................................................................98 
9.4.2.4 
Electrocardiogram Parameters............................................................98 
9.4.2.5 
Concomitant Medication and Procedures...........................................99 
9.4.3 
Other Analyses....................................................................................99 

Enpatoran (M5049)
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9.4.3.1 
Pharmacokinetic Parameters, Pharmacodynamic Parameters ............99 
9.4.3.2 
Demographics, Baseline Characteristics, Disposition, and 
Compliance.........................................................................................99 
9.4.3.3 
Patient-Reported Outcomes..............................................................100 
9.4.4 
Sequence of Analyses.......................................................................100 
10 
References.........................................................................................102 
11 
Appendices .......................................................................................107 
Appendix 1 
Abbreviations....................................................................................108 
Appendix 2 
Study Governance.............................................................................112 
Appendix 3 
Contraception and Barrier Requirements .........................................119 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................121 
Appendix 5 
Clinical Laboratory Tests .................................................................127 
Appendix 6 
Lupus Medication Guidance.............................................................129 
Appendix 7 
Corticosteroids Guidance..................................................................132 
Appendix 8 
Efficacy and Patient-Reported Outcome Assessments and 
Procedures.........................................................................................138 
 
 
Appendix 10 
Protocol Amendment History...........................................................149 
Appendix 11 
Country-specific Requirements ........................................................159 
Appendix 12 
Sponsor Signature Page....................................................................162 
Appendix 13 
Coordinating Investigator-1 Signature Page.....................................163 
Appendix 14 
Coordinating Investigator-2 Signature Page.....................................164 
Appendix 15 
Principal Investigator Signature Page...............................................165 

Enpatoran (M5049)
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Table of Tables
Table 1 
Schedule of Assessments....................................................................19 
Table 2 
Potential Risks of Clinical Significancea............................................35 
Table 3 
Study Intervention Administration .....................................................62 
Table 4 
Contraception Guidance ...................................................................120 
Table 5 
Clinical Laboratory Assessments .....................................................127 
Table 6 
Medications with Required Washout................................................129 
Table 7 
Medications with Required Duration of Stable Dose.......................130 
Table 8 
Corticosteroid Guidance for the Screening period and 24-Week 
DBPC period.....................................................................................132 
Table 9  
Corticosteroid Tapering Guidance during the 24-Week DBPC 
period (example only).......................................................................134 
Table 10 
Prednisone-equivalence Calculation (Total Daily Dose) .................136 
Table 11 
Topical Corticosteroids Class...........................................................137 
Table of Figures
Figure 1 
Study Schema .....................................................................................18 
Figure 2 
Assignment of Study Cohort Based on Disease Activity Features 
at Screening Visit................................................................................54
Figure 3 
CS (prednisone-equivalent) dosing schedule....................................133 

Enpatoran (M5049)
The WILLOW study with enpatoran in SLE and CLE (SCLE and/or DLE)
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging,
Parallel and Adaptive Study to Evaluate the Efficacy and Safety of Enpatoran in Systemic Lupus 
Erythematosus (SLE) and in Cutaneous Lupus Erythematosus (CLE: Subacute Cutaneous Lupus 
Erythematosus [SCLE] and/or Discoid Lupus Erythematosus [DLE]) Participants Receiving 
Standard of Care.
Short Title: The WILLOW study with enpatoran in SLE and CLE (SCLE and/or DLE).
Rationale: The purpose of this global Phase 2, basket proof-of-concept (PoC) and dose-finding
study is to evaluate the efficacy and safety of orally administered enpatoran over 24 weeks in
participants with active SLE or CLE (active SCLE and/or DLE) in a randomized, double-blind, 
placebo-controlled, parallel, adaptive, and dose-ranging setting.
M5049 (International nonproprietary name: enpatoran, hereafter used interchangeably in the 
protocol) is a small molecule, dual Toll-like receptor (TLR)7 and TLR8 antagonist 
 
 
 
 
 
 
 
 
 
 
 

Enpatoran (M5049)
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Objectives and Estimands:
Objectives
Estimand attributes
Primary
To evaluate the dose-response relationship of
enpatoran in reducing disease activity based on 
CLASI-A
Endpoint: Percent change from Baseline in CLASI-A at 
Week 16
Population: Patients with active SCLE, DLE, or SLE with 
predominantly active lupus rash
Note: Cohort A participants
Treatment: Enpatoran vs placebo
 
 
 
 
 
Population-Level Summary: LS mean (SE) as estimated by 
MMRM. The MCP-Mod procedure will be performed to 
evaluate the dose-response relationship.
To evaluate the dose-response relationship of 
enpatoran in reducing disease activity based on 
BICLA response rate
Endpoint: BICLA response at Week 24
Population: Patients with active SLE
Note: Cohort B participants
Treatment: Enpatoran vs placebo
 
 
 
 
Population-Level Summary: Responder rates and 95% CI. 
The MCP-Mod procedure will be performed to evaluate the 
dose-response relationship.

Enpatoran (M5049)
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Objectives
Estimand attributes
Secondary
To evaluate the safety and tolerability of enpatoran
compared to placebo
Endpoints:
From Day 1 to the end of Safety Follow-up period
Occurrence of TEAEs, SAEs, and AESI
Occurrence of abnormalities (Grade 3) in laboratory 
parameters
Occurrence of Clinically Important increases in QT 
Interval Corrected Using Fridericia's Formula (QTcF)
To evaluate the efficacy in disease control of 
enpatoran compared to placebo in lupus participants
with active lupus rash
Endpoints:
Change from Baseline in CLA-IGA at Week 16 and 
Week 24
Change 
from 
Baseline 
in 
Assessment of Cutaneous Lupus Disease Activity at 
Week 16 and 24
Population: Patients with active SCLE, DLE, or SLE with 
active lupus rash
Note: Active SCLE, DLE and SLE participants from Cohort 
A OR Cohort B with CLASI-A
8 at Screening and 
confirmed at Day 1
 
 
 
 
 
Population-Level Summary: LS mean (SE) at each visit and 
treatment difference (95% CI) as estimated by MMRM.
To demonstrate the effect of enpatoran compared 
with placebo on achieving both BICLA response and 
clinically meaningful CS reduction in SLE participants 
Endpoint:
BICLA response and clinically meaningful CS reduction, 
defined as 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
Population: Patients with active SLE (Cohort B participants)
Population-Level Summary: same as BICLA response.
To evaluate the efficacy in disease control of 
enpatoran compared to placebo in lupus participants
with predominantly active lupus rash
Endpoints:
Clinically meaningful CS reduction, defined as 
reduction of daily prednisone-equivalent dose from 
5 mg by the Week 12 visit and 
sustained through Week 24
Occurrence of CLA-IGA 0 or 1 at Week 16 and 
Week 24

Enpatoran (M5049)
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Objectives
Estimand attributes
Population: Patients with active SCLE, DLE, or SLE with 
predominantly active lupus rash
Note: Active SCLE, DLE and SLE participants from 
Cohort A
Population-Level Summary: number and proportion with 
95% CI of participants achieving the respective response 
definition at Week 12 and Week 24.
To evaluate the efficacy in disease control of 
enpatoran compared to placebo in participants with
active SLE
Endpoints:
SRI-4 response at Week 24
LLDAS attainment at Week 24
Remission attainment at Week 24
Clinically meaningful CS reduction, defined as 
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
Population: Patients with active SLE
Note: Cohort B participants
Population-Level Summary: Number and proportion with 
95% CI of participants achieving the respective response 
definition at Week 24.
Endpoint:
Change 
from 
Baseline 
in 
Physician
Global 
Assessment at Week 24
Population: as above
 
 
 
 
 
Population-Level Summary: Summary statistics at each visit

Enpatoran (M5049)
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Objectives
Estimand attributes
Endpoint:
Change in the number of joints which are tender and 
swollen in 28-joint count from Baseline at Week 24
Population: Patients with active SLE and at least 4 active 
joints
Note: Cohort B participants with at least 4 active joints
 
 
 
 
Population-Level Summary: Summary statistics at each 
visit
Endpoints:
Time to first moderate/severe BILAG flare from Day 1 
through Week 24
Time to first SFI severe flare from Day 1 through 
Week 24
Population: Patients with active SLE
Note: Cohort B participants
 
 
 
 
Population-Level Summary: HR and CI from stratified Cox 
model, Kaplan-Meier estimates
To evaluate the efficacy of enpatoran compared to 
placebo in patient-reported symptoms and functional 
status, in lupus participants with active lupus rash 
Endpoints:
Change from Baseline in the Skindex 29+3 Symptom 
domain score at Week 24
Change from Baseline in the Skindex 29+3 Functioning 
and Emotion domain scores at Week 24
Change 
from 
Baseline 
in 
the 
Skindex 
29+3 
lupus-specific domain score at Week 24
Change from Baseline in the FACIT-Fatigue scores at 
Week 24

Enpatoran (M5049)
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Objectives
Estimand attributes
Population: Patients with active SCLE, DLE, or SLE with 
active lupus rash. Note: Active SCLE, DLE and SLE 
participants from Cohort A OR Cohort B with CLASI-
8
at Screening and confirmed at Day 1. For FACIT-fatigue: 
Cohort A
 
 
 
 
 
Population-Level Summary: Descriptive statistics at each 
visit and treatment difference at Week 24 as estimated by 
MMRM.
To evaluate the efficacy of enpatoran compared to 
placebo in patient-reported symptoms, in participants
with active SLE
Endpoints:
Change from Baseline in the FACIT-Fatigue scores 
Week 24
Population: Patients with active SLE
Note: Cohort B participants
 
 
 
 
 
Population-Level Summary: descriptive statistics at each 
visit and treatment difference at each study visit as 
estimated by MMRM.
AE = Adverse Event, AESI = Adverse Events of Special Interest, BICLA = BILAG-Based Composite Lupus Assessment,
CLA-IGA = 
, CLASI = Cutaneous Lupus Erythematosus 
Disease Area and Severity Index, CLE = Cutaneous Lupus Erythematosus, CS = corticosteroids, DLE = Discoid Lupus 
Erythematosus, EAC = Endpoint Adjudication Committee, FACIT = Functional Assessment of Chronic Illness Therapy,
LLDAS = Lupus Low Disease Activity State, LS = Least square, MCP-Mod = Multiple Comparisons Procedure 
Modelling, MMRM = mixed-model with repeated measures,
SAE = Serious Adverse Event,
SCLE = Subacute 
Cutaneous Lupus Erythematosus, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index, SE = Standard 
error, SFI = SLEDAI Flare Index, SLE = Systemic Lupus Erythematosus, SRI = Systemic lupus erythematosus 
Responder Index, TEAE = Treatment-emergent Adverse Events.

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Overall Design:
This is a global, Phase 2, basket proof-of-concept, and dose-finding, randomized, double-blind, 
placebo-controlled, dose-ranging, parallel and adaptive multicenter study in participants with 
active SLE or CLE (active SCLE and/or DLE) treated with standard of care to evaluate the efficacy 
and safety of enpatoran administered orally twice per day for 24 weeks.
Brief Summary:
The purpose of this PoC and DF study is to evaluate the efficacy and safety of orally 
administered enpatoran over 24 weeks in SLE and CLE (active SCLE and/or DLE) patients 
in a randomized, double-blind, placebo-controlled, parallel, adaptive, and dose-ranging 
setting.
Study Duration: 33 weeks
Visit Frequency: every 2 or 4 weeks
Enpatoran is not available through an expanded access program.
Number of Participants: Up to 532 participants (approximately 100 in Cohort A + up to 432 in
Cohort B) will be randomized, treated, and followed-up in this study.
Study Intervention Groups and Duration:
The planned total duration of the study for each participant will be up to approximately 33 weeks:
up to a 7-Week Screening Period (5-Week Screening Period with the possibility to expand by an 
additional 2 weeks if needed to repeat a laboratory test or due to an unanticipated event), a 
24-Week Double-Blind Placebo-Controlled (DBPC) Treatment Period followed by a 2-Week
Safety Follow-up Period. Upon completion of the eligibility form, and confirmation of eligibility 
of active SLE or CLE (active SCLE and/or DLE) by the Medical Monitor as well as Primary 
Investigator assessment that participant continues to meet inclusion/exclusion criteria, the 
participant will be randomized. The study will be conducted on an outpatient basis.
The study consists of 2 cohorts to establish PoC and dose-finding for enpatoran in 2 patient 
populations: Cohort B has a dose-finding adaptive design comprised of Part 1 and Part 2. Cohort A
and Cohort B Part 1 will start in parallel with a subsequent initiation of Cohort B Part 2.
Cohort A will have participants with CLE (active SCLE, and/or DLE) (CLASI-
or SLE 
with predominantly active lupus rash (CLASI-A
8) and for SLE mild or no 
extra-mucocutaneous disease activity (BILAG 2004 1B, C, D [i.e., No BILAG 2004 A and No 
BILAG 2004 
2B]). Approximately 100 participants will be randomized 1:1:1:1 to enpatoran 
25 mg twice per day (n = 25): enpatoran 50 mg twice per day (n = 25): enpatoran 100 mg twice 
per day (n = 25): placebo twice per day (n=25). An interim analysis of Cohort A for futility may 
be performed after a minimum of 40 participants have completed at least 16 weeks of treatment 
or discontinued the study prematurely, with no pause in the enrollment.
Cohort B will have SLE participants who have moderate to high systemic disease activity 
(BILAG
1A and/or 2B) with 1 or 2 of the following: CLASI-A
8 and/or SLEDAI 
6. An

Enpatoran (M5049)
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adaptive design will be used for this cohort: Part 1 is designed to assess a clinical signal and 
based on an interim analysis of Part 1, Part 2 may be adapted to improve dose-finding in SLE,
if needed.
o Part 1 will be initiated first with approximately 60 participants randomized 2:1 to 
enpatoran 100 mg twice per day vs placebo to evaluate the futility of enpatoran vs 
placebo in SLE participants.
o Part 2 will be initiated after approximately 60 participants have been enrolled in Part 1
and participants will be randomized 1:1:1:1 to enpatoran 25 mg twice per day:
enpatoran 50 mg twice per day: enpatoran 100 mg twice per day: placebo twice per 
day. An interim analysis is planned when the first 60 participants in Part 1 complete at 
least 12 weeks of treatment, or discontinue early, to decide whether to terminate 
Cohort B for futility. It may inform potential adaptations of dose, randomization ratio,
stratification factors, and sample size for Part 2. Participants from Part 1 and Part 2 
Cohort B will continue on their dose level initiated prior to any potential adaptation 
until completion of study treatment at Week 24 unless Cohort B is terminated for 
futility. Dose adaptations, if any, will be implemented only on new Cohort B Part 2 
participants enrolled after this decision is made. Total sample size of Cohort B will not 
exceed 432 participants. In case country-specific Authorities (local IRB/IEC or local 
Health Authorities) request supporting information, dose adaptations, if any, may be 
implemented only after approval.
Participants will self-administer study intervention twice per day at a set time each day unless a 
study visit day is planned. On scheduled study visit days, study intervention will be administered 
on-site after the scheduled pre-dose study assessment/procedures have been performed.
Protocol-specified corticosteroid tapering guidance and targets will be implemented in this study. 
Sites will be instructed to follow this guidance and must taper corticosteroids.
Participants who prematurely discontinue treatment are encouraged to remain in the study and 
follow the scheduled study visits after completion of the ET assessments as soon as possible. In 
case of study withdrawal, the ET Study Visit must occur as soon as possible and will replace the 
End of Treatment Visit (and must subsequently be followed by Safety follow-up visits).
Participants who complete the 24-Week DBPC Treatment Period may be offered participation in 
an optional long-term extension (LTE) study (WILLOW LTE, MS200569_0048).
Involvement of Special Committees: Yes
Special oversight committees will include External Independent Data Monitoring Committee, 
Study Steering Committee, Endpoint Adjudication Committee, and Firewall Team. The Firewall 
Team will be composed of a restricted group of individuals within the Sponsor team who are not 
directly involved in the study conduct activities.

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2
Introduction
M5049 (International nonproprietary name: enpatoran, hereafter used interchangeably in the 
protocol) is a small molecule, dual TLR7 and TLR8 antagonist shown to specifically inhibit the 
activation of TLR7/8. 
Detailed information on the chemistry, pharmacology, efficacy, and safety of enpatoran is in the 
IB.
2.1
Study Rationale
The purpose of this global Phase 2, basket PoC, and dose-finding study is to evaluate the efficacy 
and safety of orally administered enpatoran in active SLE and CLE (active SCLE and/or DLE)
patients in a randomized, double-blind, placebo-controlled, parallel, adaptive, and dose-ranging 
24-Week study. The study design and participant safety surveillance are based on enpatoran data 
obtained from the FIH Phase 1 single and multiple ascending dose healthy volunteer PK study 
(MS200569_0001), the Japanese-Caucasian bridging study (MS200569_0005), COVID-19 
pneumonia Phase 2 study (MS200569_0026) and the ongoing SLE and CLE Phase 1b multiple 
ascending dose study (MS200569_0004), nonclinical evaluation of enpatoran, and results from 
clinical studies of other IFN suppressive agents in active SLE and CLE (active SCLE and/or 
DLE).
CLE (active SCLE and/or DLE) and SLE are in the same spectrum of lupus erythematosus that 
share some common disease characteristics (mucocutaneous manifestations) and pathogenesis 
(e.g., apoptosis, inefficient clearance of cell debris, TLR7/8 activation, excessive type I IFN 
production) while differing mainly in the extent of organ involvement: mucocutaneous 
involvement in CLE (active SCLE and/or DLE) compared with multi-organ systemic 
involvement in SLE.
Enpatoran is a small molecule, dual TLR7 and TLR8 antagonist 
Background
SLE is an autoimmune disease that can affect multiple organ systems and can be unpredictable 
in disease severity, with active disease which in some cases manifests as flares alternating with 

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periods of lower activity. Skin involvement occurs in 70% to 80% of all patients with lupus 
erythematosus (Zeidi 2019). Disease prevalence is approximately 1 in 1,000 individuals overall 
but varies with gender and ethnicity and is higher in women (female:male ratio = 9:1) and 
African American or other non-Caucasian populations. The cutaneous manifestations of lupus 
erythematosus (both SLE and CLE) include a broad spectrum of clinical and histopathological 
findings, on which classification is based. Multi-organ involvement distinguishes SLE from 
CLE, but detailed biomarker studies demonstrate the two have many overlapping features, 
including elevated Type I -IFN-GS expression (Braunstein 2012). Around 17% of CLE patients 
progress to SLE based on the ACR criteria, fulfilled mostly on the mucocutaneous criteria 
(Kuhn 2014).
CLE is categorized into acute, subacute, chronic, and intermittent based on clinical history and 
morphological characteristics that were initially established by Gillian (Kuhn 2014); in Europe 
the more specific European Society of Cutaneous Lupus Erythematosus criteria (Sigges 2013)
were established to further categorize CLE patients for reasons of prognosis and treatment. 
Overall, the most common forms of CLE in patients who do not have SLE are SCLE (annular 
and papulosquamous) and DLE (Ziemer 2014).
CSs (including topical) remain a therapeutic mainstay for short- and long-term control of disease 
activity in both SLE and CLE and are often administered in combination with chloroquine 
derivatives (Petri 2006). However, approximately one-third of CLE patients never respond to 
antimalarials (Chang 2011). Both SLE and CLE patients are chronically exposed to CS and other 
medication, including general immunosuppressive agents, with significant side effects 
(Fauci 2008, Jimenez 2003, Moghadam-Kia 2009). Belimumab (B lymphocyte stimulator 
antagonist) and anifrolumab (Type I IFN receptor antagonist) are the only biological agents 
approved for treatment of SLE. Topical calcineurin inhibitors are also used in CLE. However, 
the options for more aggressive treatment regimens for both SLE and CLE remain limited despite 
the treatment advances for other autoimmune diseases; the toxicity of the more aggressive drug 
regimens for SLE contribute significantly to morbidity and mortality. Also, there are no 
approved therapies for CLE, although when required, the off-label systemic treatments 
commonly used are mostly the same as those for SLE (Ziemer 2014).
Genome-wide association studies, experimental mouse models, and translational studies have 
provided evidence for the involvement of TLR7 and TLR8 in SLE and CLE pathogenesis. 
Production of ANA, including anti-ssRNA antibodies (e.g., anti-Sm, Ro/SSA, La/SSB, RNP)
are frequently observed in SLE and CLE patients (Wenzel 2019, Wu 2015). These antibodies 
can form RNA-containing immune complexes that can activate intracellular signaling pathways 
via TLR7 and TLR8. Activation results in Type I IFN and inflammatory cytokine (e.g., IL-6,
systemic inflammation and organ damage. Type I IFN release and IFN
receptor signaling 
leads to transcription of interferon-induced genes that can be measured as elevated Type I 
IFN-GS expression. Type I IFN gene signature is increased in SCLE and DLE and correlates
with cutaneous disease activity (Braunstein 2012) and skin biopsies from people with either CLE 
or SLE demonstrate significantly increased expression of Type I IFN-GS (Lehman 2019). 
Reports from clinical studies indicate that pDC depletion and suppression of Type I IFNs lead 
to a substantial reduction in SLE and CLE disease activity (Furie 2019, Morand 2020,

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Furie 2020; Werth 2020
reversible lupus-like symptoms (Burnett 2010, Lee 2010, Niewold 2005, Yokogawa 2014).
The in vivo efficacy of enpatoran was evaluated in mouse models of SLE; daily oral 
administration showed strong efficacy in preventing disease development in both models 
studied. Enpatoran showed improved survival and reduction in proteinuria and disease 
biomarkers (i.e., autoantibody levels and IFN-GS expression) in the BXSB Yaa model and 
prevented the development of kidney damage and reduced proteinuria and autoantibody levels 
in an IFN accelerated NZB/W F1 model.
In the FIH study (MS200569_0001), enpatoran administered as single-dose or repeat doses up 
to 200 mg daily in healthy participants suppressed secretion of ex vivo-stimulated cytokines 
including IL-
-dependent manner.
In the Japanese-Caucasian bridging study (MS200569_0005), PK characteristics of enpatoran 
were consistent between Caucasian and Japanese participants following a single-dose of 100 to 
300 mg of enpatoran.
In the COVID-19 pneumonia study (MS200569_0026), there was no clinically meaningful 
improvement of time to recovery observed in either of the enpatoran dose groups (50 mg or 
100 mg) compared to placebo. Study participants were less severely affected and recovered 
generally faster than in the published literature in hospitalized patients with COVID-19 
pneumonia. The enpatoran groups had a smaller proportion of participants with progression of 
COVID-19 compared with the placebo group.
Additional information on the pharmacology, PD, and safety of enpatoran is provided in the IB.
2.3
Benefit/Risk Assessment
There is a high unmet medical need for novel therapies with an improved benefit/risk ratio to 
verall 
quality of life (Fanouriakis 2019, Lauren 2013). More specifically, novel therapies should be 
effective in controlling the cutaneous, articular, renal, and nervous system manifestations of the 
disease. New therapeutic agents for SLE need to reduce the dependence on CS and toxic 
immunosuppressive agents, while also controlling end-organ damage, reducing morbidity, and 
mortality, and improving the quality of life. In addition, there are no therapies approved for the 
treatment of CLE, and generally systemically toxic medications that control SLE flares are used 
off-label for CLE. A therapy for controlling subacute cutaneous or discoid lupus would 
dramatically improv

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The cumulative data evaluation, including TEAEs, laboratory parameters, vital signs, and ECG 
parameters, did not reveal any evidence of effects of dose-dependency or safety concerns.
Due to the heterogenous nature of the disease, a wide spectrum of approved therapies is being 
used depending on the organ involvement, severity, and comorbidities. These therapeutic options 
include antimalarials (hydroxychloroquine, chloroquine), CS, immunosuppressant agents (e.g.,
AZA, MMF, CYC) and biologics (e.g., rituximab, belimumab, and anifrolumab). In addition, 
other disease modifying antirheumatic drugs such as MTX, leflunomide, and calcineurin 
inhibitor are also being used. The available product data show that infections, neuropsychiatric 
toxicity (seizures, tremors, headache, dizziness, anxiety, nervousness suicidal behavior and 
ideation and psychotic disorder), cardiac disorder including ventricular arrythmias and 
prolonged QT interval have been experienced at variable frequency (very common to rare) by 
some patients on these therapies. Moreover, most of these drugs are associated with embryofetal 
development toxicity. 

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More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of enpatoran may be found below (Table 2) and in the IB.
Based on the available nonclinical data and the clinical study data to date, the conduct of the 
study, as specified in this protocol, is considered justifiable.
2.3.1
Risk Assessment
The clinical experience with enpatoran is limited to 3 completed studies in healthy participants
(MS200569_0001, MS200569_0005, MS200569_0040), 1 completed Phase 2 study in 
participants with COVID-19 pneumonia (MS200569_0026), 3 ongoing studies in SLE or CLE 
(MS200569_0004, MS200569_0003 and the LTE study MS200569_0048, which will enroll
participants completing 24 weeks treatment in MS200569_0003). There is no similar class 
product available on the market. 
he AEs consistent with conditions ascribed as potential risks will be closely 
monitored and reported as AESIs during the clinical development, e.g., severe infection,
 
All study 
participants will be made aware of signs and symptoms pertaining to contemplated potential 
risks and advised to report any adverse experiences throughout the study.
Table 2
Potential Risks of Clinical Significancea
Identified and 
Potential Risks of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention
Severe Infections 
(
Grade 3)
Based on MOA, the TLR 7/8 inhibition 
increases the susceptibility to infection with 
ssRNA virus.
No clinical experience of severe infection or 
other enpatoran exposure-dependent AE 
occurrence was reported across clinical 
studies.
Exclude participants with ongoing or 
active clinically significant viral, 
bacterial or fungal infection (see 
exclusion criteria).
Clinical 
evaluation 
for 
infection 
including 
SARS-CoV-2
(per 
local 
guidelines) before Day 1 of the dosing.
SoC vaccinations should be up to date
as per local guidance.
Participant education to identify signs 
and symptoms of infection and seek 
appropriate 
medical 
attention 
(management 
and 
treatment)
per 
institutional guidelines.

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Identified and 
Potential Risks of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Identified and 
Potential Risks of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Identified and 
Potential Risks of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event, CVS = cardiovascular system, CNS = central nervous system, ECG = electrocardiogram,  
hERG = human ether-à-go-go-related gene,
ICF = informed consent form, 
MOA = mechanism of action, OTC = over-the-counter, QTc = QT interval corrected for heart rate, RNA = 
ribonucleic acid, SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2, SoC = standard of care,
ssRNA = single-stranded RNA, TLR(7/8) = Toll-Like Receptor (7 or 8), WOCBP = women of childbearing 
potential.
a Participants will be made aware of the potential risk before obtaining ICF signature.
2.3.2
Risk Assessment in the Context of SARS-CoV-2
Frequent and ongoing detailed risk assessments of the impact of the COVID-19 pandemic on the 
study will be performed. A risk mitigation plan is in place, which takes into account current 
knowledge and also potential uncertainties. Details of the contingency plan for maintaining study 
activities, including site initiation, monitoring, and close-out activities, will be included in the
study Clinical Monitoring Plan.
2.3.3
COVID-19 Vaccination
If a COVID-19 vaccine is intended to be used for a study participant during the study, the 
following guidance must be followed:
COVID-19 vaccines should be authorized or approved by local Health Authorities and 
considered appropriate for immunosuppressed patients per local guidance.
Administration of the COVID-19 vaccine timely after a scheduled visit (i.e., no later than 
2 weeks after a study visit which are occurring every 4 weeks; for the visit of 2 weeks or 
the Day 1 visit, vaccination is recommended 1 week prior to the visit) is advised but not 
mandatory to minimize any potential impact on the study data collected at each visit.
Vaccination with a COVID-19 vaccine unauthorized and not approved by the country-specific 
health agencies or with a live or live attenuated virus vaccine is not permitted during the 
treatment period of the study.

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2.3.4
Benefit Assessment
The candidate therapeutic being evaluated may or may not improve clinical outcome of an 
individual adult participant with SLE or CLE. While there may not be benefits for an individual 
participant, this study may help to further understand the immunopathogenesis of lupus and 
elucidate new pathways for treatment.
2.3.5
Overall Benefit: Risk Conclusion
Considering the measures taken to minimize risk to participants in this study, the contemplated 
potential risks in association with enpatoran are justified by the anticipated benefits that may be 
afforded to participants with SLE or CLE.

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3
Objectives and Estimands
Objectives
Estimand attributes
Primary
To 
evaluate 
the 
dose-
response 
relationship 
of 
enpatoran in reducing disease 
activity based on CLASI-A
Endpoint: Percent change from Baseline in CLASI-A at Week 16
Population: Patients with active SCLE, DLE, or SLE with predominantly active 
lupus rash
Note: Cohort A participants
Treatment: Enpatoran vs placebo
Population-Level Summary: LS means (SE) as estimated by MMRM. The 
MCP-Mod procedure will be performed to evaluate the dose-response 
relationship.
To evaluate the dose-
response relationship of 
enpatoran in reducing 
disease activity based on 
BICLA response rate 
Endpoint: BICLA response at Week 24 
Population: Patients with active SLE
Note: Cohort B participants
Treatment: Enpatoran vs placebo
Population-Level Summary: Responder rates and 95% CI. The MCP-Mod 
procedure will be performed to evaluate the dose-response relationship

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Objectives
Estimand attributes
Secondary
To evaluate the safety and 
tolerability of enpatoran
compared to placebo
Endpoints:
From Day 1 to the end of Safety Follow-up period
Occurrence of TEAEs, SAEs, and AESI
Occurrence of abnormalities (Grade 3) in laboratory parameters
Occurrence of Clinically Important increases in QT Interval Corrected 
Using Fridericia's Formula (QTcF)
To evaluate the efficacy in 
disease control of enpatoran
compared to placebo in lupus 
participants with active lupus 
rash
Endpoints:
Change from Baseline in CLA-IGA at Week 16 and Week 24
Change from Baseline in 
Lupus Disease Activity at Week 16 and 24
Population: Patients with active SCLE, DLE, or SLE with active lupus rash
Note: Active SCLE, DLE and SLE participants from Cohort A OR Cohort B with 
CLASI-A
8 at Screening and confirmed at Day 1
Population-Level Summary: LS mean (SE) at each visit and treatment difference 
(95% CI) as estimated by MMRM
To demonstrate the effect of 
enpatoran
compared 
with 
placebo on achieving both 
BICLA response and clinically 
meaningful CS reduction in 
SLE 
participants 
on 
Endpoint:
BICLA response and clinically meaningful CS reduction, defined as 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
Population: Patients with active SLE (Cohort B participants)
Population-Level Summary: same as BICLA response
To evaluate the efficacy in 
disease control of enpatoran
compared to placebo in lupus 
participants
with 
predominantly active lupus 
rash
Endpoints:
Clinically meaningful CS reduction, defined as reduction of daily prednisone-
5 mg by the Week 12 visit and 
sustained through Week 24
Occurrence of CLA-IGA 0 or 1 at Week 16 and Week 24
Population: Patients with active SCLE, DLE, or SLE with predominantly active 
lupus rash
Note: Active SCLE, DLE and SLE participants from Cohort A
Population-Level Summary: number and proportion with 95% CI of participants 
achieving the respective response definition at Week 16 and Week 24
To evaluate the efficacy in 
disease control of enpatoran
compared to placebo in
participants with active SLE
Endpoints:
SRI-4 response at Week 24
LLDAS attainment at Week 24 (Golder 2019)
Remission attainment at Week 24 (Vollenhoven 2021)
Clinically meaningful CS reduction, defined as reduction of daily prednisone-
1 to 
5 mg by the Week 12 visit and 
sustained through Week 24

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Objectives
Estimand attributes
Population: Patients with active SLE
Note: Cohort B participants
Population-Level Summary: Number and proportion with 95% CI of participants 
achieving the respective response definition at Week 24
Endpoint:
Change from Baseline in 
Global Assessment at Week 24 
Population: as above
Population-Level Summary: Summary statistics at each visit
Endpoint:
Change in the number of joints which are tender and swollen in 28-joint 
count from Baseline at Week 24
Population: Patients with active SLE and at least 4 active joints
Note: Cohort B participants with at least 4 active joints
Population-Level Summary: Summary statistics at each visit
Endpoints:
Time to first moderate/severe BILAG flare from Day 1 through Week 24
Time to first SFI severe flare from Day 1 through Week 24
Population: Patients with active SLE
Note: Cohort B participants
Population-Level Summary: HR and CI from stratified Cox model, Kaplan-Meier
estimates
To evaluate the efficacy of 
enpatoran compared to 
placebo in patient-reported 
symptoms and functional 
status, in lupus participants 
with active lupus rash 
Endpoints:
Change from Baseline in the Skindex 29+3 symptom domain score at 
Week 24
Change from Baseline in the Skindex 29+3 Functioning and Emotion domain 
scores at Week 24
Change from Baseline in the Skindex 29+3 lupus-specific domain score at 
Week 24
Change from Baseline in the FACIT-Fatigue scores at Week 24

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Objectives
Estimand attributes
Population: Patients with active SCLE, DLE, or SLE with active lupus rash. Note: 
Active SCLE, DLE and SLE participants from Cohort A OR Cohort B with CLASI-
8 at Screening and confirmed at Day 1. For FACIT-fatigue: Cohort A
participants.
Population-Level Summary: Descriptive statistics at each visit and treatment 
difference at Week 24 as estimated by MMRM
To evaluate the efficacy of 
enpatoran compared to 
placebo in patient-reported 
symptoms, in participants
with active SLE
Endpoint:
Change from Baseline in the FACIT-Fatigue scores at Week 24
Population: Patients with active SLE
Note: Cohort B participants
Population-Level Summary: descriptive statistics at each visit and treatment 

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antigen A, BICLA = BILAG-Based Composite Lupus Assessment, BILAG = British Isles Lupus Assessment Group,
CLA-IGA = 
, CLASI = Cutaneous Lupus Erythematosus 
Disease Area and Severity Index, CS = corticosteroids, DLE = Discoid Lupus Erythematosus, EAC = Endpoint 
Adjudication Committee,
FACIT = Functional Assessment of 
Chronic Illness Therapy, HR = Hazard ratio, IFNs = Interferons,
,
LLDAS = Lupus Low Disease Activity State, LS = Least square, MCP-Mod = Multiple Comparisons Procedure 
Modelling, MMRM = mixed-model with repeated measures,
, NRS = Numeric Rating Scale, PD = Pharmacodynamics, 
PK = Pharmacokinetics, 
QTcF = QT interval corrected using Fridericia's formula,
RNP = ribonucleoprotein,
SAE = Serious Adverse Event,
SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2,
SCLE = Subacute Cutaneous Lupus 
Erythematosus,
 
 
 
 
,
SE = Standard error,
, SFI = SLEDAI Flare Index,
SLE 
=
Systemic 
Lupus
Erythematosus,
 
 
TEAE = Treatment-emergent Adverse Events, UPCR = Urine Protein Creatinine Ratio.
4
Study Design
4.1
Overall Design
This is a global, Phase 2, basket PoC, and dose-finding, randomized, double-blind, 
placebo-controlled, dose-ranging, parallel and adaptive multicenter study in participants with 

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active SLE or CLE (active SCLE and/or DLE) treated with SoC to evaluate the efficacy and 
safety of enpatoran administered orally twice per day for 24 weeks.
The planned total duration of the study for each participant will be up to approximately 33 weeks: 
up to a 7-Week Screening Period (5-Week Screening Period with the possibility to expand by an 
additional 2 weeks if needed to repeat a laboratory test or due to an unanticipated event), a 
24-Week DBPC Treatment Period followed by a 2-Week Safety Follow-up Period. Upon 
completion of the eligibility form, and confirmation of eligibility of active SLE, (active SCLE
and/or DLE) by the Medical Monitor as well as Primary Investigator assessment that participant 
continues to meet inclusion/exclusion criteria, the participant will be randomized. The study will 
be conducted on an outpatient basis.
The study consists of 2 cohorts to establish PoC and dose-finding for enpatoran in 2 patient 
populations: Cohort A and Cohort B. Cohort B has a dose-finding adaptive design comprised of 
Part 1and Part 2. Cohort A and Cohort B Part 1 will start in parallel with a subsequent initiation 
of Cohort B Part 2.
Cohort A will have participants with CLE (active SCLE and/or DLE) (CLASI-
or 
SLE with predominantly active lupus rash (CLASI-A
8) and for SLE mild or no 
extra-mucocutaneous disease activity (BILAG 2004 1B, C, D [i.e., No BILAG 2004 A and 
No BILAG 2004 
2B]). Approximately 100 participants will be randomized 1:1:1:1 to
enpatoran 25 mg twice per day (n = 25): enpatoran 50 mg twice per day (n = 25): enpatoran
100 mg twice per day (n=25): placebo twice per day (n = 25). An IA of Cohort A for futility 
may be performed after a minimum of 40 participants have completed at least 16 weeks of 
treatment or discontinued the study prematurely, with no pause in the enrollment. 
Whenever possible the Cohort A IA will take place at the same time as Cohort B IA.
Cohort B will have SLE participants who have moderate to high systemic disease activity 
(BILAG A and/or 2B) with 1 or 2 of the following: CLASI-A
and/or SLEDAI
. An
adaptive design will be used for this cohort: Part 1 is designed to assess a clinical signal 
and based on an IA of Part 1; Part 2 may be adapted to improve dose-finding in SLE, if 
needed.
o
Part 1 will be initiated first with approximately 60 participants randomized 2:1 to 
enpatoran 100 mg twice per day vs placebo to evaluate the futility of enpatoran vs 
placebo in SLE participants.
o
Part 2 will be initiated after approximately 60 participants have been enrolled in Part 1
and participants will be randomized 1:1:1:1 to enpatoran 25 mg twice per day:
enpatoran 50 mg twice per day: enpatoran 100 mg twice per day: placebo twice per 
day. An IA is planned when the first 60 participants from Part 1 complete at least 
12 weeks of treatment, or discontinue early, to decide whether to terminate Cohort B
for futility. It may inform potential adaptations of dose, randomization ratio,
stratification factors, and sample size for Part 2 (see Section 4.3). Participants from 
Cohort B Part 1 and Part 2 will continue on their dose level initiated prior to any 
potential adaptation until completion of study treatment at Week 24 unless Cohort B 
is terminated for futility. Dose adaptations, if any, will be implemented only on new 
Cohort B Part 2 participants enrolled after this decision is made. Total sample size of 
Cohort B will not exceed 432 participants. In case country-specific Authorities (local 

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IRB/IEC or local Health Authorities) request supporting information, dose adaptations, 
if any, may be implemented only after approval.
Participants will self-administer study intervention twice per day at a set time each day unless a 
study visit day is planned. On scheduled study visit days, study intervention will be administered 
on-site after the scheduled pre-dose study assessment/procedures have been performed.
Protocol-specified CS tapering guidance and targets will be implemented in this study (see 
Section 6.8.1 and Appendix 7). Sites will be instructed to follow this guidance and must taper 
CSs.
Participants who discontinue treatment are encouraged to remain in the study and follow the 
scheduled study visits after completion of the ET assessments as soon as possible and revert to 
the same study schedule (Table 1
follow-up visits are completed. In case of study withdrawal, the ET Study Visit must occur as 
soon as possible and will replace the End of Treatment Visit (and must subsequently be followed 
by Safety follow-up visits).
Participants who complete the 24-Week DBPC Treatment Period may be offered participation 
in an optional LTE study (WILLOW LTE, MS200569_0048).
Special oversight committees will include External IDMC, SSC, EAC, and Firewall Team. The 
Firewall Team will be composed of a restricted group of individuals within the Sponsor team 
who are not directly involved in the study conduct activities.
4.2
Scientific Rationale for Study Design
TLR7 and TLR8 are activated by ssRNA, which is found in immune complexes present in SLE 
and CLE patients. Activation of TLR7 and TLR8 leads to release of cytokines including 
type I IFN, IL-6 and TNF
(Barrat 2005). A central role for cytokines and in particular 
type I IFN in lupus pathogenesis is supported by abundant data from SLE and CLE patients as 
well as murine lupus disease models (Furie 2019, Furie 2020, Morand 2020, Robinson 2015,
Werth 2020). The present basket study is designed to establish PoC and dose-finding by
evaluating the efficacy, safety, PK and PD (e.g., TLR7 and TLR8-induced cytokines, IFN-GS)
of enpatoran tablets taken by mouth twice per day for 24 weeks during the DBPC treatment 
period. The study design is based on enpatoran data obtained from the FIH Phase 1 study 
(MS200569_0001), the Japanese-Caucasian bridging study (MS200569_0005), COVID-19 
pneumonia Phase 2 study (MS200569_0026) and the ongoing SLE and CLE Phase 1b multiple 
ascending dose study (MS200569_0004), from animal model experiments (refer to IB), and from 
publicly available results from clinical studies of other IFN-suppressive agents in SLE.
Double-blind treatment within each cohort will be used to reduce potential bias during data 
collection and assessment of AEs, from both study staff, and participants.
Participants receiving placebo or enpatoran will also receive SoC with some predefined 
limitations (see Sections 6.8.1, 6.8.2 and 6.8.4).
In Cohort A, a randomization in a 1:1:1:1 ratio over 4 dose levels will be used to minimize bias 
in the assignment of study participants to treatment groups and to increase the likelihood that 
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evenly balanced across treatment groups. In the 2-stage Cohort B, randomization will start with 
a ratio of 2:1 over 2 dose levels (enpatoran vs placebo) in Part 1, followed by a randomization 
in a 1:1:1:1 ratio over 4 dose levels in Part 2. Cohort B is designed to allow planned adaptations 
of enpatoran dose range, randomization ratio, stratification factors and sample size based on new 
information becoming available after this study has started (see Section 4.3).
Percent change from Baseline in CLASI-A scores at Week 16 is the primary endpoint for
participants with CLE (active SCLE and/or DLE) or SLE in Cohort A and CLASI-
8
at Baseline. The activity score of CLASI correlates with changes in clinical validation measures 
related to skin health, pain and itch and can be used to identify clinically significant 
improvements in cutaneous lupus disease activity (Bonilla-Martinez 2008, Klein 2011).
BICLA response at Week 24 is the primary endpoint for participants with active SLE in 
Cohort B. BICLA requires clinically meaningful partial improvement, but improvement is 
required in all organs and may be less sensitive than SRI in determining clinically significant 
improvement in SLE disease activity, particularly patients with multi-organ involvement 
(Thanou 2014).
4.3
Justification for Dose
To evaluate the treatment effect and dose-exposure-response relationships for efficacy and safety 
of enpatoran in CLE (active SCLE and/or DLE) and SLE patients on stable background (SoC)
therapy, the following dosing regimens are proposed to be investigated in Cohort A over a 
treatment duration of at least 24 weeks: 25, 50, and 100 mg enpatoran twice daily administered 
orally in a tablet formulation without food restriction.
Cohort B has an adaptive 2-stage dose-finding design and is designed to allow for potential 
adaptations of dose levels, randomization ratio, stratification factors, and sample size based on 
observed data at IA as well as relevant information becoming available after the Phase 2 study 
start (e.g., from the ongoing Phase 1b study MS200569_0004). The adaptive design may 
improve dose-finding by allowing to explore alternative dose levels, yielding more informative 
dose-response data (see Section 9.4.4). Cohort B is comprised of Part 1 and subsequent Part 2.
In Cohort B Part 1, enpatoran 100 mg twice daily will be compared with placebo to determine 
futility of the treatment effect. The proposed dose levels in Cohort A and Cohort B Part 1 are 
selected based on the joint evaluation of clinical PK, PD, and safety data obtained in the FIH 
study in healthy participants (MS200569_0001) and guided based on nonclinical safety and 
efficacy data (see below).
Cohort B Part 2 will be initiated when approximately 60 participants have been enrolled in Part 1.
Cohort B Part 2 doses will be initiated as enpatoran 25, 50, and 100 mg enpatoran twice daily
compared to placebo. The Cohort B Part 2 dose levels may be adapted to evaluate the 150 mg
twice daily dose level (as will be specified in the Interim Analysis Plan), if adequately supported
by the totality of available clinical safety, efficacy, and dose-exposure-response data from this 
Phase 2 study and from the ongoing Phase 1b study MS200569_0004 (including data from
150 mg twice daily dosing cohort at the IA).
Preclinical in vivo efficacy in mouse models of Lupus disease together with PK/PD target 
engagement data obtained in C57/BL6 mice were used to define the following PD targets: (i) for

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anticipated minimum efficacy:
 
 
 
 
.
 and the
tablet formulation (immediate release film-coated tablets) showed very rapid dissolution profiles
for both tablet strengths of 25 and 50 mg. Hence, administration of 1 tablet of 50 mg strengths

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is expected to generate similar exposures as 2 tablets of 25 mg strengths. The 50 mg tablet 
strengths may be introduced into Cohort B Part 2 to facilitate doses from 50 to 150 mg.
Based on the above considerations, the proposed enpatoran doses in this Phase 2 study should 
provide the opportunity to evaluate a treatment effect and dose-exposure-response relationships 
for efficacy and safety in each indication, SLE, and CLE, with acceptable safety margins. Refer 
to the IB for further details.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts, including the last 
scheduled procedure shown in the Schedule of Activities (SoA; see Table 1).
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(see Table 1) for the last participant in the study.
The study may not be considered closed as long as:
Any participant is still receiving any study intervention.
Visits specified by the protocol are still taking place.
Procedures or interventions according to the protocol are still being undertaken in any 
participant.
The post-intervention Follow-up Period, defined in the clinical study protocol as being part 
of the study, has not yet been completed for any participant.
Appendix 2 provides details related to study closure and site termination.
5
Study Population
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study; thereby, ensuring the study fulfills its objectives. All relevant medical and 
nonmedical conditions are considered when deciding whether a participant is suitable for this 
study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are
has provided written informed consent, as indicated in Appendix 2.
Eligibility will be evaluated by the study Investigator, and re-evaluated, and confirmed by the 
Sponsor or designee Medical Monitors comprising the study eligibility team. Additional lupus 
experts may be consulted during the eligibility process (e.g., to confirm CLE subtypes 

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diagnosis). Sites will be required to submit an eligibility packet (consisting of an eligibility 
checklist and appropriate documentation) for consented and potential eligible participants. The 
prior to the Randomization Visit (Day 1). When a laboratory test must be repeated during the 
Screening Period or an unanticipated event occurs, the Screening Period can be extended to 
7 weeks after discussion with the Medical Monitor. See Table 1 for a list of assessments 
performed at Screening to determine the eligibility of the participant to take part in the study. 
Participants will be randomized into the study when eligibility is confirmed.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are
years of age at the time of signing the informed consent. Sites should 
follow their local guidelines for the minimum age required to sign the informed consent.
Vaccinations
2. Are up to date, according to local guidelines, with vaccination against Streptococcus 
pneumoniae and influenza virus (as seasonally required for influenza virus).
Active SCLE and/or DLE (Cohort A)
3. Diagnosis of SCLE or DLE documented in medical history. Predominant findings of 
active lupus rash must be SCLE and/or DLE,
 a case-by-case basis if their main 
diagnosis is active SCLE and/or DLE. Diagnosis must include one of the following 
options:
a.
Historical skin biopsy (i.e., pathology report; punch or shave biopsy) within 
10 years prior to Screening visit and confirmation of current diagnosis by skin 
photography at Screening visit.
OR
b. Fresh punch skin biopsy at Screening visit.
OR
c.
If target lesion is unsuitable for biopsy (e.g., malar rash, bridge of the nose), 
skin photography at Screening visit may be allowed on a case-by-case basis.
4.
5. CLASI-
Active SLE
6. Diagnosis of SLE and fulfil Systemic Lupus International Collaborating Clinics (SLICC) 
classification criteria (Petri 2006
(Hochberg 1997) and/or EULAR/ACR 2019 classification criteria (Aringer 2019).

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7.
ACR (Hochberg 1997), and/or 2019 EULAR/ACR classification criteria for SLE until 
Screening Visit.
8. Positive test results for ANA (human epithelial cell-
-dsDNA 
and/or anti-Smith antibody during Screening Period.
9. Presence of either Scenario 1 OR Scenario 2 (See Figure 1).
Scenario 1 (Cohort A predominantly active lupus rash):
Cutaneous lupus erythematosus disease area and activity index (CLASI-
8 at 
Screening Visit and confirmed at Day 1 Visit.
AND
British Isles Lupus Assessment Group (BILAG 2004) 1B, C, D (i.e., No BILAG 
2004 A and No BILAG 2004 
2B) at Screening visit.
OR
Scenario 2 (Cohort B
moderate to high systemic disease activity):
or 2B at Screening Visit;
AND 1 or 2 of the following:
a)
AND/OR
b)
CLASI-
confirmed at Day 1 Visit.

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Figure 2
Assignment of Study Cohort Based on Disease Activity Features at 
Screening Visit
See Cohort A and B classification guideline above.
Stop indicates not eligible for this study.
 
 
, BILAG
=
British Isles Lupus Assessment Group,
CLASI-A = Cutaneous Lupus Erythematosus Disease Area and Severity Index-A, CLE = Cutaneous Lupus 
Erythematosus, DLE = Discoid lupus erythematosus, SCLE = Subacute cutaneous lupus erythematosus,
SLE = Systemic lupus erythematosus, SELENA = Safety of Estrogens in Systemic Lupus Erythematosus 
National Assessment, SLEDAI = Systemic Lupus Erythematosus Disease Activity Index.
Weight
10. Have a body mass index lower or equal to 40.0 kg/m2.
Sex
11. Are male or female at birth.
12. Contraceptive use by males or females will be consistent with local regulations on 
contraception methods for those participating in clinical studies.
a.
Female participant:
Is not breastfeeding.
Is not pregnant (i.e., has a negative serum pregnancy test, as required by local 
regulations, within 24 hours before the first dose of study intervention).
Additional requirements for pregnancy testing during and after study intervention 
are in Section 8.3.4.
Not a Woman of childbearing potential (WOCBP).

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If a WOCBP, use a highly effective contraceptive method (i.e., with a failure 
rate of <1% per year), preferably with low user dependency (2 methods may be 
considered to achieve optimal results i.e. <1% failure rate per year), as 
described in Appendix 3 for the following time periods:
Before the first dose of the study intervention, if using hormonal contraception:
Has completed at least one 4-Week cycle of an oral contraception pill 
and either had or has begun her menses.
OR
Has used a depot contraceptive or extended-cycle oral contraceptive for 
least 28 days and has a documented negative pregnancy test using a 
highly sensitive assay.
AND
A barrier method, as described in Appendix 3.
During the intervention period.
After the study intervention period (i.e., after the last dose of study intervention 
is administered): for at least 90 days after the last dose of study intervention and 
agree not to donate eggs (ova, oocytes) for reproduction during this period.
The Investigator evaluates the appropriateness and effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
The Investigator reviews the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female with an early undetected pregnancy.
b. Male Participants:
Agree to the following during the study until at least 90 days (a spermatogenesis 
cycle) after the last dose of study intervention.
Refrain from donating fresh unwashed semen.
PLUS, either:
Abstain from any activity that allows for exposure to ejaculate.
OR
Use a male condom:
When having sexual intercourse with a WOCBP, who is not currently 
pregnant, and instruct her to use a highly effective method with a failure rate 
of <1% per year, as described in Appendix 3, since a condom may break or 
leak.
When engaging in any activity that allows for exposure to ejaculate.

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13. Currently receiving a stable dose of at least one of the following SoC therapies for 
lupus:
a.
Immunomodulator/immunosuppressant (antimalarial, MTX, 6-mercaptopurine, 
sulfasalazine, MMF, or sodium, AZA, tacrolimus, leflunomide, dapsone, or 
retinoids)
8 weeks prior to Screening Period.
b. Oral CSs
2 weeks prior to Screening Period.
c.
Topical CSs
2 weeks prior to Screening Period.
Informed Consent
14. Capable of giving signed informed consent, as indicated in Appendix 2, which includes 
compliance with the requirements and restrictions listed in the ICF and this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Primary diagnosis of autoimmune or rheumatic disease other than SLE or CLE (discuss 
autoimmune thyroiditis are not exclusionary.
2. Drug-induced lupus (SLE or CLE).
3. Any condition including dermatological diseases other than cutaneous manifestations of 
SLE or CLE (e.g., psoriasis), or any uncontrolled disease (e.g., asthma, interstitial lung 
disease, pulmonary arterial hyp
participation.
4. Active lupus nephritis on induction therapy, or induction therapy completed within 
3 months of Screening visit (stable maintenance therapy with mycophenolate or AZA
allowed).
5. UPCR > 339 mg/mmol, and/or eGFR < 45 mL/min/1.73 m2 as calculated by the 
Modification of Diet in Renal Disease equation by the central laboratory:
eGFR = 175 × (serum creatinine in mg/dL) 1.154 × (age in years) 0.203 × 0.742 (if female) 
× 1.212 (if race is black).
6. Any active signs, symptoms or diagnoses considered related to CNS lupus within past 
3 months or any history of uncontrolled seizures.
7. Any other history of epilepsy, other neurological disorder with seizure propensity, or 
neuropsychiatric conditions that may interfere with study evaluations.
8. Significant cardiovascular events (e.g., acute myocardial infarction, unstable angina, or
peripheral vascular disease symptoms, hospitalization for congestive heart failure, 
uncontrolled, or New York Heart Association Class 3 or 4 congestive heart failure, 
cardiac surgery, ischemic or hemorrhagic stroke, or transient ischemic attack), 
6 months before Screening Visit.

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9. Active cardiac arrhythmia or clinically significant abnormality on ECG at Screening 
inappropriate risk or contraindication for study participation or could interfere with study 
objectives, conduct or evaluation (included but not limited to long QT syndrome, Wolff 
Parkinson White syndrome, or a malignant ventricular arrhythmia [e.g., ventricular 
fibrillation or tachycardia] unless treated). Note: any sinus bradycardia or tachycardia 
detected in the ECG will not be exclusionary unless other ECG abnormalities are 
identified.
10. Significant suicide risk in the last year (including suicidal ideation and/or suicidal 
behavior on the C-SSRS during Screening or Day 1).
11. History of or planned renal or solid organ transplant.
12. Ongoing or active clinically significant viral (including SARS-CoV-2), bacterial or 
fungal infection:
requiring hospitalization or
treatment with parenteral anti-
4 weeks prior to or during Screening 
Period, or
completion of oral anti-
2 weeks prior to Day 1 Visit.
Vaginal candidiasis, onychomycosis, and genital, or oral herpes simplex virus considered to be 
sufficiently controlled will not be exclusionary.
Investigators should follow their local guidelines for SARS-CoV-2 testing during the 
Screening period (e.g., testing regardless of symptoms, or potential exposure may be
required before entering a research study, symptomatic, or exposure-based testing at 
screening only, etc.). In addition, within 3 to 5 days prior to randomization, all 
participants should be specifically questioned for coronavirus infectious disease due 
to SARS-CoV-2 symptoms or close contact with someone known to have 
SARS-CoV-2 infection to determine if SARS-CoV-2 testing (accepted according to 
local guidelines) should be performed (or repeated).
If required by local guidelines, a test for SARS-CoV-2 is needed for participants 
before the Screening visit.
13. Any of the following:
a.
A positive HIV test.
b. Positive HCV antibody (Ab) and detectable HCV RNA nucleic acid amplification 
testing (NAAT) performed reflexively at Screening, or history of treated HCV with 
detectable HCV RNA NAAT performed reflexively at Screening.
Positive HBV surface antigen, or positive HBV core Ab with negative HBV 
surface Ab and reflexive detectable HBV DNA NAAT at Screening, or no
history of HBV vaccination with positive HBV surface and/or core Abs and 
reflexive detectable HBV DNA NAAT at Screening.
14. Any of the following:

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a.
History of active TB.
Note: patients with a history of active or latent TB who have documented evidence 
of appropriate treatment and with no history of re-exposure since their treatment was 
completed would not be required to undergo the protocol-specific TB testing for PPD, 
QuantiFERON test, or T-SPOT test, but would still require a Baseline chest x-ray to 
rule out active TB and documentation of completed treatment.
b. Current diagnosis of active TB.
c.
Untreated LTBI.
d. Undergoing current treatment for LTBI.
e.
Participants with current household contacts with active TB.
In the absence of an active TB diagnosis, or clinical features consistent with an active TB 
diagnosis, LTBI is determined by any of the following:
Prior TB skin test with purified protein derivat
vaccinated with Bacille Calmette-Guérin).
Prior positive T-SPOT.TB (Elispot) result.
Positive QuantiFERON test, either at Screening, or with documented past results.
Note: All participants, except those who have previously completed appropriate and 
documented LTBI treatment, must undergo QuantiFERON testing during Screening. 
Participants with indeterminate or positive QuantiFERON results that may represent a 
false positive result by the Investigator with no clinical features consistent with active 
TB, will be evaluated with either a repeat QuantiFERON test (local or central laboratory 
test) or a T-SPOT (local laboratory test) TB at the request of the Investigator. In the case 
of a negative QuantiFERON or T-SPOT.TB result, the participant may be enrolled after 
approval by the study eligibility team. If the repeat QuantiFERON result is indeterminate, 
the participant will be excluded.
15. History of malignancy (e.g., hematologic, skin,
10 years prior to Screening 
Visit, except adequately treated basal cell or squamous cell carcinomas of the skin 
3 lesions requiring treatment in lifetime) or adequately treated carcinoma in 
situ/cervical intraepithelial neoplasia of the uterine cervix.
16. Any major surgery such as abdom
6 weeks 
prior to Screening Visit or planned major surgery during the study (including Follow-up).
17.
1 year prior to Screening Visit as per Investigator 
opinion.
18. History of splenectomy or functional asplenia.
20. Any condition that could interfere with study objectives, conduct, or evaluation in the 
opinion of the Investigator or Sponsor/designee.

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Prior/Concomitant Therapy (See Appendix 6 for further details)
21. Known hypersensitivity to any study intervention, component, or placebo.
22.
4 weeks prior to 
Screening Period.
An unstable dose 
3 months prior to Day 1, except for medications administered 
short term to treat acute symptoms (e.g., emesis), which is allowed.
24.
2 weeks prior to 
Screening:
a. Use of CS exceeding 30 mg daily prednisone-equivalent for SLE and CLE (SCLE 
and/or DLE), including but not limited to oral, topical CSs Class I, and augmented 
betamethasone dipropionate 0.05% gel or ointment, intramuscular, or injectable CS
(Table 11).
b. Use of topical calcineurin inhibitors more than 1 time per day.
c. Initiation or dose change of angiotensin-converting enzyme inhibitors or angiotensin 
receptor blocker, or NSAIDs, or use of NSAIDs above maximum prescribed dose per 
local label.
25.
4 weeks prior to Screening:
a. Vaccination with live or live attenuated virus vaccine.
b. Use of thalidomide or lenalidomide.
c. Use of intralesional therapies.
d. Use of tripterygium and total glucosides of paeony.
26. The initiation, use of a dose exceeding the maximum specified dose (see Appendix 6) or
change in therapies < 8 weeks prior to Screening for any medication considered to have 
immunomodulating and/or immunosuppressant properties (e.g., antimalarials, MTX,
6-mercaptopurine, sulfasalazine, MMF, or sodium, AZA, dapsone, or retinoids). A stable 
dose of leflunomide is not exclusionary; however, participants having changed their dose 
or discontinued leflunomide must have done so at least 8 weeks prior to Screening.
27.
12 weeks prior to Screening:
a.
Use of abatacept, antitumor necrosis factor alpha agents, intravenous Ig, 
plasmapheresis, CYC, or other disease modifying, immunosuppressive, or
immunomodulatory therapies not otherwise specified in protocol.
28.
24 weeks prior to Screening,
unless a different time frame is indicated:
a. Use of alkylating agents other than CYC (e.g., chlorambucil).

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b. B cell depleting/modulating therapy such as anti-CD20 agents (e.g., belimumab [
16 
weeks prior to Screening], atacicept, telitacicept), dual or other anti-B Lymphocyte 
Stimulator /proliferation inducing ligand neutralizing therapies (see Appendix 6).
c. IL-12/IL-23 pathway inhibitors (e.g., ustekinumab).
d. Anti-IL-6 receptor (tocilizumab, sarilumab) or anti-IL-6 (siltuximab).
e. Anti-IL-1 agents.
f. Type 1 IFN pathways inhibitors (e.g., anifrolumab).
g. JAK-STAT pathway inhibitors (e.g., tofacitinib)
4 weeks prior to Screening.
h. Vaccination with a subunit or inactivated vaccine (e.g., influenza virus, S. 
pneumoniae): < 2 weeks prior to Day 1. Vaccination during the study is allowed 
providing that vaccination completes at least 2 weeks before any study visit. For SARS 
CoV-2 vaccine or vaccine series see Section 2.3.2.
Prior/concurrent Clinical Study Experience
29. Treatment with other investigational agents within the last 12 weeks or 5 half-lives or as 
per washout requirement from the previous protocol, whichever is longest, prior to 
Screening Visit (e.g., small molecules such as Bruton's tyrosine kinase inhibitors).
Diagnostic Assessments
30. Clinically significant or predefined abnormalities in laboratory tests at Screening Visit:
AST, ALT, or alkaline phosphatase > 2.5 × ULN;
Total bilirubin > 1.5 × ULN;
Hemoglobin < 5.0 mmol/L (9 g/dL), white blood cells < 2.5 × 109/L, absolute 
neutrophil count < 1,500/mm3, or platelets < 75 × 109/L, unless any of these are 
attributable to active SLE;
results.
31. Signs of significant chest imaging (chest X-ray, CT, MRI) abnormality (e.g., interstitial 
lung disease, active TB)
are acceptable if no reason to suspect clinical changes.
Other Exclusions
32. Legal incapacity or limited legal capacity.

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5.3
Lifestyle Considerations
Participants are recommended to continue to use sunblock.
5.3.1
Meals and Dietary Restrictions
No food restrictions. On scheduled study visit days with PK assessment (see Table 1), record the 
date and time of the closest meal before and after the study-drug administration.
5.3.2
Activity
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities (e.g., 
watching television, or reading).
5.4
Screen Failures
Retesting:
During the initial Screening Period or single rescreening period, testing may be repeated once 
for participants if test results would preclude enrollment in the study and are thought to represent 
a laboratory error, or a reversible, clinically insignificant intermittent condition, or are 
during the Screening Period, or to accommodate other unanticipated events, the Screening Period 
may be extended to 7 weeks after discussion with the Medical Monitor.
Rescreening:
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, after approval by the Medical Monitor. Rescreened participants will be assigned 
a new participant number.
If a participant is rescreened, all Screening tests should be repeated with the exception of:
Hepatitis and HIV testing must have occurred within 1 month of the initial Rescreening Visit 
or will need to be repeated during the Rescreening Period.
Anti-ENA antibodies (anti Sm, RNP, Ro/SSA, La/SSB Abs) must have occurred within 
1 month of the initial Rescreening Visit or will need to be repeated during the Rescreening 
Period.
Documented TB testing must have occurred within 3 months of the initial Rescreening Visit 
or need to be repeated during the Rescreening Period.
Documented chest imaging must have occurred within 3 months of the Rescreening Period 
otherwise to be repeated during the Rescreening Period.
If inclusion/exclusion criteria are not met based on the results of the repeated testing, the 
participant should be considered a screen failure and not enrolled in the study. Reasons for 
screening failure should be recorded in the eCRF.

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6
Study Intervention and Concomitant Therapies
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol.
6.1
Study Intervention Administration
Participants will self-administer study intervention twice per day (every 12 hours ± 2 hours) 
(see Section 1.3). To maintain blinding, all participants will take 4 tablets in total per dose
administration (4 tablets in the morning and 4 tablets in the evening): 25 mg enpatoran tablets
and/or matching placebo, depending on the assigned dose level, as described in Table 3. In case 
of adaptation to include a 150 mg dose level (see Section 4.3), 50 mg enpatoran tablets and/or 
matching placebo tablets will be used for Cohort B Part 2 participants enrolled after this
implementation: these participants would take, 3 tablets in total per dose administration (3 tablets 
in the morning and 3 tablets in the evening). Table 3 describes the enpatoran and/or placebo 
tablets count per dose level. No dose modification is allowed for Cohort B participants
randomized before dose adaptation (see Section 6.5).
On scheduled study visit days, the participant will be asked not to self-administer study 
intervention at home but to bring the study intervention to the site for administration after the 
scheduled study visit assessment/procedures are performed (other than post-treatment ECGs and 
PK/PD sampling). Last study intervention will be administered prior to the End of Treatment 
Visit of the 24-Week DBPC period for those who opt out for the separate WILLOW LTE Study.
Table 3
Study Intervention Administration
Study Intervention Name
Enpatoran
Placebo
Dose Formulation:
Film-coated tablet.
All formulation components are of 
pharmacopoeial and/or food grade.
Film-coated tablet.
All formulation components are of 
pharmacopoeial and/or food grade.
Unit Dose Strengths
25 mg or 50 mg
Matching active 25 mg or 50 mg 
tablets
Dosage Levels:
25 mg, 50 mg, 100 mg or 150 mg
Not applicable.
Route of Administration:
Oral
Oral
Packaging and Labeling:
Study Intervention will be provided in 
wallets containing 24 units (for 25 mg 
tablets) or 18 units (for 50 mg tablets) 
in Alu/Alu blister. Each wallet will be 
labeled per country requirement and 
Good 
Manufacturing 
Practice 
Guidelines.
Study Intervention will be provided in 
wallets containing 24 units (for 25 mg 
tablets) or 18 units (for 50 mg tablets) 
in Alu/Alu blister. Each wallet will be 
labeled per country requirement and 
Good 
Manufacturing 
Practice 
Guidelines.

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Dosing Instructions:
-
Oral twice per day administration. To be taken with approximately 200 mL 
water.
-
No specific food restriction. On scheduled study visit days with PK 
assessment, record the date, and time of the closest meal before and after 
the study-drug administration.
All participants randomized to enpatoran arms:
For 25 mg Tablets:
For 25 mg dose: 1 × 25 mg enpatoran tablet + 3 × placebo tablets (twice per
day)
For 50 mg dose: 2 × 25 mg enpatoran tablets + 2 × placebo tablets (twice 
per day)
For 100 mg dose: 4 × 25 mg enpatoran tablets (twice per day)
For 50 mg Tablets:
For 50 mg dose: 1 × 50 mg enpatoran tablet + 2 × placebo tablets (twice per 
day)
For 100 mg dose: 2 × 50 mg enpatoran tablets + 1 × placebo tablets (twice 
per day)
For 150 mg dose: 3 × 50 mg enpatoran tablets (twice per day)
All participants randomized to placebo arm:
For 25 mg Tablets:
4 placebo tablets (twice per day)
For 50 mg Tablets:
3 placebo tablets (twice per day)
6.2
Study Intervention Preparation, Handling, Storage, and 
Accountability
Enpatoran and placebo will be provided in tablet formulation in an Alu/Alu blister package 
(see Section 6.1) and it has to
30°C (should not be frozen).
Packaging and labeling of enpatoran and placebo tablets will be in accordance with applicable 
regulatory requirements and applicable Good Manufacturing Practice guidelines. The 
information on the medication will be in accordance with approved submission documents. 
Enpatoran and placebo tablets will be packed and labeled to protect the blinded nature of the 
study. Enpatoran and placebo will not be distinguishable from each other and will be covered by 
suitable labels to prevent participants and study personnel from noticing any differences in the 
tablets of enpatoran versus placebo. Blinded treatment kit numbers will be obtained through the 
IVRS/IWRS as described in Section 6.3.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Upon receipt of the study interventions, the Investigator or designee will confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery. Further 

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guidance and information for study intervention accountability are provided in the Pharmacy 
Manual.
Only participants enrolled in the study may receive study interventions and only authorized 
site staff may supply it. All study interventions will be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, per the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff.
Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
Study interventions accountability records at the study site will include the following:
Confirmation of receipt, in good condition, and in the defined temperature range.
The inventory provided for the clinical study.
The doses each participant used during the study.
The disposition (including return, if applicable) of any unused study interventions.
Dates, quantities, batch numbers, blister package numbers, expiry dates of study 
interventions, and the participant numbers.
The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study interventions provided were 
fully reconciled.
Unused study interventions will not be discarded or used for any purpose other than the 
present study. There will be the option that unused study interventions will be redispensed to 
the same patient controlled by IRT. No study intervention that is dispensed to a participant 
may be redispensed to a different participant.
A Study Monitor will periodically collect the study interventions accountability forms.
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
Participants will record date, time, and amount of study intervention administration in the paper 
diary card provided.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
After confirmation of participant eligibility, study participants in each cohort will be centrally 
allocated to study intervention using an IVRS/IWRS and per a computer-generated 
randomization list:
In Cohort A, the randomization ratio will be 1:1:1:1 ratio (enpatoran 25 mg twice per day:
enpatoran 50 mg twice per day: enpatoran 100 mg twice per day: placebo) and the number 
of study participants randomly assigned to study intervention will be approximately 100.

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In Cohort B, the Part 1 participants will be assigned with a 2:1 ratio (enpatoran 100 mg twice 
per day: placebo). Part 2 participants will be assigned with a 1:1:1:1 ratio (enpatoran 25 mg 
twice per day: enpatoran 50 mg twice per day: enpatoran 100 mg twice per day: placebo.
Part 2 dose levels and randomization ratio might be adapted after Cohort B IA.
The IVRS/IWRS will be used to assign unique participant numbers, allocate participants to 
study intervention group at the Randomization Visit in DBPC treatment period, and allocate 
study intervention to participants at each study intervention visit.
Before the study is initiated, the telephone number and call-in directions for the IVRS and/or the 
log in information and directions for the IWRS will be provided to each site. The site will contact 
the IVRS/IWRS prior to starting study intervention administration for each participant.
Participants in Cohort A will be stratified by the following factors:
Region (3 levels: North America and Western Europe vs Asia vs Central/South America 
and rest of the world),
Disease diagnosis at Screening (2 levels: CLE [SCLE and/or DLE] vs SLE).
Participants in Cohort B will be stratified by the following factors (not all stratification factors 
might be used after Cohort B IA, as will be specified in the Interim Analysis Plan):
Region (3 levels: North America and Western Europe vs Asia vs Central/South America 
and rest of the world),
 
 
 
 
 
 
 
 
6.3.2
Blinding
Blinding Method
The study will be double-blind for Cohort A and Cohort B (Parts 1 and 2).
Randomization codes will be kept strictly confidential, accessible only to authorized staff 
(i.e., randomization statistician, unblinded Statistician, IDMC members, and statistical data 
centers, Firewall Team, unblinded Pharmacist, and laboratories responsible for analyses of the 
PK), until the time of unblinding. All other study-related individuals, ancillary site staff, clinical 
research associates/monitors, the Investigator, Sponsor, and clinical research organization staff 
will remain blinded to study intervention.
The analytical laboratories responsible for the analysis of the PK samples (requiring shipment of 
laboratory samples from the site) will be unblinded to study treatment codes to enable sample 
testing of PK of study intervention prior to database lock. Masked participant identifiers will be 
used to support association with treatment codes but prevent association of treatment codes with 
any other clinical data, such as safety, and clinical response data.

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The EAC will be blinded to treatment. Blinded efficacy and safety data will be provided to the
EAC for data monitoring (for more details see Appendix 2).
The IDMC and supporting independent statistical data centers will be unblinded to treatment.
In addition, the IDMC will present recommendations based on the results of the IAs to the 
Firewall Team to make final decision (see Section 9.4.4). The Firewall Team will be unblinded 
to treatment and will remain independent from study team. Details will be provided in the 
Firewall Team charter.
For the primary analysis and final analysis, database should be locked, and protocol violations 
determined, the drug codes will be broken and made available for data analysis.
Study intervention information that would unblind the study participants will not be reported 
with participant identifiers to investigative sites until after the study has been fully unblinded 
(i.e., after the final analysis).
Assignment Method Retention
The study blind may be broken in the event emergency unblinding is necessary for participant 
safety or the reporting of SUSARs.
Unblinding in these cases would be done via the unblinding module in IWRS. All breaks of the 
study blind must be adequately documented.
6.3.3
Emergency Unblinding
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
Participant safety is always the first 
consideration in this decision. If the Investigator decides that unblinding is warranted, the 
Investigator makes every effort to contact the Sponsor prior to the unblinding, unless this could 
delay emergency treatment. The Sponsor will be notified within 24 hours after unblinding. The 
Investigator will provide the Sponsor the reason for unblinding without revealing the study 
intervention, except to the designated global patient safety representative via the Emergency 
Unblinding Notification Form. The date of and reason for unblinding will be recorded in the 
source documents. Contact information for unblinding in an emergency is given on the 
participant emergency card provided to each participant, as noted in Appendix 2.
global patient safety department will submit any SUSAR reports to regulatory 
authorities and ethics committees with unblinded information, per applicable regulations. Only 
blinded information will be provided to the study team.
Participants undergoing emergency unblinding will be discontinued from the study intervention. 
The investigations scheduled for the ET and all subsequent Safety Follow-up Visits until EOS 
should be performed (Section 7.1).

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6.4
Study Intervention Compliance
Besides study visits where study intervention will be administered under medical supervision at 
the site, study participants will self-administer their study intervention at home. They will be 
provided with a diary card or phone application containing instructions for self-administration 
and documentation of study intervention intake. If participants use the phone application, they 
may also receive reminders to administer study intervention and perform related documentation.
When participants self-administer study interventions at home (see Section 1.2), compliance 
with study intervention will be assessed at each visit. Compliance will be assessed by direct 
questioning, counting returned tablets, and review of diary cards or data generated from the 
phone application using the vendors portal and documented in the source documents and CRF. 
Any deviation(s) from the prescribed dosage regimen are recorded.
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the CRF. The dose of 
study intervention and study participant identification may be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.
A record of the number of tablets dispensed to and taken by each participant will be maintained 
and reconciled with study intervention and compliance records. Intervention start and stop dates, 
including dates for intervention delays will also be recorded in the CRF.
6.5
Dose Selection and Modification
Participants enrolled into Cohort A will be randomized in a 1:1:1:1 ratio receiving placebo 
or one of the 3 active doses, i.e., 25, 50, or 100 mg of enpatoran, twice daily while patients 
enrolled into Cohort B (SLE) Part 1 will be randomized in a 2:1 ratio receiving either 
100 mg enpatoran or placebo twice daily for a treatment duration of at least 24 weeks.
In Cohort B Part 2, participants will start with a randomization ratio of 1:1:1:1 receiving 
placebo or one of the 3 active dose levels, i.e., 25, 50, or 100 mg of enpatoran, twice daily. 
After Cohort B IA, Part 2 dose levels (not exceeding the highest clinically investigated 
enpatoran dose in the ongoing Phase 1b study: MS200569_0004 which is 150 mg twice per 
day), randomization ratio and stratification, and sample size may be adapted.
Participants from Cohort B Part 1 and Part 2 will continue on their dose level initiated prior 
to any potential adaptation until completion of study treatment at Week 24 unless Cohort B
is terminated for futility. Dose adaptations, if any, will be implemented only for new 
Cohort B Part 2 participants enrolled after this decision is made.
6.6
Continued Access to Study Intervention After the End of the Study
Participants who complete the 24-Week DBPC Treatment Period may be offered participation 
in an optional LTE study (WILLOW LTE, MS200569_0048).

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6.7
Treatment of Overdose
For this study, any dose of study intervention greater than 300 mg (12 tablets) within 24 hours 
± 2 hours or a single-dose greater than 200 mg (8 tablets) will be considered an overdose.
The Sponsor has no specific recommendation for treating an overdose. The Investigator will use 
his/her clinical judgment to manage any overdose, considering the symptoms, and any site 
procedures or standards.
Even if not associated with an AE or a SAE, any overdose is recorded in the CRF and reported 
to global patient safety in an expedited manner. Overdoses are reported on a SAE and Overdose 
Report Form, following the procedure in Appendix 4.
6.8
Concomitant Therapy
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions, including 
topical creams and ointments) used from the time the participant signs the informed consent until 
completion of the study, including any changes. For prescription and over-the-counter 
medicines, COVID-19, and other vaccines, vitamins, and herbal supplements, record the name, 
reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.8.1
Corticosteroids
Long-term use of CS should be minimized since its use has been associated with damage, 
morbidity and mortality in SLE (Doria 2014, Gladman 2003, Ruiz-Irastorza 2012, Thamer 2009,
Urowitz 2012). Inhibitors of type I IFN pathway are potentially corticosteroid-sparing by 
increasing glucocorticoid sensitization (Guiducci 2010, Buckland 2010, Northcott 2021). In 
order to demonstrate the potential CS-sparing effect of enpatoran and its treatment effect 
compared with placebo, it is critical that medical management of these participants must include 
continuous attempts to taper CS use.
Beginning at Week 2 (~ Day 15) and continuing through Week 12, CS MUST be tapered to a 
prednisone-
5 mg/day as clinically tolerated (see protocol-specified CS 
tapering guidance in Appendix 7).
IMPORTANT: The Investigator must be familiar with and follow the rules for CS dosage during 
the study (see details of the CS rules and protocol-specified tapering guidance, in Appendix 7). 
Investigators may adjust the CS dosage of participants, if deemed clinically necessary, in a 
manner not according to the protocol-specified rules; 

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6.8.2
Corticosteroids Rescue Medication
The following CS rescue rules will apply during the 24-Week DBPC period for participants in
Cohort A or Cohort B:
Control of disease activity/flare with a brief steroid rescue is allowed only once after Day 1 
through Week 8. During this period, participants may increase the CS dose up to 30 mg/day 
prednisone-equivalent or use 1 intramuscular CS injection as rescue for worsening of SLE or 
any CS before the rescue, tapering within 7 days to 5 mg/day is allowed).
.
6.8.3
Permitted Medicines
All background therapy for SLE and CLE given prior to Screening must be stable or discontinued 
according to the specifications in the exclusion criteria for a participant to be eligible for the 
study (see Section 5.2 for Screening Period and Appendix 6 for additional details on SLE/CLE 
background therapy). As changes in standard SLE or CLE therapy can affect disease activity and 
PD endpoints, confounding the study findings, all background antimalarial, and
immunosuppressant therapies should remain stable during the Screening and 24-Week DBPC 
Periods. In addition, medication should NOT be adjusted or discontinued prior to Screening in 
order to allow the participant to become eligible.
The only permitted medications are the following:
1. Any medications required per the medical history and not specifically prohibited by the 
protocol during the study (i.e., from Screening Visit to the End of the study).
2. COVID-19 vaccines. See Section 2.3.3.
3. Vaccination with a subunit or inactivated vaccine (e.g., influenza virus, S. pneumoniae) is 
allowed providing that vaccination completes 2 weeks before any study visit.
4. CS dose up to daily equivalent of prednisone 30 mg maximum for SLE and CLE participants 
(see Appendix 7). Inhaled CS (asthma, COPD) with requirement for stable dose during the 
study. Use of 1 intramuscular injection after Day 1 through Week 8 as a rescue.
5. Topical CSs: Class II-VII in stable application for 
4 weeks, up to 2 times per day, except 
augmented betamethasone dipropionate 0.05% gel or ointment (Table 11).

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6. Topical calcineurin inhibitors in stable application up to 1 time per day. Oral tacrolimus up to 
0.1 mg/kg.
7. Use of 1 antimalarial such as hydroxychloroquine (up to 400 mg/day) or chloroquine (up to 
500 mg/day) is permitted; doses should remain stable. For any changes in doses, the Medical 
Monitor should be contacted, and then the changes should be carefully noted.
8. Permitted SoC therapy during the study for SLE and CLE including the use of 1 of the 
following single immunosuppressants or immunomodulators (see Appendix 6 for maximum
permitted doses in each case):
AZA
6-mercaptopurine
Mycophenolate (either as MMF or mycophenolate sodium)
MTX
Sulfasalazine
Leflunomide
Dapsone
Retinoids
Note: these medications must be stable throughout the 24-Week DBPC period periods in
addition to the Screening Period, see Section 5.2.
Although it is expected participants will be on SoC medications, not all therapies are 
permitted, as detailed in Section 6.8.4.
1. NSAID may be used as needed for temporary relief of symptoms. Any changes in NSAIDs 
up to 1 day prior to each study visit that could affect assessments (e.g., pain) should be 
avoided.
2. Vitamin D and calcium supplementation are encouraged per local SoC guidelines. 
Participants not already taking these medications at Screening should, according to the 
Investigator's judgment, initiate treatment as soon as possible after Screening. These 
medications will not be supplied by the Sponsor.
3. Low-
350 mg/day) for cardiovascular prophylaxis or other indications.
4. Stable dose and regimen of anticoagulants.
5. Treatment with a stable dose of over-the-counter supplements (nonherbal [e.g., iron 
supplement] is allowed if initiated before the Screening Visit). See Section 6.8.3 and 
Appendix 6 for prohibited supplements.
6. Paracetamol (acetaminophen) up to 3 g/day may be initiated or continued for pain control of 
SLE symptoms during the study. This should be titrated off as tolerated.
7. Opioids are permitted for stable use for SLE if initiated by Day 1. Initiation of opioids and/or 
as needed dosing of opioids for more than 2 weeks after Day 1 for SLE is not permitted. These 
may be titrated off as tolerated during the study.

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8. Analgesics may be used at stable doses or as needed basis for temporary relief of symptoms 
not due to SLE. Any changes in analgesics up to 1 day prior to each study visit that could 
affect the assessments (e.g., pain) should be avoided (see Section 6.8.4 and Appendix 6 for 
prohibited medicines).
9. It is recommended that angiotensin-converting enzyme inhibitors and angiotensin receptor 
blockers if used at Screening be maintained at a stable dose during the study for safety reasons 
(e.g. hypertension, cardiac failure etc.). Participan
339 mg/mmol by spot UPCR) will be permitted into the study and the proteinuria will be 
followed, unless dose change, or initiation is required for safety reasons.
10.
Medications for the treatment of infections and hypersensitivity reactions will be provided 
at the discretion of the Investigator. If systemic CS are deemed necessary, their use should 
follow the guidelines in Appendix 7, unless deviation from these guidelines are deemed
medically necessary.
11.
regardless of if it results in a 
protocol deviation and the Medical Monitor must be informed.
16.
Sunscreen.
6.8.4
Prohibited Medicines
The following types of medication are not permitted during the study; see Appendix 6 for further 
details on medication guidance and specific prohibited medications:
1. Immunomodulator or immunosuppressant therapies not listed in Section 6.8.3.
2. Use of more than 1 medication considered to have immunosuppressant or 
immunomodulatory properties, not including antimalarials, or CS.
3. Use of more than 1 antimalarial therapy.

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4. Biologic therapies for SLE or CLE. Biologic therapies for other indications must be 
discussed with the Medical Monitor with the exception of insulin or denosumab, which 
are permitted.
5. Vaccines.
a.
COVID-19 vaccines unauthorized and not approved by the country-specific health 
agencies. See Section 2.3.3.
b. Live or live attenuated virus vaccine.
c.
Vaccination with a subunit or inactivated vaccine (e.g., influenza virus, 
S. pneumoniae) if vaccination completes < 2 weeks before study visit.
6. Supplements (herbal/nonherbal/Chinese Medication). Treatment with a stable dose of 
over-the-counter supplements (nonherbal) is allowed if nonherbal supplements are 
initiated before the Screening Visit (except for those stated in Appendix 6).
7. CSs > 30 mg daily prednisone-equivalent for SLE and CLE. See Appendix 7 for 
additional CS rules.
8. Topical CSs Class II VII applied for > 4 weeks, or > 2 times per day. Topical CSs Class 
I and augmented betamethasone dipropionate 0.05% gel or ointment are not allowed
(Table 11).
9. Topical calcineurin inhibitors applicated > 1 time per day. Initiation of, or change in, 
dosing of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
10. Initiation or change in dose of anticoagulation or antiplatelet therapy.
11. Nonsteroidal anti-inflammatory drugs used above maximum prescribed dose per local 
label.
13. Other investigational agents not specified in this study.
14. Change in dosing or discontinuation of leflunomide less than 8 weeks prior to Screening.
Any medication administered during the study and related to an increase in CLE disease activity
should be discontinued (e.g., proton pump inhibitors, terbinafine).
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant therapies must be recorded in the corresponding section of the CRF, noting the 
name, dose, duration, and indication of each drug.
and CLE treatment prescribed by the 
treating clinician and will not be provided by the Sponsor.
Refer to the exclusion criteria (Section 5.2) for prohibited medication uses before study 
enrollment.

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6.8.5
Other Interventions
Use of potentially excluded procedures such as acupuncture or joint replacement therapy is to be 
discussed with the Sponsor or designee on a case-by-case basis. Use of acupuncture is allowed 
to continue if it is started before the Screening Visit. Major elective surgeries such as abdominal, 
thoracic, or joint replacement surgeries should not be planned to occur in the Study Period. 
Unplanned joint replacement surgery should be discussed at the earliest opportunity prior to the 
surgery with the Medical Monitor regarding continuation of the participant in the study.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
7.1.1
Temporary Discontinuation
Study intervention may be stopped at any time at the Investigator s discretion; however, the 
Medical Monitor must be notified if the participant has missed doses of study intervention for at 
least 5 consecutive days. The participant will continue their scheduled visits
temporary discontinuation is due to an AE, see Section 8. Consultation with the Medical Monitor 
prior to restarting study medication is advised.
If the participant is unable to resume study intervention, see Section 7.1.2.
7.1.2
Permanent Discontinuation
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant is encouraged to remain in the study until last safety follow-up (i.e., Week 26). The 
participant should complete the ET assessments as soon as possible and revert to the same study 
schedule (Table 1
until the Safety follow-up visits are 
completed (see Section 1.3).
The participant must be withdrawn from study intervention in the event of any of the following:
Enrollment despite violation of an exclusion criterion which, in the Investigator s, and/or
Sponsor s opinion, makes discontinuation of the participant necessary.
Participation in any other interventional study during the duration of this study for which the 
Investigator considers discontinuation of the study intervention necessary.
Occurrence of pregnancy.
Occurrence of a clinical condition (e.g., SAE, SFI defined severe flare) for which 
discontinuation is considered necessary by the Investigator and/or the Sponsor/designee.

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Non-compliance to study visits, study intervention etc., judged as significant by the 
Investigator or Sponsor, e.g., taking 
 of the study intervention doses.
An unplanned event that necessitates discontinuation of study intervention for more than 
4 weeks.
If a participant is unblinded.
7.2
Participant Discontinuation/Withdrawal from the Study
A participant may discontinue from the study at any time, at his/her own request or at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.
A participant is considered discontinued from the study due to death.
A participant must be discontinued from the study in the event the participant is lost to 
follow-up.
At the time of discontinuing from the study, if possible, a discontinuation visit (i.e., early 
termination visit) will be conducted, as listed in the SoA. The SoA specifies the data to collect 
at early termination and safety follow-up visits, and any additional evaluations that need to 
be completed.
If the participant revokes consent for the study, any data collected up to that point may still 
be used, but no future data can be generated, and any biological samples collected will be 
destroyed.
A participant has the right at any time to request destruction of any biological samples taken. 
The Investigator will document this in the site study records and the CRF and inform the 
Sponsor. The samples will be destroyed.
When a participant must be withdrawn from the study, the Investigator, or designee will inform 
individual (or Medical Responsible).
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions will be taken if a participant fails to return to the clinic for a required study 
visit:
The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wants to or should continue in the study.
Before a participant is deemed lost to follow-up
the Investigator or designee will make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone 
calls; 2) if necessary, send a certified letter (or an equivalent local method) to the 
, and 3) if a participant has given the appropriate 

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or caretaker (where allowed by local 
regulations) for information. These contact attempts will be documented in the 
If the participant continues to be unreachable, he/she will be 
-up
8
Study Assessments and Procedures
Study assessments and procedures and their timing are summarized in the SoA.
No protocol waivers or exemptions are allowed.
Immediate safety concerns are discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is 
essential, and required for study conduct.
All screening evaluations will be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened, to confirm eligibility, and if applicable, record 
reasons for screening failure.
medical care, the Investigator will obtain written informed consent as specified in
Appendix 2.
and obtained before signing of the ICF may be used for screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
For study visits where several assessment procedures coincide, vital signs, and PROs
should first be assessed, then ECG, collection of urine and blood including PK/PD 
sampling at their specified times, followed by physician assessments, and any remaining 
procedures. Vital signs and ECG should be performed after at least 5 minutes of rest.
Flare history in the 12 months prior to Screening should be collected as described in
Section 8.2.5.
No more than 75 mL of blood may be drawn in a 24-hour period, and no more than 150 mL 
of blood in a 4-Week period.
Where allowed by local law/regulations, samples collected during this clinical study may 
be transferred to a biobank and used for future research outside the clinical protocol when 

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additional consent for this purpose is given. Transfer to the biobank will be documented 
and any testing of coded biobank samples will not be reported in the CSR.
The long-term storage of samples after study completion for future research may be 
performed with all sample types collected in the study (e.g., PK, 
) if the participant consents to optional future medical research.
8.1
Efficacy Assessments and Procedures
Efficacy will be assessed using the instruments and outcomes described below and at the visits 
specified in Table 1.
Efficacy assessments: CLASI, BILAG 2004, 
, SFI, 28-joint 
count, CLA-IGA,
Physician
Global Assessment for SLE Disease 
Activity, Physician
Global Assessment of Cutaneous Lupus Disease Activity, and 
Patient-Reported assessments: FACIT-fatigue, 
,
,
 10a, 
, 
Skindex 29 + 3, and Itch NRS. Patient-reported assessments that do not directly support 
the secondary endpoints may only be implemented if, and when translations are available 
for use.
Skin photography. Depending on the site of the lesion, images will be collected with 
standardized photography equipment for the target lesion (close-up and global), and any 
other lesions located in the head, face, upper anterior, or upper posterior. During the 
Screening visit, collection of these images is required to confirm SCLE and/or DLE 
diagnosis for CLE participants with only historical skin biopsy or if collection of skin 
biopsy is unsuitable (e.g., malar rash bridge of the nose) and is optional for CLE 
participants with fresh skin biopsy and not required for SLE. Starting at Day 1, optional 
skin photography will be done in Cohort A participants (CLE and SLE) at selected sites 
only,
The follow-up photographs should 
re-evaluate the same area of active disease as originally assessed at Day 1. Images will 
be graphically masked by placing black boxes over eyes, tattoos, identifiable features to 
provided in the user manual.
Other patient experience assessments: In-trial qualitative interview.
Details related to efficacy assessments and procedures are summarized in Appendix 8.
Data collection and all query handling will be done via an eCRF system.
8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting, and
analysis of Baseline medical conditions, AEs, physical examination findings, vital signs, 
electrocardiograms, occurrence of suicidal behavior and ideation, and laboratory tests.

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Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the skin,
ENT, cardiovascular, respiratory, gastrointestinal, and musculoskeletal systems.
Routine neurological examination, which includes but not limited to assessment of mental 
status, cranial nerves, reflexes, motor-sensory system, and gait-coordination.
The information obtained by physical examinations will complete SLE and CLE disease 
activity assessments.
Additional examination may be performed at the discretion of the Investigator to fully 
Investigators will pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2
Vital Signs
; respiratory rate; temperature and location 
of measurement, weight, and height (at Screening only) will be measured and recorded.
Body mass index will be calculated at Screening only.
Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (e.g., television, cell phones) and 
measured with an automated device. Manual techniques will be used only if an automated 
device is not available.
8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically measures heart rate, PR, RR, QRS, QT, and QTcF 
Twelve-lead ECG recordings will be obtained after approximately 5 minutes rest in a 
supine position.
The parameters and overall evaluation (normal/abnormal) will be recorded in the eCRF. 
Abnormal values judged as clinically significant by the Investigator will be documented 
on the AE page (see Section 8.3.8).
along with a signed and dated copy (if the printouts are not on archive-quality paper).
In addition, ECGs will also be stored digitally by the Sponsor.
ECG tracings collected during the study may be evaluated ad-hoc by the Sponsor.

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8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in 
Appendix 5 at the time points listed in the SoA. All samples will be clearly identified and 
detailed in the Laboratory Manual. No fasting is required for laboratory tests.
Repeat tests may be performed at any time during the study, as determined necessary by 
the Investigator or required by local regulations.
The tests will be performed by a central laboratory with the exception of urinalysis and 
microscopy, urine pregnancy tests, ESR, reflexive HBV DNA NAAT test after Screening, 
T-SPOT TB test (if required, see Section 5.2), QuantiFERON (only if repeated and 
preferred over central laboratory, see Section 5.2), SARS-CoV-2 test if required, and any 
applicable vaccines which will be performed by a local laboratory or locally.
Local laboratory results are only required when central laboratory results are not available 
in time for study intervention administration and/or response evaluation. If a local sample 
is required, it is important that the sample for central analysis is obtained at the same time.
Additionally, if the local laboratory results are used to make a study intervention decision 
or response evaluation, the results will be recorded.
The Sponsor will receive a list of the local laboratory normal ranges before shipment of 
study intervention(s). Any changes to the ranges during the study will be forwarded to the 
Sponsor or designated organization.
The following safety laboratory assessments will be performed at Screening only:
FSH and estradiol (for women of nonchildbearing potential only to determine 
postmenopausal status).
Serum pregnancy test (for women of childbearing potential only).
Serum virology (Exclusion Criterion 12, Section 5.2), except for reflex testing.
Thyroid stimulating hormone
HBV DNA will be conducted every 4 weeks up to Week 24/ End of Treatment and at end 
of Safety follow-up (Week 26) for participants with positive anti-HBc antibody and/or 
anti-HBs antibody with non-detectable HBV DNA at Screening.
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will 
be conducted at monthly intervals during study intervention administration.
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will 
be conducted at the end of relevant systemic exposure of the study intervention and 
correspond with the time frame for female participant contraception in Section 5.1.
Additional serum or urine pregnancy testing may be conducted at any time during the study 
, or if local regulations 
require them.

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Amylase and lipase will be tested at Screening and Day 1 but may be assessed as clinically 
when total amylase levels are elevated.
The Investigator will review each laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE, unless it does not meet 
the AE definition, as specified in Appendix 4. The laboratory reports will be filed with the 
source documents.
Methods for sample identification during shipping and handling, as well as sampling 
methods, processing, and storage of samples are detailed in the Laboratory Manual.
8.2.5
Disease and Disease Treatment History
Disease history and details of prior treatment for disease must be collected at Screening, as 
described below.
For SLE, disease history, including and not limited to flare history, in the 12 months prior to 
Screening must be collected. A flare is a measurable increase in disease activity in 1 or more 
organ systems involving new or worse clinical signs and symptoms and/or laboratory 
measurements. It must be deemed clinically significant by the assessor and usually there would 
be at least consideration of a change or an increase in treatment (Ruperto 2011). Examples of 
severe flares could include new or worsening organ threatening disease, and hospitalization. 
Current documentation of ACR/SLICC/EULAR/ACR 2019 classification criteria will be 
collected and recorded in the CRF. All previous SLE manifestations should be collected on the 
Medical History page of the CRF.
For CLE subtypes, predominant findings of lupus rash must be SCLE and/or DLE based on 
clinical and histopathology (historical dermatopathology report or fresh skin biopsy) findings
and supported by laboratory results. If only historical dermatopathology report is available, 
diagnosis must be confirmed by skin photography at Screening visit. Participants with cutaneous 
lupus lesions unsuitable for biopsy (e.g., malar rash, bridge of the nose) may be evaluated by 
skin photography at Screening visit, on a case-by-case basis. Disease history including flare 
history and mucocutaneous and scalp involvement in the 12 months prior to Screening must be 
collected. A flare is a measurable increase in skin activity, which is deemed clinically significant 
by the assessor and usually accompanied by a change or an increase in treatment. Documentation 
of SCLE and/or DLE clinicopathologic criteria (and CLE subtypes) will be collected and 
recorded in the CRF based on the modified Gilliam criteria (Werth 2020).
 as long as the 
predominant features support a lead diagnosis as SCLE and/or DLE. All previous CLE 
manifestations and CLE subtypes should be collected on the Medical History page of the CRF.
Medication history 
Treatment of SLE and CLE in the 12 months prior to Screening must be 
recorded in the CRF. In addition, all previous SLE, and CLE medications, other medications 
including investigational drugs up to 12 months prior to Screening must be recorded on the 
previous treatment page of the CRF.

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8.2.6
Suicidal Ideation and Behavior Risk Monitoring
All study participants will be monitored appropriately and observed closely for suicidal 
ideation and behavior change throughout the study, especially at the beginning and end 
of the intervention, or at the time of dose changes. The Investigator will consider 
discontinuing the study intervention in participants, who experience signs of suicidal 
ideation or behavior, following a risk assessment.
When informed consent or assent has been given, participants will be instructed to alert 
family members to watch for the emergence of unusual changes in mood, behavior, as 
well as the emergence of suicidal ideation or attempts and to report such symptoms 
immediately to the Investigator.
The C-SSRS (Appendix 8) will be used for assessment of suicidal ideation and behavior 
change at the Baseline and during the study. Notable changes in the behavior or indication 
of suicide (ideation or attempt) that are documented on the questionnaires anytime during 
the study should be reported as clinical AEs. Consider immediate evaluation by 
psychiatrist or a mental health care provider to assess risk and discontinue the study 
intervention in participants, who experience signs of suicidal ideation or behavior, 
following a risk assessment.
8.3
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting
The definitions of an AE and a SAE are in Appendix 4.
The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. 
The Investigator remains responsible for following up AEs that are serious or that caused 
the participant to discontinue the study intervention, as specified in Section 8.3.2.
Requests for follow-up will usually be made via the Sponsor or CRO-designated study 
team member, although in exceptional circumstances the global patient safety department 
may contact the Investigator directly to obtain further information or to discuss the event.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
All AEs and SAEs will be collected from the signing of the ICF until final safety follow-
up visit at the time points specified in the SoA (Section 1.3). Beyond this reporting period, 
any new unsolicited SAEs that the Investigator spontaneously reports to the Sponsor will 
be collected and processed.

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All SAEs will be recorded and reported to the Sponsor or designee immediately and under 
no circumstance will this exceed 24 hours, as indicated in Appendix 4. The Investigator 
will submit any updated SAE data to the Sponsor within 24 hours of it being available 
using the same procedure that was used for the initial report.
Investigators are not obligated to actively solicit information on AEs or SAEs after the end 
of study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study intervention or study participation, the 
Investigator will promptly notify the Sponsor.
8.3.1
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AESIs (as defined in Section 8.3.7), will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). Reasonable attempts to obtain this information will be 
additional therapeutic measures and follow-up procedures are performed. Further information 
on follow-up procedures is in Appendix 4.
8.3.3
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and Investigators.
Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators, as necessary.

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An Investigator who receives an Individual Case Safety Report describing a SUSAR or other 
specific safety information (e.g., Emerging Safety Issue Report, summary or listing of 
notify the IRB/IEC, if appropriate according to local requirements.
In this global clinical multicenter study, the Sponsor is in the best position to determine an 
unanticipated problem (as defined in US Regulations 21 CFR 312.66). The Sponsor will 
immediately notify all Investigators of findings that could adversely affect the safety of 
participants, impact the conduct of the study,
continue the study. An unanticipated problem is a serious AE that by its nature, incidence, 
severity, or outcome has not been identified in the current version of the risk analysis report, 
specified in Section 2.3.
8.3.4
Pregnancy
Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 90 days post-intervention 
contraception described in Section 5.1 and Table 4.
If a pregnancy is reported, the Investigator will record the pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of female participant or 
female partner of male participant (after obtaining the necessary signed informed consent 
from the female partner) pregnancy.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication,
or elective termination of a pregnancy will be reported as an AE or SAE. Adverse
pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered and reported as SAEs. A spontaneous 
abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at > 22 weeks 
gestational age) is always considered to be an SAE and will be reported as such.
The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant /pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor.
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date for a healthy newborn. In case of a congenital anomaly or other illness of the 
newborn, follow-up will continue until the illness has resolved or there is a definite 
outcome of the event.
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as specified in 
Section 8.3.3. While the Investigator is not obligated to actively seek this information in 
former study participants pregnant female partner, he, or she may learn of an SAE through 
spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.

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8.3.5
Cardiovascular and Death Events
Not applicable.
8.3.6
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs
Not applicable.
8.3.7
Adverse Events of Special Interest (AESI)
An AESI (a serious or non-serious AEs deemed related to the study intervention) is one of the 
scientific and medical concern specific to the study intervention i.e., enpatoran, for which 
ongoing monitoring, and prompt communication by the study Investigator to the Sponsor is 
required. Such AEs of interest may warrant further investigations and in-depth evaluation to 
better characterize and understand the association between the AE and study intervention. Based 
on the enpatoran mode of action and findings of nonclinical toxicology studies, the following 
clinical experiences are considered as AESIs:
Severe infections CTCAE G
Upon observation of AE that qualifies to be an AESI, the Investigator must complete an AESI 
report Form and communicate the event/s with the Sponsor within 24 hours of occurrence of any 
AESI. AESI classified as serious based on SAE reporting criteria should always be reported as 
SAE as outlined in Section 8.3.3.
8.3.8
Management of Adverse Events (Including AESI)
Standard medical care will be provided at the study site for all AEs occurring during the study 
in accordance with the institutional guidelines. The severity of AEs will be graded per 
NCI-CTCAE (Version 5.0). The reason for study intervention withdrawal and the nature, 
duration, and results of any follow-up observations should be recorded in the appropriate section 
of the eCRF.
The study 
the Medical Monitor must be notified. Re-initiation of study intervention may occur at the 
discretion of the Investigator with consideration of the following:

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Clinical signs and symptoms 
Proposed actions
Severe Infections G
3
If severe infection (CTCAE Grade 
3), study 
intervention should be withheld until recovery.
Signs and symptoms should be managed in 
accordance with the institutional guidelines.
Re-initiation of the study intervention should be 
discussed with Medical responsible
Permanently discontinue study intervention if severe 
infection is CTCAE G
Asymptomatic Abnormal Laboratory Values
Proposed Actions
Neutrophil count: <1,000/mm³ [Grade
3]
Temporarily withhold the study intervention.
Clinical evaluation per institutional guidelines.
Repeat the test, preferably within 72 hours but no later 
than 7 days.
Withhold offending concomitant medication, if 
appropriate.
Determine alternative contributing factors
If retest confirms the G
3 toxicity and alternative 
etiology [confounding factors such as concurrent 
medications or disease, disease flare or other risk 
factors] is not confirmed, permanently discontinue the 
study intervention.
Monitor until resolution or return to Baseline, non-
clinically significant level.
Study intervention may be re-initiated if retest value 
returns to Baseline or not clinically significant value 
after discussion with Medical responsible.
3]
Lymphocyte count: <500/mm³ [Grade
3] 
Transaminase elevation i.e., ALT and /or AST 
> 3xULN (if Baseline is normal) or > 3 × Baseline 
(if B
2]
Isolated elevation of Total Bilirubin i.e., > 2 × ULN
(unaccompanied by transaminase elevation)
eGFR < 40 mL/min/1.73m²
The eGFR is calculated by the Modification of Diet 
in Renal Disease equation: eGFR = 175 × (serum 
creatinine in mg/dL) 1.154 × (age in years) 0.203 ×
0.742 (if female) × 1.212 (if race is black).
Serum creatinine > 3.0 × Baseline (Grade
3)
8.4
Pharmacokinetics
The following PK parameters will be calculated, when appropriate:

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Symbol
Definition
Ctrough
The concentration observed at the end of a dosing interval immediately before next 
dosing 
Whole blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of enpatoran. Collection times are specified in the SoA (Section 1.3). The 
actual date and time (24-hour clock time) of each sample will be recorded to calculate actual 
time elapsed since the prior dose administration. The sampling timing may be altered during 
the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.
The exact date/time of sample collection and study intervention administration must be 
recorded in the CRF and will be used in the calculation of PK parameters. Time deviations 
from planned PK sampling times will not be considered a protocol deviation provided the 
exact date/time of sample collection and study intervention administration are recorded in the 
CRF. The time at which the closest meal was consumed should also be recorded on the CRF 
on scheduled study visit days with PK assessment.
The acceptable PK time windows for the respective scheduled days and time points of the 
nominal postdose sampling times (see Section 1.3) are:
Between 1 hour and 2 hour postdose samples
Between 4 hour and 6 hour postdose samples
Week 16, Week 20, and Week 24:
Blood collected any time of the visit. Record time of previous dosing and PK sampling 
time.
The quantification of enpatoran in plasma will be performed using a validated liquid 
chromatography-mass spectrometry assay method. Concentrations will be used to evaluate 
the PK of enpatoran.
Remaining samples collected for analyses of enpatoran concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study.
Details on processes for collection and handling of these samples are in the Laboratory 
Manual. Retention time and possible analyses of samples after the End of Study are specified 
in the respective ICF.
All blood samples collected for PK analysis (except those from placebo dosed participants),
as detailed in the SoA, that are within the known stability of enpatoran at the time of receipt 
by the bioanalytical laboratory, may be analyzed.
Plasma concentrations (and PK parameters using noncompartmental methods, as appropriate) 
will be listed and summarized by study day (and time window, as appropriate) and dose group.

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8.7
Immunogenicity Assessments
Not applicable.
8.8
Health Economics
Not applicable.
9
Statistical Considerations
9.1
Statistical Hypotheses
Each cohort has its own primary objective and the respective null hypothesis will be tested with 
a 1-sided alpha of 2.5% separately.
Participants with CLE (active SCLE and/or DLE) or SLE with predominantly active rash 
(Cohort A)
The global null hypothesis for the Cohort A primary objective is the hypothesis that there is no 
dose-effect, which can also be stated as the hypothesis that the primary endpoint means across 
the study arms are equal.
The global null hypothesis is:
H0:
(1) =
(2) =
(3) =
(4)
Hypothesis of no difference between study arms
with (k) standing for the mean percent change from Baseline in CLASI-A at Week 16 in the 
study arm k, k =1 to 4, with: 1 = Placebo only, 2 = enpatoran 25 mg twice per day,
3 = enpatoran 50 mg twice per day and 4 = enpatoran 100 mg twice per day. And 
is the 
vector of (k), k =1 to 4.
H0 is tested against the alternative hypothesis (H1) is that at least one of (2),
(3) and
(4) 
is < (1).
The global null hypothesis can be rejected, if at least one of the following contrast tests can be 
rejected. An optimal contrast is defined for each candidate model M(m), m = 1 to 5 as detailed 
in Section 8.2
= 0 is 
tested against H1
< 0.

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The model M that fits the data best (e.g., smallest AIC statistic) will be chosen for 
dose-estimation and to further compare each enpatoran study arm to placebo: for each k = 2 to 4, 
(1) =
(k)
(1k)
Participants with active SLE (Cohort B)
The global null hypothesis for the Cohort B primary objective is the hypothesis that there is no 
dose-effect, which can also be stated as the hypothesis that the primary endpoint means across 
the study arms are equal.
The global null hypothesis is:
H0:
(1) =
(k)
k
2
Hypothesis of no difference between study arms
with
(k) standing for BICLA response rate at Week 24 in the study arm k, with: 1 = placebo 
only, k = enpatoran dose k. And 
is the vector of (k).
H0 is tested against the alternative hypothesis (H1) is that at least one of (k) >
(1), k
2.
This global null hypothesis will be tested in a two-stage adaptive design where stage-wise test 
statistics are combined using a weighted inverse normal method (Lehmacher 1999). In Stage 1,
participants are only assigned to study arm 1 (placebo only) and enpatoran 100 mg twice daily.
The following potential adaptations after Stage 1 are planned: extension of investigated study 
arms (i.e., assigning participants also to twice daily enpatoran doses of 25 mg, 50 mg, 100 mg,
150 mg, or other) or stop for futility. Rejection of H0 is only possible after stage 2 if 
w1Z1 + w2Z2 >
standard normal distribution and w1, w2
are pre-specified weights and w12 + w22 = 1, Z1, and Z2 the test statistic for each stage.
Z1 is a test statistic for the individual hypothesis µ(1) = µ(k100 mg). Thus, if it holds µ(1) 
< µ(k100 mg), then the global hypothesis is also not true. Note that Z1 could be regarded 
as a special case of a contrast test for H0: µ(1) = (k) k
2 where no participants are 
assigned to study arm other than placebo and enpatoran 100 mg twice daily.
Z2 is the multiplicity adjusted test statistic for the maximum of m contrast tests 
representing m candidate models, each testing the individual null hypothesis H0(m): 
true.
In case Z1 or the corresponding observed difference between study arm 1 and 2 after Stage 1 is 
below a certain boundary (i.e., low treatment effect) the trial might be stopped for futility.
9.2
Sample Size Determination
Up to 532 participants (approximately 100 in Cohort A + up to 432 in Cohort B) will be 
randomized, treated, and followed in this study.
Participants in Cohort A will be stratified by the following factors:
Region (3 levels: North America and Western Europe vs Asia vs Central/South America 
and rest of the world),
Disease diagnosis at Screening (2 levels: CLE [SCLE and/or DLE] vs SLE).

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Participants in Cohort B will be stratified by the following factors (not all stratification factors 
might be used after Cohort B IA as will be specified in the Interim Analysis Plan):
Region (3 levels: North America and Western Europe vs Asia vs Central/South America 
and rest of the world),
This study is powered for establishing that the changes in doses of enpatoran lead to a difference 
in efficacy results in each cohort separately.
CLE (active SCLE and/or DLE) or SLE participants with predominantly active rash
(participants from Cohort A): To establish the dose-response in percentage change from 
Baseline in CLASI-A scores at Week 16 in participants with CLE (active SCLE and/or DLE) or 
SLE with predominantly active rash, a multiple comparison procedure (MCP) approach 
(Bretz 2005) was used, which calculates combined (average) power across several pre-defined 
parametric dose-response functional models. Family wise type I error rate is controlled while 
performing multiple comparisons, in which process the correlations among different models are 
considered.
Considering 4 arms (0-placebo, enpatoran 25 mg twice per day, enpatoran 50 mg twice per day 
and enpatoran 100 mg twice per day), with a randomization ratio of 1:1:1:1, a minimal 
percentage decrease from Baseline in CLASI-A score at Week 16 of 15% and a maximum 
percentage decrease from Baseline in CLASI-A score at Week 16 of 43%, a standard deviation
of 35% and 6 candidate models (linear, exponential, linlog, logistic, SigEmax1 and sigEmax2) 
(see figure below) defined as:

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The power calculation is based on the estimated number of participants in the Full Analysis Set, 
considering an assumed withdrawal rate of 10%.
Participants with Active SLE (Participants from Cohort B): For the primary endpoint of 
BICLA response at Week 24, up to 432 participants are planned to be randomized in up to 5 arms
in Cohort B:
Cohort B Part 1: 60 participants in a 2:1 ratio (enpatoran 100 mg twice per day: placebo).
Cohort B Part 2 (up to 372 participants):
Up to 280 participants in a 1:1:1:1 ratio over 4 arms (placebo, enpatoran 25 mg twice per 
day, enpatoran 50 mg twice per day and enpatoran 100 mg twice per day).
In case of dose adaptation, up to 92 additional participants may be randomized and the
randomization ratio may also be adapted (as will be specified in the Interim Analysis Plan).

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9.3
Analyses Sets
The analysis populations are specified below. The final decision to exclude participants from 
any analysis population will be made during a blinded data review meeting prior to database lock 
and unblinding. The following analysis set definitions will be considered for each cohort.
Analysis Set
Description
SCR
randomization and study intervention status in the study.
FAS
All participants who were randomized to study intervention. Participants will be 
analyzed per the intervention group to which they were randomized, following the 
intention-to-treat principle.
SAF
All participants, who were administered any dose of any study intervention. 
Participants will be analyzed per the actual study intervention they received.
PK
All participants, who receive at least 1 dose of study intervention, have no important 
events affecting PK, and provide at least 1 measurable post-dose concentration. 
Participants will be analyzed per the actual study intervention they received.
All PK analyses will be based on this analysis set.
PD
All participants, who receive at least 1 dose of study intervention, have no important 
events affecting PD, and have a Baseline, and at least 1 measurable PD endpoint 
post-dose.
Participants will be analyzed per the actual study intervention they received. All PD 
analyses will be based on this analysis population.
FAS = Full Analysis Set, PD = Pharmacodynamics, PK = Pharmacokinetics, SAF = Safety, SCR = Screening

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9.4
Statistical Analyses
This section provides a description of the statistical methods to be used to analyze efficacy, 
safety, and other endpoints. Prior to locking the database, a detailed IAP will be finalized.
Unless otherwise specified, the FAS will be the primary analysis set for all efficacy analyses, 
PRO analyses, and reporting of demographic, and Baseline characteristics. The Safety analysis 
set will be used for all safety data reporting.
Continuous variables will be summarized descriptively using the number of observations, mean,
SD, median, first quartile (Q1), third quartile (Q3), minimum, and maximum. Categorical 
variables will be summarized using frequency counts and percentages. The denominator for the 
percentages will be the total number of participants in the treatment group and analysis set being 
presented, unless otherwise specified (e.g., on some occasions, percentages may be calculated 
based on the total number of participants with available data at a particular time point).
Tests of treatment effect on each primary efficacy endpoint will be conducted at a one-
-
level of 0.025. P-values and the two-sided 95% CIs will be presented where applicable. For 
secondary endpoints, p-values will be interpreted as nominal. Treatment comparisons for each 
data type are described in later sections. Alternative or additional statistical methods may be used 
as appropriate as outlined in the IAP.
Data from all investigative sites will be pooled for all planned analyses. Analysis of individual 
site findings or country findings will be considered if necessary. For those measures that are 
analyzed using change from Baseline scores, observed scores may also be presented 
descriptively.
The IAP will provide definitions of Baseline measurement for change from Baseline endpoints.
Treatment compliance will be assessed in terms of the percentage of the actual doses taken 
relative to the number of scheduled doses and summarized by descriptive statistics.
All participants will be included in individual subject data listings.
Any changes in the data analysis methods described in the protocol will require an amendment
only if the change affects a principal feature of the protocol. Any other changes to the planned 
data analysis that does not require a protocol amendment will be described in the IAP and the 
CSR.
.

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9.4.1
Efficacy Analyses
Endpoints
Statistical Analysis Methods
Primary
Percent change from Baseline in 
CLASI-A at Week 16
This endpoint will be analyzed for CLE (active SCLE and/or DLE) and SLE 
participants from Cohort A as described in Section 9.4.1.1
BICLA response at Week 24
This endpoint will be analyzed for Cohort B SLE participants as described 
in Section 9.4.1.2
Secondary
The following secondary endpoints will be analyzed for CLE (active SCLE and/or DLE) and SLE participants 
from Cohort A and Cohort B with CLASI-
ay 1
Change 
from 
Baseline in 
CLA-IGA at Week 16 and 
Week 24
Change 
from 
Baseline in 
Assessment 
of 
Cutaneous 
Lupus Disease at Week 16 
and Week 24
MMRM analysis will be used to model the score at each visit through Week 
24 with terms for intervention group, visit, intervention group by visit 
interaction, Baseline score, and randomization stratification factors. Test 
and treatment effect estimator (with 95% 2-sided CI) based on difference 
(enpatoran versus placebo) in least squares means of Week 24% CFB (or 
CFB respectively) from the model. Cumulative distribution function for Week 
24 CFB will be estimated by intervention group. Missing data assumed to be 
missing at random (MAR), with missing data status noninformative.
Descriptive statistics will be provided at each visit.
Occurrence of CLA-IGA 0 or 1 
at Week 16 and Week 24
This endpoint will be analyzed using the logistic regression model, with the 
covariates based on the randomization stratification factors. Test and 
treatment effect estimator (with 95% 2-sided CI) will be based on the odds 
ratios (each enpatoran versus placebo) in participants with prednisone-
equivalent dose
.
Descriptive statistics will be provided.
Change from Baseline in the 
Skindex 29+3 symptom domain 
score at Week 24
Change from Baseline in the 
Skindex 29+3 Functioning and 
Emotion 
domain 
scores 
at 
Week 24
Change from Baseline in the 
Skindex 29+3 lupus-specific 
domain score at Week 24
MMRM analysis where score CFB at each visit through Week 24 is modeled, 
with terms for intervention group, visit, intervention group by visit interaction, 
Baseline score, and randomization stratification factors. Test and treatment 
effect estimator (with 95% 2-sided CI) based on difference (enpatoran
versus placebo) in least squares means of Week 24 CFB from the model. 
Cumulative distribution function for Week 24 CFB will be estimated by 
intervention group. Missing data assumed to be missing at random (MAR), 
with missing data status noninformative for CFB.
Descriptive statistics will be provided at each visit.
The following secondary endpoints will be analyzed for CLE (active SCLE and/or DLE) and SLE participants from 
Cohort A and Cohort B 
Clinically 
meaningful 
CS 
reduction,
defined 
as 
reduction of daily prednisone-
10 mg 
5 mg by the 
Week 12 visit and sustained 
through Week 24
This endpoint will be analyzed using the logistic regression model, with the 
covariates of the randomization stratification factors. Test and treatment 
effect estimator (with 95% 2-sided CI) will be based on the odds ratios (each 
enpatoran versus placebo) in participants with prednisone-equivalent dose
.
Descriptive statistics will be provided

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Endpoints
Statistical Analysis Methods
Change 
from Baseline in 
FACIT-Fatigue 
scores
at 
Week 24
MMRM analysis where score CFB at each visit through Week 24 is modeled, 
with terms for intervention group, visit, intervention group by visit interaction, 
Baseline score, and randomization stratification factors. Test and treatment 
effect estimator (with 95% 2-sided CI) based on difference (enpatoran
versus placebo) in least squares means of Week 24 CFB from the model. 
Cumulative distribution function for Week 24 CFB will be estimated by 
intervention group. Missing data assumed to be MAR, with missing data 
status noninformative for CFB.
Descriptive statistics will be provided at each visit.
The following secondary endpoints will be analyzed for SLE participants from Cohort B
SRI-4 response at Week 24
LLDAS attainment at Week 24
Remission 
attainment 
at 
Week 24
These endpoints will be analyzed using the logistic regression model, with 
the randomization stratification factors as covariates. Test and treatment 
effect estimator (with 95% 2-sided CI) will be based on the odds-ratio (each 
enpatoran versus placebo).
Descriptive statistics will be provided at each timepoint through Week 24.
BICLA response and clinically 
meaningful 
CS 
reduction, 
defined as 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
Same as above, restricted to participants with a CS prednisone-equivalent 
dose 
Change in the number of joints 
which are tender and swollen 
in 28-joint count from Baseline 
at Week 24
Change 
from 
Baseline in 
Physician
Global 
Assessment at Week 24.
MMRM analysis where score CFB at each visit through Week 24 is modeled, 
with terms for intervention group, visit, intervention group by visit interaction, 
Baseline score, and randomization stratification factors. Test and treatment 
effect estimator (with 95% 2-sided CI) based on difference (enpatoran
versus placebo) in least squares means of Week 24 CFB from the model. 
Cumulative distribution function for Week 24 CFB will be estimated by 
intervention group. Missing data assumed to be MAR, with missing data 
status noninformative for CFB.
Descriptive statistics, including actual values and CFB at each visit through 
Week 24.
Time to first moderate/severe 
BILAG flare from Day 1 
through Week 24
Time to first SFI severe flare
from Day 1 through Week 24.
Time to event endpoints will be analyzed with a stratified log rank test of 
distribution of time to the event with strata defined based on randomization 
stratification factors will be used.
Estimation of treatment effect (and 95% 2-sided CI) based on hazard ratio 
from stratified Cox model of event hazard rate, with terms for intervention 
group, and strata defined based on randomization stratification factors.
Cumulative distribution function for time to event will be estimated via
Kaplan-Meier method by intervention group. Censoring assumed to be 
noninformative for event.
A participant discontinuing the study early without flare will be censored at 
the last time point at which flare could be assessed. A participant completing 
the 24-week treatment period without severe flare will be censored at 
Week 24.

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BICLA = BILAG-Based Composite Lupus Assessment, CFB = change from Baseline, CLA-IGA = Cutaneous Lupus 
, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity 
Index, CLE = Cutaneous Lupus Erythematosus, CS = Corticosteroids, DLE = Discoid Lupus Erythematosus,
FACIT = Functional Assessment of Chronic Illness Therapy, LLDAS = Lupus Low Disease Activity State,
MAR = Missing at random, MMRM = mixed-model with repeated measures, SFI = SLEDAI Flare Index,
SLE = Systemic Lupus Erythematosus, SRI = Systemic lupus erythematosus Responder Index.
9.4.1.1
Primary Analysis of Percent Change in CLASI-A at Week 16
Per ICH E9 (R1), Addendum on Estimands and Sensitivity Analysis in Clinical Trials 
(November 2019), the primary estimand targeting this primary objective is defined by the 
following attributes:
Variable (endpoint): The primary endpoint is the percentage change in CLASI-A at 
Week 16. Measurements at the participant level are the CLASI-A scores during the course of 
the treatment period.
Treatment: The intervention of interest is enpatoran during the treatment period and placebo 
during the treatment period.
Population: The population of patients targeted by the clinical question is patients with CLE 
(active SCLE and/or DLE) or SLE with predominantly active rash (defined as patients with 
SCLE, DLE or SLE and a CLASI-
.
Population-level summary: The population-level summary comparing the intervention 
groups is the LS mean estimate of mean percent change from Baseline score (SE), difference 
of the LS mean from placebo, and 2-sided 95% CI of the difference.
The primary efficacy analysis of this estimand will be conducted on the FAS population, in 
participants in Cohort A.
A generalized Multiple Comparison Procedure 
Modeling (MCP-Mod) approach accounting 
for baseline covariates (based on stratification randomization factors and Baseline CLASI-A
score) will be used to analyze the primary efficacy variable, i.e., percent change from Baseline 
in CLASI-A at Week 16.
Set of candidate models (for MCP and Mod step): A dose-effect will be detected if at least one 
of the candidate models is significant, with a one-sided family wise error rate of 2.5% accounting
for the set of models. Specifically, the approach calculates for each candidate model optimal 
contrast and identifies significant dose-response models, if exists. If an optimal contrast is 
significant (i.e., positive PoC), a dose-response relationship can be established.
The procedure on how to perform model selection: The candidate model that fits the data best 
(e.g., smallest AIC statistic) will be chosen for dose-estimation. The mean difference of each 
active study intervention arm to placebo together with its 95% confidence interval and p-value 
will be estimated.

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9.4.1.2
Primary Analysis of the Response in BICLA at Week 24.
The primary estimand targeting this primary objective is defined by the following attributes:
Variable (endpoint): The primary endpoint is the Response in BICLA at Week 24 defined 
by:
1. BILAG 2004 improvement (all A scores at Baseline improved to B/C/D, and all B scores 
improved to C or D),
2. No worsening in disease activity (no new BILAG 2004 A scores and
1 new B score)
from Baseline,
3. No worsening of total 
 score from Baseline,
4. No significant deterioration (< 0.3 increase) in visual analog PGA from Baseline (PGA 
score expressed on a 0
3 scale)
Treatment: The intervention of interest is enpatoran during the treatment period and placebo 
during the treatment period.
Population: The population of patients targeted by the clinical question is patients with active 
SLE.
Population-level summary: The population-level summary comparing the intervention 
groups is the proportion of participants achieving BICLA response at Week 24 (95 % CI).
The primary efficacy analysis will be conducted on the FAS population, in participants with 
active SLE (Cohort B).
A generalized MCP-Mod approach accounting for baseline covariates (based on randomization 
stratification factors) will be used to analyze the primary efficacy variable, i.e., proportion of 
participants achieving BICLA response at Week 24 with a similar approach to the one described 
for the primary endpoint of percent change from Baseline in CLASI-A.

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Odds-Ratio and associated two-sided 95% CI comparing each dose level to placebo based on a 
logistic model for the odds of a given BICLA response in the appropriate population, with 
treatment arm as a factor and adjustment for covariates based on randomization stratification 
factors will be presented.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis population for each cohort 
separately.
Endpoint
Statistical Analysis Methods
Primary
Not Applicable
Secondary
Adverse Events 
Descriptive statistics, AESI summaries, 3-Tier AE summaries
Clinical Laboratory Test 
Values
Descriptive statistics, shift tables, boxplots, individual participant line plots,
eDISH figures
ECG Parameters 
Descriptive statistics
Vital Signs 
Descriptive statistics
Tertiary/Exploratory
Not applicable
AE = Adverse Event, AESI = Adverse Events of Special Interest, ECG = electrocardiogram, eDISH = Evaluation of 
Drug-Induced Serious Hepatotoxicity
9.4.2.1
Adverse Events
Adverse events will be coded using the MedDRA. All TEAEs will be summarized by
intervention group. Treatment-emergent AEs are defined as AEs that occurred or worsened on 
or after the first dose of study intervention. The number and percentage of participants who 
experienced at least 1 TEAE will be summarized by System Organ Class and preferred term. 
The percentage will be based on the number of participants in each intervention group. 
Treatment-emergent AEs will also be summarized by relationship to intervention and by severity
within each intervention group. Deaths, SAEs, AESIs, and AEs leading to study discontinuation 
will be tabulated and presented in data listings. Participant level data listings of all AEs will be 
presented.
Summary and analysis of AEs will be performed based on the 3-tier approach (Crowe 2009) as 
further detailed in the IAP. Tier 1 AEs and AESIs will be predefined in the IAP.
9.4.2.2
Clinical Laboratory Test Values
Clinical laboratory results (chemistry, hematology, and urinalysis) will be summarized using
descriptive statistics for each visit by intervention group. Observed values at each visit and
changes from Baseline to each post-Baseline visit will be presented. For clinical laboratory
parameters with associated normal ranges, number and percentage of participants having
high/low/normal findings for worst on-treatment laboratory value will be summarized by
intervention group; shift tables will be used to summarize changes from Baseline finding to worst 
on-treatment finding. For clinical laboratory parameters with NCI-CTCAE grades, shift tables 
will be used to summarize changes from Baseline grade to worst on-treatment grade. The 

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distribution of selected laboratory parameters by time point and intervention group will be 
displayed via boxplots. 
All laboratory data will be provided in participant data listings.
Analyses of liver enzyme tests will include Kaplan-Meier estimates of time to ALT or AST 
events, plots supporting evaluation of Drug-Induced Serious Hepatotoxicity, and individual 
participant profiles.
9.4.2.3
Vital Signs
Observed values at each visit and changes from Baseline to each post-Baseline visit in vital signs 
(blood pressure, pulse rate, respiratory rate, and temperature) will be summarized by time point 
and intervention group using descriptive statistics. Similar summaries of descriptive statistics 
will be provided for the vital signs collected before and after the first dose of study intervention. 
Out-of-range values of vital signs will be tabulated as appropriate. All vital signs will be provided 
in participant data listings.
9.4.2.4
Electrocardiogram Parameters
Observed values at each visit and change from Baseline to the end of treatment period in ECG 
parameters (e.g., PR, HR, QRS, RR, QT, and QTcF) will be summarized by intervention group 
using descriptive
counts of participants with normal and abnormal ECG findings will be summarized by 
intervention group.
Out-of-range values of ECG parameters will be tabulated as appropriate. All ECG data will be
provided in participant data listings.
For all ECG parameters, the results for categorical analysis will be summarized by intervention 
group and visit (or time point) in frequency tables with counts and percentages of participants. 
Categories will cover absolute values and changes from Baseline (predose Day 1):
HR:
Absolute < 50 bpm, < 40 bpm, < 30 bpm
Change from Baseline > 20 bpm, > 30 bpm, > 40 bpm
PR:
Absolute > 200 ms and > 220 ms
Change from Baseline > 30 ms
QRS:
Absolute > 110 ms
QTcF:
Absolute > 450 ms, > 480 ms, and > 500 ms
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Electrocardiogram parameters will be summarized using descriptive statistics for continuous 
variables such as QTcF intervals, and frequency counts, and percentages for categorical 
variables.
9.4.2.5
Concomitant Medication and Procedures
Prior and concomitant medications will each be categorized by therapeutic class and preferred
term using WHO Drug coding dictionary. The number and percent of participants using each
prior and concomitant medication will be summarized by therapeutic class and preferred drug
name for each intervention group. Participants who reported more than 1 medication for a
particular preferred term will be counted once for each preferred term and therapeutic class.
Concomitant procedures will be categorized by ATC class and preferred term using MedDRA. 
The number and percent of participants experiencing each prior and concomitant procedure will 
be summarized by type of procedure for each intervention group.
9.4.3
Other Analyses
9.4.3.1
Pharmacokinetic Parameters, Pharmacodynamic 
Parameters
Pharmacokinetic analysis will be performed on the Pharmacokinetic Analysis Set for each 
cohort. Plasma concentrations (and PK parameters using noncompartmental methods, as 
appropriate) will be listed and summarized by study day (and time window, as appropriate) and 
dose group.
 
 
 
 
 
 
 
 
 
 
9.4.3.2
Demographics, Baseline Characteristics, Disposition, and
Compliance.
demographics, such as age, gender, race, will be summarized by study intervention 
group using descriptive statistics. Baseline disease characteristics will also be summarized by 
study intervention group.
Disposition of participants (i.e., discontinuation from treatment by reason, discontinuation from 
study by reason) and compliance of participants to intervention will be summarized by 
intervention group using descriptive statistics.

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These summaries may be repeated for subgroups of participants, such analyses will be detailed 
in the IAP.
9.4.3.3
Patient-Reported Outcomes
Change from Baseline in PRO scores at a given time point will be compared between enpatoran 
doses and Placebo in the relevant selection of participants via a MMRM adjusted for Baseline 
PRO score and covariates defined based on randomization factors. The adjusted difference in 
least-squares mean for the change from Baseline at a given time point, 2-sided 95% CI, and 
p-value will be reported. A similar analysis will be performed for all PRO scores change from 
Baseline endpoints.
9.4.4
Sequence of Analyses
Interim analyses listed below will be performed by independent statistical data center(s) in an 
unblinded fashion and the data will be evaluated by the external 
ernal 
unblinded Firewall Team independent of the study team. The study team will remain blinded.
Prior to the first IA, a detailed Interim Analyses Plan and Firewall charter as appropriate will be 
finalized, specifying at minimum the details such as the timing of the Interim Analyses, the 
endpoint(s) that will be analyzed, decision rules, and study adjustments as well as the process 
flow in order to maintain the appropriate study blinding and integrity.
Details of the primary and final analyses will be described in the IAP. Details of the IDMC 
analyses, will be described in the Interim Analysis Plan and the IDMC Charter and related 
documentation.
There may be up to 3 planned IA:

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10
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11
Appendices

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Appendix 1
Abbreviations
ACLE
Acute Cutaneous Lupus Erythematosus
ACR
American College of Rheumatology
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine transaminase
ANA
Antinuclear antibody
AOX
Aldehyde oxidase
AST
Aspartate transaminase
AZA
Azathioprine
BCRP
Breast cancer resistance protein
BICLA
BILAG-Based Composite Lupus Assessment
BILAG
British Isles Lupus Assessment Group
C-SSRS
Columbia-Suicide Severity Rating Scale
CLA-IGA
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLE
Cutaneous Lupus Erythematosus
CNS
Central Nervous System
CRF
Case Report Form
CRO
Clinical Research Organization
CS
Corticosteroids
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CYC
cyclophosphamide
DBPC
Double-Blind Placebo-Controlled
DF
Dose-finding
DLE
Discoid Lupus Erythematosus
DNA
Deoxyribonucleic Acid
EAC
Endpoint Adjudication Committee
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate

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EUCT
European Union Clinical Trials
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
EULAR
European League Against Rheumatism
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full Analysis Set
FIH
First-in-Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
IA
Interim Analysis
IAP
Integrated Analysis Plan
IB
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFNs
Interferons
IRB
Institutional Review Board
IVRS
Interactive Voice Responsive System
IWRS
Interactive Web Responsive System
JAK-STAT
Janus kinase/signal transducers and activators of transcription
LLDAS
Lupus Low Disease Activity State
LTBI
Latent TB infection
LTE
Long-term Extension
MCP-Mod
Multiple Comparison Procedure Modeling
MMF
mycophenolate mofetil
MMRM
Mixed-model with repeated measures

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MTX
methotrexate
NCI
National Cancer Institute
NOAEL
no observed adverse effect level
NSAIDs
Non-steroidal anti-inflammatory drugs
NRS
Numeric Rating Scale
PD
Pharmacodynamic
PK
Pharmacokinetic
PoC
Proof-of-Concept
PRO
Patient-Reported Outcome
QoL
Quality of Life
QTcF
QT Interval Corrected Using Fridericia
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SCLE
Subacute Cutaneous Lupus Erythematosus
SELENA
Safety of Estrogens in Systemic Lupus Erythematosus National 
Assessment
SFI
SLEDAI Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SoA
Schedule of Activities
SoC
Standard of Care
SRI
Systemic lupus erythematosus Responder Index
SSC
Study Steering Committee
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TEAE
Treatment-emergent Adverse Events

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TLR
Toll-like Receptor
ULN
Upper Limit of Normal
UPCR
Urine protein/creatinine ratio
VAS
Visual Analog Scale 
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential
VAS
Visual Analog Scale 
Yaa
Y-linked autoimmune acceleration

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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative (where allowed by local laws and 
regulations) and answer all questions on the study.
Participants will be informed that their participation is voluntary.
Participants or their legally authorized representative (where allowed by local laws and 
regulations) will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50; the Japanese ministerial ordinance on GCP; local regulations; 
ICH guidelines; HIPAA requirements, where applicable; and the IRB/IEC or study center.
In Japan, a subject information sheet in the local language and prepared in accordance with 
ic E6, 1996) will be provided by 
the Sponsor for the purpose of obtaining informed consent.
The medical record will include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent will also sign the ICF.
If the ICF is updated during their participation in the study, participants will be re-consented 
to the most current, approved version.
Participants who are rescreened are required to sign a new ICF.
Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. Any participant records or datasets that are transferred to the Sponsor will contain 
the identifier only; participant names or any identifiable information will not be transferred.
The Sponsor will inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure will also be explained to the 
participant and pregnant partners (if applicable), who will be required to give consent for their 
data to be used, as specified in the informed consent.
The participant will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
mainta

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Study Administrative
The study will be conducted at approximately 170 sites in approximately 20 countries in an 
outpatient basis.
The Coordinating Investigator listed on the title page represents all Investigators for 
decisions and discussions on this study, per ICH GCP. The Coordinating Investigator will 
provide expert medical input and advice on the study design and execution and is responsible 
for the review and signoff of the clinical study report.
An Independent data monitoring committee (IDMC) will be established to assess safety and 
tolerability of study intervention during the conduct of the study; IDMC will also review the 
interim analyses (IA) to make recommendations on the conduct of the study and if needed, 
adaptive elements for Cohort B (see Section 4.3). The IDMC will be composed of a minimum 
of 3 members who do not have any conflict of interests with the study Sponsor, including 
2 clinicians, and a biostatistician. The full membership, mandate, and processes of the IDMC 
will be detailed in the IDMC charter. The IDMC will monitor the study until the last 
participant has completed the Safety Follow-Up Visit following the DBPC Treatment Period 
or has entered into the LTE study (WILLOW LTE, MS200569_0048).
The Firewall Team will be comprised of relevant Sponsor senior experts (as described in a 
dedicated Firewall Team charter), who are independent of the study team, to review the 
IDMC recommendation(s) with regards to the conduct and adaptive elements of the trial 
design, based on unblinded data as appropriate and to review Cohort A Week 16 data.
A SSC will ensure that the study meets scientific standards and provide direction and 
oversight to the s
, and
amendments, study execution, and evaluation of study results at the End of Study.
Investigators in this clinical study and other experts who are not otherwise involved in the 
trial may serve on this committee.
 will provide CRO services and Q2 solutions will serve as central laboratory.
Sponsor will be responsible for supply and manufacture of study intervention (enpatoran and 
placebo).
The study will appear in the following clinical studies registries: EUCT number, 2024-
510872-18-00 (previously EudraCT number, 2021-004648-27); ClinicalTrials.gov identifier,
NCT05162586.
Details of structures and associated procedures will be defined in a separate Study Manual.

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Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines
Applicable ICH GCP Guidelines
For studies with Japanese sites, the Japanese ministerial ordinance on GCP
For studies with EU member states sites, with Regulation [EU] No 536/2014
Applicable laws and regulations
The protocol, protocol amendments (if applicable), ICF, IB, and other relevant documents 
(e.g., advertisements) will be submitted to an IRB/IEC for review and approve before the 
study is initiated.
For studies with Japanese sites, the Sponsor initiates the study at a site after obtaining written 
approval from the Head of the study site, based on favorable opinion/approval from the 
concerned IRB.
Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary 
to eliminate an immediate hazard to study participants. When applicable, amendments will 
be submitted to the appropriate Health Authorities.
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
The Sponsor or designee will provide Emergency Medical Support cards to participants for 
use during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the participant. The information on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact 
a Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a 
call center, whereby the health care providers will be given access to the appropriate Sponsor 
(or designee) physician to assist with the medical emergency and to provide support for the 
potential unblinding of the participant concerned.

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Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
In Japan, the Sponsor is entirely responsible for AEs that are associated with this study and 
cause damage to the health of the participants, except for AEs caused by an intentional and/or 
significant deviation on the part of the Investigator, the study site, and/or the participants.
The Sponsor will provide insurance to fulfill this responsibility.
Clinical Study Report
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator, and any Steering Committee, or other relevant study-appointed 
committees or groups.
Publication
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows Merck to protect proprietary information and to provide comments.
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data.
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 and will be submitted in 
accordance with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in 
this protocol or elsewhere should be considered the confidential and proprietary property of 
the Sponsor. The Investigator shall hold such information in confidence and shall not disclose 
the information to any third-
d staff 
who had been made aware that the information is confidential and who are bound to treat it 
as such and to whom disclosure is necessary to evaluate that information. The Investigator 
shall not use such information for any purpose other than for determining mutual interest in 
performing the study and, if the parties decide to proceed with the study, for the purpose of 
conducting the study.
The Investigator understands that the information developed from this clinical study will be 
used by the Sponsor in connection with the development of the study intervention and 
therefore may be disclosed as required to other clinical Investigators, to the USA Food and 
Drug Administration, and to other government agencies. The Investigator also understands 
that, to allow for the use of the information derived from the clinical study, the Investigator 

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has the obligation to provide the Sponsor with complete test results and all data developed 
in the study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement.
The first publication will include the results of the analysis of at least the primary endpoints 
and will include data from the study site. The Investigator will inform the Sponsor in advance 
about any plans to publish or present data from the study. Any publications and presentations 
of the results (abstracts in journals or newspapers, oral presentations, etc.), either in whole,
or in part, by Investigators, or their representatives will require review by the Sponsor before
submission. The Sponsor will not suppress publication but maintain the right to delay 
publication to protect intellectual property rights.
A summary of study results will be provided if required by local regulations (e.g., Regulation 
[EU] No 536/2014). It should be noted that in this multicountry study provision of such 
summary may occur > 1 year after end of clinical study was notified in an individual country 
(including any or all EU member states). Due 
justified to await completion in all countries and provide a summary of study results within 
1 year from global end of clinical study, rather than providing summary results based on 
partial information.
Posting of data on www.ClinicalTrials.gov is planned and will occur 12 months after the last 
visit, or scheduled procedure, or another appropriate date to meet applicable requirements.
Data Quality Assurance
All participant study data will be recorded on printed or electronic CRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically, or
electronically signing the CRF. Details for managing CRFs are in the eCRF Completion 
Guidelines.
For PRO data (e.g., Quality of life [QoL] and pain assessments), electronic PRO will be used.
The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF.
The Investigator will permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections, and provide direct access to the study file and 
source data.
QTLs will be predefined and documented in the Quality Risk Management Plan to help
support the identification of systematic issues that could potentially impact participant safety 
and/or reliability of study results. These predefined parameters will be monitored during the 
study and important deviations from the QTL thresholds and remedial actions taken will be 
summarized in the clinical study report.
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 

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methods, responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan.
The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once 
quality control and quality assurance procedures have been completed. Details will be 
outlined in Data Management documents and procedures.
Study Monitors will perform ongoing source data verification to confirm that data in the CRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, the Japanese ministerial ordinance on GCP, and all 
applicable regulatory requirements.
The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional 
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
The archiving period is 25 years in EU member states.
For studies with EU member states sites, the data will be collected and processed in 
accordance with Directive 95/46/EEC.
Source Documents
Source data is defined as all data in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical study that are necessary for 
the reconstruction and evaluation of the study.
The SDV process is described in a separate manual.
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
The Investigator will maintain source documents that support the data recorded in the CRFs.
Data recorded on CRFs that are transcribed from source documents will be consistent with 
the source documents or the discrepancies will be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records will be available.
Source documents are stored at the site for the longest possible time permitted by the
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures
written approval. In Japan, the head of the study site must retain all records, including 
documents, and data, which relate to the clinical study in accordance with GCP. The head of 
the study site must retain the records at the site (hospital, research institute, or practice) for 
lines, 
whichever is longer. In any case, the head of the study site should ensure that no destruction 
of medical records is performed without the written approval of the Sponsor.

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Definition of what constitutes source data is found in the CRF guidelines.
Study and Site Start and Closure
The study start date is when the first participant signs the Informed Consent Form.
Study and Site Closure
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended closure.
Reasons for the early closure of a study site by the Sponsor or Investigator may include:
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local Health Authorities, the Sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the Investigator
Discontinuation of further developm
If a new safety or efficacy information leads to an unfavorable risk-benefit judgment for 
enpatoran
If the IA indicates that the study is unlikely to achieve the primary endpoint at the time 
of the primary analysis
If the study is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any third-party service 
providers of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator will promptly inform the participants and 
assure appropriate participant therapy and/or follow-up.
In addition, the clinical study may be terminated prematurely or suspended at the request of 
Health Authorities.
Health Authorities and IECs or IRBs will be informed about the discontinuation of the study in 
accordance with applicable regulations.

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Appendix 3
Contraception and Barrier Requirements
Woman of Childbearing Potential (WOCBP):
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation.
Postmenopause:
Postmenopause is defined as no menses for 12 months without an alternative medical cause.
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in a female not using hormonal contraception or HRT. However, in the absence of 
12 months of amenorrhea, confirmation with more than 1 FSH measurement is required.
A female on HRT and whose menopausal status are in doubt will be required to use one of 
the hormonal highly effective contraception methods if she wishes to continue her HRT 
during the study. Otherwise, she must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Permanent Sterilization:
For this study, permanent sterilization includes:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry.

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Table 4
Contraception Guidance
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP, and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That are User Dependent
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation
Oral
Intravaginal
Transdermal
Injectable
Progestogen-only hormone contraception associated with inhibition of ovulation
Oral
Injectable
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods 
for clinical study participants.
Highly effective methods are those with a failure rate of < 1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
Acceptable methods are considered effective, but not highly effecti
1% per 
year). If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure from friction).

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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
AE Definition
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to the 
study intervention or not.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention. For surgical or diagnostic procedures, the condition/illness 
leading to such a procedure is considered as the AE rather than the procedure itself.
Events Meeting the AE Definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from Baseline and are judged to be more severe than expected 
considered clinically significant in the medical and 
scientific judgment of the Investigator (i.e., not related to progression of underlying 
disease, but may be leading to study intervention discontinuation).
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
reported as an AE or a SAE. However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as an AE or a SAE if they fulfil the
definition of an AE or SAE.
Events NOT Meeting the AE Definition
Unless judged by the I
condition, any clinically significant abnormal laboratory findings, other abnormal safety 
assessments that are associated with the underlying disease, the disease/disorder being 
studied
tor.
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the surgical procedure is the AE.
SLE flares are not to be reported as an AE unless considered as unexpected in the context 
. The AE reported verbatim should describe the event term 

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instead of reporting an AE term 
SLE flares meeting 
SAE reporting criteria are always reported whether or not it is consistent with the subjects
prior history. As for SAE reports, the SAE report should describe the events, and avoid 
reporting an SAE term of SLE flare
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Other Adverse Events to be Reported Using a Specialized Procedure or Form
-
All pregnancies occurring during the study and their outcome will be documented on the 
Pregnancy report form and Parent-Child/Fetus Adverse Event Report form as outlined in 
Section 8.3.4.
-
The following procedures should be followed for reporting overdoses (refer to CRF 
guidelines for further details):
Overdoses without an AE should be reported using the paper SAE Overdose Report 
form only, stating if the overdose was accidental or intentional.
Overdoses associated with a non-serious AE must be recorded on the AE CRF and 
also the paper SAE Overdose Report form. Overdoses associated with an SAE must 
be recorded on the AE CRF and the paper SAE Report form.
SAE Definition
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
is to be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
Baseline is not considered an AE.

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However, all events leading to unplanned hospitalizations or unplanned prolongation of an 
elective hospitalization must be documented and reported as SAEs.
d. Results in persistent disability/incapacity
The term disability means
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
Medical or scientific judgment will be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events are usually to be considered as 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
SLE disease flare meeting criteria of SAEs will be reported whether or not it is consistent 
Any suspected transmission of an infectious agent via a study intervention is also considered 
an SAE for reporting purposes, as specified below for reporting SAEs, AESIs.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
The Investigator must record all relevant AE/SAE information in the CRF.
As needed, Sponsor/designee may ask for copies of certain medical records (e.g., autopsy 
reports, supplemental lab reports, documents on medical history/concomitant medications, 
discharge letters), as supporting source documentation. All participant identifiers, except 
the participant number, must be redacted on these copies before submission to 
Sponsor/designee.

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The Investigator must attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) must be documented as the AE/SAE.
Specific guidance is in the CRF Completion and Monitoring Conventions. 
Assessment of Intensity
The Investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories:
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, and 
not interfering with everyday activities.
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
Severe: An event that prevents normal everyday activities. Do not confuse an AE that is 
assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; 
both AEs and SAEs can be assessed as severe.
An
criteria specified 
in the definition of an SAE, NOT when it is rated as severe.
If death occurs, the primary cause of death or event leading to death will be recorded and 
will not be recorded as separate event. Only, if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might then be reported as an SAE.
Assessment of Causality
The Investigator will assess the relationship between study intervention and each AE/SAE 
occurrence:
Unrelated: Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention. A reasonable 
alternative explanation will be available.
Related: Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention.
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The Investigator must use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration must be considered and investigated.

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The Investigator must also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and assessed causality.
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or its designee. To meet the 
reporting timeline, the causality assessment is not required for the initial report.
The Investigator may change his/her causality assessment after considering follow-up 
information and must then send a SAE follow-up report with the updated causality 
assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
The Investigator must perform or arrange for the conduct of supplemental measurements 
and/or evaluations, as medically indicated or as requested by Sponsor/designee to elucidate 
the nature and/or causality of the AE or SAE, as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor/designee with a copy of any post-mortem 
findings including histopathology.
New or updated information will be recorded in the originally completed CRF.
The Investigator will submit any updated SAE data to Sponsor within 24 hours of receipt 
of the information.
Reporting of SAEs
SAE Reporting by an Electronic Data Collection Tool
The primary mechanism for reporting an SAE in multicenter studies to the Sponsor or its 
designee is the electronic data collection tool.
If the electronic system is unavailable, then the site must use the paper SAE form, specified 
below, to report the event within 24 hours.
The site must enter the SAE data into the electronic system as soon as it becomes available.
After the study is completed at a site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-

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safety department.
By exception, an SAE (or follow-up information) may be reported by telephone. The site 
will complete the electronic SAE data entry immediately thereafter.
SAE Reporting by a Paper Form
SAE reporting on a paper report form may be used in single center studies in addition to 
the standard electronic CRF and as a back-up method for an EDC system failure. The form 
includes completion instructions for the Investigator, names, addresses, and telephone, and
fax numbers. All information from the paper form will be transcribed into the electronic 
form as soon as the system becomes available.
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee.
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the form sent by overnight mail or courier service.
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the form within 24 hours after becoming aware of the event.
Additional documents (e.g., laboratory reports, autopsy report, hospital discharge letter) 
and relevant pages from the CRF may be required in addition (e.g. medical history, 
concomitant medication). The data provided will be consistent with the information in the 
CRF.
Reporting of AESIs
For a non-serious AESI, the site must complete the specific AESI report form and notify 
the Sponsor immediately (within 24 hours), using the same process for reporting SAEs, as 
specified above.
For a serious AESI, the site must complete an SAE report form, using the SAE reporting 
process, specified above.
Reporting of Pregnancies
Pregnancy will be reported whether related to the study intervention using the applicable 
paper form.
The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event.
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and must be done within 24 hours to the Sponsor or its 
designee.

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Appendix 5
Clinical Laboratory Tests
The protocol-required clinical laboratory assessments are in the following table:
Table 5
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
MCV
White Blood Cell 
Count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
MCH
Hematocrit
ESR, CRP
RBC count
Coagulation profile (INR, 
PT, aPTT, etc.)
Biochemistry
Blood Urea Nitrogen
Potassium
Aspartate 
aminotransferase
Alanine aminotransferase
Bilirubin
Creatinine
Sodium
Gamma-glutamyl-
transferase
Total Protein
Glucose
Calcium
Alkaline phosphatase
eGFR 
Chloride
CO2
Albumin
First morning 
Clean-Catch 
Urinalysis
Frequent reminders/instructions must be provided to ensure the urine specimen is a 
clean-catch from the first morning void. Urinalysis will be performed by the local 
UPCR Before morning of collection, provide participant with specimen cup. The 
participant will collect first morning void, clean-catch midstream sample at home in 
the morning of clinic visit and bring to the site. The sample will be sent to the central 
laboratory. The same sample taken for UPCR may be used to perform the 
urinalysis.
Specific gravity.
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick.
Microscopic examination (if blood, leukocyte esterase, or protein is abnormal).
Other Screening 
Tests
FSH and estradiol (for non-WOCBP only).
Serum hCG pregnancy test (as needed for a WOCBP).
Serology: hepatitis B (HBs antigen, HBsAb, HBcAb with reflexive HBV DNA NAAT) 
and hepatitis C (HCVAb and reflexive HCV RNA NAAT), per exclusion criteria.
HIV laboratory test (either antibody or nucleic acid amplification test)
Tuberculosis assessment (QuantiFERON, T-SPOT).
Antinuclear antibodies.
Thyroid stimulating hormone.
All study-required laboratory assessments will be performed by a central laboratory, except for urinalysis, and
microscopy, ESR, T-SPOT, QuantiFERON (only if repeated and preferred over central laboratory, see 
Section 5.2), reflexive HBV DNA NAAT (after Screening) and urine pregnancy tests.
PK
See Section 8.4

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Laboratory 
Assessments
Parameters
Pregnancy test after 
Screening
Urine pregnancy test: Highly sensitive urine pregnancy test. If required by local 
regulations, a serum testing will be done instead
Other tests
Amylase/lipase
At Screening and Day 1 only. Additional tests may be assessed as clinically indicated 
amylase level is elevated.
Chest imaging
CXR, CT, MRI
SARS-CoV-2 test
Only if applicable (See Section 5.2)
Vaccine immunization 
status
Antibody titers to tetanus toxoid, diphtheria toxoid, pneumococcal antigens, and SARS-
CoV-2. Note: pneumococcal antigens and SARS-CoV-2 antibody titers not performed 
in China (and potentially other countries if test not available).
BILAG-2004
associated laboratory 
tests 
 
 
 
 
 
 
 
aPTT = activated partial thromboplastin time, BILAG = British Isles Lupus Assessment Group, CT = computerized 
tomography, CXR = chest X-ray, eGFR = estimated glomerular filtration rate, FSH = follicle stimulation hormone, 
HCG = human chorionic gonadotropin, HBcAb = Hepatitis B core antibody, HBsAb = Hepatitis B surface antibody,
HCVAb = Hepatitis C virus antibodies, HIV = human immunodeficiency virus, INR = international normalized ratio,
, MCH = mean corpuscular hemoglobin, MCV = mean corpuscular volume, MRI = magnetic 
resonance imaging, NAAT = nucleic acid amplification tests, PT = prothrombin time, RBC = red blood cell, 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, UPCR = urine protein: creatinine ratio,
WOCBP = women of childbearing potential.

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Appendix 6
Lupus Medication Guidance
Table 6
Medications with Required Washout
Medication type
Medications
Discontinuation (weeks) 
before the Screening Visit or 
as specified
CS
> 30
mg daily prednisone-equivalent, 
including but not limited to oral, topical CS 
Class I, and augmented betamethasone 
dipropionate 0.05% gel or ointment,
intramuscular, or injectable CS
2
Intralesional therapies 
4
NSAIDs
Above maximum prescribed dose per local 
label
2
Immunomodulators/ 
Immunosuppressants a
Thalidomide or lenalidomide
4
Calcineurin inhibitors: 
e.g., cyclosporine, voclosporin. Including 
topical use > 1 time per day 
(e.g., pimecrolimus)
Topical calcineurin inhibitors applied more 
than one time per day
2
Cyclophosphamide
12
Plasmapheresis
Alkylating agents (not 
cyclophosphamide): e.g., chlorambucil
24
Exceeding the maximum specified dose 
for antimalarials, methotrexate, 
6-mercaptopurine, sulfasalazine, 
mycophenolate mofetil, or sodium, 
azathioprine, dapsone, or retinoids
< 8
JAK-STAT pathway inhibitors (e.g., 
tofacitinib)
4
or as Biologic therapies
Abatacept
12
Intravenous Ig
Anti-TNF : e.g., etanercept, adalimumab
Belimumab
16
Anti-IFN: e.g., anifrolumab
24
Anti-IL-6 receptor (tocilizumab, sarilumab) 
or anti-IL-6 (siltuximab)
B cell depleting/modulating therapy such 
as anti-CD20 agents, telitacicept, 
atacicept, dual or other anti-B
Lymphocyte Stimulator /proliferation 
inducing ligand neutralizing therapies
IL-12/IL-23 inhibitor: e.g., ustekinumab
Anti-IL-1 agents

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Medication type
Medications
Discontinuation (weeks) 
before the Screening Visit or 
as specified
Vaccination
Subunit or inactivated vaccines (e.g., 
influenza virus and S. pneumoniae). For 
SARS-CoV-2 vaccine or vaccine series
see Section 2.3.3.
2 (before any study visit)
Live or live attenuated virus vaccine
4
Supplements (Herbal/nonherbal 
/Chinese medication)
Tripterygium, total glucosides of paeony
4
Investigational agents
BTK inhibitors: e.g., ibrutinib
Within the last 12 weeks or 
5 half-lives, or as per washout 
requirement from the previous 
protocol, whichever is longest
Any medication administered 
during the study and related to an 
increase in CLE disease activity
(e.g., proton pump inhibitors, terbinafine).
During the study
a
Use of more than 1 medication considered to have immunosuppressant or immunomodulatory properties as 
permitted by the protocol, not including antimalarials, or CS, is not permitted.
BTK = Bruton's tyrosine kinase, CLE = cutaneous lupus erythematosus, CS = Corticosteroids, IFN = interferon, 
Ig = immunoglobulin, IL = interleukin, JAK-STAT = Janus kinase/signal transducers and activators of transcription,
NSAIDs = nonsteroidal anti-inflammatory drugs, OTC = over-the-counter, SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2,
= tumor necrosis factor alpha.
Table 7
Medications with Required Duration of Stable Dose
Medication type
Medications
Stable/unchanged dosage
(weeks) before the Screening 
Visit or as specified
CS
30 mg prednisone-equivalent
2
Topical CSs Class II-VI up to 2 
times daily 
4
Angiotensin-converting enzyme 
inhibitor or angiotensin receptor 
blocker
2
NSAIDs
2
Immunomodulators and/or 
immunosuppressants 
Antimalarials: hydroxychloroquine 
(up to 400 mg/day), chloroquine 
(up to 500 mg/day)
8
Dapsone (up to 100 mg/day) or 
retinoids (to discuss with Medical 
Monitor)
Sulfasalazine (up to 3 g/day)
Methotrexate (up to 25 mg/week)
Azathioprine (up to 2.5 mg/kg/day)
6-mercaptopurine (up to 
1.5 mg/kg/day)
Mycophenolate mofetil or sodium
(either as mycophenolate mofetil at 
up to 3 g/day or mycophenolate 
sodium up to 2,160 mg/day)

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Medication type
Medications
Stable/unchanged dosage
(weeks) before the Screening 
Visit or as specified
Leflunomide (up to 20 mg/day)
Anticoagulation or antiplatelet 
therapy 
Vitamin K antagonists
Clopidogrel
4
 
 
,
CS = Corticosteroids, 
NSAIDs 
= 
nonsteroidal anti-inflammatory 
drugs,
OTC = Over-the-counter.

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Appendix 7
Corticosteroids Guidance
In order to demonstrate the potential CS-sparing effect of enpatoran and its treatment effect 
compared with placebo, CS must be tapered as clinically tolerated.
This guidance applies to Cohort A and Cohort B participants.
Table 8
Corticosteroid Guidance for the Screening period and 24-Week DBPC 
period
Time period/Other
CS rules and guidance
Outcome if rules not followed
Screening period (prior to Day 1)
CS dosage must remain unchanged. 
Maximum prednisone-equivalent daily 
dose is 30 mg.
Screening failure and participant 
could be rescreened.
Day 1 visit to Week 2
CS dosage must remain unchanged. 
Maximum prednisone-equivalent daily 
dose is 30 mg/day.
 
 
 
 
 
 
Week 2 (starting on Day 15) to 
Week 12
MUST taper CS to a target 
prednisone-equivalent daily dose of 
5 mg/day at Week 12 or earlier, as 
clinically tolerated (see Table 1 for 
protocol-specified CS tapering 
guidance)
Week 12 to Week 24
CS dosage must remain unchanged
(i.e., initiation or increase is not 
allowed but decrease is permitted)
since changes in CS may affect the 
clinical endpoints (e.g., BICLA 
response, CLASI-A reduction, CS-
sparing effect, etc.).
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 24 to Week 26 (Safety 
Follow-Up)
CS dosage must remain unchanged.
CS rescue
Allowed only once after Day 1 through 
Week 8: up to prednisone-equivalent 
daily dose of 30 mg or use 1 
intramuscular CSR injection as rescue 
for worsening of SLE or CLE activity. 
The CS dose must be tapered within 7 
rescue (if not on any CS before the 
rescue, tapering within 10 days to 
prednisone-equivalent daily dose of 5
mg is allowed).

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Time period/Other
CS rules and guidance
Outcome if rules not followed
Injectable CS
CS injected intravenously, 
intra-articularly or SC are prohibited 
during the study (from the Screening 
Visit). CS injected intramuscularly after 
Week 8 are prohibited (only 1 injection 
allowed from Day 1 through Week 8).
CS = Corticosteroids, EAC = Endpoint Adjudication Committee.
Figure 3
CS (prednisone-equivalent) dosing schedule
BICLA = BILAG-based Combined Lupus Assessment, CLASI = Cutaneous Lupus Erythematosus Disease Area and 
Severity Index, CS = Corticosteroids, FU = follow-up, LTE = Long-term extension, EAC = Endpoint Adjudication 
Committee.

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Table 9
Corticosteroid Tapering Guidance during the 24-Week DBPC period
(example only)
Investigators may choose to follow a tapering schedule different to the recommended guidance 
below due to different participant responses and tolerability of CS taper, but MUST reduce CS 
doses, as clinically tolerated, from Week 2 (~ Day 15) to Week 12 to reach and maintain a target 
5 mg/d at Week 12 or earlier. Participants starting with a prednisone-equivalent daily 
5 mg/d at Day 1 must not increase their daily dose above 5 mg of 
prednisone-equivalent.
Study 
week
Prednisone-equivalent
daily dose (mg)
0
(Day 1)
30
25
20
15
12.5
10
7.5
1
30
25
20
15
12.5
10
7.5
2
25
20
20
15
12.5
10
7.5
3
25
20
15
12.5
10
10
7.5
4
20
15
15
12.5
10
7.5
7.5
5
20
15
12.5
10
10
7.5
5
6
15
12.5
12.5
10
7.5
7.5
5
7
15
12.5
10
10
7.5
7.5
5
8
12.5
10
10
7.5
7.5
5
5
9
10
10
7.5
7.5
5
5
5
10
7.5
7.5
7.5
7.5
5
5
5
11
7.5
7.5
5
5
5
5
5
12
5
5
5
5
5
5
5

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13 to 24
5
5
5
5
5
5
5
Study 
week
Methylprednisolone-equivalent
daily dose (mg)
0
(Day 1)
24
20
18
16
12
10
8
1
24
20
18
16
12
10
8
2
20
18
16
12
10
8
6
3
20
18
16
12
10
8
6
4
16
16
12
10
8
6
4
5
16
16
12
10
8
6
4
6
12
12
10
8
6
6
4
7
12
12
10
8
6
4
4
8
10
10
8
6
4
4
4
9
10
10
8
6
4
4
4
10
8
8
4
4
4
4
4
11
8
8
4
4
4
4
4
12
4
4
4
4
4
4
4
13 to 24
4
4
4
4
4
4
4

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In Case of Failure to Taper CS
It is important to understand why CS are not tapered, especially in instances where participants 
seem to meet the criteria for taper (improving and/or maintaining an improvement of disease 
-being.
A CS dose decrease, or a series of decreasing doses, must be tapered for any participant whose 
disease is stable or improving from Week 2 (~ Day 15) to Week 12. The Investigator makes the 
final determination about whether tapering at a given time point is appropriate for a given patient. 
If tapering is initiated, the schedule will be collected on an eCRF. If tapering is not initiated, the 
Investigator will be required to explain the medical rationale for that. Either the Investigator or 
the Medical Monitor may initiate contact in order to clarify the rationale for tapering decisions.
The Medical Monitor and the EAC will review CS use and Medical Monitors will follow-up
with the site for further discussions of all cases where there has been no decrease in CS dosing 
in participants who appear to be improving and/or maintaining an improvement of disease 
activity.
Table 10
Prednisone-equivalence Calculation (Total Daily Dose)
Medication
Equivalent (mg) to 1 mg of Prednisone
Betamethasone
0.15
Cortisone
5
Dexamethasone
0.15
Deflazacort
1.2
Hydrocortisone
4
Meprednisone
0.8
Methylprednisolone
0.8
Prednisolone
1
Triamcinolone
0.8
Non-systemic corticosteroids
From Screening to Week 24 of the DBPC treatment period, generally, there are no restrictions 
on non-systemic CS dosage (defined as optic, otic, intranasal, stable inhaled, and ophthalmic); 
For topical CS use, see Permitted medicines, and prohibited medicines.
Topical Corticosteroids Class and Cross-reactivity
Topical CS Class II VII applied for > 4 weeks, or > 2 times per day or use of topical CS Class I 
or augmented betamethasone dipropionate 0.05% gel or ointment are not allowed. (Reference: 
https://emedicine.medscape.com/article/2172256-overview).

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Table 11
Topical Corticosteroids Class
Potency
Class
Medication
Super potent
I
Clobetasol propionate 0.05%
Diflorasone diacetate 0.05%
High potency
II
Amcinonide ointment (0.1%)
Betamethasone dipropionate ointment (0.05%)
Desoximetasone (cream or ointment) (0.025%)
Fluocinonide (cream, ointment, or gel) (0.05%)
Halcinonide cream (0.1%)
III
Betamethasone dipropionate cream (0.05%)
Betamethasone valerate ointment (0.1%)
Diflorasone diacetate cream (0.05%)
Triamcinolone acetonide ointment (0.1%)
Moderate potency
IV
Desoximetasone cream (0.05%)
Fluocinonide acetonide ointment (0.025%)
Hydrocortisone valerate ointment (0.2%)
Triamcinolone acetonide cream (0.1%)
V
Betamethasone dipropionate lotion (0.02%)
Betamethasone valerate cream (0.1%)
Fluocinonide acetonide cream (0.025%)
Hydrocortisone butyrate cream (0.1%)
Hydrocortisone valerate cream (0.2%)
Triamcinolone acetonide lotion (0.1%)
Low potency
VI
Betamethasone valerate lotion (0.05%)
Desonide cream (0.05%)
Fluocinolone acetonide solution (0.01%)
VII
Dexamethasone sodium phosphate cream (0.1%)
Hydrocortisone acetate cream (1%)
Methylprednisolone acetate cream (0.25%)

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Appendix 8
Efficacy and Patient-Reported Outcome Assessments and 
Procedures
Refer to Table 1 for the study population and frequency for each assessment and procedure.
Columbia-Suicide Severity Rating Scale (C-SSRS)
Patients with SLE, especially those with neuropsychiatric manifestations, are at higher risk for 
suicide than expected. In a review of the medical records of 300 SLE patients over a 20-year 
period, 2% had a documented history of attempted suicide; one of them was fatal. All patients 
had a history of depression at the time of the suicide attempt (Karassa 2003).
The C-SSRS (Posner 2007) assesses the suicidal behavior and suicidal ideation in participants. 
least 1 of the 4 suicidal behavior subcategories (actual attempt, interrupted attempt, aborted 
attempt, and preparatory acts, or behavior). Occurrence of suicidal ideation after randomization 
- categories (wish to 
be dead, nonspecific active suicidal thoughts, active suicidal ideation with any methods [not 
plan] without intent to act, active suicidal ideation with some intent to act [without specific plan], 
and active suicidal ideation with specific plan and intent).
Rationale
The C-SSRS is a low burden, tool designed to track suicidal AEs throughout any intervention 
the clinician or trained designee during the Screening Visit. The measure succinctly covers the 
full spectrum of suicidality addressing both behavior and ideation and is now strongly 
recommended by the US Food and Drug Administration in clinical studies. It is the prospective 
version of the Columbia-suicide classification system commissioned by the Food and Drug 
Administration, which provided the data for their safety analyses, and is used across numerous 
industry and National Institutes of Mental Health-sponsored studies.
Assessments
The C-SSRS is a unique and simple method of assessing both behavior and ideation that tracks 
all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and 
other features of ideation (frequency, duration, controllability, reasons for ideation and 
deterrents), all of which are significantly predictive of completed suicide.
The C-SSRS will be performed at the visits specified in Section 1.3. The trained rater will record 
the clinical observation on the scale which will be used as the source document.
questions 4 or 5 on the C-SSRS during the study should be reported as clinical AEs. Consider a
referral to appropriate psychiatric care to assess risk and discontinue the study intervention in 
participants, who experience signs of suicidal ideation or behavior, following a risk assessment
and notify the Medical Monitor.

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Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)
The CLASI evaluates disease activity and damage in 2 separate scores. The activity scale 
includes measurements of erythema, scale, and hypertrophy, active alopecia, and mucous 
membrane disease, whereas the damage scale measure hyperpigmentation, atrophy, and scarring. 
This distinction between activity and damage assures that the activity part of CLASI is 
responsive to short term therapy-induced changes while the damage indicators can examine 
accumulation of damage over time (Bonilla-Martinez ZL 2008). The CLASI is more reactive to 
therapy-induced changes of activity rather than remaining stable as the activity wanes and the 
chronic damage develops.
Scores range from 0 to 70 points for CLASI activity scale (CLASI-A) score. Mild, moderate, 
and severe disease corresponds with CLASI activity score ranges of 0 to 9, 10 to 20, and 21 to 
70, respectively. It would be unusual to see a CLASI score of more than 30.
A copy of the CLASI form and glossary is provided in the Investigator portal.
participants with 
CLASI-A
8 at Screening and Day 1 in Cohort A or B)
The CLA-IGA is a 5 point score that defines the level of disease severity based on overall lesion 
characteristics
. Severity is determined by a combination of 
3 plaque characteristics (erythema, scale, elevation) based on descriptions of each characteristic.
Erythema is the primary characteristic that influences the rating, with plaque elevation, scaling,
and other secondary characteristics considered secondarily. Severity of the morphologic features 
are averaged over the burden of lesions.
of Cutaneous Lupus Disease Activity (participants with 
CLASI-A
8 at Screening and Day 1 in Cohort A or B)
The 
Global Assessment is used to quantify disease activity and is measured using an 
anchored VAS. The Investigator will rate the overall disease activity status of the participant 
with respect to the lupus rash signs and symptoms of the participant, using a 100 mm VAS where 
0 is no cutaneous lupus disease activity
and 100 is maximum cutaneous lupus disease
activity

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Phys
A
or B)
The 
Global Assessment is used to quantify disease activity and is measured using an 
anchored VAS. The 
Global Assessment will be determined on a continuous VAS 
from 0 (no 
disease) to 3 (maximally severe disease), with the assessment made relative not to the 
ere state possible in SLE per the 
Assessment SLEDAI 
Global Assessment requires Investigators to compare the 
current visit to the previous visit in determining the score. Thus, they should look back at the last 
assessment and consider whether to move the mark to the right (patient worsening) or to the left 
(patient improving).
28-Joint Count
The swollen joint count reflects the number of joints with inflamed synovial tissue and the tender 
joint count is the number with tenderness on palpation. A 28-joint count includes 
metacarpophalangeal and proximal interphalangeal joints, wrists, elbows, shoulders and knees, 
and excludes the joints of the feet (Fuchs 1989). Since patients with SLE frequently present with 
joint pain and/or swelling (i.e., inflammatory arthritis), a 28-joint count form will be used in this 
Phase 2 clinical study to assess joint involvement. The number of swollen joints will be collected 
separately from the number of tender joints.
British Isles Lupus Assessment Group 2004
The BILAG 2004 Disease Activity Index (Yee 2010) evaluates SLE activity in a number of
-to-
Procedures). The primary purpose of the BILAG in this study is to assess possible worsening in 
specific organ systems. Additional analyses of improvements in disease activity as assessed by 
the BILAG 2004 will also be done.

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A separate alphabetic score is assigned to each organ system, corresponding in general to the 
following definitions:
BILAG A: Severe disease activity requiring any of the following treatments (e.g., systemic 
high dose oral CS, intravenous pulse CS, systemic immunosuppressants, or therapeutic high 
dose anticoagulation in the presence of high dose CS or
20 mg prednisone). Note that in the 
context of a CTP with medication restrictions and blinded study intervention, the term 
degree of treatment indicated. It is also understood that some participants respond to different 
levels of medication than others, so that in assessing participants
participants with this degree of symptom would require this level 
of treatment, not necessarily the participants in question
BILAG B: Moderate disease activity requiring treatment with systemic low-dose oral 
glucocorticoids, intramuscular, or intra-articular or soft tissue CS injection, topical CS or 
immunosuppressants, or symptomatic therapy such as antimalarials or NSAIDs
BILAG C: Mild disease
BILAG D: System previously affected but now inactive
BILAG E: System never involved
The BILAG 2004 is evaluated by scoring each of a list of signs and symptom as: improving (1); 
same (2); worse (3); new (4); not present (0); not done (ND). For some items, appropriate 
responses may be: Y/N or numerical values where indicated or Y/N confirm this is due to SLE 
activity.
All signs and symptoms scored must be due to SLE. Use of a glossary provided with the 
BILAG 2004 instrument and training of assessors in use of the instrument are essential to 
obtaining reliable and consistent results.
Requirements for BILAG-based Composite Lupus Assessment (BICLA) response are: (1) 
BILAG 2004 improvement (all A scores at Baseline improved to B/C/D, and all B scores 
improved to C or D); (2) no worsening in disease activity (no new BILAG 2004 A scores and
1
new B score); (3) no worsening of total SLEDAI score from Baseline; (4) no significant 
deterioration (< 10% worsening) in visual analog PGA and (5) no treatment failure (defined as 
non-protocol treatment, i.e., protocol-prohibited medications as determined by EAC (i.e., new,
or increased immunosuppressives or antimalarials, CS use not compliant with protocol rules), or
premature discontinuation from study treatment) (Wallace 2014).
BILAG Flare
Use of the BILAG index for evaluating flares has been identified as a meaningful way of 
evaluating the efficacy of drugs; this judgment has been corroborated by external advisors and 
regulatory authorities.
BILAG assessments should be conducted by a trained evaluator.

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The BILAG index flare definition were used in the SLICC Flare study in May 2009 published 
in Annals of Rheumatic Diseases (Isenberg 2011).
On the participant level:
1.
A severe flare is defined as at least one BILAG A score in any organ systems due to one 
or more items that are new or worse*, in the month leading up to the current visit, compared to 
2.
A moderate flare is defined as at least 2 BILAG B organ scores due to items that are new 
or worse* in the moth leading up to the current visit previous month, when the participant does 
not meet the criteria for the severe flare
3.
A mild flare is defined as one single BILAG B score in any organ systems due to items 
that are new or worse* in the month leading up to the current visit, compared to previous month,
or at least 3 BILAG C scores in any organ systems due to items that are new or worse
4.
No flare is defined as without meeting any of these criteria.
*On the organ system level:
Investigators will be trained to score worse only if there is significant deterioration compared to 
the prior month and to score new only when the item was not present in the prior month according 
to the BILAG glossary. In organs (renal and hematological) in which an A, B, or C score depend 
on whether or not laboratory results are attributed to SLE, Investigators will be queried to ensure 
that there is medical justification for this decision.
A copy of the BILAG 2004 and glossary is provided in the Investigator portal.
SLEDAI Flare Index
The SFI can be used with any version of the SLEDAI and will be used with the 
 
for the purposes of this trial.
A mild/moderate flare is defined as any of the following:
Increase in SLEDAI instrument score of 3 points or more (but total score not to more than 12).
A severe flare is defined as any of the following:
Increase in SLEDAI instrument score leading to total score > 12.

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Increase in PGA score > 2.5 (assuming the PGA score has been transformed to a 0-3 point 
scale).
The 
 and SFI assessments must be conducted by a trained evaluator.
A copy of the 
 form is provided in a separate Manual of Procedures.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-Reported Assessments
Functional Assessment of Chronic Illness Therapy-Fatigue
The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact 
upon daily activities and function (Wolfe 1996). It uses a 5-point Likert-type scale (0 = not at 
all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). As each of the 13 items of the 
FACIT-Fatigue scale ranges from 0 4, the range of possible scores is 0-52, with 0 being the 
worst possible score and 52 the best. To obtain the 0-52 score, each negatively worded item 
response is recoded so that 0 is a bad response and 4 is good response. All responses are added 
with equal weight to obtain the total score. Fatigue is among the most prevalent symptoms of 
Wolfe 1996; Yellen 1997). The 
FACIT-Fatigue has been validated in subjects with SLE being a valid and responsive measure 
of fatigue in subjects with SLE (Hewlett 2005; Kosinski 2013; Lai 2011; Strand 2015) and will 
also be evaluated in CLE patients.

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Patient Experience In-trial Qualitative Interviews
Patient experience in-trial qualitative interviews will be performed as part of the clinical trial, to 
document the experience of treatment from the patient perspective and to understand the impact 
of enpatoran in the treatment of lupus. Specifically, the interviews are expected to capture 1) the
patient experience of treatment in the clinical study, 2) the patient experience of changes (or no 
change) in symptoms and the ability to function or perform activities that are important to the 
patient, and 3) the patient perspective on the meaningfulness and importance of score change in 
PRO assessments.
The interviews will follow a one-on-one format and will be conducted via telephone, based on a 
semi-structured interview guide. Each interview will be approximately 60 minutes and will be 
completed within 2 weeks
End of Treatment visit.
The interviews will be offered to all participants from a subset of sites from selected countries 
participating in the clinical study. Participants from the selected sites will be provided with a 
description of the qualitative interview and will be invited to participate. Details about the 
qualitative interviews will be included in the clinical trial informed consent form and ethics and 
IRB review submissions.
All interviews will be conducted by experienced moderators and will be audio recorded. The 
content of the interview will be transcribed, and the audio recording will be destroyed to protect 
participant privacy. All personal information will be removed from the transcripts. Using the 
interview transcripts, dominant trends will be identified in each interview and then compared 
across the results of the other interviews to generate themes or patterns in the way participants
describe their treatment and clinical trial experiences as well as their perceptions of treatment 
benefit and meaningful change in PRO measure scores over the trial period.
Should an interviewer become aware of any potential adverse event during the telephone 
interview, the interviewer will share the relevant information with the 
clinical site 
staff within 24 hours. The clinical site will be responsible for follow-up with the participants and 
Principal Investigator will be responsible for determining the clinical significance of 
the event.

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Skindex 29+3
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 (Ogunsanya 2019; Chren 1996). Subscale 
scores are generated for each of the 3 original domains of the Skindex-29 i.e., symptoms, 
functioning, and emotional well-being. In addition, a photosensitivity subscale score is 
calculated based on 2 of the additional lupus-specific items related to photosensitivity 
(Foering 2012). For all subscale scores, higher scores indicate lower functioning/worse 
symptoms.
This scale will be completed by study participants with SCLE, DLE or SLE with active skin rash 
(CLASI-A
8 at Screening and Day 1 in Cohort A or B) only.
Itch Numeric Rating Scale (NRS)
The Itch NRS is a self-rated single item scale designed for assessing worst itch in the past 7 days. 
The scale utilizes an 11-point NRS, scored from of 0 (no itch) to 10 (worst imaginable itch).
This scale will be completed by study participants with SCLE, DLE or SLE with active skin rash 
(CLASI-A
8 at Screening and Day 1 in Cohort A or B) only.
Multidimensional Psychological Questionnaire (MPsQ)
The MPsQ is a package of modules assessing psychological traits and states, contextual, and
social factors. It was developed by Cognivia to collect informative features to be used in the 
Placebell
methodology, designed to improve the statistical power in Randomized Clinical 
Trials (Branders 2022). This methodology integrates usual 
baseline features with 
baseline MPsQ data in baseline prognostic covariate(s) (covariate(s) that are likely to be 
associated with the endpoint(s)).

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Appendix 10
Protocol Amendment History
The information for the current amendment is on the title page.
Protocol Version 3.1-Korea (12 June 2023)
Overall Rationale for the Amendment
The rationale for this local protocol amendment is to provide additional details on the changes 
done in Protocol Version 2.0, as requested by the Korean Ministry of Food and Drug Safety.
Section # and Name
Description of Change
Brief Rationale
Appendix 11
Country-specific 
Requirements
Added appendix listing country-specific 
requirements for Korea, to include further details of 
the changes done in Protocol Version 2.0. 
For completeness.
Protocol Version 3.0 (17 March 2023)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The rationale for this protocol amendment is the following:
To update the protocol in alignment with the Investigator Brochure (IB) Version 6.0 and 
Version 7.0 and to include more details on the potential dose adaptations and study intervention 
administration after the planned Cohort B Part 1 interim analysis.
Section # and Name
Description of Change
Brief Rationale
Synopsis
Section 1.2 Schema
Section 3 Objectives and 
Estimands
Section 4 Study Design
Section 6.3.1 Study Intervention 
Assignment
Section 6.5 Dose Selection and 
Modification
Section 9.1 Statistical 
Hypotheses
Section 9.2 Sample Size 
Determination 
Section 9.4 Statistical Analyses
Updated text and statistical 
considerations to include potential 
adaptation based on Cohort B interim 
analysis of sample size and 
stratification factors. Increased 
maximum number of Cohort B
participants to 432.
Increase of sample size and 
reduction of stratification factor 
might be required if dose adaptation 
is implemented after a large number 
of Cohort B participants have been 
enrolled.
Synopsis
Section 4.1 Overall design
Added clarification that for certain 
countries, potential dose adaptation 
may only be implemented after 
approval.
To comply with country-specific 
requirements.

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Section # and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities
Removed serum virology from Phone 
safety follow-up visit.
To correct an error.
Section 1.3 Schedule of 
Activities
Edited timing dependency to dosing 
of ECG and of immune cell subset 
sample collection.
To improve clarity and provided 
flexibility for the EOT/ET visit, as 
dosing will finalize before those 
visits.
Section 1.3 Schedule of 
Activities
Section 8.3.8 Management of 
Adverse Events
Added ECG assessment at Week 2.
Added QTc prolongation on ECG of 
500 ms as clinical sign to be 
managed.
Based on preliminary inhouse PK 
data from MS200569_0004, 
enpatoran exposure tends to be 
higher in lupus patients compared to 
healthy participants. An ECG 
assessment at Week 2 has been 
added to have an early ECG 
timepoint once enpatoran 
steady-state is achieved.
Section 1.3 Schedule of 
Activities
Added clarification on overlap of 
WILLOW with WILLOW LTE visits.
To align with WILLOW LTE 
protocol.
Section 2.2 Background
Section 2.3 Benefit/Risk 
Assessment
Updated information (including 
adverse events) based on completed 
Study MS200569_0040.
To align with IB v7.
  
Section 5.1 Inclusion Criteria
Removed lower BMI limit.
To allow representation of various 
body composition  
Section 5.1 Inclusion Criteria
Changed window for stable dose of 
concomitant lupus therapies.
To correct an inconsistency.
Section 5.2 Exclusion Criteria
Section 6.8.3 Permitted 
Medicines
Section 6.8.4 Prohibited 
Medicines
Appendix 6
Updated the vaccine restrictions 
allowing vaccination with other 
subunit or inactivated vaccines.
To adapt study to real-life clinical 
practice situation not previously 
considered.

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Section # and Name
Description of Change
Brief Rationale
Section 6.1 Study Intervention
Administration
Section 6.5 Dose Selection and 
Modification
Included information on potential 
150 mg dose and/or 50 mg film-
coated tablets
To update for potential dose 
adaptation scenario.
Section 6.3.2 Blinding
Removed bioanalytical monitors from 
list of unblinded personnel. 
To correct an error.
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Appendix 5
Updated information that reflexive 
HBV DNA NAAT test after Screening 
is to be done locally.
To complete the information as this 
assessment can be done locally.
Section 8.2.6 Suicidal Ideation 
and Behavior Risk Monitoring
Appendix 8
Added clarification on required action 
in case of suicidal behavior or 
ideation risk as per C-SSRS.
To align wording throughout the 
protocol.
Section 9.4.4 Sequence of 
Analyses
analysis of Cohort
Clarified the sequence of analyses 
between the primary analysis of 
Cohort A, the primary analysis of 
Cohort B, and the final analysis. 
To account for other possible 
enrollment completion timings of 
Cohort A with respect to Cohort B.
Appendix 2
Increased number of sites.
To support additional recruitment.
Throughout
Changed phase of Study 
MS200569_0004 from Phase 1 to 
Phase 1b. 
To correct an error.
Throughout
Minor editorial and document 
formatting revisions.
Administrative and editorial updates.
Protocol Version 2.0 (12 September 2022)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The rationale for this protocol amendment is the following:
To update the protocol in alignment with the Investigator Brochure (IB) Version 5.0, specifically 
the relaxation of concomitant medications restricted in previous study protocol versions based 
on new data and incorporate updates from the Integrated Analysis Plan (IAP) Version 1.0. In 
addition, Protocol Version 1.1-JPN (10 December 2021) changes have been incorporated into 
this global amendment Version 2.0, including the reflex monitoring of Hepatitis B virus (HBV) 
DNA.

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Section # and Name
Description of Change
Brief Rationale
Title Page
Appendix 13
Coordinating 
Investigator - 2 Signature 
Page
Added additional Coordinating Investigator details
Added additional Coordinating Investigator 
Signature Page
Administrative update a
second Coordinating 
Investigator included in the 
study
Section 1.1
Synopsis
Section 9.4.4 
Sequence 
of Analyses
Updated text for the Cohort A interim analysis.
Alignment with IAP
Section 1.1
Synopsis 
and Section 3 
Objectives and Estimands
Added Additional endpoint for the 28-joint count 
along with population, 
, and
population-level summary
Alignment with IAP
Section 1.1
Synopsis
Section 4.1 
Overall 
design
Section 6.5 
Dose 
Selection and Modification
Added Part 1 and Part 2 for Cohort B
Clarification on the study 
design
Section 1.1
Synopsis
Section 4.1 
Overall 
design
Section 6.5 
Dose 
Selection and Modification
Added information about dose adaptations to be 
implemented on Cohort B Part 2 participants
Clarification on the study 
design
Section 1.3 
Schedule of 
Assessments (SoA 
Table 1)
Added guidance on assessments
To clarify the assessments that 
must be completed for 
participants with dual 
diagnosis
Section 1.3 
Schedule of 
Assessments (SoA 
Table 1)
Section 8.1 
Efficacy 
Assessments and 
Procedures
Appendix 8
Efficacy and 
Patient-Reported 
Outcome Assessments 
and Procedures
Section 1.3 
Schedule of 
Assessments (SoA 
Table 1) and Appendix 5 -
Clinical Laboratory Tests
Additional clarification on BILAG-2004 associated 
laboratory tests
These laboratory tests are 
contingent on the 
Section 1.3
Schedule of 
Assessments (SoA 
Table 1)
Additional clarification on UPCR
To specify how to proceed if 
the specimen cup is not 
provided prior to the Screening 
visit
Section 1.3
Schedule of 
Assessments (SoA 
Table 1) and Appendix 5 -
Clinical Laboratory Tests
Additional clarification on Urine pregnancy test
To specify the type of test and 
alternative options if requested 
by regulators

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Section # and Name
Description of Change
Brief Rationale
Section 1.3
Schedule of 
Assessments (SoA 
Table 1) and Appendix 5 -
Clinical Laboratory Tests
Added text pertaining to China and potentially 
other countries/sites
-
CoV-2 antibody titers not performed in China and
potentially other countries/sites
Not performed in countries/ 
sites where the test is not 
available (e.g., China)
Section 1.3 
Schedule of 
Assessments (SoA 
Table 1)
Clarification on test availability
Section 1.3
Schedule of 
Assessments (SoA 
Table 1)
Additional clarification for Safety follow-up visits
Alignment with 
MS200569_0048 study 
protocol
Section 1.3
Schedule of 
Assessments (SoA 
Table 1) and Section 6.2 
Study Intervention 
Preparation, Handling, 
Storage, and 
Accountability
D
Not used in this study
Section 2.1 
Study 
Rationale
Section 2.3.1 
Risk 
assessment
Section 4.3 
Justification 
for Dose
Updated previous study numbers
Alignment with protocol 
Version 1.1 in Japan per 
PMDA inquiries to identify 
studies in a consistent and 
globally applicable manner.
Section 2.2 
Background
Added additional information of only biological 
approved agents for SLE
Update on latest information
Section 2.2 
Background
Added additional information about 
MS200569_0005 and MS200569_0026 studies
Update on latest information in 
alignment with IB Version 5.0
Section 2.3
Benefit/Risk 
Assessment
Additional information of Benefit/risk assessment 
from MS200569_0001, MS200569_0005 and 
MS200569_0026 studies
Section 2.3.1 
Risk 
assessment
Additional information on adverse events
Update on latest information 
per IB Version 5.0
Section 2.3.1 
Risk 
assessment
(potential risks of clinical 
significance Table 2)
Updated the information and revision to the 
summary of data and mitigation strategies
Section 3 
Objectives 
and Estimands
Section 9.4.1 
Efficacy 
Analyses
Change 
from Baseline in the Skindex 29+3 lupus-specific 
domain score at Week
Alignment with IAP

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Section # and Name
Description of Change
Brief Rationale
Section 3 
Objectives 
and Estimands
Replaced Screening with Baseline
Section 5.1 
Inclusion 
Criteria
Removed country-specific (Japan) statement for 
age as an inclusion criterion
Added guidance on the minimum age for the sites 
while obtaining informed consent
Japanese civil code change in 
April 2022
To align with local guidelines
Section 5.1 
Inclusion 
Criteria
Extended upper limit for body mass index
MS200569_0026 and 
MS200569_0005 PK data 
showed low impact of high BMI 
on drug exposure
Section 5.2 
Exclusion 
Criteria
Section 6.8.3 
Permitted 
Medicines
Removed > 4 mg/mg and retained 339 mg/mmol 
for Urine Protein Creatinine ratio
Correction as these 2 values 
are not equivalent
Section 5.2 
Exclusion 
Criteria
Changed the duration of use oral anti-infectives 
from 
2 weeks prior to Screening Visit to 
2
weeks prior to Day 1 Visit
Correction to avoid 
unnecessary exclusion of 
study population eligible 
otherwise (well treated for 
systemic infections before 
enrollment).
Section 5.2 
Exclusion 
Criteria
8.2.4 Clinical Safety 
Laboratory Assessments
Added clarification for QuantiFERON test
To allow testing flexibility in 
case of indeterminate central 
laboratory results

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Section # and Name
Description of Change
Brief Rationale
Section 5.2 
Exclusion 
Criteria
Section 6.8.3 
Permitted 
Medicines
Section 6.8.4 
Prohibited 
Medicines
Added clarification to the sections that allow use 
of medications associated with QTc interval 
prolongation
Correction as wording included 
in certain sections could be 
misinterpreted since these 
medications are indeed 
allowed
Section 5.2 
Exclusion 
Criteria
Updated the washout period of JAK-STAT 
pathway inhibitors (tofacitinib) 
Correction as previous 
washout period was 
unnecessarily long
Section 6.1 
Study 
Intervention 
Administration
(Table 3)
Updated packaging and labeling details of 
enpatoran and placebo
Correction to describe the 
actual packaging
Section 6.2 
Study
intervention Preparation, 
Handling, Storage, and
Accountability
Appendix 2
Study 
Governance
Appendix 8
Efficacy and 
Patient-Reported 
Outcome Assessments 
and Procedures
Pharmacy Manual
eCRF 
Completion Guidelines
Replaced 
Investigator portal
Correction of document name
Section 6.8.1 
Corticosteroids
Section 6.8.2 
Corticosteroids Rescue 
Medication
Section 6.8.4 
Prohibited 
Medicines
Alignment with IAP
Section 6.8.2 
Corticosteroids Rescue 
Medication 
Section 6.8.3 
Permitted 
Medicines
Added use of 1 intramuscular CS injection as a 
rescue for worsening SLE
Per recommendation of clinical 
lupus experts

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Section # and Name
Description of Change
Brief Rationale
Exclusion criteria 5.2
Section 6.8.3 
Permitted 
Medicines
Section 6.8.4 
Prohibited 
Medicines
Appendix 7
Corticosteroids guidance -
Table 11
Updated topical corticosteroids categories
Modified from WHO categories 
for topical corticosteroids
1.3 Schedule of 
Assessments
5.2 Exclusion Criteria
Section 8.2.4 
Clinical 
Safety Laboratory 
Assessments
Added HBV DNA assessments at Weeks 0, 2, 4, 
8, 12, 16, 20, 24/End of Treatment, 25 and 
26/end of safety follow-up for participants who 
are positive for anti-HBc antibody and/or anti-HBs 
antibody with non-detectable HBV DNA at 
Screening.
Edited HBV exclusion criteria to exclude 
participants with no history of HBV vaccination 
with positive HBV surface AND/OR core 
antibodies with reflexive detectable HBV DNA 
NAAT at Screening
To conduct eligibility and 
regular monitoring of HBV 
DNA in alignment with the 
Japan Society of Hepatology 
Guideline for Hepatitis B Virus 
Infection (2019 update) and in 
alignment in alignment with 
protocol Version 1.1-JPN per 
PDMA inquiries
Section 6.3.2 
Blinding
Added clarification on unblinding of study and 
breaking of drug codes
Updated in relevance to 
primary and final analysis of 
the study
Section 8 
Study 
Assessments and 
Procedures
Additional laboratory parameters were added that 
could potentially unblind the study
Alignment with Sponsor 
unblinding documentation
Section 8.2.4 
Clinical 
Safety Laboratory 
Assessments and 
Appendix 5
Clinical 
Laboratory Tests
Updated list of laboratory assessments that are 
exceptional to be performed by central laboratory
Correction
Section 8.3.4 
Pregnancy
Removed guidance on continuation of study 
intervention following pregnancy
Not relevant for this study
Section 9.3 
Analyses 
Sets
Removed wording related to the analysis in the 
subgroup of SLE participants from Cohort B with 
CLASI-A
8
Alignment with IAP
Section 9.4.1 
Efficay 
Analyses
Updated wording to reflect estimand
Section 9.4.1.2 
Primary 
Analyses of the response 
in BICLA at Week 24
0.3 
Section 9.4.2 
Safety 
Analyses
Rephrased the wording for Safety analysis 
population
Section 9.4.4 
Sequence 
of Analysis
Updated text for Primary analysis (Cohort A)
Section 10 
References
Appendix 3
Contraception and Barrier 
Requirements

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Section # and Name
Description of Change
Brief Rationale
Appendix 6 
Lupus 
Medication Guidance
Updated guidance for lupus medications with 
required washout and duration of stable dose
Based on the review of the 
half-lives for the relevant 
medications and the updates 
in Section 5.2-Exclusion 
criteria, Section 6.8.3-
Permitted medicines, and 
Section 6.8.4-Prohibited 
medicines
Appendix 7 
Corticosteroids Guidance
Updated corticosteroid guidance and the list of 
topical corticosteroids class.
Updated reference corresponding to topical 
Corticosteroids Class
 Used a 
modified version of the WHO 
categories for topical 
corticosteroids to facilitate site 
instructions.
Relevant with updated 
information
Throughout
Minor editorial and document formatting revisions 
(including abbreviations and addition of 
Appendix 10)
Administrative and editorial 
updates
Protocol Version 1.1-Japan (10 December 2021)
Overall Rationale for the Amendment
The rationale for this local protocol amendment is the following:
As response to the PMDA inquiries, HBV exclusion criteria were edited to exclude participants 
with no history of HBV vaccination with positive HBV surface AND/OR core antibodies with 
reflexive detectable HBV DNA NAAT at Screening. Moreover, in alignment with the Japan 
Society of Hepatology Guideline for the Management of Hepatitis B Virus Infection (2019 
update), participants with negative HBs antigen and positive anti-HBc antibody and/or anti-HBs
antibody with non-detectable HBV DNA at Screening will undergo regular HBV DNA testing 
during the study period.

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Section # and Name
Description of Change
Brief Rationale
2.1 Study Rationale;
2.2 Background;
2.3.1 Risk Assessment;
4.2 Scientific Rational;
4.3 Justification for Dose;
6.5 Dose Selection and 
Modification;
9.4.4 Sequence of 
Analysis.
Replaced NCT identification codes by Merck 
study numbers.
To identify studies in a consistent 
and globally applicable manner.
1.3 Schedule of Activities;
8.2.4
Clinical Safety 
Laboratory Assessments;
10 References;
Appendix 5 Clinical 
Laboratory Tests.
Added HBV DNA assessments at Weeks 4, 
8, 12, 16, 20, 24/End of Treatment and 
26/end of safety follow-up for participants who 
are positive for anti-HBc antibody and/or 
anti-HBs antibody with non-detectable HBV 
DNA at Screening.
To conduct regular monitoring of 
HBV DNA in alignment with the
Japan Society of Hepatology
Guideline for Hepatitis B Virus 
Infection (2019 update).
5.2 Exclusion Criteria
Edited HBV exclusion criteria to exclude 
participants with no history of HBV 
vaccination with positive HBV surface 
AND/OR core antibodies with reflexive 
detectable HBV DNA NAAT at Screening.
To conduct eligibility of HBV in 
alignment in alignment with PDMA 
inquiries.
Appendix 5 Clinical 
Laboratory Tests
Added ESR and T-SPOT to the listing of local 
laboratory tests for completeness. This 
information was already contained in 
Section 8.2.4 Clinical Safety Laboratory 
Assessments.
Information added for 
completeness.
Throughout
Minor editorial and document formatting 
revisions (including addition of Appendix 10).
Minor editorial and document 
formatting revisions.

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Appendix 11
Country-specific Requirements
South Korea:
Additional rationale for changes done in Protocol Version 2.0 as requested by the Korean
Ministry of Food and Drug Safety is provided in the table below.
Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria
Section 6.8.3 Permitted 
Medicines
Section 5.2 Exclusion
Criteria
Changed the duration of
use oral anti-infectives from 
2 weeks prior to
Screening Visit to 
2 weeks prior to Day 1
Visit.
Correction to avoid unnecessary exclusion of 
study population eligible otherwise (well treated for 
systemic infections before enrollment).
Section 5.2 Exclusion
Criteria
Section 8.2.4 Clinical Safety 
Laboratory Assessments
Added clarification for
QuantiFERON test.
To allow testing flexibility in case of indeterminate
central laboratory results by permitting local
laboratory results.

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Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria
Section 6.8.3 Permitted 
Medicines
Section 6.8.4 Prohibited 
Medicines
Added clarification to the 
sections that allow use of 
medications associated 
with QTc interval 
prolongation.

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Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria
Updated the washout 
period of JAK-STAT 
pathway inhibitors 
(tofacitinib)
Correction of previous washout period from 
24 weeks to 4 weeks due to short half-life.
, ADME = absorption distribution metabolism and excretion, AE = adverse event, 
AOX = aldehyde oxidase, CNS = central nervous system; DDI = drug-drug interaction, 
EEG = electroencephalogram, JAK-STAT = Janus kinase/signal transducers and activators of transcription, 
QTc = QT interval corrected for heart rate, PK = pharmacokinetic, 
.

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Appendix 15
Principal Investigator Signature Page
Study Title:
A 
Phase 
2, 
Randomized, 
Double-Blind, 
Placebo-Controlled 
Dose-Ranging, 
Parallel 
and 
Adaptive Study to Evaluate the Efficacy and Safety of 
Enpatoran in Systemic Lupus Erythematosus and in 
Cutaneous Lupus Erythematosus (Subacute Cutaneous 
Lupus 
Erythematosus 
and/or 
Discoid 
Lupus 
Erythematosus) Participants Receiving Standard of Care
Regulatory Agency Identifying 
Numbers:
EUCT Number: 2024-510872-18-00
(Previously EudraCT: 2021-004648-27)
Clinical Study Protocol Version:
4.0/ 23 May 2024
Site Number:
I am responsible for the conduct of the study at this site and understand and will conduct it per 
the clinical study protocol, any approved protocol amendments, ICH GCP (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain 
and supply details about ownership interests in the Sponsor or Investigational Medicinal Product 
and any other financial ties with the Sponsor. The Sponsor will use any such information solely 
for complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with 
any necessary information regarding ownership interest and financial ties including those of my 
spouse and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address: