Clinical trial NCT05600036
Conditions: Plaque Psoriasis
Sponsor: Alumis Inc
Start date: 2022-09-27; Completion date: 2023-07-25
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-blind, placebo-controlled study in patients with moderate to severe plaque psoriasis.

Detailed description:
This study will consist of a 4 week screening period, 12 week treatment period, and a 4 week follow up period for a total of 20 weeks. Each participant will be randomized to receive ESK-001 or placebo daily for 12 weeks. An open label extension study will be available for those patients who complete the study.

Arms: arm 1: ESK-001 administered as an oral tablet arm 2: ESK-001 administered as an oral tablet arm 3: ESK-001 administered as an oral tablet arm 4: ESK-001 administered as an oral tablet arm 5: ESK-001 administered as an oral tablet arm 6: Placebo administered as an oral tablet
Interventions: intervention 1: ESK-001 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol documents:
Prot_000.pdf: 
Alumis Inc. 
Clinical Study Protocol 
ESK-001-006 
CONFIDENTIAL 
Version 3.0 
Page 1 of 63 
09 August 2022 
TITLE PAGE 
Clinical Study Protocol 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of ESK-001 in Patients 
with Moderate to Severe Plaque Psoriasis 
Protocol Number: 
ESK-001-006 
Protocol Version/Date: 
Version 3.0, 09 August 2022 
Investigational Product: 
ESK-001 
Study Phase: 
Phase 2 
Sponsor Name: 
Alumis Inc.  
Legal Registered Address: 
611 Gateway Blvd, Suite 820 
South San Francisco, CA 94080, United States 
Regulatory Agency Identifier(s): 
IND Number 159386  
EudraCT Number 2022-002633-34
NCT Number NCT05600036
Confidentiality Statement 
This is an Alumis Inc. document and contains confidential information. It is provided for the sole use of the 
principal investigator, sub-investigators, staff, institutional review boards, human research ethics committees, and 
regulatory authorities. By accepting this document, you agree to maintain the information as confidential and to use 
it only for the purpose of conducting the clinical investigation or reviewing the study protocol. 


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Clinical Study Protocol 
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Version 3.0 
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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................. 1 
TABLE OF CONTENTS ................................................................................................................ 2 
List of Appendices ............................................................................................................. 4 
List of Tables ..................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 5 
1.
PROTOCOL SUMMARY ................................................................................................ 7 
1.1. 
Protocol Synopsis ................................................................................................. 7 
1.2. 
Study Schema ..................................................................................................... 11 
1.3. 
Schedule of Assessments .................................................................................... 12 
2.
INTRODUCTION ........................................................................................................... 15 
2.1. 
Background ........................................................................................................ 15 
2.5. 
Risk-Benefit Assessment .................................................................................... 17 
3.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 18 
4.
STUDY DESIGN ............................................................................................................ 20 
4.1. 
Overview ............................................................................................................ 20 
4.3. 
Order of Assessments ......................................................................................... 20 
4.4. 
Study Duration ................................................................................................... 21 
4.5. 
Study Completion ............................................................................................... 21 
5.
STUDY POPULATION .................................................................................................. 22 
5.1. 
Number of Patients ............................................................................................. 22 
5.2. 
Inclusion Criteria ................................................................................................ 22 
5.3. 
Exclusion Criteria ............................................................................................... 22 
5.4. 
Lifestyle Restrictions .......................................................................................... 25 
5.4.1. 
Dietary Restrictions ........................................................................................ 25 
5.4.2. 
Highly Effective Contraception ...................................................................... 25 
6.
STUDY DRUGS AND CONCOMITANT THERAPY .................................................. 27 
6.4. 
Study Drug Accountability ................................................................................. 27 
6.5. 
Destruction of Study Drug.................................................................................. 28 
6.6. 
Patient Identification and Randomization Procedure ......................................... 28 
6.7. 
Blinding and Emergency Unblinding ................................................................. 29 


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6.9. 
Continued Access to Investigational Product ..................................................... 29 
6.10. 
Treatment of Overdose ....................................................................................... 30 
6.11. 
Treatment Compliance ....................................................................................... 30 
6.12. 
Prior and Concomitant Medication .................................................................... 30 
6.12.1. 
Allowed Vaccinations ..................................................................................... 30 
6.12.2. 
Prohibited Medications ................................................................................... 30 
7. 
DISCONTINUATION .................................................................................................... 32 
7.1. 
Discontinuation of the Study or Site .................................................................. 32 
7.2. 
Study Drug Discontinuation ............................................................................... 32 
7.3. 
Discontinuation of Individual Patients ............................................................... 33 
8. 
STUDY ASSESSMENTS AND PROCEDURES........................................................... 34 
8.1. 
Eligibility Screening ........................................................................................... 34 
8.2. 
Efficacy Assessments ......................................................................................... 34 
8.2.1. 
Psoriasis Area and Severity Index .................................................................. 34 
8.2.2. 
Psoriasis Body Surface Area ........................................................................... 34 
8.2.3. 
Physician’s Global Assessment ...................................................................... 34 
8.2.4. 
Patient-Reported Outcomes ............................................................................ 34 
8.3. 
Safety Assessments ............................................................................................ 35 
8.3.1. 
Adverse Events ............................................................................................... 35 
8.3.2. 
Clinical Laboratory Assessments .................................................................... 41 
8.3.3. 
Vital Signs ...................................................................................................... 42 
8.3.4. 
Electrocardiograms ......................................................................................... 42 
8.3.5. 
Physical Examinations .................................................................................... 42 
8.4. 
Pharmacokinetic Assessments ............................................................................ 43 
8.5. 
Pharmacodynamic Assessments ......................................................................... 43 
8.5.1. 
Skin Biopsy and Tape Stripping (Skin Biomarker Profile) ............................ 43 
8.5.2. 
Plasma Biomarker Profile ............................................................................... 43 
8.5.3. 
Blood RNA-seq Profile (Exploratory Transcriptomics) ................................. 44 
8.5.4. 
Blood Cell-Based Biomarkers ........................................................................ 44 
8.6. 
Genetics .............................................................................................................. 44 
9. 
SAFETY MONITORING COMMITTEE ....................................................................... 45 
10. 
STATISTICAL CONSIDERATIONS ............................................................................ 46 
10.1. 
Analysis of the Conduct of the Study ................................................................. 46 
10.2. 
Analysis of Treatment Group Comparability ..................................................... 46 
10.3. 
Efficacy Analyses ............................................................................................... 46 
10.3.1. 
Primary Efficacy Endpoint ............................................................................. 46 
10.3.2. 
Secondary Efficacy Endpoints ........................................................................ 47 
10.3.3. 
Exploratory Endpoints .................................................................................... 47 
10.4. 
Safety Analyses .................................................................................................. 47 
10.4.1. 
Adverse Events ............................................................................................... 48 
10.4.2. 
Laboratory Tests ............................................................................................. 48 
10.4.3. 
12-Lead Electrocardiogram ............................................................................ 48 


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10.4.4. 
Vital Signs ...................................................................................................... 49 
10.5. 
Pharmacokinetic Analysis .................................................................................. 49 
10.6. 
Missing Data ....................................................................................................... 49 
10.7. 
Sample Size ........................................................................................................ 49 
10.8. 
Interim Analyses ................................................................................................. 49 
11. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ......................................... 50 
11.1. 
Data Quality Assurance ...................................................................................... 50 
11.2. 
Protocol Amendments and Study Completion ................................................... 50 
11.3. 
Informed Consent ............................................................................................... 51 
11.4. 
Data Handling and Record Keeping ................................................................... 51 
11.4.1. 
Patient Confidentiality and Disclosure of Data .............................................. 51 
11.4.2. 
Electronic Case Report Forms (eCRFs) .......................................................... 52 
11.4.3. 
Retention and Availability of Records ............................................................ 52 
11.4.4. 
Audits and Inspections .................................................................................... 52 
11.5. 
Publication Policy ............................................................................................... 53 
12. 
REFERENCE LIST ......................................................................................................... 54 
13. 
APPENDICES ................................................................................................................. 55 
 
List of Appendices 
Appendix A 
Psoriasis Area and Severity Index (PASI) ............................................................ 55 
Appendix B 
Static Physician’s Global Assessment (sPGA) ..................................................... 56 
Appendix C 
Dermatology Life Quality Index (DLQI) ............................................................. 58 
Appendix D 
EQ-5D-5L ............................................................................................................. 59 
Appendix E 
Pruritus Numerical Rating Scale (NRS) ............................................................... 61 
Appendix F 
Signature Page: Declaration of Sponsor or Responsible Medical Expert ............. 62 
Appendix G 
Signature Page: Investigator Study Acknowledgement/Disclosure ..................... 63 
 
List of Tables 
 
 
Table 2 
Prohibited Treatments ........................................................................................... 31 
Table 3 
Assessment of Relationship of Adverse Events to Study Drug ............................ 37 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
BID 
twice per day (bis in die) 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRO 
clinical research organization 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
EQ-5D 
Standardized measure of health-related quality of life developed by the 
EuroQol Group 
EQ-5D-5L 
Standard layout for recording an adult person’s current self-reported health 
state. Consists of a standard format for respondents to record their health 
state according to the EQ-5D-5L descriptive system and the EQ VAS 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL 
interleukin  
IRB 
Institutional Review Board 
IxRS 
interactive voice/web response system 
JAK 
Janus kinase 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
NRS 
Pruritus numerical rating scale 
PASI 
Psoriasis Area and Severity Index 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
QD 
once per day (quaque die) 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
RNA-seq 
RNA sequencing 
SAE 
serious adverse event 
SMC 
safety monitoring committee  
SOA 
Schedule of Assessments 
sPGA 
static Physician’s Global Assessment 
STAT 
signal transducers and activators of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Th 
T helper 
TYK2 
tyrosine kinase 2 
ULN 
upper level of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of ESK-001 in Patients with Moderate to Severe Plaque Psoriasis 
Protocol No. 
ESK-001-006 
Sponsor: 
Alumis Inc. 
Investigational Product: 
ESK-001 
Objectives and 
Endpoints: 
Objectives 
Endpoints 
Primary 
To compare the Psoriasis Area and 
Severity Index (PASI-75) 
between doses of ESK-001 and placebo 
after 12 weeks of treatment  
Proportion of patients with moderate to 
severe psoriasis achieving ≥75% 
reduction in PASI score at 12 weeks 
between doses of ESK-001 and placebo 
Secondary 
To assess the safety and tolerability of 
ESK-001 dose in moderate to severe 
psoriasis patients 
Incidence of treatment-emergent 
adverse events (TEAEs) and serious 
adverse events (SAEs)  
To characterize the pharmacokinetics 
(PK) of ESK-001 
Plasma concentrations and PK 
parameters of ESK-001 
To assess the response rate in static 
Physician’s Global Assessment (sPGA) 
score after 12 weeks of treatment 
Proportion of patients achieving an 
sPGA score of “0” (“cleared”) or “1” 
(“minimal”) after 12 weeks of 
treatment compared with placebo 
To assess the response rate in PASI-50, 
90, and 100 score after 12 weeks of 
treatment 
Proportion of patients achieving PASI-
50, 90, and 100 after 12 weeks of ESK-
001 treatment compared with placebo 
To compare the response rate in PASI-
75 among ESK-001 treatments 
Proportion of patients achieving PASI-
75 at 12 weeks compared among the 
ESK-001 treatments 
To assess the effect on body surface 
area (%BSA) involved with psoriasis 
after 12 weeks of treatment 
Change from baseline in %BSA after 
12 weeks of ESK-001 treatment 
compared with placebo 
To assess the change in Dermatology 
Life Quality Index (DLQI) 
Change from baseline in DLQI at Week 
12 in ESK-001 compared with placebo 
Exploratory 
To assess the change in pruritus 
numerical rating scale (NRS) after 12 
weeks of treatment 
Change from baseline in NRS score 
after 12 weeks of ESK-001 treatment 
compared with placebo 
To assess the change in EQ-5D  
Change from baseline in EQ-5D at 
Week 12 in ESK-001 compared with 
placebo 


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To assess the change in psoriasis and 
TYK2-related skin-based biomarkers 
with ESK-001 treatment 
Change from baseline in psoriasis and 
TYK2-related skin biomarkers in 
response to ESK-001 treatment 
To assess the change in psoriasis and 
TYK2-related blood-based biomarkers 
with ESK-001 treatment 
Change from baseline in psoriasis and 
TYK2-related blood-based biomarkers 
in response to ESK-001 treatment  
To assess the change transcriptomic- 
and proteomic-based biomarkers in 
blood and skin with ESK-001 treatment 
Change from baseline in transcriptomic 
and proteomic expression in response 
to ESK-001 treatment 
Overall Design: 
This is a randomized, double-blind, placebo-controlled study in patients with 
moderate to severe psoriasis. 
Brief Summary: 
The purpose of this study is to assess the clinical efficacy, safety, PK, and PD of 
ESK-001 compared to placebo in patients with moderate to severe psoriasis. 
Study details include: 
• Overall study duration will be approximately 20 weeks. 
• The treatment period will be 12 weeks. 
• Study will be conducted at approximately 65 sites in North America and 
Europe. 
• Study size is planned for a total of approximately 210 patients randomized 
across 6 study arms. 
• Efficacy (including PASI, sPGA, QoL measures), safety, and PK will be 
assessed. 
• Exploratory pharmacodynamic (PD) assessments include blood- and skin-based 
RNA, proteomic, and other molecular markers.  
• Continued treatment will be offered in a separate open-label extension study. 
Treatment Arms: 
Patients fulfilling all eligibility criteria will be randomized in a 1:1:1:1:1:1 manner 
to receive oral doses of ESK-001 at one of 5 dose levels 
 
 or placebo.  
Number of Patients: 
Approximately 210 patients will be randomly assigned to one of the 6 study arms 
(35 patients per arm). 
Study Duration: 
The total duration of study participation for each patient will be approximately 20 
weeks. The study includes a screening period of approximately 4 weeks. The 
treatment period of 12 weeks is followed by a safety follow-up period of 4 weeks. 
Eligible patients may participate in an open-label extension study following 
completion of the End-of-Study Visit at Week 16. 
Safety Monitoring 
Committee: 
A safety monitoring committee (SMC) comprising representatives from the 
Sponsor, clinical research organization (CRO), two independent physicians and a 
statistician will be utilized in this study. 
Study Population 
Inclusion Criteria: 
1. Able and willing to provide signed informed consent to participate in this 
study 
2. Males or females, age 18-75 years, inclusive, at the Screening Visit 
3. Total body weight >40 kg (88 lb) 
4. Diagnosis of plaque psoriasis for ≥6 months 
5. Plaques covering ≥10% of body surface area (BSA) 


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6. Psoriasis area severity index (PASI) score ≥12 and static Physician’s Global 
Assessment (sPGA) score ≥3 
7. Women of childbearing potential (WOCBP) must agree to adhere to highly 
effective methods of contraception for the entirety of the study and for 30 
days after the last dose of study drug 
8. Males who are sexually active with WOCBP must agree to use highly 
effective methods of contraception for the entirety of the study and for 90 
days after the last dose of study drug 
Exclusion Criteria: 
1. Diagnosis of non-plaque psoriasis (guttate, inverse, pustular, erythrodermic, 
drug induced) 
2. Diagnosis of immune-mediated conditions that are commonly associated with 
psoriasis (e.g., uveitis, inflammatory bowel disease) or other inflammatory 
skin conditions that may interfere with the study assessment 
3. Patients with psoriatic arthritis, who are receiving systemic (oral, SC, IM or 
IV) immunosuppressant medications (including corticosteroids, 
immunosuppressants, biologics) or who has or is expected, in the opinion of 
the investigator, to develop unstable disease.  
• Patients who are receiving a stable therapeutic regimen for their psoriatic 
arthritis that does not include immunosuppressants (e.g., NSAIDs) may be 
included in the study  
4. Pregnant, lactating, or planning to get pregnant during the study period 
5. Has used topical medications/treatments that could affect psoriasis evaluation 
within 2 weeks of the first administration of study drug 
6. Has received phototherapy or any systemic medications/treatments that could 
affect psoriasis evaluation within 4 weeks of Study Day 1 
7. Has received any therapeutic agent targeted to IL-12 or IL-23 within 6 
months, IL-17 within 4 months, or any TNFα inhibitor(s) within 2 months of 
first administration of study drug  
8. Is currently receiving or has received any systemic immunosuppressants or 
immunomodulatory drugs (e.g., methotrexate, cyclosporine) within 4 weeks 
of the first administration of study drug or 5 half-lives whichever is longer 
9. Has received agents that modulate B cells (e.g., rituximab, ocrelizumab) 
within 6 months of first administration of study drug 
10. Has received agents that modulate T cells (e.g., abatacept, alemtuzumab) 
within 3 months of first administration of study drug 
11. Has received JAK inhibitors (e.g., baricitinib, tofacitinib) or TYK2 inhibitors 
within 4 weeks of first administration of study drug 
12. History of lack of clinical response to any therapeutic agent targeted to IL-12, 
IL-17 or IL-23 (e.g., ustekinumab, risankizumab, secukinumab, ixekizumab) 
at approved doses after at least 3 months of treatment 
13. History of lack of clinical response, in the Investigator’s opinion, to 2 or more 
biologic therapies at approved doses after at least 3 months of treatment 
14. Has received any investigational agent, within 30 days or 5 half-lives 
(whichever is longer) of any study drug or is currently enrolled in an 
investigational study 
15. Is currently receiving proton pump inhibitors such as omeperazole or 
esomeprazole. It is acceptable to substitute a histamine 2 receptor blocking 
drug or oral antacids prior to Study Day 1 


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16. Patients with QTcF >450 msec (males) or >470 msec (females) at screening 
17. Unstable cardiovascular disease, defined as a recent clinical deterioration 
(e.g., unstable angina, rapid atrial fibrillation) or a cardiac hospitalization 
within the last 3 months  
• Patients requiring medications to treat underlying stable chronic 
cardiovascular disease, including but not limited to β-blockers, should be 
on a stable dose for at least 4 weeks before Study Day 1 
18. Active herpes viral infection, including herpes simplex 1 and 2 and herpes 
zoster identified on examination and/or medical history within 2 months of 
administration of study drug 
19. Patients with hepatitis C virus (HCV), or hepatitis B virus (HBV) or human 
immunodeficiency virus (HIV) or active or inadequately treated latent 
tuberculosis (TB) infection at screening 
20. Has any of the following lab abnormalities: 
• Absolute neutrophil count <1.5 X 10^9/L 
• Hemoglobin <9 g/dL 
• AST/ALT ≥2 x upper limit of normal (ULN) 
• Albumin <3 g/dL 
• Total bilirubin ≥2 x ULN (patients with a history of Gilbert’s syndrome 
are not eligible) 
• Glomerular filtration rate <50 (Cockcroft and Gault method) 
21. History of any immune-mediated or inflammatory medical condition for 
which patient requires current systemic (oral, SC, IM or IV) corticosteroids 
• Stable doses of inhaled corticosteroids for treatment of asthma are allowed 
22. History of serious bacterial, fungal, or viral infections that led to 
hospitalization and IV antibiotic treatment within 90 days prior to screening, 
or any recent serious infection requiring antibiotic treatment within 30 days of 
Study Day 1 
23. Known current malignancy or current evaluation for a potential malignancy or 
history of malignancy within the past 5 years prior to screening, except for 
adequately treated basal cell skin carcinoma, carcinoma in situ of the cervix 
and breast ductal carcinoma in situ  
24. Live vaccines (e.g., varicella, measles, mumps, rubella, cold-attenuated 
intranasal influenza vaccine, and bacillus Calmette-Guérin) within 4 weeks of 
Study Day 1 
25. Patient has a known hypersensitivity to any component of the study drug 
26. Patient has planned surgery during the study period 
27. Any acute or chronic illness/condition or evidence of an unstable clinical 
condition that in the investigator’s judgement will substantially increase the 
risk to the patient if he or she participates in the study 
28. History of mental illness within the last 5 years, unless the patient fulfills one 
of the following conditions: 
• Receiving a fixed regimen of psychiatric medications for at least 6 
months before screening and displays no sign of acute mental illness 
and, in the opinion of the investigator, the patient is able and safe to 
participate in the study 
• Has not required or been prescribed any psychiatric medication 
(including but not limited to antidepressants or anxiolytics) within 12 


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months before screening and, in the opinion of the investigator, the 
patient is able and safe to participate in the study 
29. Patient who, for any reason, is deemed by the investigator to be inappropriate 
for this study or is unable to comply with the study protocol 
Statistical Considerations: 
Randomization will be stratified by prior use of biologics and geographic region. 
Efficacy analyses will be based on the intent-to-treat (ITT) approach. All patients 
randomized will be included in the analysis, and subjects will be analyzed 
according to their randomized treatment. The primary efficacy analysis will 
compare the proportion of patients in the active treatment groups with ≥75% 
improvement in PASI at Week 12 relative to baseline to placebo using the 
Cochran-Mantel-Haenszel test and will be stratified by prior use of biologics and 
geographic region. Safety will be assessed through the summary of adverse events, 
serious adverse events, laboratory test results, ECG parameters, and vital signs. 
Safety analyses will include all subjects who receive at least one dose of either 
ESK-001 or placebo. Subjects will be analyzed according to the actual treatment 
received. 
 
 
 
1.2. 
Study Schema 
 
 


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1.3. 
Schedule of Assessments 
Procedure 
Screening  
Treatment Period (Weeks) 
ET 
Safety Follow-up 
(Weeks) 
 
1 
2 
4 
8 
12 
US 
14 
16 
EOS 
Timing of Visit (Days) 
-28 to -1 
1 
8 
15 
29 
57 
84 
- 
- 
98 
115 
Visit Window (Days) 
28 to -1 
 
±1 
±1 
±3 
±3 
±3 
- 
- 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history  
X 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy test (WOCBP only) B 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
FSH (postmenopausal women only) C 
X 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, HCV screening 
X 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB test D 
X 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistry  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Fasting lipid panel 
 
X 
 
 
 
X 
 
 
 
 
X 
Immunoglobulin levels (total) 
 
X E 
 
 
X 
X 
X 
 
 
 
X 
12-lead ECG 
X 
X E 
 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
DNA sample F 
 
X 
 
 
 
 
 
 
 
 
 


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Procedure 
Screening  
Treatment Period (Weeks) 
ET 
Safety Follow-up 
(Weeks) 
 
1 
2 
4 
8 
12 
US 
14 
16 
EOS 
Timing of Visit (Days) 
-28 to -1 
1 
8 
15 
29 
57 
84 
- 
- 
98 
115 
Visit Window (Days) 
28 to -1 
 
±1 
±1 
±3 
±3 
±3 
- 
- 
±3 
±3 
Study drug administration at site G 
 
X 
 
 
X 
X 
X 
 
 
 
 
Study drug dispensing H 
 
X 
 
 
X 
X 
 
 
 
 
 
AE/con-med review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease activity skin assessments I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRO J 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PD/biomarkers 
Skin biopsy and tape stripping F,K 
 
X 
 
 
 
 
X 
 
 
 
 
Plasma biomarker profile L 
 
X E  
 
X 
X 
X 
X 
 
X 
 
X 
Blood RNA-seq profile M 
 
X E 
 
X 
X 
X 
X 
 
X 
 
X 
Blood cell-based PD biomarkers N,O 
 
X 
 
 
X 
X 
 X 
 
 
X 
 
T/B/NK counts 
 
X E 
 
 
X 
X 
X 
 
 
 
X 
PK blood sampling P 
 
X 
 
 
X 
X 
X 
 
X Q 
X 
 
Footnotes 
EOS = end of study; ET = early termination; US = unscheduled visit  
A. Full physical examination at Screening and Day 1; abbreviated physical examination symptom driven at all other visits. 
B. Serum pregnancy test at Screening; urine pregnancy test at other indicated visits. 
C. Menopause is defined as absence of menses for 12 consecutive months. 
D. QuantiFERON TB tests should not be performed within 4 weeks of COVID-19 mRNA vaccinations or boosters.  If a patients test result is indeterminate it 
may be retested one time.  If both tests are indeterminate the patient will be considered a screen fail. 
E. Predose 
F. Optional, collected only if patient provides specific consent.  
G. Administration of the visit day dose of study drug by the site staff. Patients should be reminded to bring their study drug with them to the clinic and take 
their dose when instructed by the site staff. Randomization occurs prior to first administration of study drug on Day 1. 


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H. Dispense sufficient study drug to last until the next study visit 
I. 
Includes PASI, BSA and sPGA 
J. 
Patient reported outcomes (DLQI, EQ-5D and NRS) 
K. Lesional and nonlesional samples; predose on Day 1  
L. Biomarker panel, exploratory proteomics 
M. Exploratory transcriptomics 
N. To be conducted at selected study sites. Fresh blood needs to be collected and cell assays conducted on the day of collection. 
O. PD Samples for patients will be collected on Day 1 and Week 8 predose and 2 hours (±15 min) and 4 hours (±15 min) postdose. At Week 4 and 12 patients 
will take their dose in the clinic and a PD sample will be collected predose.  A random sample will be taken at Week 14. 
P. PK Samples for patients will be collected on Day 1 and Week 8 predose and 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±15 min) and 4 hours (±15 min) 
postdose in a fasted condition. Patients may have a snack between the 2- and 4-hour draw. At Week 4 and 12 patients will take their dose in the clinic and a 
PK sample will be collected predose.  A random sample will be taken at Week 14. 
Q. Collected if the ET visit is within 14 weeks of the initiation of study drug treatment. 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Psoriasis is a chronic inflammatory immune-mediated skin disease, characterized by abnormal 
epidermal growth, usually presenting as red, scaly patches, papules or plaques (plaque psoriasis). 
(Rendon and Schäkel, 2019). The prevalence of psoriasis in the US is approximately 2 to 3% 
(World Health Organization [WHO], 2016). 
The pathogenesis of psoriasis is complex involving the interplay of genetic and environmental 
factors, resulting in a dysregulated immune response involving T helper (Th) type 1 and Th17 
cells (Polese et al., 2020). Interleukin (IL)-23 and IL-12 are believed to key cytokines in the 
immune-pathogenesis of psoriasis. In response to the release of IL-23, activated T cells migrate 
from the dermis to epidermis and secrete cytokines such as IL-17, which causes proliferation of 
keratinocytes and the classic inflammatory lesions of psoriasis (Zeng et al., 2017). The clinical 
relevance of these cytokine pathways for moderate to severe psoriasis has been established by 
the respective FDA-approved targeted therapies including ustekinumab (anti-IL-12/23) and 
secukinumab(anti-IL17). The pathogenic effect of the IL-23/IL-17 axis is mediated by the Janus 
kinase/signal transducers and activators of transcription (JAK/STAT) pathway (Winthrop, 2017).  
The search for effective small molecules to block JAK/STAT signaling led to the discovery of 
tyrosine kinase 2 (TYK2) inhibitors (Nogueira, Puig et al. 2020). TYK2 signaling pathways 
include the central cytokines IL-12 and IL-23. Importantly, TYK2 has also been validated as a 
therapeutic target in psoriasis by oral TYK2 inhibitors and particularly from positive Phase 3 
studies with deucravacitinib (Bristol Myers Squibb, 2021). Based on available clinical data it 
appears these inhibitors’ specificity for TYK2 avoids the safety liabilities of JAK inhibitors. 
Although these findings are encouraging, considerable unmet need remains for patients with 
psoriasis and ESK-001 has the potential for improved efficacy and safety associated with higher 
target engagement and greater target specificity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.5. 
Risk-Benefit Assessment 
ESK-001 is being developed as an oral treatment for moderate to severe psoriasis. Based on the 
mechanism of action of ESK-001, the likelihood of benefit for patients enrolled in this study is 
expected to be high since substantial clinical efficacy has already been demonstrated by other 
molecules with the same mechanism of action, i.e., inhibition of TYK2 (Papacharalambous et al., 
2020; Papp et al., 2018). Furthermore, patients will be offered the opportunity to receive 
ESK-001 after they complete the study by enrolling in a long-term open label extension study. 
Initial studies in healthy participants have demonstrated ESK-001 was tolerated well and had no 
safety findings of clinical concern. The nature and frequency of safety assessments in this study 
are guided by the safety profile of other TYK2 inhibitors being developed in psoriasis and the 
potential immunomodulatory effects of TYK2 inhibition. These inhibitors have been generally 
well tolerated and with an acceptable safety profile. Based on ESK-001’s high specificity for 
TYK2, the safety concerns associated with JAK inhibition are considered to have been reduced. 
In addition, a safety monitoring committee will be convened, including a cardiologist, to oversee 
overall patient safety, including the potential for adverse events associated with JAK inhibition.  
Taken together the overall benefit-risk assessment is favorable and supports this Phase 2 study in 
psoriasis patients with moderate to severe disease.  


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To compare the Psoriasis Area and Severity Index 
(PASI-75) between doses of ESK-001 and placebo 
after 12 weeks of treatment 
• Proportion of patients with moderate to severe 
psoriasis achieving ≥75% reduction in PASI score 
at 12 weeks between doses of ESK-001 and placebo 
Secondary 
 
• To assess the safety and tolerability of ESK-001 
dose in moderate to severe psoriasis patients 
• Incidence of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs)  
• To characterize the pharmacokinetics (PK) of 
ESK-001 
• Plasma concentrations and PK parameters of 
ESK-001   
• To assess the response rate in static Physician’s 
Global Assessment (sPGA) score after 12 weeks of 
treatment 
• Proportion of patients achieving an sPGA score of 
“0” (“cleared”) or “1” (“minimal”) after 12 weeks 
of ESK-001 treatment compared with placebo 
• To assess the response rate in PASI-50, 90, and 100 
score after 12 weeks of treatment 
• Proportion of patients achieving PASI-50, 90, and 
100 after 12 weeks of ESK-001 treatment compared 
with placebo 
• To compare the response rate in PASI-75 among 
ESK-001 treatments 
• Proportion of patients achieving PASI-75 at 12 
weeks compared among the ESK-001 treatments 
• To assess the effect on body surface area (%BSA) 
involved with psoriasis after 12 weeks of treatment 
• Change from baseline in %BSA after 12 weeks of 
ESK-001 treatment compared with placebo 
• To assess the change in Dermatology Life Quality 
Index (DLQI) 
• Change from baseline in DLQI at Week 12 in 
ESK-001 compared with placebo 
Exploratory 
 
• To assess the change in pruritus numerical rating 
scale (NRS) after 12 weeks of treatment 
• Change from baseline in NRS score after 12 weeks 
of ESK-001 treatment compared with placebo 
• To assess the change in EQ-5D 
• Change from baseline in EQ-5D at Week 12 in 
ESK-001 compared with placebo 
• To assess the change in psoriasis and TYK2-related 
skin-based biomarkers with ESK-001 treatment 
• Change from baseline in psoriasis and TYK2-
related skin biomarkers in response to ESK-001 
treatment 
• To assess the change in psoriasis and TYK2-related 
blood-based biomarkers with ESK-001 treatment 
• Change from baseline in psoriasis and TYK2-
related blood-based biomarkers in response to ESK-
001 treatment 


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Objectives 
Endpoints 
• To assess the change in transcriptomic- and 
proteomic-based biomarkers in blood and skin with 
ESK-001 treatment 
• Change from baseline in transcriptomic and 
proteomic expression in response to ESK-001 
treatment 
 


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4. 
STUDY DESIGN 
4.1. 
Overview 
This is a randomized, double-blind, placebo-controlled study in patients with moderate to severe 
psoriasis. The purpose of this study is to assess the clinical efficacy, safety, and PK of ESK-001 
compared to placebo in patients with moderate to severe psoriasis. 
Study details include: 
• Overall study duration will be approximately 20 weeks. 
• The treatment period will be 12 weeks. 
• Study will be conducted at approximately 65 sites in North America and Europe. 
• Study size is planned for a total of approximately 210 patients randomized across 6 study 
arms (5 assigned to ESK-001 and 1 assigned to placebo). 
• Efficacy (including PASI, sPGA, QoL measures), safety, and PK will be assessed. 
• Exploratory PD assessments include blood- and skin-based RNA, proteomic, and other 
molecular markers  
• Patients completing the study will be eligible to enter an open-label extension study to 
receive ESK-001 long term (if all extension study entry criteria are met). 
 
 
 
 
 
 
 
 
   
 
 
4.3. 
Order of Assessments 
The following priority order will be in effect, if applicable, when more than one assessment is 
required at a predose and postdose time point, with PK blood sampling being performed nearest 
to the specified time: 


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1.  12-lead ECG 
2.  Vital signs 
3. PROs (DLQI, EQ-5D, NRS) 
4. Adverse Event and Concomitant Medication collection 
5. Disease activity skin assessments (PASI, BSA, sPGA); physical examination 
6.  PK and PD/biomarkers blood sampling 
7.  Blood and urine sampling for safety assessments 
8. Skin biopsy and skin tape stripping (if consent obtained) 
9. Study drug administration by the site staff 
4.4. 
Study Duration 
The estimated study duration for each patient is approximately 20 weeks and includes: 
1. The screening period: up to 4 weeks 
2. Treatment period: 12 weeks 
3. Safety follow-up period: 4 weeks 
4.5. 
Study Completion 
For the entire study, study completion is defined as the last visit of the last patient for any 
protocol related activity (last patient, last visit). For individual patients, study completion is 
defined as the time of the patient’s last data collection. 


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5. 
STUDY POPULATION 
The study population will consist of male and female adult patients with moderate to severe 
psoriasis. Patients must meet all the inclusion criteria and none of the exclusion criteria. 
5.1. 
Number of Patients 
Approximately 210 patients will be enrolled in the clinical study according to the 
inclusion/exclusion criteria. Patients who discontinue study drug or the study early for any 
reason may be replaced by enrollment of another patient. The Sponsor may choose, based on the 
evolving data (e.g., safety) from ESK-001 studies, to enroll up to 50 additional patients. 
5.2. 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Able and willing to provide signed informed consent to participate in this study 
2. Males or females, age 18-75 years, inclusive, at the Screening Visit 
3. Total body weight >40 kg (88 lb) 
4. Diagnosis of plaque psoriasis for ≥6 months 
5. Plaques covering ≥10% of body surface area (BSA) 
6. Psoriasis area severity index (PASI) score ≥12 and static Physician’s Global Assessment 
(sPGA) score ≥3 
7. Women of childbearing potential (WOCBP) must agree to adhere to highly effective methods 
of contraception for the entirety of the study and for 30 days after the last dose of study drug 
8. Males who are sexually active with WOCBP must agree to use highly effective methods of 
contraception for the entirety of the study and for 90 days after the last dose of study drug 
5.3. 
Exclusion Criteria 
Patients who meet one or more of the following criteria will be ineligible to participate in the 
clinical study: 
1. Diagnosis of non-plaque psoriasis (guttate, inverse, pustular, erythrodermic, drug induced) 
2. Diagnosis of immune-mediated conditions that are commonly associated with psoriasis (e.g., 
uveitis, inflammatory bowel disease) or other inflammatory skin conditions that may 
interfere with the study assessment 
3. Patients with psoriatic arthritis who are receiving systemic (oral, SC, IM or IV) 
immunosuppressant medications (including corticosteroids, immunosuppressant biologics) or 
who has or is expected, in the opinion of the investigator, to develop unstable disease.  
• 
Patients who are receiving a stable therapeutic regimen for their psoriatic arthritis that 
does not include immunosuppressants (e.g. NSAIDs) may be included in the study  


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4. Pregnant, lactating, or planning to get pregnant during the study period 
5. Has used topical medications/treatments that could affect psoriasis evaluation within 2 weeks 
of the first administration of study drug 
6. Has received phototherapy or any systemic medications/treatments that could affect psoriasis 
evaluation within 4 weeks of Study Day 1 
7. Has received any therapeutic agent targeted to: IL-12or IL-23 within 6 months, IL-17 within 
4 months, or any TNFα inhibitor(s) within 2 months of first administration of study drug  
8. Is currently receiving or has received any systemic immunosuppressants or 
immunomodulatory drugs (e.g., methotrexate, cyclosporine) within 4 weeks of the first 
administration of study drug or 5 half-lives whichever is longer 
9. Has received agents that modulate B cells (e.g., rituximab, ocrelizumab) within 6 months of 
first administration of study drug 
10. Has received agents that modulate T cells (e.g., abatacept, alemtuzumab) within 3 months of 
first administration of study drug 
11. Has received JAK inhibitors (e.g., baricitinib, tofacitinib) or TYK2 inhibitors within 4 weeks 
of first administration of study drug 
12. History of lack of clinical response to any therapeutic agent targeted to IL-12, IL-17 or IL-23 
(e.g., ustekinumab, risankizumab, secukinumab, ixekizumab) at approved doses after at least 
3 months of treatment 
13. History of lack of clinical response, in the Investigator’s opinion, to 2 or more biologic 
therapies at approved doses after at least 3 months of treatment  
14. Has received any investigational agent, within 30 days or 5 half-lives (whichever is longer) 
of any study drug or is currently enrolled in an investigational study 
15. Is currently receiving proton pump inhibitors such as omeperazole or esomeprazole. It is 
acceptable to substitute a histamine 2 receptor blocking drug or oral antacids prior to Study 
Day 1 
16. Patients with QTcF >450 msec (males) or >470 msec (females) at screening 
17. Unstable cardiovascular disease, defined as a recent clinical deterioration (e.g., unstable 
angina, rapid atrial fibrillation) or a cardiac hospitalization within the last 3 months  
• 
Patients requiring medications to treat underlying stable chronic cardiovascular disease, 
including but not limited to β-blockers, should be on a stable dose for at least 4 weeks 
before Study Day 1 
18. Active herpes viral infection, including herpes simplex 1 and 2 and herpes zoster identified 
on examination and/or medical history within 2 months of administration of study drug 


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19. Patients with hepatitis C virus (HCV), or hepatitis B virus (HBV) or human 
immunodeficiency virus (HIV) or active or inadequately treated latent tuberculosis (TB) 
infection at screening 
20. Has any of the following lab abnormalities: 
• Absolute neutrophil count <1.5 X 10^9/L 
• Hemoglobin <9 g/dL 
• AST/ALT ≥2 x upper limit of normal (ULN) 
• Albumin <3 g/dL 
• Total bilirubin ≥2 x ULN (patients with a history of Gilbert’s syndrome are not eligible) 
• Glomerular filtration rate <50 (Cockcroft and Gault method) 
21. History of any immune-mediated or inflammatory medical condition for which patient 
requires current systemic (oral, SC, IM or IV) corticosteroids 
• 
Stable doses of inhaled corticosteroids for treatment of asthma are allowed 
22. History of serious bacterial, fungal, or viral infections that led to hospitalization and IV 
antibiotic treatment within 90 days prior to screening, or any recent serious infection 
requiring antibiotic treatment within 30 days of Study Day 1 
23. Known current malignancy or current evaluation for a potential malignancy or history of 
malignancy within the past 5 years prior to screening, except for adequately treated basal cell 
skin carcinoma, carcinoma in situ of the cervix and breast ductal carcinoma in situ  
24. Live vaccines (e.g., varicella, measles, mumps, rubella, cold-attenuated intranasal influenza 
vaccine, and bacillus Calmette-Guérin) within 4 weeks of Study Day 1 
25. Patient has a known hypersensitivity to any component of the study drug 
26. Patient has planned surgery during the study period 
27. Any acute or chronic illness/condition or evidence of an unstable clinical condition that in the 
investigator’s judgement will substantially increase the risk to the patient if he or she 
participates in the study 
28. History of mental illness within the last 5 years, unless the patient fulfills one of the 
following conditions: 
• Receiving a fixed regimen of psychiatric medications for at least 6 months before 
screening, displays no sign of acute mental illness and, in the opinion of the 
investigator, the patient is able and safe to participate in the study 
• Has not required or been prescribed any psychiatric medication (including but not 
limited to antidepressants or anxiolytics) within 12 months before screening and, in the 
opinion of the investigator, the patient is able and safe to participate in the study 
29. Patient who, for any reason, is deemed by the investigator to be inappropriate for this study 
or is unable to comply with the study protocol 


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5.4. 
Lifestyle Restrictions 
5.4.1. 
Dietary Restrictions 
Foods such as star fruit juice, Seville orange juice, and grapefruit juice that are strong to 
moderate inhibitors of P450 (CYP) 3A4 should be avoided. 
Study drug can be taken with or without food. 
5.4.2. 
Highly Effective Contraception  
Highly effective methods of birth control are defined as those which result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly.  
For female patients - WOCBP: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
Note: Hormonal contraception must be supplemented with another form of contraception 
that may include but is not limited to another form of highly effective contraception (e.g., 
IUD) or other barrier methods (such as male condom plus spermicide or female 
diaphragm). 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal ligation 
• Vasectomized partner. Note that a vasectomized partner is a highly effective birth control 
method provided that partner is the sole sexual partner of the woman of childbearing 
potential trial patient and that the vasectomized partner has received medical assessment 
of the surgical success. 
• Sexual abstinence. Sexual abstinence is considered a highly effective method only if the 
subject is refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 
• Same sex partner 


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Women who have not menstruated for at least 12 months and with follicle-stimulating hormone 
(FSH) levels ≥30 mIU/mL will be considered postmenopausal and will not be required to use 
contraception. 
For male patients with a partner of childbearing potential: 
Men must agree to use two acceptable methods of contraception (e.g., condom plus spermicide), 
at least one of which must be a barrier method for the entire duration of the study, and for 
3 months following last study drug administration. 


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6. 
STUDY DRUGS AND CONCOMITANT THERAPY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.4. 
Study Drug Accountability 
The Investigator or his/her designated representatives will dispense study drug per the Schedule 
of Assessments (see Section 1.3). 
The Investigator is responsible for the control of drugs under investigation. Adequate records of 
the receipt (e.g., Drug Receipt Record) and disposition (e.g., Investigation Drug Dispensing Log) 
of the study drug must be maintained. The Investigation Drug Dispensing Log must be kept 
current and should contain the following information: 


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• The identification (ID) if the patient to whom the study drug was dispensed (that is, 
patient ID number and year of birth) 
• The date(s), quantity, and lot number(s) of the study drug dispensed to the patient 
• The ID of the person who dispense the study drug 
All used and unused drug supplies must be returned by the patient at every visit. 
All records and used and unused drug supplies must be available for inspection by the study 
monitor at every monitoring visit. Reconciliation of all drug supplies (ESK-001 or placebo) will 
be performed by the study monitor.  
6.5. 
Destruction of Study Drug 
When the study is completed, the Investigator will destroy or return to the Sponsor any used and 
unused study drug (e.g., empty, partially used, and unused containers), to the Sponsor as 
requested. Copies of the completed Drug Dispensing Log and Drug Return Record(s) will be 
returned to the Sponsor. The Investigator’s copy of the Drug Return Record(s) must accurately 
document the return or destruction of all drug supplies to the Sponsor. 
Local or institutional regulations may require immediate destruction of used study drug for 
safety reasons. In these cases, it may be acceptable for investigational study center staff to 
destroy dispensed study drug before a monitoring inspection, provided that source document 
verification is performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, and destroyed, and provided that adequate storage and 
integrity of drug has been confirmed. Written authorization must be obtained from the Sponsor 
or Sponsor designees after final accountability prior to destruction. 
Unused study drug from the site that has not been stored properly should not be destroyed until 
the monitor and/or Sponsor approve the destruction. 
Written documentation of destruction must contain the following: 
• Identity of study drug destroyed 
• Quantity of study drug destroyed 
• Date of destruction 
• Method of destruction 
• Name and signature of responsible person who destroyed the study drug 
6.6. 
Patient Identification and Randomization Procedure 
All screened patients are assigned unique identification number. Screened patients who drop out 
of the clinical study before randomization will retain their unique identification number. 
Blister card wallets will provide blinded serial numbers for allocation using randomization 
through an interactive voice/web response system (IxRS) or equivalent process of distribution of 
the study drug throughout the duration of the study. Patients will be randomized 1:1:1:1:1:1 one 
of the 6 treatment arms (5 dose levels of ESK-001, placebo). 


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Randomization will be stratified by prior use of biologics and geographic region. A permuted 
block randomization scheme will be used to obtain approximately a 1:1:1:1:1:1 ratio among the 
treatment arms within each stratum.   
6.7. 
Blinding and Emergency Unblinding 
ESK-001 tablets and placebo-to-match ESK-001 tablets will be matched for shape, size and 
color. 
Study drug assignment for each patient will not be disclosed to the Investigator, study center 
personnel, patients, or the Sponsor or representatives on the clinical study team. Study site 
personnel will remain blinded throughout the entirety of the study.  
If at any time during the study a decision about a patient’s medical condition requires knowledge 
of the treatment assignment, the study blind may be broken by the Principal Investigator, 
(through the IxRS), for that specific patient only. If in the opinion of the Investigator, there is no 
impact on patient safety, the Investigator is strongly encouraged to contact the Sponsor’s 
Medical Monitor prior to unblinding. The reason for unblinding must be documented in the IxRS 
or appropriate study documentation. 
At the study site, only the Principal Investigator should be unblinded. If, in the Investigator’s 
opinion, and for the safety of the patient other study site personnel are required to be aware of 
the treatment assignment, the Investigator will contact the Sponsor’s Medical Monitor prior to 
further unblinding and ensure that the minimum number of personnel are informed.  
The SMC must be informed by the Sponsor’s Medical Monitor of any case of unblinding. 
Additionally, the SMC may unblind individual treatment assignment for further safety evaluation 
at their discretion. 
6.8. 
Administration of Study Drug 
The study site staff will administer a dose of study drug to each patient on Day 1 (first dose), and 
on the Week 4, 8, and 12 visit days. Patients should be clearly instructed not to take study drug 
on these study Days, but to bring their study drug with them to the clinic and take
 
  
Study drug will be dispensed to patients as a 4-week supply at the Day 1, Week 4, and Week 8 
visits. 
 
 
At the Week 4, 8 and 12 study visits patients must return all study drug 
 
 
6.9. 
Continued Access to Investigational Product  
After completion of the Week 16 End-of-Study (EOS) Visit, Patients will be eligible to receive 
extended open-label treatment with ESK-001 by participating in a separate open-label extension 
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completed this study, ESK-001-006, meet all eligibility criteria for the OLE study, and be willing 
and able to complete all of its required assessments.  
6.10. 
Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. No antidotes are available. 
6.11. 
Treatment Compliance 
Accountability and patient compliance will be assessed by maintaining adequate study drug 
dispensing records and tablet counts. The Investigator is responsible for ensuring that dosing is 
administered in compliance with the protocol. See Section 6.4 for instructions on drug 
accountability procedures.  
6.12. 
Prior and Concomitant Medication 
Prior and concomitant medication as well as vaccination use after screening will be recorded on 
the prior and concomitant eCRF. Prior medications should be collected from the past 10 years. 
Antiviral Medications 
Based on in vitro assessments, ESK-001 has the potential for drug-drug interaction with antiviral 
medications metabolized through CYP3A4, CYP2D6 and P-gp pathways (eg, Paxlovid 
[nirmatrelvir + ritonavir]). Co-administration with ESK-001 may affect the systemic exposure 
levels of antiviral medications or ESK-001. The benefit:risk assessment for administration of 
anti-viral medications with a narrow therapeutic index should be discussed with the medical 
monitor whenever possible.   
Acid Reducing Agents 
The use of Proton Pump Inhibitors (PPIs) are not permitted on study due to the potential to 
decrease ESK-001 exposure.  However, the use of H2 blockers (e.g., famotidine or ranitidine) 
and calcium carbonate-containing antacids (eg, Tums or Rolaids) are allowed during the study 
but should be taken at least 2 hours after a dose of study drug. 
6.12.1. 
Allowed Vaccinations 
Inactivated vaccines (including but not limited to COVID-19 vaccines and boosters) will be 
allowed while on study. The study site should follow local guidelines related to COVID-19. 
6.12.2. 
Prohibited Medications 
Medication and treatment restrictions applicable before the dosing period are listed as exclusion 
criteria in Section 5.3. These restrictions are applicable for the duration of the study and are 
summarized in Table 2. Prior and concomitant medication will be recorded. 


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Table 2 
Prohibited Treatments 
Treatment Category 
Examples A 
Washout Period B 
Topical medications or treatments that could 
affect psoriasis evaluation 
corticosteroids, anthralin, 
calcipotriene, vitamin D derivatives, 
retinoids 
2 weeks 
Phototherapy or systemic medications or 
treatments that could affect psoriasis 
evaluation 
oral or injectable corticosteroids, 
retinoids, 1,25-dihydroxy vitamin D3 
4 weeks 
Therapeutic agents targeted to IL-12 or IL-23 
ustekinumab,  guselkumab, 
tildrakizumab, risankizumab 
6 months 
Therapeutic agents targeted to IL-17  
secukinumab, ixekizumab, 
brodalumab 
4 months 
TNFα inhibitors 
etanercept, infliximab, adalimumab  
2 months 
Systemic immunosuppressants or 
immunomodulatory drugs 
corticosteroids (oral/IV/IM/SC), 
methotrexate, azathioprine, 
cyclosporine, mycophenolate mofetil 
4 weeks or 5 half-lives C 
Agents that modulate B cells  
rituximab, ocrelizumab 
6 months 
Agents that modulate T cells 
abatacept, alemtuzumab  
3 months 
JAK inhibitors or TYK2 inhibitors 
baricitinib, tofacitinib, upadacitinib, 
ruxolitinib, fedratinib, deucravacitinib 
4 weeks 
Investigational agents 
 
30 days or 5 half-lives C 
Proton pump inhibitors 
omeperazole, esomeprazole, 
pantoprazole 
Prior to Study Day 1 
A. Including but not limited to 
B. Prior to randomization on Study Day 1 
C. Whichever is longer 


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7. 
DISCONTINUATION 
7.1. 
Discontinuation of the Study or Site 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to:  
• Incidence or severity of adverse events in this or other studies indicating a potential 
safety risk to patients. 
• Unsatisfactory patient recruitment e.g., excessively slow 
• Poor protocol adherence 
• Incomplete or inaccurate data recording 
• Poor compliance with the International Conference on Harmonisation (ICH) guidelines 
for Good Clinical Practice (GCP) 
In any instance of early discontinuation of the study, the Sponsor will notify, in writing, the 
investigators, regulatory authorities and ethics committees, and will specify the reason(s) for 
termination. 
7.2. 
Study Drug Discontinuation 
Patients should discontinue study drug for any of the following reasons: 
• Malignancy, not including local and non-serious basal, squamous cell skin cancer or 
ductal carcinoma in situ 
• Pregnancy 
• Anaphylaxis, anaphylactoid or serious hypersensitivity reaction 
• Use of any medication, intended to chronically treat psoriasis (refer to Section 6.12.2), 
other than those documented at screening 
• Adverse event which in the opinion of the investigator or SMC precludes the patient from 
safely continuing in the study 
• Patient is noncompliant with study requirements 
The date and reason for discontinuation should be documented in the eCRF. 
Patients who discontinue study drug should continue in the study to complete all scheduled 
assessments. 
Those patients who are unwilling or unable to complete all remaining study assessments should 
return to the study site 2 weeks (± 7 days) after the date study drug was discontinued, to 
complete the early study termination assessments (ET Visit). 


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7.3. 
Discontinuation of Individual Patients 
Reasons for patient discontinuation from the study may include but are not limited to any of the 
following reasons: 
• Patient withdrawal of consent 
• Discretion of the Investigator, if it is deemed not safe, or in the patient’s best interest, to 
continue 
• SMC recommendation 
• Patient is lost to follow-up 
The date and reason for discontinuation should be documented in the eCRF.  
Patients who discontinue the study should return to the site to complete the early study 
termination assessments (ET Visit) within 2 weeks (± 7 days) from the date of discontinuation. 
If a patient discontinues the study without notifying the Investigator, every effort should be made 
to contact the patient to identify the reason for discontinuation and to encourage the patient to 
complete the applicable ET visit assessments.  If documented attempts to contact the patient fail, 
and a reason for the patient’s discontinuation is undiscoverable, a patient can be declared as "lost 
to follow up" at the end of the study. All efforts to contact the patient should be documented in 
the source documents. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
For timing of assessments, refer to the Schedule of Assessments (SOA) in Section 1.3.  
8.1. 
Eligibility Screening 
Informed consent will be obtained at Screening before performing any study procedures. 
Patients will undergo Screening assessments, including, but not limited to blood sampling, ECG, 
clinical assessment and various QoL assessments. Patients may be rescreened once no sooner 
than 2 weeks after an initial screen failure after discussion with the medical monitor. 
Medical and medication history as well as demographic data, including biological sex, age, race, 
body weight (kg) and height (cm) will be recorded.  
8.2. 
Efficacy Assessments 
8.2.1. 
Psoriasis Area and Severity Index  
Disease activity will be assessed by the Psoriasis Area and Severity Index (PASI) at the 
timepoints indicated in the Schedule of Assessments (see Section 1.3). The PASI system derives 
a score for the severity of psoriatic lesions by evaluating erythema, induration, and scaling in 
each of 4 body regions, as detailed in Appendix A. The primary and secondary endpoints are 
based on the PASI response at the end of treatment (12-week timepoint). 
8.2.2. 
Psoriasis Body Surface Area 
Measurement of psoriasis body surface area (BSA) involvement is estimated using the handprint 
method with the size of a patient’s handprint representing ~1% of body surface area involved. 
The total BSA = 100% with breakdown by body region as follows: head and neck = 10% (10 
handprints), upper extremities = 20% (20 handprints), trunk including axillae and groin = 30% 
(30 handprints), lower extremities including buttocks = 40% (40 handprints). BSA assessments 
should be performed by a dermatologist or appropriately trained investigator who is experienced 
in the assessment of psoriasis patients. 
8.2.3. 
Physician’s Global Assessment 
Patients will be assessed by the static Physician’s Global Assessment (sPGA) at the timepoints 
indicated in the Schedule of Assessments (see Section 1.3). Appendix B presents the scoring 
system used for the sPGA. 
8.2.4. 
Patient-Reported Outcomes  
Quality of life (QoL) will be assessed by patient-reported outcomes: the Dermatology Life 
Quality Index (DLQI), the EQ-5D, and the pruritus numerical rating scale (NRS) at the 
timepoints indicated in the Schedule of Assessments (see Section 1.3). The 10-question DLQI is 
presented in Appendix C, the 5-question EQ-5D-5L is shown in Appendix D, and the pruritus 
NRS is presented in Appendix E.  


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8.3. 
Safety Assessments 
ESK-001 is not an approved drug and as a result the entire safety profile is not known at this 
time. This Phase 2 study will contribute to the understanding of the safety profile for ESK-001 
and for its use in patients with moderate to severe psoriasis. 
Safety assessments will consist of recording all AEs and SAEs, protocol-specified laboratory 
variables, vital signs, and the results from other protocol-specified tests that are deemed critical 
to the safety evaluation of ESK-001. Dedicated eCRFs will be used to collect information on 
specific AEs, including SAEs, and pregnancies. 
8.3.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in any study participant enrolled in a 
clinical investigation administered a pharmaceutical product regardless of causal attribution.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational product, 
whether or not it is thought to be related to the investigational product. 
In addition to new events, any increase in the severity or frequency of a pre-existing condition 
that occurs is considered an AE. 
Only clinically significant laboratory test abnormalities (in the medical opinion of the 
Investigator) that require active management (e.g., abnormalities that require study drug 
discontinuation, more frequent follow-up assessments, further diagnostic investigation, etc.) 
should be listed as AEs. See Section 8.3.1.3 for more details. 
If the AE constitutes a disease or syndrome (e.g., upper respiratory tract infection), only the 
diagnosis (e.g., upper respiratory tract infection) should be recorded as an AE and not the 
individual symptoms (fever, headaches, body aches, runny nose, sore throat, etc.). If an AE is 
due to an inactivated vaccine, the AE together with the etiology should clearly be recorded. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, 
e.g., those occurring during treatment-free periods (including Screening or post-treatment 
follow-up periods) in association with study-related procedures and assessments, or under 
placebo. For study drugs, lack of efficacy may be an expected potential outcome and should not 
be reported as an AE unless the event is unusual in some way, e.g., greater in severity. 
Concomitant illnesses: Medical conditions which existed prior to entry into the clinical study 
will not be considered AEs unless they worsen (frequency or severity) during the treatment 
period. Pre-existing conditions will be recorded as part of the participant’s medical history. Day 
to day fluctuations of pre-existing disease should not be recorded as an AE on the AE eCRF. 
Disease under study (psoriasis):  Disease related progression and worsening signs or symptoms 
of the disease under study are not AEs and are not to be recorded on the AE page of the eCRF 
unless the event meets the definition of an SAE or is not consistent with the typical clinical 
course of the patient’s disease as established by the patient’s medical history. 
Surgical or diagnostic procedures: For medical or surgical procedures (e.g., colonoscopy, 
biopsy), the medical condition that led to the procedure is an AE. Elective procedures (e.g., 


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vasectomy), planned hospitalization, and procedures for treatment of conditions noted in the 
patient’s medical history that have not worsened (e.g., hernia repair) are not considered AEs. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
8.3.1.1. 
Recording of Adverse Events 
Adverse events should be collected and recorded for each patient from the date of the first 
screening/eligibility assessment until the end of their participation in the study, i.e., the patient 
has discontinued or completed the study. 
Reporting of AEs prior to first dose should only include SAEs or AEs resulting from any 
protocol-related interventions. 
Adverse events are to be recorded on the AE page of the eCRF. The following information will 
be recorded at the time the AE is reported and during follow up during the course of the AE: 
• Whether or not the AE is an SAE (see Section 8.3.1.2.1) 
• AE severity using CTCAE criteria (see Section 8.3.1.2.2) 
• AE relationship to study drug (see Section 8.3.1.2.3) 
• Action taken; including but not limited to, none, study drug dose modification or 
discontinuation, required concomitant medication, required procedure, or other 
• Outcome:  recorded as event resolved, resolved with sequelae, ongoing, or death 
If an adverse event is persistent i.e. continues between various study assessment timepoints 
without resolution it should be recorded only once (see Section 8.3.1.3). 
8.3.1.2. 
Assessment of Adverse Events 
Each AE will be assessed by the Principal Investigator per the categories discussed in the 
following sections. 
8.3.1.2.1. 
Serious Adverse Events (SAEs) 
The Investigator is responsible for determining whether an AE meets the definition of an SAE. 
An SAE is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening, i.e., an AE that, in the investigator’s opinion, places the subject at 
immediate risk of death  
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity, i.e., a substantial disruption in the 
subject’s ability to conduct normal life functions 
• A congenital anomaly or birth defect in a neonate or infant born to a mother exposed to 
study drug 


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• Significant medical events that, in the opinion of the Investigator, may jeopardize the 
subject or may require medical or surgical intervention to prevent any of the outcomes 
listed in this definition.  
8.3.1.2.2. 
Severity 
The severity of an event describes the degree of impact upon the subject and/or the need for 
medical care necessary to treat the event. All clinical AEs encountered during the clinical study 
will be reported on the AE page of the eCRF. Severity of AEs will be graded based on a 
modified CTCAE, Version 5.0 and reported in detail as indicated on the eCRF. For any AEs not 
found in the CTCAE, a description of intensity grading can be found below: 
Grade 1 - Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 - Moderate 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
Grade 3 - Severe 
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. 
Grade 4 - Life-threatening 
Life threatening consequences; urgent intervention indicated 
Grade 5 – Death 
Death related to AE 
 
Any change in severity of a persistent AE will be captured by recording a new AE with the 
current severity and a start date of when the severity changed. The prior event will be updated 
with a stop date of when the severity changed. When changes in the severity of an AE occur 
more frequently than once a day, the maximum intensity for the event should be noted for that 
day.  
8.3.1.2.3. 
Relationship to Study Drug 
The Principal Investigator will assess the causality/relationship between the study drug and the 
AE. One of the categories described in Table 3 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 
Table 3 
Assessment of Relationship of Adverse Events to Study Drug  
The Investigator should assess causality by answering either “related” or “unrelated” to the 
question, “Is there a reasonable possibility that the event may have been caused by the study 
treatment?”.  
 
 


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Related 
A clinical event, including laboratory test abnormality, occuring in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs 
or chemicals cannot explain.  
Unrelated 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  
 
The following factors may be used in consideration of causality assessment:  
 
• Temporal relationship of the event onset to initiation of study drug  
• Amount and duration of study treatment exposure 
• Course of the event, including consideration for challenge/rechallenge:  
◦ 
Did the event abate after study treatment was reduced or interrupted? Did the 
event reappear after study treatment was reintroduced?  
• Confounding risk factors in the patient that may explain or are associated with the event  
• Concomitant medications known to cause or are associated with the event  
• Known association of the event with the disease under study 
• Known association of the event with similar study treatments 
 
 
8.3.1.2.4. 
Suspected Unexpected Adverse Reactions (SUSARs) 
Suspected unexpected adverse reactions (SUSARs) are SAEs that are unexpected per the 
Reference Safety Information section of the IB and judged by the Investigator and/or Sponsor to 
be related to ESK-001. 
 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the study drug: 
• In the case of a product with a marketing authorization, in the summary of product 
characteristics for that product. 
• In the case of any other investigational product, in the Investigator’s Brochure relating to 
the trial in question 
 
The Sponsor or designee will report SUSARs to the appropriate regulatory authorities and 
Investigator’s as required, according to the local law. 
 
8.3.1.3. 
Reporting Adverse Events 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 


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should be recorded as an AE or SAE on the eCRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information and the diagnosis entered in the eCRF. 
AEs Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the eCRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the eCRF. 
Persistent or Recurrent AEs 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
time points. Such events should only be recorded once in the eCRF unless their severity changes. 
If a persistent AE changes in severity, it should be recorded as a separate AE on the Adverse 
Event eCRF.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded on an Adverse Event eCRF. 
Abnormal Lab Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF including but not limited to association with clinical 
findings, change to study drug (e.g. study drug discontinuation), more frequent follow-up 
assessments, further diagnostic investigation. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
increased alkaline phosphatase associated with cholecystitis), only the diagnosis (e.g., 
cholecystitis) should be recorded on the eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be recorded 
as the AE or SAE. For example, an elevated serum potassium level should be recorded as 
“hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the Adverse Event eCRF, unless their severity, 
seriousness, or etiology changes. 
Follow up of abnormal lab values: Repeat testing of the abnormal labs should be performed as 
clinically indicated, in the opinion of the Investigator, until they have returned to the normal 
range and/or an adequate explanation of the abnormality is found and the lab value stabilizes.  


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8.3.1.4. 
Reporting of SAEs 
Any AE that is serious and that occurs during the course of the study from the signing of the 
informed consent to end of study for each patient must be reported by the Investigator to the 
following: 
• The Sponsor (or designee) and study monitor within 24 hours of the Investigator 
becoming aware of the event (expedited reporting). 
• The investigation site’s IRB/IEC by the Investigator in accordance with their regulations. 
Initial Notification of a Serious Adverse Event (SAE) 
Pharmacovigilance must be informed in writing 24 hours from the time the site investigational 
team first becomes aware of the event using the EDC system, as well as completing a paper SAE 
report forms. 
A paper SAE form including a written, narrative description of any SAE must be sent via email 
(preferred) or fax within 24 hours after awareness of the event to: 
Email: 
 
Phone: 
 
Fax: 
 
Paper SAE forms must be retained in the Investigator Site File. 
In addition to reporting the SAE in the EDC and emailing the paper form, the local CRA and the 
Medical Monitor must be alerted via phone.  
As further information regarding the SAE becomes available, follow-up information should be 
documented as an update using the paper SAE form.  Follow-up information should be reported 
with 24 hours of awareness. 
Related SAEs must be collected and reported regardless of the time elapsed from the last 
administration of study drug, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study and for up to 30 days after the 
last dose of study medication. 
SUSARs are reported to Investigators at each site and associated IRB/IEC when the following 
conditions occur: 
• The event is an SAE 
• There is reasonable possibility that the event is an adverse reaction caused by the 
administered drug 
• The adverse reaction is unexpected, that is to say, not foreseen in the IB 
Individual SUSARs considered to be a significant safety issues and/or which result in a change 
to the informed consent form will be reported in an expedited manner to all Investigators and 
IRB/IECs. 


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Reporting of any SAEs to applicable regulatory authorities will be the responsibility of the Local 
Sponsor in compliance with local regulations. 
8.3.1.5. 
Follow-up of Adverse Events 
AEs, especially those for which the relationship to study drug is “related”, should continue to be 
followed during the patient’s participation in the study until they have returned to baseline status 
or stabilized at a level acceptable to the Principal Investigator and Medical Monitor. 
If after patient study completion, return to baseline status or stabilization cannot be established, 
an explanation should be recorded in the source documents. 
8.3.1.6. 
Pregnancy 
Pregnancies occurring in a female patient or in a male patient’s partner while enrolled in this 
clinical study through 1 month after the last dose of study drug administration, must be reported 
on a Pregnancy Reporting Form within 24 hours of the investigator, designee, or site personnel 
learning of the pregnancy. 
Pregnancy Reporting Forms should be sent via email (preferred) or fax to: 
Email: 
 
Phone: 
 
Fax: 
 
If a patient becomes pregnant while taking study drug, the study drug will be immediately 
discontinued and the pregnancy must be reported within 24 hours of learning of the event. The 
investigator will discuss the risks and concerns of investigational drug exposure to a developing 
fetus and counsel the subject and/or pregnant partner (or ensure such counselling is provided). 
An uncomplicated pregnancy will not be considered an AE or SAE. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions . 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
All pregnancies will be followed through birth.  In the event there is a congenital anomaly or 
birth defect in a neonate or infant born to a mother exposed to study drug both the offspring and 
mother will be followed for 3 months post-delivery. Any congenital anomaly or birth defect in 
the offspring of a subject who received investigational product will be reported as an SAE. The 
outcome of any pregnancy and the presence or absence of any congenital anomaly or birth defect 
will be recorded in the source documentation and reported to the Sponsor and/or its designee. 
The investigator will complete the Pregnancy Reporting Form or paper SAE form, as applicable, 
and report the information regarding the pregnancy, outcome, and status of the newborn, as 
appropriate. 
8.3.2. 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected at the time points detailed in the 
Schedule of Assessments (see Section 1.3).  


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Laboratory safety tests may be performed at unscheduled time points, if deemed necessary by the 
Investigator. Screening laboratory safety tests may be repeated upon discussion with the 
Sponsor/Medical Monitor. 
The Laboratory Manual will supply complete written instructions for collection, handling, 
processing, storage, and shipping of samples. 
8.3.3. 
Vital Signs 
Vital signs will be assessed at the time points detailed in the Schedule of Assessments (see 
Section 1.3). The following vital signs will be measured: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Heart rate (bpm) 
• Body temperature (°C) 
BP and heart rate recordings will be made after the patient has been resting supine or semi-
recumbent for ≥5 minutes. 
8.3.4. 
 Electrocardiograms 
12-lead ECGs will be performed at time points detailed in the Schedule of Assessments (see 
Section 1.3). 
The12-lead ECGs will be performed after the patient has been resting supine or semi-reclined for 
≥ 5 minutes. The ECG paper tracing will be assessed by the study investigator for any 
abnormality and for clinical significance. The ECG parameters that will be measured include but 
are not limited to: PR interval, QRS interval, RR interval, QT interval, and QTc. 
The ECGs will be sent electronically to a central location to be analyzed and over-read. The 
study site should review the centrally read report as soon as possible once available. The central 
report findings should be compared to the local paper ECG findings reported by the site. Any 
difference in reported ECG findings should be reconciled by the Investigator. The study team 
does not require a report back from this central location to act on any findings identified on the 
paper ECG tracing that, in the opinion of the study investigator, are clinically significant. 
8.3.5. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the Schedule of 
Assessments (see Section 1.3). 
Complete Physical Examination 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic and psychiatric systems). A gynecological or genital 
examination is not required unless it is deemed necessary in the opinion of the Principal 
Investigator.  


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Abbreviated Physical Examination 
An assessment of the general appearance, skin, cardiovascular system, respiratory system and 
abdomen and any symptom-driven assessment as appropriate. 
The abbreviated physical examination should be extended to a full physical examination based 
on the clinical condition of the patient and if considered necessary by the Principal Investigator.  
8.4. 
Pharmacokinetic Assessments 
Blood samples for the analysis of plasma concentration levels of ESK-001 (PK) and ESK-001 
metabolites will be collected at the time points detailed in the Schedule of Assessments (see 
Section 1.3). 
Samples will be used to evaluate the PK of ESK-001 and its metabolites.  Samples collected for 
analyses of ESK-001 and ESK-001 metabolite plasma concentrations may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study.  After the 
blood samples are analyzed for plasma ESK-001 and ESK-001 metabolite concentrations, any 
residual samples may be used for exploratory analysis such as additional metabolite profiling and 
identification, interacting drug concentration measurements, ex vivo protein binding, or 
development of PK or PD assays. 
Details regarding the collection, handling, processing, storage and shipping of samples will be 
provided in the Laboratory Manual. 
8.5. 
Pharmacodynamic Assessments 
Samples for the exploratory analysis of ESK-001 PD effects will be collected at the time points 
detailed in the Schedule of Assessments (see Section 1.3). 
Details regarding the collection, handling, processing, storage and shipping of samples will be 
provided in the Laboratory Manual. 
8.5.1. 
Skin Biopsy and Tape Stripping (Skin Biomarker Profile) 
Skin samples will be collected via skin biopsy and/or tape-stripping at time points specified in 
the Schedule of Assessments for patients who provide specific consent. The samples will be used 
to assess skin biomarker response for a number of exploratory purposes that may include but are 
not limited to studying the ESK-001 mechanism, patient treatment response, and disease 
progression. 
8.5.2. 
Plasma Biomarker Profile 
Plasma-based samples will be collected at time points specified in the Schedule of Assessments 
to assess blood-based biomarker response for a number of exploratory purposes that may include 
but are not limited to studying biomarkers of ESK-001 mechanism, treatment response, and 
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8.5.3. 
Blood RNA-seq Profile (Exploratory Transcriptomics) 
RNA-based samples will be collected at time points specified in the Schedule of Assessments to 
assess transcriptomic biomarker response for a number of exploratory purposes that may include 
but are not limited to studying the mechanism of ESK-001, patient treatment response, and 
disease progression. 
8.5.4. 
Blood Cell-Based Biomarkers 
Whole blood will be collected at timepoints specified in the Schedule of Assessments to assess 
the response of immune-stimulated biomarkers for a number of exploratory purposes that may 
include but are not limited to studying biomarkers of ESK-001 mechanism, treatment response, 
and disease progression. 
8.6. 
Genetics 
Unless prohibited by local ethics committees, a DNA sample will be collected from patients who 
provide specific consent. The sample will be used for genetic analyses that may include but are 
not limited to patient-specific ESK-001 metabolism, drug-transport, and ESK-001 response. 


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9. 
SAFETY MONITORING COMMITTEE 
A Safety Monitoring Committee (SMC) will be convened to review the safety data throughout 
this study. The SMC will consist of the Sponsor’s Medical Director; the study Medical Monitor 
(from the CRO); two independent physicians with clinical trial experience, one with dermatology 
expertise and the other a cardiologist; and an independent statistician.  
The SMC may meet at any time during the study to review blinded (or unblinded, if required) 
data when deemed necessary by the SMC. 
The SMC will initially convene to review all available safety data after approximately 50 
patients have been randomized and completed their Week 4 visit. The SMC will also meet 
regularly thereafter, based upon accumulating safety data and patient enrollment. The final 
prescheduled meeting of the SMC will be after study completion; to evaluate all safety data from 
all patients enrolled in the study. The SMC may also review safety data from eligible patients 
who complete this study and who enter an ESK-001 open label extension study. 
The roles and responsibilities of SMC members and the SMC procedures and communication 
pathways are detailed in the SMC Charter.  


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10. 
STATISTICAL CONSIDERATIONS 
Before database lock, a statistical analysis plan will be issued as a separate document, providing 
detailed methods for the analyses outlined below. Any deviations from the planned analyses will 
be described and justified in the clinical study report. 
The baseline value of any variable will be defined as the last available value prior to the first 
administration of study drug (ESK-001 or placebo). A patient is considered randomized into the 
study following treatment assignment by IxRS. 
All statistical tests will be two-sided. Except where noted, evaluation of continuous variables 
will be performed using ANOVA; ANOVA will be replaced by the nonparametric counterpart if 
normality assumptions are severely violated. Between-group comparisons involving discrete data 
will be performed using contingency table methodology. Descriptive summaries of continuous 
data will present the group mean, SD, median, range, and sample size. Descriptive summaries of 
discrete data will report the number of patients and incidence as a frequency and as a percentage. 
Statistical comparisons will be performed at the 0.05 level of significance. 
10.1. 
Analysis of the Conduct of the Study 
The disposition of patients will be summarized by treatment group with respect to the number of 
patients randomized, treated, and completing the study. For patients who discontinue treatment 
early, reasons for discontinuation will be summarized by treatment group. 
Important Protocol Deviations (IPD) will be summarized. ICH E3 defines important protocol 
deviations as a subset of protocol deviations that may significantly impact the completeness, 
accuracy, and/or reliability of the study data or that may significantly affect a subject’s rights, 
safety, or well-being. 
10.2. 
Analysis of Treatment Group Comparability 
Demographics (age, sex, race/ethnicity) and baseline characteristics (e.g., duration of psoriasis, 
psoriasis severity at baseline, baseline PASI) will be summarized by treatment group. 
10.3. 
Efficacy Analyses 
Efficacy analyses will be based on the intent-to-treat (ITT) approach. All patients randomized 
(ITT population) will be included in the analysis, and subjects will be analyzed according to their 
randomized treatment. Unless otherwise noted, analyses of efficacy outcome measures will be 
stratified by prior use of biologics and geographic region.  
10.3.1. 
Primary Efficacy Endpoint 
The proportion of patients in the active treatment groups with ≥75% improvement in PASI at 
Week 12 relative to baseline will be compared between each treatment group and placebo using 
the Cochran-Mantel-Haenszel test adjusting for stratification factors.  


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10.3.2. 
Secondary Efficacy Endpoints 
Similar analyses as in the primary efficacy analyses will be performed to compare any two active 
arms. 
The proportion of patients in each treatment group and placebo with sPGA categories 0 or 1 
(cleared or minimal) at Week 12 will be compared using the Cochran-Mantel-Haenszel test 
adjusting for stratification factors. 
The proportion of patients in each treatment group and placebo with response rate in PASI-50, 
90, and 100 at Week 12 relative to baseline will be compared using methods similar to those 
used for PASI-75. 
Change in percent BSA at Week 12 relative to baseline will be performed using ANOVA or 
analogous nonparametric methods. 
Change from baseline in DLQI at Week 12 relative to baseline will be performed using ANOVA 
or analogous nonparametric methods. 
The proportion of patients in each treatment group and placebo with ≥75% improvement in PASI 
Week 12 relative to baseline will be compared using the Cochran-Mantel-Haenszel test adjusting 
for stratification factors. 
No adjustments for multiplicity will be performed. 
Graphical methods may be used to display efficacy data. 
10.3.3. 
Exploratory Endpoints 
• Change from baseline in pruritus NRS score at Week 12 will be performed using ANOVA or 
analogous nonparametric methods. 
• Change from baseline in EQ-5D at Week 12 will be performed using ANOVA or analogous 
nonparametric methods. 
• Change from baseline in psoriasis and TYK2-related skin biomarkers in response to 
ESK-001 treatment. 
• Change from baseline in psoriasis and TYK2-related blood-based biomarkers in response to 
ESK-001 treatment. 
• Change from baseline in transcriptomic and proteomic expression in response to ESK-001 
treatment. 
Exploratory PD endpoint analyses may not be included in the CSR. 
10.4. 
Safety Analyses 
Safety will be assessed through the summary of adverse events, serious adverse events, 
laboratory test results, ECG parameters, and vital signs. Safety analyses will include all subjects 
who receive at least one dose of either ESK-001 or placebo. Subjects will be analyzed according 
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Patient deaths (if any) will be listed. 
10.4.1. 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be mapped to thesaurus terms 
using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be 
tabulated by body system and preferred term. Summaries of adverse events by severity will be 
provided. Adverse events judged by the investigator to be related to treatment (ESK-001 or 
placebo) will be prepared. Serious adverse events will be summarized similarly. Adverse events 
leading to discontinuation from the study or treatment will be listed and tabulated. 
10.4.2. 
Laboratory Tests 
Descriptive summaries of laboratory values, including changes from baseline and 
treatment-emergent abnormalities, will be generated. Shift tables reflecting changes from 
baseline (e.g., normal to low, high) will be presented for a subset of laboratory parameters.  
The liver function tests, namely ALT, AST, ALP, and TBL, are used to assess possible drug-
induced liver toxicity (DILI). A listing of liver function test results that meet DILI criteria will be 
generated. 
10.4.3. 
12-Lead Electrocardiogram 
The RR, PR, QRS, and QT intervals will be measured and read by a central laboratory. HR will 
be calculated as 60/ (RR × 1000) (with RR expressed in msec) and rounded to the nearest 
integer. 
Correction for Heart Rate 
Corrected QT interval (QTc) will be calculated using the manually over-read QT values. Each 
individual ECG QT value will be corrected for HR. The measured QT data will be corrected for 
HR using QTcF as per the following formulae/method (with QT, RR and QTc expressed in 
msec): 
Fridericia’s Correction: 
 
ECG Numeric Variables 
HR, PR, QRS, and QTcF will be summarized using descriptive statistics. For each time point of 
measurement, the changes from baseline will be summarized using descriptive statistics. 
Categorical Analysis 
The incidence count and percentage of patients with any postdose QTcF values of >450 msec, 
>480 msec, and >500 msec will be tabulated. Patients with QTcF values >520 msec will be listed 
with corresponding baseline values, ∆QTcF, and baseline and treatment HR. The incidence count 
and percentage of patients with ∆QTcF increase from baseline of >30 msec and >60 msec will be 
tabulated. 


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10.4.4. 
Vital Signs 
Descriptive summaries of vital signs measurements and changes from baseline will be generated. 
10.5. 
Pharmacokinetic Analysis 
Plasma concentrations of ESK-001 will be summarized descriptively by treatment group and 
time point. 
10.6. 
Missing Data 
Detailed missing data methodology will be described in the Statistical Analysis Plan. 
10.7. 
Sample Size 
The sample size is determined based on the primary efficacy endpoint. Calculations are based on 
a 1:1:1:1:1:1 randomization ratio (ESK-001 doses 1-5 vs. placebo) and will provide at least 99% 
power to detect 50% increase in the PASI-75 response rate in an active arm (i.e., 60% response 
rate) compared to the placebo assuming the response rate is 10% in the placebo arm. With a two-
sided, two-sample test at a significance level of 0.05, a sample size of 35 patients per arm for a 
total of 210 patients is planned. 
10.8. 
Interim Analyses 
An independent SMC will be established to monitor safety data during the study. See Section 9 
for details.  


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11. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
11.1. 
Data Quality Assurance 
The overall procedure for quality assurance of clinical study data, including data collection and 
management, will be described in the Data Management Plan. 
Accurate and reliable data collection will be assured by verification and cross-check of the eCRF 
against the Investigator's records by the study monitor (source document verification), and the 
maintenance of Drug Accountability by the Investigator. Monitoring details describing strategy, 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques are provided in the Monitoring Plan and contracts. 
Electronic data capture (EDC) will be utilized. All patient data relating to the study will be 
entered by the study center from the source documents into the electronic case report forms 
(eCRFs) unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). In no 
case is the eCRF to be considered as source data for the study. 
Validation checks will be programmed within the EDC system to identify potential data 
discrepancies. Additionally, Sponsor personnel or designee will review the data entered by 
investigational staff for completeness and accuracy. If potential discrepancies are discovered, 
electronic data queries stating the nature of the potential discrepancy and requesting clarification 
will be sent to the site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and make necessary changes to the data. The sponsor assumes 
accountability for actions delegated to other individuals (e.g., contract research organizations) 
For classification purposes, preferred terms will be assigned to the original terms recorded on the 
eCRF, using MedDRA for AEs, diseases and surgical and medical procedures, and the 
WHODrug dictionary for drug and herbal treatments. 
11.2. 
Protocol Amendments and Study Completion 
Protocol amendments must be made only with the prior approval of the Sponsor or its designees. 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be informed of 
all amendments and give approval for all amendments. For studies conducted out of the US, 
approval of all substantial amendments must be obtained from the relevant Competent 
Regulatory Authority before implementation. The Investigator must send a copy of the approval 
letter from the IRB/IEC to the Sponsor and/or its designees. 
Approval must be obtained before any changes can be implemented, except for Changes 
necessary to eliminate an immediate hazard to study patients, or when the change(s) involves 
only logistical or administrative aspects of the study (e.g., change in monitor, change of 
telephone number). 
The Sponsor reserves the right to terminate the study, according to the Clinical Study 
Agreement. 
Study completion is defined as the date when all patients have completed the final study visit, 
and the study database has been locked. 


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11.3. 
Informed Consent 
The Investigator and Sponsor must agree upon the format and content of the informed consent 
for (ICF) before it is submitted to the IRB/IEC for approval. A copy of the IRB/IEC approved 
ICF will be forwarded to the Sponsor. Written IRB/IEC approved informed consent and Health 
Insurance Portability and Accountability Act (HIPAA) release (or other privacy protection 
release, as governed by local regulations) must be obtained from each patient before any study-
related activities are conducted. The Investigator must retain all original signed and dated ICFs 
in the patient’s file. A copy of the signed and dated ICF must be given to the patient. 
The ICF documents the study-specific information the Investigator provides to the patient for the 
patient’s agreement to participate. Among other things, the Investigator or his/her designee will 
fully explain in layman's terms the nature of the study, along with the aims, methods, anticipated 
benefits, potential risks, and any discomfort participation may entail. The ICF must be 
appropriately signed and dated before the patient enters the study. 
Patients will be informed of findings from the earlier or concurrent clinical studies (including 
AEs), if it is considered that such information could potentially affect patients’ willingness to 
participate or continue in the study. Depending on the nature, severity, and seriousness of these 
AEs, the ICF may be amended as deemed appropriate. All amended signed and dated ICF(s) 
must be retained in the patients’ files at the study sites; and a copy must be given to the patient. 
11.4. 
Data Handling and Record Keeping 
11.4.1. 
Patient Confidentiality and Disclosure of Data 
The Investigator must ensure that each patient’s anonymity is maintained as described below. On 
the eCRFs or other documents submitted to the Sponsor and/or its designees, patients must only 
be identified by study, Patient Identification Number, and demographics, and pertinent 
restrictions of local regulations. No other personal identifies will be used, and data will be de-
identified in a manner compliant with Privacy Laws and, for US patients, the HIPAA 
regulations. Documents that are not for submission to the Sponsor and/or its designee (e.g., 
signed ICFs and Patient Information Sheets) should be kept in strict confidence by the 
Investigator in compliance with Federal regulations or other applicable laws or ICF and GCP 
guidelines. The Investigation and institution must permit authorized representatives of the 
Sponsor and/or its designee, representatives of the FDA, national and local health authorities, 
and the IRB/IEC direct access to review the patients’ original medical records for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying and 
reproducing any records and reports that are needed for the evaluation of the study. The 
Investigation is obligated to inform the patient in the ICF that his/her study-related records will 
be reviewed, by the above-named representatives.  
Patients will be informed that data will be held on file, by the Sponsor, and that these data may 
be viewed by staff including the study monitor and by external auditors on behalf of the Sponsor 
and appropriate regulatory authorities. Patients will also be informed that a study report will be 
prepared and may be submitted to regulatory authorities and for publication. However, patients 
will be identified in such reports only by Patient Identification Number and demographics, 


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pertinent to restrictions of local regulations. All patient data will be held in strict confidence, as 
allowed by law. 
Upon the patient’s permission, medical information may be given to the patient’s personal 
physician or other appropriate medical personnel responsible for the patient's welfare. 
11.4.2. 
Electronic Case Report Forms (eCRFs) 
The data collected in the source documents for this study will be entered by designated study 
staff into the eCRF which uses fully validated software that conforms to 21 CFR Part 11 
requirements. An audit trail will maintain a record of initial entries and changes made, time and 
date of entry, and name of person making the entry or change. Site staff will not be given access 
to the EDC system until they have been trained.  
Guidance on completion of eCRFs will be provided in CRF completion guidelines. 
The Investigator must ensure that complete data for the clinical study are collected, accurately 
documented in the appropriate sections of the eCRF, and adequately supported by appropriate 
source documentation. For each patient enrolled, the Investigator is responsible for verifying the 
accuracy, completeness, and timeliness of the data entries by electronically signing the eCRF. 
A site-specific eCRF archive and audit trail will be provided at the close of the study to each 
Investigator. The Sponsor or designee will retain the eCRF archive and audit trail for all 
investigative sites. 
11.4.3. 
Retention and Availability of Records 
The Investigator is required to retain the study records and reports until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. If no marketing 
application is to be filed, or an application is not approved for the drug, the Investigator will 
retain the study records for 2 years after shipment and delivery of the drug for investigational use 
is discontinued and the Sponsor has so notified the FDA, per 21 CFR 312.27. Study records 
should, however, be retained longer if required by the applicable national and/or local regulatory 
requirements or by agreement with the Sponsor. 
The Investigator must make study data accessible to the monitor, other authorized representative 
of the Sponsor, and regulatory agency inspectors upon request. A file for each patient must be 
maintained that includes the signed ICF and the Investigators copies of all source documentation 
related to that patient. The Investigator must ensure the reliability and availability of source 
documents from which the information on the eCRF was transcribed. 
11.4.4. 
Audits and Inspections 
In accordance with ICH, GCP and the Sponsor and/or its designee audit plans, this study may be 
selected for audit. Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) 
and review of study-related records will occur to evaluate the study conduct and compliance with 
the protocol, ICH, GCP, and applicable regulatory requirements. The Investigator/institution 
should make available for direct access all requested study-related records (ICH GCP 4.9.7) to 


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appropriately qualified personnel from the Sponsor or its designees, or to health authority 
inspectors after appropriate notification. The verification of the eCRF data must be by direct 
inspection of source documents. The Investigation/institution should take measures to prevent 
accidental or premature destruction of these documents. 
If for any reason the study records are moved to another location, the Investigator should notify 
the Sponsor of the new location. 
11.5. 
Publication Policy 
Alumis assumes full responsibility relating to this function and retains exclusive property rights 
over the results of the study, which Alumis may use as it deems fit. 
If the study has multiple centers, the first publication must include complete results from data 
analyzed by Alumis from multiple centers. The Investigator commits himself not to publish or 
communicate data collected in only one center or part of a center before the publication of the 
complete results of the study unless prior written agreement from the other Investigators and 
Alumis has been obtained. 
A copy of any intended publication or communication related to the study or related to the results 
obtained during or after the study shall be submitted to Alumis at least 90 days before the 
forecasted date of distribution or submission for publication. The authoring Investigator shall 
take Alumis’s comments into due consideration and hereby agrees to incorporate any changes in 
any such publication or communication that Alumis may reasonably require to protect Alumis’s 
proprietary rights and interests. Should the authoring Investigator decide to not incorporate 
changes reasonably required by Alumis, the authoring Investigator shall provide the reasons in 
writing to Alumis. 
In the case where Alumis is in the process of filing a patent application on the results of the 
study, Alumis may delay its authorization for publication or communication of the results of the 
study until the date of international registration of the patent.  


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12. 
REFERENCE LIST 
Bristol Myers Squibb. Bristol Myers Squibb Presents Positive Data from Two Pivotal Phase 3 
Psoriasis Studies Demonstrating Superiority of Deucravacitinib Compared to Placebo and 
Otezla® (apremilast). 2021 Apr 23. 
JAMA. World Medical Association Declaration of Helsinki: ethical principles for medical 
research involving human subjects JAMA. 2013 Nov 27;310(20):2191-4. doi: 
10.1001/jama.2013.281053. 
Papacharalambous J, Tehlirian C, Peeva E. TYK2/JAK1 Inhibitor PF-06700841 in Patients with 
Plaque Psoriasis: Phase IIa, Randomized, Double-Blind, Placebo-Controlled Trial. J Invest 
Dermatol. 2020 Dec;140(12):2359-2370.e5. doi: 10.1016/j.jid.2020.03.962 
Papp K, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, Girgis IG, Kundu S, Banerjee S. 
Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med. 2018 Oct 
4;379(14):1313-1321. doi: 10.1056 /NEJMoa1806382 
Polese B, Zhang H, et al (2020). Innate lymphocytes in psoriasis. Frontiers in Immunology 
11(242). PubMed PMID: 32153574 
Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment. Int J Mol Sci. 2019;20(6):1475. 
Published 2019 Mar 23. doi:10.3390/ijms20061475. 
WHO. WHO Global Report on Psoriasis. Feb 2016. 
Winthrop K (2017). The emerging safety profile of JAK inhibitors in rheumatic disease. Nature 
Reviews Rheumatology 13(4): 234-243. PubMed PMID: 28250461  
Zeng J, Luo S, et al (2017). Critical role of environmental factors in the pathogenesis of 
psoriasis. The Journal of Dermatology 44(8): 863-872. PubMed PMID: 28349593 
 


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13. 
APPENDICES 
Appendix A Psoriasis Area and Severity Index (PASI) 
The PASI is a grading system used for the evaluation of the severity of psoriatic lesions and 
their  response to treatment. The PASI produces a numeric score that can range from 0 to 72. 
The severity of a subject’s disease is calculated as described below: 
The body is divided into 4 regions for determining total body surface area (BSA):  
• the head (h), trunk (t), upper extremities (ux) and lower extremities (lx),  
• which account for 10% (0.1), 30% (0.3), 20% (0.2), and 40% (0.4) respectively of BSA  
Each of these areas are evaluated for erythema (E), induration (I) and scaling (S), which are 
rated on a scale from 0 to 4. 
The scoring system for the signs of disease (erythema, induration and scaling) is below: 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
The scoring system for estimating the area (A) of involvement for psoriatic lesions is outlined 
below: 
0 = no involvement 
1 = 1% to 9% involvement 
2 = 10% to 29% involvement 
3 = 30% to 49% involvement 
4 = 50% to 69% involvement 
5 = 70% to 89% involvement 
6 = 90% to 100% involvement 
To aid in the area assessments, the following conventions are followed: 
a. the neck is considered part of the head 
b. the axilla and groin are considered part of the trunk 
c. the buttocks are considered part of the lower extremities 
The PASI formula is: 
PASI = 0.1(Eh + Sh + Ih)Ah + 0.3(Et + St + It)At + 0.2(Eux + Sux + Iux)Aux + 0.4(Elx + Slx + Ilx)Alx 
Clinical assessments of response should be performed by the same assessor(s). 


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Appendix B Static Physician’s Global Assessment (sPGA) 
The Physician Global Assessment (PGA) is used to determine the subject’s psoriasis lesions 
overall at a given time point. Overall lesions will be graded for induration, erythema, and scaling 
based on the scales below. The sum of the 3 scales will be divided by 3 to obtain a final PGA 
score. 
 
Induration (I) (averaged over all lesions; use the National Psoriasis Foundation Reference card  
for measurement) 
0 = no evidence of plaque elevation 
1 = minimal plaque elevation, = 0.25 mm  
2 = mild plaque elevation, = 0.5 mm 
3 = moderate plaque elevation, = 0.75 mm  
4 = marked plaque elevation, = 1 mm 
5 = severe plaque elevation, = 1.25 mm or more 
 
 
Erythema (E) (averaged over all lesions) 
0 = no evidence of erythema, hyperpigmentation may be present  
1 = faint erythema 
2 = light red coloration 
3 = moderate red coloration 4 = bright red coloration 
5 = dusky to deep red coloration 
 
 
Scaling (S) (averaged over all lesions) 
0 = no evidence of scaling 
1 = minimal; occasional fine scale over less than 5% of the lesion  
2 = mild; fine scale dominates 
3 = moderate; coarse scale predominates 
4 = marked; thick, nontenacious scale dominates 
5 = severe; very thick tenacious scale predominates 
 
 


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Appendix B, continued 
 
Add I + E + S = / 3 = (Total Average) 
 
 
Physician’s Static Global Assessment based upon above Total Average 
0 = Cleared, except for residual discoloration 
1 = Minimal - majority of lesions have individual scores for I + E + S / 3 that averages 1 
2 = Mild - majority of lesions have individual scores for I + E + S / 3 that averages 2 
3 = Moderate - majority of lesions have individual scores for I + E + S / 3 that averages 3 
4 = Marked - majority of lesions have individual scores for I + E + S / 3 that averages 4  
5 = Severe - majority of lesions have individual scores for I + E + S / 3 that averages 5 
 
Note: Scores should be rounded to the nearest whole number. If total ≤1.49, score = 1; if total 
≥1.50, score = 2. 


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Appendix C Dermatology Life Quality Index (DLQI) 
 
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
Hospital No: ……………………………………. 
Date: 
……………………. 
Name: 
……………………………………. 
Score: 
……………………. 
Address: 
……………………………………. 
Diagnosis: ……………………. 
……………………………………. 
 
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK. Please tick () one box for each question. 
1. 
Over the last week, how itchy, sore, painful or stinging 
has your skin been? 
2. 
Over the last week, how embarrassed or self conscious 
have you been because of your skin? 
3. 
Over the last week, how much has your skin interfered with 
you going shopping or looking after your home or garden? 
4. 
Over the last week, how much has your skin influenced the 
clothes you wear? 
5. 
Over the last week, how much has your skin affected any 
social or leisure activities? 
6. 
Over the last week, how much has your skin made it difficult 
for you to do any sport? 
7. 
Over the last week, has your skin prevented you from 
working or studying? 
If "No", over the last week how much has your skin been a 
problem at work or studying? 
8. 
Over the last week, how much has your skin created 
problems with your partner or any of your close friends or 
relatives? 
9. 
Over the last week, how much has your skin caused any 
sexual difficulties? 
10. Over the last week, how much of a problem has the 
treatment for your skin been, for example by making your 
home messy, or by taking up time? 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Yes 
No 
 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
 
 
 
 
 
Not relevant 
 
 
 
 
 
Not relevant 
 
 
 
 
 
Not relevant 
 
 
 
 
 
Not relevant 
 
 
 
Not relevant 
 
 
 
 
 
 
 
 
 
Not relevant 
 
 
 
 
 
Not relevant 
 
 
 
 
 
Not relevant 
 


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Appendix D EQ-5D-5L 
 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 


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• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
• Mark an X on the scale to indicate how your health is TODAY. 
 
• Now, please write the number you marked on the scale in the box 
below. 
The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
60 
55 
YOUR HEALTH TODAY = 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health 
you can imagine 


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Appendix E Pruritus Numerical Rating Scale (NRS) 
 
Phan NQ et al. Acta Derm Venereol. 2012;92:502-7 
Verweyen E at al. Acta Derm Venereol. 2019;99:657-66 


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Appendix F Signature Page: Declaration of Sponsor or Responsible Medical Expert 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ESK-001 in Patients with Moderate to Severe Plaque Psoriasis 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, as well 
as with the moral, ethical and scientific principles governing clinical research as set out in the 
guidelines on Good Clinical Practice (GCP) applicable to this clinical study. 
Sponsor Signatory/Responsible Medical Expert 
Date 
 
 


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Appendix G Signature Page: Investigator Study Acknowledgement/Disclosure 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ESK-001 in Patients with Moderate to Severe Plaque Psoriasis  
Version 3.0, 09 August 2022 
By my signature, I confirm that my staff and I understand that the protocol and the Investigators 
Brochure are the confidential and proprietary property of the Sponsor. Further, I/we have 
carefully read and understand the protocol and agree to comply with the conduct and terms of the 
study specified therein. In particular, I/we have agreed to: 
1. Comply with the E6 International Conference on Harmonisation (ICH) Tripartite Guideline 
on Good Clinical Practice (GCP) applicable Food and Drug Administration (FDA) Code of 
Federal Regulations (CRFs) and all applicable country regulations. 
2. Have read and understood the Investigators Brochure, including potential risks and side 
effects of the drug. 
3. Personally conduct or oversee the study according to the protocol, its amendments, study 
manuals, and study guides. 
4. Ensure that written and dated approval/favorable opinion from the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) for the protocol, any amendments to the 
protocol, written informed consent form, any consent form updates, and Investigators 
Brochure (IB) are available before initiation of any study-related procedure and assure 
periodic review by the IRB/IEC as required per local and country regulations. 
5. Obtain written informed consent from each study patient or his/her legally acceptable 
representative (if applicable). 
6. Report all serious adverse events (SAEs) to Alumis or its agents and the IRB/IEC, as 
required by the protocol and country and IRB/IEC requirements. 
7. Assure access by study monitors to original source documents. 
8. Cooperate fully with any study-related Good Clinical Practice (GCP) audit as performed by 
Alumis, its agents, the US Food and Drug Administration (FDA), and/or the Regulatory 
Health Authorities of the participating country(ies). 
9. Maintain confidentiality and assure security of confidential documents such as the protocol, 
informed consent, case report forms, IB, final study reports, study data, study reference 
manuals, study guides, manuscript and/or unpublished data and correspondence. 
 
 
 
Principal Investigator Name 
 
Site Number 
 
 
 
Principal Investigator Signature 
 
Date 
 

SAP_001.pdf: 
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Statistical Analysis Plan 
A Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of ESK-001 in Patients 
with Moderate to Severe Plaque Psoriasis 
ESK-001-006 
Version 3.0, 09 August 2022 
Version 3.1 CZ, 10 January 2023 
ESK-001 
Phase 2 
Alumis Inc. 
611 Gateway Blvd, Suite 820 
South San Francisco, CA 94080, United States 
Version 1.0, 20 July 2023 
NCT05600036
Protocol Title: 
Protocol Number: 
Protocol Version/Date: 
Investigational Product: 
Study Phase: 
Sponsor Name: 
Legal Registered Address: 
SAP Version/Date:
NCT Number:
Confidentiality Statement 
This is an Alumis Inc. document and contains confidential information. It is provided for the sole 
use of the principal investigator, sub-investigators, staff, institutional review boards, human 
research ethics committees, and regulatory authorities. By accepting this document, you agree to 
maintain the information as confidential and to use it only for the purpose of conducting the 
clinical investigation or reviewing the study protocol. 


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SIGNATURE PAGE 
 
 
Protocol Number: 
ESK-001-006 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of ESK-001 in Patients 
with Moderate to Severe Plaque Psoriasis 
SAP Version: 
Date: 
Version 1.0 
20JUL2023 
 
Name, Title, Function 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ....................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 4 
LIST OF FIGURES ........................................................................................................................ 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 8 
3 
STUDY DESIGN ............................................................................................................ 10 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................ 12 
5 
GENERAL STATISTICAL CONSIDERATIONS ......................................................... 12 
5.1 
Analysis Populations .......................................................................................... 13 
5.2 
Stratification Factors and Subgroups ................................................................. 13 
5.3 
Missing Data ....................................................................................................... 14 
5.4 
Multiplicity Control ............................................................................................ 15 
5.5 
Data Handling Conventions ............................................................................... 15 
 
 
6 
SUBJECT DISPOSITION ............................................................................................... 17 
6.1 
Demographics and Baseline Characteristics ...................................................... 17 
6.2 
Study Drug Exposure and Compliance .............................................................. 17 
6.3 
Protocol Deviations ............................................................................................ 18 
6.4 
Medical History and Concomitant Procedures ................................................... 18 
6.5 
Prior and Concomitant Medications ................................................................... 18 
7 
EFFICACY ANALYSES ................................................................................................ 19 
7.1 
Primary Efficacy Analyses ................................................................................. 20 
7.1.1 
Psoriasis Area and Severity Index .................................................................. 20 
7.2 
Secondary Efficacy Analyses ............................................................................. 20 
7.2.1 
Psoriasis Area and Severity Index .................................................................. 20 
7.3 
Psoriasis Body Surface Area .............................................................................. 20 
7.4 
Physician’s Global Assessment .......................................................................... 21 
7.5 
Patient-Reported Outcomes ................................................................................ 21 
8 
SAFETY ANALYSES .................................................................................................... 22 
8.1 
Adverse Events ................................................................................................... 22 
8.2 
12-lead Electrocardiogram ................................................................................. 23 


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8.2.1 
ECG Numeric Variables ................................................................................. 23 
8.2.2 
Categorical Analysis ....................................................................................... 23 
8.3 
Safety Laboratory Data....................................................................................... 23 
8.3.1 
Potential Drug-induced Liver Injury ............................................................... 23 
8.4 
Vital Signs .......................................................................................................... 24 
8.5 
Other Safety Data ............................................................................................... 24 
9 
PHARMACOKINETIC ANALYSES ............................................................................. 24 
9.1 
PK Concentration ............................................................................................... 24 
10 
PHARMACODYNAMIC ANALYSES .......................................................................... 25 
11 
INTERIM ANALYSIS .................................................................................................... 25 
12 
SUMMARY OF CHANGES FROM PROTOCOL-DEFINED ANALYSES ................ 25 
Appendix A 
Schedule of Assessments ..................................................................... 26 
Appendix B 
Analysis Visits ...................................................................................... 29 
Appendix C 
Psoriasis Area and Severity Index (PASI) ........................................... 30 
Appendix D 
Static Physician’s Global Assessment (sPGA) .................................... 32 
LIST OF TABLES 
 
 
Table 2 
Analysis Visits for Disease Activity Skin Assessments ..................................... 29 
Table 3 
Analysis Visits for Patient Reported Outcomes ................................................. 29 
LIST OF FIGURES 
Figure 1 
Study Schema ..................................................................................................... 10 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
BID 
twice per day (bis in die) 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BSA 
body surface area 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRO 
clinical research organization 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
EQ-5D 
Standardized measure of health-related quality of life developed by the 
EuroQol Group 
EQ-5D-5L 
Standard layout for recording an adult person’s current self-reported health 
state. Consists of a standard format for respondents to record their health state 
according to the EQ-5D-5L descriptive system and the EQ VAS 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation 
IFN 
interferon 
IL 
interleukin  
IxRS 
interactive voice/web response system 
JAK 
Janus kinase 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
NRS 
Pruritus numerical rating scale 
PASI 
Psoriasis Area and Severity Index 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PRO 
patient-reported outcomes 
QD 
once per day (quaque die) 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
RNA-seq 
RNA sequencing 
ROW 
Rest of world 
SAE 
serious adverse event 
SMC 
safety monitoring committee  
SOA 
Schedule of Assessments 
sPGA 
static Physician’s Global Assessment 
STAT 
signal transducers and activators of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Th 
T helper 
TYK2 
tyrosine kinase 2 
ULN 
upper level of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for the clinical study ESK-001-006 
Protocol Version 3.0 (Dated 09Aug2022). The SAP will be finalized prior to study unblinding 
and database lock for the clinical study report (CSR). Biomarker analysis defined in the 
biomarker-related exploratory objectives in the protocol is not included as part of the scope of 
the CSR (with the exception of T/B/NK cell counts as described in Section 10) and therefore will 
not be defined in this SAP. The analysis plan for these exploratory objectives will be detailed in 
a separate SAP authored by Precision Immunology at Alumis. 




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Objectives 
Endpoints 
• To assess the change in psoriasis and TYK2-
related blood-based biomarkers with ESK-001 
treatment 
• Change from baseline in psoriasis and TYK2-related 
blood-based biomarkers in response to ESK-001 
treatment 
• To assess the change in transcriptomic- and 
proteomic-based biomarkers in blood and skin 
with ESK-001 treatment 
• Change from baseline in transcriptomic and proteomic 
expression in response to ESK-001 treatment 






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4 
DETERMINATION OF SAMPLE SIZE 
The sample size is determined based on the primary efficacy endpoint. Calculations are based on 
a 1:1:1:1:1:1 randomization ratio (ESK-001 doses 1-5 vs. placebo) and will provide at least 99% 
power to detect 50% increase in the PASI-75 response rate in an active arm (i.e., 60% response 
rate) compared to the placebo assuming the response rate is 10% in the placebo arm. With a two-
sided, two-sample test at a significance level of 0.05, a sample size of 35 patients per arm for a 
total of 210 patients is planned. 
5 
GENERAL STATISTICAL CONSIDERATIONS 
The primary analysis for the efficacy endpoints will be conducted using data collected through 
the 12-week treatment period. Data will be cleaned and locked prior to conducting the primary 
analysis.  
The final analysis will be conducted after all subjects have completed their Week 16 or end of 
study (EOS) visit and after all study data is cleaned and locked.  
SAS® version 9.4 or higher will be used for statistical analyses, tabulations, and graphical 
presentations. 
In general, descriptive summaries will be presented by treatment groups (placebo and ESK-001 
dose levels) and overall, for values at each visit. The descriptive summary for continuous 
variables will also be provided for the change from baseline and, if appropriate, for the change 
from week 12 to week 16. Summaries of continuous variables will include the number of 
subjects (N), mean, standard deviation (SD), median, Q1, Q3, minimum, and maximum. If there 
are variables with highly skewed distribution (e.g. log-normal distribution), then the geometric 
mean and %CV will also be reported in descriptive summaries. Inferential analysis for those 
variables may be performed after log-transformation as deemed appropriate. Descriptive 
summaries for categorical variables will include the number and percentage of subjects. Unless 
otherwise stated, denominators for percentages will be the number of subjects in the analysis 
population. 
Between-group comparisons will focus on the comparative performance of a single ESK-001 
dose versus placebo. All statistical tests will be conducted at a 2-sided significance level of 0.05. 
The corresponding p-values and two-sided 95% confidence intervals will be reported. 
In general, baseline is defined as the last non-missing value prior to the first dose date and time. 
For subjects randomized but not dosed, the last non-missing value prior to the randomization 
date will be used as baseline. For any additional considerations, refer to each specific data 
section for details. 
In general, efficacy data and other non-safety data will be presented by analysis visits as defined 
by the analysis visit window. Data collected at unscheduled or early termination (ET) visits will 
also be mapped to analysis visits as defined in Appendix B. If a value does not fall within an 
analysis window, it will not be included in the summary analysis or comparative analysis. 


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However, these values will be included in data listings and SAS data sets. When more than 
1 value is available within the same analysis visit, the value collected closest to the target visit 
day will be used for analysis. If 2 values are equidistant to a target visit day (for example, 1 value 
is before and the other value is after the target day), then the value from the later date will be 
used for analysis.  
Safety lab, ECG and PK data will be summarized by the nominal visit (per protocol). 
Unscheduled visits will be presented in listings only.  
5.1 
Analysis Populations 
The following analysis populations are defined in this study: 
• Modified Intent-to-Treat (mITT) Population: All randomized subjects who received at least 
one dose of study drug, with analyses conducted according to the assigned treatment. This 
will be the analysis population used for the primary efficacy analysis at Week 12. 
• Intent-to-treat (ITT) Population: All randomized subjects, regardless of whether they receive 
study drug, with analyses conducted according to the assigned treatment.  
• Per-protocol (PP) Population: All subjects in the ITT population who have received at least 
one dose of study drug as assigned, have both baseline and at least one post-baseline PASI 
score, and have no important protocol deviations (IPD) which may affect key primary and 
secondary efficacy endpoints in the treatment period.  
• Safety Analysis Population: All randomized subjects who receive at least one dose of study 
drug with analyses conducted by actual treatment received. 
• PK Analysis Population: All randomized subjects who receive at least 1 dose of ESK-001 
and have at least one non-missing PK concentration with analysis conducted by actual 
treatment received. 
 
5.2 
Stratification Factors and Subgroups 
The baseline values for the following stratification factors will be summarized using descriptive 
statistics: 
• Prior use of biologics or JAK inhibitors (yes/no) 
• Geographic region (North America /rest of world (ROW)) 
 
The assigned (IXRS) and actual stratification factors will be summarized and listed for the mis-
stratified subjects. In the event which any errors are made in specifying the stratification factors 
for randomization, all efficacy analyses will be based on the actual classification according to the 
clinical database.  


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The following subgroups may be included in the analysis of safety and/or efficacy data. 
• BSA involvement (10–20 %, > 20 %)  
• PASI (≤ 20, > 20) 
• Baseline modified sPGA score (3, 4, 5) 
• Sex (Male, Female) 
• Race (White, Non-white) 
• Age category (< 40 years, 40–65 years, ≥ 65 years) 
• Geographical region (North America, ROW) 
• Baseline weight category (<90 kg, ≥ 90 kg) 
• Baseline BMI category (<30 kg/m2, ≥30 kg/ m2) 
• Prior use of psoriasis medication (yes, no) 
• Prior use of systemic therapies (yes, no) 
• Prior use of phototherapies (yes, no) (as collected in MH where MHTERM=’Phototherapy’ 
or ‘UV light therapy’) 
• Prior use of biologics (yes, no) 
• Prior use of JAK inhibitors (yes, no) 
• Prior use of TYK 2 molecules (yes, no) 
• Presence of co-morbidities (yes, no; co-morbidities considered include a history of diabetes, 
cardiovascular diseases, obesity, depression, hypertension, psoriatic arthritis) 
 
5.3 
Missing Data 
In general, missing data will not be imputed unless specifically stated in this SAP. Refer to 
Section 7 on handling of missing data for responder analyses. 
Handling of Missing Data: 
For data collected with start and end dates such as medical history and concomitant medications, 
the following may be applied to missing or partial dates: 
• Start Dates: 


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o If day is missing, then impute it to be the start of the month (eg, 01MMMYYYY); except 
if the month and year is equal to the first dose date month and year then impute the day to 
be the same day as the first  dose date. 
o If month is missing, then impute it to be the start of the year (eg, 01JANYYYY), except 
if the year is equal to the first dose date year then  impute the day and month to be the 
same as the first dose date. 
o If year is missing, then do not impute. 
• End Dates: 
o If day is missing, then impute it to be the end of the month (eg, 31MMMYYYY), except 
if the month and year is equal to the last assessment date month and year then the day 
should be imputed to the last participation date day . 
o If month is missing, then impute it to be the end of the year (eg, 31DECYYYY), except if 
the year is equal to the last participant date year  then the day and month should be 
imputed to the last participant date day and month. 
o If year is missing, then do not impute. 
• For all other type of dates: 
o If only day is missing, then impute it to be the start of the month (eg, 01MMMYYYY).  
o If month and day are missing, then impute it to be the start of the year (eg, 01JANYYYY).   
o If year is missing, then do not impute. 
 
5.4 
Multiplicity Control 
No adjustments for multiplicity control will be performed in this study. 
5.5 
Data Handling Conventions 
For safety laboratory data that are continuous in nature the following rules will be applied: 
• If a result is less than the lower limit of quantitation (LLOQ), it will be imputed to the value 
of the lower limit minus 1 significant figure (e.g., if the result of the laboratory test is < 30, a 
value of 29 will be assigned; if the result of the laboratory test is < 30.0, then a value of 29.9 
will be assigned; if the result of the laboratory test is < 1, a value of 0.9 will be assigned; if 
the results of the lab test is <  0.1, a value of 0.09 will be assigned). 
• If a result is above the upper limit of quantitation (ULOQ), it will be imputed to the value of 
the upper limit plus 1 significant figure. 
 
For PK concentration data, the following rules will be applied: 






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statistics for the duration of interruption (based on the maximum duration of interruption if more 
than one interruption per subject) will be presented. 
6.3 
Protocol Deviations 
Prior to database lock, all protocol deviations will be reviewed and confirmed by the Sponsor. 
Important protocol deviations (IPD) will be identified and summarized by category and listed for 
the Safety Analysis Population. 
International Council for Harmonisation (ICH) E3 guidance defines IPD as a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a participant’s rights, safety, or well-being. 
Any IPDs which impact the interpretation of key primary and secondary efficacy analyses and 
considered for the Per Protocol Population will be identified through the study protocol deviation 
review process. 
The number of subjects that met IPD category of drug compliance below 80% will be 
programmatically derived based on calculated subject drug compliance as described in 
Section 6.2. 
6.4 
Medical History and Concomitant Procedures 
Medical history terms and concomitant procedures will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) version 25.0. Frequency of medical history and 
concomitant procedures will be summarized by treatment group, SOC and PT for the Safety 
Analysis Population. A by subject listing will also be provided. 
6.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the Anatomical Therapeutic Chemical 
(ATC) coding scheme of the World Health Organization Drug Dictionary (WHO DD Global B3 
March 2022). All concomitant, prior and prior Psoriasis medications will be summarized by 
treatment group, ATC2 level and standardized medication name for the Safety Analysis 
Population. A by-subject listing will also be provided. 
Prior medication is defined as medication with an end date prior to the first dose in the study and 
medication taken at any time during the study (ie, first dose through EOS) is considered 
concomitant. 
Prior psoriasis medications collected on a dedicated CRF will be presented separately and will be 
classified as phototherapies, biologic therapies, or systemic therapies through manual review by 
the medical monitor. 
 
 




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7.1 
Primary Efficacy Analyses 
7.1.1 
Psoriasis Area and Severity Index 
Disease activity will be assessed by the Psoriasis Area and Severity Index (PASI) which derives 
a score for the severity of psoriatic lesions by evaluating erythema, induration, and scaling in 
each of 4 body regions, as detailed in Appendix C.  
The primary endpoint is the proportion of subjects achieving >=75% reduction in PASI score 
(PASI-75) at Week 12. 
The proportion of subjects achieving PASI-75 will be summarized for each post-dose timepoint 
by treatment group. The primary efficacy analysis will compare the proportion of subjects 
achieving PASI-75 at Week 12 between each active treatment and placebo using the CMH 
method as described in Section 7. This analysis will be repeated at Weeks 4 and 8.  
The absolute value, change and percent change from baseline in PASI score will be summarized 
using descriptive statistics by timepoint and treatment group. Additionally, the difference in the 
change from baseline between each active treatment and placebo will be assessed using 
ANCOVA model as described in Section 7. The analysis will be repeated with percent change 
from baseline as the dependent variable. Estimates of least-squares (LS) means, SEs, 2-sided 
95% CIs and p-values will be presented by treatment group for Weeks 4, 8 and 12.  
Absolute PASI scores and the proportion of subjects achieving PASI-75, PASI-90, PASI-100, 
PASI-50 will also be plotted over time by treatment. The proportion of subjects achieving 
PASI-50, PASI-75, PASI-90 and PASI-100 at Week 12 by treatment will be presented using a 
bar chart. The percent reduction in PASI at Week 12 for each individual subject will be 
presented by waterfall plot. Each treatment group will be presented on a separate plot.  
7.2 
Secondary Efficacy Analyses 
7.2.1 
Psoriasis Area and Severity Index 
To compare the proportion of subjects achieving PASI-75 at 12 weeks among the active 
treatment groups, the adjusted treatment difference, its associated 95% CI, and two-sided p-value 
will be presented for all 1:1 treatment comparison using the CMH method. 
Time to achievement of each PASI endpoint will also be summarized using descriptive statistics 
and Kaplan-Meier curves . 
7.3 
Psoriasis Body Surface Area 
Measurement of psoriasis body surface area (BSA) involvement is a continuous variable and 
estimated using the handprint method with the size of a patient’s handprint representing ~1% of 
body surface area involved.  


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The absolute value and change from baseline in %BSA will be summarized using descriptive 
statistics by timepoint and treatment group. The absolute value and change from baseline in 
%BSA will be summarized using descriptive statistics by timepoint and treatment group. 
Additionally, the difference in the change from baseline between each active treatment and 
placebo will be assessed using ANCOVA model as described in Section 7. Estimates of least-
squares (LS) means, SEs, 2-sided 95% CIs and p-values will be presented by treatment group for 
Weeks 4, 8 and 12. The absolute value and change from baseline in %BSA over time will be 
plotted by treatment.  
7.4 
Physician’s Global Assessment 
Efficacy will also be assessed by the static Physician’s Global Assessment (sPGA) and the 
scoring system is presented in Appendix D. The frequency and percentage of subjects for each 
discrete sPGA score (0 through 5) will be summarized by timepoint and treatment group. The 
proportion of subjects who achieve a sPGA response (defined as sPGA score of “0” (“cleared”) 
or “1” (“minimal”)) will be summarized for each post-dose timepoint by treatment group. The 
adjusted treatment difference in proportion of subjects with a sPGA response of 0 or 1 for each 
active treatment compared to placebo, its associated 95% CI, and two-sided p-value will be 
presented for Week 4, 8 and 12 using the CMH method. 
Bar charts of the proportion of subjects with the following sPGA scores will be plotted by 
treatment for each visit: 0, 0/1, 1, 2, 3, 4, 5.  
7.5 
Patient-Reported Outcomes  
Quality of life (QoL) will be assessed by the following patient-reported outcomes (PRO): the 
Dermatology Life Quality Index (DLQI), the EQ-5D-5L, and the pruritus numerical rating scale 
(NRS). The two questions collected in NRS questionnaire will be assessed separated as the 
average itch within the past 24 hours and the worst itch within the past 24 hours. Since the EQ-
5D-5L value sets used to calculate the index score are country-specific and there currently are 
none available for Czech Republic where some subjects are enrolled in this study, the value set 
for Poland will be used instead as the closest Eastern European country with available scoring 
instrument. 
DLQI score, NRS average and worst itch scores, and the EQ-5D-5L index score are continuous 
variables, and the absolute value, change and percent change from baseline in each PRO 
assessment will be summarized using descriptive statistics by timepoint and treatment group. 
The absolute value, change and percent from baseline for each PRO measure will be summarized 
using descriptive statistics by timepoint and treatment group. Additionally, the difference in the 
change from baseline between each active treatment and placebo will be assessed using 
ANCOVA model as described in Section 7. The analysis will be repeated with percent change 
from baseline as the dependent variable. Estimates of least-squares (LS) means, SEs, 2-sided 
95% CIs and p-values will be presented by treatment group for Weeks 4, 8 and 12. The absolute 
value over time will be plotted by treatment for the EQ-5D-5L index score, the DLQI score, the 
NRS average itch and worst itch scores.  


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Additionally, a responder analysis will be conducted for DLQI where a responder is defined as 
the subject who achieved a post-baseline score of 0 or 1.  
A responder analysis will also be conducted for NRS questionnaire where a responder is defined 
as a subject who has achieved a post-baseline itch score of < 4.   
8 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Population and will be presented by 
each treatment group and the combined active treatment. In general safety data will be presented 
by descriptive statistics only and by nominal visit (if applicable). Safety data collected on 
unscheduled visits will be presented in listings only.  
The treatment emergent period is defined as first dose through the end of study for subjects who 
complete the full treatment period of 12 weeks. If a subject discontinues study drug early, then 
the treatment emergent period will be first dose through four weeks after last dose.  
8.1 
Adverse Events 
AEs will be coded to MedDRA version 25.0. AEs will be presented by SOC and PT, unless 
otherwise noted, in order of descending frequency on the overall total, and multiple occurrences 
of the same event in the same participant will be counted only once in the tables.  
The following summaries of AEs will be provided: 
• Overall summary of TEAEs 
• All TEAEs  
• Study drug related TEAE 
• TEAEs by severity 
• Grade 3 or higher TEAE 
• Serious TEAEs (SAEs) 
• Study drug-related SAEs 
• TEAE leading to treatment discontinuation 
• TEAE leading to death 
By-subject listings of all AEs, SAEs, TEAEs leading to treatment discontinuation, TEAE leading 
to death will also be provided. 


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8.2 
12-lead Electrocardiogram 
12-lead electrocardiogram (ECG) data will be measured and read by local and central laboratory, 
and will be summarized for all subjects in the Safety Analysis Population.  
8.2.1 
ECG Numeric Variables 
HR, PR, QRS, and Fridericia-corrected QT (QTcF) interval based on central ECG read and 
changes from baseline will be summarized by treatment group using descriptive statistics. The 
change from baseline of these ECG parameters at each time point will be listed for each subject. 
8.2.2 
Categorical Analysis 
The number and percentage of subjects with maximum treatment-emergent post-dose QTcF 
values based on central ECG read in the following mutually exclusive categories will be 
summarized by treatment group: > 450 msec, > 480 msec, >500 msec, > 520 msec, and >550 
msec. The number and percentage of subjects with maximum post-dose QTcF increase from 
baseline of > 30 msec and > 60 msec (mutually exclusive) will be summarized by treatment 
group.  
Clinical significance will be summarized by treatment group and overall for the local and central 
ECG reads separately. 
8.3 
Safety Laboratory Data 
Safety laboratory data and change from baseline will be summarized by treatment group and visit 
using descriptive statistics.  
Laboratory parameters that are graded in CTCAE Version 4.03 will be summarized by CTCAE 
grade. In the summary of laboratory parameters by CTCAE grade, for parameters with CTCAE 
grading in both high and low direction (e.g., calcium, glucose, magnesium, potassium, sodium), 
CTCAE in high and low directions will be summarized separately. Subjects with treatment-
emergent laboratory abnormalities of Grade 3 or higher will also be summarized. Shift from 
baseline to the worst post-baseline CTC grade of Grade 3 or higher will also be presented for 
select laboratory tests of interest including neutrophils, platelets, hemoglobin, creatine kinase, 
AST, ALT, total bilirubin, triglycerides, and cholesterol.  
Absolute values over time will also be plotted for select laboratory tests of interest including 
neutrophils, platelets, hemoglobin, creatine kinase, AST, ALT, total bilirubin, triglycerides, and 
cholesterol. Listings of laboratory values will be generated and the results that are out of the 
reference range will be flagged. 
8.3.1 
Potential Drug-induced Liver Injury 
The liver function tests, namely alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), and total bilirubin (TBL) are used to assess possible drug -
induced liver injury (DILI). 






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APPENDIX A 
SCHEDULE OF ASSESSMENTS 
Procedure 
Screening  
Treatment Period (Weeks) 
ET 
Safety Follow-up 
(Weeks) 
 
1 
2 
4 
8 
12 
US 
14 
16/EOS 
Timing of Visit (Days) 
-28 to -1 
1 
8 
15 
29 
57 
84 
- 
- 
98 
115 
Visit Window (Days) 
28 to -1 
 
±1 
±1 
±3 
±3 
±3 
- 
- 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history  
X 
X 
 
 
 
 
 
 
X 
 
 
Pregnancy test (WOCBP only) B 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
FSH (postmenopausal women only) C 
X 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, HCV screening 
X 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB test D 
X 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistry  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Fasting lipid panel 
 
X 
 
 
 
X 
 
 
 
 
X 
Immunoglobulin levels (total) 
 
X E 
 
 
X 
X 
X 
 
 
 
X 
12-lead ECG 
X 
X E 
 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
DNA sample F 
 
X 
 
 
 
 
 
 
 
 
 


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Procedure 
Screening  
Treatment Period (Weeks) 
ET 
Safety Follow-up 
(Weeks) 
 
1 
2 
4 
8 
12 
US 
14 
16/EOS 
Timing of Visit (Days) 
-28 to -1 
1 
8 
15 
29 
57 
84 
- 
- 
98 
115 
Visit Window (Days) 
28 to -1 
 
±1 
±1 
±3 
±3 
±3 
- 
- 
±3 
±3 
Study drug administration at site G 
 
X 
 
 
X 
X 
X 
 
 
 
 
Study drug dispensing H 
 
X 
 
 
X 
X 
 
 
 
 
 
AE/con-med review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease activity skin assessments I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRO J 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
PD/biomarkers 
Skin biopsy and tape stripping F,K 
 
X 
 
 
 
 
X 
 
 
 
 
Plasma biomarker profile L 
 
X E  
 
X 
X 
X 
X 
 
X 
 
X 
Blood RNA-seq profile M 
 
X E 
 
X 
X 
X 
X 
 
X 
 
X 
Blood cell-based PD biomarkers N,O 
 
X 
 
 
X 
X 
 X 
 
 
X 
 
T/B/NK counts 
 
X E 
 
 
X 
X 
X 
 
 
 
X 
PK blood sampling P 
 
X 
 
 
X 
X 
X 
 
X Q 
X 
 
Footnotes 
EOS = end of study; ET = early termination; US = unscheduled visit  
A. Full physical examination at Screening and Day 1; abbreviated physical examination symptom driven at all other visits. 
B. Serum pregnancy test at Screening; urine pregnancy test at other indicated visits. 
C. Menopause is defined as absence of menses for 12 consecutive months. 
D. QuantiFERON TB tests should not be performed within 4 weeks of COVID-19 mRNA vaccinations or boosters.  If a patients test result is indeterminate it 
may be retested one time.  If both tests are indeterminate the patient will be considered a screen fail. 
E. Predose 
F. Optional, collected only if patient provides specific consent.  


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G. Administration of the visit day dose of study drug by the site staff. Patients should be reminded to bring their study drug with them to the clinic and take 
their dose when instructed by the site staff. Randomization occurs prior to first administration of study drug on Day 1. 
H. Dispense sufficient study drug to last until the next study visit 
I. 
Includes PASI, BSA and sPGA 
J. 
Patient reported outcomes (DLQI, EQ-5D and NRS) 
K. Lesional and nonlesional samples; predose on Day 1  
L. Biomarker panel, exploratory proteomics 
M. Exploratory transcriptomics 
N. To be conducted at selected study sites. Fresh blood needs to be collected and cell assays conducted on the day of collection. 
O. PD Samples for patients will be collected on Day 1 and Week 8 predose and 2 hours (±15 min) and 4 hours (±15 min) postdose. At Week 4 and 12 patients 
will take their dose in the clinic and a PD sample will be collected predose.  A random sample will be taken at Week 14. 
P. PK Samples for patients will be collected on Day 1 and Week 8 predose and 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±15 min) and 4 hours (±15 min) 
postdose in a fasted condition. Patients may have a snack between the 2- and 4-hour draw. At Week 4 and 12 patients will take their dose in the clinic and a 
PK sample will be collected predose.  A random sample will be taken at Week 14. 
Q. Collected if the ET visit is within 14 weeks of the initiation of study drug treatment. 
 


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APPENDIX B 
ANALYSIS VISITS 
The following analysis windows will be used to define the analysis visits for each study 
assessment type.  
Table 2 
Analysis Visits for Disease Activity Skin Assessments 
Analysis Visit 
Target Day 
Visit Window (Days) 
Baseline 
1 
Screening – Day 1 
Week 1 
8 
2 – 11 
Week 2 
15 
12 – 21 
Week 4 
29 
22 – 42 
Week 8 
57 
43 – 70 
Week 12 
85 
71 – 91 
Week 14 
99 
92 – 105 
Week 16 
113 
  105 – 126 
 
Table 3 
Analysis Visits for Patient Reported Outcomes 
Analysis Visit 
Target Day 
Visit Window (Days) 
Baseline 
1 
Screening – Day 1 
Week 2 
15 
2 – 21 
Week 4 
29 
22 – 42 
Week 8 
57 
43 – 70 
Week 12 
85 
71 – 98 
Week 16 
113 
  99 – 126 
 


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APPENDIX C 
PSORIASIS AREA AND SEVERITY INDEX (PASI) 
The PASI is a grading system used for the evaluation of the severity of psoriatic lesions and their  
response to treatment. The PASI produces a numeric score that can range from 0 to 72. The 
severity of a subject’s disease is calculated as described below: 
The body is divided into 4 regions for determining total body surface area (BSA):  
• the head (h), trunk (t), upper extremities (ux) and lower extremities (lx),  
• which account for 10% (0.1), 30% (0.3), 20% (0.2), and 40% (0.4) respectively of BSA  
 
Each of these areas are evaluated for erythema (E), induration (I) and scaling (S), which are rated 
on a scale from 0 to 4. 
The scoring system for the signs of disease (erythema, induration and scaling) is below: 
0 = none 
1 = slight 
2 = moderate 
3 = severe 
4 = very severe 
 
The scoring system for estimating the area (A) of involvement for psoriatic lesions is outlined 
below: 
0 = no involvement 
1 = 1% to 9% involvement 
2 = 10% to 29% involvement 
3 = 30% to 49% involvement 
4 = 50% to 69% involvement 
5 = 70% to 89% involvement 
6 = 90% to 100% involvement 
 
To aid in the area assessments, the following conventions are followed: 
a. the neck is considered part of the head 


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b. the axilla and groin are considered part of the trunk 
c. the buttocks are considered part of the lower extremities 
 
The PASI formula is: 
PASI = 0.1(Eh + Sh + Ih)Ah + 0.3(Et + St + It)At + 0.2(Eux + Sux + Iux)Aux + 0.4(Elx + Slx + Ilx)Alx 
Clinical assessments of response should be performed by the same assessor(s). 


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APPENDIX D 
STATIC PHYSICIAN’S GLOBAL ASSESSMENT (SPGA) 
The Physician Global Assessment (PGA) is used to determine the subject’s psoriasis lesions 
overall at a given time point. Overall lesions will be graded for induration, erythema, and scaling 
based on the scales below. The sum of the 3 scales will be divided by 3 to obtain a final PGA 
score. 
Induration (I) (averaged over all lesions; use the National Psoriasis Foundation Reference card 
for measurement) 
0 = no evidence of plaque elevation 
1 = minimal plaque elevation, = 0.25 mm  
2 = mild plaque elevation, = 0.5 mm 
3 = moderate plaque elevation, = 0.75 mm  
4 = marked plaque elevation, = 1 mm 
5 = severe plaque elevation, = 1.25 mm or more 
 
Erythema (E) (averaged over all lesions) 
0 = no evidence of erythema, hyperpigmentation may be present  
1 = faint erythema 
2 = light red coloration 
3 = moderate red coloration 4 = bright red coloration 
5 = dusky to deep red coloration 
 
Scaling (S) (averaged over all lesions) 
0 = no evidence of scaling 
1 = minimal; occasional fine scale over less than 5% of the lesion  
2 = mild; fine scale dominates 
3 = moderate; coarse scale predominates 
4 = marked; thick, nontenacious scale dominates 
5 = severe; very thick tenacious scale predominates 
 


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Add I + E + S / 3 = (Total Average) 
 
Physician’s Static Global Assessment based upon above Total Average 
0 = Cleared, except for residual discoloration 
1 = Minimal - majority of lesions have individual scores for I + E + S / 3 that averages 1 
2 = Mild - majority of lesions have individual scores for I + E + S / 3 that averages 2 
3 = Moderate - majority of lesions have individual scores for I + E + S / 3 that averages 3 
4 = Marked - majority of lesions have individual scores for I + E + S / 3 that averages 4  
5 = Severe - majority of lesions have individual scores for I + E + S / 3 that averages 5 
Note: Scores should be rounded to the nearest whole number. If total ≤ 1.49, score = 1; if total 
≥ 1.50, score = 2.