Clinical trial NCT05623345
Conditions: Psoriatic Arthritis
Keywords: psoriatic arthritis (PsA) psoriasis inflammatory arthritis enthesitis
Sponsor: ACELYRIN Inc.
Start date: 2022-11-21; Completion date: 2024-08-08
Enrollment: 351 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Izokibep is a potent and selective inhibitor of interleukin (IL)-17A that is being developed for treatment of psoriatic arthritis (PsA).

This study will evaluate the efficacy of izokibep in subjects with PsA.

Detailed description:

Arms: arm 1: Placebo from Day 1/Week 0 to Week 15, then izokibep from Week 16 to Week 51 arm 2: Izokibep Dose 1 from Day 1/Week 0 to Week 51 arm 3: Izokibep Dose 2 from Day 1/Week 0 to Week 51 arm 4: Izokibep Dose 3 from Day 1/Week 0 to Week 51
Interventions: intervention 1: Izokibep intervention 2: Placebo to izokibep
Intervention descriptions: intervention 1: Biologic: IL-17A inhibitor

Form: Solution for injection

Route of administration: Subcutaneous (SC) intervention 2: Form: Solution for injection

Route of administration: Subcutaneous (SC)

Protocol documents:
Prot_000.pdf: 
Protocol Number: 22104 
 
Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b/3 Study to 
Evaluate the Efficacy and Safety of Izokibep in Subjects with Active Psoriatic Arthritis 
 
NCT Number: NCT05623345 
 
Document Date: 29 May 2024 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 22104
Date: 07May2024Version 7.0
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Title Page 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b/3 Study to 
Evaluate the Efficacy and Safety of Izokibep in Subjects with Active Psoriatic Arthritis 
Protocol Number: 22104 
Protocol Version: 7.0 
Protocol Date: 07 May 2024 
Compound: Izokibep 
Brief Title: Psoriatic Arthritis Phase 2b/3 Study of Izokibep 
Study Phase: Phase 2b/3 
Sponsor Name: ACELYRIN, INC. 
Legal Registered Address: 
4149 Liberty Canyon Rd, Agoura Hills, CA 91301 
United States of America 
Regulatory Agency Identifier Number(s): 
EU trial number: 2022-501362-22-00 
Approval Date:  
Previous version 
Date 
3.0 
30 March 2023 (EU and Canada) 
5.0 
08 January 2024 (US) 




CONFIDENTIAL 
ACELYRIN Izokibep Protocol 22104
Date: 07May2024Version 7.0
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Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................3 
List of Tables ..................................................................................................................................7 
List of Figures .................................................................................................................................7 
1.
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................21 
1.3. 
Schedule of Activities .....................................................................................................22 
2.
Introduction ...................................................................................................................27 
2.1. 
Study Rationale ...............................................................................................................27 
2.2. 
Background .....................................................................................................................27 
2.2.1. 
Disease Background........................................................................................................27 
2.2.2. 
Interleukin-17 ..................................................................................................................28 
2.2.3. 
Izokibep Background ......................................................................................................29 
2.3. 
Benefit/Risk Assessment ................................................................................................32 
2.3.1. 
Risk Assessment .............................................................................................................32 
2.3.2. 
Benefit Assessment .........................................................................................................33 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................33 
2.3.4. 
COVID-19 Benefit/Risk Assessment .............................................................................34 
3.
Objectives, Endpoints and Estimands ........................................................................35 
4.
Study Design ..................................................................................................................46 
4.1. 
Overall Design ................................................................................................................46 
4.1.1. 
Independent Data Monitoring Committee ......................................................................47 
4.1.2. 
Number of Sites ..............................................................................................................47 
4.1.3. 
Number of Subjects.........................................................................................................47 
4.1.4. 
Study Duration for Subjects ............................................................................................47 
4.2. 
Scientific Rationale for Study Design ............................................................................48 
4.3. 
Justification for Dose ......................................................................................................48 
4.4. 
End of Study Definition ..................................................................................................50 
5.
Study Population ...........................................................................................................52 
5.1. 
Inclusion Criteria ............................................................................................................52 
5.2. 
Exclusion Criteria ...........................................................................................................54 
5.3. 
Lifestyle Considerations .................................................................................................58 
5.4. 
Screen Failures ................................................................................................................58 
5.5. 
Criteria for Temporarily Delaying Dosing .....................................................................58 
5.6. 
COVID-19-related Precautions.......................................................................................58 
6.
Study Drug(s) and Concomitant Therapy ..................................................................59 
6.1. 
Study Drug(s) Administered ...........................................................................................59 
6.1.1. 
Dosage, Administration, and Schedule: Izokibep and Placebo ......................................59 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................60 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................60 
6.3.1. 
Subject Enrollment..........................................................................................................60 
6.3.2. 
Rescreening .....................................................................................................................61 
6.3.3. 
Randomization ................................................................................................................62 
6.3.4. 
Site Personnel Access to Individual Treatment Assignments.........................................62 
6.4. 
Study drug Compliance ..................................................................................................63 
6.5. 
Dose Modification ..........................................................................................................63 
6.6. 
Continued Access to Study Drug After the End of the Study ........................................63 
6.7. 
Overdose .........................................................................................................................63 
6.8. 
Prior and Concomitant Therapy ......................................................................................63 
6.8.1. 
Prior Therapies ................................................................................................................64 
6.8.2. 
Concomitant Therapies ...................................................................................................64 
6.8.3. 
Prohibited Medications ...................................................................................................64 
6.8.4. 
7.
Discontinuation of Study drug and Subject Discontinuation/
Withdrawal ....................................................................................................................66 
7.1. 
Discontinuation of Study Drug .......................................................................................66 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................67 
7.1.2. 
Rechallenge .....................................................................................................................68 
7.2. 
Subject Discontinuation/Withdrawal from the Study .....................................................69 
7.3. 
Lost to Follow-up............................................................................................................69 
8.
Study Assessments and Procedures.............................................................................71 
8.1. 
Efficacy Assessments .....................................................................................................71 
8.1.1. 
Composite Measures .......................................................................................................72 
8.1.2. 
Patient-reported Outcomes ..............................................................................................74 
8.1.3. 
Investigator’s Assessments .............................................................................................76 
8.1.3.3. Psoriasis Area and Severity Index and Affected Body Surface Area .............................78 
8.2. 
Safety Assessments .........................................................................................................80 
8.2.1. 
Medical and Medication History ....................................................................................81 
8.2.2. 
Physical Examination......................................................................................................81 
8.2.3. 
Physical Measurements ...................................................................................................81 
8.2.4. 
Vital Signs .......................................................................................................................81 
8.2.5. 
Electrocardiograms .........................................................................................................81 
8.2.6. 
Chest X-ray .....................................................................................................................81 
8.2.7. 
Hospital Anxiety and Depression Scale ..........................................................................82 
8.2.8. 
Clinical Safety Laboratory Tests ....................................................................................82 
8.2.9. 
Pregnancy Testing ...........................................................................................................82 
8.2.10. Hepatitis Testing .............................................................................................................83 
8.2.11. Inflammatory Bowel Disease Screening......................................................................83 
8.2.12. Tuberculosis Test ............................................................................................................83 
8.2.13. Rheumatoid Factor and Anti-cyclic Citrullinated Peptide Antibodies ...........................84 
8.2.14. Home Study Drug Administration Diary ........................................................................84 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .........................84 


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8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .............................................................................................84 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...............................85 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................85 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................85 
8.3.5. 
Pregnancy ........................................................................................................................85 
8.3.6. 
Events of Special Interest................................................................................................86 
8.3.7. 
Overdose .........................................................................................................................87 
8.4. 
Pharmacokinetics ............................................................................................................87 
8.5. 
Genetics ..........................................................................................................................87 
8.6. 
Biomarkers ......................................................................................................................87 
8.7. 
Immunogenicity Assessments.........................................................................................88 
8.8. 
Health Economics ...........................................................................................................88 
9.
Statistical Considerations .............................................................................................89 
9.1. 
Statistical Hypotheses .....................................................................................................89 
9.1.1. 
Multiplicity Adjustment and Type I Error Rate ..............................................................89 
9.2. 
Analysis Sets ...................................................................................................................90 
9.3. 
Statistical Analyses .........................................................................................................91 
9.3.1. 
General Considerations ...................................................................................................91 
9.3.2. 
Primary Endpoint and Estimand .....................................................................................92 
9.3.3. 
Secondary Endpoints and Estimands ..............................................................................93 
9.3.4. 
Exploratory Endpoints ....................................................................................................94 
9.3.5. 
Safety Analyses ...............................................................................................................95 
9.4. 
Interim Analysis and Early Stopping Rules ....................................................................95 
9.5. 
Sample Size Determination ............................................................................................96 
10.
Supporting Documentation and Operational Considerations ..................................97 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .............................................97 
10.1.1. Regulatory and Ethical Considerations ...........................................................................97 
10.1.2. Financial Disclosure........................................................................................................97 
10.1.3. Informed Consent Process ..............................................................................................98 
10.1.4. Data Protection................................................................................................................98 
10.1.5. Dissemination of Clinical Study Data.............................................................................99 
10.1.6. Monitoring and Data Quality Assurance ........................................................................99 
10.1.7. Source Documents ........................................................................................................100 
10.1.8. Study and Site Start and Closure ..................................................................................101 
10.1.9. Publication Policy .........................................................................................................102 
10.2. 
Clinical Laboratory Tests..............................................................................................102 
10.3. 
Adverse Events and Serious Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting .................................................105 
10.3.1. Definition of Adverse Events........................................................................................105 
10.3.2. Definition of SAE .........................................................................................................106 
10.3.3. Recording and Follow-up of Adverse Event and/or Serious Adverse 
Event .............................................................................................................................107 
10.3.4. Reporting of SAEs ........................................................................................................110 


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10.4. 
Contraceptive and Barrier Guidance .............................................................................112 
10.4.1. Definitions.....................................................................................................................112 
10.4.2. Contraception Guidance................................................................................................113 
10.5. 
Liver Safety: Actions and Follow-up Assessments and Study drug 
Restart/Rechallenge Guidelines ....................................................................................115 
10.6. 
Abbreviations and Definitions ......................................................................................118 
11. 
References ....................................................................................................................121 
 
 
 


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List of Tables 
Table 1. Cmax and AUC0-τ at NOAEL in Cynomolgus Monkey Versus Predicted Exposure Levels 
in Man and Respective Margins ................................................................................................... 49 
Table 2. Predicted Exposure at Steady State for 160 mg Izokibep SC QW ................................. 49 
Table 3. Study Drug(s) Administered: Izokibep and Placebo ...................................................... 59 
Table 4. Tender and Swollen Joint Counts ................................................................................... 77 
Table 5. Entheseal sites assessed for enthesitis according to SPARCC and LEI ......................... 79 
Table 6. Protocol-required Safety Laboratory Tests ................................................................... 103 
 
List of Figures 
 
Figure 1. Observed and Simulated PK Profiles for 10 mg/kg IV Q2W×4 Secukinumab Versus 
Simulated Profiles for 160 mg Izokibep SC QW and Q2W ......................................................... 49 
Figure 2. Modeling and Simulation of PsA Endpoints by Dose ................................................... 41 
Figure 3. Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm ....... 67 
 






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Objectives 
Endpoints 
and to estimate the efficacy of each regimen 
after week 16, as measured by: 
• Proportion of subjects achieving 70% 
improvement in ACR core set 
measurements (ACR70) at Weeks 16, 
24, and 52 
• Change in DAS28-CRP at Weeks 16, 
24, and 52 as compared to baseline 
• Change in DAPSA score at Weeks 16, 
24, and 52 as compared to baseline 
• Change in clinical DAPSA (cDAPSA) 
score at Weeks 16, 24, and 52, as 
compared to baseline 
• Proportion of subjects achieving 
DAPSA and proportion of subjects 
achieving cDAPSA low disease activity 
or remission at Weeks 16, 24, and 52 
• Proportion of subjects achieving 
DAPSA and proportion of subjects 
achieving cDAPSA remission at Weeks 
16, 24, and 52 
• Change in PASDAS at Weeks 16, 24, 
and 52 as compared to baseline 
• Proportion of subjects achieving 75% or 
greater reduction in PASI score from 
baseline (PASI75) at Weeks 16, 24, and 
52 in subjects with ≥ 3% BSA psoriasis 
at baseline 
• Proportion of subjects achieving 
PASI90 at Weeks 24 and 52 in subjects 
with ≥3% BSA psoriasis at baseline  
• Proportion of subjects achieving 100% 
reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline  
 
 
 
• ACR70 at Weeks 16, 24, and 52 
 
• Change in DAS28-CRP at 
Weeks 16, 24, and 52 
• Change in DAPSA at Weeks 16, 24, 
and 52 
• Change in cDAPSA at Weeks 16, 
24, and 52 
• DAPSA/cDAPSA ≤ 14 at Weeks 16, 
24, and 52 
 
• DAPSA/cDAPSA ≤ 4 at Weeks 16, 
24, and 52        
• Change in PASDAS at Weeks 16, 
24, and 52      
                                        
• PASI75 at Weeks 16, 24, and 52 with 
≥3% BSA psoriasis at baseline 
 
• PASI90 at Weeks 24 and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline  
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline 
 


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Objectives 
Endpoints 
• Proportion of subjects achieving 75% or 
greater reduction in PASI score from 
baseline (PASI75) at Weeks 16, 24, and 
52 in subjects with ≥ 10% BSA 
psoriasis at baseline 
• Proportion of subjects achieving 
PASI90 at Weeks 16, 24 and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline  
• Proportion of subjects achieving 100% 
reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in 
subjects with ≥ 10% BSA psoriasis at 
baseline 
• Proportion of subjects achieving 
PASI90 at weeks 16, 24, and 52 in 
subjects with baseline PASI score >10  
• Proportion of subjects achieving 
PASI100 at weeks 16, 24, and 52 in 
subjects with baseline PASI score >10  
 
• Proportion of subjects achieving MDA 
at Weeks 24 and 52 
• 
Proportion of subjects achieving VLDA 
response at Weeks 16, 24, and 52 
• Proportion of subjects with resolution 
of dactylitis at Weeks 16, 24, and 52 in 
subpopulation that had dactylitis at 
baseline (pooled izokibep doses), as 
assessed with LDI 
• Change from baseline in mNAPSI at 
Weeks 16, 24, and 52 in subpopulation 
with nail psoriasis at baseline (pooled 
izokibep doses) 
• Progression of structural damage 
assessed radiographically and expressed 
as the change in mTSS at Weeks 16 and 
52, compared to baseline 
• PASI75 at Weeks 16, 24, and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline 
 
 
• PASI90 at Weeks 16, 24 and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline  
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline 
 
• 
PASI90 at Weeks 16, 24 and 52 in 
subjects with baseline PASI score 
≥10 
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with baseline PASI score 
≥10 
 
• MDA at Weeks 24 and 52 
• VLDA at Weeks 16, 24, and 52 
• Resolution of dactylitis at Weeks 16, 
24, and 52 in subjects with LDI >0 at 
baseline 
 
• Change in mNAPSI at Weeks 16, 24, 
and 52 in subjects with mNAPSI >0 
at baseline 
• Change in mTSS at Weeks 16 and 52 
 


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Objectives 
Endpoints 
•
Change in SPARCC enthesitis score at 
Weeks 16, 24, and 52, as compared to 
baseline in subpopulation with enthesitis 
(SPARCC > 0) at baseline
•
Change in spinal pain NRS at
Weeks 16, 24, and 52, as compared to 
baseline in subjects reporting spinal pain 
at baseline
•
Change from baseline in spine pain 
NRS in those with sacroiliitis on pelvic
x-ray at Weeks 16, 24 and 52
•
Change from baseline in spinal pain 
NRS in those with investigator assessed 
spinal involvement at Weeks 16, 24 and 
52
•
Association of investigator assessed 
sacroiliac involvement with sacroiliitis 
on x-ray at baseline
•
Proportion of subjects achieving each 
MDA component (TJC68, SJC66, PASI, 
BSA, SAPVAS, SGADA, HAQ-DI, 
tender entheseal points from LEI) at 
Weeks 16, 24 and 52
•
Change in quality of life as assessed by 
SF-36 total score, physical component 
summary (PCS), and mental component 
summary (MCS) change from baseline 
to Weeks 16, 24, and 52
•
Fatigue as assessed by FACIT-F change 
from baseline to Weeks 16, 24, and 52
•
Proportion of subjects achieving ACR50 
at Weeks 24 and 52
•
Proportion of subjects with resolution of 
enthesitis at Weeks 24 and 52 as
•
Change in SPARCC enthesitis score
at Weeks 16, 24, and 52
•
Change in spinal pain NRS at
Weeks 16, 24, and 52
•
Change from baseline in spine pain
NRS in those with sacroiliitis on
pelvic x-ray at Weeks 16, 24 and 52
•
Change from baseline in spinal pain
NRS in those with investigator
assessed spinal involvement at Weeks
16, 24 and 52
•
Clinical and radiographic sacroiliitis
•
Each MDA component (TJC68,
SJC66, 
PASI, 
BSA, 
SAPVAS,
SGADA, HAQ-DI, tender entheseal
points from LEI) at Weeks 16, 24 and
52
•
Change in SF-36 total score, PCS,
and MCS at Weeks 16, 24, and 52
•
Change in FACIT-F at Weeks 16, 24
and 52
•
ACR50 at Weeks 24 and 52
•
Resolution of enthesitis (LEI = 0) at
Weeks 24 and 52


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Objectives 
Endpoints 
assessed by LEI in subpopulation that 
had enthesitis (LEI >0) at baseline  
• Proportion of subjects achieving an 
improvement in PsAID of at least 3 
units at Weeks 24 and 52 compared to 
baseline in subjects with PsAID ≥3 at 
baseline  
• Proportion of subjects achieving 
ACR20 at Weeks 24 and 52 
• Mean (median) ACR-N at Week 16, 24, 
and 52, where ACR-N is defined as the 
largest number N such that ACR-N is 
met (analogous to the primary endpoint 
definition of ACR 50) 
• Change in enthesitis at Weeks 16, 24 
and 52 as assessed by change from 
baseline in LEI 
• Time to resolution of enthesitis at 
weeks 4, 12,  16, 24 and 52 among 
subjects with enthesitis (LEI > 0) at 
baseline 
• Occurrence of enthesitis (LEI > 0)  at 
weeks 4, 12,  16, 24 and 52 among 
subjects without enthesitis (LEI = 0) at 
baseline 
• Depression and anxiety as assessed by 
change in HADS score from baseline to 
Weeks 16 and 52 
• Change in physical function as assessed 
by HAQ-DI change from baseline to 
Weeks 24 and 52  
 
• Proportion of subjects with a decrease 
of at least 2 from baseline in LEI, 
among subjects with baseline LEI of at 
least 2, at weeks 4, 12  16, 24 and 52 
 
• PsAID response at Weeks 24 and 52 
 
 
• ACR20 at Weeks 24 and 52  
                                                      
• ACR-N at Weeks 16, 24 and 52 
 
 
• LEI change from baseline to Weeks 
16, 24 and 52 
 
• Time to resolution of enthesitis at 
weeks 4, 12  16, 24 and 52 among 
subjects with enthesitis (LEI > 0) at 
baseline 
• Occurrence of enthesitis (LEI > 0) at 
week 4, 12,  16, 24 and 52 among 
subjects without enthesitis (LEI = 0) 
at baseline 
• HADS change from baseline to 
Weeks 16 and 52 
• HAQ-DI change from baseline to 
Weeks 24 and 52 
 
 
• LEI decrease of at least 2 from 
baseline at Weeks 4, 12 16, 24 and 
52 
 


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Objectives 
Endpoints 
• Subject's Global Impression of Change 
Questionnaire at weeks 16 and 52 
• Mean (median) Area under the curve 
(AUC) for ACR-N through weeks 16, 
24 and 52 
• Change from baseline in LEI at Weeks 
16, 24 and 52 
• Time to first achievement of ACR50 
• Time to first achievement of PASI90 
among subjects with at least 3% BSA at 
baseline 
 
• Time to first achievement of MDA 
• Time to first achievement of ACR20 
• Time to first achievement of PsAID 
improvement of at least 3 among 
subjects with PsAID at least 3 at 
baseline 
• Time to first achievement of PASI100 
among subjects with at least 3% BSA at 
baseline 
 
 
To investigate whether 1 or both regimens of 
izokibep (160 mg QW and 160 mg Q2W) are 
efficacious compared to placebo up to Week 16 
and to estimate the efficacy of each regimen 
after week 16 in the subpopulation with 
enthesitis as baseline, as measured by: 
• Proportion of subjects achieving an 
improvement in PsAID of at least 3 
units at Weeks 16, 24 and 52 compared 
to baseline in subjects with PsAID ≥3 at 
baseline 
• Change from baseline in PsAID at 
Weeks 16, 24 and 52 
• Subject’s Global Impression of 
Change Questionnaire at Weeks 16 
and 52 
• AUC for ACR-N through week 16, 
24 and 52 
• LEI change from baseline to Weeks 
16, 24 and 52 
 
• Time to first achievement of ACR50 
• Time to first achievement of PASI90 
among subjects with at least 3% BSA 
at baseline 
• Time to first achievement of MDA 
• Time to first achievement of ACR20 
• Time to first achievement of PsAID 
improvement of at least 3 among 
subjects with PsAID at least 3 at 
baseline 
• Time to first achievement of 
PASI100 among subjects with at 
least 3% BSA at baseline  
 
 
 
 
 
• PsAID response at Weeks 16, 24 and 
52 
 
 
• PsAID change from baseline to 
Week 16, 24 and 52 


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Objectives 
Endpoints 
• Proportion of subjects with a HAQ-DI 
decrease of at least 0.35 at Weeks 16, 
24 and 52 compared to baseline in 
subjects with HAQ-DI >0.35 at baseline  
• Change in physical function as assessed 
by HAQ-DI change from baseline to 
Weeks 16, 24 and 52 
• Proportion of subjects achieving MDA 
at Weeks 16, 24 and 52 
• Change in DAPSA and cDAPSA at 
Weeks 16, 24 and 52 as compared to 
baseline 
• Proportion of subjects achieving VLDA 
at Weeks 16, 24 and 52 
• Change in quality of life as assessed by 
SF-36 total score, physical component 
summary (PCS), and mental component 
summary (MCS) change from baseline 
to Weeks 16, 24 and 52 
 
To investigate the durability of response 
after Weeks 16 in subjects on izokibep 
160mg QW and Q2W who achieved the 
primary and secondary endpoints at W16  
 
To investigate the incremental response 
after Week 16 in subjects in all treatment 
groups (izokibep 160mg QW, izokibep 
Q2W and placebo/izokibep cross-over) who 
did not achieve the primary and secondary 
endpoints at Week 16  
 
 
To investigate the relationship between ACR50 
response and other factors 
•  Association of baseline WPI positive 
WPI >=7 with ACR50 response  
• HAQ-DI response at Weeks 16, 24 
and 52 
 
 
• HAQ-DI change from baseline to 
Week 16, 24 and 52 
 
• MDA at Weeks 16, 24 and 52 
 
• DAPSA/cDAPSA change from 
baseline to Week 16, 24 and 52 
• VLDA at Weeks 16, 24 and 52 
 
• Change in SF-36 total score, PCS, 
and MCS at Weeks 16, 24 and 52 
 
ACR50, PASI 90, LEI, MDA, ACR20, and 
PsAID responses at Weeks 24 and 52 
 
 
ACR50, PASI 90, LEI, MDA, ACR20, and 
PsAID responses at Weeks 24 and 52 
 
 
 
 
 
• Baseline positive WPI >=7 and 
ACR50 response  
 


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Objectives 
Endpoints 
 
To investigate that the 80 mg Q4W regimen is 
efficacious compared to placebo, as measured 
by the same primary, secondary and 
exploratory endpoints 
To compare the three regimens of izokibep for 
assessment of dose-response relationships, as 
measured by the primary and secondary 
endpoints 
To evaluate the pharmacokinetics of izokibep 
in subjects with psoriatic arthritis 
To evaluate the immunogenicity of izokibep in 
subjects with PsA 
• Trough plasma concentrations of 
izokibep at collected timepoints 
• Presence of anti-drug antibodies 
(positive or negative) 
Abbreviations: ACR = American College of Rheumatology; ADAs = anti-drug antibodies; BSA = body surface 
area; cDAPSA =  Change in Clinical Disease Activity in Psoriatic Arthritis; CRP = C-reactive protein; 
DAPSA = Disease Activity in Psoriatic Arthritis; DAS28 = Disease Activity Score in 28 joints; FACIT-
F = Functional Assessment of Chronic Illness Therapy – Fatigue; HAQ-DI = Health Assessment Questionnaire – 
Disability Index; LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MCS=Mental Component Summary; 
MDA = Minimal Disease Activity; mNAPSI = modified Nail Psoriasis Severity Index; mTSS = modified total Sharp 
score; NRS = numeric rating scale; PASDAS = Psoriatic Disease Activity Score; PASI = Psoriasis Area and 
Severity Index; PCS=Physical Component Summary; PsAID = Psoriatic Arthritis Impact of Disease; SAE = serious 
adverse event; SF-36 = 36-Item Short Form Survey; SPARCC = Spondyloarthritis Research Consortium of Canada; 
TEAE = treatment-emergent adverse event; VLDA = very low disease activity. 
 
 
Overall Design: 
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2b/3 Study to 
evaluate the efficacy and safety of izokibep in subjects with active PsA who are TNFi naïve,  
who have had an inadequate response or intolerance to TNFi, or for whom TNFi is 
contraindicated. This study will be conducted at study sites in North America and Europe. 
 
Brief Summary: 
Approximately 325 subjects with active PsA will be enrolled. 
Subjects will be screened within 28 days of study drug administration. Subjects meeting 
eligibility criteria will be randomized 4:4:4:1 to 1 of 4 treatment groups on Day 1, and will 
receive via subcutaneous injection: 
• Group 1 (n = 100): placebo every week (QW) from Day 1/Week 0 to Week 15, then 
izokibep 160 mg QW from Week 16 to Week 51. 


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• Group 2 (n = 100): izokibep 160 mg QW from Day 1/Week 0 to Week 51. 
• Group 3 (n = 100): izokibep 160 mg every 2 weeks (Q2W) from Day 1/Week 0 to 
Week 50, with matching placebo Q2W until Week 51 for the weeks in between izokibep 
doses to maintain the blind. 
• Group 4 (n = 25): izokibep 80 mg every 4 weeks (Q4W) from Day 1/Week 0 to Week 48, 
with matching placebo QW until Week 51 for the weeks in between izokibep doses to 
maintain the blind. 
 
Randomization will be stratified by prior TNFi use (Yes/No) and enthesitis (Leeds Enthesitis 
Index [LEI] > 0/LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 
20% to 30%. The number of subjects without enthesitis entering into the study (LEI = 0 at 
baseline) will be capped at 70%. 
Subjects will complete study assessments according to the study visits outlined in the Schedule 
of Activities below. The primary endpoint will be assessed at Week 16. The last dose of study 
drug will be administered on Week 51. 
Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low 
disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 and Week 24) will be 
discontinued from study drug and can receive SOC as deemed appropriate by the investigator.  
An End of Treatment (EOT) visit will be conducted at Week 52. A Safety Follow-up visit will be 
conducted at Week 59. A pharmacokinetic/anti-drug antibody (PK/ADA) Follow-up and End of 
Study Visit will be conducted at Week 65. For subjects that prematurely discontinue study drug 
for any reason, the EOT visit should be completed within 14 days of withdrawal. Safety 
follow-up visit should be completed at 8 weeks and PK/ADA follow-up visit should be 
completed 14 weeks after the last dose of study drug, respectively, where possible. Subjects 
should continue to complete study assessments as outlined in the SoA (Section 1.3) where 
possible, with the exception of study drug administration and anti-drug antibody sample and PK 
sample collection. 
The final analysis of primary and secondary endpoints will be conducted after the last subject has 
had the opportunity to complete Week 16 assessments or prematurely discontinues the study 
drug and/or  study. 
Number of Subjects: 
Approximately 325 subjects will be enrolled into this study. 
Intervention Groups and Duration: 
• Group 1 (n = 100): placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg 
QW from Week 16 to Week 51. 
• Group 2 (n = 100): izokibep 160 mg QW from Day 1/Week 0 to Week 51. 


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• Group 3 (n = 100): izokibep 160 mg Q2W from Day 1/Week 0 to Week 50, with 
matching placebo Q2W until Week 51 for the weeks in between izokibep doses to 
maintain the blind. 
• Group 4 (n = 25): izokibep 80 mg Q4W from Day 1/Week 0 to Week 48, with matching 
placebo QW until Week 51 for the weeks in between izokibep doses to maintain the 
blind. 
 
Izokibep and matching placebo (collectively referred to as study drug) will be visually 
indistinguishable to prevent unblinding during preparation or administration of study material. 
Study drug doses are fixed and will not be adjusted for individual subjects during the study. 
 
Eligibility Criteria: 
Refer to Section 5 in Protocol. 
Data Monitoring/ Other Committee: 
An independent data monitoring committee (DMC) will be established to monitor data on an 
ongoing basis to ensure the continuing safety of the subjects enrolled in this study and to make 
recommendations on further development activities for izokibep. 
The DMC will consist of at least 1 medical expert with expertise in the relevant therapeutic area 
and at least 1 statistician and will have a minimum of 3 members, 1 of whom will serve as the 
Chair. The DMC responsibilities, members (including their qualifications and possible conflicts 
of interest), authorities, meeting frequency to review unblinded interim data, and procedures will 
be documented in the DMC charter. The committee will meet as needed to review significant 
safety findings.. After each review, the DMC will make recommendations regarding the 
continuation of the study based on safety. The DMC will review unblinded efficacy data when 
approximately 120 subjects have had the opportunity to complete the Week 12 visit.  Data from 
the first 105 subjects randomly assigned to receive izokibep 160 mg QW, izokibep 160 mg Q2W 
or placebo will be used for these DMC summaries.  The DMC may make a recommendation on 
further development activities for izokibep based on this data review. The DMC will not be 
empowered to recommend stopping this study or changing the sample size due to a 
demonstration of positive efficacy. The study team operationalizing the day-to-day of the study, 
the subjects, and the investigators will remain blinded to these interim results until after the study 
is completed.  
Statistical Considerations: 
Summaries of continuous variables will include mean, median, standard deviation, minimum, 
and maximum; change from baseline will additionally include standard error. Summaries of 
dichotomous, categorical, and ordinal variables will include counts and percentages. 
Baseline characteristics and demographics will be summarized by randomized treatment group 
using the last value obtained before randomization. Efficacy and safety data will be summarized 


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by randomized treatment group during the first 16 weeks of treatment; these data will also be 
summarized by randomized treatment group over 52 weeks for subjects randomized to receive a 
dose of izokibep during the first 16 weeks, and separately over the last 36 weeks for subjects 
randomized to receive placebo during the first 16 weeks. Efficacy variables (primary, secondary, 
and exploratory) will be summarized at each planned collection timepoint. Incidence of 
treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs; percent of 
subjects reporting each TEAE and each SAE) will be summarized. Anti-drug antibodies will be 
summarized at each planned collection timepoint.                                                                                                  
Comparisons of efficacy between doses will test each dose group of izokibep versus placebo in a 
single analysis. Response rates will be compared with a stratified test for differences: the strata 
used for randomization (prior TNFi use and enthesitis), using Cochran-Mantel-Haenszel weights. 
P-values for each pairwise comparison of a dose of izokibep versus placebo will be reported, 
with a 2-sided 95% confidence interval on the difference in response rates. Continuous endpoints 
will be analyzed with a longitudinal model using values at each post-randomization timepoint. 
The primary efficacy comparison will be of American College of Rheumatology 50% (ACR50) 
response rates at Week 16. The statistical comparisons for the primary efficacy endpoint and the 
secondary endpoints, all at Week 16, will be carried out in sequential order. The primary 
endpoint, comparing izokibep dosed QW to placebo, will be tested first, with significance 
concluded if p < 0.05. Testing of secondary endpoints, comparing izokibep dosed QW to 
placebo, will only be carried out if all prior tests, including the tests of the primary endpoint, first 
show significance with p < 0.05. If all primary and secondary endpoints, comparing izokibep 
doses QW to placebo, are significant, testing of izokibep doses Q2W to placebo will begin and 
follow the same order. As long as all prior tests showed statistically significant differences 
compared to placebo, testing will proceed using α = 0.05. If any comparison (primary or 
secondary) results in p > 0.05, p-values for subsequent comparisons will be reported but not 
considered conclusive. 
Exploratory endpoints will be compared analogously, with the exception of a prespecified 
alpha-controlling testing strategy. P-values for exploratory endpoints will be considered 
descriptive and not considered conclusive. 
The primary efficacy analyses will use the treatment policy estimands, using all available data 
from all randomized subjects regardless of treatment compliance. Subjects will be analyzed in 
the group to which they are randomized. Subjects who do not have an evaluation for a 
dichotomous endpoint at a given timepoint will be imputed as nonresponders. Subjects who do 
not have a continuous measure at a given timepoint will have available data at other timepoints 
included in the longitudinal model, resulting in an analysis that is robust to data that are missing 
at random or missing completely at random. Sensitivity and supplementary analyses will be used 
to assess the impact of missing data assumptions. 
Incidence of TEAEs over the first 16 weeks will be summarized by randomized treatment group. 
No p-values will be reported. Incidence will also be summarized over all 52 weeks for subjects 
randomized to receive izokibep, and summarized over the last 36 weeks for subjects randomized 
to receive placebo for the first 16 weeks. Serious adverse events will be summarized 
analogously. Subjects will be summarized for safety according to treatment actually received. 


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Available PK data will be summarized by dose group of izokibep. 
Incidence of ADAs at any time will be summarized by treatment group and overall. 
At Week 16 response rates for ACR50 are expected to be 20% for placebo and 45% for a dose 
regimen of 160 mg izokibep (QW or Q2W or both). With 100 subjects receiving placebo and 
100 subjects receiving a dose regimen of izokibep, there will be 97% power to show a difference 
in the primary endpoint of ACR50 response rate. If a 45% response rate is observed with a dose 
regimen of izokibep, the 2-sided 95% confidence interval for the true response rate will have a 
half-width of approximately 10 percentage points. 
Up to 60% of subjects are expected to have enthesitis at baseline, based on the LEI. Response 
rates, proportion of subjects who have LEI = 0 at Week 16, are expected to be 25% for placebo 
and 60% for subjects receiving izokibep, with on treatment groups combined. With 50 subjects 
with enthesitis at baseline receiving placebo and 50 subjects receiving a dose regimen of 
izokibep, there will be 95% power to show a difference in the secondary endpoint of resolution 
of enthesitis. 


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1.2. 
Schema 
 
 
 
 
 
 
 
 
Abbreviations: EOS = End of Study; EOT = End of Treatment; Q2W = every 2 weeks; QW = every week; TNFi = tumor necrosis factor-alpha inhibitor; 
LEI = Leeds Enthesitis Index 
a Randomization will be stratified by prior TNFi use (Yes/No) and enthesitis (LEI > 0/LEI = 0). Anticipated enrollment of subjects previously treated with TNFi 
is 20% to 30%.  The number of subjects without enthesitis entering into the study (LEI = 0 at baseline) will be capped at 70%. 
b Subjects in Group 1 (placebo QW) will receive placebo weekly until Week 15, then izokibep weekly until Week 51. Subjects in Group 2 (izokibep QW) will 
receive izokibep weekly. Subjects in Group 3 (izokibep Q2W) will receive izokibep every other week, with matching placebo in between izokibep doses to 


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maintain the blind. Subjects in Group 4 (izokibep Q4W) will receive izokibep every 4 weeks, with matching placebo between izokibep doses to maintain the 
blind.  
c Two follow-up visits will be completed by all subjects at Weeks 59 and 65. For subjects that early terminate the follow-up visits should be completed at 8 weeks 
and 14 weeks after the last dose of study drug. 
d  
 Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at 
Week 20 and Week 24) will be discontinued from study drug.  
 
 
 
1.3. 
Schedule of Activities 
 
Procedure 
 
 
Screening  
(≤ 28 
days 
before 
Day 1) 
Day 1 
/ W0 
 
Study Week (± 3 days) a 
EOT b  
(±3 
days) 
Safety 
FU b 
(±5 
days) 
PK &ADA 
FU/ End of 
Study b 
(±5 days) 
1 
2 
3 
4 
8 
12 
16 c 
17 18 
20 
c 
24 
c  
32 
c 
36  
40 
52 b 
59 
65 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and nicotine use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG e 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Chest x-ray f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








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All subjects who do not achieve cDAPSA low disease activity (cDAPSA <14) for 2 consecutive visits starting at Week 24 (e.g. at Week 20 and Week 24) will be 
required to discontinue study drug as described in Section 7.1. Participation in the study should be continued, with EOT visit and assessments as described in 
Section 4.1 and in footnote b and n.  
d Vital signs include measurements of temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. Measurements should be taken in a sitting 
position after 5 minutes’ rest. 
e Electrocardiograms in triplicate will be recorded (one minute apart) after subject has been supine for at least 5 minutes. 
fChest x-ray (posterior/anterior or anterior/posterior) will be performed at screening in subjects who do not have a chest x-ray available within 3 months of 
screening. Women of childbearing potential must have a negative pregnancy test before an x-ray is performed. 
gSerious adverse events should be recorded from the signing of informed consent through the Safety Follow-up visit (ie, 8 weeks after the last dose of study 
drug); adverse events will be recorded from Day 1 (ie, administration of study drug) until 4 weeks after the last dose of study drug. 
h Joint assessment will be performed for ACR66/68 and DAS28 joints for swollen and tender joint counts. 
i Radiographs of hands/wrists/feet will be done on all subjects who discontinue from the study drug or the study at Week 16 or later and it has been at least 12 
weeks from the time the last radiographs were obtained.  Radiographs should be obtained as close as possible to the EOT date.  
jHepatitis B surface antigen will be conducted. A positive result for the HBsAg will be exclusionary. Samples negative for HBsAg will be tested for HBsAb and 
HBcAb. If test results are positive for HBcAb or HBsAb, then HBV DNA polymerase chain reaction will be performed and any result that meets or exceeds 
detection sensitivity will be exclusionary. 
k QuantiFERON test (or equivalent) for TB will be performed. Note: T-SPOT testing may be allowed after consultation with medical monitor. 
l Serum pregnancy test required for screening and urine pregnancy test required at all other times for WOCBP. Local authorities may require more frequent 
pregnancy testing. 
m Fecal calprotectin at screening only required if subject has: a) Prolonged or recurrent diarrhea b) Prolonged or recurrent abdominal pain  c) blood in stool or d) 
any other symptoms in the opinion of the Investigator that may be suggestive of IBD 
n Pharmacokinetic and anti-drug antibody blood sampling will be taken prior to administration of study drug (predose) on dosing days. For subjects who 
prematurely discontinue study treatment for any reason, follow-up sampling should be taken at a PK & ADA FU visit 14 weeks after the last dose of study drug 
where possible, but do not need to be completed at other timepoints.  
o Subjects will be monitored at the study site for at least 1 hour after study drug administrations for the following visits: Day 1/Week 0, Week 1, Week 2, 
Week 16, Week 17, and Week 18. 
p After Week 4, subjects may perform home dosing of study drug at weeks without study visits (see footnote “a”) and do not need to return to the clinical site on 
those weeks. Subjects may begin self-administration of study drug from Week 5. Subjects will be trained on study drug handling and self-administration of study 
drug at the study visits prior to beginning self-administration. Subject’s caregiver or designee can also be trained on home dosing based on subject’s preference. 
q Last dose of study drug will be administered on Week 51. 
rA dosing diary will be completed for every home dosing administration.


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2. 
Introduction 
Izokibep has been investigated in nonclinical and clinical studies including healthy subjects, and 
subjects with psoriasis and psoriatic arthritis (PsA). The clinical development plan also includes 
axial spondyloarthritis, uveitis, and hidradenitis suppurativa. 
2.1. 
Study Rationale 
Izokibep is a small protein molecule that acts as a selective, potent inhibitor of 
interleukin (IL)-17A, to which it binds with high affinity. Izokibep has been investigated in 
nonclinical and clinical studies including healthy subjects, and subjects with psoriasis and PsA. 
The clinical development plan also includes axial spondyloarthritis, uveitis, and hidradenitis 
suppurativa. The study investigates izokibep in subjects with active PsA, including tumor 
necrosis factor-alpha (TNF) inhibitor (TNFi) naïve subjects, and those who had an inadequate 
response or intolerance to TNFi, or for whom TNFi is contraindicated. The study is intended to 
be 1 of 2 adequate and well-controlled studies to support a claim of efficacy of izokibep in 
subjects with PsA. 
2.2. 
Background 
2.2.1. 
Disease Background 
Psoriasis and PsA are types of psoriatic disease. Psoriasis is a chronic relapsing/remitting, 
immune-mediated systemic disease characterized by skin lesions including red scaly plaques, 
resulting from an abnormally excessive and rapid growth of the epidermal layer of the skin. The 
most common form is plaque psoriasis, and other disease types include pustular, guttate, and 
erythrodermic psoriasis (Merola et al, 2016; Raharja et al, 2021). 
Psoriatic arthritis is a chronic, immune-mediated, inflammatory musculoskeletal disease 
associated with psoriasis, manifesting most commonly with peripheral arthritis, dactylitis, 
enthesitis, and spondylitis (Singh et al, 2019; Veale and Fearon, 2018). Nail lesions, including 
pitting and onycholysis, occur in about 80% to 90% of patients with PsA (Sobolewski et al, 
2017; Colunga-Pedraza et al, 2021). 
The incidence of PsA in the general population ranges from 3.6 to 7.2 per 100,000 person years. 
Prevalence estimates in the US range from 0.06% to 0.25%, and in Europe range from 0.05% 
(Turkey, Czech Republic) to 0.21% (Sweden; Ogdie and Weiss, 2015). The annual incidence of 
PsA in patients with psoriasis is 2.7% (Singh et al, 2019; Ritchlin et al, 2017), and the reported 
prevalence of PsA among patients with psoriasis varies between 6% and 41% (Singh et al, 2019; 
Gladman et al, 2005; Ogdie and Weiss, 2015). In the majority of patients, the skin symptoms 
develop first, followed by the arthritis; however, in some patients the skin and joint symptoms 
appear at the same time, and in 10% to 15% the arthritis presents first (Singh et al, 2019; Ritchlin 
et al, 2017). The common scenario is that psoriasis has its onset approximately 10 years before 
PsA (Gladman et al, 2005). 
Psoriatic arthritis affects men and women equally (Gladman et al, 1998) and can start at any age. 
It occurs most often in adults between the ages of 45 and 55 (American College of 
Rheumatology, 2019; Augustin and Radtke, 2017). Psoriatic arthritis is associated with an 


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adverse impact on health-related quality of life (Adams et al, 2010; American College of 
Rheumatology, 2019; Husted et al, 2001; Singh and Strand, 2009a) and high health care costs 
and utilization (American College of Rheumatology, 2019; Javitz et al, 2002; Singh and Strand, 
2009b). 
Psoriatic arthritis-specific clinical features include the common involvement of distal joints. The 
condition is also associated with periosteal reaction, enthesitis (observed in 30% to 50% of 
patients [Kehl et al, 2016]), dactylitis (reported in 40% to 50% of patients [Gladman et al, 
2013]), and spinal involvement (Gladman et al, 2005). Most frequent extra-articular 
manifestations of PsA found in 26% to 33% of the patients are inflammatory bowel 
disease (IBD; eg, Crohn’s disease, ulcerative colitis), cardiovascular (eg, aortic insufficiency, 
conduction disturbances, major cardiac events), ocular (uveitis and conjunctivitis), and 
urogenital (eg, urethritis, prostatitis, vaginitis; Peluso et al, 2015). 
Greater disease activity is associated with progressive joint damage and higher mortality 
(American College of Rheumatology, 2019; Bond et al, 2007; Cresswell et al, 2011; Gladman et 
al, 1998; Gladman, 2008), being early identification of PsA and early initiation of therapy 
important for improving long-term outcomes (Gladman, 2012). 
The “treat to target” is disease remission or at least minimal disease activity (MDA) in order to 
maximize clinical improvement and minimize long-term damage (Mease, 2011). The quality of 
life and comorbidities of the patients must be taken into account when selecting the therapy. 
Depending on the predominant involvement (peripheral, axial, dactylitis, enthesitis, skin, nails) 
the therapy is different (Augustin and Radtke, 2017). There is currently a wide variety of 
pharmacologic therapies for PsA including symptomatic treatments such as nonsteroidal 
anti-inflammatory drugs (NSAIDs) and intra-articular (IA) injections, as well as 
immunomodulatory therapies (American College of Rheumatology, 2019). 
2.2.2. 
Interleukin-17 
Interleukin-17A, which is produced by T-helper (Th)17 and other immune cells, is one of the 
major proinflammatory cytokines that contributes to the pathogenesis of several inflammatory 
disorders (Miossec and Kolls, 2012). Dysfunction of the Th17/IL-17 axis is a source of 
inflammation in the pathogenesis of psoriasis and PsA, and IL-17A is considered to be involved 
as a key driver cytokine (Gooderham et al, 2015; Raychaudhuri et al, 2015). 
Interleukin-17A inhibiting agents have demonstrated to be efficacious in the treatment of PsA. 
The clinical development program for secukinumab in PsA included patients with active disease 
despite current or previous NSAIDs, conventional-synthetic disease-modifying anti-rheumatic 
drugs (csDMARDs), and/or previous anti-TNF therapy (biological disease-modifying 
antirheumatic drug [DMARD]). In 2 pivotal secukinumab studies in 1003 patients with PsA 
(FUTURE-1 and FUTURE-2), approximately 50% of patients on 150 mg or 300 mg 
secukinumab (the approved doses) achieved ≥ 20% improvement from baseline in tender and 
swollen joint counts (and American College of Rheumatology [ACR] 20% [ACR20] response 
score) after 24 weeks. This was in comparison to approximately 15% ACR20 responders in 
patients on placebo. Sustained inhibition of radiographic progression and improved quality of 
life measures were also achieved (Patel et al, 2017). Ixekizumab has been shown to be similarly 


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effective in treating PsA in pivotal studies. In SPIRIT-P1 (biologic-naïve patients), 62.1%, 
57.9%, and 30.2% of patients treated with ixekizumab 80 mg every 2 weeks (Q2W), 
every 4 weeks (Q4W), or placebo achieved ACR20 response, respectively. In SPIRIT-P2 
(patients who failed anti-TNF therapy), 48.0%, 53.3%, and 19.5% of patients treated with 
ixekizumab 80 mg Q2W, Q4W, or placebo achieved ACR20 response, respectively (Canadian 
Agency for Drugs and Technologies in Health 2018). 
2.2.3. 
Izokibep Background 
Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency 
corresponding to clinically tested monoclonal antibodies in terms of blocking the biological 
activity of IL-17A. Izokibep has the potential to be an efficacious treatment for a variety of 
IL-17A-related diseases. The smaller size of izokibep compared to monoclonal antibodies offers 
advantages in terms of required dosing volumes and potential for alternative pharmacological 
formulations. 
Izokibep is based on a small protein binding to and blocking the biological effect of the cytokine 
IL-17A. The izokibep protein molecule also contains an albumin-binding domain that confers 
specific binding to a single site on endogenous serum albumin and thereby prolonging 
half-life (t½) in the circulation and in tissues after parenteral administration. 
IL-17 inhibitors have already demonstrated efficacy and a favorable safety profile in different 
inflammatory diseases, including psoriasis, PsA, and axial spondyloarthritis. These include 
secukinumab (Cosentyx) and ixekizumab (Taltz) in the US, Canada, and the European Union. 
Doses up to 160 mg Q2W have been tested and were well tolerated. A detailed description of the 
chemistry, pharmacology, pharmacokinetics (PK), efficacy, and safety of izokibep is provided in 
the Investigator’s Brochure. 
2.2.3.1. 
Nonclinical Studies 
Assessments of target-binding specificity have demonstrated high specificity and affinity of 
izokibep to IL-17A and to albumin. The in vitro and in vivo pharmacodynamic evaluations show 
that izokibep has a 3-to 5-fold higher potency than the anti-IL-17A monoclonal antibody 
secukinumab on a molar basis and appears to be approximately equipotent to ixekizumab on a 
molar basis. 
Pharmacokinetic data for intravenous (IV)- and subcutaneous (SC)-administered izokibep have 
been obtained in rat and monkey. Pharmacokinetic assessments in rat and monkey indicate that 
the time course of izokibep concentrations after a bolus IV injection and SC injection is well 
described by a 2- or 3-compartment model. Pharmacokinetic assessments indicate that the 
elimination rate of izokibep is similar to that of albumin in the respective species. 
Repeated (10 days to 3 months) SC or IV administration of izokibep to cynomolgus monkeys 
was well tolerated, with no observed adverse effect levels (NOAELs) of 40 mg/kg/dose 
administered every third day (IV, 28-day study), 20 mg/dose administered every third day (SC, 
28-day study), and 20 mg/kg/week (SC, 3-month study), being the highest dose levels tested in 
the respective studies. 


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In the 26-week repeated dose toxicity study in cynomolgus monkeys, weekly SC injection of 10, 
20, or 40 mg/kg/week izokibep to monkeys for 26 weeks was generally well tolerated. However, 
due to the presence of local abscessation and systemic sequelae in 1 female administered 
40 mg/kg/week, which was considered adverse, the NOAEL for SC administration is considered 
to be 20 mg/kg/week. 
In the enhanced pre and postnatal developmental toxicity study in cynomolgus monkeys, SC 
izokibep administration of up to 40 mg/kg/week to pregnant monkeys for approximately 
21 weeks was well tolerated. The NOAEL was 40 mg/kg/week. 
The results from the immunotoxicity screening assays do not suggest that izokibep has an 
intrinsic capacity for immune system activation. 
Metabolism and genotoxicity have not been investigated, since izokibep is a protein molecule 
and contains only naturally occurring amino acids. 
For additional information please refer to the Investigator’s Brochure. 
2.2.3.2. 
Clinical Overview 
A first-in-human multipart clinical study (Study ABY-035-001, EudraCT number 
2015-004531-13, NCT02690142) has been conducted with the parenteral formulation of 
izokibep. Izokibep was administered IV and SC to healthy subjects and plaque psoriasis patients, 
in doses ranging from 2 mg to 40 mg in a single- or multiple-dose regimen. 
A Phase 2 dose-finding study in subjects with moderate to severe plaque psoriasis was recently 
completed with up to 3 years of exposure (Study ABY-035-002, EudraCT number 
2017-001615-36, NCT03591887). One hundred eight subjects were randomized into 5 dose 
groups: 2 mg, 20 mg, 80 mg, and 160 mg izokibep or placebo. The treatment period consisted of 
an induction period (12 weeks), an optimization period (12 weeks), and an individualization 
period including 4 weeks follow-up (28 weeks), and 2 further years of extension. The induction 
period was double blind and placebo controlled. 
The primary endpoint of the study was the proportion of patients that achieved a Psoriasis Area 
and Severity Index (PASI) response of 90% (PASI90) after 12 weeks of treatment. The PASI90 
at 12 weeks was 71.4% and 59.1% in subjects treated with 80 mg and 160 mg Q2W of izokibep, 
respectively. In the lower dose groups, 2 mg and 20 mg izokibep, only 5.0% and 19.0% of 
subjects, respectively, reached the primary endpoint. None of the subjects receiving placebo 
reached PASI90 response at Week 12. At Week 24, PASI90 responses were comparable between 
the initial 80 mg and 160 mg treatment groups. The safety and efficacy data obtained from the 
52-week core period of the study with izokibep suggest a favorable benefit-risk profile in plaque 
psoriasis (Investigator’s Brochure). 
A Phase 2 clinical trial in subjects with active PsA has recently been completed 
(Study ABY-035-202). Study ABY-035-202 is a dose-finding trial of 40 mg or 80 mg izokibep 
or placebo SC Q2W. The primary endpoint is the ACR 50% (ACR50) response at Week 16; 
further key secondary endpoints comprise other ACR responses, PASI scores, enthesitis 
endpoints, proportion of subjects achieving MDA, adverse events (AEs; safety), and izokibep 
blood levels (PK), and ADA assessments. 


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The primary endpoint of ACR50 at 16 weeks was met with 52% response rate in subjects 
receiving 80 mg Q2W of izokibep versus 13% for placebo (p-value = 0.0006). Subjects receiving 
40 mg Q2W had an ACR50 response rate of 48%. The PASI response of 75%, in subjects with a 
minimum psoriasis body surface area (BSA) ≥ 3% at baseline, at 16 weeks was 85% and 83% in 
subjects treated with 80 mg and 40 mg Q2W, respectively versus 14% for those receiving 
placebo. In subjects with enthesitis at baseline utilizing the Leeds Enthesitis Index (LEI), 
resolution of enthesitis was achieved by 88% of subjects receiving 80 mg Q2W, 63% of subjects 
receiving 40 mg Q2W of izokibep and 10% receiving placebo. 
2.2.3.3. 
Safety Overview 
In the first-in-human study in healthy subjects and subjects with psoriasis (Study ABY-035-001), 
doses of up to 40 mg IV and SC of izokibep (n = 62) were well tolerated, with no deaths or 
treatment-related serious AEs (SAEs). 
Intravenous administration (single doses up to 40 mg in 46 subjects in total) resulted in the 
following treatment-emergent AEs (TEAEs) by preferred term: oropharyngeal pain (10.9%), 
nasopharyngitis (6.5%), diarrhea (4.3%), and headache (4.3%). A further 9 TEAEs were 
reported, which affected 1 subject each (2.2% each). Subcutaneous administration (single and 
multiple doses up to 40 mg in 21 subjects in total) resulted in the following TEAEs by preferred 
term: injection site reaction (61.9%) and injection site pain (28.6%). A further 11 TEAEs were 
reported, which affected 1 subject each (5.2% each). The majority of the injection site reactions 
were of mild intensity and required no treatment or limited therapy. 
In the Phase 2, 52-week core period in subjects with plaque psoriasis (ABY-035-002), multiple 
doses of up to 160 mg Q2W SC of izokibep (n = 108) were well tolerated with no deaths or 
treatment-related SAEs. A total of 65 subjects (60.2%) experienced at least 1 izokibep-related 
TEAE. The most common izokibep-related TEAEs (n/%) were injection site reaction 
(42/38.9%), nasopharyngitis (13/12.0%), diarrhea (7/6.5%) and fatigue (6/5.6%) consistent with 
the first-in-human study. 
In the Phase 2, randomized, double-blind, placebo-controlled clinical trial in subjects with active 
PsA (ABY-035-202), doses of 40 mg and 80 mg Q2W were well tolerated. Safety evaluation 
showed no serious or severe AEs up to Week 16. Treatment-emergent AE rate overall was 
52.3% for placebo, 65.9% for 40 mg Q2W and 55.3% for 80 mg Q2W. The most common AEs 
(≥ 5% in either arm with active treatment) were injection site reaction or erythema, headache, 
hyperkalemia, and upper respiratory tract infection. Three patients had AEs of special interest: 2 
subjects experienced injection site reaction and 1 subject experienced vulvovaginal candidiasis. 
For more details on the safety and tolerability of izokibep, refer to the Investigator’s Brochure. 
2.2.3.4. 
Pharmacokinetics 
Following SC administration of single izokibep doses in the first–in-human study 
(Study ABY-035-001), median time to maximum observed concentration (tmax) was 60 hours 
postdose. After reaching maximum observed plasma concentration (Cmax), plasma levels of 
izokibep declined in an apparent mono or biphasic manner with the geometric mean t½ being 
278 hours which was similar to that after IV administration (288 hours). Individual t½ estimates 


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ranged from 199 to 464 hours and 220 to 340 hours for SC and IV treatments, respectively. The 
absolute SC bioavailability after a 40-mg dose of izokibep was estimated to 77%. In general, as 
assessed by the geometric percent coefficient of variation (CV%) low between-subject variability 
was noted for area under the concentration-time curve (AUC) extrapolated to infinity (AUC0-∞) 
and Cmax for both dose routes, with values ranging from 20% to 22% and 14% to 15%, 
respectively. 
Following 40 mg repeated SC doses, maximum plasma concentrations occurred at a median tmax 
of 48.0 hours postdose on Days 1 and 29 (individual range: 24.0 to 71.0 hours postdose). On 
Day 85, median tmax was slightly later at 71.6 hours postdose (individual range: 66.6 
to 73.1 hours postdose). After reaching Cmax on Day 85, plasma concentrations of izokibep 
declined in an apparent mono or biphasic manner with a geometric mean t½ of 279 hours with 
individual patients ranging from 229 to 423 hours. Predose trough izokibep plasma 
concentrations showed that steady state was achieved by Day 71, following 5 doses of izokibep 
administered Q2W. There was evidence of accumulation following repeated dosing by Day 85 
with geometric mean accumulation ratio, based on AUC over the dose interval (AUC0-τ) of 1.95, 
and individual patients ranging from 1.35 to 5.09. Between-patient variability, based on 
geometric CV%, was moderate on the monitored study days for AUC0-τ with values ranging 
from 29.4% to 36.0%, and low-to-moderate for Cmax with values ranging from 20.4% to 28.8%. 
For more details on the PK of izokibep, refer to the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of izokibep may be found in the Investigator’s Brochure. 
2.3.1. 
Risk Assessment 
Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency 
corresponding to clinically tested monoclonal antibodies in terms of blocking the biological 
activity of IL-17A. 
• IL-17A inhibitors, including secukinumab at 10 mg/kg and 30 mg/kg and ixekizumab as 
well as izokibep at doses up to 160 mg SC, do not appear to have dose-limiting AEs. 
• Class effects and potential risks seen with other IL-17 inhibitors have not been identified 
with izokibep. Given the small numbers of subjects treated to date, class effects and 
potential risks of IL-17 inhibitors will be explicitly monitored (ie, events of special 
interest) and have been taken into consideration in the development of inclusion and 
exclusion criteria. These events include Candida infections and IBD. 
• Non-serious, mild-to-moderate injection site reactions are the most common adverse 
event reported in association with SC administration of izokibep.  These are typically 
self-resolving; however, additional measures to mitigate/manage injection site reactions 
include the following: 
• Allow study drug to warm to room temperature prior to administration, about 15 
to 20 minutes  


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• Administer study drug slowly   
• Use ice/ice packs to the area prior to and following study drug administration 
• Rotate sites of administration; avoid injecting the same site twice during any visit 
• Use of oral antihistamines  
• Use of acetaminophen or ibuprofen for pain or discomfort 
• Topical corticosteroids may be used on area affected by the injection site reaction 
for localized erythema, edema, or pruritis. 
 
• No genotoxicity or carcinogenicity is foreseen as izokibep is a protein consisting of 
natural amino acids. However, since no data are available at this stage of clinical 
development on possible effects on the reproductive system, the following precautionary 
measure will be taken: 
• Females of childbearing potential as well as reproductive female partners of male 
subjects must use an adequate method of contraception while participating in the 
clinical study until 8 weeks after the last dose of study drug. Pregnancy testing 
will be performed at regular intervals prior to, during treatment and after the end 
of treatment (ie, 8 weeks after last investigational medicinal product dosing). 
2.3.2. 
Benefit Assessment 
The safety, efficacy, and PK data obtained in clinical trials with izokibep in healthy volunteers 
and in patients with psoriasis and PsA suggest a favorable benefit-risk profile. Based on results 
from the izokibep Phase 2 randomized, double-blind, placebo-controlled clinical trial in subjects 
with active PsA and published data showing efficacy and safety for other IL-17 inhibitors in 
patients with PsA, the benefit-risk relationship in these patients appears favorable and justifies 
clinical development of izokibep in PsA as well. 
The investigator is referred to the current Investigator's Brochure where additional and more 
detailed information (including nonclinical toxicology, metabolism, pharmacology, and safety 
experience) regarding potential risks and benefits of izokibep can be found. 
2.3.3. 
Overall Benefit: Risk Conclusion 
The following considerations are important for the benefit-risk assessment: 
• Only subjects with active PsA will be enrolled. Subjects must have had an inadequate 
response to NSAIDs or a DMARD, demonstrated intolerance to, or have a 
contraindication to NSAIDs or a DMARD for treatment of their PsA. Subjects previously 
treated with TNFi, or TNFi naïve, are eligible. 
• The inclusion and exclusion criteria will ensure that subjects who might be predisposed 
to a higher risk of drug-related TEAEs are either excluded or identified and treated with 
caution. Class effects seen with other IL-17 inhibitors have been taken into account when 
designing the eligibility criteria. Subjects with active infections will be excluded from 
participating in the study. 


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• Subjects will be monitored at the study site for at least 1 hour after administration of 
izokibep at designated visits. 
• Placebo treatment will be limited to 16 weeks. After Week 16, subjects randomized to 
placebo will begin blinded active treatment (izokibep 160 mg QW) in order to potentially 
derive benefit from the disease-relevant effect of IL-17 inhibition. 
• Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA 
(cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 
and Week 24) will be discontinued from study drug and can receive SOC as deemed 
appropriate by the investigator. 
• Given the known possibility of disease progression if PsA goes untreated, subjects across 
all treatment arms of this study will be allowed to continue methotrexate, leflunomide, 
sulfasalazine, apremilast, hydroxychloroquine, corticosteroids, or NSAIDS during the 
study provided the dose has been stable within the time defined in Section 5.1 prior to 
Day 1 and within the acceptable limits listed in Section 5.1. Additionally, subjects must 
have had an inadequate response to NSAIDs, DMARDs, or TNFi, or demonstrated 
intolerance to, or have a contraindication to NSAIDs, DMARDs, or TNFi for treatment of 
their PsA. Prior treatment failure and the use of concomitant background 
medications/treatments to mitigate the risk of progression of disease in the placebo group, 
and a short-term exposure to placebo to 16 weeks all justify a placebo cohort. 
• Participation in the study is voluntary. Each subject may refuse to participate or withdraw 
from the study, at any time, without penalty or loss of benefits to which the subject is 
otherwise entitled. 
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the lack of clear dose-limiting AEs associated with izokibep at the doses under study, and the 
pre-existing data on the effects of izokibep and other IL-17 inhibitors in PsA, the potential risks 
identified in association with izokibep in this study are justified by the anticipated benefits that 
may be afforded to subjects with PsA. 
2.3.4. 
COVID-19 Benefit/Risk Assessment 
A benefit-risk assessment related to severe acute respiratory syndrome 
coronavirus (SARS-CoV-2) has been considered for this study and concluded that the 
coronavirus disease of 2019 (COVID-19) pandemic does not alter the overall benefit-risk for 
conducting this study. Risk mitigation measures will be implemented based on the prevailing 
situation during study conduct, at the investigator’s discretion and in accordance with local and 
institutional guidelines as applicable. The benefit-risk of the study in relation to the COVID-19 
pandemic will continue to be assessed during the study and additional or revised measures may 
be implemented based on any updates to the benefit-risk assessment. 
 






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Objectives 
Endpoints 
baseline (PASI75) at Weeks 16, 24, and 
52 in subjects with ≥ 3% BSA psoriasis 
at baseline 
• Proportion of subjects achieving 
PASI90 at Weeks 24 and 52 in subjects 
with ≥3% BSA psoriasis at baseline  
• Proportion of subjects achieving 100% 
reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline  
 
• Proportion of subjects achieving 75% or 
greater reduction in PASI score from 
baseline (PASI75) at Weeks 16, 24, and 
52 in subjects with ≥ 10% BSA 
psoriasis at baseline 
• Proportion of subjects achieving 
PASI90 at Weeks 16, 24 and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline  
• Proportion of subjects achieving 100% 
reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in 
subjects with ≥ 10% BSA psoriasis at 
baseline 
• Proportion of subjects achieving 
PASI90 at weeks 16, 24, and 52 in 
subjects with baseline PASI score >10  
• Proportion of subjects achieving 
PASI100 at weeks 16, 24, and 52 in 
subjects with baseline PASI score >10  
 
• Proportion of subjects achieving MDA 
at Weeks 24 and 52 
• 
Proportion of subjects achieving VLDA 
response at Weeks 16, 24, and 52 
 
• PASI90 at Weeks 24 and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline  
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with ≥3% BSA psoriasis at 
baseline 
 
• PASI75 at Weeks 16, 24, and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline 
 
 
• PASI90 at Weeks 16, 24 and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline  
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with ≥10% BSA psoriasis at 
baseline 
 
• 
PASI90 at Weeks 16, 24 and 52 in 
subjects with baseline PASI score 
≥10 
 
• PASI100 at Weeks 16, 24, and 52 in 
subjects with baseline PASI score 
≥10 
 
• MDA at Weeks 24 and 52 
• VLDA at Weeks 16, 24, and 52 


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Objectives 
Endpoints 
•
Proportion of subjects with resolution of 
dactylitis at Weeks 16, 24, and 52 in 
subpopulation that had dactylitis at 
baseline (pooled izokibep doses), as 
assessed with LDI
•
Change from baseline in mNAPSI at 
Weeks 16, 24, and 52 in subpopulation 
with nail psoriasis at baseline (pooled 
izokibep doses)
•
Progression of structural damage 
assessed radiographically and expressed 
as the change in mTSS at Weeks 16 and 
52, compared to baseline
•
Change in SPARCC enthesitis score at 
Weeks 16, 24, and 52, as compared to 
baseline in subpopulation with enthesitis 
(SPARCC > 0) at baseline
•
Change in spinal pain NRS at
Weeks 16, 24, and 52, as compared to 
baseline in subjects reporting spinal pain 
at baseline
•
Change from baseline in spine pain 
NRS in those with sacroiliitis on pelvic
x-ray at Weeks 16, 24 and 52
•
Change from baseline in spinal pain 
NRS in those with investigator assessed 
spinal involvement at Weeks 16, 24 and 
52
•
Association of investigator assessed 
sacroiliac involvement with sacroiliitis 
on x-ray at baseline
•
Proportion of subjects achieving each 
MDA component (TJC68, SJC66, PASI, 
BSA, SAPVAS, SGADA, HAQ-DI, 
tender entheseal points from LEI) at 
Weeks 16, 24 and 52
•
Resolution of dactylitis at Weeks 16,
24, and 52 in subjects with LDI >0 at
baseline
•
Change in mNAPSI at Weeks 16, 24,
and 52 in subjects with mNAPSI >0
at baseline
•
Change in mTSS at Weeks 16 and 52
•
Change in SPARCC enthesitis score
at Weeks 16, 24, and 52
•
Change in spinal pain NRS at
Weeks 16, 24, and 52
•
Change from baseline in spine pain
NRS in those with sacroiliitis on
pelvic x-ray at Weeks 16, 24 and 52
•
Change from baseline in spinal pain
NRS in those with investigator
assessed spinal involvement at Weeks
16, 24 and 52
•
Clinical and radiographic sacroiliitis
•
Each MDA component (TJC68,
SJC66, 
PASI, 
BSA, 
SAPVAS,
SGADA, HAQ-DI, tender entheseal
points from LEI) at Weeks 16, 24 and
52


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Objectives 
Endpoints 
• Change in quality of life as assessed by 
SF-36 total score, physical component 
summary (PCS), and mental component 
summary (MCS) change from baseline 
to Weeks 16, 24, and 52 
• Fatigue as assessed by FACIT-F change 
from baseline to Weeks 16, 24, and 52 
• Proportion of subjects achieving 
ACR50 at Weeks 24 and 52 
 
• Proportion of subjects with resolution 
of enthesitis at Weeks 24 and 52 as 
assessed by LEI in subpopulation that 
had enthesitis (LEI >0) at baseline  
• Proportion of subjects achieving an 
improvement in PsAID of at least 3 
units at Weeks 24 and 52 compared to 
baseline in subjects with PsAID ≥3 at 
baseline  
• Proportion of subjects achieving 
ACR20 at Weeks 24 and 52 
• Mean (median) ACR-N at Week 16, 24, 
and 52, where ACR-N is defined as the 
largest number N such that ACR-N is 
met (analogous to the primary endpoint 
definition of ACR 50) 
• Change in enthesitis at Weeks 16, 24 
and 52 as assessed by change from 
baseline in LEI 
• Time to resolution of enthesitis at 
weeks 4, 12,  16, 24 and 52 among 
subjects with enthesitis (LEI > 0) at 
baseline 
• Occurrence of enthesitis (LEI > 0)  at 
weeks 4, 12,  16, 24 and 52 among 
subjects without enthesitis (LEI = 0) at 
baseline 
• Change in SF-36 total score, PCS, 
and MCS at Weeks 16, 24, and 52 
 
 
• Change in FACIT-F at Weeks 16, 24 
and 52 
• ACR50 at Weeks 24 and 52 
 
 
• Resolution of enthesitis (LEI = 0) at 
Weeks 24 and 52 
 
• PsAID response at Weeks 24 and 52 
 
 
• ACR20 at Weeks 24 and 52  
                                                      
• ACR-N at Weeks 16, 24 and 52 
 
 
• LEI change from baseline to Weeks 
16, 24 and 52 
 
• Time to resolution of enthesitis at 
weeks 4, 12  16, 24 and 52 among 
subjects with enthesitis (LEI > 0) at 
baseline 
• Occurrence of enthesitis (LEI > 0) at 
week 4, 12,  16, 24 and 52 among 
subjects without enthesitis (LEI = 0) 
at baseline 


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Objectives 
Endpoints 
• Depression and anxiety as assessed by 
change in HADS score from baseline to 
Weeks 16 and 52 
• Change in physical function as assessed 
by HAQ-DI change from baseline to 
Weeks 24 and 52  
 
• Proportion of subjects with a decrease 
of at least 2 from baseline in LEI, 
among subjects with baseline LEI of at 
least 2, at weeks 4, 12  16, 24 and 52 
• Subject's Global Impression of Change 
Questionnaire at weeks 16 and 52 
• Mean (median) Area under the curve 
(AUC) for ACR-N through weeks 16, 
24 and 52 
• Change from baseline in LEI at Weeks 
16, 24 and 52 
• Time to first achievement of ACR50 
• Time to first achievement of PASI90 
among subjects with at least 3% BSA at 
baseline 
 
• Time to first achievement of MDA 
• Time to first achievement of ACR20 
• Time to first achievement of PsAID 
improvement of at least 3 among 
subjects with PsAID at least 3 at 
baseline 
• Time to first achievement of PASI100 
among subjects with at least 3% BSA at 
baseline 
 
 
• HADS change from baseline to 
Weeks 16 and 52 
• HAQ-DI change from baseline to 
Weeks 24 and 52 
 
 
• LEI decrease of at least 2 from 
baseline at Weeks 4, 12 16, 24 and 
52 
 
• Subject’s Global Impression of 
Change Questionnaire at Weeks 16 
and 52 
• AUC for ACR-N through week 16, 
24 and 52 
• LEI change from baseline to Weeks 
16, 24 and 52 
 
• Time to first achievement of ACR50 
• Time to first achievement of PASI90 
among subjects with at least 3% BSA 
at baseline 
• Time to first achievement of MDA 
• Time to first achievement of ACR20 
• Time to first achievement of PsAID 
improvement of at least 3 among 
subjects with PsAID at least 3 at 
baseline 
• Time to first achievement of 
PASI100 among subjects with at 
least 3% BSA at baseline  
 
 


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Objectives 
Endpoints 
To investigate whether 1 or both regimens of 
izokibep (160 mg QW and 160 mg Q2W) are 
efficacious compared to placebo up to Week 16 
and to estimate the efficacy of each regimen 
after week 16 in the subpopulation with 
enthesitis as baseline, as measured by: 
• Proportion of subjects achieving an 
improvement in PsAID of at least 3 
units at Weeks 16, 24 and 52 compared 
to baseline in subjects with PsAID ≥3 at 
baseline 
• Change from baseline in PsAID at 
Weeks 16, 24 and 52 
• Proportion of subjects with a HAQ-DI 
decrease of at least 0.35 at Weeks 16, 
24 and 52 compared to baseline in 
subjects with HAQ-DI >0.35 at baseline  
• Change in physical function as assessed 
by HAQ-DI change from baseline to 
Weeks 16, 24 and 52 
• Proportion of subjects achieving MDA 
at Weeks 16, 24 and 52 
• Change in DAPSA and cDAPSA at 
Weeks 16, 24 and 52 as compared to 
baseline 
• Proportion of subjects achieving VLDA 
at Weeks 16, 24 and 52 
• Change in quality of life as assessed by 
SF-36 total score, physical component 
summary (PCS), and mental component 
summary (MCS) change from baseline 
to Weeks 16, 24 and 52 
 
• To investigate the durability of response 
after Weeks 16 in subjects on izokibep 
160mg QW and Q2W who achieved the 
primary and secondary endpoints at W16  
 
 
 
• PsAID response at Weeks 16, 24 and 
52 
 
 
• PsAID change from baseline to 
Week 16, 24 and 52 
• HAQ-DI response at Weeks 16, 24 
and 52 
 
 
• HAQ-DI change from baseline to 
Week 16, 24 and 52 
 
• MDA at Weeks 16, 24 and 52 
 
• DAPSA/cDAPSA change from 
baseline to Week 16, 24 and 52 
• VLDA at Weeks 16, 24 and 52 
 
• Change in SF-36 total score, PCS, 
and MCS at Weeks 16, 24 and 52 
 
ACR50, PASI 90, LEI, MDA, ACR20, and 
PsAID  responses at Weeks 24 and 52 
 
 
ACR50, PASI 90, LEI, MDA, ACR20, and 
PsAID  responses at Weeks 24 and 52 
 


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Objectives 
Endpoints 
 
To investigate the incremental response 
after Week 16 in subjects in all treatment 
groups (izokibep 160mg QW, izokibep 
Q2W and placebo/izokibep cross-over) who 
did not achieve the primary and secondary 
endpoints at Week 16  
 
 
To investigate the relationship between ACR50 
response and other factors 
•  Association of baseline WPI positive 
WPI >=7 with ACR50 response  
 
To investigate that the 80 mg Q4W regimen is 
efficacious compared to placebo, as measured 
by the same primary, secondary and 
exploratory endpoints 
To compare the three regimens of izokibep for 
assessment of dose-response relationships, as 
measured by the primary and secondary 
endpoints 
 
 
 
 
• Baseline positive WPI >=7 and 
ACR50 response  
 
To evaluate the pharmacokinetics of izokibep 
in subjects with psoriatic arthritis 
To evaluate the immunogenicity of izokibep in 
subjects with PsA 
• Trough plasma concentrations of 
izokibep at collected timepoints 
• Presence of anti-drug antibodies 
(positive or negative) 
 
 
 
Abbreviations: ACR = American College of Rheumatology; ADAs = anti-drug antibodies; BSA = body surface 
area; cDAPSA =  Change in Clinical Disease Activity in Psoriatic Arthritis; CRP = C-reactive protein; DAPSA 
= Disease Activity in Psoriatic Arthritis; DAS28 = Disease Activity Score in 28 joints; FACIT-F = Functional 
Assessment of Chronic Illness Therapy – Fatigue; HAQ-DI = Health Assessment Questionnaire – Disability Index; 
LDI = Leeds Dactylitis Index; LEI = Leeds Enthesitis Index; MCS=Mental Component Summary; MDA = Minimal 
Disease Activity; mNAPSI = modified Nail Psoriasis Severity Index; mTSS = modified total Sharp score; NRS = 
numeric rating scale; PASDAS = Psoriatic Disease Activity Score; PASI = Psoriasis Area and Severity Index; 
PCS=Physical Component Summary PsAID = Psoriatic Arthritis Impact of Disease; SAE = serious adverse event; 
SF-36 = 36-Item Short Form Survey; SPARCC = Spondyloarthritis Research Consortium of Canada; 
TEAE = treatment-emergent adverse event; VLDA = very low disease activity. 


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Primary Estimand 
Estimands are discussed in Section 9.3.2. 
The 5 components of the estimand to address the primary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria. 
• Variable of interest: achievement of ACR50 after 16 weeks of treatment. 
• Summary measure: response rate, achievement of ACR50 (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
Secondary Estimand(s) 
Estimands are discussed in Section 9.3.3. 
The 5 components of the estimand to address each secondary objective are as follows. 
First secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria who 
have at least 3% BSA affected at baseline. 
• Variable of interest: achievement of PASI90 after 16 weeks of treatment. 
• Summary measure: response rate, achievement of PASI90 (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
Second secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria who 
have enthesitis at baseline (LEI > 0). 
• Variable of interest: resolution of enthesitis after 16 weeks of treatment. 
• Summary measure: response rate, achievement of LEI = 0 (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
 


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Third secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria. 
• Variable of interest: achievement of MDA after 16 weeks of treatment. 
• Summary measure: response rate, achievement of MDA (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
Fourth secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria. 
• Variable of interest: achievement of ACR20 after 16 weeks of treatment. 
• Summary measure: response rate, achievement of ACR20 (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
Fifth secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria who 
have a Psoriatic Arthritis Impact of Disease (PsAID) score of at least 3 at baseline. 
• Variable of interest: change in PsAID after 16 weeks of treatment. 
• Summary measure: response rate, improvement in PsAID of at least 3 units (Yes/No). 
• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
Sixth secondary objective: 
• Treatment: izokibep versus placebo. 
• Population of interest: subjects with PsA who meet all inclusion/exclusion criteria. 
• Variable of interest: Health Assessment Questionnaire – Disability Index (HAQ-DI) 
change from baseline. 
• Summary measure: mean change from baseline in HAQ-DI. 


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• Intercurrent event handling: treatment policy strategy, with all subjects included in the 
analysis regardless of treatment discontinuation, concomitant medication, protocol 
deviations, or other actions. 
 


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4. 
Study Design 
4.1. 
Overall Design 
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2b/3 study. The plan 
is to evaluate the efficacy and safety of izokibep in subjects with active PsA who are TNFi naïve, 
who have had an inadequate response or intolerance to TNFi, or for whom TNFi is 
contraindicated.  
Approximately 325 subjects with active PsA will be enrolled. The study consists of up to a 
28-day (4-week) screening period, a 51-week treatment period, and a follow-up period with 
visits at 8 weeks and 14 weeks after the last dose of study drug to assess safety and 
immunogenicity. 
Subjects meeting eligibility criteria will be randomized into 1 of 4 treatment groups in a 4:4:4:1 
ratio as follows: 
• Group 1 (n = 100): placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg 
QW from Week 16 to Week 51. 
• Group 2 (n = 100): izokibep 160 mg QW from Day 1/Week 0 to Week 51. 
• Group 3 (n = 100): izokibep 160 mg Q2W from Day 1/Week 0 to Week 50, with 
matching placebo Q2W until Week 51 for the weeks in between izokibep doses to 
maintain the blind. 
• Group 4 (n = 25): izokibep 80 mg Q4W from Day 1/Week 0 to Week 48, with matching 
placebo QW until Week 51 for the weeks in between izokibep doses to maintain the 
blind. 
The first dose of study drug (ie, izokibep or placebo) will be administered on Day 1 (Week 0). 
Randomization will be stratified by any prior treatment with a systemic TNFi (Yes/No) and 
enthesitis (LEI > 0/LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 
20% to 30%. The number of subjects without enthesitis entering into the study (LEI = 0 at 
baseline) will be capped at 70%. 
Subjects will complete study assessments according to the study visits outlined in the Schedule 
of Activities (SoA; Section 1.3). The primary endpoint will be assessed at Week 16. The last 
dose of study drug will be administered on Week 51. 
Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) low 
disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 and Week 24) will be 
discontinued from study drug and can receive SOC as deemed appropriate by the Investigator.  
An End of Treatment visit will be conducted at Week 52. A Safety Follow-up visit will be 
conducted at Week 59. A PK/anti-drug antibody (ADA) Follow-up and End of Study Visit will 
be conducted at Week 65. 
For subjects that prematurely discontinue study drug for any reason, the End of Treatment (EOT) 
visit should be completed within 14 days of withdrawal and follow-up visits should be completed 
at 8 weeks (Safety FU) and 14 weeks (PK & ADA FU) after the last dose of study drug, where 


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possible. Refer to Section 7.1 for discontinuation of study drug. Afterwards, subjects should 
continue to complete study assessments as outlined in the SoA (Section 1.3) where possible, with 
the exception of study drug administration, anti-drug antibody sample and PK sample collection, 
and calculation for cDAPSA if discontinuation occurs prior to Week 24.The final analysis of 
primary and secondary endpoints will be conducted after the last subject has had the opportunity 
to complete Week 16 assessments or early terminates from the study. Analysis of data at later 
timepoints may occur after all subjects have had the opportunity to complete that timepoint. 
4.1.1. 
Independent Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established to monitor data on an 
ongoing basis to ensure the continuing safety of the subjects enrolled in this study and to make 
recommendations on further development activities for izokibep. 
The DMC will consist of at least 1 medical expert with expertise in the relevant therapeutic area 
and at least 1 statistician and will have a minimum of 3 members, 1 of whom will serve as the 
Chair. The DMC responsibilities, members (including their qualifications and possible conflicts 
of interest), authorities, and procedures will be documented in the DMC charter. The committee 
will meet approximately every  12 months to review unblinded interim data and will meet as 
needed to review significant safety findings. After each review, the DMC will make 
recommendations regarding the continuation of the study based on safety. 
The DMC will review unblinded efficacy data when approximately 120 subjects have had the 
opportunity to complete the Week 12 visit. Data from the first 105 subjects randomly assigned to 
receive izokibep 160 mg QW, izokibep 160 mg Q2W or placebo will be used for these DMC 
summaries.  The DMC may make a recommendation on further development activities for 
izokibep based on this data review. The DMC will not be empowered to recommend stopping 
this study or changing the sample size due to a demonstration of positive efficacy. The study 
team operationalizing the day-to-day of the study, the subjects, and the investigators will remain 
blinded to these interim results until after the study is completed. 
4.1.2. 
Number of Sites 
Approximately 100 sites across North America and Europe will participate in this study. 
Additional sites and regions may be added. Sites that do not screen subjects within 2 months of 
site initiation may be closed. 
4.1.3. 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. Approximately 325 
subjects will be randomized. Subjects who are withdrawn or removed from treatment or the 
study will not be replaced. 
4.1.4. 
Study Duration for Subjects 
The maximum planned length of participation in the study for an individual subject is up to 
69 weeks, which includes the following: 
• screening period of up to 28 days (4 weeks) 


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• treatment period of 51 weeks 
• follow-up visits at 8 weeks and 14 weeks after the last dose of study drug. 
4.2. 
Scientific Rationale for Study Design 
The design of this clinical study was chosen to evaluate izokibep in subjects with active PsA 
previously treated with TNFi, or TNFi naïve. The primary aim of the study is to evaluate the 
safety and efficacy of izokibep administered SC at a dose of 160 mg QW and 160 mg Q2W for 
the treatment of active PsA. The primary endpoint of ACR50 response will be evaluated after all 
subjects have the opportunity to complete the 16-week placebo-controlled study period. At Week 
16, subjects randomized to placebo will receive blinded active treatment (izokibep 160 mg QW) 
until Week 51. Long-term efficacy beyond Week 16 will be explored up to Week 52 and safety 
will be explored up to the End of Study visit at Week 65. 
Standard statistical procedures will be utilized in this study. Efficacy measurements in this study 
have been selected or designed to assess disease activity in subjects with active PsA. All clinical 
and laboratory procedures in this study are standard and generally accepted. 
Males and females ≥ 18 years and ≤ 75 years with active PsA who meet all inclusion criteria and 
who do not meet any of the exclusion criteria are eligible for this study. The population being 
studied represents a population normally seen in clinical practice. This ensures the activity of 
izokibep can be evaluated across a distribution of disease severity in the study. 
4.3. 
Justification for Dose 
The doses of izokibep are: 80 mg SC Q4W, 160 mg SC QW and 160 mg SC Q2W administered 
from Day 1 (Week 0) through Week 51 in subjects randomized to izokibep. Subjects randomized 
to placebo will switch to active treatment at Week 16 and will receive izokibep 160 mg QW until 
Week 51.  
The selection of the dosing regimen is informed by the following facts. The 80 mg Q4W and 160 
mg dose groups will support dose-response analyses along with the 40 mg Q2W dosing in the 
prior phase 2 study. A dose of 160 mg QW has 10-fold margin for Cmax and 9-fold margin for 
AUC0-τ based on NOAEL from nonclinical cynomolgus monkey toxicity studies (Table 1).  
Finally, based on PK modeling of the izokibep and secukinumab plaque psoriasis data and the 
available data with secukinumab in uveitis, the sponsor aimed to approximate the observed 
exposure of 10 mg/kg secukinumab IV Q2W (administered on 4 occasions) with the 160 mg QW 
SC dose of izokibep as shown in Figure 1 and Table 2 (internal data to ACELYRIN Inc). 
 


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Table 1. Cmax and AUC0-τ at NOAEL in Cynomolgus Monkey Versus Predicted Exposure 
Levels in Man and Respective Margins 
Parameter 
NOAEL (20 mg/kg/week)  
in Cynomolgus Monkey 
Predicted in Subjects  
at Steady State (160 mg QW) 
Margin 
Cmax  
409 µg/mL 
40.8 µg/mL 
10 
AUC0-τ 
52500 h·µg/mL 
5850 h·µg/mL 
9.0 
Abbreviations: AUC0-τ = area under the concentration-time curve over a dosing interval; Cmax= maximum observed 
plasma concentration; h = hour; NOAEL = no observed adverse effect level; QW = once a week. 
 
Figure 1. Observed and Simulated PK Profiles for 10 mg/kg IV Q2W×4 Secukinumab 
Versus Simulated Profiles for 160 mg Izokibep SC QW and Q2W 
 
Abbreviations: IV = intravenous; PK = pharmacokinetic; QW/Q1W = once a week; Q2W = every 2 weeks; 
SC = subcutaneous. 
 
Table 2. Predicted Exposure at Steady State for 160 mg Izokibep SC QW 
Parameter 
Unit 
Value 
Unit 
Value 
Cmax 
nmol/L 
2190 
µg/mL 
40.8 
Cmin 
nmol/L 
1460 
µg/mL 
27.2 
Caverage 
nmol/L 
1870 
µg/mL 
34.8 
AUC0-τ 
h·nmol/L 
31.5·104 
h·µg/mL 
5850 
Abbreviations: AUC0-τ = area under the concentration-time curve over the dose interval; Caverage = average observed 
plasma concentration; Cmax= maximum observed plasma concentration; Cmin = minimum observed plasma 
concentration; h = hour; QW = once a week; SC = subcutaneous. 


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Current agents leave considerable room to improve responses, with ACR 50 responses in 35 to 
50% of patients at 24 weeks and less than 60% at 52 weeks. Population pharmacokinetic 
modeling with IV and SC data from Phase 1 and 2 izokibep studies in healthy volunteers, plaque 
psoriasis, and PsA predict that meaningfully higher ACR50, ACR70, and PASI100 responses 
may be observed with izokibep 160mg QW and Q2W regimens when compared with 40 mg and 
80 mg Q2W regimens in the treatment of PsA, with improvement in responses increasing with 
longer duration of treatment (Figure 2). Achieving higher levels of response, such as ACR70 for 
a majority of patients remains an unmet need and modelling from the phase 2 data with 40 mg 
and 80 mg Q2W suggests higher levels of response are possible. Furthermore, in the clinical 
setting, izokibep has not demonstrated dose-limiting safety/tolerability up to 160 mg QW with 
multiple doses across multiple indications, with up to 3 years of exposure, so that safety data 
available to date suggests the higher doses proposed here are unlikely to lead to additional safety 
risks. 
Figure 2.  Modeling and Simulation of PsA Endpoints by Dose 
 
 
The doses of izokibep used in this study supports the maximum likelihood of demonstrating the 
potential efficacy for izokibep in subjects with active PsA within an acceptable safety profile. 
Measures have also been taken to ensure the well-being of subjects by applying appropriate 
inclusion and exclusion criteria to recruit a broad population that is most likely to benefit from 
treatment, while excluding subjects with an unacceptable risk to enter the study (Section 5). 
Further, during the study, measures are in place to monitor the safety of subjects on a regular 
basis. An independent DMC will also review the data on an ongoing basis. 
4.4. 
End of Study Definition 
The primary completion for the study is the date all subjects have had the opportunity to 
complete the Week 16 assessment for the purpose of the primary endpoint. A subject will be 
considered to have had the opportunity to complete the Week 16 assessment if the subject has the 
Week 16 assessment, has a visit after Week 16, or permanently discontinues the study before 
Week 16. 


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The end of the study is defined as the date of the last scheduled procedure including the last 
follow-up visit (ie, Week 65) shown in the SoA (Section 1.3) for the last subject in the study 
globally. 
A subject is considered to have completed the study if the subject has completed all periods of 
the study including the last scheduled procedure shown in the SoA (Section 1.3; ie, Week 65 
follow-up visit). 
 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
General 
1. Subject has provided signed informed consent including consenting to comply with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
2. Subject must be ≥ 18 (or the legal age of consent in the jurisdiction in which the study 
is taking place) and ≤ 75 years of age, at the time of signing the informed consent. 
Type of Subject and Disease Characteristics 
3. Clinical diagnosis of PsA with symptom onset at least 6 months prior to first dose of 
study drug and fulfillment of the ClASsification for Psoriatic ARthritis (CASPAR) 
criteria at Screening 
4. Active PsA as defined by: 
a. ≥ 3 swollen joints out of 66 joints (SJC66) at screening and baseline visits. 
b. ≥ 3 tender joints out of 68 joints (TJC68) at screening and baseline visits. 
5. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) negative at 
screening. 
6. Subject must have had an inadequate response, intolerance, or contraindication to at 
least one of the following: 
a. NSAID 
b. csDMARD (e.g.. methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, 
cyclosporine A) 
c. TNFi (e.g. adalimumab, infliximab, etanercept, golimumab, certolizumab). 
7. For subjects using methotrexate, leflunomide, sulfasalazine, hydroxychloroquine or 
apremilast, treated for ≥ 3 months and a stable dose (not to exceed 25 mg methotrexate 
per week, 20 mg leflunomide per day, sulfasalazine 3 g per day, hydroxychloroquine 
400 mg per day or apremilast 60 mg per day) for ≥ 4 weeks prior to first dose of study 
drug. 
8. For subjects using corticosteroids, must have been on a stable dose and regimen and 
not to exceed 7.5 mg per day of prednisone (or other corticosteroid equivalent to 
7.5 mg per day of prednisone) for ≥ 4 weeks prior to first dose of study drug. 


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9. Subjects using NSAIDs or low potency opioid medications (tramadol, paracetamol in 
combination with hydrocodone or with codeine) must have been on a stable dose and 
regimen for ≥ 2 weeks prior to first dose of study drug. 
Other Inclusions 
10. No known history of active tuberculosis (TB). 
11. Subject has a negative TB test at screening, as defined by1: 
• Negative QuantiFERON test 
• Subjects with a positive QuantiFERON test are allowed if all of the following is 
satisfied: 
 No symptoms of TB as determined by the investigator. 
 Documented history of adequate prophylaxis initiation prior to receiving 
study drug per local guidelines. 
 No known exposure to a case of active TB after most recent 
prophylaxis. 
 No evidence of active TB on chest radiograph within 3 months prior to 
first dose of study drug. 
• Subjects with an indeterminate QuantiFERON test are permitted to retest once.  
If the retest result is indeterminate, subject may be randomized if all of the 
following is satisfied: 
 No symptoms of TB as determined by the investigator. 
 Documented history of adequate prophylaxis initiation prior to receiving 
study drug per local guidelines. 
 No known exposure to a case of active TB. If subject has previously 
received TB prophylaxis, no known exposure to active TB after most 
recent prophylaxis. 
 No evidence of active TB on chest radiograph within 3 months prior to 
first dose of study drug. 
 Deemed to be low risk per risk determination questionnaire and medical 
monitor review 
1 T-SPOT TB test may be used to establish eligibility if agreed upon with the medical 
monitor. 
Sex and Contraceptive/Barrier Requirements 
12. Male and female subjects: 
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male subjects: 


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Male subjects are eligible to participate if they agree to the following during the 
study drug period and for at least 8 weeks after the last dose of study drug: 
• Refrain from donating semen, plus either: 
o Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long-term and persistent basis) and agree to 
remain abstinent. 
OR 
o Must agree to use contraception/barrier as detailed below: 
 Agree to use a male condom (and should also be advised of the 
benefit for a female partner to use a highly effective method of 
contraception as a condom may break or leak) when having sexual 
intercourse with a woman of childbearing potential (WOCBP) who 
is not currently pregnant. 
b. Female subjects: 
A female subject is eligible to participate if she is not pregnant or breastfeeding, 
and 1 of the following conditions applies: 
• Is a woman of nonchildbearing potential as defined in Section 10.4 
(Contraceptive and Barrier Guidance). 
OR 
• Is a WOCBP and uses a contraceptive method that is highly effective, with 
a failure rate of < 1%, as described in Section 10.4 during the study drug 
period and for at least 8 weeks after the last dose of study drug. The 
investigator should evaluate the potential for contraceptive method failure 
(eg, noncompliance, recently initiated) in relationship to the first dose of 
study drug. 
A WOCBP must have a negative highly sensitive serum pregnancy test at screening 
and a negative urine pregnancy test on Day 1 prior to the first dose of study drug, 
see Section 8.3.5.  
 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease-related Medical Conditions 
1.  Any history or current confirmed diagnosis of IBD 
OR 
Any of the following symptoms (of unknown etiology) or any signs or symptoms 
within the last year that in the opinion of the Investigator may be suggestive of IBD, 
with fecal calprotectin > 500 µg/g; OR if fecal calprotectin > 150 to 500 µg/g without 


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confirmed approval from a GI consult that an IBD diagnosis is clinically unlikely (see 
Section 8.2.11) when the following clinical signs and symptoms are present: 
a.    prolonged or recurrent diarrhea  
b.  prolonged or recurrent abdominal pain 
c.  blood in stool 
2.  History of fibromyalgia or any arthritis with onset prior to age 17 years or current 
diagnosis of inflammatory joint disease other than PsA (including, but not limited to 
rheumatoid arthritis, gout, connective tissue diseases). Prior history of axial 
spondyloarthritis or fibromyalgia is permitted if documentation of change in diagnosis 
to PsA or documentation that the diagnosis was made incorrectly. Prior history of 
reactive arthritis or axial spondyloarthritis is permitted if an additional diagnosis of 
PsA is made. Chronic osteoarthritis symptoms that in the Investigator’s opinion may 
interfere with study assessments. 
3. Uncontrolled, clinically significant system disease such as: 
a. diabetes mellitus 
b. hypertension 
c. cardiovascular disease including moderate to severe heart failure (New York 
Heart Association class III/IV) 
d. renal disease 
e. moderate to severe liver disease. 
4. Malignancy within 5 years except treated and considered cured cutaneous squamous or 
basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma. 
5. Severe, uncontrolled, medically unstable mood disorder, such as severe depression. 
6. History or evidence of any clinically significant disorder (including psychiatric), 
condition, or disease that, in the opinion of the investigator, may pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion. 
7. Active infection or history of infection as follows: 
a. Any active infection for which oral anti-infectives (antibiotics, antivirals, 
antifungals) were used ≤ 14 days prior to first dose of study drug. 
b. A serious infection requiring hospitalization or IV anti-infectives (antibiotics, 
antivirals, antifungals) ≤ 30 days prior to first dose of study drug. 
c. Recurrent or chronic infections or other active infections that in the opinion of 
the investigator might cause this study to be detrimental to the subject. 
8. Candida infection requiring systemic treatment within 3 months prior to first dose of 
study drug. 


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9. Tuberculosis or fungal infection seen on available chest x-ray taken within 3 months
prior to first dose of study drug or at screening (Exception: documented evidence of
completed treatment and clinically resolved).
10. Known history of human immunodeficiency virus (HIV) or positive HIV test at
screening.
Laboratory Abnormalities and Measurements 
11. Positive hepatitis B surface antigen (HBsAg) or detected sensitivity on the hepatitis B
virus (HBV) DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core
antibody (HbcAb)/hepatitis B surface antibody (HbsAb) positive subjects OR positive
hepatitis C virus antibody test at screening.
12. Laboratory abnormalities at screening:
a.
hemoglobin < 9 g/dL
b. platelet count < 100 000/mm3
c.
white blood cell count < 3 000 cells/mm3 
d. aspartate aminotransferase and/or alanine aminotransferase ≥ 2.5 times the upper
limit of normal
e.
estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening
f.
any other laboratory abnormality that in the opinion of the investigator, will pose a
risk to subject safety or interfere with the study evaluation, procedures, or
completion.
Note: Laboratory value(s) out of range due to sampling error or that might be within 
range after medically appropriate supplementation may be repeated up to 2 times 
within the screening window before the subject is considered a screen failure. 
 Washouts and Nonpermitted Drugs 
13. Previous exposure to izokibep or any other IL-17 inhibitor and IL-17 receptor
inhibitors (eg, secukinumab, ixekizumab, bimekizumab, brodalumab).
14. Prior exposure to biologics that had a potential or known association with progressive
multifocal leukoencephalopathy (ie, natalizumab [Tysabri], rituximab [Rituxan], or
efalizumab [Raptiva]).
15. Exposure to the following within 24 weeks prior to first dose of study drug:
a.
intramuscular (IM) or oral gold
b. cytotoxic agents such as cyclophosphamide, D-penicillamine.
16. Exposure to the following within 12 weeks prior to first dose of study drug:
a.
TNFi (except etanercept within 4 weeks)
b. other experimental or commercially available biologic or biosimilar therapies
(within 12 weeks or 5 half-lives, whichever is longer)


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c. cyclosporine, azathioprine, tacrolimus 
d. IV gamma-globulin or Prosorba column therapy. 
17. Exposure to the following within 4 weeks prior to first dose of study drug: 
a. janus kinase (JAK) inhibitor (eg, tofacitinib, upadacitinib) 
b. any other conventional systemic DMARD not covered above (other than 
methotrexate and hydroxychloroquine unless maintaining on a stable dose through 
the study as allowed in inclusion criteria) 
c. IA hyaluronic acid injections 
d. IA, IM, or IV corticosteroids including adrenocorticotropic hormone 
e. other psoriasis treatments not listed above (eg,, mycophenolate mofetil, retinoids, 
fumarates, or phototherapy [eg, PUVA, UVA, UVB, high potency topical 
corticosteroids]). 
18. Exposure to leflunomide within 8 weeks prior to first dose of study drug (unless 
maintaining on a stable dose through the study as allowed in inclusion criteria). 
19. Exposure to sulfasalazine and apremilast within 1 week prior to first dose of study drug 
(unless maintaining a stable dose through the study as allowed in inclusion criteria). 
20. Chronic use of medium or high potency narcotic analgesics such as morphine or 
morphine-derived medications, fentanyl, hydromorphone, levorphanol, meperidine, 
methadone, or oxycodone at screening, as determined by investigator.   
 
21. Received live vaccination ≤ 12 weeks prior to dosing or scheduled to receive a live 
vaccine within 12 weeks following the last dose of study drug. 
 
22. Participating in another interventional clinical study or participated in a clinical study 
involving administration of a study drug within the following time period prior to 
dosing: 12 weeks, 5 half-lives, or twice the duration of the biological effect of the study 
drug (whichever is longer). 
General 
23. History of hypersensitivity or allergy to izokibep or its excipients. 
24. Previously randomized or withdrawn from this study. 
25. Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study 
drug, as determined by the investigator. 
26. Any condition that compromises the ability of the subject to give written informed 
consent and/or subject’s unwillingness or inability to comply with study procedures. 
 
 


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5.3. 
Lifestyle Considerations 
Investigator should encourage subject to limit alcohol consumption to < 2 per day, < 7 alcoholic 
drinks per week. An alcoholic drink is defined as a 6 oz (175 mL) glass of wine, a 1 oz (30 mL) 
glass of hard liquor (eg, whiskey), or an 8 oz (250 mL) glass of beer. 
5.4. 
Screen Failures 
A screen failure occurs when a subject who consents to participate in the clinical study is not 
subsequently enrolled/randomized to the study. A minimal set of screen failure information will 
be collected to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography (ie, age, sex), screen failure reason, and 
any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 times (ie, total of 3 screens including initial screen). Refer to Section 6.3.2 for 
details on rescreening. 
5.5. 
Criteria for Temporarily Delaying Dosing 
Subject should be dosed within the window as detailed in the SoA (Section 1.3). 
All missed or delayed doses should be documented. If the investigator determines a subject 
should not be dosed within the defined window for a safety reason (eg, an AE, SAE), then a 
missed dose should be recorded. 
5.6. 
COVID-19-related Precautions 
Risk mitigation measures, including COVID-19-related precautions and procedures (including 
SARS-CoV-2 testing/screening) will be implemented based on the prevailing situation during the 
study conduct, at the investigator’s discretion, and in accordance with local and institutional 
guidelines as applicable. 
Subjects should be routinely monitored for any AEs at every visit, including signs or symptoms 
of infection. Should subjects demonstrate any symptoms or AEs (including known COVID-19 
symptoms or tested positive for COVID-19), the symptoms or AEs will be reported to the site as 
per study procedures and assessed by the investigator. As with any AEs, AE data will be 
collected on the appropriate electronic case report form (eCRF). 
If a subject has received, or is planning to receive, COVID-19 vaccination, the investigator 
should refer to vaccine considerations in eligibility criteria (Section 5.2) and concomitant 
medications (Section 6.8) requirements in the protocol. 


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6. 
Study Drug(s) and Concomitant Therapy 
Study drug is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study subject according to the study protocol. 
6.1. 
Study Drug(s) Administered 
The study drugs include izokibep and matching placebo. 
Table 3. Study Drug(s) Administered: Izokibep and Placebo 
 
Investigational drug 
Placebo 
Drug name 
Izokibep 
Placebo to izokibep 
 
 
 
Pharmacological group 
Biologic: IL-17A inhibitor 
None 
Form 
Solution for injection 
Solution for injection 
Active ingredient per form 
Each 2R (2 mL) glass vial contains 
1.2 mL of izokibep (nominal 
concentration 80 mg/mL ±10%)  
Not applicable 
Route of administration 
SC 
SC 
Nonactive ingredients (excipients) 
10 mM sodium phosphate 
150 mM NaCl 
0.5 mM EDTA 
10 mM sodium phosphate 
150 mM NaCl 
0.5 mM EDTA 
Special storage recommendations 
Vials are to be stored at 2°C to 8°C. 
Once removed from the refrigerator, 
the solution should be allowed to 
warm to room temperature (about 15 
to 20 minutes) prior to 
administration. For further details, 
refer to Pharmacy Manual. 
Store at room temperature  
(do not store above 25°C). 
Given placebo and izokibep 
will be provided in blinded, 
matching vials, both should be 
stored at 2°C to 8°C. Once 
removed from the refrigerator, 
the solution should be allowed 
to warm to room temperature 
(about 15 to 20 minutes) prior 
to administration. For further 
details, refer to Pharmacy 
Manual. 
Abbreviations: EDTA = ethylenediaminetetraacetic acid; IL = interleukin; NaCl = sodium chloride; 
SC = subcutaneous. 
6.1.1. 
Dosage, Administration, and Schedule: Izokibep and Placebo 
Study drug (izokibep 80 mg Q4W, izokibep 160 mg QW, izokibep 160 mg Q2W or placebo) will 
be dosed by SC injection. Study drug vials for placebo and izokibep will be visually 
indistinguishable. 
Study drug doses are fixed and will not be adjusted for individual subjects during the study. 
Throughout treatment period, 2 SC injections are to be given for each study drug administration. 
The anatomical sites for administration of study drug are the upper arm, upper thigh, or 
abdomen. 
At the study site, only authorized investigational site study staff members are to administer study 
drug (see Section 6.2). Subjects should be monitored for at least 1 hour after study drug 


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administrations at the following visits: Day 1/Week 0, Week 1, Week 2, Week 16, Week 17, and 
Week 18. 
Subjects will be randomized to 1 of 4 dosing groups as follows: 
• Group 1 (n = 100): placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg 
QW from Weeks 16 to Week 51. 
• Group 2 (n = 100): izokibep 160 mg QW from Day 1/Week 0 to Week 51. 
• Group 3 (n = 100): izokibep 160 mg Q2W from Day 1/Week 0 to Week 50, with 
matching placebo Q2W until Week 51 for the weeks in between izokibep doses to 
maintain the blind. 
• Group 4 (n = 25): izokibep 80 mg Q4W from Day 1/Week 0 to Week 48, with matching 
placebo QW until Week 51 for the weeks in between izokibep doses to maintain the 
blind. 
The dosing schedule is described by a schema in Section 1.2. 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received, and any discrepancies are reported 
and resolved before use of the study drug. 
2. Only subjects randomized in the study may receive study drug. All study drug must be 
stored prior to dispensing in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, the sponsor or 
designee requires a copy of the site’s written institutional review board (IRB)/independent ethics 
committee (IEC) approval of the protocol, ICF, and all other subject information and/or 
recruitment material, if applicable (see Section 10.1.3). All subjects must personally sign and 
date the ICF before commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met all 
eligibility criteria and registered the subject as enrolled/randomized within the Interactive 
Response Technology (IXRS) system. The investigator is to document this decision and date in 
the subject’s medical record. The screening period starts when the subject signs and dates the 


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ICF and ends when the subject is enrolled/randomized, or screen failed. The screening period is 
up to 28 days. Certain initial screening period procedures may be repeated during the original 
initial screening period. (Note: Repeating procedures during the original initial screening period 
is a part of screening and is not considered “rescreening”). These procedures include laboratory 
assessments due to value(s) out of range due to sampling error or that could be within range with 
repeat sampling. Laboratory value(s) out of range due to sampling error or that might be within 
range after medically appropriate supplementation may be repeated up to 2 times within the 
screening window before the subject is considered a screen failure. 
All subjects who enter the screening period for the study receive a unique subject identification 
number assigned by the IXRS system. This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical study; it 
must not be changed after initial assignment, including if a subject is rescreened. 
The subject identification number consists of 12 digits that correspond to the site number 
(9 digits) plus the sequential number (3 digits) as follows: 
• Site number (first 9 digits) 
• first 3 digits correspond to the last 3 digits of the study protocol number (ie, 104) 
• middle 3 digits correspond to the 3-digit ISO 3166-1 number code for the country 
(eg, US country code = 840; for country codes with only 2 digits, a lead “0” will 
be added) 
• last 3 digits are sequential numbers given to sites within a country (eg, for a US 
site = 104840001). 
• Sequential numbering of subjects within a site (last 3 digits) 
• the last 3 digits are sequential numbers assigned by IXRS within a site (eg, for US 
Site 104840001, their first subject = 104840001001). 
A subject who is determined to be ineligible must be registered as a screen failure in the IXRS 
system. 
6.3.2. 
Rescreening 
Investigators may rescreen a subject if the investigator is reasonably certain that reasons for 
screen failure will be resolved prior to or during a repeat screening attempt. Reasons to rescreen 
may include but are not limited to the following: 
• Laboratory value(s) out of range due to sampling error or that might be within range after 
medically appropriate supplementation. (Note: Before screen failing and then rescreening 
the subject, efforts should be made to repeat the laboratory assessment(s) during the 
original initial screening period.) 
• The subject has a medical condition that can be stabilized or resolved prior to the repeat 
screening/rescreening attempt 
• Additional time is required following the subject’s last dose of an excluded medication. 
Investigators are encouraged to consult with the medical monitor prior to rescreening subjects for 
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A subject must provide informed consent prior to the initiation of any rescreening procedures 
only if 30 or more days have elapsed since the date of the subject’s initial informed consent. The 
subject is entered into rescreening in the IXRS system, and all screening procedures must be 
repeated except as noted in the inclusion/exclusion criteria. A subject may be screened up to 
3 times (ie, no more than 2 rescreens). Near to the end of study enrollment, sites may be notified 
when no additional subjects will be screened or rescreened. 
If a subject rescreens, a chest x-ray does not need to be repeated if a previous chest x-ray was 
performed < 3 months prior to Day 1. 
If a subject rescreens, hepatitis, TB, HIV, urinalysis, and electrocardiogram (ECG) tests do not 
need to be repeated if a previous test was performed < 60 days prior to Day 1. 
6.3.3. 
Randomization 
Subjects will be randomized to the study drug (izokibep QW, izokibep Q2W with alternating 
Q2W placebo, izokibep Q4W with placebo at other weeks, to maintain the blind or placebo QW) 
on Day 1 by IXRS system. Randomization will be based on a schedule generated by the sponsor 
or sponsor designee before the start of the study and will be centrally executed using the IXRS 
system. The subject, site personnel, and sponsor/Contract Research Organization (CRO) study 
personnel and designees will be blinded to the randomization treatment group assignment (ie, 
izokibep or placebo) and matching placebo administered on the weeks in between izokibep doses 
for the izokibep Q2W and Q4W arms will be used to blind the dosing schedule (QW or Q2W or 
Q4W). The randomization dates are to be documented in the subject’s medical record. 
Randomization will be stratified by any prior treatment with a systemic TNFi (Yes/No) and 
enthesitis (LEI > 0/LEI = 0). 
Izokibep and matching placebo will be visually indistinguishable to prevent unblinding during 
preparation or administration of study material. 
6.3.4. 
Site Personnel Access to Individual Treatment Assignments 
Subject’s treatment assignment should be unblinded only when knowledge of the treatment is 
essential for the further management of the subject in this study. Unblinding at the study site for 
any other reason will be considered a protocol deviation. The investigator is requested to contact 
the medical monitor before unblinding any subject’s treatment assignment, whenever possible, 
but must do so within 1 working day after the event. If an urgent therapeutic intervention is 
necessary which warrants unblinding prior to contacting the medical monitor, the investigator 
can directly access the IXRS system to unblind without medical monitor notification or 
agreement but must still contact the medical monitor within 1 working day after the event. 
If an SAE requires an expedited regulatory report to be sent to 1 or more regulatory agencies, 
sponsor/designee’s safety staff may unblind the intervention assignment for the subject. A copy 
of the report, identifying the subject’s intervention assignment, may be sent to that regulatory 
agency in accordance with local regulations. 
Please refer to the Study Pharmacy Manual for details. 


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6.4. 
Study drug Compliance 
When subjects are dosed at the site, they will receive study drug directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents. 
After Week 4, subjects may perform home dosing of study drug. Site staff will administer the 
first 2 doses of study drug and train the subject on handling and self administration of study drug 
during those study visits. Prior to beginning self-administration, the subject will need to self 
administer the following 2 doses of study drug at the site and demonstrate competency prior to 
being allowed to perform home dosing. Subject’s caregiver or designee can also be trained on 
home dosing based on subject’s preference. Only those subjects/caregivers or designees who 
demonstrate competency to perform home dosing will be allowed to do so; otherwise, the subject 
will need to return to the site for all study drug administrations. 
When study drug(s) is/are administered at home by the subject/caregiver, compliance with study 
drug will be assessed at each visit. Compliance will be assessed by review of the subject dosing 
diary during the site visits and documented in the source documents and relevant form. 
Deviation(s) from the prescribed dosage regimen should be recorded and reported to sponsor (or 
designee). 
A record of the quantity of study drug dispensed and administered to each subject must be 
maintained and reconciled with study drug and compliance records. Intervention dose dates, 
including intervention delays will also be recorded. Partial dose administration will be explained. 
6.5. 
Dose Modification 
No dose modifications are allowed in the study. 
6.6. 
Continued Access to Study Drug After the End of the Study 
There is no plan to continue access to study drug after the end of study. The choice of further 
therapy for PsA at the end of the clinical study depends on the subject's individual needs and is 
left at the physician's discretion. 
6.7. 
Overdose 
Excessive dosing of study drug should be recorded in the eCRF. Any SAE or nonserious AE 
associated with excessive dosing must be followed as any other SAE or nonserious AE as 
specified in Section 8.3. 
These events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess medicine itself is an AE or SAE (eg, suicide attempt). 
6.8. 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the subject is receiving at the time of enrollment 
or receives during the study must be recorded along with: 


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• reason for use 
• dates of administration including start and end dates 
• dosage information including route, dose, and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1. 
Prior Therapies 
Any treatments for PsA since initial diagnosis (as determined through medical history records or 
through subject interview) prior to study entry will be recorded in the source documents and on 
the eCRF, along with the reason for discontinuation. 
A detailed history of prior DMARDs, biologics, and steroids use, response, and reason for 
discontinuation will be collected. 
6.8.2. 
Concomitant Therapies 
Subjects will be allowed to continue the following concomitant medications/treatments during 
the study provided the dose has been stable within the time defined in Section 5.1 prior to Day 1 
and within the acceptable limits listed below, and must remain unchanged throughout the study: 
• methotrexate ≤ 25 mg/week 
• leflunomide ≤ 20 mg/day 
• sulfasalazine ≤ 3 g/day 
• apremilast ≤ 60 mg/day 
• hydroxychloroquine ≤ 400 mg/day 
• corticosteroids equivalent to prednisone ≤ 7.5mg/day 
• NSAIDs, unless indicated for treatment of ISRs as described in Section 2.3.1 
• Low potency opioid medications (tramadol or combination formula of paracetamol with 
codeine or with hydrocodone) 
Use of methotrexate in combination with leflunomide is prohibited. Concomitant medications 
should be used in alignment with the approved label in the respective country, and per doses 
permitted per inclusion criteria. 
6.8.3. 
Prohibited Medications 
The following medications are prohibited from enrollment through Week 52, unless otherwise 
specified or unless study drug has been permanently discontinued: 
1. all other biologic therapies with a potential therapeutic impact on PsA including but not 
limited to: 
a. IL-17 receptor inhibitors (eg, secukinumab, ixekizumab, bimekizumab, 
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b. biologics with potential for or known association with progressive multifocal 
leukoencephalopathy (ie, natalizumab, rituximab, efalizumab) 
c. TNFi (eg, adalimumab, etanercept, infliximab, golimumab) 
2. IM or oral gold 
3. cytotoxic agents (eg, cyclophosphamide, D-penicillamine) 
4. any other immunomodulatory therapy (eg, cyclosporine, azathioprine, tacrolimus, IV 
gamma-globulin, or Prosorba column therapy) 
5. JAK inhibitors (eg, tofacitinib, upadacitinib) 
6. other conventional systemic DMARDs (csDMARDs) (other than methotrexate, 
leflunomide, hydroxychloroquine, and sulfasalazine with stable doses as specified in 
Section 6.8.2) 
7. IA hyaluronic acid injections 
8. IA, IM, or IV corticosteroids including adrenocorticotropic hormone. Corticosteroid 
injections into trigger points, tender points, bursae, or entheses are not permitted  
9. other psoriasis treatments not listed above (eg, mycophenolate mofetil, retinoids, 
fumarates, vitamin D analogues, keratolytics, coal tar, or phototherapy [eg, PUVA, UVA, 
UVB, high potency topical corticosteroids unless indicated for injection site reactions to 
be used only on affected reaction area]) 
10. medium or high potency narcotic analgesics (eg, morphine or morphine-derived 
medications, fentanyl, hydromorphone, levorphanol, meperidine, methadone, or 
hydrocodone). Tramadol or combination formula of paracetamol with codeine or with 
hydrocodone are permitted at stable doses as specified in Section 6.8.2  
11. live vaccines (during the study and for 12 weeks following the last dose of study drug) 
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7. 
Discontinuation of Study drug and Subject Discontinuation/ 
Withdrawal 
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1.8. 
7.1. 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a subject to permanently discontinue study drug. The 
reason for permanent discontinuation of study drug will be documented. If study drug is 
prematurely and permanently discontinued, the subject will be encouraged to remain in the study 
to be evaluated for safety and efficacy. Subjects should continue to complete study assessments 
as outlined in the SoA (Section 1.3) where possible, with the exception of study drug 
administration, and anti-drug antibody sample and PK sample collection. Reasons for removal 
from study drug include any of the following: 
• subject request 
• death 
• lost to follow-up 
• termination of study by sponsor 
• emergency unblinding 
• liver chemistry stopping criteria (see Section 7.1.1) 
• serious infections  
• the subject becomes pregnant while on study drug 
• malignancy 
• subject develops CTCAE v5.0 grade 3 or higher SAE or AE(s) that is considered by the 
investigator to be related to study drug 
• subject develops an illness that, in the opinion of the Investigator, would interfere with 
his or her continued participation, if the risk of continuing with study drug outweighs the 
potential benefit 
• subject uses prohibited concomitant medications, as defined in Section 6.8.3, that may 
present a risk to the safety of the subject in the opinion of the Investigator or the Medical 
Monitor 
• subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any 
time during the study 
• subject is significantly non-compliant with study procedures which would put the subject 
at risk for continued participation in the trial as determined by the Investigator or Medical 
Monitor 
• subjects with disease progression or not responding to treatment are to be withdrawn 
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• Starting at Week 24, subjects who have not met clinical Disease Activity for PsA 
(cDAPSA) low disease activity (cDAPSA ≤ 14) at 2 consecutive visits (e.g. at Week 20 
and Week 24) will be discontinued from study drug and can receive standard of care 
treatment as deemed appropriate by the Investigator.  
 
Subjects with newly diagnosed IBD during the study must: 
• discontinue study drug and be followed-up until resolution of active IBD symptoms 
• be referred, as appropriate, to a health care professional treating IBD, such as a 
gastroenterologist 
If the subject has a clinical laboratory value meeting any of the following criteria, study drug must 
be interrupted. The laboratory test must be repeated in 1 to 2 weeks at a scheduled or unscheduled 
visit. If any one of the following criteria are met and continues to be met at the repeat test and no 
alternative cause of the laboratory abnormality is identified, the study drug must be discontinued 
permanently and the subject may continue in the study for protocol-specified study assessments: 
• neutrophil count < 1.0 × 109/L 
• platelets < 50,000/mm3  
• hemoglobin < 8.5 g/dL with decrease of at least 2 g/dL from Baseline 
• creatinine > 2 × Baseline 
• any other laboratory abnormality that in the Investigator’s judgement could indicate a 
medical condition that puts the subject’s safety at risk and that cannot be readily treated 
(eg, hyperkalemia) 
7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study drug for abnormal liver tests is required by the investigator when a 
subject meets 1 of the conditions outlined in the algorithm or in the presence of abnormal liver 
chemistries not meeting protocol-specified stopping rules if the investigator believes that it is in 
the best interest of the subject (Figure 2). The investigator may consider rechallenge if a 
reasonable alternative explanation is identified, liver tests have returned to baseline levels, and 
after consultation with the medical monitor. 
Figure 3. Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm1 


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Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; INR = international normalized ratio; 
SAE = serious adverse event; Tbili = total bilirubin; ULN = upper limit of normal. Note: INR will be collected only 
if ALT or AST ≥ 3 x ULN 
1 Liver Safety: Suggested actions and follow-up assessments can be found in Section 10.5. 
7.1.2. 
Rechallenge 
7.1.2.1. 
Study Drug Restart or Rechallenge After Liver Stopping Criteria Met 
Study drug restart/rechallenge after liver chemistry stopping criteria are met is allowed in this 
study. If the subject meets liver chemistry stopping criteria, do not restart/rechallenge the subject 
with study drug unless: 
• liver tests have returned to subject’s baseline values 
• sponsor medical monitor approval is granted 
• ethics and/or IRB approval is obtained, if required 
NOTE: If study drug was interrupted for suspected intervention-induced liver injury, the 
subject should be informed of the risk of death, liver transplantation, hospitalization, and 
jaundice before resumption of dosing. 


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Refer to Section 10.5 for details on the restart/rechallenge process. 
If sponsor medical monitor approval to restart/rechallenge the subject with study drug is not 
granted, then the subject must permanently discontinue study drug and may continue in the 
study for protocol-specified study assessments. 
7.2. 
Subject Discontinuation/Withdrawal from the Study 
Reasons for removal of a subject from the study are: 
• termination of study by sponsor 
• death 
• withdrawal of consent from study 
• lost to follow-up 
Withdrawal of consent from study: 
• A subject may withdraw from the study at any time without jeopardizing subsequent 
medical care. 
• At the time of discontinuing from the study, if possible, an End of Treatment visit should 
be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to 
be completed. See Section 7.1 for procedures if the study drug is prematurely 
discontinued and does not withdraw from the study. 
• The subject will be permanently discontinued from the study drug and the study at that 
time. 
• If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records and 
notify the sponsor or its designee. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 attempts at known 


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effective points of contact [eg, phone, e-mail, text], and if necessary, a certified letter to 
the subject’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered lost to 
follow-up. 


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8. 
Study Assessments and Procedures 
• Informed consent must be obtained before any study-related procedures are performed. In 
regions where the legal age of consent is older than 18 years, informed consent must be 
obtained from and signed by the subject. 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Day 1 corresponds to the date of the first dose of study drug. 
• Visit/dosing windows of ±3 days on either side of the scheduled visits/dosing are 
permitted. In case of a delayed or missed dose, the investigator should return subjects on 
the original visit/dosing schedule in relation to Day 1 for subsequent doses. The window 
of ±3 days is relative to Day 1 and applicable for all subsequent visits/dosing. The 
minimum time between doses should be no less than 4 days and no more than 10 days. 
• All assessments are to be completed before study drug administration, unless otherwise 
specified. It is recommended that patient-reported outcome assessments be completed 
first. X-rays required at Week 16 and at the End of Treatment visit may be completed ±3 
days of dosing. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
drug. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (eg, chest 
x-rays) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA (Section 1.3). 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). The study 
site should make every attempt to have the same investigator conduct efficacy assessments 
throughout the study for each subject. 


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8.1.1. 
Composite Measures 
The calculation of the composite scores will be performed by the sponsor or designee based on 
the assessments entered by the study investigator(s) on the appropriate eCRFs. 
8.1.1.1. 
American College of Rheumatology Response Criteria 
The ACR criteria are standard criteria to measure the effectiveness of various arthritis 
medications or treatments in clinical trials. The ACR criteria were developed for rheumatoid 
arthritis but now are also frequently used for primary outcome measure in PsA clinical trials 
(American College of Rheumatology, 2019). 
The ACR criteria are reported as percentage (%) improvement, comparing disease activity at 
2 discrete timepoints (baseline and postbaseline comparison). The ACR criteria are indicated as: 
• ACR20 is ≥ 20% improvement 
• ACR50 is ≥ 50% improvement; ACR50 responders include ACR20 responders 
• ACR 70% (ACR70) is ≥ 70% improvement; ACR70 responders include ACR20 and 
ACR50 responders 
The ACR20 criteria require that the subject experiences an improvement in the following 
parameters compared to baseline: 
• ≥ 20% reduction in TJC68 (see Section 8.1.3.1) 
• ≥ 20% reduction in SJC66 (see Section 8.1.3.1) 
• ≥ 20% reduction in 3 of 5 additional measures: 
• Subject’s Assessment of Pain (see Section 8.1.2.3) 
• Subject’s Global Assessment of Disease Activity (see Section 8.1.2.2) 
• Investigator’s Global Assessment of Disease Activity (see Section 8.1.3.2) 
• HAQ-DI (see Section 8.1.2.6) 
• Acute phase reactant (C-reactive protein [CRP]). 
Analyses of ACR50 and ACR70 include the same criteria as ACR20, with the use of a higher 
percentage improvement (50% and 70%, respectively) instead of 20% (European Medicines 
Agency, 2007). 
The proportion of subjects achieving ACR20, ACR50, and ACR70 will be evaluated at Week 16. 
8.1.1.2. 
Disease Activity Score in 28 Joints 
The Disease Activity Score in 28 joints (DAS28)-CRP was developed to measure disease 
activity in subjects with rheumatoid arthritis. It is a composite score derived from the following 
measures (Mease, 2011): 
• 28 tender joint count (see Section 8.1.3.1) 
• 28 swollen joint count (see Section 8.1.3.1) 


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• CRP 
• Subject’s Global Health Assessment (corresponds to Subject’s Global Assessment of 
Disease Activity, see Section 8.1.2.2). 
Generally, remission is considered achieved if the score is between 0 and < 2.6. Low activity 
corresponds to 2.6 to < 3.2. Moderate activity is between 3.2 and ≤ 5.1, while high activity is 
strictly above 5.1. 
Change in DAS28-CRP composite score will be evaluated at Week 16. 
8.1.1.3. 
Disease Activity in Psoriatic Arthritis 
The Disease Activity in Psoriatic Arthritis (DAPSA) is a composite score calculated by summing 
the following variables (Mease, 2011): 
• 68 tender joint count (see Section 8.1.3.1) 
• 66 swollen joint count (see Section 8.1.3.1) 
• Subject’s Assessment of Pain (see Section 8.1.2.3) 
• Subject’s Global Assessment of Disease Activity (see Section 8.1.2.2) 
• CRP level in mg/dL. 
Change in DAPSA and clinical DAPSA (cDAPSA; sum of the above variables, but omitting 
CRP) composite scores will be evaluated at Week 16. 
Proportion achieving DAPSA and cDAPSA low disease activity (DAPSA/cDAPSA ≤ 14) and 
remission (DAPSA/cDAPSA ≤ 4) will be evaluated starting at Week 16.  
8.1.1.4. 
Psoriatic Arthritis Disease Activity Score 
The Psoriatic Disease Activity Score (PASDAS) is a weighted index comprising the following 
assessments: 
• 68 tender joint count (see Section 8.1.3.1) 
• 66 swollen joint count (see Section 8.1.3.1) 
• Subject’s Global Assessment of Disease Activity (see Section 8.1.2.2) 
• Investigator’s Global Assessment of Disease Activity (see Section 8.1.3.2) 
• 36-Item Short Form Survey (SF-36; see Section 8.1.2.8) 
• Leeds Enthesitis Index (see Section 8.1.3.5) 
• Leeds Dactylitis Index (see Section 8.1.3.6) 
• CRP level in mg/dL. 
The score range of the PASDAS is 0 to 10, with worse disease activity represented by higher 
scores. Change in PASDAS index will be evaluated at Week 16. 


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8.1.1.5. 
Minimal Disease Activity and Very Low Disease Activity 
The criteria for MDA were developed for rheumatoid arthritis, but a PsA-specific definition of 
MDA has been constructed (Coates et al, 2010). These criteria were validated and are now 
considered as a step towards “treatment to target” in PsA, ie, the goal of achieving remission or 
low disease activity state (Coates et al, 2010; Mease, 2011). 
A subject is classified as in MDA when 5 of the following 7 criteria are met (Mease, 2011): 
• 68 tender joint count ≤ 1 (see Section 8.1.3.1) 
• 66 swollen joint count ≤ 1 (see Section 8.1.3.1) 
• PASI ≤ 1 or BSA ≤ 3% (see Section 8.1.3.3) 
• Subject’s Pain Assessment (visual analogue scale [VAS]) ≤ 15 mm (see Section 8.1.2.3) 
• Subject’s Global Activity VAS ≤ 20 mm (corresponds to Subject’s Global Assessment of 
Disease Activity, see Section 8.1.2.2) 
• HAQ-DI ≤ 0.5 (see Section 8.1.2.6) 
• Tender entheseal points ≤ 1 site out of 6 sites included in LEI (see Section 8.1.3.5). 
A subject is classified as in very low disease activity (VLDA) when all 7 criteria described above 
are met. 
The proportion of subjects achieving MDA and VLDA will be evaluated at Week 16. 
8.1.2. 
Patient-reported Outcomes 
8.1.2.1. 
Subject’s Global Impression of Change 
Subjects will complete a global impression of change questionnaire at the designated study visits 
listed in SoA (Section 1.3). 
The questionnaire consists of 1 self-administered item that assesses change in disease activity. 
Subjects will be asked to indicate their impression of change compared with start of treatment. 
8.1.2.2. 
Subject’s Global Assessment of Disease Activity 
Subject’s global health assessment will be evaluated at the designated study visits listed in SoA 
(Section 1.3) using a VAS. 
The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and 
on the right (100 mm). The subject will be asked to place a single vertical line through the VAS 
at the point that best corresponds to their feeling of disease activity. 
The score is obtained by measuring the distance from 0 to the line drawn by the subject. 
8.1.2.3. 
Subject’s Assessment of Pain (VAS) 
Pain will be assessed by the subject at the designated study visits listed in SoA (Section 1.3) 
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The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and 
on the right (100 mm). The subject will be asked to place a single vertical line through the VAS 
at the point that best corresponds to their feeling of pain. 
The score is obtained by measuring the distance from 0 to the line drawn by the subject. 
8.1.2.4. 
Subject’s Assessment of Spinal Pain (NRS) 
Spinal pain will be assessed by the subject at the designated study visits listed in SoA 
(Section 1.3) using a numeric rating scale (NRS). 
The subject will be asked to circle the number between 0 and 10 that fits best to their spinal pain 
intensity, with “0” indicating “no pain” and 10 indicating “worst imaginable pain”. 
8.1.2.5. 
Widespread Pain Index 
The Widespread Pain Index (WPI) is a self-report measure used to assess bodily distribution of 
pain and to specifically quantify the degree of widespread body pain and assess for centralized 
pain features. The WPI assesses the presence of pain in 19 designated body locations over the 
past 7 days (eg, neck, right upper arm, left lower leg). Each location is equal to a score of 1. 
Items are summed to yield a total score, with higher scores indicating greater widespread pain 
(Dudeney et al, 2019). 
The WPI will be presented in local language and is to be completed by the subject at the 
designated study visits listed in SoA (Section 1.3). 
8.1.2.6. 
Health Assessment Questionnaire – Disability Index 
The HAQ-DI questionnaire is a patient-reported outcome that is self-administered by the subject. 
It covers 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. 
The HAQ-DI will be presented in local language and is to be completed by the subject at the 
designated study visits listed in SoA (Section 1.3). 
8.1.2.7. 
Psoriatic Arthritis Impact of Disease 
The PsAID is a questionnaire developed by EULAR to assess the subject’s physical and 
psychological domains related to PsA. The questionnaire used in clinical trials consists of 
9 questions (PsAID-9; Gossec et al, 2014). 
The PsAID-9 score gives a number between 0 and 10. A higher score on the PsAID-9 indicates 
more impact of the disease. A score below 4 out of 10 is considered a patient-acceptable status. 
A change of 3 or more points is considered a relevant absolute change. 
The PsAID-9 questionnaire will be presented in local language and is to be completed by the 
subject at the designated study visits listed in the SoA (Section 1.3). 
The subject should complete the questionnaire before site personnel perform any clinic 
assessments and before any interaction with the site personnel has occurred to avoid biasing the 
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8.1.2.8. 
Short Form-36 
The acute Short Form-36v2 Health Survey (SF-36) is 36-item questionnaire that measures 
8 dimensions related to functioning and well being including physical functioning, role-function, 
bodily pain, general health, vitality, social functioning, role-emotional, and mental health. 
The SF-36 questionnaire will be presented in local language and is to be completed by the 
subject at the designated study visits listed in the SoA (Section 1.3). 
The subject should complete the questionnaire before site personnel perform any clinic 
assessments and before any interaction with the site personnel has occurred to avoid biasing the 
subject’s response. 
8.1.2.9. 
Functional Assessment of Chronic Illness Therapy-Fatigue 
The FACIT measurement system was originally developed to assess health-related quality of life 
in subjects with chronic illnesses. The additional questions of the Functional Assessment of 
Chronic Illness Therapy – Fatigue (FACIT-F) survey were compiled to assess anemia-related 
fatigue (Mease, 2011). 
The FACIT-F comprises 13 items in total and each item is answered based on a 5-point Likert 
scale. Responses of “not at all”, “a little bit”, “somewhat”, “quite a bit”, and “very much” are 
available for each question, and correspond to scores of 0, 1, 2, 3, and 4, respectively. 
The FACIT-F questionnaire will be presented in local language and is to be completed by the 
subject at the designated study visits listed in the SoA (Section 1.3). 
8.1.3. 
Investigator’s Assessments 
The following investigator assessments should be performed by an independent and blinded 
assessor, if available, who should not perform any other study related procedures. 
• Psoriasis Area Severity Index (PASI) 
• body surface area (BSA) 
• TJC and SJC Assessment 
• Dactylitis assessments 
• Enthesitis assessments 
• modified nail psoriasis severity index (mNAPSI) 
In order to minimize variability, the same assessor should evaluate the subject at each visit for 
the duration of the trial. A back-up assessor should be identified. The assessor should be a 
qualified medical professional (e.g. nurse, physician's assistant, or physician) or be pre-approved 
by the Medical Monitor or Sponsor as an assessor after review of assessor training and 
experience. Any assessor must be trained and competent in performing such assessments. It is 
the responsibility of the Investigator to ensure that all assessors are qualified and trained to 
perform assessments and that all training is documented. If the assessor is not available, the 
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8.1.3.1. 
Joint Assessments 
Joints are palpated for the purpose of determining if they are tender and/or swollen, the latter 
implying the presence of active synovitis, and both implying the presence of inflammation 
(Mease, 2011). 
Joint assessment will be performed at the designated study visits listed in the SoA (Section 1.3) 
for 68 tender and 66 swollen joint count. The tender and swollen joint counts will be used to 
determine the response (ACR; see Section 8.1.1.1) and disease activity (DAS28-CRP, DAPSA, 
PASDAS, MDA, and VLDA; see Sections 8.1.1.2 to 8.1.1.5). 
Table 4 shows an overview of the joints assessed for tenderness and swelling (Sokka and 
Pincus, 2005), and of which joint counts will be used for each composite measure. 
A rule of thumb is to apply approximately 4 kg/cm2 of pressure (enough to blanch the tip of the 
examiner’s fingernail) at the joint line (Mease, 2011). To ensure the most accurate assessment of 
change, the joint counts should be undertaken by the same person in each individual subject 
where possible. 
Documentation of the total number of tender joints and total number of swollen joints will be 
done on a joint count worksheet provided by the sponsor. 
Table 4. Tender and Swollen Joint Counts 
Joints (bilateral assessment) 
ACR/DAPSA/PASDAS/ 
MDA/VLDA 
DAS28 
68 tender 
joint count 
66 swollen 
joint count 
28 tender 
joint count 
28 swollen 
joint count 
Temporomandibular (R, L) 
2 joints 
2 joints 
- 
- 
Sternoclavicular (R, L) 
2 joints 
2 joints 
- 
- 
Acromioclavicular (R, L) 
2 joints 
2 joints 
- 
- 
Shoulder (R, L) 
2 joints 
2 joints 
2 joints 
2 joints 
Elbow (R, L) 
2 joints 
2 joints 
2 joints 
2 joints 
Wrist (R, L) 
2 joints 
2 joints 
2 joints 
2 joints 
Hand (R, L) 
 
MCP joints I-V 
10 joints 
10 joints 
- 
- 
PIP joints I-V 
10 joints 
10 joints 
- 
- 
DIP joints II-V 
8 joints 
8 joints 
- 
- 
Hip (R, L) 
2 joints 
- 
- 
- 
Knee (R, L) 
2 joints 
2 joints 
2 joints 
2 joints 
Ankle (R, L) 
2 joints 
2 joints 
- 
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Foot (R, L) 
 
Tarsus 
2 joints 
2 joints 
- 
- 
MTP joints I-V 
10 joints 
10 joints 
10 joints 
10 joints 
PIP joints I-V (toes) 
10 joints 
10 joints 
10 joints 
10 joints 
Abbreviations: ACR = American College of Rheumatology; DAPSA = Disease Activity in Psoriatic Arthritis; 
DAS28 = Disease Activity Score in 28 joint; DIP = distal interphalangeal; L = left; MCP = metacarpophalangeal; 
MDA = Minimal Disease Activity; MTP = metatarsophalangeal; PASDAS = Psoriatic Disease Activity Score; 
PIP = proximal interphalangeal; R = right; VLDA = very low disease activity. 
8.1.3.2. 
Investigator’s Global Assessment of Disease Activity 
Investigator’s global health assessment related to subject’s disease activity will be evaluated at 
the designated study visits listed in SoA (Section 1.3) using VAS. 
The VAS is a horizontal line, 100 mm in length, with anchor statements on the left (0 mm) and 
on the right (100 mm). 
The investigator will be asked to place a single vertical line through the VAS at the point that 
best corresponds to the subject’s disease activity. 
The score is obtained by measuring the distance from 0 to the line drawn by the investigator. 
8.1.3.3. 
Psoriasis Area and Severity Index and Affected Body Surface Area 
Psoriasis Area and Severity Index is an index used to express the severity of psoriasis. Because 
its performance characteristics are diminished in subjects with low lesional burden, it is not 
typically calculated in subjects with < 3% BSA involvement with psoriasis lesions 
(Mease, 2011). 
After start of treatment, PASI will only be assessed if psoriasis affects > 3% of subject’s BSA at 
baseline. The BSA assessment measures the total area of the body affected by psoriasis. 
Psoriasis Area and Severity Index evaluates the severity of erythema, induration, and 
desquamation in 4 body sections (head, arms, trunk, and legs). 
Psoriasis Area and Severity Index and affected BSA will be assessed at the designated study 
visits listed in the SoA (Section 1.3). 
8.1.3.4. 
Modified Nail Psoriasis Severity Index 
The Nail Psoriasis Severity Index is a numeric, reproducible, objective, simple tool for 
evaluation of nail psoriasis (Rich and Scher, 2003). Nail bed psoriasis includes onycholysis, 
splinter hemorrhages, hyperkeratosis, and “oil-drop change”, while nail matrix psoriasis includes 
pitting, leukonychia, lunular red spots, and nail plate crumbling (Mease, 2011). 
A modification of this system, the modified Nail Psoriasis Severity Index (mNAPSI), is a shorter 
and more feasible scoring system that has demonstrated excellent interrater reliability and has 
been used in PsA clinical trials (Mease, 2011; Cassell et al, 2007). For each fingernail, 7 groups 
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leukonychia, splinter hemorrhages, hyperkeratosis, and red spots in the lunula. Pitting, 
onycholysis and oil-drop dyschromia, and crumbling (including fragmentation and horizontal 
ridging of the nail bed) are graded from 0 to 3 in severity. Leukonychia, splinter hemorrhages, 
hyperkeratosis, and red spots in the lunula are graded as either present or absent. 
An mNAPSI will be calculated at the designated study visits listed in the SoA (Section 1.3). 
8.1.3.5. 
Leeds Enthesitis Index and Spondyloarthritis Research Consortium of Canada 
Enthesitis Index 
The LEI and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index 
are both used to assess enthesitis in subjects with PsA. The LEI assesses 6 entheseal sites, while 
the SPARCC Enthesitis Index assesses enthesitis at 16 anatomical sites (see Table 5). Tenderness 
on examination will be recorded as either present (1) or absent (0) for each of the sites, for an 
overall score range of 0 to 6 (LEI) and 0 to 16 (SPARCC Enthesitis Index). Higher count 
represents greater enthesitis burden (Mease, 2011). 
The investigator will assess the 16 sites of the SPARCC Enthesitis Index plus 2 sites of the LEI 
(right and left medial condyle femur; see Table 5) at the designated study visits listed in the SoA 
(Section 1.3). 
Table 5. Entheseal sites assessed for enthesitis according to SPARCC and LEI 
Anatomical sites assessed for tenderness 
SPARCC 
(16 sites) 
LEI 
(6 sites) 
Supraspinatus insertion into the greater tuberosity of the humerus 
R, L 
- 
Lateral epicondyle humerus 
R, L 
R, L 
Medial epicondyle humerus 
R, L 
- 
Achilles tendon 
R, L 
R, L 
Greater trochanter 
R, L 
- 
Medial condyle femur 
- 
R, L 
Plantar fascia insertion at the calcaneus 
R, L 
- 
Quadriceps insertion into the superior border of the patella 
R, L 
- 
Patellar tendon insertion at the inferior pole of the patella 
R, L 
- 
Abbreviations: L = left; LEI = Leeds Enthesitis Index; R = right; SPARCC = Spondyloarthritis Research 
Consortium of Canada. 
8.1.3.6. 
Leeds Dactylitis Index 
Using the Leeds Dactylitis Index, one can quantify the size and tenderness of a swollen digit, 
enabling differentiation between tender and nontender dactylitis. Each of 20 digits (ie, all fingers 
and toes) will be evaluated for size (circumference close to the base measured in millimeter) and 
tenderness. For use in clinical trials, circumferences of the affected and contralateral digits are 


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measured using a measuring tape or a precalibrated loop. The circumference of the affected 
digits, circumference of contralateral digits, and tenderness of affected fingers are all assessed 
for a total score. A difference in digital circumference of > or =10% is used to define a finger 
with dactylitis (Mease, 2011; Kaeley et al, 2018). 
The presence or absence of tenderness at 20 digits and the circumference of each digit will be 
assessed and documented by the investigator at the designated study visits listed in the SoA 
(Section 1.3). 
8.1.3.7. 
Investigator Question on Presence of Axial Involvement 
The presence of axial involvement will be recorded at baseline. 
Investigator will respond Yes/No to the following question: “Does the subject have axial 
involvement?”. 
8.1.3.8. 
Radiographic Assessment and modified total Sharp score 
Radiographs of hands, wrists, and feet will be performed at baseline, Week 16, and Week 52 or 
EOT in order to evaluate the presence and extent of PsA-related structural damage over the 
course of the study. Radiograph of the pelvis will be performed at baseline.  
Radiographs of hands, wrists, and feet will be performed if subjects discontinue the study drug 
after Week 16 and it has been at least 12 weeks from the date of last radiographs obtained. 
Radiographs should be obtained as close as possible to the last dose of study drug. 
Psoriatic arthritis radiographic progression will be measured by the modified total Sharp 
score (mTSS). The mTSS is a detailed scoring method evaluating erosions, joint space 
narrowing, (sub)luxation, ankylosis, gross osteolysis, and pencil in cup phenomena. It typically 
assesses joints of the hands and feet, including the second to fifth distal interphalangeal joints of 
both hands (van der Heijde et al, 2005). 
The maximum score for erosions is 5 in the joints of the hands and 10 in the joints of the feet. 
Scores for erosions are as follows: 0 = no erosions; 1 = discrete erosion; 2 = large erosion not 
passing the midline; 3 = large erosion passing the midline. 
A combination of the above scores may lead to a maximum of 5 per entire joint in the hands, and 
5 at each site of the joint (for the entire joint a maximum of 10) in the feet. The joint space 
narrowing score is based on the following features: 0 = normal; 1 = asymmetrical or minimal 
narrowing up to a maximum of 25%; 2 = definite narrowing with loss of up to 50% of the normal 
space; 3 = definite narrowing with loss of 50 to 99% of the normal space or subluxation; 
4 = absence of a joint space, presumptive evidence of ankylosis, or complete luxation. 
Gross osteolysis and pencil in cup are scored separately. In the final summary score, joints with 1 
of these abnormalities get the maximum score assigned for both erosions and for joint space 
narrowing. The maximum possible scores are 320 for erosions, 208 for joint space narrowing, 
and 528 for the total score. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 


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8.2.1. 
Medical and Medication History 
A complete medical and medication history, as well as history of alcohol and nicotine use, will 
be obtained from each subject during the screening visit. An updated medical history will be 
obtained at the Day 1 visit prior to study drug administration and updated as necessary 
throughout the study. 
A PsA history obtained at screening will capture date of onset of PsA and psoriasis (if 
applicable). 
Any systemic treatment for plaque psoriasis and PsA (ie, DMARDs, biologics, steroids) since 
diagnosis will be recorded. Any other treatment used for any other reasons (including 
contraception) prior to randomization will be recorded as per eCRF Completion Guidelines. 
Any changes in concomitant medication will be recorded throughout the study, from Day 1 until 
End of Study at Week 65. 
8.2.2. 
Physical Examination 
A complete physical examination will include, at a minimum, assessments of the dermatological, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
Clinically significant findings observed prior to first dose of study drug should be listed as 
medical history in the eCRF and reported as AEs if observed after first dose of study drug. 
8.2.3. 
Physical Measurements 
Height and weight measurements are to be performed at the designated study visits listed in the 
SoA (Section 1.3) and data will be recorded in cm and kg, respectively. Height and weight are to 
be measured without shoes. 
8.2.4. 
Vital Signs 
Vital signs will be measured in a sitting position after 5 minutes’ rest and will include 
temperature, systolic and diastolic blood pressure, and pulse and respiratory rate. 
8.2.5. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained one minute apart after subject has been supine for at 
least 5 minutes as outlined in the SoA (Section 1.3) using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, intervals. 
8.2.6. 
Chest X-ray 
Chest x-ray (posterior/anterior or anterior/posterior) in addition to the TB blood test will be 
performed at screening in subjects who do not have a chest x-ray available within 3 months of 
screening. A subject must not be included in the study if his/her chest x-ray reveals evidence of 
active TB or fungal infection (refer to Section 5.2). Women of childbearing potential must have a 
negative pregnancy test before an x-ray is performed. 


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8.2.7. 
Hospital Anxiety and Depression Scale 
Depression and anxiety will be monitored with the Hospital Anxiety and Depression 
scale (HADS). The HADS was chosen for its well-established psychometric properties and its 
use in clinical research on biological therapy in subjects with other inflammatory skin diseases 
(Langley et al, 2010). The HADS scores for anxiety and for depression range from 0 to 21 with 
higher scores indicating a worse state. A score < 8 is considered to be normal, whereas a score of 
≥ 11 is considered clinically significant (Snaith, 2003). 
The HADS questionnaire will be presented in local language and is to be completed by the 
subject at the designated study visits listed in the SoA (Section 1.3). 
8.2.8. 
Clinical Safety Laboratory Tests 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
• Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the subject’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 8 weeks after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
a. If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified, and 
the sponsor notified. 
b. All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
c. If laboratory values from nonprotocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in subject management or are 
considered clinically significant by the investigator (eg, SAE or AE), then the 
results must be recorded within source documents. 
8.2.9. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• Pregnancy testing in WOCBP will be conducted throughout the study. A serum 
pregnancy test will be performed at screening and urine pregnancy testing will be 
performed at subsequent visits as detailed in the SoA (Section 1.3). 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation or regulatory agency, to establish the 
absence of pregnancy at any time during the subject’s participation in the study. 


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• The investigator is responsible for the review of medical history, menstrual history, and 
recent sexual activity to decrease the risk of inclusion of a woman with an early 
undetected pregnancy. 
8.2.10. 
Hepatitis Testing 
All subjects will be tested for the presence of HBV and HCV at screening. A positive result for 
the HBsAg will be exclusionary. Samples negative for HBsAg will be tested for HBsAb and 
HBcAb. If test results are positive for HBcAb or HBsAb, then HBV DNA PCR will be 
performed and any result that meets or exceeds detection sensitivity will be exclusionary. 
Positive HCV antibody tests at screening will be tested for HCV RNA by PCR; any detectable 
HCV RNA will be exclusionary.   
8.2.11. 
Inflammatory Bowel Disease Screening 
Given that subjects with psoriatic arthritis appear to have a higher lifetime risk of IBD compared 
to the general population and given that approved IL-17 inhibitors have reported worsening or 
new onset IBD in clinical trials, all subjects will be screened for IBD by history and a subset will 
undergo additional laboratory screening. During screening, all subjects will be assessed for the 
following symptoms within the last year: 
• prolonged or recurrent diarrhea without established etiology  
• prolonged or recurrent abdominal pain without established etiology 
• blood in stool without established etiology 
• any other symptoms in the opinion of the Investigator that may be suggestive of IBD 
If any are marked affirmative, a fecal calprotectin test must be performed.  
• If the resulting fecal calprotectin level is > 150 - 500 µg/g, the subject must undergo a GI 
consultation and obtain documented approval from the GI consultation to enroll in the 
clinical trial before continuing with the screening process. If the consultation cannot be 
completed within the screening window, the subject will be screen-failed but may 
rescreen. 
• fecal calprotectin levels > 500 ug/g will be exclusionary. 
 
8.2.12. 
Tuberculosis Test 
Determination of TB status will be required before the subject’s inclusion in the study. A 
QuantiFERON test (or equivalent) will be performed on each subject to assess the TB status at 
screening. Subjects with a positive test result may not be included in the study (refer to 
Section 5.1). T-SPOT TB test may be used to establish eligibility if agreed upon with the medical 
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8.2.13. 
Rheumatoid Factor and Anti-cyclic Citrullinated Peptide Antibodies 
All subjects will be tested for the presence of RF and anti-CCP antibodies at screening. Since 
these parameters are a potential indicator for rheumatoid arthritis, only subjects with a negative 
test result are eligible for participation in the study (refer to Section 5). 
8.2.14. 
Home Study Drug Administration Diary 
The subject (or caregiver/designee) will complete a diary for every study dose taken outside of 
the study site (ie, at home). The study drug should be administered on the dates as directed by the 
site staff. Information regarding the study drug administration (eg, date and time of study drug 
administration, if the full dose was administered) will be recorded in the study drug 
administration diary. Instructions on proper study drug administration will be provided to the 
subject (caregiver/designee). Subjects will be instructed to call the study site if they are having 
problems administering the study drug or have missed or delayed administering a dose. Subjects 
will be instructed to bring the study drug administration diary to each study visit. 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Section 10.3. 
Adverse events will be reported by the subject (or, when appropriate, by a care giver). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. The investigator is responsible for 
following up all AEs that are serious, considered related to the study drug or study procedures, or 
that caused the subject to discontinue the study drug (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs will be collected from the signing of the ICF until the 8-week follow-up visit at the 
timepoints specified in the SoA (Section 1.3). 
All AEs will be collected from the first dose of study drug until the 4 weeks after the last dose of 
study drug as specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from investigator’s knowledge of the event, as 
indicated in Section 10.3.4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 


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time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
the sponsor pharmacovigilance team. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.6) will 
be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost 
to follow-up (as defined in Section 7.3). Further information on follow-up procedures is provided 
in Section 10.3.3. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor or designee of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study drug under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor or 
designee will review and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate, according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor or designee 
policy and forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies after the start of study drug and until 8 weeks after the last dose 
of study drug in female subjects and, if indicated, female partners of male subjects will be 
collected. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor or designee within 24 hours of learning of a 
pregnancy in a female subject or female partner of male subject (after obtaining the 
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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such (refer to Section 10.3.4) 
• The subject/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the subject/pregnant 
female partner and the neonate, and the information will be forwarded to the sponsor or 
designee. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study drug by 
the investigator will be reported to the sponsor or designee as described in Section 8.3.4. 
While the investigator is not obligated to actively seek this information in former study 
subjects/pregnant female partner, he/she may learn of an SAE through spontaneous 
reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study drug. 
8.3.6. 
Events of Special Interest 
Based on the class effects or potential risks with IL-17 inhibitors, the following events of special 
interest (preferred term) will be monitored: 
• Candida infection 
• Inflammatory bowel disease. 
In addition, based on the potential risk with an IL-17 receptor inhibitor the following events of 
special interest will also be monitored: 
• suicidal ideation 
• malignancies 
• MACE (major adverse cardiovascular and cerebrovascular events : cerebrovascular 
accident and transient ischemic attack, non-fatal myocardial infarction or unstable angina, 
cardiovascular death) 
 
• TB 
• infections (serious, opportunistic, or fungal only) 
• cytopenias  
• systemic hypersensitivity reactions. 


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8.3.7. 
Overdose 
These events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess medicine itself is an AE or SAE (eg, suicide attempt). 
Refer to Section 6.7. 
If an overdose occurs associated with an SAE in the course of the study, then the investigator 
follows the immediate safety reporting requirement for SAE with describing the overdose in an 
SAE description. 
8.4. 
Pharmacokinetics 
• Blood samples will be collected for measurement of plasma concentrations of izokibep as 
specified in the SoA (Section 1.3). 
• Instructions for the collection and handling of biological samples will be provided in the 
Laboratory Manual by the sponsor or designee. The actual date and time (24-hour clock 
time) of each sample will be recorded. 
• Samples will be used to evaluate the PK of izokibep. Each plasma sample will be divided 
into 2 aliquots (1 each for PK, and a backup). Samples collected for analyses of izokibep 
(plasma) concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study. 
• Genetic analyses will not be performed on these plasma samples. 
• Study drug concentration information will not be reported to investigative sites. 
• Pharmacokinetic samples will be shipped frozen from clinical sites to the central 
laboratory and later shipped from central laboratory to the PK laboratory for analysis. 
The PK plasma samples will be stored in a secure storage space with adequate measures 
to protect confidentiality. 
• The PK plasma samples will be retained while research on izokibep or interventions of 
this class or PsA continues but no longer than 20 years or other period as per local 
requirements. 
8.5. 
Genetics 
Not applicable. 
8.6. 
Biomarkers 
Not applicable. 


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8.7. 
Immunogenicity Assessments 
• Antibodies to izokibep will be evaluated in serum samples collected from all subjects 
according to the SoA (Section 1.3). Additionally, serum samples should also be collected 
at the final visit from subjects who discontinued study drug or were withdrawn from the 
study. These samples will be tested by the sponsor or sponsor’s designee. 
• Instructions for the collection and handling of biological samples will be provided in the 
Laboratory Manual by the sponsor or designee. 
• Samples testing positive for binding antibodies may be further characterized and may be 
tested for neutralizing antibodies. 
• The detection and characterization of antibodies to izokibep will be performed using a 
validated assay method by or under the supervision of the sponsor. 
• The immunogenicity serum samples will be retained while research on izokibep or 
interventions of this class or PsA continues but no longer than 20 years or another period 
as per local requirements. 
8.8. 
Health Economics 
Refer to Section 8.1.2.8. 


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9. 
Statistical Considerations 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. 
9.1. 
Statistical Hypotheses 
The primary objective of this study is to demonstrate that izokibep (160 mg dosed QW or 
160 mg dosed Q2W) is superior to placebo in the proportion of subjects achieving ACR50 at 
Week 16 of the study. The statistical null and alternative hypotheses to be used to assess the 
primary objective are: 
H0: πABY – πPBO = 0 
HA: πABY – πPBO ≠ 0 
Where πABY and πPBO are the proportion of subjects achieving ACR50 at Week 16 among 
subjects randomly assigned to receive izokibep and placebo, respectively. One set of hypotheses 
will be tested for each dose frequency of izokibep 160 mg (QW and Q2W). 
Analogous statistical hypotheses will be used for the secondary objective of assessing the 
proportion of subjects achieving PASI90 at Week 16 among subjects with ≥ 3% BSA psoriasis at 
baseline, the proportion of subjects achieving resolution of enthesitis at Week 16 among subjects 
that had enthesitis at baseline, achievement of MDA at Week 16, the proportion of subjects 
achieving ACR20 at Week 16 compared to baseline, the proportion of subjects achieving 
improvement in PsAID of at least 3 units at Week 16 compared to baseline in subjects with 
PsAID ≥ 3 at baseline.  
The statistical null and alternative hypotheses to be used to assess the secondary objective of 
change in physical function of HAQ-DI from baseline to Week 16 are: 
H0: μABY – μPBO = 0 
HA: μABY – μPBO ≠ 0 
Where μABY and μPBO are the mean change from baseline to Week 16 among subjects randomly 
assigned to receive izokibep and placebo, respectively. One set of hypotheses will be tested for 
each dose frequency of izokibep 160 mg (QW and Q2W). 
9.1.1. 
Multiplicity Adjustment and Type I Error Rate 
Hypotheses tested will be adjusted to control the familywise error rate in the strong sense at 
α = 0.05, 2-sided. 
The statistical comparisons for the primary efficacy endpoint and the secondary endpoints, all at 
Week 16, will be carried out in sequential order. The primary endpoint, comparing izokibep 
dosed QW to placebo, will be tested first, with significance concluded if p < 0.05.  
Testing of secondary endpoints, comparing izokibep dosed QW to placebo, will only be carried 
out if all prior tests, including the tests of the primary endpoint, first show significance with p < 
0.05. If all primary and secondary endpoints, comparing izokibep doses QW to placebo, are 


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significant, testing of izokibep doses Q2W to placebo will begin and follow the same order. As 
long as all prior tests are significant, testing will proceed in the following order: 
• The primary endpoint, achieving ACR50 at Week 16, comparing izokibep dosed QW to 
placebo. 
• The first secondary endpoint, achieve PASI90 at Week 16 in subjects with ≥ 3% BSA 
psoriasis at baseline, comparing izokibep dosed QW to placebo. 
• The second secondary endpoint, achieving resolution of enthesitis at Week 16 in subjects 
that had enthesitis (LEI > 0) at baseline, comparing izokibep dosed QW to placebo. 
• The third secondary endpoint, achieving MDA at Week 16, comparing izokibep dosed 
QW to placebo. 
• The fourth secondary endpoint, achieving ACR20 at Week 16, comparing izokibep dosed 
QW to placebo. 
• The fifth secondary endpoint, achieving improvement in PsAID of at least 3 units at 
Week 16 compared to baseline in subjects with PsAID ≥ 3 at baseline, comparing 
izokibep dosed QW to placebo. 
• The sixth secondary endpoint, change in physical function of HAQ-DI from baseline to 
Week 16, comparing izokibep dosed QW to placebo. 
• The primary endpoint, achieving ACR50 at Week 16, comparing izokibep dosed Q2W to 
placebo. 
• The first secondary endpoint, achieve PASI90 at Week 16 in subjects with ≥ 3% BSA 
psoriasis at baseline, comparing izokibep dosed Q2W to placebo. 
• The second secondary endpoint, achieving resolution of enthesitis at Week 16 in subjects 
that had enthesitis (LEI > 0) at baseline, comparing izokibep dosed Q2W to placebo. 
• The third secondary endpoint, achieving MDA at Week 16, comparing izokibep dosed 
Q2W to placebo. 
• The fourth secondary endpoint, achieving ACR20 at Week 16, comparing izokibep dosed 
Q2W to placebo. 
• The fifth secondary endpoint, achieving improvement in PsAID of at least 3 units at 
Week 16 compared to baseline in subjects with PsAID ≥ 3 at baseline, comparing 
izokibep dosed Q2W to placebo. 
• The sixth secondary endpoint, change in physical function of HAQ-DI from baseline to 
Week 16, comparing izokibep dosed Q2W to placebo. 
 
 
9.2. 
Analysis Sets 
Full Analysis Set 


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For assessing the primary and secondary efficacy objectives, all subjects randomized will be 
included in the analyses as the Full Analysis Set. Intercurrent events such as missed or 
discontinued treatment and protocol deviations will be addressed as described in the definition of 
the estimands in Section 9.3. Subjects will be included according to randomized treatment 
assignment. 
Safety Analysis Set 
For assessing the safety objectives, all subjects randomized who receive at least 1 administration 
of test material will be included in the summaries and analyses. In the event that a subject 
receives incorrect study drug, that subject will be grouped according to treatment received, and 
such subjects will be listed and counted in the final report. 
 
PK Analysis Set 
For assessing PK parameters, all subjects who receive at least 1 administration of test material 
and have at least 1 sample collected and analyzed for drug concentration will be included in 
summaries and analyses. 
ADA Analysis Set 
For assessing ADA, all subjects who receive at least 1 administration of test material and have 
both baseline ADA and at least 1 postdose ADA measurements will be included in summaries 
and analyses. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
All data collected will be summarized by planned timepoint without imputation. Continuous data 
will be summarized with count, mean, Q1, median, Q3, standard deviation, minimum, and 
maximum. Change from baseline will additionally include standard error. Categorical data will 
be summarized with count and percent. Time to event data will be summarized with 
product-limit estimators of median and quartiles. 
All hypothesis tests will be reported with 2-sided p-values. Comparison of QW dosing to placebo 
will use only subjects assigned to receive izokibep 160 mg QW or placebo; comparison of Q2W 
dosing to placebo will use only subjects assigned to receive izokibep 160 mg Q2W or placebo; 
comparison of Q4W izokibep to placebo will use only subjects assigned to receive izokibep 
80 mg Q4W or placebo.  All confidence intervals will be 2-sided with nominal 95% coverage. 
Data will be summarized by planned timepoint, using data collected at the visit. Study day will 
be calculated as postbaseline date minus randomization date, plus 1 (except that study day for 
pre-randomization dates will not include the plus 1). Day range windows will not be applied for 
summaries (but may be applied for protocol deviations). Baseline values will be the last value 
collected before randomization and change from baseline will be calculated as postbaseline value 
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Stratified tests will use the strata of prior TNFi use (Yes/No) and enthesitis at baseline (LEI = 0 
versus > 0) from the randomization process. If a subject is incorrectly classified into a stratum 
during the randomization process, the analysis will use the correct classification, not the 
classification used during randomization. 
Primary and secondary endpoints will be tested using only three treatment groups: izokibep 
160 mg Q2W, izokibep 160 mg QW and placebo. The treatment group receiving izokibep 80 mg 
Q4W will only be used for exploratory analyses and endpoints. 
9.3.2. 
Primary Endpoint and Estimand 
The primary endpoint is ACR50 response, as defined in Section 3. The primary analysis will 
occur when all subjects have had the opportunity to complete at Week 16 visit or discontinued 
the study. 
The statistical comparisons for the primary efficacy endpoint and the secondary endpoints, all at 
Week 16, will be carried out in sequential order. The primary endpoint, comparing izokibep 
dosed QW to placebo, will be tested first, with significance concluded if p < 0.05. Testing of 
secondary endpoints, comparing izokibep dosed QW to placebo, will only be carried out if all 
prior tests, including the tests of the primary endpoint, first show significance with p < 0.05. If 
all primary and secondary endpoints, comparing izokibep doses QW to placebo, are significant, 
testing of izokibep doses Q2W to placebo will begin and follow the same order. 
The primary efficacy analyses will use the treatment policy estimands, using all available data 
from all randomized subjects regardless of treatment discontinuation, concomitant medication, 
protocol deviations, or other actions. Subjects will be analyzed in the group to which they are 
randomized. Subjects who do not have an evaluation for a dichotomous endpoint at a given 
timepoint will be imputed as nonresponders. 
The null hypothesis of equal response rates will compare each dosing regimen of izokibep to the 
placebo group. A stratified test of response rates will be used. Within each of the strata used for 
randomization, the response rate for each treatment group and corresponding standard error will 
be calculated. If a subject is incorrectly classified into a stratum during the randomization 
process, the analysis will use the correct classification, not the classification used during 
randomization. The difference in response rates (risk difference) will be calculated for each 
stratum. The common risk difference among the strata and associated standard error will be 
estimated by combining the observed risk differences using Cochran-Mantel-Haenszel 
weighting. The estimated risk difference divided by the standard error will be used as the test 
statistic and a p-value calculated assuming that the test statistic follows a standard normal 
distribution under the null hypothesis. Analyses at earlier timepoints when data to calculate the 
ACR50 are collected will also be presented using the same methodology. P-values from earlier 
timepoints will be presented for descriptive purposes, not part of the alpha-preserving multiple 
testing strategy. 
A tipping point analysis will be performed in order to evaluate the robustness of the results of the 
primary analysis. This analysis will use simulations to assess the impact of different response 
rates in subjects with missing primary endpoint data, and how different the response rates must 
be to change the conclusions of the study. The tipping point analysis will impute mean response 


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rates in the two groups. Imputed response rates will be based on the response rates among 
subjects with observed primary endpoint data at Week 16. Sets of imputed mean response rates 
will include the observed response rates (𝜋𝜋ොABY, 𝜋𝜋ොPBO), and rates that differ in increments of 
±0.02, adjusted independently in each arm. For each set of imputed mean response rates, 1000 
simulations will be reported. Within each simulation, a random number mechanism will be used 
to assign each subject who is missing the primary endpoint at Week 16 to either response or 
non-response. The primary stratified analysis will be reported on each simulation, and the 
probability that the null hypothesis of equal response rates is rejected will be reported for each 
set of imputed response rates. A graphical output will summarize the rejection probability for 
various sets of response rates. The same tipping point analysis will be performed with another 
dose regimen of izokibep group, ie, izokibep Q2W compared to the placebo group. 
Other sensitivity and supplementary analyses will be used to assess the impact of missing data 
assumptions and other intercurrent events. These will be defined before the database is unblinded. 
9.3.3. 
Secondary Endpoints and Estimands 
The secondary endpoints will be tested analogously. Testing of secondary endpoints, comparing 
izokibep dosed QW to placebo, will only be carried out if all prior tests, including the tests of the 
primary endpoint, first show significance with p < 0.05. If all primary and secondary endpoints, 
comparing izokibep doses QW to placebo, are significant, testing of izokibep doses Q2W to 
placebo will begin and follow the same order.  As long as all prior tests showed statistically 
significant differences compared to placebo, testing will proceed using α = 0.05. If any 
comparison (primary or secondary) results in p > 0.05, p-values for subsequent comparisons will 
be reported but not considered conclusive. 
The treatment policy strategy similar to the primary endpoint will be used to construct estimands 
for each secondary endpoint. Subjects will be included in the analysis regarding treatment 
discontinuation, concomitant medication, protocol deviations, or other actions. 
For the secondary endpoint of achieving PASI90 at Week 16, the analysis only includes subjects 
with ≥ 3% BSA psoriasis at baseline. For the secondary endpoint of achieving resolution of 
enthesitis at Week 16, the analysis only includes subjects that had enthesitis at baseline. For the 
secondary endpoint of achieving an improvement in PsAID of at least 3 units at Week 16 
compared to baseline, the analysis only includes subjects with PsAID ≥ 3 at baseline. 
The following secondary endpoints will be analyzed as dichotomous endpoints and analogously 
to the primary endpoint: 
• proportion of subjects achieving PASI90 at Week 16 in subjects with ≥ 3% BSA psoriasis 
at baseline  
• proportion of subjects achieving resolution of enthesitis at Week 16 in subjects that had 
enthesitis (LEI > 0) at baseline 
• proportion of subjects achieving MDA 
• proportion of subjects achieving ACR20 


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• proportion of subjects achieving improvement in PsAID of at least 3 units at Week 16 
compared to baseline in subjects with PsAID ≥ 3 at baseline 
Subjects who have missing data at Week 16 will be imputed as nonresponders and included in 
the analysis. 
The secondary endpoint of change in physical function of HAQ-DI from baseline to Week 16 
will be analyzed as a continuous variable. The treatment policy strategy will be used to construct 
estimands for change in physical function of HAQ-DI from baseline to Week 16. Subjects will 
be included in the analysis regarding treatment discontinuation, concomitant medication, 
protocol deviations, or other actions. A mixed-effects model with repeated measures will be used 
for change in physical function of HAQ-DI. The model will use available data of change in 
physical function of HAQ-DI from baseline at all scheduled postbaseline assessments. The 
model includes the baseline physical function of HAQ-DI, treatment group, and stratification 
variables as covariates. If a subject is incorrectly classified into a stratum during the 
randomization process, the analysis will use the correct classification, not the classification used 
during randomization. 
Sensitivity analyses will use analysis of covariance on change in physical function of HAQ-DI 
from baseline to Week 16, with stratification variables used for randomization also included as 
covariates, along with baseline physical function of HAQ-DI.  
Sensitivity analysis for physical function of HAQ-DI will also use multiple imputations. Physical 
function of HAQ-DI missing as Week 16 will be replaced with the imputed value from the 
imputation dataset. The imputation dataset will be created from the placebo subjects who have 
complete data. 
9.3.4. 
Exploratory Endpoints 
Exploratory endpoints will be analyzed analogously to primary and secondary endpoints, with 
the exception of a prespecified alpha-controlling testing strategy. Exploratory endpoints of 
dichotomous measurements will be analyzed analogously to primary endpoints. Exploratory 
endpoints of continuous measurements will be analyzed analogously to the secondary endpoint 
of change in physical function of HAQ-DI from baseline to Week 16. P-values for exploratory 
endpoints will be considered descriptive and not considered conclusive. 
All primary, secondary and exploratory endpoints defined for comparing izokibep 160 mg QW 
or izokibep 160 mg Q2W to placebo will also be reported for comparing izokibep 80 mg Q4W to 
placebo. 
Dose-response will be investigated through analyses of the primary and secondary endpoints, 
which will use all four treatment arms (izokibep 160 mg QW, izokibep 160 mg Q2W, izokibep 
80 mg Q4W and placebo) in a single analysis for each endpoint. A p-value for the global test of 
the hypothesis that all groups have identical response rates will be reported for each endpoint, 
not subject to type I error rate control or any multiple comparison procedure. P-values will also 
be reported for all pairwise comparisons for each endpoint. Dose-response relationships will be 
assessed qualitatively from these analyses. 


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Pharmacokinetic concentration data will be summarized by dose group at all planned collection 
times with mean, geometric mean, minimum, and maximum. Pharmacokinetic parameters will 
be determined where possible from the plasma concentrations of izokibep. Pharmacokinetic data 
collected from this study may be combined with PK data collected from other studies for a 
comprehensive modeling of drug concentrations. 
9.3.5. 
Safety Analyses 
Safety data will include summaries of exposure, AEs, TEAEs, SAEs, and laboratory data. No 
inferential statistics (p-values) will be reported for safety data. 
Exposure will include the number of doses administered (including complete and incomplete 
doses) and reasons for missed or incomplete doses. Exposure will be reported through the 
planned collection of the primary endpoint and for the entire study. For subjects assigned to 
receive placebo who later receive izokibep, exposure will further be summarized by placebo and 
izokibep. Compliance will be summarized by placebo and izokibep and by phase (placebo 
controlled and after crossing over to active). 
Adverse events and SAEs reported before the first administration of the study drug will be listed. 
All summaries will include only treatment-emergent events. The number of subjects who report 
1 or more AEs, the number who report 1 or more severe AEs, the number who report 1 or more 
SAEs, and the number who report 1 or more AEs that lead to discontinuation of study drug will 
be summarized by treatment group during the primary phase of the study and overall. Subjects 
assigned to receive placebo who later receive izokibep will additionally be summarized by phase 
(placebo-controlled and after crossing over to active). 
Laboratory data including ADAs will be summarized by treatment group and overall, at each 
planned collection timepoint. 
9.4. 
Interim Analysis and Early Stopping Rules 
No interim analyses will be conducted for the purpose of stopping the study or altering the study 
design. 
The DMC will review unblinded efficacy data when approximately 120 subjects have had the 
opportunity to complete the Week 12 visit. Data from the first 105 subjects randomly assigned to 
receive izokibep 160 mg QW, izokibep 160 mg Q2W or placebo will be used for these DMC 
summaries. The DMC may make a recommendation on further development activities for 
izokibep based on this data review. The DMC will not be empowered to recommend stopping 
this study or changing the sample size due to a demonstration of positive efficacy. The study 
team operationalizing the day-to-day of the study, the subjects, and the investigators will remain 
blinded to these interim results until after the study is completed.  
The primary analysis of primary and secondary endpoints will occur after all subjects have had 
an opportunity to complete the Week 16 assessments (have completed the Week 16 assessments, 
or have completed a subsequent timepoint assessment, or permanently discontinued the study 
before Week 16). For the primary and secondary objectives, this will include all data for all 
subjects for the final analysis, and so it will be the final analysis. The final analysis will be 
conducted at the end of the study when all subjects have completed the study or permanently 


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discontinued the study. For the primary endpoint, all available data at visits after Week 16 will 
be included in the summaries at these timepoints, but some subjects will be ongoing and may 
have data collected after the primary analysis is reported. Data collected at subsequent timepoints 
may be summarized when all data at that timepoint have been collected. All data collected for 
the primary endpoint for all subjects through the end of the study will be reported in a 
subsequent analysis, but the p-values from each comparison of a regimen of izokibep to placebo 
in this subsequent analysis will not be used for any alpha-preserving hypothesis testing. 
Investigators, site personnel, and all sponsor personnel who have contact with subjects will 
remain blinded to individual subject treatment assignments until the final analysis. 
When the primary efficacy analysis is conducted, safety data will be summarized. Summaries 
will include all safety data through Week 16 and all available safety data on all subjects through 
the end of the study. All safety data will be summarized through the end of the study when all 
subjects have completed all visits. 
At various timepoints after the primary analysis is reported, data may be summarized for 
regulatory submissions, to plan additional studies, or for other corporate needs. 
9.5. 
Sample Size Determination 
Response rates for ACR50 are expected to be 20% for placebo and 45% for a dose regimen of 
160 mg izokibep (QW or Q2W or both). With 100 subjects receiving placebo and 100 subjects 
receiving a dose regimen of 160 mg izokibep, there will be 97% power to show a difference in 
the primary endpoint of ACR50 response rate. If a 45% response rate is observed with a dose 
regimen of izokibep, the 2-sided 95% confidence interval for the true response rate will have a 
half-width of approximately 10 percentage points. 
Up to 60% of subjects are expected to have enthesitis at baseline, based on the LEI. Response 
rates, proportion of subjects who have LEI = 0 at Week 16, are expected to be 25% for placebo 
and 60% for subjects receiving izokibep, with on treatment groups combined. With 50 subjects 
with enthesitis at baseline receiving placebo and 50 subjects receiving a dose regimen of 
izokibep, there will be 95% power to show a difference in the secondary endpoint of resolution 
of enthesitis. A lower rate of enthesitis at baseline will result in a lower power, but power will be 
at least 80% with the same assumptions on response rate, if 30 subjects with enthesitis at 
baseline receive placebo and 30 subjects receive a dose regimen of izokibep. 
With 25 subjects receiving izokibep 80 mg Q4W, the 2-sided 95% confidence interval for the 
true response rate will have a half-width of up to approximately 20 percentage points. 
 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
o applicable International Council for Harmonisation (ICH) good clinical 
practice (GCP) guidelines 
o applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• Approval for protocols and any substantial amendments to the protocol that requires 
health authority approval prior to initiation will be obtained except for changes necessary 
to eliminate an immediate hazard to study subjects. 
• The investigator will be responsible for the following: 
• providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable) and all 
other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor or designee with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain, in a language and at a level of 
complexity understandable by the subject, the nature of the study, including the risks and 
benefits, to the subject and answer all questions regarding the study and its alternatives. 
• Subjects must be informed that their participation is voluntary, and they may withdraw 
their consent to participate in the study at any time. Subjects will be required to sign and 
date a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign and date 
the ICF. 
• If the Informed Consent form is amended during the study, subjects must be reconsented 
to the most current version of the ICF(s) during their participation in the study. 
• A copy of the ICF(s) must be provided to the subject. 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
30 days from the previous ICF signature date. 
 
10.1.4. 
Data Protection 
• Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
• The subject must be informed that the subject’s personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject who will be required to give consent for their data to be 
used as described in the informed consent. 
• The subject must be informed that the subject’s medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members and by inspectors from regulatory authorities. 
• The sponsor and investigator will implement appropriate measures to monitor and 
identify any breach of security leading to accidental or unlawful destruction, loss, 
alteration, unauthorized disclosure, or access to that data. In the event of a personal data 
breach, the sponsor and investigator will take appropriate measures to address the breach, 
including measures to mitigate its adverse effects. The investigator will notify the 
sponsor without undue delay after having become aware of the breach. Such notification 
will contain the details of a contact point where more information can be obtained, a 
description of the nature of the breach (including, where possible, categories and 
approximate number of data subjects and personal data records concerned), its likely 
consequences and the measures taken or proposed to address the breach including, where 


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appropriate, measures to mitigate its possible adverse effects. Upon becoming aware of 
any data breach, the sponsor will notify all competent data protection authorities of the 
breach, where required by local regulations. Where feasible and permissible by 
applicable law, such notification will occur within 72 hours of becoming aware of the 
breach. Such notification will contain the details of a contact point where more 
information can be obtained, a description of the nature of the breach (including, where 
possible, categories and approximate number of data subjects and personal data records 
concerned), its likely consequences and the measures taken or proposed to address the 
breach including, where appropriate, measures to mitigate its possible adverse effects. 
• Taking into account the nature, scope, context, and purpose of the processing, and the 
risks for the rights and freedoms of natural persons, the investigator will implement 
technical and organizational measures to ensure adequate security and confidentiality of 
the data. Such measures will include without limitation pseudonymization and data 
encryption in transit and at rest, identity and access management procedures to restrict 
physical and logical access to the data, network perimeter and endpoint protection using 
firewalls and other intrusion detection systems, documented policies taking account of 
the state of the art, and regular training of all personnel responsible for the processing of 
personal data. 
10.1.5. 
Dissemination of Clinical Study Data 
The results of the study will be reported in a clinical study report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Study subject identifiers will not be 
used in publication of results. Any work created in connection with the performance of the study 
and contained in the data that can benefit from copyright protection (except any publication by 
the investigator see Section 10.1.9) shall be the property of the sponsor as author and owner of 
copyright in such work. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law including posting company-sponsored study information on the US National 
Institutes of Health website www.clinicaltrials.gov. 
10.1.6. 
Monitoring and Data Quality Assurance 
• Qualified, assigned monitors from the sponsor (or designee) will conduct regular on-site 
and remote monitoring visits to monitor various aspects of the study. These visits and 
communications, along with regular inspection of the eCRFs, will be conducted to assess 
subject enrollment, compliance with protocol procedures, completeness and accuracy of 
data entered on the eCRFs, verification of data against source documents, and occurrence 
of AEs, etc. The investigator must provide the monitor with full access to all source and 
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• All subject data relating to the study will be recorded on eCRFs unless transmitted to the 
sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by signing the eCRF. 
• Guidance on completion of eCRFs will be provided. 
• The investigator or site staff will promptly report to the sponsor (or designee) all 
deviations that occur at their clinical site, and report protocol deviations to their IRB/EC 
according to local requirements 
• Sponsor (or designee) may audit investigator sites regarding, but not limited to, the 
informed consent process, presence of required documents, adherence to protocol, 
accountability and storage of drug supplies, comparison between eCRF with source 
documents, etc. All medical records and study-related documents must be available for 
audit, and the investigator and study staff agree to participate and cooperate in audits 
conducted in a reasonable manner. 
• Government regulatory authorities and ethics committees may also inspect the 
investigator site during or after the study. The investigator or designee should contact the 
sponsor (or its designee) immediately if this occurs. The investigator must cooperate fully 
with regulatory authorities or other audits conducted in a reasonable manner. 
• The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator 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 applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however if required by the applicable regulatory 
requirements or by an agreement with the sponsor. 
• No records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
• Quality tolerance limits will be defined before the start of the study and monitored by the 
CRO and sponsor during the course of the study. They will also be reported in the clinical 
study report. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress 


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notes), computer printouts, screening logs, and recorded data from automated 
instruments. Information from medical records and other source documents will be 
promptly transcribed to the appropriate section of the eCRF. The eCRF is not considered 
and should not be used as source documentation. 
• Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP and all applicable regulatory requirements. 
10.1.8. 
Study and Site Start and Closure 
Study Start 
The study start date is the date on which the first subject is enrolled into the study. 
Study/Site Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study drug development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by 
the investigator. 
• Total number of subjects included earlier than expected. 


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate subject therapy 
and/or follow-up. 
10.1.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. The clinical study agreement/site contract will cover additional 
details regarding publications. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2. 
Clinical Laboratory Tests 
• The tests detailed in Table 6 will be performed by the central laboratory. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• All study-required laboratory tests will be performed by a central laboratory, with the 
exception of: 
• urine pregnancy test 
• Investigators must document their review of each laboratory safety report. 


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Table 6. Protocol-required Safety Laboratory Tests 
















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• Investigator signature is required to be collected on the SAE Report Form prior to 
submission. With rare exception, the form may be sent without signature in order to 
meet the reporting deadline, however the investigator signature is required to be 
obtained as soon as possible after submission (refer to SAE Completion Guideline). 
 
 


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10.4. 
Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Woman of Childbearing Potential 
Women in the following categories are considered WOCBP (fertile): 
• Following menarche. 
• From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below). 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o A high follicle-stimulating hormone level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than 1 follicle-stimulating hormone measurement is required. 
o Females on HRT and whose menopausal status is in doubt will be required 
to use 1 of the nonestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical 
cause other than the above, (eg, Mullerian agenesis, androgen 
insensitivity, gonadal dysgenesis), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
• If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a 
menstrual cycle cannot be confirmed before first dose of study drug, 
additional evaluation should be considered. 


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10.4.2. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb that have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: Documentation of azoospermia for a male subject can come from the site personnel’s review of the 
subject’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb that are User Dependent Failure rate of < 1% per year when used consistently 
and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
• oral 
• intravaginal 
• transdermal 
• injectable. 
Progestogen-only hormone contraception associated with inhibition of ovulation 
• oral 
• injectable. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject. 
Effective Methodsc that are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods) 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 


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b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Considered effective, but not highly effective failure rate of ≥ 1% per year. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea methods are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction). 
 
 


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10.5. 
Liver Safety: Actions and Follow-up Assessments and Study drug 
Restart/Rechallenge Guidelines 
Phase 2 liver chemistry stopping criteria are designed to assure subject safety and to evaluate 
liver event etiology. The guidelines provided below are based on the EASL Clinical Practice 
Guidelines: Drug Induced Liver Injury (2019) and Food and Drug Administration 2009 
Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation. 
Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments 
 
 
Liver Chemistry Stopping Criteria 
ALT or AST-absolute ALT or AST ≥ 5 × ULN 
ALT or AST Increase ALT or AST ≥ 3 × ULN persists for ≥ 4 weeks 
Bilirubin1,2 
ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN (> 35% 
direct bilirubin) 
International 
Normalized Ratio 
(INR)2 
ALT or AST ≥ 3 × ULN and INR > 1.5 
Cannot Monitor 
ALT or AST ≥ 3 × ULN and cannot be monitored twice weekly for 
4 weeks 
Symptomatic3 
ALT or AST ≥ 3 × ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
 
Suggested Actions, Monitoring, and Follow-up Assessments  
Actions 
Follow-up Assessments 
• Immediately discontinue study drug. 
• Report the event to the sponsor/designee 
within 24 hours. 
• 
Complete a serious adverse event (SAE) 
eCRF if the event met the criteria for an SAE.2 
• Perform follow-up assessments as described 
in the Follow-up Assessment column. 
• Monitor the subject until liver chemistry test 
abnormalities resolve, stabilize, or return to 
baseline. 
• Viral hepatitis serology. 
• Obtain blood samples for 
pharmacokinetic (PK) analysis after 
the most recent dose.4 
• Obtain serum creatine phosphokinase, 
lactate dehydrogenase, gamma 
glutamyl transferase, glutamate 
dehydrogenase, and serum albumin. 
• Fractionate bilirubin if total bilirubin 
≥2 × ULN. 


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MONITORING: 
If ALT or AST ≥ 3 × ULN AND total bilirubin 
≥ 2 × ULN or INR > 1.5: 
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, and 
INR) and perform liver event follow-up 
assessments within 24 hours. 
• Monitor subject twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline. 
• A hepatology consultation is recommended. 
If ALT or AST ≥ 3 × ULN AND total bilirubin 
< 2 × ULN and INR ≤ 1.5: 
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, and 
INR) and perform liver chemistry follow-up 
assessments within 24 to 72 hours. 
• Monitor subjects twice weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline, or the study drug has been 
discontinued; then decrease monitoring to 
once weekly or less. 
• Do not restart/rechallenge subject with study 
drug unless allowed per-protocol and sponsor 
approval is granted. 
 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the eCRF. 
• Record use of concomitant 
medications (including acetaminophen, 
herbal remedies, and other over-the-
counter medications) on the 
concomitant medications eCRF. 
• Record alcohol use on the liver event 
alcohol intake form. 
If ALT or AST ≥3 × ULN AND total 
bilirubin ≥2 × ULN or INR > 1.5 obtain 
the following in addition to the 
assessments listed above: 
• Antinuclear antibody, anti-smooth 
muscle antibody, type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G or 
gamma globulins. 
• Serum acetaminophen adduct assay, 
when available, to assess potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) to evaluate liver disease. 
• Liver biopsy may be considered and 
discussed with local specialist if 
available, for instance: 
o In subjects when serology raises 
the possibility of autoimmune 
hepatitis. 


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o In subjects when suspected 
drug-induced liver injury 
progresses or fails to resolve on 
withdrawal of study drug. 
o In subjects with acute or chronic 
atypical presentation. 
• If liver biopsy conducted provides 
biopsy information. 
Abbreviation: ALT = alanine transaminase; AST = aspartate transaminase; eCRF = electronic case report form; 
ULN = upper limit of normal. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing 
is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative 
of direct bilirubin elevations suggesting liver injury. 
2. All events of ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT or AST 
≥ 3 × ULN and INR > 1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to 
sponsor in an expedited manner and as an SAE. The INR stated threshold value will not apply to subjects 
receiving anticoagulants. 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
4. Record the date/time of the PK blood sample draw and the date/time of the last dose of study drug prior to the 
blood sample draw on the eCRF. If the date/time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the Study Laboratory Manual. 
 
 


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10.6. 
Abbreviations and Definitions 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ACR20 
American College of Rheumatology 20% 
ACR50 
American College of Rheumatology 50% 
ACR70 
American College of Rheumatology 70% 
ADA  
anti-drug antibody 
AE  
adverse event 
anti-CCP 
anti-cyclic citrullinated peptide 
AUC 
area under the concentration-time curve 
AUC0-τ  
area under the concentration-time curve over the dose interval 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
BSA 
body surface area 
CASPAR 
ClASsification of Psoriatic Arthritis criteria 
cDAPSA 
CFR 
clinical Disease Activity in Psoriatic Arthritis 
Code of Federal Regulations 
Cmax 
maximum observed plasma concentration 
COVID-19  
coronavirus disease of 2019 
CRO  
contract research organization 
CRP 
C-reactive protein 
CV% 
coefficient of variation 
csDMARD 
conventional-synthetic disease-modifying anti-rheumatic drugs 
DAPSA 
Disease Activity in Psoriatic Arthritis 
DAS28 
Disease Activity Score in 28 joints 
DMARD 
disease-modifying antirheumatic drug 
DMC  
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG  
electrocardiogram 
EDC 
electronic data capture 
FACIT-F 
Functional Assessment of Chronic Illness Therapy – Fatigue 
eCRF  
electronic case report form 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression scale 


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Abbreviation 
Definition 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV  
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IA 
intra-articular 
IBD 
inflammatory bowel disease 
ICF  
informed consent form 
ICH  
International Council for Harmonisation 
IEC  
independent ethics committee 
IL  
interleukin 
IM 
intramuscular 
IRB  
institutional review board 
IV 
intravenous(ly) 
IXRS  
Interactive Response Technology 
JAK 
janus kinase 
LEI 
Leeds Enthesitis Index 
MCS 
Mental Component Summary 
MDA 
minimal disease activity 
mNAPSI 
modified Nail Psoriasis Severity Index 
mTSS 
modified total Sharp score 
NOAEL 
no observed adverse effect level 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
PASDAS 
Psoriatic Disease Activity Score 
PASI 
Psoriasis Area and Severity Index 
PASI90 
Psoriasis Area and Severity Index response of 90% 
PCR 
polymerase chain reaction 
PCS 
Physical Component Summary 


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Abbreviation 
Definition 
PK  
pharmacokinetic(s) 
PsA 
psoriatic arthritis 
PsAID 
Psoriatic Arthritis Impact of Disease 
PsO 
Psoriasis 
QW 
every week 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
RF 
rheumatoid factor 
SAE  
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 
SC 
subcutaneous(ly) 
SF-36 
Short Form-36v2 Health Survey 
SoA 
Schedule of Activities 
SPARCC 
Spondyloarthritis Research Consortium of Canada 
t½ 
half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
Th  
T-helper  
tmax 
time to maximum observed concentration 
TNF 
tumor necrosis factor-alpha 
TNFi  
tumor necrosis factor-alpha inhibitor(s) 
US  
United States 
VAS 
visual analogue scale 
VLDA 
very low disease activity 
WOCBP 
women of childbearing potential 
WPI 
Widespread Pain Index 
 
 
 


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11. 
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Augustin M, Radtke MA. Arzneimitteltherapie der Psoriasis-Arthritis. Arzneimitteltherapie. 
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Bond SJ, Farewell VT, Schentag CT, Gladman DD. Predictors for radiological damage in 
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Cassell SE, Bieber JD, Rich P, et al. The modified Nail Psoriasis Severity Index: validation of an 
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Gladman DD, Antoni C, Mease P, et al. Psoriatic arthritis: epidemiology, clinical features, 
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Gladman DD. Mortality in psoriatic arthritis. Clin Exp Rheumatol. 2008;26(51):62-65. 
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Gladman DD, Ziouzina O, Thavaneswaran A, Chandran V. Dactylitis in psoriatic arthritis: 
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Husted JA, Gladman DD, Farewell VT, Cook RJ. Health-related quality of life of patients with 
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2001;45:151-158. 
Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The direct cost of care for psoriasis and 
psoriatic arthritis in the United States. J Am Acad Dermatol. 2002;46:850–860. 
Kaeley GS, Eder L, Aydin SZ, Gutierrez M, Bakewell C. Dactylitis: A hallmark of psoriatic 
arthritis. Semin Arthritis Rheum. 2018;48(2):263-273. 
Kehl AS, Corr M, Weisman MH. Review: Enthesitis: New insights into pathogenesis, diagnostic 
modalities, and treatment. Arthritis Rheumatol. 2016;68(2):312-322. 
Langley R, Feldman S, Han C, et al. Ustekinumab significantly improves symptoms of anxiety, 
depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: Results 
from a randomized, double-blind, placebo-controlled phase 3 trial. J Am Acad of Dermatol. 
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Mease PJ. Measures of Psoriatic Arthritis: Tender and Swollen Joint Assessment, Psoriasis Area 
and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis 
Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index 
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in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). 
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Merola JF, Li T, Li WQ, Cho E, Qureshi AA. Prevalence of psoriasis phenotypes among men 
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Patel NU, Vera NC, Shealy ER, et al. A review of the use of secukinumab for psoriatic arthritis. 
Rheumatol Ther. 2017;4(2):233–246. 


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SAP_001.pdf: 
Protocol Number: 22104 
 
Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b/3 Study to 
Evaluate the Efficacy and Safety of Izokibep in Subjects with Active Psoriatic Arthritis 
 
NCT Number: NCT05623345 
 
Document Date: 09 January 2024 


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Statistical Analysis Plan 
A Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2b/3 
Study to Evaluate the Efficacy and Safety of Izokibep in Subjects with 
Active Psoriatic Arthritis 
Statistical Analysis Plan: Final 
Statistical Analysis Plan: 2.0 
Statistical Analysis Plan Date: 09JAN2024 
Investigational Product: Izokibep 
Protocol Reference: 22104 
 
Sponsor: ACELYRIN, INC. 
 
 
 
 
Author: 
 
Senior Principal Biostatistician 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 
 
 


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Table of Contents 
Glossary of Abbreviations ....................................................................................................... 7 
1. Source Documents ............................................................................................................... 9 
2. Protocol Details .................................................................................................................. 10 
2.1. Overall Study Design .................................................................................................. 10 
2.2. Study Objectives ......................................................................................................... 12 
2.2.1. Primary Objective ................................................................................................. 12 
2.2.2. Secondary Objectives ........................................................................................... 12 
2.2.3. Exploratory Objectives ......................................................................................... 12 
2.3. Sample Size and Power ............................................................................................... 16 
2.4. Primary Efficacy Variable ........................................................................................... 16 
2.5. Secondary Efficacy Variables ..................................................................................... 16 
2.6. Exploratory Efficacy Variables ................................................................................... 17 
2.7. Safety Variables .......................................................................................................... 19 
2.7.1. Adverse Events, Serious Adverse Events, and Other Safety Reporting ............... 19 
2.7.1.1. Events of Special Interest............................................................................... 19 
2.7.2. Clinical Safety Laboratory Tests .......................................................................... 19 
2.7.3. Vital Signs ............................................................................................................. 20 
2.7.4. Physical Examination ............................................................................................ 20 
2.7.5. Electrocardiograms ............................................................................................... 21 
2.7.6. Hospital Anxiety and Depression Scale ............................................................... 21 
2.7.7. Pharmacokinetics Variable(s) ............................................................................... 21 
2.8. Immunogenicity .......................................................................................................... 21 
3. Estimands ........................................................................................................................... 22 
3.1. Estimand for the Primary Objective ............................................................................ 22 
3.1.1. Treatment Condition of Interest ........................................................................... 22 
3.1.2. Population of Subjects Targeted by the Clinical Question ................................... 22 
3.1.3. Variable Obtained from Each Subject Required to Address the Clinical 
Question .......................................................................................................................... 22 
3.1.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest ...... 23 
3.1.5. Population-level Summary for Comparison between Treatment Conditions....... 23 


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3.2. Estimands for the secondary objectives ...................................................................... 23 
3.2.1. Treatment Condition of Interest ........................................................................... 23 
3.2.2. Population of Subjects Targeted by the Clinical Question ................................... 24 
3.2.3. Variable Obtained from Each Subject Required to Address the Clinical 
Question .......................................................................................................................... 25 
3.2.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest ...... 25 
3.2.5. Population-level Summary for Comparison between Treatment Conditions....... 25 
4. Analysis Sets ...................................................................................................................... 27 
4.1. All Screened Set .......................................................................................................... 27 
4.2. Full Analysis Set ......................................................................................................... 27 
4.3. Safety Analysis Set...................................................................................................... 27 
4.4. Pharmacokinetics Analysis Set ................................................................................... 27 
4.5. ADA Analysis Set ....................................................................................................... 27 
5. Data Handling .................................................................................................................... 28 
5.1. Time Points and Visit Windows.................................................................................. 28 
5.1.1. General Definitions ............................................................................................... 28 
5.1.2. Screening Period ................................................................................................... 28 
5.1.3. Treatment Period .................................................................................................. 28 
5.1.4. Visit Windows ...................................................................................................... 29 
5.2. Handling of Dropouts, Missing Data, and Outliers ..................................................... 30 
5.2.1. Handling of Missing Efficacy Data ...................................................................... 30 
5.2.2. Handling of Missing Safety Data ......................................................................... 31 
5.2.3. Handling of Missing Age and Partial and Missing Dates for Adverse Events, 
Prior/Concomitant Medications...................................................................................... 31 
5.2.4. Handling of Plasma Concentrations that are Below the Lower Limit of 
Quantification ................................................................................................................. 32 
6. Statistical Methods ............................................................................................................. 33 
6.1. General Principles ....................................................................................................... 33 
6.2. Subject Disposition and Data Sets Analyzed .............................................................. 34 
6.3. Protocol Deviations ..................................................................................................... 35 
6.4. Demographic and Other Baseline Characteristics ....................................................... 36 


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6.4.1. Demographic Characteristics................................................................................ 36 
6.4.2. Baseline Characteristics........................................................................................ 36 
6.4.3. Medical History .................................................................................................... 39 
6.4.4. Prior and Concomitant Medications/Procedures .................................................. 39 
6.5. Measurements of Study Drug Compliance ................................................................. 40 
6.6. Efficacy ....................................................................................................................... 41 
6.6.1. Primary Efficacy Analysis .................................................................................... 42 
6.6.2. Supplementary Analyses for the Primary Efficacy Analysis ............................... 44 
6.6.3. Secondary Efficacy Analysis ................................................................................ 46 
6.6.4. Supplementary Analyses for the Secondary Efficacy Analysis ........................... 47 
6.6.5. Exploratory Analysis ............................................................................................ 48 
6.6.6. Subgroup Analysis................................................................................................ 52 
6.7. Safety ........................................................................................................................... 54 
6.7.1. Extent of Exposure ............................................................................................... 54 
6.7.2. Adverse Events ..................................................................................................... 55 
6.7.3. Laboratory Evaluations ........................................................................................ 58 
6.7.3.1. Liver toxicity review ...................................................................................... 59 
6.7.4. Vital Signs ............................................................................................................ 61 
6.7.5. Electrocardiograms ............................................................................................... 61 
6.7.6. Physical Examination ........................................................................................... 62 
6.7.7. Interim Analysis and Data Monitoring ................................................................. 62 
6.8. Pharmacokinetic Assessments..................................................................................... 63 
6.9. Anti-Drug Antibodies .................................................................................................. 63 
7. Appendices ......................................................................................................................... 65 
Appendix 1: Document History ......................................................................................... 65 
Appendix 2: End Points Definitions and Scoring Method ................................................. 65 
Appendix 2.1 Health Assessment Questionnaire Disability Index (HAQ-DI) ............... 65 
Appendix 2.2 36-Item Short Form Survey (SF-36)........................................................ 67 
Appendix 2.3 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 71 


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Appendix 2.4 Disease Activity Score in 28 joints-C-reactive protein (DAS28-CRP) ... 72 
Appendix 2.5 Disease Activity index for Psoriatic Arthritis (DAPSA) ......................... 73 
Appendix 2.6 Psoriatic Arthritis Disease Activity Score (PASDAS) ............................ 74 
Appendix 2.7 Psoriatic Arthritis Impact of Disease Scoring and Calculation Rules 
(PsAID)........................................................................................................................... 75 
Appendix 2.8 Psoriasis Area and Severity Index and Affected Body Surface Area 
(PASI) ............................................................................................................................. 76 
Appendix 2.9 modified Nail Psoriasis Severity Index (mNAPSI) ................................. 78 
Appendix 2.10 van der Heijde modified Total Sharp Score (mTSS) ............................. 79 
Appendix 2.11 Minimal Disease Activity (MDA) and Very Low Disease Activity 
(VLDA) .......................................................................................................................... 80 
8. References .......................................................................................................................... 81 
 


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List of Tables 
 
Table 1 Laboratory Tests ....................................................................................................... 20 
Table 2 Definition of Time Point Windows for Efficacy Analyses ....................................... 29 
 
 








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2. Protocol Details 
2.1. Overall Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 2b/3 Study to 
evaluate the clinical question of the effects of the efficacy and safety of izokibep in subjects 
with active psoriatic arthritis (PsA) who are tumor necrosis factor-alpha inhibitor (TNFi) 
naïve, who have had an inadequate response or intolerance to TNFi, or for whom TNFi is 
contraindicated. Approximately 325 subjects with active PsA will be enrolled. The study 
consists of up to a 28-day (4-week) screening period, a 51-week treatment period, and a 
follow-up period with visits at 8 weeks and 14 weeks after the last dose of study drug to assess 
safety and immunogenicity. 
Subjects meeting eligibility criteria will be randomized into 1 of 4 treatment groups in a 
4:4:4:1 ratio as follows: 
• 
Group 1 (n=100): placebo every week (QW) from Day 1/Week 0 to Week 15, then 
izokibep 160 mg QW from Week 16 to Week 51. 
• 
Group 2 (n=100): izokibep 160 mg QW from Day 1/Week 0 to Week 51.  
• 
Group 3 (n=100): izokibep 160 mg every 2 weeks (Q2W) from Day 1/Week 0 to Week 
50, with matching placebo Q2W until Week 51 for the weeks in between izokibep 
doses to maintain the blind. 
• 
Group 4 (n=25): izokibep 80 mg every 4 weeks (Q4W) from Day 1/Week 0 to Week 
48, with matching placebo QW until Week 51 for the weeks in between izokibep doses 
to maintain the blind.  
Randomization will be stratified by prior TNFi use (Yes/No) and enthesitis (Leeds Enthesitis 
Index [LEI] > 0/LEI = 0). Anticipated enrollment of subjects previously treated with TNFi is 
20% to 30%.  The number of subjects without enthesitis entering into the study (LEI = 0 at 
baseline) will be capped at 70%. 
Subjects will complete study assessments according to the study visits outlined in the 
Schedule of Activities (SoA) in the protocol. The primary endpoint will be assessed at Week 
16. The last dose of study drug will be administered on Week 51.  
Starting at Week 24, subjects who do not meet clinical Disease Activity for PsA (cDAPSA) 
low disease activity (cDAPSA ≤14) at 2 consecutive visits (e.g. at Week 20 and Week 24) 
will be discontinued from study drug and can receive standard of care as deemed appropriate 
by the investigator. 
An End of Treatment (EOT) visit will be conducted at Week 52. A Safety Follow-up visit will 
be conducted at Week 59. A pharmacokinetic/anti-drug antibody (PK/ADA) Follow-up and 


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End of Study Visit will be conducted at Week 65. For subjects that prematurely discontinue 
study drug for any reason, the EOT visit should be completed within 14 days of withdrawal, 
Safety follow-up visit should be completed at 8 weeks and PK/ADA follow-up visit should 
be completed 14 weeks after the last dose of study drug, respectively, where possible. Subjects 
should continue to complete study assessments as outlined in the SoA (Section 1.3 of 22104 
protocol) where possible, with the exception of study drug administration and anti-drug 
antibody sample and PK sample collection. 
The final analysis of primary and secondary endpoints will be conducted after the last subject 
has had the opportunity to complete Week 16 assessments or prematurely discontinues the 
study drug and/or study. 
Before database lock, an error was discovered in dosing for subjects who were randomized to 
receive izokibep 160 mg every 2 weeks (Q2W) from Day 1/Week 0 to Week 50, with 
matching placebo Q2W and subjects who were randomized to receive izokibep 80 mg every 
4 weeks (Q4W) from Day 1/Week 0 to Week 48, with matching placebo QW until Week 51. 
Subjects were assigned study drug in groups of four visits at a time. The order in which the 
subject was instructed to receive the drug was incorrect. Therefore, each subject was assigned 
the correct amount of study drug over each 4-week period, but possibly in the wrong sequence, 
resulting in subjects who were randomized to receive active drug Q2W receiving active drug 
on two or more consecutive weeks and/or placebo at two or more consecutive weeks. Subjects 
who were randomized to receive active drug Q4W similarly received active drug at two or 
more consecutive weeks and/or placebo at four or more consecutive weeks. As a result of this 
error, the following changes were made to the analysis plan: 
 Testing of all primary and secondary endpoints, comparing izokibep Q2W versus 
placebo, will only be done after testing of all primary and secondary endpoints, 
comparing izokibep QW versus placebo, in the alpha-controlled testing sequence. 
o Justification: subjects randomized to receive izokibep Q2W received the 
correct amount of study drug, but in incorrect order. Some quantities will be 
as planned (total drug received, possibly area under the concentration-time 
curve) while others may not (Ctrough, Cmax, possibly area under the concentration-
time curve). Therefore the group that was treated as planned will be tested first, 
and the group treated not as planned will be tested second. 
 Exploratory analyses of the impact of incorrect dosing will be evaluated during 
Period 1. 
o Subjects randomized to receive izokibep Q2W will be grouped according to 
the largest number of consecutive doses of active drug received to understand 
the impact of various dosing schedules on outcome. 


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 Summaries of subjects dosed correctly at earlier time points (week 4 and 12 for the 
primary endpoint). 
2.2. Study Objectives 
2.2.1. Primary Objective 
The primary objective of the study is to demonstrate that 1 or both regimens of izokibep (160 
mg QW and 160 mg Q2W) are efficacious compared to placebo, as measured by the 
proportion of subjects achieving 50% improvement in ACR core set measurements (ACR50) 
at Week 16. 
2.2.2. Secondary Objectives 
The secondary objectives of the study are: 
 To demonstrate that 1 or both regimens of izokibep are efficacious (160 mg QW and 
160 mg Q2W) compared to placebo, as measured by: 
o Proportion of subjects achieving 90% or greater reduction in PASI score from 
baseline (PASI90) at Week 16 in subjects with ≥3% BSA psoriasis at baseline  
o Proportion of subjects with resolution of enthesitis at Week 16 as assessed by 
LEI in subpopulation that had enthesitis (LEI >0) at baseline 
o Proportion of subjects achieving minimal disease activity (MDA) at Week 16 
o Proportion of subjects achieving 20% improvement in ACR core set 
measurements (ACR20) at Week 16 
o Proportion of subjects achieving an improvement in PsAID of at least 3 units 
at Week 16 compared to baseline in subjects with PsAID ≥3 at baseline  
o Change in physical function as assessed by HAQ-DI change from baseline to 
Week 16  
 To assess the safety and tolerability of izokibep as measured by the incidence of 
Treatment Emergent Adverse Events (TEAEs), events of interest, Serious Adverse 
Events (SAEs), and clinically significant laboratory values and vital signs 
 To assess the immunogenicity of izokibep as measured by the presence of ADAs 
2.2.3. Exploratory Objectives 
The exploratory objectives of the study are: 
 To demonstrate that 1 or both regimens of izokibep (160 mg QW and 160 mg Q2W) 
are efficacious compared to placebo, as measured by:  
o Proportion of subjects achieving 70% improvement in ACR core set 
measurements (ACR70) at Weeks 16, 24, and 52 
o Change in DAS28-CRP at Weeks 16, 24, and 52 as compared to baseline  


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o Change in DAPSA score at Weeks 16, 24, and 52 as compared to baseline  
o Change in clinical DAPSA (cDAPSA) score at Week 16, 24, and 52, as 
compared to baseline  
o Proportion of subjects achieving DAPSA and cDAPSA low disease activity or 
remission at Week 16, 24, and 52  
o Proportion of subjects achieving DAPSA and cDAPSA remission at Week 16, 
24, and 52  
o Change in PASDAS at Weeks 16, 24, and 52 as compared to baseline  
o Proportion of subjects achieving 75% or greater reduction in PASI score from 
baseline (PASI75) at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis 
at baseline  
o Proportion of subjects achieving PASI90 at Weeks 24 and 52 in subjects with 
≥3% BSA psoriasis at baseline  
o Proportion of subjects achieving 100% reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis at 
baseline  
o Proportion of subjects achieving 75% or greater reduction in PASI score from 
baseline (PASI75) at Weeks 16, 24, and 52 in subjects with ≥ 10% BSA 
psoriasis at baseline 
o Proportion of subjects achieving PASI90 at Weeks 16, 24 and 52 in subjects 
with ≥10% BSA psoriasis at baseline  
o Proportion of subjects achieving 100% reduction in PASI score from baseline 
(PASI100) at Weeks 16, 24, and 52 in subjects with ≥ 10% BSA psoriasis at 
baseline 
o Proportion of subjects achieving PASI90 at weeks 16, 24, and 52 in subjects 
with baseline PASI score >10  
o Proportion of subjects achieving PASI100 at weeks 16, 24, and 52 in subjects 
with baseline PASI score >10  
o Proportion of subjects achieving MDA at Weeks 24, and 52  
o Proportion of subjects achieving VLDA response at Weeks 16, 24, and 52  
o Proportion of subjects with resolution of dactylitis at Weeks 16, 24, and 52 in 
subpopulation that had dactylitis at baseline (pooled izokibep doses), as 
assessed with Leeds Dactylitis Index (LDI)  
o Change from baseline in mNAPSI at Weeks 16, 24, and 52 in subpopulation 
with nail psoriasis at baseline (pooled izokibep doses)  
o Progression of structural damage assessed radiographically and expressed as 
the change in mTSS at Weeks 16 and 52, compared to baseline  
o Change in SPARCC enthesitis score at Weeks 16, 24, and 52, as compared to 
baseline in subpopulation with enthesitis (SPARCC >0) at baseline  


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o Change in spinal pain NRS at Weeks 16, 24, and 52, as compared to baseline 
in subjects reporting spinal pain at baseline  
o Change from baseline in spine pain NRS in those with sacroiliitis on pelvic 
x-ray at Weeks 16, 24 and 52 
o Change from baseline in spine pain NRS in those with investigator assessed 
spinal involvement at Weeks 16, 24 and 52 
o Association of investigator assessed sacroiliac involvement with sacroiliitis 
on x-ray 
o Proportion of subjects achieving each MDA component (TJC68, SJC66, 
PASI, BSA, SAPVAS, SGADA, HAQ-DI, tender entheseal points from LEI) 
at Weeks 16, 24 and 56 
o Change in quality of life as assessed by SF-36 total score, physical component 
summary (PCS), and mental component summary (MCS) change from 
baseline to Weeks 16, 24, and 52  
o Fatigue as assessed by FACIT-F change from baseline to Weeks 16, 24, and 
52  
o Proportion of subjects achieving ACR50 at Weeks 24 and 52  
o Proportion of subjects with resolution of enthesitis at Weeks 24 and 52 as 
assessed by LEI in subpopulation that had enthesitis (LEI >0) at baseline  
o Proportion of subjects achieving an improvement in PsAID of at least 3 units 
at Weeks 24 and 52 compared to baseline in subjects with PsAID ≥3 at baseline  
o Proportion of subjects achieving ACR20 at Weeks 24 and 52 
o Mean (median) ACR-N at Week 16, where, ACR-N is defined as the largest 
number N such that ACR-N is met (analogous to the primary endpoint 
definition of ACR 50) 
o Change in enthesitis at Weeks 16, 24 and 52 as assessed by change from 
baseline in LEI 
o Time to resolution of enthesitis at weeks 4, 12 and 16 among subjects with 
enthesitis (LEI > 0) at baseline 
o Occurrence of enthesitis (LEI > 0)  at weeks 4, 12 and 16 among subjects 
without enthesitis (LEI = 0) at baseline 
o Depression and anxiety as assessed by change in HADS score from baseline 
to Weeks 16 and 52 
o Change in physical function as assessed by HAQ-DI change from baseline to 
Weeks 24 and 52  
o Proportion of subjects with a decrease of at least 2 from baseline in LEI, 
among subjects with baseline LEI of at least 2, at weeks 4, 12 and 16 
o Subject's Global Impression of Change Questionnaire at weeks 16 and 52 
o Mean (median) Area under the curve (AUC) for ACR-N through week 16 
o Change from baseline in LEI at Weeks 16, 24 and 52 
o Time to first achievement of ACR50 


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o Time to first achievement of PASI90 among subjects with at least 3% BSA at 
baseline 
o Time to first achievement of MDA 
o Time to first achievement of ACR20 
o Time to first achievement of PsAID improvement of at least 3 among subjects 
with PsAID at least 3 at baseline 
o Time to first achievement of PASI100 among subjects with at least 3% BSA 
at baseline 
 
 To investigate whether 1 or both regimens of izokibep (160 mg QW and 160 mg Q2W) 
are efficacious compared to placebo, in the subpopulation with enthesitis as baseline, 
as measured by: 
o Proportion of subjects achieving an improvement in PsAID of at least 3 units 
at Week 16 compared to baseline in subjects with PsAID ≥3 at baseline 
o Change from baseline in PsAID at Week 16 
o Proportion of subjects with a HAQ-DI decrease of at least 0.35 at Week 16 
compared to baseline in subjects with HAQ-DI >0.35 at baseline (Response to 
HAQ-DI at Week 16) 
o Change in physical function as assessed by HAQ-DI change from baseline to 
Week 16 
o Proportion of subjects achieving MDA at Week 16 
o Change in DAPSA and cDAPSA at Week 16 as compared to baseline 
o Proportion of subjects achieving VLDA at Week 16 
o Change in quality of life as assessed by SF-36 total score, physical component 
summary (PCS), and mental component summary (MCS) change from 
baseline to Weeks 16 
o Proportion of subjects achieving individual MDA components at Week 16 as 
compared to baseline 
 To investigate the relationship between ACR50 response and other factors 
o  Association of baseline positive WPI ≥7 with ACR50 response  
 To investigate that the 80 mg Q4W regimen is efficacious compared to placebo, as 
measured by the same primary, secondary and exploratory endpoints  
 To compare the three regimens of izokibep for assessment of dose-response 
relationships, as measured by the primary and secondary endpoints  
 To evaluate the pharmacokinetics of izokibep in subjects with PsA 
 To evaluate the immunogenicity of izokibep in subjects with PsA 


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2.3. Sample Size and Power 
Response rates for ACR50 are expected to be 20% for placebo and 45% for a dose regimen 
of 160 mg izokibep (QW or Q2W or both). With 100 subjects receiving placebo and 100 
subjects receiving a dose regimen of 160 mg izokibep, there will be 97% power to show a 
difference in the primary endpoint of ACR50 response rate. If a 45% response rate is observed 
with a dose regimen of izokibep, the 2-sided 95% confidence interval for the true response 
rate will have a half-width of approximately 10 percentage points. 
Up to 60% of subjects are expected to have enthesitis at baseline, based on the LEI. Response 
rates, proportion of subjects who have LEI = 0 at Week 16, are expected to be 25% for placebo 
and 60% for subjects receiving izokibep. With 50 subjects with enthesitis at baseline receiving 
placebo and 50 subjects receiving a dose regimen of izokibep, there will be 95% power to 
show a difference in the secondary endpoint of resolution of enthesitis. A lower rate of 
enthesitis at baseline will result in a lower power, but power will be at least 80% with the 
same assumptions on response rate, if 30 subjects with enthesitis at baseline receive placebo 
and 30 subjects receive a dose regimen of izokibep. 
With 25 subjects receiving izokibep 80 mg Q4W, the 2-sided 95% confidence interval for the 
true response rate will have a half-width of up to approximately 20 percentage points. 
2.4. Primary Efficacy Variable 
The primary efficacy variable for the study is the ACR50 response rate, defined as the 
proportion of subjects who achieve a 50% improvement from baseline in ACR core set 
measurements. The primary timepoint for analysis is Week 16.  
ACR50 criteria require that the subject experiences an improvement in the following 
parameters compared to baseline: 
 ≥50% reduction in 68 Tender Joint Count (TJC68)  
 ≥50% reduction in 66 Swollen Joint Count (SJC66) 
 ≥50% reduction in 3 of 5 additional measures:  
o Subject’s Assessment of Pain (SAPVAS) 
o Subject’s Global Assessment of Disease Activity (SGADA) 
o Investigator’s Global Assessment of Disease Activity (IGADA) 
o HAQ-DI 
o Acute phase reactant (C-reactive protein [CRP])  
2.5. Secondary Efficacy Variables 
The secondary efficacy variables of the study are:  


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 PASI90 at Week 16 in subjects with ≥3% BSA psoriasis at baseline 
 Resolution of enthesitis (LEI >= 0) at Week 16  
 MDA at Week 16  
 ACR20 at Week 16   
 PsAID response at Week 16 in subjects with PsAID ≥3 at baseline 
 HAQ-DI change from baseline to Week 16  
 
2.6. Exploratory Efficacy Variables 
The exploratory efficacy variables of the study are: 
 ACR70 at Weeks 16, 24, and 52  
 Change in DAS28-CRP at Weeks 16, 24, and 52 
 Change in DAPSA at Weeks 16, 24, and 52  
 Change in cDAPSA at Weeks 16, 24, and 52  
 DAPSA ≤14 at Weeks 16, 24, and 52  
 cDAPSA ≤14 at Weeks 16, 24, and 52  
 DAPSA ≤4 at Weeks 16, 24, and 52  
 cDAPSA ≤4 at Weeks 16, 24, and 52  
 Change in PASDAS at Weeks 16, 24, and 52  
 PASI75 at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis at baseline 
 PASI90 at Weeks 24 and 52 in subjects with ≥3% BSA psoriasis at baseline  
 PASI100 at Weeks 16, 24, and 52 in subjects with ≥3% BSA psoriasis at baseline 
 PASI75 at Weeks 16, 24, and 52 in subjects with ≥10% BSA psoriasis at baseline 
 PASI90 at Weeks 16, 24 and 52 in subjects with ≥10% BSA psoriasis at baseline  
 PASI100 at Weeks 16, 24, and 52 in subjects with ≥10% BSA psoriasis at baseline 
 PASI90 at Weeks 16, 24, and 52 in subjects with baseline PASI score ≥10 
 PASI100 at Weeks 16, 24, and 52 in subjects with baseline PASI score ≥10 
 MDA at Weeks 24, and 52  
 VLDA at Weeks 16, 24, and 52  
 Resolution of dactylitis (LDI=0) at Weeks 16, 24, and 52 in subjects with LDI >0 at 
baseline 
 Change in mNAPSI at Weeks 16, 24, and 52 in subjects with mNAPSI >0 at baseline 
 Change in mTSS at Weeks 16 and 52  
 Change in SPARCC enthesitis score at Weeks 16, 24, and 52 in subjects with 
SPARCC >0 at baseline 
 Change in spinal pain NRS at Weeks 16, 24, and 52  
 Change from baseline in spine pain NRS in those with sacroiliitis on pelvic x-ray at 
Weeks 16, 24 and 52 


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 Change from baseline in spine pain NRS in those with investigator assessed spinal 
involvement at Weeks 16, 24 and 52 
 Correlation of investigator assessed spinal involvement with sacroiliitis on x-ray 
 Proportion of subjects achieving MDA component (TJC68, SJC66, PASI, BSA, 
SAPVAS, SGADA, HAQ-DI, tender entheseal points from LEI) at Week 16 
 Change in SF-36 total score, physical component summary (PCS), and mental 
component summary (MCS) at Weeks 16, 24, and 52  
 Change in FACIT-F at Weeks 16, 24 and 52  
 ACR50 at Weeks 24 and 52  
 HAQ-DI change from baseline to Weeks 16, 24 and 52  
 Resolution of enthesitis (LEI = 0) at Weeks 24 and 52  
 PsAID response at Weeks 24 and 52 in subjects with PsAID ≥3 at baseline 
 ACR20 at Weeks 24 and 52  
 ACR-N at week 16 
 Change from baseline in LEI at Week 16, 24, 52 
 Time to resolution of enthesitis at weeks 4, 12 and 16 among subjects with enthesitis 
(LEI > 0) at baseline 
 Occurrence of enthesitis (LEI > 0) at week 4, 12 and 16 among subjects without 
enthesitis (LEI = 0) at baseline  
 HADS change from baseline to Weeks 16 and 52 
 Decrease of at least 2 from baseline in LEI, among subjects with baseline LEI of at 
least 2, at weeks 4, 12 and 16 
 Subject's Global Impression of Change Questionnaire at weeks 16 and 52 
 AUC for ACR-N through week 16 
 Time to first achievement of ACR50 
 Time to first achievement of PASI90 among subjects with at least 3% BSA at baseline 
 Time to first achievement of MDA 
 Time to first achievement of ACR20 
 Time to first achievement of PsAID improvement of at least 3 among subjects with 
PsAID at least 3 at baseline 
 Time to first achievement of PASI100 among subjects with at least 3% BSA at 
baseline 
 Trough plasma concentrations of izokibep at collected timepoints 
 Presence of anti-drug antibodies (positive or negative) 


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2.7. Safety Variables 
2.7.1. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an Adverse Event (AE) or SAE. The investigator 
is responsible for following up on all AEs that are serious, considered related to the study 
drug or study procedures, or that caused the subject to discontinue the study drug. 
2.7.1.1. Events of Special Interest 
Based on the class effects or potential risks with IL-17 inhibitors, the following events of 
special interest will be monitored:  
 Candida infection  
 Inflammatory bowel disease 
In addition, based on the potential risk with an IL-17 receptor inhibitor the following events 
of special interest will also be monitored: 
 Suicidal ideation 
 Malignancies  
 Major cardiovascular and cerebrovascular events (MACE): cerebrovascular accident 
and transient ischemic attack, non-fatal myocardial infarction or unstable angina, 
cardiovascular death) 
 Tuberculosis (TB)  
 Infections (serious, opportunistic, or fungal only) 
 Cytopenias  
 Systemic hypersensitivity reactions 
2.7.2. Clinical Safety Laboratory Tests  
See SAP Table 1 for the list of clinical laboratory tests to be performed and the SoA in the 
protocol for the timing and frequency.  
 
 




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Clinically significant findings observed prior to the first dose of study drug will be listed as 
medical history in the eCRF and reported as AEs if observed after the first dose of the study 
drug.  
2.7.5. Electrocardiograms  
Triplicate 12-lead ECGs will be obtained to calculate the heart rate and measure PR, QRS and 
QT intervals. 
2.7.6. Hospital Anxiety and Depression Scale  
Depression and anxiety will be monitored with the Hospital Anxiety and Depression scale 
(HADS). The HADS questionnaire will be completed by the subject. 
2.7.7. Pharmacokinetics Variable(s) 
Blood samples will be collected for measurement of plasma concentrations of izokibep as 
specified in the SoA in the protocol.  
2.8. Immunogenicity 
Anti-drug antibodies to izokibep will be evaluated in serum samples collected from all 
subjects according to the SoA in the protocol. These samples will be tested for positive or 
negative by the sponsor or sponsor’s designee.  
Samples may be further tested for IL-17A binding domain and Albumin binding domain 
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3. Estimands 
The ICH1 E9 (R1) addendum on estimands2 and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials came into effect on 30 July 2020. This 
section addresses the construction of estimands for the primary, secondary, and exploratory 
objectives. Each estimand is defined according to the following five attributes: 
 The treatment condition of interest, and as appropriate, the alternative condition to 
which comparison will be made. 
 The population of subjects targeted by the clinical question. 
 The variable (or endpoint) to be obtained for each subject that is required to address 
the clinical question. 
 The clinical question of interest in respect of other intercurrent events not covered 
through the precise specifications of treatment, population and variable. 
 A population-level summary for the variable providing a basis for comparison 
between treatment conditions. 
3.1. Estimand for the Primary Objective 
The main estimand is defined through the following five attributes: 
3.1.1. Treatment Condition of Interest 
The primary treatment condition of interest is izokibep 160 mg QW and izokibep 160 mg 
Q2W. The reference treatment condition is placebo administered QW. Izokibep 160 mg QW 
and izokibep 160 mg Q2W will each be compared to placebo. Subjects will be analyzed 
according to their randomized treatment regardless of treatment compliance, use of 
concomitant medications or rescue medications, or any other protocol deviations.  
3.1.2. Population of Subjects Targeted by the Clinical Question  
The population of subjects is males and females ≥ 18 years and ≤ 75 years with active PsA 
(≥3 SJC66 and ≥3 TJC68 at screening and baseline visits) as further defined by the inclusion 
criteria and exclusion criteria. The population being studied represents a population normally 
seen in clinical practice. This ensures the activity of izokibep can be evaluated across a 
distribution of disease severity in the study. 
3.1.3. Variable Obtained from Each Subject Required to Address the Clinical Question 
For each subject in the study, the variable to address the clinical question is ACR50 response 
at Week 16.  


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3.1.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest 
The treatment strategy approach for the estimand will be used in general, so subjects will be 
included using observed data at Week 16 regardless of treatment discontinuation, concomitant 
medication, protocol deviations, or other actions. Subjects with missing full ACR50 
assessments at Week 16 will be imputed as non-responders (non-response imputation or NRI). 
Subjects missing one or more components of ACR50 will be included as defined in Section 
5.2.1, with subjects having missing ACR50 due to missing components also imputed as non-
responders. 
3.1.5. Population-level Summary for Comparison between Treatment Conditions 
The population level summary is the response rate, or proportion of subjects who meet ACR50 
at Week 16. The null hypothesis of equal response rates will compare each dosing regimen of 
izokibep to the placebo group respectively. A stratified test of response rates will be 
implemented in the analysis. Stratified tests will use the strata of prior TNFi use (Yes/No) and 
enthesitis at baseline (LEI = 0 versus >0) from the randomization process. If a subject is 
incorrectly classified into a stratum during the randomization process, the analysis will use 
the correct classification, not the classification used during randomization. Within each of the 
strata used for randomization, the response rate for each treatment group and corresponding 
standard error will be calculated. The difference in response rates (risk difference) will be 
calculated for each stratum. The common risk difference among the strata and associated 
standard error will be estimated by combining the observed risk differences using Cochran-
Mantel-Haenszel weighting. The estimated risk difference divided by the standard error will 
be used as the test statistic and a p-value calculated assuming that the test statistic follows a 
standard normal distribution under the null hypothesis. Analyses at earlier timepoints when 
data to calculate the ACR50 are collected will also be presented using the same methodology. 
P-values from earlier timepoints will be presented for descriptive purposes, not part of the 
alpha-preserving multiple testing strategy. 
The treatment effect will be quantified by the response rate difference of ACR50 at Week 16 
between placebo and each dosing regimen of izokibep at Week 16. 
3.2. Estimands for the secondary objectives 
The main estimands for each of the secondary objectives are defined through the following 
five attributes: 
3.2.1. Treatment Condition of Interest 
The primary treatment condition of interest is izokibep 160 mg QW and izokibep 160 mg 
Q2W. The reference treatment condition is placebo administered QW. Izokibep 160 mg QW 


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and izokibep 160 mg Q2W will each be compared to placebo. Subjects will be analyzed 
according to their randomized treatment regardless of treatment compliance, use of 
concomitant medications, or any other protocol deviations.  
3.2.2. Population of Subjects Targeted by the Clinical Question  
The population of subjects is all randomized males and females ≥ 18 years and ≤ 75 years 
with active PsA (≥3 SJC66 and ≥3 TJC68 at screening and baseline visits) as further defined 
by the inclusion and exclusion criteria.  
For some of the secondary endpoints, further restrictions on inclusion in the analysis result in 
a smaller target population, a subset of the FAS: 
 First secondary endpoint: achieving PASI90. This endpoint will be assessed in 
subjects with ≥3% BSA psoriasis at baseline, to allow for a calculation of PASI90. 
 Second secondary endpoint: resolution of enthesitis. This endpoint will be assessed 
using only subjects with enthesitis at baseline (LEI >0), to ensure this represents 
improvement in enthesitis rather than having no enthesitis at baseline.  
 Sixth secondary endpoint: proportion of subjects achieving an improvement in PsAID 
of at least 3 units. This endpoint will be assessed using only subjects with PsAID of 
at least 3 at baseline, to ensure subjects are capable of meeting endpoint, since negative 
values of PsAID are not possible. 
As for the secondary endpoints, further restriction on inclusion in the analysis result in a 
smaller target population, a subset of the FAS: 
 The exploratory endpoint: change from baseline in spine pain NRS.  This endpoint 
will be assessed using only subjects with sacroiliitis at baseline. 
 The exploratory endpoint: change from baseline in spine pain NRS. This endpoint 
will be assessed in those with investigator assessed spinal involvement. 
 The exploratory endpoint: time to resolution of enthesitis. This endpoint will be 
assessed using only subjects with enthesitis at baseline (LEI >0), to ensure this 
represents improvement in enthesitis rather than having no enthesitis at baseline.  
 The exploratory endpoint: occurrence of enthesitis. This endpoint will be assessed 
using only subjects with enthesitis at baseline (LEI=0), with occurrence defined as of 
enthesitis (LEI > 0) summarized at weeks 4, 8, 12 and 16. 
Other secondary and exploratory endpoints will be assessed using the full analysis set. The 
population being studied represents a population normally seen in clinical practice. This 
ensures the activity of izokibep can be evaluated across a distribution of disease severity in 
the study. 


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3.2.3. Variable Obtained from Each Subject Required to Address the Clinical Question 
For each subject in the study, the variables to address the clinical questions are:  
 Achieving 90% or greater reduction in PASI score from baseline (PASI90) at Week 
16 in subjects with ≥3% BSA psoriasis at baseline  
 Resolution of enthesitis at Week 16 as assessed by LEI in subpopulation that had 
enthesitis (LEI > 0) at baseline  
 Achieving MDA at Week 16  
 Achieving 20% improvement in ACR core set measurements (ACR20) at Week 16  
 Achieving an improvement in PsAID of at least 3 units at Week 16 compared to 
baseline in subjects with PsAID ≥ 3 at baseline  
 Change in physical function as assessed by HAQ-DI change from baseline to Week 
16  
3.2.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest 
The treatment policy strategy similar to the primary endpoint will be used to construct 
estimands for each secondary endpoint. Subjects will be included in the analysis regardless of 
treatment discontinuation, concomitant medication, protocol deviations, or other actions. 
Subjects who have missing data at Week 16 will be imputed as nonresponders and included 
in the analysis using composite strategy. 
The secondary endpoint of change in physical function as assessed by HAQ-DI change from 
baseline from baseline to Week 16 will be analyzed as a continuous variable. The treatment 
policy strategy will be used to construct estimands for change in physical function of HAQ-
DI from baseline to Week 16. Subjects will be included in the analysis regarding treatment 
discontinuation, concomitant medication, protocol deviations, or other actions. 
3.2.5. Population-level Summary for Comparison between Treatment Conditions 
o Proportion of subjects achieving 90% or greater reduction in PASI score from baseline 
(PASI90) at Week 16 in subjects with ≥3% BSA psoriasis at baseline  
o Proportion of subjects with resolution of enthesitis at Week 16 as assessed by LEI in 
subpopulation that had enthesitis (LEI > 0) at baseline  
o Proportion of subjects achieving MDA at Week 16  
o Proportion of subjects achieving 20% improvement in ACR core set measurements 
(ACR20) at Week 16  
o Proportion of subjects achieving an improvement in PsAID of at least 3 units at Week 
16 compared to baseline in subjects with PsAID ≥ 3 at baseline  
o Mean change in physical function as assessed by HAQ-DI change from baseline to 
Week 16  


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Pairs of treatment arms will be compared for each summary by assessing the difference in 
response rates or difference in means between the two arms.  


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4. Analysis Sets 
In accordance with ICH E3 and E93, the following analysis sets will be used for the analyses. 
4.1. All Screened Set 
The All Screened Set will include every subject who has signed the informed consent form. 
The All Screened Set will be used for summaries of disposition and the associated listing. 
4.2. Full Analysis Set 
For assessing the primary and secondary efficacy objectives, all subjects randomized will be 
included in the analyses as the FAS. Intercurrent events (ICEs) such as missed assessments, 
missed or discontinued treatment, and protocol deviations, will be addressed as described in 
the definition of the estimands in Section 3. Subjects will be included according to randomized 
treatment. 
4.3. Safety Analysis Set 
For assessing the safety objectives, all subjects randomized who receive at least one 
administration of test material will be included in the summaries and analyses. In the event 
that a subject receives incorrect study drug, that subject will be grouped according to the 
treatment received more often or, if tied, the first study treatment received, and such subjects 
will be listed and counted in the final report. 
4.4. Pharmacokinetics Analysis Set 
The Pharmacokinetics analysis set for subjects will include all subjects who received at least 
one administration of test material and with having at least one quantifiable PK concentration.  
4.5. ADA Analysis Set 
The ADA analysis set for subjects will include all subjects who received at least one 
administration of izokibep and have both a baseline ADA measurement and at least one post-
dose ADA measurement. 
 


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5. Data Handling 
5.1. Time Points and Visit Windows 
5.1.1. General Definitions 
All assessment days will be related to the first day of the first dose of the study drug. 
Day 1 is defined as the date of the first dose of the study drug. Relative days after Day 1 are 
calculated as (assessment date – Day 1 date) + 1. Relative days prior to Day 1 are calculated 
as (assessment date – Day 1 date). The day prior to Day 1 is Day -1. There is no Day 0. 
The date of the first dose of study drug for each subject will be taken from the Study Drug 
Administration eCRF page. If the date in this eCRF page is missing, alternatively the date of 
enrollment/randomization will be used. 
The date of the last dose of study drug for each subject will be taken from the Study Drug 
Administration form, with the last study drug administration date from any visit used as the 
date of last study drug. 
5.1.2. Screening Period 
For all subjects, the screening period starts when the subject signs and dates the ICF and ends 
when the subject is enrolled/randomized, or screen failed. The screening period is up to 28 
days.  Certain initial screening period procedures may be repeated during the original initial 
screening period. This is not considering “rescreening”. 
The baseline value for a variable is therefore defined as the last non-missing value collected 
before randomization. 
5.1.3. Treatment Period 
Data collected on Day 1 will be assigned to the Treatment Period unless the time (HH:MM) 
of data collection and time (HH:MM) of the first dose of study drug are both recorded and the 
data collection time is before the time of the first dose of study drug. In this case, the 
assessment will be assigned to the screening period.  If the time (HH:MM) of data collection 
is not recorded but the protocol and/or eCRF includes an instruction to the effect that all Day 
1 assessments are to be performed prior to the first dose of study drug, the data collected at 
Day 1 will be assigned to the screening period.  However, adverse events and concomitant 
medications starting on Day 1, will be assigned to the Treatment Period, unless the time 
(HH:MM) demonstrates otherwise. 
The Treatment Period is defined as the period from the date/time of the first dose of study 
drug to Week 52 (one week after the last dose) or early termination (end of treatment visit 


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should be completed within 14 days of withdrawal and follow-up visits should be completed 
at 8 weeks and 14 weeks after the last dose of study drug, where possible). 
Treatment will be divided into two periods, Period 1 and Period 2, Period 1 will start at the 
first dose of study drug and ends at Week 16 when Week 16 assessments are completed and 
before administration of study drug. Period 2 will start at the time of administration of study 
drug at Week 16 and end at Week 52 or early termination/end of treatment visit.  
5.1.4. Visit Windows 
All data will be analyzed using the nominal study visit as defined in the SoA in the protocol 
and eCRF. 
In the event that a subject discontinues the study early, the subject will have an early 
termination visit which includes efficacy assessments. If the early termination visit or an 
unscheduled visit occurs in a timeframe that corresponds to a scheduled efficacy assessment 
(week 2, 4, 12, 16, 20, 24, 32, 36, 40 or 52), and if the subject does not have an actual visit at 
or after the corresponding scheduled efficacy assessment, the following day ranges will be 
used to map the early termination/unscheduled visit to a scheduled efficacy assessment for 
use in all efficacy summaries at that timepoint. Similarly, if an unscheduled efficacy 
assessment occurs during a timeframe that corresponds to a scheduled efficacy assessment, it 
will be windowed accordingly, provided the subject does not have an actual visit at the same 
nominal time. 
Table 2 Definition of Time Point Windows for Efficacy Analyses 
Time Point 
Time Point Window a 
Baseline 
<=Day 1  
Week 2 
Days 12 to 21 
Week 4 
Days 22 to 56 
Week 12 
Days 57 to 98 
Week 16 
Days 99 to 126 
Week 20 
Days 127 to 154 
Week 24 
Days 155 to 196 
Week 32 
Days 197 to 238 
Week 36 
Days 239 to 266 
Week 40 
Days 267 to 322 
Week 52 
Days 323 or later 
a relative to the date of first dose of study drug during the Treatment Period/date of Baseline Visit (Day 1) 


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5.2. Handling of Dropouts, Missing Data, and Outliers 
5.2.1. Handling of Missing Efficacy Data 
Tender (and swollen) joint count will be the sum of the joints where tenderness (or swelling) 
is marked as Present on the CRF. A missing response will be treated the same as an Absent 
response, in that, it will not contribute to the joint count.  
Subjects with missing efficacy assessments will be imputed as non-responders (non-response 
imputation or NRI) for dichotomous endpoints. Subjects with a missing component of a 
composite endpoint will be imputed as non-responders for that component. The subject may 
therefore be a responder to the endpoint, if the subject met a sufficient number of criteria from 
other components. 
Subjects missing one or more components of composite endpoints will be included, illustrated 
for the primary endpoint, ACR50, as follows: 
Situation 
ACR50 result 
If both SJC66 and TJC68 have reductions ≥ 50%: 
- If at least 3 of the other 5 components have reductions ≥ 50%, 
irrespective of missing/available on the others 
- If at least 3 of the other 5 components have a reduction of < 50%, 
irrespective of missing/available on the others 
- All other situations 
 
Responder 
 
Non-responder 
 
Missing 
If result is available on both of SJC66 and TJC68, and at least one 
has <50%: 
- Irrespective of results or missingness on the other 5 components 
 
 
Non-responder 
If one of SJC66 and TJC68 is missing, and the other has reduction ≥ 
50%: 
- If at least 3 of the other 5 components have reductions ≥ 50%, 
irrespective of missing/available on the others 
- If at least 3 of the other 5 components have a reduction of < 50%, 
irrespective of missing/available on the others 
- All other situations 
 
 
Missing 
 
Non-responder 
 
Missing 
If one of SJC66 and TJC68 is missing, and the other has reduction 
<50%: 
- Irrespective of results or missingness on the other 5 components 
 
 
Non-responder 
If both SJC66 and TJC68 missing: 
- If at least 3 of the other 5 components have a reduction of < 50%, 
irrespective of missing/available on the others 
- All other situations 
 
Non-responder 
 
Missing 
 
 


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For continuous efficacy endpoints, inference will be done using mixed-effects models 
repeated-measures4, which is robust to missing outcomes that are missing at random or 
missing complete at random. 
5.2.2. Handling of Missing Safety Data 
In general, missing clinical laboratory data, vital signs, and ECG data will not be imputed.  
Adverse event imputations for missing severity or relationship are given in Section 6.7.2.  
Unknown or partial medication and AE date imputations are given below and are to be used 
only for the assessment of prior/concomitant status for medications and treatment-emergent 
status for AEs. 
5.2.3. Handling of Missing Age and Partial and Missing Dates for Adverse Events, 
Prior/Concomitant Medications 
Missing Age at Time of Informed Consent 
Where the age at time of informed consent is missing and year of birth is collected, the 
following convention will be used: 
The day and month will be completed as 02JUL (the 183rd day of the year). For example, 
Date of Birth specified as -----1980 will be completed as 02JUL1980. 
Missing or Partial Adverse Event and Prior/Concomitant Medication Start/Stop Dates 
Missing and/or incomplete dates for medications and AEs are imputed in a manner resulting 
in the earliest onset or the longest duration during the Treatment Period, whilst ensuring that 
the start date does not occur after the stop date. The stop date will not be imputed if the 
medication or AE is “Ongoing”. Technically, this will be done as follows: 
For a missing/incomplete start date/time the earliest date/time of the following will be 
imputed: 
 The later date of: the earliest possible start date/time, and the date/time of the first dose 
of treatment. 
 The latest possible start date/time. 
 The latest possible stop date/time. 
For a missing/incomplete stop date/time the later date/time of the following will be imputed: 
 The earlier date/time of the latest possible stop date/time and the date/time of last dose 
of treatment. 
 The earliest possible stop date/time. 


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 The earliest possible start date/time. 
Here, the earliest possible date/time is defined as: 
 The date/time itself if available. 
 The date/time of the first day of the month at 00:00hrs, if month and year are available 
but the day/time is missing. 
 The date/time of the first day of the year at 00:00hrs, if year is available but day/time 
and month are missing. 
 00:00hrs on the day of informed consent, if the date/time is completely missing. 
The latest possible date/time is defined as: 
 The date/time itself if available. 
 The date/time of the last day of the month at 23:59hrs, if month and year are available 
but the day/time is missing.  
 The date/time of the last day of the year at 23:59hrs, if year is available but day/time 
and month are missing. 
 23:59hrs on the date of last known date on the study for the subject plus one year, if 
the date/time is completely missing. 
5.2.4. Handling of Plasma Concentrations that are Below the Lower Limit of 
Quantification 
Plasma concentrations that are below the lower limit of quantification (BLQ) will be handled 
as follows for descriptive statistics: 
 Predose concentrations that are BLQ will be treated as zero. 
 Post-dose concentrations that are BLQ will be treated as missing elsewhere. 
 For pre-dose BLQ results treated as 0, geometric mean and coefficient of variation 
(CV) % of geometric mean will be reported as not calculated (NC). 
 


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6. Statistical Methods 
6.1. General Principles 
All data processing, summarization, and analyses will be performed using 
 SAS 
Environment/Version 9.4 (or later) of the SAS statistical software package. 
The default summary statistics for quantitative variables will be the number of observations 
(n), mean, standard deviation (SD), median, minimum (min), and maximum (max), for those 
subjects with data. 
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing 
data per category will be the default summary presentation, and where appropriate and 
present, the number of missing values as a “Missing” category. Number of subjects in the 
analysis population will be used as denominator for percentages calculation, unless stated 
otherwise in TFLs mock shell(s). 
The treatment group labels and presentation order are given below: 
Full treatment group label: 
Short treatment 
group label:  
Treatment 
group 
ordering: 
Placebo QW Week 0 to Week 15; Izokibep 
160 mg QW Week 16 to Week 51 
Placebo QW - 
Izokibep QW 
1 
Izokibep 80 mg Q4W Week 0 to Week 48; 
Placebo QW Week 1 to Week 51 for the 
Weeks in Between Izokibep Doses 
Izokibep SC 80 mg 
Q4W 
2 
Izokibep 160 mg Q2W Week 0 to Week 50; 
Placebo Q2W Week 1 to Week 51 
Izokibep SC 160 mg 
Q2W 
3 
Izokibep 160 mg QW Week 0 to Week 51 
Izokibep SC 160 mg 
QW 
4 
 
All statistical comparisons of the primary and secondary endpoints will be made using two-
sided tests at the  = 0.05 significance level (with decisions also requiring consideration of 
multiplicity as defined below) unless specifically stated otherwise. All null hypotheses will 
be of no treatment difference. All alternative hypotheses will be two-sided. 


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All laboratory test results will be received from the central/local laboratories, and the results 
will be provided in either standard internal (SI) or conventional units, or both. For the TFLs, 
the results will be summarized or presented in International System of Units (SI) units. Refer 
to Appendix of the TFLs mock shells for the SI unit corresponding to each laboratory test. 
Refer to Appendix of the TFL shells for the precision level in which each laboratory test is 
reported by the central laboratories. 
Specifications for table, figures and data listing formats can be found in the TFL shells 
specifications for this study. Please refer to “2. General Format Guidelines” section within 
TFL shells for more details on presentation of results. 
For comparisons of izokibep to placebo, the three dosing regimens of izokibep (QW, Q2W 
and Q4W) will be compared separately to placebo. Binary endpoints including the primary 
endpoint of ACR50 will be compared with a stratified test of risk difference. Continuous 
endpoints will be compared with a repeated measures mixed model.  
Safety data, such as adverse events, serious adverse events, and laboratory data, will be 
summarized. 
6.2. Subject Disposition and Data Sets Analyzed 
Subject disposition will be summarized by treatment group and overall for the All Screened 
Set. The following information will be reported:  
 Number of subjects for the following categories: 
o Screened 
 Number and percentage of subjects for the following categories: 
o Randomized 
o Treated 
o Not Treated 
o Permanently discontinued study medication 
o Did not meet cDAPSA low disease activity (cDAPSA ≤ 14) criteria at two 
consecutive visits, starting at Week 24 or after  
o Discontinued study prior to the Week 16 assessment 
o Completed the Week 16 assessment 
o Completed the study 
o Ongoing in the study 
o Discontinued the Study 
o Reasons for study discontinuation 
 Number and percentage of subjects included in, and excluded from, each study 
population together with the reasons for exclusion from the analysis set 


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 Number and percentage of subjects who completed/discontinued treatment, including 
the reasons for treatment discontinuation 
 Number and percentage of subjects who met/did not meet all eligibility criteria, 
together with the criteria not met 
 Number and percentage of subjects who failed screening prior to randomization, 
including the primary reason for screen failure 
 Number and percentage of subjects at each region (and each country within region) 
o Regions are defined using the following countries: 
 North America (US or Canada) 
 Europe (Bulgaria, Czech Republic, Spain, Hungary, Poland, or 
Germany) 
 Non-US (Bulgaria, Czech Republic, Spain, Hungary, Poland, 
Germany, or Canada) 
 Number and percentage of subjects by stratification factors. Each stratification 
variable, prior TNFi use (Yes/No) and enthesitis at baseline (LEI = 0 versus >0) 
o By the stratum collected in Interactive Voice/Web Response System (IXRS) 
o By the stratum according to the clinical database 
A subject will be regarded as having completed the study if the status recorded on the End of 
Study eCRF form is Complete, or assessments at Week 65 have been completed. A subject 
will be considered as having discontinued the study if they have an eCRF status of premature 
study discontinuation. Otherwise, the subject will be considered as ongoing in the study, for 
summaries before final study completion. 
A listing of all subjects with their treatment and study completion status, including the 
respective reasons for treatment discontinuation will be presented for all subjects randomized 
in the FAS. 
A listing of all screen failed subjects with their reasons for screen failure will be presented for 
the All Screened Set. A separate listing of subjects who failed at least one inclusion/exclusion 
criteria including a text description of the criterion failed will be presented for the All 
Screened Set. 
A listing of all randomized subjects with their randomization details, including first dose date 
and time, and actual treatment received will be presented for the FAS. 
A listing of all randomized subjects excluded from the FAS will be presented. 
6.3. Protocol Deviations 
All important protocol deviations will be summarized for the FAS by treatment group and 
overall as described below: 


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 The number of unique subjects with at least one important protocol deviation as well 
as the number of subjects in each important protocol deviation category will be 
presented by default descriptive summary statistics for categorical variables.  
A listing of all subjects with one or more protocol deviations will be presented for the FAS. 
6.4. Demographic and Other Baseline Characteristics 
6.4.1. Demographic Characteristics 
Demographic characteristics will be summarized for the FAS by treatment group and overall 
as described below. All missing data will be presented as part of a missing category, if 
appropriate. Standard descriptive statistics will be presented for the continuous variables of: 
 Age (years) 
Total counts and percentages of subjects will be presented for the categorical variables of: 
 Age group (years): 
o < 65 
o ≥ 65 - < 75 
o ≥ 75 
 Sex 
 Ethnicity 
 Race 
Demographic characteristics will be listed for the FAS by treatment group. 
6.4.2. Baseline Characteristics 
Baseline characteristics will be summarized for the FAS by treatment group and overall as 
described below. All missing data will be presented as part of a missing category, if 
appropriate. 
Standard descriptive statistics will be presented for the continuous variables of: 
 
Disease duration (years) 
o calculated as (date of randomization - date of first diagnosis of psoriatic 
arthritis) + 1/365.25 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (kg/m2) 


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o calculated as (body weight / height2) where weight is in kg and height is in m, 
and presented to one decimal precision  
 
Body Temperature (degrees Celsius) 
 
Respiration Rate (breaths per minute) 
 
Systolic Blood Pressure (SBP [mmHg]) 
 
Diastolic Blood Pressure (DBP [mmHg]) 
 
Heart Rate (beats per minute [bpm]) 
 
Swollen joint count based on 66 joints (SJC66) 
 
Tender joint count based on 68 joints (TJC68) 
 
Swollen joint count based on 28 joints (SJC28) 
 
Tender joint count based on 28 joints (TJC28) 
 
Subject’s Assessment of Pain (VAS) (SAPVAS) 
 
Subject’s Global Assessment of Disease Activity (SGADA) 
 
Investigator’s Global Assessment of Disease Activity (IGADA) 
 
Health Assessment Questionnaire Disability Index (HAQ-DI) total score 
 
Acute phase reactant (C-reactive protein [CRP]) in mg/dL 
 
Psoriatic Arthritis Impact of Disease (PsAID) 
 
Psoriasis Area and Severity Index Score (PASI) in subjects with ≥ 3% BSA psoriasis 
at baseline 
 
Affected Body Surface Area (BSA) 
 
Disease Activity Score in 28 Joints (DAS28-CRP) 
 
Disease Activity in Psoriatic Arthritis (DAPSA) 
 
Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) 
 
36-Item Short Form Survey (total score, PCS, and MCS) 
 
Functional assessment of chronic illness Therapy-Fatigue (FACIT-F) 
 
Leeds Enthesitis Index among those with enthesitis (LEI > 0 at baseline) 
 
Leeds Dactylitis Index among those with dactylitis (LDI>0 at baseline) 
 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
 
Subject’s Assessment of Spinal Pain (NRS)  
 
Widespread Pain Index (WPI) 
 
Modified Nail Psoriasis Severity Index (mNAPSI)  in those with nail psoriasis at 
baseline (mNAPSI>0) 
 
SPARCC Enthesitis Index among those with enthesitis (SPARCC >0 at baseline) 
 
mTSS 
 
Hospital Anxiety and Depression Scale (HADS) 
 
Number of prior biologic Disease-Modifying Antirheumatic Drugs (DMARDs) 
o Number of prior TNFi 
o Number of prior biologic DMARDs other than TNFi 


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 
Number of prior failed biologic DMARDs 
Total counts and percentages of subjects will be presented for the categorical variables of: 
 
Any csDMARD at Baseline group (Yes/No) 
 
Any csDMARD at Baseline group (MTX alone, MTX and other csDMARD, 
csDMARD other than MTX) 
 
Number of prior failed biologic DMARDs group (0, 1, 2 or more) 
 
Prior TNFi Use (Yes/No) 
o Failed prior TNFi (Yes/No) 
 
Number of prior failed biologics group (0, 1, 2 or more) 
 
Prior JAK Inhibitor Use 
 
Concurrent use of oral NSAID on the first dosing date of study drug administration 
 
Concurrent use of oral corticosteroids on the first dosing date of study drug 
administration 
 
Presence of enthesitis (Yes/No)  
o LEI = 0 
o LEI > 0 
o LEI = 1 
o LEI = 2 
o LEI = 1 or 2 
o LEI < 3 
o LEI ≥ 3 
o LEI < 4 
o LEI ≥ 4 
o SPARCC (SPARCC > 0 at baseline) 
 
Combination of enthesitis and prior TNFi exposure 
o LEI = 1 or 2 and no prior TNFi exposure 
o LEI ≥ 3 and no prior TNFi exposure 
o LEI = 1 or 2 and prior TNFi exposure 
o LEI ≥ 3 and prior TNFi exposure 
 
Presence of dactylitis (Yes/No) 
 
Investigator Question on Presence of Axial Involvement (yes/no) 
 
Childbearing Potential 
 
Alcohol (Never, Former, Current) 
 
Nicotine (Never, Former, Current) 
Baseline characteristics will be listed for the FAS. 


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6.4.3. Medical History 
Medical history is defined as any condition, with the exception of the study indication, that 
the subject may have prior to study drug administration in the study, including any chronic 
conditions diagnosed prior to entry into the study. See section 5.2.3 for imputation of missing 
or partial dates for medical history. Non-serious AEs with onset after signing ICF but before 
the randomization will be included as medical history. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [version 24.0 (or a later version if updated during the study)] and will be presented 
by System Organ Class (SOC) and Preferred Term (PT) and total. The SOCs and PTs are to 
be sorted by Internationally Agreed order SOCs and descending PTs in the total column. 
Medical history records will be summarized for the FAS by treatment group and overall as 
follows: 
 
The number and percentage of subjects with at least one medical history record will 
be presented.  
 
The number and percentage of subjects with at least one medical history record within 
each primary SOC and PT will be presented. The summary will be sorted using the 
internationally agreed order for SOC and using descending order of overall numerical 
counts for PT. Where terms tie, these will be sorted alphabetically. 
Medical history records will be listed by-subject and within-subject by medical history start 
date for the FAS. 
6.4.4. Prior and Concomitant Medications/Procedures 
All medications will be coded using the WHO Drug Global Dictionary, Format B3 [Version 
March 2022 (or a later version if updated during the study)], Anatomical Therapeutic 
Chemical (ATC) Classification codes. 
Prior medications and concomitant medications are defined as follows: 
 
Prior medications are those taken prior to screening with a stop date and time prior to 
the start of the Treatment Period. 
 
Concomitant medications are those with a start date and time on or before the end of 
the Treatment Period and a stop date on or after the start of the treatment period, 
including prior medications that are ongoing at the start of the treatment period. 
See Section 5.2.3 for imputation of missing or partial dates for medication. 


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Prior and concomitant medications will be summarized for the FAS by treatment group and 
overall as follows: 
 
The number and percentage of subjects with at least one prior/concomitant medication 
will be presented. 
 
The number and percentage of subjects with at least one prior/concomitant medication 
within each Anatomical Group (ATC Level 1), Therapeutic Subgroup (ATC Level 2), 
and preferred term will be presented. The summary will be sorted using numerical 
counts by descending order of Anatomical Group, then descending order of 
Therapeutic Subgroup, then descending order of preferred term in the total column. 
Where groups or terms tie these will be sorted alphabetically. 
 
Number and percentage of subjects with each primary reason for stopping NSAID, 
csDMARD, TNFi or biologic medication taken for Plaque Psoriasis or PsA. 
Prior medications and concomitant medications will be listed separately for the FAS. In the 
listings the relative start and stop day of prior/concomitant medication use will be calculated 
relative to the first dose date and time of study drug and will be presented for those subjects 
who received at least one dose of study drug. If the concomitant medication is “Ongoing” it 
will be indicated as such in the listing and the relative stop day will not be calculated.  Only 
original dates will be presented in the listing even though the relative day may be based on an 
imputed date. 
All prior and concomitant procedures will also be presented in the listing. 
6.5. Measurements of Study Drug Compliance 
Study Drug compliance is defined as the number of doses that were actually taken relative to 
the number of doses that should have been taken as per the protocol for the planned duration 
of treatment exposure. A partial dose in eCRF will be treated as a half dose. Study drug 
compliance will be summarized for period 1 and period 2 separately.  
In general, the percentage of overall compliance, assessed by dose count, will be calculated 
as follows: 
For Period 1 
Compliance (%) = 
(Total doses administered from Week 0 up to before Week 16) 
100% 
Total doses expected to be administered from Week 0 to before Week 16 
For Period 2 
Compliance (%) = 
(Total doses administered from Week 16 to EOT) 
100% 
Total doses expected to be administered from Week 16 to EOT 
 


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For group 3 and group 4, matching placebo will be counted in the calculation of total doses 
administered and total doses expected. The total number of doses expected to be administered 
during Period 1 is therefore 16 for all groups. The total number of doses expected to be 
administered during Period 2 will be different after accounting for study drug withdrawal for 
those who meet criteria at or after week 24. 
The calculated percentage compliance will be categorized as: 
 
< 80% compliance 
 
≥ 80% 
Compliance will be summarized for the Safety Analysis Set by treatment group as follows: 
 Number of doses will be presented by default summary statistics. This will include 
both number of doses of izokibep and number of doses of placebo. 
 Percent compliance will be presented by default summary statistics.  
 Number and percentage of subjects within each of the compliance categories will be 
presented. Treatment compliance will be listed for the Safety Analysis Set. Missing 
data will not be imputed and only original data for those fields (for example, date 
fields) will be presented in the listing together with derived variables such as the 
calculated compliance (%) and exposure duration. 
Treatment compliance will be listed for the Safety Analysis Set. Missing data will not be 
imputed and only original data for those fields (for example, date fields) will be presented in 
the listing together with derived variables such as the calculated compliance (%) and exposure 
duration. 
6.6. Efficacy 
Hypotheses tested will be adjusted to control the familywise error rate in the strong sense at α = 
0.05, 2-sided. 
The statistical comparisons for the primary efficacy endpoint and the secondary endpoints, all 
at Week 16, will be carried out in sequential order. The primary endpoint, comparing izokibep 
dosed QW to placebo, will be tested first, with significance concluded if p < 0.05.  
Testing of secondary endpoints, comparing izokibep dosed QW to placebo, will only be 
carried out if all prior tests, including the tests of the primary endpoint, first show significance 
with p < 0.05. If all primary and secondary endpoints, comparing izokibep doses QW to 
placebo, are significant, testing of izokibep doses Q2W to placebo will begin and follow the 
same order. As long as all prior tests are significant, testing will proceed in the following 
order: 


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 The first secondary endpoint, achieve PASI90 at Week 16 in subjects with ≥3% BSA 
psoriasis at baseline, comparing izokibep dosed QW to placebo.  
 The second secondary endpoint, achieving resolution of enthesitis at Week 16 in 
subjects that had enthesitis (LEI > 0) at baseline, comparing izokibep dosed QW to 
placebo.  
 The third secondary endpoint, achieving MDA at Week 16, comparing izokibep 
dosed QW to placebo. 
 The fourth secondary endpoint, achieving ACR20 at Week 16, comparing izokibep 
dosed QW to placebo. 
 The fifth secondary endpoint, achieving improvement in PsAID of at least 3 units at 
Week 16 compared to baseline in subjects with PsAID ≥3 at baseline, comparing 
izokibep dosed QW to placebo.  
 The sixth secondary endpoint, change in physical function of HAQ-DI from baseline 
to Week 16, comparing izokibep dosed QW to placebo.  
 The primary endpoint, achieving ACR50 at Week 16, comparing izokibep dosed Q2W 
to placebo. 
 The first secondary endpoint, achieve PASI90 at Week 16 in subjects with ≥3% BSA 
psoriasis at baseline, comparing izokibep dosed Q2W to placebo.  
 The second secondary endpoint, achieving resolution of enthesitis at Week 16 in 
subjects that had enthesitis (LEI > 0) at baseline, comparing izokibep dosed Q2W to 
placebo.  
 The third secondary endpoint, achieving MDA at Week 16, comparing izokibep dosed 
Q2W to placebo. 
 The fourth secondary endpoint, achieving ACR20 at Week 16, comparing izokibep 
dosed Q2W to placebo. 
 The fifth secondary endpoint, achieving improvement in PsAID of at least 3 units at 
Week 16 compared to baseline in subjects with PsAID ≥3 at baseline, comparing 
izokibep dosed Q2W to placebo.  
 The sixth secondary endpoint, change in physical function of HAQ-DI from baseline 
to Week 16, comparing izokibep dosed Q2W to placebo.  
6.6.1. Primary Efficacy Analysis 
The primary efficacy variable is defined as ACR50, the proportion of subjects achieving 50% 
improvement in ACR core set measurements. 
The statistical null and alternative hypotheses to be used to assess the primary objective are: 
H0: πABY – πPBO = 0 


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HA: πABY – πPBO ≠ 0 
where πABY and πPBO are the proportion of subjects achieving ACR50 at Week 16 among 
subjects randomly assigned to receive izokibep and placebo, respectively. One set of 
hypotheses will be tested for each dose frequency of izokibep (QW and Q2W). 
The treatment strategy approach for the estimand will be used in general, so subjects will be 
included using observed data at Week 16 regardless of treatment discontinuation, concomitant 
medication, protocol deviations, or other actions. Subjects with missing ACR50 assessments 
at Week 16 will be imputed as non-responders (non-response imputation or NRI). 
Three components of the primary endpoint (subject’s assessment of pain, subject’s global 
assessment of disease activity, and investigator’s global assessment of disease activity) were 
assessed using a visual analog scale (VAS), consisting of a horizontal line, 100 mm in length, 
with anchor statements at either end. The subject or investigator was asked to place a single 
vertical line through the VAS at the point that best corresponds to assessment.  At some sites, 
and for some subjects, the VAS was not administered as intended. If a line was not 100 mm 
in length, the score used for analysis was calculated as 100 x (distance from left to mark)/(total 
length of horizontal line). If the subject was requested to write a number or was verbally asked 
for a number, that value will be used for analysis. Such protocol deviations will be noted in 
listings, and sensitivity analyses will be reported to assess the impact of such deviations. A 
spreadsheet will be created, after database lock and before unblinding, to note which subjects 
answered questions using a different length line, or by writing or verbally responding with a 
number. This spreadsheet will be signed and dated, and entered into the study files, before 
database lock to verify the protocol deviations and sensitivity analyses defined below. 
The null hypothesis of equal response rates will compare each dosing regimen of izokibep to 
the placebo group. A stratified test of response rates will be used. Within each of the strata 
used for randomization, the response rate for each treatment group and corresponding 
standard error will be calculated. If a subject is incorrectly classified into a stratum during the 
randomization process, the analysis will use the correct classification, not the classification 
used during randomization. The difference in response rates (risk difference) will be 
calculated for each stratum. The common risk difference among the strata and associated 
standard error will be estimated by combining the observed risk differences using Cochran-
Mantel-Haenszel weighting. The estimated risk difference divided by the standard error will 
be used as the test statistic and a p-value calculated assuming that the test statistic follows a 
standard normal distribution under the null hypothesis. A confidence interval on the difference 
will be calculated using analogous methods. Analyses at earlier timepoints when data to 
calculate the ACR50 are collected will also be presented using the same methodology. P-
values from earlier timepoints will be presented for descriptive purposes, not part of the alpha-
preserving multiple testing strategy.  


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The number and proportion of subjects achieving ACR50 in each treatment group will be 
reported at each scheduled assessment, along with Clopper-Pearson 95% CI without strata. 
The common risk difference with Cochran-Mantel-Haenszel weighting will be used to 
calculate a 95% CI for difference in response rates. A bar graph showing the proportion of 
subjects achieving ACR50 for each treatment group along with the associated p-value will be 
produced. ACR50 results will also be listed.  
Sample SAS code with stratification factors of comparing each dosing regimen of izokibep to 
the combined placebo group is given as following: 
 
ods output commonpdiff = ;  
            proc freq data= ;  
  tables stratum * treatment * response / cmh commonriskdiff (test=mh cl=mh); 
  weight count / zeros; 
run;  
6.6.2. Supplementary Analyses for the Primary Efficacy Analysis 
Tipping point analysis: A tipping point analysis will be performed in order to evaluate the 
robustness of the results of the primary analysis. This analysis will use simulations to assess 
the impact of different response rates in subjects with missing primary endpoint data, and how 
different the response rates must be to change the conclusions of the study. The tipping point 
analysis will impute mean response rates in the two groups. Imputed response rates will be 
based on the response rates among subjects with observed primary endpoint data at Week 16. 
Sets of imputed mean response rates will include the observed response rates (𝜋̂ABY, 𝜋̂PBO), as 
observed in each stratum, and rates that differ in increments of ±0.02, adjusted independently 
in each arm. For each of the 121 imputed mean response rates (𝜋̂ABY + a, 𝜋̂PBO + b), with a 
and b each taking on all values from -0.10 to +0.10 in increments of 0.02, 1000 simulations 
will be reported. Within each simulation, a random number mechanism will be used to assign 
each subject who is missing the primary endpoint at Week 16 to either response or non-
response. The primary stratified analysis will be reported on each simulation, and the 
probability that the null hypothesis of equal response rates is rejected will be reported for each 
set of imputed response rates. A graphical output will summarize the rejection probability for 
various sets of response rates. The same tipping point analysis will be performed in comparing 
each izokibep group to placebo. 
Multiple Imputation: Multiple imputation5 using a Markov chain Monte Carlo (MCMC) 
technique will be implemented to replace missing endpoint data using multiple draws from a 
posterior predictive distribution estimated from the placebo group only. For ACR50, 
assuming monotone missingness pattern, missing ACR50 at Weeks 2, 4, 12 and 16 will be 
imputed by first imputing the 7 components of the ACR50 criteria (SJC66, TJC68, subject’s 
VAS assessment of pain, SGADA, IGADA, HAQ-DI, and CRP), then assigning ACR50 


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status from the imputed values. Predictors in the regression model for missing values at Week 
2 will be the randomization stratification factors of prior TNFi use, and LEI>0/LEI=0, as well 
as sex (male/female), race (white/non-white), age (continuous), and BMI (continuous). For 
each of the 7 components, baseline value will be included as a continuous predictor. Predictors 
in the regression model for missing values after Week 2 will be all of these variables, plus the 
value of the component being predicted at all prior scheduled assessments. Missing ACR50 
values in both the placebo group and three izokibep groups will be imputed using observed 
data from the placebo group only. Data will be processed sequentially by repeatedly calling 
SAS® PROC MI to impute missing outcomes. A total of 100 imputations will be imputed to 
form the complete data set with a pre-specified seed (6848251) to ensure reproducibility. 
These multiple imputed data sets are then analyzed by using the same method for the primary 
analysis for complete data as specified in Section 6.6.1. The final inference on treatment 
difference is conducted from the multiple datasets using Rubin’s combining rules6. Other 
imputation, fully conditional specification method may be implemented if the multiple 
imputation model does not converge. Sample SAS code: 
proc mi nimpute=100 seed=6848251; 
  var acr50; 
  ods select misspattern; 
run; 
 
VAS Supplemental Analyses: A supplemental primary analysis using the VAS data on a 
scale from 0 to 100 mm will be performed in order to evaluate the robustness of the results 
when variations in the collection of the VAS data were reported by the investigator. The 
impact of  VAS collection on paper (single vertical line through the VAS at the point that best 
corresponds to their feeling of pain), VAS collection via verbal response from the subject, 
and VAS scales that that measured 100 mm will be examined by conducting the following 
analyses: 
 Using only VAS data collected on a 0 to 100 scale (paper or verbal), excluding data 
collected on a 0 to 10 scale. 
 Using only VAS data collected on a 0 to 100 horizontal line (paper only), excluding 
data collected verbally. 
 Using only VAS data collected on a 0 to 100 scale (paper only, with line that 
measured 100 mm), excluding those collected with lines of a different length (0 to 
10, 0 to <100mm, 0 to >100mm), excluding data collected verbally. 
 
If there are no subjects who meet one of the protocol deviation criteria (data collected on a 0 
to 10 scale, data collected verbally, or data collected using a line not 100 mm) then the 
corresponding subgroup analysis above will be omitted. 
 


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Q2W and Q4W Supplemental Analyses: A supplemental analysis is planned for subjects 
who were randomized to receive izokibep Q2W or izokibep Q4W. The analysis of subjects 
randomized to receive izokibep Q2W will group subjects according to the longest number of 
consecutive doses of izokibep or placebo that were received within the first 16 weeks of 
treatment of Period 1: 
 Did not receive consecutive doses of izokibep or placebo 
 Received consecutive doses, but no more than two consecutive doses of either 
izokibep or placebo 
 Received at least three consecutive doses of izokibep or placebo, but not four 
consecutive doses. 
 Received four or more consecutive doses of izokibep or placebo. 
Because the number of subjects in the first group who did not receive consecutive doses of 
izokibep or placebo is expected to be small, the first two groups will be combined. The 
primary analysis will be run in each of the resulting three subsets of subjects, comparing 
each subset of subjects to the entire group of placebo subjects. Subjects will be classified 
according to doses actually received (not assigned), and included only if the subjects receive 
at least 8 total doses (izokibep or placebo) and have an assessment after the 8th dose (with 
other subjects excluded from this supplemental analysis). Informal comparisons of the 
resulting analyses (p-values, point estimates and treatment differences) will be used to 
assess whether the three subsets of subjects, with different PK characteristics, have similar 
responses. 
 
All subjects who were randomized to receive Q2W and who received correct treatment at 
each administration until week 12 (or until discontinuation of study drug, whichever came 
first) will be summarized with week 12. The number and proportion of subjects achieving 
ACR50, as an additional supplemental analysis to understand the impact of dosing errors. 
 
An analogous analysis of subjects who were randomized to receive izokibep Q4W will also 
be reported. This will classify such subjects into two subsets: 
 Received no more than four consecutive doses of placebo 
 Received more than four consecutive doses of placebo. 
 
6.6.3. Secondary Efficacy Analysis 
The following secondary endpoints will be analyzed as dichotomous endpoints and 
analogously to the primary endpoint: 
 proportion of subjects achieving PASI90 at Week 16 in subjects with ≥3% BSA 
psoriasis at baseline 
 proportion of subjects achieving resolution of enthesitis at Week 16 in subjects that 
had enthesitis (LEI > 0) at baseline 
 proportion of subjects achieving MDA at Week 16 
 proportion of subjects achieving ACR20 at Week 16  


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 proportion of subjects achieving improvement in PsAID of at least 3 units at Week 16 
compared to baseline in subjects with PsAID ≥3 at baseline 
Subjects who have missing data at Week 16 will be imputed as nonresponders and included 
in the analysis. 
The secondary endpoint of change in physical function of HAQ-DI from baseline to Week 16 
will be analyzed using the mixed-effects model for repeated measures (MMRM) that includes 
data at postbaseline visits up to the time point of interest. Subjects that have a baseline value 
and at least 1 post-baseline value are included in the analysis. The model includes the baseline 
physical function of HAQ-DI, treatment group, and stratification variables, visit week as fixed 
effects and subject being the random effect. An unstructured variance-covariance matrix will 
be used. Other variance-covariance matrices, such as autoregressive, and compound-
symmetric will be considered in this order if the model does not converge. The Kenward-
Roger method will be used to estimate the degrees of freedom. Missing change scores will 
not be imputed using the MMRM approach. The least squares (LS) means and 95% CIs of 
the difference in mean change from Baseline in HAQ-DI between each dose regimen of 
izokibep group and placebo group from MMRM will be provided. Sample SAS code is given 
as following: 
 
proc mixed; 
class week subjectid treatment(ref = "placebo") 
model change_y = baseline_y treatment week prior_tnfi baseline_lei 
repeated week / subject = subjectid (treatment) TYPE = UN;  
lsmeans treatment * week /slice = week cl;  
slice treatment * week/ sliceby = week pdiff cl;  
run;  
 
6.6.4. Supplementary Analyses for the Secondary Efficacy Analysis 
Sensitivity analyses will use analysis of covariance on change in physical function of HAQ-
DI from baseline to Week 16, with stratification variables used for randomization also 
included as covariates, along with baseline physical function of HAQ-DI. 
Sensitivity analysis for physical function of HAQ-DI will also use multiple imputations. 
Physical function of HAQ-DI missing as Week 16 will be replaced with the imputed value 
from the imputation dataset. The imputation dataset will be created from the placebo subjects 
who have complete data. 
Multiple Imputation: Multiple imputations7 will be implemented to replace missing 
endpoint data using multiple draws from a posterior predictive distribution estimated from the 
placebo group only. For HAQ-DI at Week 2, 4, 12, and 16, assuming monotone missingness 


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pattern, missing HAQ-DI will be imputed using previous HAQ-DI (except for Week 2) up to 
the time point of interest and randomization strata using placebo group only. Missing HAQ-
DI in the placebo group and two izokibep groups will be imputed. Monotonicity in missing 
data will first be imputed with MCMC. The resulting data will then be processed sequentially 
by repeatedly calling SAS® PROC MI to impute missing outcomes. A total of 100 
imputations will be imputed to form the complete data set with a pre-specified seed (36767) 
to ensure reproducibility. These multiple imputed data sets will then be analyzed by using the 
same method for the HAQ-DI endpoint analysis as specified in Section 6.6.3. The final 
inference on treatment difference is conducted from the multiple datasets using Rubin’s 
combining rules8. Other imputation, fully conditional specification method may be 
implemented if the multiple imputation model does not converge. 
6.6.5. Exploratory Analysis 
Exploratory endpoints will be analyzed analogously to primary and secondary endpoints, with 
the exception of a prespecified alpha-controlling testing strategy. Exploratory endpoints of 
dichotomous measurements will be analyzed analogously to primary endpoints. Exploratory 
endpoints of continuous measurements will be analyzed analogously to the secondary 
endpoint of change in physical function of HAQ-DI from baseline to Week 16. P-values for 
exploratory endpoints will be considered descriptive and not considered conclusive. A 
summary table of all primary, secondary and exploratory endpoints will be presented using 
point estimates only, to visually assess izokibep 160 mg dosed QW, izokibep 160 mg dosed 
Q2W, izokibep 80 mg dosed Q4W and placebo. 
All primary, secondary and exploratory endpoints defined for comparing izokibep 160 mg 
QW or izokibep 160 mg Q2W to placebo will also be reported for comparing izokibep 80 mg 
Q4W to placebo. 
Dose-response will be investigated through analyses of the primary and secondary endpoints, 
which will use all four treatment arms (izokibep 160 mg QW, izokibep 160 mg Q2W, izokibep 
80 mg Q4W and placebo) in a single analysis for each endpoint. A p-value for the global test 
of the hypothesis that all groups have identical response rates will be reported for each 
endpoint, not subject to type I error rate control or any multiple comparison procedure. P-
values will also be reported for all pairwise comparisons for each endpoint. Dose-response 
relationships will be assessed qualitatively from these analyses. Due to the error in dose 
sequence in the Q2W and Q4W arms, additional investigations will include assessment of 
endpoints that may be achieved earlier, including ACR20 and PASI75 at week 4 (at which 
time all subjects received correct dose sequencing). 
The following binary endpoints before or on Week 16 will be analyzed analogously to the 
primary endpoints of ACR50 at Week 16. The number and proportion of subjects for binary 


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endpoints in each treatment group will be reported without strata along with Clopper-Pearson 
95% CI. Common risk difference with Cochran-Mantel-Haenszel weighting will be used to 
calculate a 95% CI, and p-values from the stratified test will be reported as well. The binary 
endpoints after week 16 will include number and proportion along with Clopper-Pearson 95% 
CI without strata according to the four randomized treatment groups. No p-value will be 
reported. 
 ACR70 at Weeks 16, 24, and 52  
 DAPSA ≤14 at Weeks 16, 24, and 52 
 cDAPSA ≤14 at Weeks 16, 24, and 52  
 DAPSA ≤4 at Weeks 16, 24, and 52 
 cDAPSA ≤4 at Weeks 16, 24, and 52  
 PASI75 at Weeks 16, 24, and 52  
 PASI100 at Weeks 16, 24, and 52  
 MDA at Weeks 24, and 52  
 VLDA at Weeks 16, 24, and 52  
 Resolution of dactylitis at Weeks 16, 24, and 52 among those with dactylitis at 
baseline 
 ACR50 at Weeks 24 and 52  
 PASI90 at Weeks 24 and 52 among those with ≥3% BSA psoriasis at baseline 
 Resolution of enthesitis (LEI = 0) at Weeks 24 and 52 among those with LEI > 0 at 
baseline  
 Resolution of enthesitis (SPARCC = 0) at Weeks 24 and 52 among those with 
SPARCC > 0 at baseline 
 PsAID response at Weeks 24 and 52  
 ACR20 at Weeks 24 and 52  
 Occurrence of enthesitis (LEI > 0) at weeks 4, 8, 12 and 16, among subjects with no 
enthesitis (LEI = 0) at baseline 
 Decrease of at least 2 in LEI, among subjects with baseline LEI of at least 2, at weeks 
4, 8, 12 and 16. 
The following continuous endpoints will be analyzed at week 16 with an MMRM model as 
specified in sec 6.6.3, and after week 16 with standard summary statistics for continuous 
endpoints. LS mean changes and associated SEs with associated 95% CI and p-values will be 
presented. Models through week 16 will include all data up to Week 16. The following 
continuous endpoints after Week 16 will be analyzed according to the four randomized 
treatment groups. Mean changes and associated SEs along with 95% CI according to the four 
randomized treatment groups will be presented without strata. No p-values will be reported. 
 Change from baseline in DAS28-CRP at Weeks 16, 24, and 52 
 Change from baseline in DAPSA/cDAPSA at Weeks 16, 24, and 52  
 Change from baseline in PASDAS at Weeks 16, 24, and 52  


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 Change from baseline in mNAPSI at Weeks 16, 24, and 52 in those with nail psoriasis 
at baseline 
 Change from baseline in mTSS at Weeks 16 and 52  
 Change from baseline in SPARCC enthesitis score at Weeks 16, 24, and 52 in those 
with enthesitis at baseline (SPARCC>0) 
 Change from baseline in spinal pain NRS at Weeks 16, 24, and 52  
 Change from baseline in spine pain NRS in those with sacroiliitis on pelvic x-ray 
 Change from baseline in spine pain NRS in those with investigator assessed spinal 
involvement 
 Correlation of investigator assessed spinal involvement with sacroiliitis on x-ray 
 Change from baseline in SF-36 total score, PCS, and MCS at Weeks 16, 24, and 52  
 Change from baseline in FACIT-F at Weeks 16, 24, and 52  
 Change from baseline in LEI enthesitis score at Weeks 16, 24, and 52 in those with 
enthesitis at baseline (LEI>0) 
 HAQ-DI change from baseline to Weeks 24 and 52  
 HADS change from baseline to Week 24 and 52 
Change from baseline for the individual components of the ACR and MDA scores will be 
summarized at Week 16. Summary statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided 
 Swollen Joint Count 
 Tender Joint Count 
 SAPVAS 
 SGADA 
 IGADA 
 HAQ-DI 
 CRP 
 PASI 
 BSA 
 Tender entheseal points ≤ 1 site out of 6 sites included in LEI  
The following will be analyzed with a time to event model, using a log rank test with 
stratification by the factors used to stratify randomization. Subjects who do not achieve the 
endpoint at or before the week 16 visit will be censored at the time of the last assessment 
could be derived at or before week 16. 
 Time to resolution of enthesitis (LEI = 0) among subjects with enthesitis (LEI = 0) at 
baseline. 
 Time to first achievement of ACR50 


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 Time to first achievement of PASI90 among subjects with ≥3% BSA psoriasis at 
baseline 
 Time to first achievement of MDA 
 Time to first achievement of ACR20 
 Time to first achievement of PsAID improvement of at least 3 among subjects with 
PsAID ≥3 at baseline 
 Time to first achievement of PASI100 among subjects with PsAID ≥3 at baseline 
WPI will be calculated at baseline. WPI is a scale of 0-19, and is a count of how many of 19 
body sites the subject reports pain or tenderness in the prior 7 days. Standard summary 
statistics for binary data will be calculated by baseline WPI (WPI ≥7 vs. <7) for the following 
endpoints: 
 ACR50 at week 16 (observed responder, observed non-responder, missing) 
 LEI responders at week 16 (observed responder, observed non-responder, 
missing)PsAID at week 16 (observed responder, observed non-responder, missing) 
 HAQ-DI at week 16: improvement of at least 0.35 (observed responder, observed non-
responder, missing) 
Area under the curve (AUC) for ACR-N will be calculated for each subject by triangulating 
the observed values at baseline (by definition ACR-N = 0 at baseline) and weeks 2, 4, 12 and 
16. The area for consecutive visits, using nominal time from Week t and Week u, will be 
calculated as  
AUC Week t to Week u = ((u - t) × (ACR-NWeek t + ACR-NWeek u)/2 
The AUC for the period through week 16 will be the sum of the individual values from week 
0 through week 16. Any visits at which ACR-N cannot be calculated (including Week 0) will 
be imputed as ACR-N = 0. In case one or more components of ACR is missing, the smallest 
value N for which ACR-N is known to be achieved will be used. 
Listings of all efficacy data, including derived composite values will be provided for the Full 
Analysis Set. 
PK concentrations will be summarized by dose group and scheduled visit. Summary statistics 
reported will be number of samples, number of samples that are BLQ, arithmetic mean, 
standard deviation, coefficient of variation in percent (CV), minimum, median, maximum, 
geometric mean and the CV of the geometric mean in percent.  


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6.6.6. Subgroup Analysis 
Various subgroup analyses of the efficacy data will be reported. These analyses will 
investigate the treatment response within specific subgroups of interest, and assess whether 
the treatment response is consistent across different subgroup levels. All analyses will be 
performed on the FAS data set. Treatment effect will be summarized by comparison (QW 
versus placebo; Q2W versus placebo) and presented in tables and a forest plot. 
Summaries of primary and secondary efficacy endpoints will be presented by subgroup: 
The following subgroups are of interest for the primary and all secondary endpoints: 
 Race (Asian, White, Black or African American, other) 
 Sex (male, female) 
 Age (< 65, ≥ 65) 
 Prior TNFi use (Yes/No) 
The following subgroups are also of interest for ACR50 at Week 16 and all secondary 
endpoints: 
 
Any csDMARD at Baseline (Yes/No) 
o MTX only 
o MTX + other csDMARD 
o Non-MTX csDMARD only 
o No csDMARD at baseline 
 
Any prior TNFi exposure (Yes/No) 
 
Prior TNFi failure (Yes/No) 
 Number of prior failed biologics group (0, 1, 2 or more) 
 Geographic region 
o North America (US or Canada) 
o Europe (Bulgaria, Czech Republic, Spain, Hungary, Poland or Germany) 
o Non-US (Bulgaria, Czech Republic, Spain, Hungary, Poland, Germany or 
Canada) 
 Country 
o United States 
o Canada 
o Bulgaria 
o Czech Republic 
o Poland 
o Hungary 
o Spain 
o Germany 
 BMI (≤ 18, > 18 - ≤ 25, > 25 - ≤ 30, > 30 - ≤ 35, > 35) 
 Smoking status (never, former, current) 


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 Enthesitis at baseline  
o LEI = 0 
o LEI > 0 
o LEI = 1 
o LEI = 2 
o LEI = 1 or 2 
o LEI < 3 
o LEI ≥ 3 
o LEI < 4 
o LEI ≥ 4 
 Combination of enthesitis and prior TNFi exposure 
o LEI = 1 or 2 and no prior TNFi exposure 
o LEI ≥ 3 and no prior TNFi exposure 
o LEI = 1 or 2 and prior TNFi exposure 
o LEI ≥ 3 and prior TNFi exposure 
 
The following endpoints are of interest for the subjects with enthesitis at baseline (LEI > 0) 
and subjects without enthesitis (LEI = 0) at baseline: 
 PsAID response at Week 16 
 PsAID change from baseline to Week 16 
 HAQ-DI response at Week 16 
 HAQ-DI change from baseline to Week 16 
 Change in DAPSA and cDAPSA from baseline to Week 16 
 VLDA at Week 16 
 Change in SF-36 total score, physical component summary (PCS), and mental 
component summary (MCS) from baseline to Week 16 
 MDA at Week 16 (including each component of MDA) 
The following subgroups are of interest for summarizing Time to resolution of enthesitis (LEI 
= 0) among subjects with enthesitis (LEI = 0) at baseline. 
 Sex (male, female) 
 Prior exposure to TNFi (yes, no) 
 LEI score at baseline 
o LEI = 1 
o LEI = 2 
o LEI = 1 or 2 
o LEI ≥3 
The following subgroup is of interest for the endpoints of PASI75, PASI90 and PASI100: 
 Baseline BSA 10% or greater 


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Response rates and difference in response rate will be reported for each subgroup.  Cochran-
Mantel-Haenszel weighting will be used to calculate a 95% CI for subgroup analyses for each 
endpoint similar to Section 6.6.1 and 6.6.3 using stratified tests. A forest plot for the difference 
in response rate and 2-sided 95% CI will also be presented. No p-values will be reported for 
the subgroup analyses. 
PsAID and HAQ-DI response rates will be determined by the proportion of subjects who 
achieve at least a minimum clinically important difference (MCID) improvement from 
baseline to Week 16. MCID values are 3 units for PsAID and 0.35 units for HAQ-DI. 
 
Similar to the subgroup analysis above, difference in response rate and 2-sided Cochran-
Mantel-Haenszel weighted stratified 95% CI will be reported for subgroup analyses for each 
binary endpoint. 
6.7. Safety 
For all Safety Tables, data will be summarized as follows, unless otherwise specified:  
 Period 1 will include the first 16 weeks, summarized by the randomized treatment 
arms (Placebo QW; Izokibep QW; Izokibep Q2W, Izokibep Q4W) 
 Period 2 will include data after Week 16 visit, summarized by the randomized 
treatment groups (Placebo - Izokibep QW; Izokibep QW; Izokibep Q2W, Izokibep 
Q4W) 
o Selected AE summaries will be presented as: Period 2 will include data after 
Week 16 visit, summarized by Placebo - Izokibep QW; Izokibep QW (those 
who receive QW during any part of period 2); Izokibep Q2W (those who 
receive Q2W during any part of period 2); Izokibep Q4W (those who receive 
Q4W during any part of period 2);  Izokibep QW only (those who receive only 
izokibep QW during period 2); Izokibep Q2W only (those who receive only 
izokibep Q2W during period 2); Izokibep Q4W only (those who receive only 
izokibep Q4W during period 2) 
6.7.1.  Extent of Exposure 
Exposure will be reported through the planned collection of the primary endpoint and for the 
entire study for the Safety Analysis Set.  Exposure duration will also be summarized and will 
be calculated as (last dose – first dose + 1). Descriptive statistics will be presented for duration 
of exposure. 
A listing of overall treatment exposure data, including the first and last dates of treatment will 
be presented together with compliance for the Safety Analysis Set. Further, study treatment 
administration data will be listed for the Safety Analysis Set. 


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6.7.2. Adverse Events 
All SAEs will be collected from the signing of the ICF until the 8-week follow-up visit. All 
AEs will be collected from the first dose of study drug until 4 weeks after the last dose of 
study drug. All AEs recorded on the eCRF will be coded using the latest MedDRA dictionary 
around the time of Database Lock and classified as either AEs or treatment–emergent AEs 
(TEAEs) as follows: 
 
TEAEs are either events with start date and time after the start of the Treatment Period 
and up to 4 weeks after the end of the Treatment Period, or events with start date and 
time prior to the start of the Treatment Period whose severity worsens on or after the 
start of the Treatment Period. TEAEs for period 2 are either events with start date and 
time after the start of administration of Week 16 treatment and up to 4 weeks after the 
end of the Treatment Period, or events with start date and time prior to the start of 
administration of Week 16 treatment whose severity worsens on or after the start of 
administration of Week 16 treatment. For subjects who receive treatment in period 2, 
TEAEs with start date after the start of period 2 will be assigned to period 2 only, not 
to period 1. 
 
Treatment-Emergent Serious AEs (TESAEs) will be defined as TEAEs which meet 
the criteria as Serious = “Yes”. 
 
The relationship between a TEAE and treatment is assessed as related or not related. 
A treatment-related TEAE will be defined as a TEAE considered by the investigator 
as related to treatment or with unknown/missing relationship to treatment. 
 
Assessment of AE severity will be based on eCRF AEs form.  
 
TEAEs leading to discontinuation of treatment are defined as TEAEs where “Action 
Taken with Study Treatment” is indicated as “Drug Withdrawn”. 
In addition to the aforementioned AE types, the following TEAEs of special interest will be 
monitored:  
 Candida infection, 
 Inflammatory bowel disease, 
 Suicidal ideation.  
 Malignancies 
 MACE (major adverse cardiovascular and cerebrovascular events: cerebrovascular 
accident and transient ischemic attack, non-fatal myocardial infarction or unstable 
angina, cardiovascular death) 
 Tuberculosis (TB) 
 Infections (serious, opportunistic, or fungal only) 
 Cytopenias 


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 Systemic hypersensitivity reaction 
Adverse events of special interest will be identified manually. After all data are entered into 
the database and before database unblinding, a list of all unique PTs will be generated. 
ACELYRIN pharmacovigilance and clinical development representatives will review the list 
and determine which are TEAEs of special interest in each category listed above. This 
determination will be documented in a memo, signed and dated before database lock, and 
stored in the study trial master file. The database will not be unblinded until the memo is 
finalized and signed. 
Adverse events will be summarized by default descriptive summary statistics for categorical 
variables for the Safety Analysis Set as follows: 
 An overview of TEAEs including the number and percentage of subjects with at least 
one of each mentioned TEAE type according to both Period 2 groupings as described 
in section 6.7: 
o Any TEAE 
 Leading to discontinuation of study treatment 
 Mild (Grade 1) 
 Moderate (Grade 2) 
 Severe (Grade 3) 
 Life-threatening (Grade 4) 
 Death (Grade 5) 
 Any TEAE  
 Grade 2 or higher 
 Grade 3 or higher 
 Grade 4 or higher 
o Any study treatment related TEAE 
 Leading to discontinuation of study treatment 
o Any serious TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
o Any serious study treatment related TEAE 
 Leading to discontinuation of study treatment 
 Leading to death 
 The number and percentage of subjects reporting each TEAE and the count of number 
of events will be summarized by SOC and PT for the following types of TEAEs.  
o TEAEs 
o TEAEs of Special Interest 
o TEAEs Leading to Discontinuation of Study Treatment 


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o TEAEs leading to interruption of study treatment 
o TEAEs by Maximum Severity 
o TEAEs by Relationship to Treatment 
o TEAEs by Relationship and Maximum Severity 
o Study Treatment related TEAEs 
o Study Treatment Related TEAEs Leading to Discontinuation of Study 
Treatment 
o Serious TEAEs 
o Serious TEAEs Leading to Discontinuation of Study Treatment 
o Serious TEAEs Leading to Death 
o Study Treatment Related Serious TEAEs 
o Study Treatment Related Serious TEAEs Leading to Discontinuation of Study 
Treatment 
o Study Treatment Related Serious TEAEs Leading to Death 
 The number and percentage of subjects reporting each TEAE and the count of number 
of events will be summarized by SOC and PT for two subgroups: 
o Subjects < 65 years of age at baseline 
o Subjects ≥ 65 years of age at baseline 
 The number and percentage of subjects who died will be summarized  
 The number and percentage of subjects reporting each TEAE and the number of events 
will be summarized by PT for all TEAEs  
 The number and percentage of subjects reporting each TEAE and the number of events 
will be summarized by PT for TEAEs of Special Interest 
 The number and percentage of subjects reporting each TEAE and the count of number 
of events according to the 5 Period 2 groupings as described in section 6.7 will be 
summarized by SOC and PT for the following types of TEAEs.  
 All TEAEs 
 Serious TEAEs 
In the above summaries, subjects with more than one TEAE within a particular SOC are 
counted only once for that SOC. Similarly, subjects with more than one TEAE within a 
particular PT are counted only once for that PT. 
For summaries by maximum severity, subjects with multiple TEAEs within a particular SOC 
or PT will be counted under the category of their most severe TEAE within that SOC or PT. 
TEAEs with missing severity will be included in the counts as severe (Grade 3) unless the 
TEAE has an outcome of fatal; in that case, the TEAE with missing severity will be included 
in the counts as death (Grade 5). 


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Summaries by SOCs and PTs will be sorted by SOCs by their Internationally Agreed Order 
(MedDRA) and PTs within SOC by descending order of total incidence. Where PTs tie, PTs 
will be sorted alphabetically. 
All AE data will be listed and AEs and TEAEs will be presented together. Treatment-
emergence status will be flagged in the listing. The listing will present the relative start and 
stop day of the AE calculated relative to the first dose of treatment and will be presented for 
those subjects who received at least one dose of treatment. If the AE is “Ongoing” it will be 
indicated as such in the listing and the relative stop day will not be calculated. Only original 
dates will be presented in the listing even though the relative day may be based on an imputed 
date. 
In addition, the following listings will be presented: 
 Listing of Deaths 
 Listing of TEAEs 
 Listing of Serious TEAEs 
 Listing of AEs Leading to Interruption of Study Treatment 
 Listing of AEs Leading to Discontinuation of Study Treatment 
 Listing of AEs of Special Interest 
6.7.3. Laboratory Evaluations 
Data for the following hematology, clinical chemistry, routine urinalysis, pregnancy testing, 
other screening tests, and other tests analytes received from the central laboratory are to be 
measured at the scheduled timepoints (Baseline, Week 4, 8, 12, 16, 20, 24, 32, 36, 40, 52 and 
59).  
In accordance with the baseline value definition in Section 5.1.2, the change from baseline 
will be derived as follows:  
Change (unit) = (post-baseline value – baseline value) 
All laboratory data will be reported in SI units. All quantitative laboratory test values at each 
assessed timepoints will be compared with the relevant reference range in SI units and 
categorized as: 
o Low: Below the lower limit of the reference range.  
o Normal: Within the reference range (upper and lower limits included). 
o High: Above the upper limit of the reference range.  
For summaries which present the worst value with respect to the reference range at the subject 
level, low and high are each chosen in preference to normal values. For parameters with both 


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low and high reference ranges, subjects who have assessments within both low and high 
ranges will be counted within each category for worst value summary tables. 
For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those below or above the 
limits of quantification) will be considered equal to the lower or upper limit of quantification, 
respectively.  
Laboratory values will be assigned toxicity grades, when available, using criteria based on the 
National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 5.0 or higher scale. 
For those parameters which are graded with two toxicities such as potassium 
(hypokalemia/hyperkalemia), the toxicities will be summarized separately. Low direction 
toxicity (e.g., hypokalemia) grades at baseline and post baseline will be set to 0 when the 
variables are derived for summarizing high direction toxicity (e.g., hyperkalemia), and vice 
versa. 
Laboratory data will be summarized by default descriptive summary statistics for continuous 
and categorical variables for the Safety Analysis Set: 
 Observed values and change from baseline at each assessed timepoint for each 
standard continuous laboratory parameter 
 Number and percentage of subjects with categorized shift (low, normal, and high) 
values relative to the reference range at baseline compared to each post-baseline 
timepoint for hematology and clinical chemistry 
 Number and percentage of subjects with worst categorized (low, normal, and high) 
values relative to the reference range 
 Number and percentage of subjects with NCI-CTCAE Grade 1, 2, 3, 4, 3/4, and any 
grade during post-baseline 
 Number and percentage of subjects with categorized shift NCI-CTCAE toxicity 
values at baseline compared to worst post-baseline result 
Listings of all clinical laboratory data including derived change from baseline will be 
provided for the Safety Analysis Set. Within each listing, laboratory values outside the 
normal ranges will be flagged as either high or low. 
6.7.3.1. Liver toxicity review 
Potential liver toxicity will be assessed by listing subjects who met potential drug induced 
liver injury (DILI) criteria as described in the protocol and by summarizing subjects who met 
Hy’s Law. 


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Subjects who met any (one or more) of the following criteria will be included in a listing for 
consideration of DILI: 
 ALT or AST ≥5 x ULN at any time 
 ALT or AST ≥3 x ULN at all (2 or more) assessments in a span of ≥4 weeks  
 ALT or AST ≥3 x ULN and total bilirubin ≥2 x ULN (>35% direct bilirubin) 
simultaneously at any time 
 ALT or AST ≥3 x ULN and international normalized ratio (INR) ≥1.5 
simultaneously at any time 
 ALT or AST ≥3 x ULN at any time during the study and weekly assessments after 
this finding are not available for at least 4 weeks  
 ALT or AST ≥3 x ULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity at any time 
To determine subjects who meet the last criterion, a listing of all subjects who have at least 
one ALT or AST ≥3 x ULN at any time, and who do not meet any of the first five criteria, 
will be reviewed by qualified medical professionals along with a listing of all AEs reported 
by such subjects. In coordination with the investigator, the medical professionals will assess 
whether any AE is believed to be related to liver injury or hypersensitivity and, if so, whether 
the elevated ALT or AST is in temporal association with the AE. Any subjects who meet these 
criteria will be included on a memo that will be filed in the TMF prior to database lock and 
unblinding, and included in the listings.  For subjects who meet any of the six criteria, all liver 
function test results at any time during the study will be listed, sorted by subject and date. 
Listing will include subject, treatment assignment, ALT, AST, bilirubin and INR, along with 
specific criterion met. 
Subjects who meet the criteria for Hy’s Law will be displayed in shift tables. Hy’s Law is met 
when ALT or AST is ≥3 x ULN, total bilirubin ≥2 x ULN and ALP is <2 x ULN, with all 
occurring simultaneously (at the same draw). At each assessment, subjects will be classified 
as meeting Hy’s Law or not meeting Hy’s Law. The shift tables will be presented as follows: 
 Period 1 
o Baseline (meet Hy’s Law / not meet Hy’s Law) 
o Any time during period 1 (meet Hy’s Law at least one time / not meet Hy’s 
Law at any time) 
 Period 2 
o Baseline prior to period 2 (meet Hy’s Law / not meet Hy’s Law) 
o Any time during period 2 (meet Hy’s Law at least one time / not meet Hy’s 
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A listing of all liver function test results from all subjects who meet Hy’s Law at least one 
time during the study will be produced, sorted by subject and date. This listing will show 
subject, treatment assignment, period, ALT, AST, ALP, bilirubin and INR. 
6.7.4. Vital Signs 
The analyses described below will be conducted for the following vital signs assessments 
respectively: 
 SBP (mmHg) 
 DBP (mmHg) 
 Heart Rate (bpm) 
 Respiratory Rate (breaths/min) 
 Body Temperature (°C) 
In accordance with the baseline value definition in Section 5.1.2, the change from baseline 
will be derived as follows:  
Change (unit) = (post-baseline value – baseline value) 
The following will be summarized for the Safety Analysis Set: 
 Observed values and change from baseline at each assessed timepoint for each 
standard vital sign parameter using default summary statistics for continuous 
variables. 
A listing of all vital signs data including derived change from baseline will be provided for 
the Safety Analysis Set. 
6.7.5. Electrocardiograms 
The following electrocardiogram (ECG) assessments will be taken at baseline: 
 An overall assessment classified as normal or abnormal 
 Abnormal assessments will be further classified as clinically significant or not 
clinically significant 
At baseline assessment, the subject will be classified as abnormal if any (one or more) of the 
replicate assessments are classified as abnormal. Similarly, the abnormal assessment will be 
classified as clinically significant if any (one or more) abnormal assessments are classified 
as clinically significant. The subject will be classified based on the worst finding of 
triplicate 12-Lead ECG. A list of ECG assessments will be presented. 


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6.7.6. Physical Examination 
Clinically significant findings observed prior to the first dose of study drug will be entered 
in the CRF and reported as medical history. Clinically significant findings observed after the 
first dose of study drug will be reported as AEs in the CRF and reported as AEs. 
Physical examination findings (normal/abnormal/clinically significant) and details of 
abnormalities will be listed only for each subject at each assessment. 
6.7.7. Interim Analysis and Data Monitoring 
An independent Data Monitoring Committee (DMC) will be established to monitor data on 
an ongoing basis to ensure the continuing safety of the subjects enrolled in this study.  
The DMC will consist of two clinicians and a biostatistician that, collectively, has 
experience in the management of subjects with Psoriatic Arthritis and in the conduct and 
monitoring of randomized clinical trials. The DMC responsibilities, authorities, and 
procedures will be documented in the DMC charter. The committee will meet 
approximately every 6 months to review interim data. After each review, the DMC will 
make recommendations regarding the continuation of the study based on safety.  
The DMC will review unblinded efficacy data when approximately 120 subjects have had 
the opportunity to complete the Week 12 visit. Data from the first 105 subjects randomly 
assigned to receive izokibep 160 mg QW, izokibep 160 mg Q2W or placebo will be used for 
these DMC summaries. The DMC may make a recommendation on further development 
activities for izokibep based on this data review. The DMC will not be empowered to 
recommend stopping this study or changing the sample size due to a demonstration of 
positive efficacy. The study team operationalizing the day-to-day of the study, the subjects, 
and the investigators will remain blinded to these interim results until after the study is 
completed. 
No interim analyses will be conducted for the purpose of stopping the study or altering the 
study design. 
The primary analysis of primary and secondary endpoints will occur after all subjects have 
had an opportunity to complete the Week 16 assessments (have completed the Week 16 
assessments, or have completed a subsequent timepoint assessment, or permanently 
discontinued the study before Week 16). For the primary and secondary objectives, this will 
include all data for all subjects for the final analysis, and so it will be the final analysis. The 
final analysis will be conducted at the end of the study when all subjects have completed the 
study or permanently discontinued the study. For the primary endpoint, all available data at 
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subjects will be ongoing and may have data collected after the primary analysis is reported. 
Data collected at subsequent timepoints may be summarized when all data at that timepoint 
have been collected. All data collected for the primary endpoint for all subjects through the 
end of the study will be reported in a subsequent analysis, but the p-values from each 
comparison of a regimen of izokibep to placebo in this subsequent analysis will not be used 
for any alpha-preserving hypothesis testing. Investigators, site personnel, and all sponsor 
personnel who have contact with subjects will remain blinded to individual subject 
treatment assignments until the final analysis. 
When the primary efficacy analysis is conducted, safety data will be summarized. 
Summaries will include all safety data through Week 16 and all available safety data on all 
subjects through the end of the study. All safety data will be summarized through the end of 
the study when all subjects have completed all visits. 
6.8. Pharmacokinetic Assessments  
PK concentrations will be summarized by dose group and scheduled visit. Summary 
statistics will be reported with the number of samples, number of samples that are BLQ, 
arithmetic mean, standard deviation, coefficient of variation in percent (CV), minimum, 
median, maximum, geometric mean and the CV of the geometric mean in percent. For the 
calculation of summary statistics, predose concentrations that are below the limit of 
quantification (BLQ) will be treated as zero and post-dose concentrations that are BLQ will 
be treated as missing. 
Plots of arithmetic mean time courses by dose group will be provided using linear and semi-
logarithmic scale.  
6.9. Anti-Drug Antibodies 
Samples tested for ADAs will be reported as positive or negative based on a non-domain 
specific confirmatory assay. Samples that are positive, and are further tested, will be 
reported as positive or negative for the IL-17A binding domain, positive or negative for the 
albumin binding domain, and/or positive or negative as a neutralizing ADA. Any continuous 
values of concentration (titers) will be summarized using observed data.  
Subjects will be summarized at each scheduled visit according to the confirmatory test, with 
number (%) positive. Positive samples on the confirmatory test, that are further tested, will 
be reported according to each specific binding domain, with number (%) positive for the IL-
17A binding domain, number (%) positive for the albumin binding domain, and number (%) 
positive for either (one or both) binding domain. Samples that are further tested on a 
neutralizing antibody assay will be reported as number (%) positive for neutralizing activity, 
with percentage calculated using the number that were positive according to the screening 


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test as the denominator. In addition, incidence persistent ADA will be summarized for IL-
17A and albumin binding domain. Persistent ADA is characterized as treatment-induced 
ADA detected at two or more sampling time points during the treatment irrespective of any 
negative samples in between (including follow-up period if any). 




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Arising 
Special or built up chair 
Arising 
Eating 
Built up or special utensils 
Eating 
Walking 
Crutches, Cane, Wheelchair, Walker Walking 
Hygiene 
Raised toilet seat, Bathtub bar, 
Bathtub seat, Long-handled 
appliances in bathroom 
Hygiene 
Reach 
Long-handled appliances for reach 
Reach 
Grip 
Jar opener (for jars previously 
opened) 
Gripping and opening things 
Activities 
 
Errands and chores 
 


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Appendix 2.2 36-Item Short Form Survey (SF-36)10 
The SF-36 questionnaire consists of eight scales yielding two summary measures: physical 
and mental health. The physical health measure includes four scales of physical functioning 
(10 items, PF), role limitations due to physical health (4 items, RP), bodily pain (2 items, BP), 
and general health (5 items, GH). The mental health measure is composed of vitality (4 items, 
VT), social functioning (2 items, SF), role limitations due to emotional problems (3 items, 
RE), and mental health (5 items, MH). 
Two versions of the SF-36 were used in this study. SF-36v1 and SF-36v2®. A small subset 
of subjects received v1. For these subjects, coding will be done programmatically as follows. 
 Step 1: Recoding Items 
Item numbers 
Change 
original 
response 
category * 
To recoded value of: 
1, 2, 20, 22, 34, 36 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 
0 
2 
50 
3 
100 
13, 14, 15, 16, 17, 18, 19 
1 
0 
2 
100 
21, 23, 26, 27, 30 
1 
100 
2 
80 
3 
60 
4 
40 


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5 
20 
6 
0 
24, 25, 28, 29, 31 
1 
0 
2 
20 
3 
40 
4 
60 
5 
80 
6 
100 
32, 33, 35 
1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
* Precoded response choices as printed in the questionnaire. 
 Step 2: Averaging Items to Form Scales 
Scale 
Number of items 
After recoding per Step 
1, average the following
item 
Physical functioning 
10 
3 4 5 6 7 8 9 10 11 12 
Role limitations due to physical 
health 
4 
13 14 15 16 
Role 
limitations 
due 
to 
emotional problems 
3 
17 18 19 
Energy/fatigue/vitality 
4 
23 27 29 31 


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Emotional 
well-being/mental 
health 
5 
24 25 26 28 30 
Social functioning 
2 
20 32 
Bodily pain 
2 
21 22 
General health 
5 
1 33 34 35 36 
 
The SF-36 questionnaire consists of eight scales yielding two summary measures: physical 
and mental health. The physical health measure includes four scales of physical functioning 
(10 items, PF), role limitations due to physical health (4 items, RP), bodily pain (2 items, BP), 
and general health (5 items, GH). The mental health measure is composed of vitality (4 items, 
VT), social functioning (2 items, SF), role limitations due to emotional problems (3 items, 
RE), and mental health (5 items, MH). 
From the individual subscales, two component summary scores are generated for physical 
(PCS) and mental health (MCS). The mean of the first five subscales (PF, RP, BP, GH, and 
VT) produce the PCS and the mean of the last five subscales (GH, VT, SF, RE, MH) produce 
the MCS; the GH and VT subscales overlap between the two overall components. 
Items that are left blank (missing data) are not taken into account when calculating the scale 
scores. Hence, scale scores represent the average for all items in the scale that the respondent 
answered.   
Scoring of the SF-36v.2 will be done using Quality Metrics10.  
Abbreviated Item Content for the SF-36v2® Health Survey Health Domain Scales 
Scale  
Item  
Abbreviated Item Content 
Physical Functioning (PF)  
3a 
Vigorous activities, such as running, lifting 
heavy objects, or participating in strenuous 
sports 
 
3b 
Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or 
playing golf 
 
3c 
Lifting or carrying groceries 
 
3d 
Climbing several flights of stairs 
 
3e 
Climbing one flight of stairs 
 
3f 
Bending, kneeling, or stooping 
 
3g 
Walking more than a mile 
 
3h 
Walking several hundred yards 


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3i 
Walking one hundred yards 
 
3j 
Bathing or dressing oneself 
Role-Physical (RP)  
4a  
Cut down the amount of time one spent on 
work or other activities 
 
4b 
Accomplished less than you would like 
 
4c 
Limited in kind of work or other activities 
 
4d 
Had difficulty performing work or other 
activities (e.g., it took extra effort) 
Bodily Pain (BP)  
7 
Intensity of bodily pain 
 
8 
Extent pain interfered with normal work 
General Health (GH)  
1 
Is your health: excellent, very good, good, 
fair, poor 
 
11a 
Seem to get sick a little easier than other 
people 
 
11b 
As healthy as anybody I know 
 
11c 
Expect my health to get worse 
 
11d 
Health is excellent 
Vitality (VT)  
9a 
Feel full of life 
 
9e 
Have a lot of energy 
 
9g  
Feel worn out 
 
9i  
Feel tired 
Social Functioning (SF)  
6 
Extent health problems interfered with 
normal social activities 
 
10 
Frequency health problems interfered with 
social activities 
Role-Emotional (RE)  
5a 
Cut down the amount of time spent on work 
or other activities 
 
5b  
Accomplished less than you would like 
 
5c  
Did work or other activities less carefully 
than usual 
Mental Health (MH) 
9b  
Been very nervous 
 
9c  
Felt so down in the dumps that nothing 
could cheer you up 
 
9d  
Felt calm and peaceful 
 
9f  
Felt downhearted and depressed 
 
9h  
Been happy 
Reported Health Transition (HT)  
2 
How health is now compared to 1 year ago 
 
An excerpt from the User's Manual for the SF-36v2 Health Survey 
 
 
 


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Appendix 2.3 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)11 
For any FACIT measure, items are scored on a 0 – 4 response scale with anchors ranging from 
“Not at all” to “Very much so”. To score the FACIT-F, scores are calculated by first reversing 
negatively stated-items (subtracting the response from ‘4’) and then summing the reverse 
scores. A total score is then derived by summing all scores. 
In cases where individual items are missing, subscale scores can be prorated using the average 
of the other answers in the scale. This is acceptable as long as more than 50% of the items 
were answered in the subscale (e.g., a minimum of 7 of 13 items.).  
 
 


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Appendix 2.4 Disease Activity Score in 28 joints-C-reactive protein (DAS28-CRP)12 
The DAS28-CRP considers 28 tender and swollen joint counts, general health (subject’s 
global assessment of disease activity (SGADA) using a 100 mm visual analogue scale (VAS) 
with 0 = best, 100 = worst), plus levels of an acute phase reactant (CRP (mg/L)). 
DAS28 values were calculated as follows:  
DAS28-CRP = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014* SGADA + 0.36*ln(CRP+1) + 0.96;  
where TJC = tender joint count and SJC = swollen joint count; 
SGADA = subject’s global assessment of disease activity on a 0-100 VAS. 
If one or more components are missing in the formula, then DAS28-CRP is set to be missing. 
 
 


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Appendix 2.5 Disease Activity index for Psoriatic Arthritis (DAPSA)13 
DAPSA is the numerical sum of 66 swollen and 68 tender joint counts, pain, SGADA (pain 
and SGADA scored on a 0–10 scale) and CRP (mg/dL)) 
DAPSA = TJC68 + SJC66 + SGADA/10 + SAPVAS/10 + CRP; 
where TJC = tender joint count and SJC = swollen joint count; 
ln = natural logarithm;  
SGADA = subject’s global assessment of disease activity on a 0-100 VAS; 
SAPVAS = subject's global assessment of pain on a 0-100 VAS; 
CRP = C-reactive protein measured in mg/dL. 
The cDAPSA, which was derived from the DAPSA, includes all DAPSA components but 
excludes CRP to obtain a fully clinical score. 
A DAPSA, cDAPSA score of ≤14 represents low disease activity, and a score of ≤4 represents 
remission.  
 
 


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Appendix 2.6 Psoriatic Arthritis Disease Activity Score (PASDAS)14 
The PASDAS is calculated using the following formula:  
PASDAS = (0.18√IGADA) + (0.159√SGADA) – (0.253√SF-36PCS) + (0.101*ln(SJC66+1)) 
+ (0.048*ln(TJC68+1)) + (0.23*ln(LEI+1)) + (0.37*ln(LDI+1)) + (0.102*ln((CRP*10) +1) 
+2) * 1.5 
where swollen and tender joint counts can range from 0 to 66 and 68 joints, respectively; and 
CRP = C-reactive protein measured in mg/L. The PASDAS score ranges from 0-10 with 
higher scores indicating worse disease activity. 
where TJC = tender joint count and SJC = swollen joint count; 
ln = natural logarithm; all VAS scores are from 0-100mm;  
IGADA = investigator’s global assessment of disease activity; 
SGADA = subject’s global assessment of disease activity; 
PCS = physical component summary scale of the SF-36; 
LEI = Leeds enthesitis index; 
LDI = Leeds dactylitis index; 
CRP = C-reactive protein measured in mg/dL. 
The score range of the PASDAS is 0 to 10, with worse disease activity represented by higher 
scores. 
 
 


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Appendix 2.7 Psoriatic Arthritis Impact of Disease Scoring and Calculation Rules 
(PsAID)15 
The PsAID is calculated based on 9 Numerical rating scales (NRS) questions. Each NRS is 
assessed as a number between 0 and 10. 
1. Calculation  
PsAID final value = (PsAID1 (pain) NRS value (range 0-10) x 0.174) + (PsAID2 (fatigue) 
NRS value (range 0-10) x 0.131) + (PsAID3 (skin) NRS value (range 0-10) x 0.121) + 
(PsAID4 (Work and/or leisure activities) NRS value (range 0-10) x 0.110) + (PsAID5 
(function) NRS value (range 0-10) x 0.107) + (PsAID6 (discomfort) NRS value (range 0-10) 
x 0.098) + (PsAID7 (sleep) NRS value (range 0-10) x 0.089) + (PsAID8 (coping) NRS value 
(range 0-10) x 0.087) + (PsAID9 (anxiety) NRS value (range 0-10) x 0.085)  
Thus, the range of the final PsAID value is 0-10 where higher figures indicate worse status. 
2. Missing data imputation  
If one of the 9 NRS values composing the PsAID is missing, the imputation is as follows:  
a. calculate the mean value of the 8 other (non-missing) NRS (range, 0-10)  
b. impute this value for the missing NRS  
c. Then, calculate the PsAID as explained above. 
If 2 or more of the NRS are missing, the PsAID is considered as missing value (no 
imputation). 
 
 


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Appendix 2.8 Psoriasis Area and Severity Index and Affected Body Surface Area 
(PASI)16 
Psoriasis Area and Severity Index is an index used to express the severity of psoriasis. 
1. Intensity 
A representative area of psoriasis is selected for each body region. The intensity of redness/ 
erythema, thickness, and scaling of the psoriasis is assessed as absent/none (0), mild (1), 
moderate (2), severe (3), or very severe (4). 
2. Calculation for intensity 
The three intensity scores are added up for each of the four body regions to give subtotals A1, 
A2, A3, A4. 
Each subtotal is multiplied by the body surface area represented by that region. 
 
A1 x 0.1 gives B1 
 
A2 x 0.2 gives B2 
 
A3 x 0.3 gives B3 
 
A4 x 0.4 gives B4 
3. Area 
The percentage area affected by psoriasis is evaluated in the four regions of the body. In each 
region, the area is expressed as nil (0), 1-9% (score 1), 10-29% (score 2), 30-49% (score 3), 
50-69% (score 4), 70-89% (score 5) or 90-100% (score 6). 
 
Head and neck 
 
Upper limbs 
 
Trunk 
 
Lower limbs 
4. Calculations for area 
Each of the body area scores is multiplied by the area affected. 
 
B1 x (0 to 6)= C1 
 
B2 x (0 to 6)= C2 
 
B3 x (0 to 6)= C3 
 
B4 x (0 to 6)= C4 
5. Total score 


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The PASI score is C1 + C2 + C3 + C4. 
 
 


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Appendix 2.9 modified Nail Psoriasis Severity Index (mNAPSI) 
mNAPSI is a scale used to evaluate the severity of nail bed psoriasis and nail matrix 
psoriasis by area of involvement in the nail unit. 
NAPSI is used to assign a score to each nail for nail bed and nail matrix psoriasis: Nail plate 
is assessed for nail matrix psoriasis by the presence of any feature of nail matrix psoriasis, 
including nail pitting, leukonychia, red spots in the lunula, and crumbling in each quadrant 
of the nail. Nail bed psoriasis is assessed by the presence of any features of nail bed 
psoriasis, including onycholysis, oil drop (salmon patch) dyschromia, splinter hemorrhages, 
and nail bed hyperkeratosis in each quadrant of the nail. 
The score is 0 if the findings are not present, 1 if they are present in 1 quadrant of the nail, 2 
if present in 2 quadrants of a nail, 3 if present in 3 quadrants of a nail, and 4 if present in 4 
quadrants of a nail. Thus, each nail has a matrix score (0-4) and a nail bed score (0-4), and 
the total nail score is the sum of those 2 individual scores (0-8). Sum of the total score of all 
involved fingernails is the total mNAPSI score. 
 


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Appendix 2.10 van der Heijde modified Total Sharp Score (mTSS)  
The mTSS is a detailed scoring method evaluating erosions, joint space narrowing, 
(sub)luxation, ankylosis, gross osteolysis, and pencil in cup phenomena. 
Hands/wrists radiographs will be obtained by sites and sent for central review. The central 
reviewers will use the modified total Sharp Score (mTSS) to evaluate for radiographic damage 
and progression.  
 
 


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Appendix 2.11 Minimal Disease Activity (MDA) and Very Low Disease Activity 
(VLDA)  
A subject is classified as in MDA when 5 of the following 7 criteria are met: 
 
68 tender joint count ≤ 1  
 
66 swollen joint count ≤ 1  
 
PASI ≤ 1 or BSA ≤ 3%  
 
Subject’s Pain Assessment (visual analogue scale [VAS]) ≤ 15 mm  
 
Subject’s Global Activity VAS ≤ 20 mm (corresponds to Subject’s Global 
Assessment of Disease Activity)  
 
HAQ-DI ≤ 0.5 
 
Tender entheseal points ≤ 1 site out of 6 sites included in LEI.  
A subject is classified as in very low disease activity (VLDA) when all 7 criteria described 
above are met. 


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8. References 


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1ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://database.ich.org/sites/default/files/E9 Guideline.pdf 
 
2ICH. Addendum on Estimands and Sensitivity Analysis in Clinical Trials, Guideline 
E9(R1). Available at 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
 
3ICH. Structure and Content of Clinical Study Reports, Guideline E3, 1995. Available at  
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
 
4Brown H and Prescott R. Applied Mixed Models in Medicine. John Wiley & sons 
(Chichester), 1999. 
 
5 Fairclough D L. Design and Analysis of Quality of Life Studies in Clinical Trials. 
Chapman & Hall/CRC, 2002. 
 
6Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley & Sons. 
 
7Fairclough D L. Design and Analysis of Quality of Life Studies in Clinical Trials. Chapman 
& Hall/CRC, 2002. 
 
8Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley & Sons. 
 
9THE HEALTH ASSESSMENT QUESTIONNAIRE (HAQ) DISABILITY INDEX (DI) 
OF THE CLINICAL HEALTH ASSESSMENT QUESTIONNAIRE (VERSION 96.4): 
https://www.niehs.nih.gov/research/resources/assets/docs/haq_instructions_508.pdf 
 
1036-Item Short Form Survey (SF-36) Scoring Instructions 
QualityMetric, Inc., September 2022 
 
11Scoring OF THE FACIT MEASURES 
https://www.facit.org/scoring#:~:text=For%20any%20FACIT%20measure%2C%20subscal
e,derived%20by%20summing%20subscale%20scores 
 
12Table 1 Formulae to calculate the different DAS and SDAI score 
https://arthritis-research.biomedcentral.com/articles/10.1186/ar1787/tables/1 
 
13 DAPSA (Disease Activity in PSoriatic Arthritis) Score 
https://rheuma.charite.de/fileadmin/user_upload/microsites/ohne_AZ/m_cc13/rheuma/Temp
lates/DAPSA_ENG.pdf 
 
                                                 


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14TREATING PSORIATIC ARTHRITIS TO TARGET: DEFINING PSORIATIC 
ARTHRITIS DISEASE ACTIVITY SCORE (PASDAS) THAT REFLECTS STATE OF 
MINIMAL DISEASE ACTIVITY (MDA) 
https://www.jrheum.org/content/jrheum/early/2019/06/11/jrheum.181472.full.pdf 
 
 
15 The EULAR Psoriatic Arthritis Impact of Disease: PsAID9 for clinical trials 
https://oml.eular.org/sysModules/obxOML/docs/id_5/PSAID-English.pdf 
 
16 PASI score 
https://dermnetnz.org/topics/pasi-score