Clinical trial NCT05355805
Conditions: Hidradenitis Suppurativa
Keywords: hidradenitis suppurativa Izokibep
Sponsor: ACELYRIN Inc.
Start date: 2022-05-05; Completion date: 2024-02-21
Enrollment: 205 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

This study will evaluate the efficacy, safety, and immunogenicity of izokibep administered subcutaneously (SC) in adult subjects with moderate to severe HS.

Detailed description:

Arms: arm 1: Participants will receive izokibep every week from Day 1 through Week 31 arm 2: Participants will receive izokibep every week for 31 weeks. arm 3: Participants will receive izokibep every other week for 30 weeks. arm 4: Participants will receive placebo every week up to Week 15, then izokibep from Week 16 to Week 31. arm 5: Participants will receive placebo every other week up to Week 14, then izokibep from Week 16 to Week 30.
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:
SAP_002.pdf: 
Protocol Number: 21102 
 
Official Title: A Phase 2b Pivotal Study to Evaluate the Efficacy and Safety of Izokibep in Subjects 
with Moderate to Severe Hidradenitis Suppurativa 
 
NCT Number: NCT05355805 
 
Document Date: 04 April 2024 




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Table of Contents 
Glossary of Abbreviations ....................................................................................................... 6 
1. Source Documents ............................................................................................................... 8 
2. Protocol Details .................................................................................................................... 9 
2.1. Overall Study Design .................................................................................................... 9 
2.2. Study Objectives ......................................................................................................... 10 
2.2.1. Primary Objective ................................................................................................. 10 
2.2.2. Secondary Objectives ........................................................................................... 11 
2.2.3. Exploratory Objectives ......................................................................................... 11 
2.3. Sample Size and Power ............................................................................................... 12 
2.4. Primary Efficacy Variable ........................................................................................... 12 
2.5. Secondary Efficacy Variables ..................................................................................... 13 
2.6. Exploratory Efficacy Variables ................................................................................... 13 
2.7. Safety Variables .......................................................................................................... 14 
2.7.1. Adverse Events, Serious Adverse Events, and Other Safety Reporting ............... 14 
2.7.2. Clinical Safety Laboratory Tests .......................................................................... 15 
2.7.3. Vital Signs ............................................................................................................ 15 
2.7.4. Physical Examination ........................................................................................... 15 
2.7.5. Suicidal Ideation and Behavior Risk Monitoring ................................................. 15 
2.7.6. Pharmacokinetics Variable(s) ............................................................................... 15 
2.8. Immunogenicity .......................................................................................................... 16 
3. Estimands ........................................................................................................................... 17 
3.1. Estimand for the Primary Objective ............................................................................ 17 
3.1.1. Treatment Condition of Interest ........................................................................... 17 
3.1.2. Population of Subjects Targeted by the Clinical Question ................................... 17 
3.1.3. Variable Obtained from Each Subject Required to Address the Clinical Question
 
17 
3.1.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest ...... 18 
3.1.5. Population-level Summary for Comparison Between Treatment Conditions ...... 18 
3.2. Estimands for the secondary objectives ...................................................................... 18 
3.2.1. Treatment Condition of Interest ........................................................................... 19 
3.2.2. Population of Subjects Targeted by the Clinical Question ................................... 19 


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3.2.3. Variable Obtained from Each Subject Required to Address the Clinical Question
 
19 
3.2.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest ...... 19 
3.2.5. Population-level Summary for Comparison between Treatment Conditions ....... 20 
3.2.6. Sensitivity Estimators for the Secondary Estimand ............................................. 20 
3.3. Estimands for the exploratory objectives .................................................................... 20 
4. Analysis Sets ...................................................................................................................... 21 
4.1. All Screened Set .......................................................................................................... 21 
4.2. Full Analysis Set ......................................................................................................... 21 
4.3. Safety Analysis Set...................................................................................................... 21 
4.4. Pharmacokinetics Analysis Set ................................................................................... 21 
4.5. ADA Analysis Set ....................................................................................................... 22 
5. Data Handling .................................................................................................................... 23 
5.1. Time Points and Visit Windows.................................................................................. 23 
5.1.1. General Definitions............................................................................................... 23 
5.1.2. Screening Period ................................................................................................... 23 
5.1.3. Treatment Period .................................................................................................. 23 
5.1.4. Visit Windows ...................................................................................................... 24 
5.2. Handling of Dropouts, Missing Data, and Outliers ..................................................... 24 
5.2.1. Handling of Missing Efficacy Data ...................................................................... 24 
5.2.2. Handling of Missing Safety Data ......................................................................... 25 
5.2.3. Handling of Partial and Missing Dates for Date of Birth, Adverse Events, Prior/ 
Concomitant Medications ............................................................................................... 25 
5.2.4. Handling of Plasma Concentrations that are Below the Lower Limit of 
Quantification ................................................................................................................. 27 
6. Statistical Methods ............................................................................................................. 28 
6.1. General Principles ....................................................................................................... 28 
6.2. Subject Disposition and Data Sets Analyzed .............................................................. 30 
6.3. Protocol Deviations ..................................................................................................... 31 
6.4. Demographic and Other Baseline Characteristics ....................................................... 31 
6.4.1. Demographic Characteristics ................................................................................ 31 
6.4.2. Baseline Characteristics ........................................................................................ 32 


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6.4.3. Medical History .................................................................................................... 33 
6.4.4. Prior and Concomitant Medications ..................................................................... 34 
6.5. Measurements of Study Drug Compliance ................................................................. 34 
6.6. Efficacy ....................................................................................................................... 36 
6.6.1. Primary Efficacy Analysis .................................................................................... 37 
6.6.2. Supplementary Analyses for the Primary Efficacy Analysis ............................... 38 
6.6.3. Secondary Efficacy Analysis ................................................................................ 40 
6.6.4. Supplementary Analyses for the Secondary Efficacy Analysis ........................... 43 
6.6.5. Exploratory Analysis ............................................................................................ 44 
6.6.6. Subgroup Analysis ................................................................................................ 46 
6.6.7. Post-Week 16 (Part B, Period 2) Additional Analyses ......................................... 47 
6.7. Safety ........................................................................................................................... 52 
6.7.1. Extent of Exposure ............................................................................................... 52 
6.7.2. Adverse Events ..................................................................................................... 53 
6.7.3. Laboratory Evaluations ......................................................................................... 58 
6.7.4. Vital Signs ............................................................................................................ 62 
6.7.5. Electrocardiograms ............................................................................................... 63 
6.7.6. Physical Examination ........................................................................................... 63 
6.7.7. C-SSRS ................................................................................................................. 63 
6.7.8. Interim Analysis and Data Monitoring ................................................................. 64 
6.8. Pharmacokinetic Assessments..................................................................................... 65 
6.9. Anti-Drug Antibodies .................................................................................................. 65 
7. Appendices ......................................................................................................................... 66 
8. References .......................................................................................................................... 75 


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List of Tables 
 
Table 1 Definition of Time Point Windows for Analyses ..................................................... 24 
Table 2 Laboratory Tests ....................................................................................................... 51 
 
 
 
 
 








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2. Protocol Details 
2.1. Overall Study Design 
This is a phase 2b pivotal, multi-center, dose-finding study to evaluate the efficacy, safety, 
and immunogenicity of izokibep in subjects with moderate to severe Hidradenitis Suppurativa 
(HS).  
This study consists of 2 parts, Part A and Part B as described below.  
Part A: Single Arm, Open Label 
Part A is a single-arm, open-label, proof-of-concept investigation to explore preliminary 
efficacy and safety of izokibep in adult subjects with moderate to severe HS. Part A consists 
of up to a 28-day screening period, a 31-week treatment period, and a follow-up period that 
includes 2 visits to be completed by all subjects at Week 39 and Week 45. For subjects that 
early terminate the follow-up visits should be completed 8-weeks (± 5 days) and 14 weeks (± 
5 days) after the last dose of study drug. A minimum of 20 subjects and up to 30 subjects will 
be enrolled in Part A (Group 0: izokibep SC 160 mg QW from Day 1/week 0 to Week 31). 
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.  
After enrollment and through the end of the study if the subject’s abscess and inflammatory 
nodule (AN) count is ≥ 150% of Day 1 AN count, antibiotic rescue medication is permitted. 
Subjects who qualify may initiate treatment with minocycline or doxycycline up to 100 mg 
BID. The dosing regimen must remain stable throughout study participation. In the case that 
a subject was previously intolerant or has a contraindication to both minocycline and 
doxycycline for the treatment of HS, the medical monitor should review to determine whether 
another rescue medication would be more appropriate. Rescue antibiotic therapy should be 
captured in the source and on the Prior and Concomitant Medications form of the CRF. 
Once enrollment in Part A has finished, enrollment will begin into Part B.  
Part B: Randomized, Double-blind, Dose-finding 
Part B is a randomized, double-blind, placebo-controlled, parallel group, dose-finding 
investigation to evaluate the efficacy, safety, and immunogenicity of izokibep in subjects with 
moderate to severe HS. Subjects will complete up to a 28-day screening period, followed by 
a 16-week double-blind treatment period. At completion of the Week 16 visit procedures, 
subjects randomized to placebo will be switched to active treatment in a blinded manner for 
the Week 16 dose through Week 30 (Q2W dose group) or Week 31 (QW dose group). 
Subjects randomized to izokibep will remain on the same dose through Week 30 (Q2W dose 


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group) or Week 31 (QW dose group). After their respective treatment periods, all subjects 
will enter a follow-up period that includes 2 visits to be completed at Week 39 and Week 45. 
For subjects that early terminate the follow-up visits should be completed 8-weeks (± 5 days) 
and 14 weeks (± 5 days) after the last dose of study drug.  
Approximately 170 subjects will be randomized into 1 of 4 groups in a 1:1:2:2 ratio as follows:  
• Group 1 (n = 28-29): placebo SC QW from Day 1 (Week 0) to Week 15, then izokibep 
SC 160 mg QW from Week 16 to Week 31.  
• Group 2 (n = 28-29): placebo SC Q2W from Day 1 (Week 0) to Week 14, then 
izokibep SC 160 mg Q2W from Week 16 to Week 30.  
• Group 3 (n = 56-57): izokibep SC 160 mg QW from Day 1 (Week 0) to Week 31.  
• Group 4 (n = 56-57): izokibep SC 160 mg Q2W from Day 1 (Week 0) to Week 30.  
Randomization will be stratified by any prior biologic/Janus Kinase (JAK) inhibitor used for 
HS (Yes/No) and Hurley Stage (II or III).  
Subjects will complete study assessments according to the study visits outlined in the SoA in 
the protocol. Day 1 corresponds to the first dose of study drug. All subsequent visits will be 
scheduled based on the Day 1 visit. 
Subjects in the QW dosing groups (Group 0 [Part A], Groups 1 and 3 [Part B]) will have study 
visits at screening, Day 1 (Week 0), and at Weeks 1, 2, 3, 4, 8, 12, 13, 14, 15, 16, 17, 20, 24, 
28, and 32 as well as at the follow-up visits.  
Subjects in the Q2W dosing regimens (Groups 2 and 4 in Part B) will have study visits at 
screening, Day 1 (Week 0), and at Weeks 2, 4, 8, 12, 14, 16, 18, 20, 24, 28, and 32 as well as 
at the follow-up visits.  
Subjects assigned to placebo SC QW and placebo SC Q2W will be grouped into a single 
placebo group for comparison to each dosing regimen of izokibep for Part B. The primary 
endpoint will be assessed at Week 16.  
After randomization and through the end of the study if the AN count is ≥ 150% of Day 1 AN 
count, antibiotic rescue medication will be permitted, similar to what is allowable in Part A.  
2.2. Study Objectives 
2.2.1. Primary Objective 
The primary objective for Part A is to explore the efficacy of izokibep as measured by 
HiSCR75 at Week 12. 
The primary objective for Part B is to demonstrate that one or both treatment regimens of 
izokibep is efficacious compared to placebo, as measured by HiSCR75 at Week 16. 


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2.2.2. Secondary Objectives 
The secondary objectives for Part A are: 
• To explore the safety and tolerability of izokibep 
• To explore the immunogenicity of izokibep as measured by the presence of Anti-Drug 
Antibodies (ADAs) 
The secondary objectives for Part B are: 
• To demonstrate that one or both regimens of izokibep is efficacious, as measured by: 
o Percentage of subjects achieving HiSCR90 at Week 16; 
o Percentage of subjects achieving HiSCR100 at Week 16; 
o Percentage of subjects achieving HiSCR50 at Week 16; 
o Percentage of subjects who experience ≥ 1 disease flare through 16 weeks of 
treatment;  
o Percentage of subjects with baseline Hurley Stage II who achieve AN count of 
0, 1, or 2 at Week 16; 
o Percentage of subjects achieving at least 3 points reduction from baseline in 
Numeric Rating Scale (NRS) in Patient Global Assessment of Skin Pain at its 
worst at Week 16 among participants with baseline NRS ≥ 4. 
• 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 for Part B are: 
• To explore if one or both regimens of izokibep is efficacious, as measured by: 
o Percentage of subjects who achieve HiSCR75 at Weeks 4, 8, 12, and 32; 
o Percentage of subjects who achieve HiSCR90 at Weeks 4, 8, 12 and 32; 
o Percentage of subjects who achieve HiSCR100 at Weeks 4, 8, 12, and 32; 
o Percentage of subjects who achieve HiSCR50 at Weeks 4, 8, 12, and 32; 
o Percentage of subjects with baseline Hurley Stage II who achieved AN count 
of 0, 1, or 2 at Weeks 4, 8, 12, 24, and 32; 
o NRS Patient Global Assessment of Skin Pain from baseline after 4, 8, 12, 16, 
24, and 32 weeks of treatment; 
o Modified Sartorius Score after 4, 8, 12, 16, 24, and 32 weeks of treatment; 
o HS flare rates through 4 and 32 weeks of treatment; 


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o International Hidradenitis Suppurativa Severity Score System (IHS4), after 4, 
8, 12, 16, 24, and 32 weeks of treatment; 
o Hidradenitis Suppurativa-Physician’s Global Assessment (HS-PGA). 
• To explore the effect of izokibep on PROs as measured by change from baseline over 
time in: 
o European Quality of Life-5 Dimensions (EQ-5D); 
o Dermatology Life Quality Index (DLQI); 
o Hospital Anxiety and Depression Scale (HADS). 
• To evaluate the pharmacokinetics of izokibep in subjects with HS. 
2.3. Sample Size and Power 
In Part A, a minimum of 20 subjects and up to 30 subjects will be enrolled. With the minimum 
of 20 subjects enrolled if the true HiSCR response rate is 50%, an observed rate of 30% to 
70% will be observed with 95% probability. Conversely, an observed response rate of 25% 
or lower suggests that the true rate is < 50% and an observed rate of 75% or higher suggests 
that the true rate is > 50%, based on limits of a two-sided 95% CI.  
For Part B, power calculations were reported in protocol 21102 version 3.0, dated 26 April 
2023, for the original primary endpoint of HiSCR50 and not for the updated primary endpoint 
of HiSCR75. Using the updated primary endpoint of HiSCR75, the comparisons of a regimen 
of izokibep to placebo will have approximately 55 subjects in each izokibep regimen 
compared to approximately 55 subjects on placebo (QW and Q2W combined). In prior studies 
of adalimumab in a similar patient population, a HiSCR75 response rates of 10% to 15% was 
observed with placebo compared with response rates of 25% to 35% with adalimumab. If true 
response rates with placebo and izokibep are 15% and 40%, respectively, this study will have 
approximately 80% power to reject the null hypothesis of equal response rates. This 
calculation was made in SAS® using the POWER procedure on an unstratified test of 
binomial proportions. 
2.4. Primary Efficacy Variable 
The primary efficacy variable for Part A and Part B is HiSCR75, the proportion of subjects 
who achieve at least a 75% reduction from baseline in the total AN count, with no increase 
from baseline in abscess or draining fistula count. The primary timepoint for analysis is Week 
12 for Part A and Week 16 for Part B.  
HiSCR50/75/90/100 is defined as meeting all three criteria below: 
• (AN count at baseline - AN count at current visit) / AN count at baseline × 100% ≥ 
50/75/90/100% 
• Abscess count at baseline ≥ abscess count at the current visit 
• Draining fistula count at baseline ≥ draining fistula count at the current visit 


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where AN count is abscess count + inflammatory nodule count, and abscess count and fistula 
count are summed across all regions and are inclusive of all abscesses, inflammatory nodules 
and fistula that have previously undergone localized surgical or medical intervention and are 
no longer present. The baseline value for lesion count (including draining fistula count) and 
Hurley stage is the latest value on or before the randomization day (Day 1). 
2.5. Secondary Efficacy Variables 
The secondary efficacy variables for Part B are:  
• HiSCR90 at Week 16 
• HiSCR100 at Week 16 
• HiSCR50 at Week 16 
• HS flare through Week 16, where HS flare is defined as proportion meeting the 
following two criteria at any assessment after baseline and at or before Week 16: 
o (AN count at current visit- AN count at baseline) / AN count at baseline ×100% 
≥ 25% 
o AN count at current visit- AN count at baseline ≥ 2 
• Achieving AN count of 0, 1, or 2 at Week 16 among subjects with baseline Hurley 
Stage II 
• NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 among subjects 
with baseline NRS ≥ 4. NRS in Patient Global Assessment of Skin Pain at its worst is 
the answer from Question: In the last 24 hours, which number best describes your skin 
pain at its WORST due to your HS? The answer is in the range of 0 (No skin pain) to 
10 (Skin pain bad as you can imagine). The skin pain score at each visit will be 
calculated using average of daily scores among the 7 days up to and including the day 
of visit, with a minimum of 4 days (consecutive or non-consecutive) with scores 
required. The skin pain at baseline will be calculated using average of daily scores 
among the 7 days up to and including the first study drug administration day, with a 
minimum of 4 days with scores required. For any visit, if Patient Global Assessment 
of Skin Pain at its worst is available for 3 or few of the 7 days up to and including the 
day of visit, the pain score will be missing for analysis. 
2.6. Exploratory Efficacy Variables 
The exploratory efficacy variables for Part B are: 
• HiSCR75 at Weeks 2, 4, 8, 12, and 32 
• HiSCR90 at Weeks 2, 4, 8, 12, and 32 
• HiSCR100 at Weeks 2, 4, 8, 12, and 32 
• HiSCR50 at Weeks 2, 4, 8, 12 and 32 


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• Achieving AN count of 0, 1, or 2 at Weeks 4, 8, 12, 24, and 32 among subjects with 
baseline Hurley Stage II 
• Change in PGA of Skin Pain (at its worst and average respectively) from baseline at 
Weeks 4, 8, 12, 16, 24, and 32 
• Modified Sartorius Score after Weeks 4, 8, 12, 16, 24, and 32 (see Appendix for 
scoring method) 
• HS flares through Weeks 4 and 32 
• IHS4 scores at Weeks 4, 8, 12, 16, 24, and 32, where IHS4 is defined as: 
IHS4 score (points) = (number of inflammatory nodules × 1) + (number of abscesses 
× 2) + (number of draining tunnels [fistulae/sinuses] × 4) 
• IHS4-55 response rates at Weeks 4, 8, 12, 16, 24 and 32, where IHS4-55 is defined as 
a decrease in IHS4 of 55% or more from baseline 
• Change from baseline to Week 16 in HS-PGA 
• Change from baseline to Week 16 in EQ-5D (see Appendix for scoring method) 
• Change from baseline to Week 16 in DLQI (see Appendix for scoring method) 
• Change from baseline to Week 16 in HADS, HADS-anxiety, and HADS-depression 
(see Appendix for scoring method)  
• Trough plasma concentrations of izokibep at collected timepoints (baseline, Week 4, 
8, 12, 16, 24, 32, 39, and 45) 
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, a 
surrogate, or the subject’s legally authorized representative).  
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 event of 
special interest will also be monitored: 


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• Suicidal ideation 
• Malignancies  
• Major cardiovascular and cerebrovascular events  
• Tuberculosis  
• Infections (including opportunistic infections and serious infections)  
• Cytopenias  
• Hypersensitivity reactions  
2.7.2. Clinical Safety Laboratory Tests  
• See SAP  
 


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• Table 1 Laboratory Tests for the list of clinical laboratory tests to be performed and the 
SoA in the protocol for the timing and frequency.  
 
2.7.3. Vital Signs  
Vital signs will be measured in a sitting position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, pulse, (collected as “Heart rate” in the 
CRF) and respiratory rate.  
2.7.4. 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 the first dose of study drug should be listed 
as medical history in the CRF and reported as AEs if observed after the first dose of the study 
drug.  
2.7.5. Suicidal Ideation and Behavior Risk Monitoring  
Suicidal ideation and behavior will be assessed during the study by trained study personnel 
using the Columbia–Suicide Severity Rating Scale (C-SSRS). The visits at which the C-SSRS 
assessments will be performed are specified in the SoA in the protocol. The C-SSRS defines 
5 subtypes of suicidal ideation and behavior in addition to self-injurious behavior with no 
suicidal intent.  
2.7.6. 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 
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 by the sponsor or sponsor’s 
designee.  
Samples may be further tested for IL-17A binding domain and albumin binding domain 
(positive vs negative) and/or in a neutralizing antibody assay.  


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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 the combined placebo, administered either QW or 
Q2W. Izokibep 160 mg QW and izokibep 160 mg Q2W will each be compared to the 
combined placebo. Subjects will be analyzed according to their randomized treatment 
regardless of treatment compliance, use of rescue medications except as noted below, 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 moderate to 
severe HS (AN count of ≥ 5) 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 HiSCR75 at Week 
16.  


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3.1.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest 
The treatment policy strategy approach for the estimand will be used in general, so subjects 
will be included using observed data at Week 16 regardless of treatment compliance, use of 
rescue medications except as noted below, or any other protocol deviation. Subjects with 
missing HiSCR75 assessments at Week 16 will be imputed as non-responders (non-response 
imputation or NRI). A composite strategy will be used for intercurrent events of receiving 
oral antibiotic therapy that could affect HS: a list of all subjects who received oral antibiotic 
therapy that results in such imputation will be finalized after review of all oral antibiotic 
therapy received by any subject and before unblinding of the study, and will include any 
subject who initiated a new regimen of tetracycline, clindamycin, and possibly other products, 
and any subject who was on a stable dose of minocycline or doxycycline at randomization but 
received a higher dose during the study. The endpoint for such subjects will be imputed using 
NRI. 
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 
HiSCR75 at Week 16 and did not use oral antibiotic therapy that could affect HS before Week 
16. The null hypothesis of equal response rates will compare each dosing regimen of izokibep 
to the combined placebo group respectively. A stratified test of response rates will be 
implemented in the analysis. If a subject was incorrectly classified during the randomization 
process, the analysis will use the correct classification, not the classification used during 
randomization. Within each of the four strata, any prior biologic/Janus Kinase (JAK) inhibitor 
use for HS (Yes/No) and Hurley Stage (II or III), 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 four 
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 HiSCR75 are collected will also be presented 
using the same methodology. 
The treatment effect will be quantified by the response rate difference of HiSCR75 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 same five 
attributes as listed in the beginning of Section 3. 


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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 the combined placebo, administered either QW or 
Q2W. Izokibep 160 mg QW and izokibep 160 mg Q2W will each be compared to the 
combined placebo. Subjects will be analyzed according to their randomized treatment 
regardless of treatment compliance, use of rescue medications except as noted below, 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 moderate to severe HS (AN count of ≥ 5) as further defined by the inclusion 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. Additional restrictions for some endpoints are specified in 
Section 3.2.3 respectively. 
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:  
• HS flares through Week 16 
• Achieve AN count of 0, 1, or 2 at Week 16. The population will be restricted to the 
subject with baseline Hurley Stage II 
• Achieve at least 3 points reduction from baseline in NRS in Patient Global Assessment 
of Skin Pain at its worst at Week 16. The population will also be restricted to the 
subject with baseline NRS ≥ 4 
3.2.4. Handling of Intercurrent Events to Reflect the Clinical Question of Interest 
The secondary efficacy variables of the percentage of subjects who experience HS flare and 
percentage of subjects who achieved AN count of 0, 1, or 2 among participants with baseline 
Hurley Stage II will be analyzed analogously to the primary efficacy variable, using a 
treatment policy strategy approach. Subjects will be analyzed as randomized treatment using 
observed data regardless of treatment compliance, use of rescue medications, or any other 
protocol deviation, except for receiving an oral antibiotic that could impact HS. Subjects who 
received an oral antibiotic that could impact HS will be included in the analysis with NRI in 
line with a composite strategy.  
The secondary efficacy variable of the percentage who achieve at least 3 points reduction 
from baseline in NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 will 
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be used in general, whereby subjects will be included using observed data regardless of 
treatment compliance, use of rescue medications (except prohibited pain medications), or any 
other protocol deviation. Using prohibited pain medications at Week 16 will be handled by 
the composite strategy. Subjects using prohibited pain medications within 28 days of Week 
16 will be treated as non-responder with NRI. 
3.2.5. Population-level Summary for Comparison between Treatment Conditions 
• Percentage of subjects that experience ≥ 1 HS flare through 16 weeks of treatment 
• Percentage of subjects who achieved AN count of 0, 1, or 2 at Week 16 among 
participants with baseline Hurley Stage II 
• Percentage of subjects achieving at least 3 points reduction from baseline in NRS in 
Patient Global Assessment of Skin Pain at its worst at Week 16 among participants 
with baseline NRS ≥ 4. Those who receive prohibited pain medications will be 
imputed as non-responders. 
For each of these endpoints, the difference in proportions will be summarized. 
3.2.6. Sensitivity Estimators for the Secondary Estimand 
No sensitivity estimators are specified. 
3.3. Estimands for the exploratory objectives 
Analyses of exploratory objectives will be consistent with analogous primary and secondary 
objectives. 


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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 
Part A  
For assessing efficacy in Part A, the full analysis set (FAS) will include all subjects who 
receive at least one administration of study drug.  
Part B  
For assessing the primary and secondary efficacy objectives, all subjects randomized in Part 
B will be included in the analyses as 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 17. Subjects will be included according 
to randomized treatment.  
4.3. Safety Analysis Set 
Part A  
The safety analysis set for subjects in Part A will include all subjects who received at least 
one administration of test.  
Part B  
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. The subject 
will be grouped according to the actual treatment received; if a subject receives both, the 
subject will be grouped according to the first actual treatment received.  
4.4. Pharmacokinetics Analysis Set 
The Pharmacokinetics analysis set for subjects in Part A and Part B will include all subjects 
who received at least one administration of test material (izokibep or placebo) and have at 
least 1 quantifiable PK concentration.  


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4.5. ADA Analysis Set 
The ADA analysis set for subjects in Part A and Part B will include all subjects who received 
at least 1 administration of test material (izokibep or placebo) and have both baseline ADA 
and at least 1 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 CRF page. If the date in this CRF 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 informed 
consent form (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 considered “rescreening,” which may 
occur in this study. These procedures include laboratory assessments due to value(s) out of 
range due to potential sampling error or that could be within range with repeat sampling. 
The baseline value for a variable is therefore defined as the last non-missing value collected 
before enrollment/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 CRF 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. 


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The Treatment Period is defined as the period from the date/time of the first dose of study 
drug to Week 32 (four weeks after the last dose) or early termination/end of treatment visit 
(within two weeks from the last dose). 
Treatment will be divided into two periods, Period 1 and Period 2. In Part B, Period 1 will 
start at the first dose of study drug and end at Week 16 when Week 16 assessments are 
completed and before administration of study drug. Period 2 will start at the time of first 
administration of study drug at or after Week 16 and end at Week 32 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 CRF.   
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 occurs in 
a timeframe that corresponds to a scheduled efficacy assessment (week 4, 8, 12, 16, 24 or 32), 
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 visit to a 
scheduled efficacy assessment for use in all efficacy summaries at that timepoint. 
Table 1 Definition of Time Point Windows for Analyses 
Time Point 
Time Point Window a 
Baseline 
Day 1  
Week 4 
Days 21 to 42  
Week 8 
Days 43 to 70  
Week 12 
Days 71 to 98  
Week 16 
Days 99 to 112  
Week 24 
Days 113 to 196  
Week 32 
Days 197 or later  
a relative to the date of first dose of study drug during the Treatment Period/date of Baseline Visit (Day 1) 
 
5.2. Handling of Dropouts, Missing Data, and Outliers 
5.2.1. Handling of Missing Efficacy Data 
Subjects with missing HiSCR75 assessments at Week 16 will be imputed as non-responders 
(non-response imputation or NRI). A composite strategy will be used for intercurrent events 
of receiving oral antibiotic therapy that could affect HS. A list of all oral antibiotic therapy 
that results in such imputation will be finalized after review of all oral antibiotic therapy 
received by any subject and before unblinding of the study, and will include tetracycline, 


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clindamycin, and possibly other products. Such subjects will be imputed using NRI. The 
number of subjects imputed with NRI will be tabulated with reasons for imputation at Week 
16. 
To assess the sensitivity of the results, additional analyses will be performed where the 
response for HiSCR75 for all subjects will be used for sensitivity analysis, regardless of 
receipt of oral antibiotic therapy. Another sensitivity analysis will impute non-response for 
any subject who received any new oral antibiotic or an increased dose of oral antibiotic before 
Week 16. 
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 (MAR) 
or missing complete at random (MCAR). 
The secondary endpoints of the percentage of subjects who experience HS flare and the 
percentage of subjects who achieved AN count of 0, 1, or 2 among participants with baseline 
Hurley Stage II will be analyzed analogously to the primary endpoint. Subjects who have 
missing data at Week 16 or who received an oral antibiotic that could impact HS will be 
included in the analysis as non-responders with NRI (did experience HS flare, or did not 
achieve AN count of 0, 1, or 2). 
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 Partial and Missing Dates for Date of Birth, Adverse Events, 
Prior/ Concomitant Medications 
Partial and Missing Dates of Birth 
Where the Date of Birth is missing the following convention will be used: 
Where the day is missing and month and year are available the day will be completed as the 
15th. For example, Date of Birth specified as --JAN1980 will be completed as 15JAN1980. 
If the day and month are missing and the year is available, 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 


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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. 
• 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. 
 


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5.2.4. Handling of Plasma Concentrations that are Below the Lower Limit of 
Quantification 
Plasma concentrations that are below the limit of quantification (BLQ) will be handled as 
follows for descriptive statistics: 
• Pre-dose concentrations that are BLQ will be treated as zero. 
• Post-dose concentrations that are BLQ will be treated as missing elsewhere. 
• Values below the limit of quantification (BLQ) that are set to 0 in the source dataset 
will be treated as 0 in the calculation of summary statistics. 
• Missing values will be excluded from the calculation of means, and n will reflect the 
actual number of values used in the calculation. 
• Arithmetic mean or median values that are BLQ will be presented as 0. 
• If any pre-dose BLQ results (treated as 0) are in a series of summarized data, 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 
 
’s SAS Environment/Version 9.4 (or later) of the SAS statistical software 
package.  When data are collected both in IRT and EDC, all data for summaries and analyses 
will come from the EDC unless it is specifically stated that a particular data point will come 
from IRT. 
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. The 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: 
Part A 
Full treatment group label: 
Short treatment 
group label:  
Treatment 
group ordering: 
Open label izokibep 160 mg QW from Day 
1/week 0 to Week 31 
Open label Izokibep 
160 mg QW 
1 
 
Part B 
Full treatment group label: 
Short treatment 
group label:  
Treatment 
group ordering: 
Placebo SC Q2W Week 0 to Week 14; 
Izokibep SC 160 mg Q2W Week 16 to Week 
30 
Placebo Q2W- 
Izokibep Q2W  
1 
Placebo SC QW Week 0 to Week 15; Izokibep 
SC 160 mg QW Week 16 to Week 31 
Placebo QW- 
Izokibep QW 
2 


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Placebo SC QW Week 0 to Week 15; Izokibep 
SC 160 mg QW Week 16 to Week 31 
or 
Placebo SC Q2W Week 0 to Week 14; 
Izokibep SC 160 mg Q2W Week 16 to Week 
30 
Combined Placebo 
- Izokibep QW or 
Q2W 
3 
Izokibep SC 160 mg Q2W Week 0 to Week 30 
Izokibep SC 160 
mg Q2W  
4 
Izokibep SC 160 mg QW Week 0 to Week 31 
Izokibep SC 160 
mg QW  
5 
 
All statistical comparisons will be made using two-sided tests at the  = 0.05 significance 
level unless specifically stated otherwise. All null hypotheses will be of no treatment 
difference. All alternative hypotheses will be two-sided. 
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 TLFs mock shells for the SI unit corresponding to each laboratory test. 
Refer to Appendix of the TLF 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. Refer to “2. General Format Guidelines” section within TFL 
shells for more details on presentation of results. 
Data from Parts A and B will be summarized separately. Objectives and statistical hypotheses 
will be addressed using data from Part B only. The treatment policy estimand will be used in 
general for efficacy data, with all treated subjects contributing to Part A and all randomized 
subjects contributing to Part B. All treated subjects will contribute to safety analyses in both 
Parts A and B.  
For comparisons of izokibep to placebo in Part B, the two dosing regimens of izokibep (QW 
and Q2W) will be compared separately to placebo. The 2 placebo dosing regimens (QW and 
Q2W) will be combined for comparison to each izokibep dosing regimen. Binary endpoints 
including the primary endpoint of HiSCR75 will be compared with a stratified test of risk 
difference. Continuous endpoints will be compared with a repeated measures mixed model.  


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Safety data will be summarized separately for Part A and Part B. 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 Enrolled (Part A)/Randomized (Part B) 
o Treated 
o Not Treated 
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 
• Number and percentage of subjects who completed/discontinued treatment by period, 
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 enrollment (Part 
A)/randomization (Part B), 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 (Spain, Hungary, Poland, or Germany) 
▪ Non-US (Spain, Hungary, Poland, Germany, or Canada) 
• Number and percentage of subjects by stratification factors (Part B only). Each 
stratification variable will be presented by the stratum collected in Interactive 
Voice/Web Response System (IXRS) 
A subject will be regarded as having completed the study if the status recorded on the End of 
Study CRF form is Complete, or assessments at Week 45 have been completed. A subject will 
be considered as having discontinued the study if they have an CRF status of premature study 
discontinuation. Otherwise, the subject will be considered as ongoing study. 
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 enrolled 
(Part A) and randomized (Part B) in the FAS. 


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A listing of all screen failed subjects with their reasons for screen failure will be presented for 
the All Screen 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 Screen 
Set. Subjects who screen failed will be assigned to Part A if the subject was screened at a site 
in the United States and the date of screen fail is before 27-Jul-2022 and assigned to Part B if 
the screen fail date is on or after 27-Jul-2022 or the subject was screened at a site outside of 
the United States. 
A listing of all randomized subjects from Part B with their randomization details, including 
first dose date and time, and actual treatment received will be presented for the FAS. 
A listing of all enrolled (Part A) and randomized (Part B) subjects excluded from the FAS 
will be presented. 
6.3. Protocol Deviations 
All important protocol deviations will be summarized for the FAS for Part A (overall) and 
Part B by treatment group and overall as described below: 
• 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 for Part A (overall) and Part B 
by treatment group and overall as described below. All missing data will be presented as part 
of a missing category. 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 
• Sex 
• Ethnicity 
• Race 


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Demographic characteristics will be listed for the FAS for Part A (overall) and Part B by 
treatment group. 
6.4.2. Baseline Characteristics 
Baseline characteristics will be summarized for the FAS for Part A (overall) and Part B by 
treatment group and overall as described below. All missing data will be presented as part of 
a missing category. 
Standard descriptive statistics will be presented for the continuous variables of: 
• 
Disease duration (years) 
• 
Number of previous systemic treatments 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (kg/m2) 
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]) 
• 
Time Since Diagnosis with HS (calculated as year IC signed minus year of diagnosis, 
plus 1) 
• 
AN Count - Total Number of abscesses plus inflammatory nodules  
• 
Number of Abscesses 
• 
Number of Inflammatory Nodules 
• 
Number of Draining Fistulae 
• 
Number of Non-draining Fistulae 
• 
Number of total Fistulae (Draining plus Non-draining) 
• 
HADS total score 
• 
HADS-Anxiety 
• 
HADS-Depression 
• 
HS-PGA 
• 
Erythema Score 
• 
DLQI total score 
• 
IHS4 
• 
EQ-5D-3L (Domain Scores, Index Score, and VAS Score) 


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• 
SF-12 (Physical Component Score and Mental Component Score) (see Appendix 2 
for scoring method) 
Total counts and percentages of subjects will be presented for the categorical variables of: 
• 
Hurley Stage (II, III) 
• 
Prior Biologic/Janus Kinase (JAK) Inhibitor Use for HS (yes/no) 
• 
Alcohol (Never, Former, Current) 
• 
Nicotine (Never, Former, Current) 
• 
Presence of draining fistulae at baseline (yes/no) 
The subject’s Hurley Stage and erythema score (see Appendix 2 for scoring method) will be 
the worst reported for any anatomical region for that subject. Baseline characteristics will be 
listed for the FAS. 
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 enrollment in the study, including any chronic conditions 
diagnosed prior to entry into the study. Non-serious AEs with onset after signing ICF but 
before the first dose (Part A) or randomization (Part B) will be included as medical history. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) using the latest MedDRA dictionary around the time of Database Lock 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 for Part A (overall) and for Part B 
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. 


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6.4.4. Prior and Concomitant Medications 
All medications will be coded using the WHO Drug Global Dictionary, Format B3 using the 
latest version around time of database lock, Anatomical Therapeutic Chemical (ATC) 
Classification codes. 
Prior medications and concomitant medications are defined as follows: 
• 
Prior medications are those taken with a stop date 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. 
Prior and concomitant medications will be summarized separately for the FAS for Part A 
(overall) and Part B 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. 
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. 
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 CRF will be treated as a half dose. Study drug 
compliance in Part B will be summarized for period 1 and period 2 separately.  


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In general, the percentage of overall compliance, assessed by dose count, will be calculated 
as follows: 
For Part A 
Compliance (%) = 
(Total doses administered from Week 0 to Week 31) 
 100% 
Total doses expected to be administered from Week 0 to Week 31 
 
 
For Part B 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 Part B Period 2 
Compliance (%) = 
(Total doses administered from Week 16 to EOT) 
 100% 
Total doses expected to be administered from Week 16 to EOT 
 
For Part A, the total number of doses expected to be administered from Week 0 to Week 31 
is 32 for all subjects. For Part B, the total doses expected to be administered differs by 
treatment assignment: for QW dosing, the total doses expected to be administered is 16 for 
Period 1 and 16 for Part 2; for Q2W dosing, the total doses expected to be administered is 8 
for Period 1 and 8 for Part 2. 
The calculated percentage compliance will be categorized as: 
• 
< 80% compliance 
• 
≥ 80% compliance 
Compliance will be summarized for the Safety Analysis Set for Part A (overall) and for Part 
B by treatment group and Period as follows: 
• Number of doses will be presented by default summary statistics. 
• 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.  


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6.6.  Efficacy 
Primary, secondary and exploratory endpoints will be presented by study part, timepoint and, 
for Part B, randomized treatment group. Observed data for binary endpoints, with NRI, will 
be presented with 2-sided 95% confidence intervals calculated using asymptotic Wald 
method. Observed data for continuous endpoints, with no imputation for missing values, will 
be presented with 2-sided confidence intervals calculated using normal approximations. 
No statistical hypotheses will be tested in Part A of this study.  
Hypotheses tested using data from Part B will be adjusted to control the family-wise error rate 
in the strong sense at α = 0.050, two-sided. An adjustment of 0.0001 will be made to account 
for the unblinded data summaries reviewed by the DMC. The hypotheses will therefore be 
tested at α = 0.0499. 
The statistical comparisons in Part B 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 dosed QW or Q2W, will be tested first, with 
significance concluded if p < 0.0499. If significant, the primary endpoint, comparing izokibep 
dosed Q2W to placebo dosed QW or Q2W will be tested next, with significance concluded if 
p < 0.0499. Testing of secondary endpoints will only be carried out if all prior tests, including 
both tests of the primary endpoint, first show significance with p < 0.0499. As long as all prior 
tests are significant, testing will proceed in the following order: 
• The first secondary endpoint, proportion of subjects who experience ≥ 1 disease flare 
through 16 weeks of treatment, comparing izokibep dosed QW to placebo dosed QW 
or Q2W. 
• The first secondary endpoint, proportion of subjects who experience ≥ 1 disease flare 
through 16 weeks of treatment, comparing izokibep dosed Q2W to placebo dosed QW 
or Q2W. 
• The second secondary endpoint, achieving AN count of 0, 1, or 2 at Week 16 among 
subjects with baseline Hurley Stage II, comparing izokibep dosed QW to placebo 
dosed QW or Q2W. 
• The second secondary endpoint, achieving AN count of 0, 1 or 2 at Week 16 among 
subjects with baseline Hurley Stage II, comparing izokibep dosed Q2W to placebo 
dosed QW or Q2W.  
• The third secondary endpoint, proportion of subjects who achieve at least 3 points 
reduction from baseline in NRS at Week 16 among participants with baseline NRS 
≥4, comparing izokibep dosed QW to placebo dosed QW or Q2W. 
• The third secondary endpoint, proportion of subjects who achieve at least 3 points 
reduction from baseline in NRS at Week 16 among participants with baseline NRS 
≥4, comparing izokibep dosed Q2W to placebo dosed QW or Q2W. 


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If a null hypothesis is not rejected, p-values for subsequent hypotheses in the sequence will 
be reported as nominal, and will not be used to assess objectives or make determinations of 
efficacy. 
For Part B, efficacy endpoints will be summarized by Period 1 and Period 2 separately. For 
Period 2, in general, no hypothesis test will be performed and p-value will not be reported. 
For binary endpoints, stratified tests will use the four strata from the randomization process. 
If a subject was incorrectly classified during the randomization process, the analysis will use 
the correct classification as recorded in EDC, not the classification used during randomization 
as recorded in IRT. 
For each primary and secondary efficacy endpoint, the number and proportion of subjects 
achieving the endpoint in each treatment group will be reported by stratum and overall. 
Confidence intervals will be present with stratification (CMH weighting) and without 
stratification (Wald method). P-values will be reported for the stratified analysis. A bar graph 
showing the proportion of subjects achieving the endpoint for each treatment group along 
with the associated p-value will be produced. Results will also be listed. 
6.6.1. Primary Efficacy Analysis 
The primary efficacy variable is defined as HiSCR75, the proportion of subjects who achieve 
at least a 75% reduction from baseline in the total AN count, with no increase from baseline 
in abscess or draining fistula count at Week 16 (comparing to baseline).  
For Part B, 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 HiSCR75 at Week 16 among 
subjects randomly assigned to receive izokibep and placebo, respectively. One set of 
hypotheses will be tested for each dosing frequency of izokibep. 
The treatment policy strategy approach for the estimand will be used in general, so subjects 
will be included using observed data at Week 16 regardless of treatment compliance, use of 
rescue medications or procedures except as noted below, or any other protocol deviations. 
Subjects with missing HiSCR75 assessments at Week 16 will be imputed as non-responders 
(non-response imputation or NRI). A composite strategy will be used for intercurrent events 
of receiving oral antibiotic therapy that could affect HS. A list of all oral antibiotic therapy 
that results in such imputation will be finalized after review of all oral antibiotic therapy 
received by any subject and before unblinding of the study and will include tetracycline, 
clindamycin, and possibly other products. Such subjects will be imputed using NRI. The 


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number of subjects imputed with NRI will be tabulated with reasons for imputation at Week 
16. Additionally, any lesions that received lesional incision and drainage or intralesional 
steroid injection will be counted as continuing to exist in the AN count, even if fully healed, 
at all later timepoints. 
The null hypothesis of equal response rates will compare each dosing regimen of izokibep to 
the combined placebo group.  
 
A stratified test of response rates will be used for the primary analysis. Within each of the 
four 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 four 
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 HiSCR75 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. No P-values 
after Week 16 will be presented. 
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 
As a supplementary analysis, Clopper-Pearson 95% CI for the difference between 2 
proportions will be calculated using the asymptotic Wald method. Sample SAS codes of 
comparing each dosing regimen of izokibep to the combined placebo group is given as 
following are: 
ods output RiskDiffCol2= ; 
proc freq ; 
              tables treatment*response / riskdiff(cl=wald); 
              weight count / zeros; 
run; 


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 This analysis will assess whether stratification impacted the conclusions. 
 
For Part B, supplementary analyses using other assumptions about ICEs and other ways to 
address missing data will also be reported. These will be defined before the database is locked 
and treatment assignments are unblinded. 
Worst Case Scenario Imputation: All subjects with prohibited medication will be imputed 
as NR in active arms, and as Responder in the placebo arm. A stratified test will be used with 
the actual randomization factors as strata. 
Lesional incision and intralesional steroid: An analysis imputing subjects as non-
responders if any lesion received lesional incision and drainage or intralesional steroid 
injection will be reported. This analysis will match the primary analysis, except that subjects 
who received any (one or more) such treatments will be imputed as non-responders in this 
analysis (instead of only continuing to count the lesion as present, as in the primary 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), 
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, with response probability of the mean 
response rate for that treatment arm in that simulation. The primary stratified analysis will be 
reported on each simulated study, and the probability that the null hypothesis of equal 
response rates is rejected will be reported for each set of 1000 imputed response rates. A 
graphical output will summarize the rejection probability for various sets of response, with 
different shadings representing probabilities of >95%, 80-95%, 50-80%, 20-50% and ≤20%.  
Multiple Imputation: Multiple imputation5 will be implemented to replace missing endpoint 
data using multiple draws from a posterior predictive distribution estimated from the placebo 
group only. First, a monotone missingness pattern will be enforced using Markov Chain 
Monte Carlo (MCMC). The MCMC process will use predictor variables of baseline abscess 
count (continuous), baseline inflammatory nodule count (continuous), baseline draining 
fistula count (continuous), age (continuous), baseline BMI (continuous) for nonmonotone 
missingness at Week 4 (missing at Week 4 but available at a later timepoint). MCMC 
predictors in the regression model for missing values after Week 4 will be all of these 
variables, plus counts of abscess (continuous), inflammatory nodule (continuous), and 


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draining fistula (continuous) at prior scheduled assessments. After monotone missingness is 
enforced, missing HiSCR75 at Week 4, 8, 12, and 16 will be imputed, assuming monotone 
missingness pattern. Any missing HiSCR75 will be imputed by first imputing components of 
the AN count (abscess and inflammatory nodules) and draining fistula count, then assigning 
HiSCR75 status from the imputed values. Predictors in the regression model for missing 
values at Week 4 will be baseline Hurley stage (II/III), baseline abscess count (continuous), 
baseline inflammatory nodule count (continuous), baseline draining fistula count 
(continuous), sex (male/female), race (white/non-white), age (continuous), BMI (continuous) 
and Prior Biologic/Janus Kinase (JAK) Inhibitor Use for HS (yes/no). Predictors in the 
regression model for missing values after Week 4 will be all of these variables, plus counts of 
abscess (continuous), inflammatory nodule (continuous), and draining fistula (continuous) at 
prior scheduled assessments. Missing HiSCR75 values in both the placebo group and two 
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 
at Week 4, 8, 12, and 16. A total of 100 imputations will be imputed to form the complete 
data set with a pre-specified seed (3617627) 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. If imputation is not possible due to sparseness of data for certain predictor variables, 
that predictor variable will be collapsed. If the predictor variable is race, race will be first 
collapsed into three categories (Black, White and Other) and, if further collapsing is 
necessary, into two categories (Black and Other). If the predictor variable is other than race, 
that predictor variable will be collapsed into a single category, in essence removing that 
predictor from the predictor model. 
6.6.3. Secondary Efficacy Analysis 
The secondary efficacy variables are HiSCR50, HiSCR90 and HiSCR100 at Week 16. The 
same primary efficacy analysis approach will be applied on the secondary efficacy variables. 
  
Other secondary efficacy variables are percentage of subjects who experience HS flare 
through Week 16, percentage of subjects who achieved AN count of 0, 1, or 2 at Week 16 
among participants with baseline Hurley Stage II, and percentage of subjects achieving at 
least 3 points reduction from baseline in NRS in Patient Global Assessment of Skin Pain at 
its worst at Week 16 among participants with baseline NRS ≥ 4.  
Analogous statistical hypotheses to the primary objective will be used for the secondary 
objectives.  


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6.6.3.1. Subjects Experiencing HS flare through Week 16 
The secondary endpoints of percentage of subjects who experience HS flare through Week 
16 will be analyzed analogously to the primary endpoint. HS flare will be determined 
programmatically at each assessment of AN count. To be counted as a HS flare, the AN count 
must increase from baseline by at least 25% and by at least 2 compared to baseline. A subject 
will be counted as having HS flare if they have a HS flare at any assessment after baseline, 
up to and including the assessment at Week 16 (including scheduled and unscheduled visits 
and early termination visits). The statistical null and alternative hypotheses to be used to 
assess these objectives are: 
H0: πABY – πPBO = 0 
HA: πABY – πPBO ≠ 0 
where πABY and πPBO are the proportion experiencing HS flares through Week 16 among 
subjects randomly assigned to receive izokibep and placebo, respectively. One set of 
hypotheses will be tested for each dosing frequency of izokibep. 
Subjects who received an oral antibiotic that could impact HS at any point before the Week 
16 assessment will be included in the analysis with NRI (did experience HS flare).  Subjects 
who have missing assessments will be included with multiple imputation, as described below. 
The number and proportion of subjects for subjects who experience a HS flare in each 
treatment group will be reported, along with p-values, 95% CI without strata calculated using 
asymptotic Wald method will be reported as well. A bar plot showing the proportion of 
subjects experiencing HS flare for each treatment will be produced. Results will also be listed. 
Multiple imputation will be used to impute data for subjects with missing data. The multiple  
imputation process will be the same the supplementary analysis defined in section 6.6.2 for 
HiSCR75, except that draining fistula counts do not play a role in flare and will therefore not 
be imputed when missing. Subjects with missing AN counts at any scheduled visit (week 4, 
week 8, week 12 and/or week 16) will have their abscess and inflammatory nodules counts 
imputed (separately) for each visit with missing data. The imputed counts will be summed 
and compared to criteria for flare. If the observed or imputed value at any visit meets the 
definition of flare, the subject will be counted as having a flare; otherwise, the subject will be 
counted as not having a flare. A total of 100 imputations will be imputed to form the complete 
data set with a pre-specified seed (3617627) 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 rules7. Other imputation, fully conditional 
specification method may be implemented if the multiple imputation model does not 
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Note that NRI will not be used for the primary analysis of flare. The number of subjects with 
missing data may be larger than the number of subjects who experience a flare, so using NRI 
may result in an analysis dominated by missing data. A supportive analysis, described below, 
will be reported using NRI.  
6.6.3.2. Hurley Stage II Subjects Achieving AN Count of 0, 1, or 2 at Week 16 
The secondary endpoints of percentage of subjects with baseline actual Hurley Stage II who 
achieved AN count (including those lesions that had interventions before Week 16 and were 
no longer present at Week 16) of 0, 1, or 2 at Week 16 will be analyzed analogously to the 
primary endpoint. The statistical null and alternative hypotheses to be used to assess these 
objectives are: 
H0: πABY – πPBO = 0 
HA: πABY – πPBO ≠ 0 
where πABY and πPBO are the proportion achieving AN count of 0, 1, or 2 at Week 16 among 
subjects randomly assigned to receive izokibep and placebo, respectively. One set of 
hypotheses will be tested for each dosing frequency of izokibep. 
Subjects who have missing data at Week 16 or who received an oral antibiotic that could 
impact HS will be included in the analysis with NRI (did not achieve AN count of 0, 1, or 2). 
Only subjects with Hurley Stage II at baseline will be included in the hypothesis test for AN 
count, while other subjects will be summarized, and a p-value reported for descriptive use 
only. Methodology will be identical to that used for the primary endpoint with the exception 
of stratification factors. For the secondary endpoint, achieve AN count of 0, 1, or 2 at Week 
16, which uses only subjects with Hurley Stage II at baseline, the stratification factor of 
baseline Hurley Stage will be omitted from the analysis. For the analysis using all subjects, 
the stratification factor of baseline Hurley Stage will be used, as in the primary endpoint 
analysis. 
The number and proportion of subjects who achieved AN count of 0, 1, or 2 among 
participants with baseline Hurley Stage II in each treatment group will be reported, along with 
p-values, 95% CI without strata calculated using asymptotic Wald method will be reported as 
well. A bar plot showing the proportion of subjects who achieved AN count of 0, 1, or 2 
among participants with baseline Hurley Stage II for each treatment will be produced. 
Secondary endpoint results will also be listed. 
6.6.3.3. NRS of Skin Pain at Week 16 
The secondary endpoint of percentage of subjects achieving at least 3 points reduction from 
baseline in NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 among 
participants with baseline NRS ≥ 4 will be analyzed analogously to the primary endpoint. 


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Hypotheses to assess percentage of subjects achieving at least 3 points reduction from baseline 
in NRS:  
H0: πABY – πPBO = 0 
HA: πABY – πPBO ≠ 0 
where πABY and πPBO are the proportion of subject achieve NRS Week 16.  
The number and proportion of subjects achieving at least 3 points reduction from baseline in 
NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 among participants 
with baseline NRS ≥ 4 in each treatment group will be reported, along with a bar plot showing 
the proportion of subjects with baseline NRS ≥ 4 who achieved NRS each treatment will be 
produced. Results will also be listed.  
If a subject received certain prohibited analgesic therapy within 28 days of the visit (including 
the day of the visit), the subject will be imputed as a non-responder due to the ICE. A list of 
all subjects who took prohibited analgesic therapy which results in NRI will be created after 
the data is final and before unblinding, and will include justification for choosing the subjects 
based on specific analgesic, timing relative to Week 16, and other factors considered.  
Since the NRS in Patient Global Assessment of Skin Pain is collected as a daily diary, the 
score used for analysis will be the average of the scores recorded 6 days prior to and including 
the Week 16 visit (7 days total for the average).  
6.6.4. Supplementary Analyses for the Secondary Efficacy Analysis 
For Part B, supplemental analyses of NRS pain will use MMRM among subjects with baseline 
NRS ≥ 4, using observed change in NRS Patient Global Assessment of Skin Pain (average in 
the last 24 hours) at all scheduled post-baseline assessments up to Week 16. The model will 
include baseline NRS Patient Global Assessment of Skin Pain, visit week, treatment, and 
treatment by visit week interaction as covariates and will use an unstructured variance-
covariance matrix. Other variance-covariance matrices, such as autoregressive, and 
compound-symmetric will be considered if the model does not converge. Sample SAS code 
is given as following: 
 
proc mixed ; 
class week subjectid treatment(ref = "placebo") 
model change_y = baseline_y week treatment * week treatment  
repeated week / subject = subjected (treatment) TYPE = UN;  
lsmeans treatment * week /slice = week cl;  
slice treatment * week/ sliceby = week pdiff cl;  
run;  
 


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Another supplemental analysis of pain will be analogous but will use all subjects, including 
those with baseline NRS < 4. 
Two supplemental analyses of flare will be reported. The first will impute any subject with 
missing AN count at any time after baseline as having a flare (missing = yes). The analysis 
will be analogous to that of the primary endpoint. The second will impute any subject with 
missing AN count at any time after baseline as not having a flare at that timepoint (but as 
having a flare if other observed data meet the definition of flare). This is equivalent to using 
only observed data for assessing flare. The analysis will again be analogous to that of the 
primary endpoint. 
A supplementary analysis of HiSCR75 at week 16 will impute as non-responder any subject 
who received a new antibiotic or increased dose of antibiotic at any time after randomization 
and before week 16. 
6.6.5. Exploratory Analysis 
Exploratory endpoints will be analyzed analogously to primary and secondary endpoints with 
the same strategies for ICEs. Binary endpoints will be analyzed with a stratified test of risk 
difference and continuous endpoints will be analyzed with an MMRM model in general. 
Continuous data at timepoints before and including the primary timepoint will use all data 
from planned assessments up to and including the primary timepoint; continuous data after 
the primary timepoint will use all data from all planned assessments. Visit week, treatment 
group and interaction will be included in the MMRM model. 
The number and proportion of subjects for binary endpoints in each treatment group will be 
reported, along with p-values, 95% CI without strata calculated using asymptotic Wald 
method will be reported as well. Results for continuous endpoints will presented as LS mean 
changes and associated SEs with associated 95% CI and p-values. For binary endpoints, a line 
plot showing the proportion of subjects experiencing such endpoints will be produced. For 
continuous endpoints, a line plot showing the LS mean and SE for each treatment group will 
be produced. Exploratory endpoint results will also be listed. 
The following binary endpoints before or on Week 16 will be analyzed analogously to the 
primary endpoints of HiSCR75 at Week 16. The number and proportion of subjects for binary 
endpoints in each treatment group, p-values, 95% CI without strata calculated using 
asymptotic Wald method 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. 
• HiSCR50, HiSCR75, HiSCR90 and HiSCR100 at Weeks 2, 4, 8, 12, 24 and 32; 
• AN count of 0, 1, or 2 at Weeks 4, 8, 12, 24, and 32 among subjects with baseline 
Hurley Stage II; 


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• HS flares through Weeks 4 and 32; 
• IHS4-55 response rates at Weeks 4, 8, 12, 16, 24 and 32;  
• Draining fistula count of 0 at weeks 4, 8, 12, 16, 24 and 32 
• Draining fistula count of 0 at weeks 4, 8, 12, 16, 24 and 32, among subjects with 
baseline draining fistula count of at least 1 
• Draining fistula count of 0 at weeks 4, 8, 12, 16, 24 and 32, among subjects with 
baseline draining fistula count of at least 2 
• Proportion with at least 3 points reduction from baseline in NRS in Patient Global 
Assessment of Skin Pain at its worst, among subjects with baseline NRS ≥ 4, at weeks 
4, 8 12, 24 and 32. NRI will be handled analogously to the corresponding secondary 
endpoint analysis. 
• ≥ 50% reduction from baseline in total inflammatory lesion count (abscesses + 
inflammatory nodules + draining fistula) at Weeks 4, 8, 12, 16, 24 and 32 
• ≥ 50% reduction from baseline in draining fistula count (draining fistula alone) 
• No increase in abscesses from baseline at Weeks 4, 8, 12, 16, 24 and 32 
The following continuous endpoints before or on Week 16 will be analyzed with an MMRM 
model as specified in sec 6.6.4. LS mean changes and associated SEs with associated 95% CI 
and p-values will be presented. Model will include all data up to Week 16. The following 
continuous endpoints after Week 16 will be reported at all collected timepoints and be 
summarized according to the four randomized treatment groups. Mean values, mean changes 
and associated descriptive statistics along with 95% CI  (for change from baseline) according 
to the four randomized treatment groups will be presented. 
• Change of Modified Sartorius Score from baseline, Weeks 4, 8, 12, 16, 24, and 32; 
• Change in PGA of Skin Pain (at its worst and average respectively) from baseline to 
Weeks 4, 8, 12, 16, 24, and 32; 
o If a subject received certain prohibited analgesic therapy within 28 days of the 
visit (including the day of the visit), the subject will be imputed as a non-
responder (PGA of Skin Pain = 10) due to the ICE at the visit.  
• Change in draining fistula count at Weeks 4, 8, 12, 16, 24 and 32; 
• Change from baseline to Week 16 in EQ-5D; 
• Change from baseline to Week 16 in DLQI; 
• Change from baseline to Week 16 in HADS, HADS-anxiety, and HADS-depression; 
• Change from baseline in IHS4 scores at Weeks 4, 8, 12, 16, 24, and 32 
HS-PGA is an ordinal scale, as defined as below, 
- 
Clear: No inflammatory or non-inflammatory nodules  
- 
Minimal: Only the presence of non-inflammatory nodules 


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- 
Mild: < 5 inflammatory nodules or 1 abscess or draining fistula and no inflammatory 
nodules 
- 
Moderate: < 5 inflammatory nodules or 1 abscess or draining fistula and ≥ 1 
inflammatory nodules or 2 to 5 abscesses or draining fistulas and < 10 inflammatory 
nodules 
- 
Severe: 2 to 5 abscesses or draining fistulas and ≥ 10 or more inflammatory nodules 
- 
Very severe: > 5 abscesses or draining fistulas 
A shift table will be present by treatment to display the numbers of subjects change from 
baseline to Week 16. Data at Week 16 will be presented as observed data, and separately with 
missing data imputed using the last observed value before Week 16. 
The HAD questionnaire comprises seven questions for anxiety and seven questions for 
depression. HADS will be summarized as HADS (total), HADS-anxiety, and HADS-
depression respectively. 
The EQ-5D (3L) comprises the following five dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, 
some problems, and extreme problems. EQ-5D will be summarized as one utility score. 
DLQI comprises 10 items arranged in six categories: symptoms and feelings (questions 1 and 
2), daily activity (3 and 4), leisure (5 and 6), work or study (7), interpersonal relationships (8 
and 9), and treatment (10). The total score can vary from 0 (no impact) to 30 (maximum 
impact). 
SF-12 v2 questionnaire is an abbreviated version of the 36-Item Short Form Health Survey 
with 12 items in eight domains. Physical Component Score and Mental Component Score 
derived from the SF-12 v2 questionnaire will be summarized by treatment groups at baseline 
and each timepoint (Week 8, 16, and 32) with mean values and changes from baseline and 
associated 95% CI without further divided into Period 1 and 2. 
The Patient Global Assessment of Skin Pain is collected as a daily diary, so the score used for 
analysis at visits prior to Week 16 will be the average of the scores recorded 6 days prior to 
and including the visit (7 days total for the average). For Patient Global Assessment of Skin 
Pain collected after Week 16, the value collected on the visit day will be used for analysis. No 
averaging will be done. If more than one value is collected at the visit, the first value collected 
will be used. 
Erythema score at each visit will be listed. 
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 


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performed on the FAS data set using methods analogous to those used for the primary analysis 
of that endpoint, defined above. 
Summaries of these variables will be presented by subgroup: 
• HiSCR50/75/90/100 at Week 16 
• NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 among subjects 
with baseline NRS ≥ 4 
• HS flare through Week 16  
• Achieved AN count of 0, 1, or 2 at Week 16 
The following subgroups are of interest: 
• Race (White, Black or African American, other) 
• Sex (male, female) 
• Age (< 65, ≥ 65) 
• Hurley stage at baseline (II, III) 
 
The following subgroups are also of interest for HiSCR50/75/90/100 at Week 16: 
• Geographic region 
o North America (US or Canada) 
o Europe (Spain, Hungary, Poland or Germany) 
o Non-US (Spain, Hungary, Poland, Germany or Canada) 
• Country 
o United States 
o Canada 
o Poland 
o Hungary 
o Spain 
o Germany 
• BMI (≤ 18, > 18 - ≤ 25, > 25 - ≤ 30, > 30 - ≤ 35, > 35) 
• Smoking status (never, former, current) 
• Prior biologic or JAK inhibitor (Any prior biologic or JAK inhibitor, any prior 
biologic, and prior TNF inhibitor, no prior biologic or JAK inhibitor) 
Difference in response rate and 2-sided Mantel-Haenszel 95% CI will be reported 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. 
6.6.7. Post-Week 16 (Part B, Period 2) Additional Analyses 
The following analyses will be done for all four randomized treatment groups in the FAS: 


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• Proportion with at least 3 points reduction from baseline in NRS in Patient Global 
Assessment of Skin Pain at its worst, among subjects with baseline NRS ≥ 4, at weeks 
24 and 32 will be summarized by number and proportion along with Clopper-Pearson 
95% CI without strata according to the four randomized treatment groups.  
o NRI will be handled analogously to the corresponding secondary endpoint 
analysis, except subjects who took Tramadol as allowed per-protocol (at a 
dose of up to 100 mg po every 4 hours, not to exceed 400 mg per 24 hours) 
during the 28 days prior to the visit will not be counted as a non-responder. 
• Descriptive MMRM analyses will be performed by randomized treatment group, for 
the continuous endpoints described below. The measured value at the visit will be 
used as the response variable, with visit week, treatment, and treatment * visit week 
interaction included as predictors. The model will include all visits from Day 1 
through Week 32. Unstructured covariance matrix will be used. Other variance-
covariance matrices, such as autoregressive, and compound-symmetric will be 
considered if the model does not converge. Estimated LSMean, corresponding SE 
values, and 95% confidence intervals will be summarized at the timepoints defined 
below.  
o Modified Sartorius Score at Weeks 24 and 32; 
o NRS PGA of Skin Pain (at its worst and average respectively) at Weeks 24 
and 32. To maintain consistency between all visits, only the score collected 
on the visit day will be used for this analysis. 
o Draining fistula count at Weeks 24 and 32; 
o EQ-5D at Weeks 24 and 32; 
o DLQI at Weeks 24 and 32; 
o HADS, HADS-anxiety, and HADS-depression at Weeks 24 and 32; 
o IHS4 scores at Weeks 24, and 32 
These summaries will address the question of expected results if a subject is 
assigned to either 32 weeks of izokibep or 16 weeks of placebo followed by 16 
weeks of izokibep. 
 
• A time-to-event analysis using Kaplan-Meier (KM) curves by randomized treatment 
group will be created for the events listed below.). If estimable, quartiles of the time 
to each event will be summarized by randomized treatment group. Product limit 
estimate at Week 32 (Day 224) will be provided. Participants will be censored at the 
time of last recorded assessment on study: 
o First achievement of HiSCR75 
o First achievement of HiSCR100 
o First achievement of HiSCR90 
o First achievement of HiSCR50 


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o First achievement of AN count of 0, 1, or 2 for subjects with baseline Hurley 
Score II 
o First achievement of >= 3 point reduction in NRS in Patient Global 
Assessment of Skin Pain at its worst among subjects with baseline NRS ≥ 4 
▪ To maintain consistency between all visits, only the score collected 
on the visit day will be used for this analysis. 
These graphics will address the question of whether subjects originally randomized to 
placebo catch up in efficacy to the subjects who were randomized to izokibep by week 32. 
The following analyses will be done by all four randomized treatment groups for the FAS 
subjects who had at least one dose of izokibep on or after Week 16. The analyses in subjects 
who received izokibep for the first 16 weeks will be done to address the question of whether 
responders/non-responders in the first 16 weeks of treatment experience subsequent 
sustained or added benefit in the following 16 weeks of treatment. The analyses in subjects 
who received placebo for the first 16 weeks will be done to evaluate if there is additional 
benefit after initial placebo response, or if placebo non-responders catch up to the subjects 
receiving 32 weeks of izokibep.  
• The subgroup of subjects who were responders by HiSCR75 at Week 16 will be 
further evaluated by randomized treatment group at Week 24 and Week 32: 
o Response rate for HiSCR75, HiSCR100, HiSCR90, HiSCR50 will be 
summarized by randomized treatment group at Week 24 and Week 32. The 
responder proportions and Clopper-Pearson 95% CI without strata will be 
presented. The NRI approach to missing data will be the same as for the 
primary analysis.  
 
o Response rate for AN count of 0, 1, or 2 among those with Hurley stage II at 
baseline will be summarized by randomized treatment group at Week 24 and 
Week 32. The responder proportions and Clopper-Pearson 95% CI without 
strata will be presented. NRI approach will be the same as for the primary 
analysis.  
 
o Descriptive MMRM analyses will be performed by randomized treatment 
group, for change from baseline of IHS4 score and draining fistula count at 
Week 24 and Week 32. The change from baseline value will be used as the 
response variable, with baseline value, visit week, treatment, and treatment * 
visit week interaction included as predictors in the model. Estimated LSMean 
change from baseline, corresponding SE values, and 95% confidence 
intervals will be presented in the table summaries.  
 


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• The subgroup of subjects who were responders at Week 16 by AN count of 0, 1, or 2 
(among those with Hurley stage II at baseline) will also be evaluated at Week 24 and 
Week 32 in the same manner as described for HiSCR75 responders. 
 
• The subgroup of subjects who were non-responders at Week 16 by HiSCR75 will 
also be evaluated at Week 24 and Week 32 in the same manner as described for 
HiSCR75 responders. 
 
• The subgroup of subjects who were non-responders at Week 16 by AN count of 0, 1, 
or 2 among those with Hurley stage II at baseline will also be evaluated at Week 24 
and Week 32 in the same manner as described for the HiSCR75 responders. 
 
• McNemar test will be used to evaluate the relationship between HiSCR75 response 
at Week 16 vs various response criteria at Week 32. P-values will be provided for 
descriptive purposes. The following response criteria at Week 32 will be used for 
this analysis: 
o HiSCR75 
o HiSCR90 
o HiSCR100 
o HiSCR50 
o AN count of 0, 1, or 2 
 
• McNemar test will be used to evaluate the relationship between “AN count of 0, 1, 
or 2” response at Week 16 vs various response criteria at Week 32. P-values will be 
provided for descriptive purposes. The following response criteria at Week 32 will 
be used for this analysis: 
o HiSCR75 
o HiSCR90 
o HiSCR100 
o HiSCR50 
o AN count of 0, 1, or 2 
 
The following analyses will be done (by randomized treatment groups) for only the FAS 
subjects randomized to placebo who had least one dose of izokibep in Period 2 of the study 
AND who had a total AN count of ≥ 5 at Week 16 and HS lesions present in at least 2 
distinct anatomic areas (to correspond to the inclusion criteria), to address the question of 
how subjects respond to izokibep after 16 weeks of placebo, when they still meet original 
eligibility criteria: 


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• The baseline characteristics summary described in section 6.4.2 will be repeated for 
this analysis set at Week 16. 
 
• The following binary endpoints will be analyzed analogously to the primary endpoint 
by randomized treatment group. The number and proportion of subjects for binary 
endpoints in each treatment group, 95% CI without strata calculated using asymptotic 
Wald method will be reported as well. 
o HiSCR50, HiSCR75, HiSCR90 and HiSCR100 calculated with respect to Day 
1 at weeks 24 and 32; 
HiSCR50, HiSCR75, HiSCR90 and HiSCR100 calculated with respect to 
Week 16 at weeks 24 and 32  
HiSCR50/75/90/100 with respect to Week 16 is defined as meeting all three 
criteria below: 
• (AN count at Week 16 - AN count at current visit) / AN count at Week 16 
× 100% ≥ 50/75/90/100% 
• Abscess count at Week 16 ≥ abscess count at the current visit 
• Draining fistula count at Week 16 ≥ draining fistula count at the current 
visit 
o AN count of 0, 1, or 2 at weeks 24 and 32 among subjects with baseline Hurley 
Stage II; 
o AN count of 0, 1, or 2 at weeks 24 and 32 among subjects with Week 16 Hurley 
Stage II; 
o HS flares from week 16 through 32, where HS flare is defined as proportion 
meeting the following two criteria at any assessment after Week 16 and at or 
before Week 32: 
▪ (AN count at current visit- AN count at Week 16) / AN count at Week 
16 ×100% ≥ 25% 
▪ AN count at current visit- AN count at baseline ≥ 2 
o IHS4-55 response rates at weeks 24 and 32;  
o Draining fistula count of 0 at weeks 24 and 32 
o Proportion with at least 3 points reduction from baseline in NRS in Patient 
Global Assessment of Skin Pain at its worst, among subjects with Week 16 
NRS ≥ 4, at weeks 24 and 32 
 
• Descriptive MMRM analyses will be performed by randomized treatment group, for 
the continuous endpoints described below. The measured value at the visit will be 
used as the response variable, with visit week, treatment, and treatment * visit week 
interaction included as predictors. The model will include all visits from Day 1 


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through Week 32. Estimated LSMean, corresponding SE values, and 95% 
confidence intervals will be summarized. Line plots by treatment group will be 
produced:  
o NRS Patient Global Assessment of Skin Pain (WORST). To maintain 
consistency between all visits, only the score collected on the visit day will 
be used for this analysis. 
o Draining fistula count, Modified Sartorius Score, IHS4 Score, HS-PGA 
score, all HADS scores (Total, Anxiety, Depression), EQ-5D Utility Score 
and DLQI Total Score. 
6.7. Safety 
For all Safety Tables, data in Part A and Part B will be summarized as follows, unless 
otherwise specified:  
• Part A summarized with all subjects for the entire time (Week 0 to Week 32) 
• Part B, for Period 1, will include the first 16 weeks until the first dose of treatment 
administered in Period 2 at or after Week 16, summarized by the randomized treatment 
arms and the combined placebo group (Placebo QW/ Placebo Q2W; Izokibep QW; 
Izokibep Q2W), and includes all subjects who received at least one dose of study 
treatment. AEs will be included if date of onset is on or after the day of the first dose 
received in Period 1 and before the date of the first dose received in Period 2. If a 
subject did not receive any dose of study treatment in Period 2, all AEs with onset on 
or after the day of first dose received in Period 1 through 4 weeks (28 days) after the 
last dose received will be included. 
• Part B, Period 2, will include data collected on and after the first dose of study 
treatment administered at Week 16 visit (or after Week 16 visit, if Week 16 visit is 
missing), summarized by the randomized treatment groups (Placebo - Izokibep QW; 
Placebo - Izokibep Q2W; Izokibep QW; Izokibep Q2W), and includes all subjects 
who took at least one dose of study treatment in Period 2. AEs  will be included if date 
of onset is on or after the day of first dose received in Period 2 through 4 weeks (28 
days) after the last dose received. 
6.7.1.  Extent of Exposure  
Exposure will be reported for Period 1, Period 2, and for the entire study for the Safety 
Analysis Set.  Exposure duration will also be summarized and will be calculated as (last dose 
[in the period of interest] – first dose [in the period of interest] + 1). The total number of doses 
taken and the total number of active doses of izokibep taken in each period (and overall for 
the study) as well as the total study will be reported.  


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Descriptive statistics will be presented for duration of exposure. The summary will include 
exposure duration, and number of doses administered, and number of doses of active izokibep 
administered (for the full study period summary only). 
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. 
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 CRF will be coded using the latest MedDRA dictionary 
around the time of Database Lock and classified as either AEs or TEAEs as follows: 
• 
TEAEs for Part A and Period 1 in Part B 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 (for subjects in Part A or those who don’t enter Part B Period 2), or events with 
start date and time prior to the start of the Period 1 whose severity worsens on or after 
the start of Period 1 and up to 4 weeks after the end of the Treatment Period (for 
subjects in Part A or those who don’t enter Part B Period 2).  
• 
TEAEs for period 2 in Part B 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 through 4 weeks after the end of the treatment period. 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 intensity will be based on CRF AEs form. Severe TEAEs are 
defined as TEAEs assessed as being “Severe” in intensity and include those events 
where the intensity is missing. 
• 
TEAEs leading to discontinuation of treatment are defined as TEAEs where “Action 
Taken with Study Treatment” is indicated as “Drug Withdrawn”. 
• 
Injection site reactions (ISRs) will be defined as any adverse event where the preferred 
term contains the words “injection site”. 


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In addition to the aforementioned AE types, the following TEAEs of special interest will be 
summarized:  
• Candida infection, 
• Inflammatory bowel disease, 
• Suicidal ideation.  
• Malignancies 
• Major adverse cardiovascular and cerebrovascular events (cerebrovascular accident 
and transient ischemic attack, non-fatal myocardial infarction or unstable angina, and 
cardiovascular death) 
• Tuberculosis 
• Infections (opportunistic, serious, or fungal only) 
• Cytopenias 
• 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 after database lock and prior 
to unblinding for the primary analysis (and after final database lock for the final analysis), 
and stored in the study trial master file. The memo will specify the subjects and preferred 
terms to be included as TEAEs of special interest, including justification for including or 
excluding events as appropriate. 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: 
o Any TEAE 
▪ Leading to discontinuation of study drug 
▪ Mild 
▪ Moderate 
▪ Severe 
▪ Any moderate or severe AE 
o Any study treatment related TEAE 
▪ Leading to discontinuation of study treatment 
o Any serious TEAE 
▪ Leading to discontinuation of study treatment 


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▪ 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 of Special Interest 
o TEAEs Leading to Discontinuation 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 count of number 
of events will be summarized by descending incidence PT (by total group) for the 
following types of TEAEs.  
• All TEAEs 
• TEAEs of Special Interest 
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. 


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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. Summaries by PTs only will be sorted by descending order of 
total incidence. 
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. 
AESIs and ISRs will be summarized for by treatment group, SOC, and PT. A similar 
summary will be provided by PT only for ISRs. These tables will be presented for the whole 
study period as well as by period (Period 1 and Period 2, separately, for Part B). Only 
subjects who have at least one dose of study drug in Period 2 are included in the summaries 
during Period 2.  
 
To assess the pattern of initial onset, AESIs and ISRs will also be presented by Kaplan-
Meier plot. This summary will be done for the full study period  and, separately, only for 
Period 2. For the Period 2 summary, the day of onset will be calculated with respect to the 
Week 16 date of dosing (Date of AE – Date of Week 16 dose + 1). 
Separate Kaplan Meier (KM) plots will be created for the study duration and Period 2 for time 
to: 
• First onset of an event in each AESI category 
o If an AESI category has < 3 events in a treatment arm, then this analysis will 
not be done. 
o Subjects who do not experience an event will be censored at their date of last 
contact. 
• First ISR 
o Subjects who do not experience an event will be censored at the date of their 
last injection. 
The date/time of onset of the first instance of the event of interest (AESIs or ISRs) will be 
used as the date/time of the event in the analysis. 
The product limit estimator will be presented by treatment group for Week 4 (Day 28), Week 
8 (Day 56), Week 12 (Day 84), Week 16 (Day 112), Week 20 (Day 140) , Week 24 (Day 
168), Week 28 (Day 196), and Week 32 (Day 224) for each AESI category and for ISRs. 


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Incidence of ISRs will be summarized for the whole study period by treatment group, and 
injection visit week (Day 1, Week 1, Week 2, etc). If a subject didn’t have an injection at the 
visit week, they will not be counted in the denominator for the incidence calculation.  
A similar presentation of ISRs by treatment group and injection visit week will also be done, 
but the cumulative number of ISRs up to the injection visit week will be summarized at the 
visit week. This summary will be done for the full study period as well as by treatment period. 
An overall summary of ISRs will be produced by treatment group, Period 1, Period 2, and for 
the full 32 week treatment period. The summary will include the number of subjects with:  
• ISRs leading to discontinuation 
• ISR at each maximum intensity/severity 
• Related ISRs 
• Serious ISRs 
• Serious related ISRs 
An ISR is considered to correspond to a particular visit week if it occurs on or after the 
indicated injection visit date/time, and prior to the next inject visit date/time. If no subsequent 
injection visit date/time is available, then the ISR will correspond to the closest injection visit 
date occurring prior to it. 
To evaluate the pattern of subjects experiencing multiple ISRs in Period 1 of the study (or the 
full treatment period in Part A), the number and percent of subjects with ISRs on or after Day 
29 (through the end of the period) will be presented by the four treatment groups and by the 
following subgroups:  
• Subjects who had at least one ISR on Days 1-28  
• Subjects who had no ISRs on Days 1-28 
A similar analysis by the four treatment groups will be presented for Period 2 Part B, where 
the two subgroups of interest are: 
• Subjects who had at least one ISR up to Week 16  
• Subjects who had no ISRs up to Week 16 
ISRs will also be graphically presented by treatment group using a lasagna plot. The y-axis 
will be each injection visit week, the x-axis will represent each subject, and each ‘square’ on 
the plot will be color coded into the following categories: missing injection, no ISR at the 
visit, mild, moderate, and severe ISRs. The lasagna plot will be presented by treatment group, 
and sorted by ISR first onset and severity (earliest and most severe will be sorted at the top). 
In addition, the following listings will be presented: 


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• 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, 24, 32, and 39).  
 
 


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Table 1 Laboratory Tests 
Laboratory 
Tests  
Parameters 
Hematology  
Platelet count  
RBC indices:  
Mean corpuscular volume 
(MCV)  
Mean corpuscular 
hemoglobin (MCH)  
%Reticulocytes  
White blood cell (WBC) count 
with differential:  
Neutrophils  
Lymphocytes  
Monocytes  
Eosinophils  
Basophils  
Red blood cell (RBC) 
count 
Hemoglobin  
Hematocrit  
Clinical 
chemistry1  
Blood urea nitrogen 
(BUN)  
Potassium  
Aspartate 
aminotransferase 
(AST)/serum 
glutamic-
oxaloacetic 
transaminase 
(SGOT)  
Total and direct bilirubin  
 
Creatinine  
Sodium  
Alanine 
aminotransferase 
(ALT)/serum 
glutamic-pyruvic 
transaminase 
(SGPT)  
Total protein  
 
Glucose (non-fasting)  
Calcium  
Alkaline 
phosphatase2  
Fasting lipid (total 
cholesterol, triglycerides 
& HDL)  
Routine 
urinalysis  
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, by dipstick  
• 
Microscopic examination (if blood or protein is abnormal)  
 
Pregnancy 
testing  
• 
Highly sensitive serum human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential) at screening 
Other screening 
tests  
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only)  
• 
Serology hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody  
• 
Tuberculosis testing: QuantiFERON® test or purified protein derivative (PPD) 
test  
• 
Note: T-SPOT® tuberculosis test may be acceptable if agreed upon with the 
medical monitor  
 
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 (Baseline, Week 4, 8, 12, 16, 24, 32, and 39) will be compared with the 
relevant reference range in SI units and categorized as: 


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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 
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 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 (Week 4, 8, 12, 
16, 24, 32, and 39) 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 (Week 4, 8, 12, 16, 24, 32, and 39) for hematology and clinical chemistry 
• Number and percentage of subjects with worst categorized (low, normal, and high) 
values relative to the reference range 
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. 
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 


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• 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 LFT 
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: 
• Treatment 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) 
o One table presented for each treatment arm (160 mg QW / 160 mg Q2W / 
combined placebo) 
• Treatment period 2 
o Baseline prior to treatment period 1 (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 
Law at any time) 
o One table presented for each treatment arm (160 mg QW / 160 mg Q2W / 
placebo – 160 mg QW / placebo – 160 mg Q2W) 
Separate Kaplan Meier (KM) analyses plots will be created for time to: 
• First instance of meeting Hy’s Law 
• First instance of ALT or AST ≥5 x ULN 
• First instance of ALT or AST ≥3 x ULN and total bilirubin ≥2 x ULN (>35% direct 
bilirubin) simultaneously  


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• First instance of ALT or AST ≥3 x ULN and international normalized ratio (INR) ≥1.5 
simultaneously 
• First instance of ALT or AST ≥3 x ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity at any time 
for the study duration (Day 1 through Week 32). In each plot, the subjects taking any treatment 
with Q2W frequency will be indicated by a solid line. The subjects taking any treatment with 
QW frequency will be indicated by a dashed line. Separate colors will be used to distinguish 
subjects randomized to izokibep and those randomized to placebo.  
Subjects who do not experience an event will be censored at their last attended assessment. 
The date/time of onset of the first instance of the event of interest will be used as the date/time 
of the event in the analysis. 
The product-limit estimator at Week 16 and Week 32 will be summarized by treatment group. 
If there are < 3 events in a treatment arm for an event, then the KM analysis will not be done. 
A listing of all LFT 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 (Week 1, 2, 3, 
4, 8, 12, 13,14, 15,16, 17 18, 20, 24, 28, 32, and 39) for each standard vital sign 
parameter using default summary statistics for continuous variables. 


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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, Weeks 16, 32 
and 39: 
• 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. 
6.7.6. Physical Examination 
Clinically significant findings observed prior to the first dose of study drug will be entered on 
the CRF in medical history 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. 
For each physical examination body system, the number and percentage of subjects with 
abnormalities at baseline and at each assessed timepoint (Screen and Week 32) will be 
summarized for the Safety Analysis Set. 
Physical examination findings (normal/abnormal/clinically significant) and details of 
abnormalities will be listed for each subject at each assessment timepoint (Screen and Week 
32). 
6.7.7. C-SSRS 
Suicidal ideation and behavior will be assessed during the study (Screen, Week 0, 4, 8, 12, 
16, 20, 24, 28, 32, and 39) by trained study personnel using the C-SSRS. C-SSRS evaluates 
suicidal ideation (Category 1 - Category 5) and behavior (Category 6 - Category 10). The 
following outcomes are C-SSRS categories and have binary responses (yes/no). 
• Category 1 – Wish to be Dead 
• Category 2 – Non-specific Active Suicidal Thoughts 
• Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act 
• Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 


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• Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
• Category 6 – Preparatory Acts or Behavior 
• Category 7 – Aborted Attempt 
• Category 8 – Interrupted Attempt 
• Category 9 – Actual Attempt (non-fatal) 
• Category 10 – Completed Suicide 
At the screen visit, the C-SSRS will be listed by lifetime and past 6 months from suicidal 
ideation, and lifetime and past two years from suicidal behavior for each category. At the 
post-screen visit, the C-SSRS will be listed as since the last visit for each category. 
6.7.8. 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 at least one medical expert with the relevant therapeutic area and at 
least one statistician. The DMC will also have a minimum of three members, one of whom will 
serve as the Chair. 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. In addition, the DMC will meet as indicated below to review data 
from Part A and Part B. 
Part A  
The DMC will review data in Part A after all subjects have had the opportunity to complete 
the Week 8 visit (or discontinued the study early). Based on this review, the DMC may 
recommend continuing, stopping, or altering Part B.  
Part B  
In Part B, no formal interim analysis is planned for purposes of stopping or altering this study. 
The DMC will review unblinded data when the first approximately 105 subjects randomized 
into Part B have had the opportunity to complete the Week 8 visit to make a recommendation 
on further development activities for izokibep. The DMC will not be empowered to 
recommend stopping this study or changing the sample size due to a demonstration of positive 
efficacy. The type I error rate for hypothesis tests at the end of the study will be decreased by 
0.0001 to account for this interim summary of unblinded data. The study team and the 
investigators will remain blinded to these interim results until after the study is completed.  
After all subjects have had an opportunity to complete the Week 16 visit (complete the visit, 
or complete a subsequent visit, or permanently discontinue the study), the primary endpoint 
analyses may be conducted. These will be the final analyses for the primary endpoint, so no 


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adjustment of the type I error will be applied. Site staff, and all Sponsor staff who interact 
with site staff, will remain blinded to individual subject treatment assignment until the final 
subject has completed the final visit. 
6.8. Pharmacokinetic Assessments  
Pharmacokinetic data will be summarized by treatment group and scheduled visit, including 
N (number of non-missing data), N BLQ (for concentrations only), arithmetic mean, standard 
deviation (SD), arithmetic coefficient of variation (CV%), geometric mean, geometric CV%, 
median, minimum, and maximum. Only trough collections are planned, so no calculations of 
PK parameters (maximum concentration, area under the concentration curve, etc.) will be 
provided.  
For the calculation of summary statistics, pre-dose 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. 
Pharmacokinetic data may be combined with data from other studies of izokibep for 
modeling. If this is done, details will be described in a separate document. 
6.9. Anti-Drug Antibodies 
Samples tested for ADAs will be reported as positive or negative based on a non-specific 
screening 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 screening test, with 
number (%) positive. Positive samples on the screening 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 test 
as the denominator. 




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4 
Longest distance between two 
relevant lesions within a 
region or size of the lesion if 
single 
< 5 cm 
1 
 
 
5 - 10 cm 
3 
 
 
> 10 cm 
9 
 
 
 
 
 
5 
Lesions separated by normal 
skin?* 
Yes 
0 
 
 
No 
9 
 
 
 
 
 
Score for the region 
 
 
Sum of 
above 
* If Lesions separated by normal skin = “No” and/or Hurley Stage = “STAGE III” then 9 
points is added for the region.  
Score for each region is (if the region involved) = 3 + (number of inflammatory nodule) × 1 
+ {(number of draining fistula) × 6 +{0 < (The longest distance between two relevant lesions 
[or size of lesion if single]) <5} × 1+ {5≤(The longest distance between two relevant lesions 
[or size of lesion if single]) ≤ 10} × 3 + {(The longest distance between two relevant lesions 
[or size of lesion if single]) > 10 } × 9 + (all lesions separated by normal skin = Yes or Hurley 
Stage = “STAGE III”) × 9 
Modified Sartorius score is the sum of the score of each region. Any region with no 
involvement will have a score of zero for purposes of calculating the modified Sartorius score. 
A region is considered “affected” if any of the following conditions are true: 
• Abscess Count > 0 OR 
• Any “Interventions needed” questions response = YES 
• Any “Interventions needed DATE” question is not missing. 
• Any “How many lesions had intervention” question > 0 
• Any “How many lesions had intervention AND are no longer present” > 0 
• Non-draining fistula count > 0 
• Draining fistula count > 0 
• Non-inflammatory nodule count > 0 


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• Inflammatory nodule count > 0 
• Hypertrophic scar > 0 
• Longest distance > 0 
• Normal appearance tissue = NO 
Hurley Stage contains “STAGE” 
EQ-5D9 
The EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no 
problems, some problems, and extreme problems. A unique health state is defined by 
combining 1 level from each of the 5 dimensions. There are 243 possible health states defined 
in this way. Each state is referred to in terms of a 5-digit code. No health state value will be 
calculated if any of the dimensions are missing.  
Domain Scores of EQ-5D-3L Descriptive System  
Response Category 
Score 
No problems 
1 
Moderate problems 
2 
Severe problems 
3 
Note: Missing values are coded as ‘.’. Ambiguous values (e.g., 2 boxes are ticked for a single 
dimension) should be treated as missing values.  
EQ-5D-3L = sum(non-missing question score)/(number of non-missing questions) × 5. If the 
number of questions with a missing answer is ≥ 3 (≥ 50%) then EQ-5D-3L is missing. 
For example, if a patient provides the following responses: Mobility = No problems, Self-care 
= No problems, Usual Activities = Moderate problems, Pain/Discomfort = Moderate 
problems, Anxiety/Depression = Extreme problems, his response sequence is 11223. The 243 
theoretical possible sequences can then be mapped to an index value to provide a summary 
across all dimensions. For the calculation of the index value, the UK value set based on Time 
Trade-Off method will be used. The scoring algorithm is as follows: 
 
Full health (11111) =  
 
At least one domain at 2 or 3 (N2): 
At least one domain at 3 (N3): 
 
Mobility level 1: 
1.000 
 
-0.081 
-0.269 
 
0 


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Mobility level 2:  
Mobility level 3:  
Self-care level 1: 
Self-care level 2:  
Self-care level 3:  
Usual activities 1: 
Usual activities 2:  
Usual activities 3:  
Pain/discomfort 1: 
Pain/discomfort 2:  
Pain/discomfort 3: 
Anxiety/depression 1:  
Anxiety/depression 2:  
Anxiety depression 3:  
-0.069 
-0.314 
0 
-0.104 
-0.214 
0 
-0.036 
-0.094 
0 
-0.123 
-0.386 
0 
-0.071 
-0.236 
 
The index for the patient with example sequence 11223 = 0.255, calculated as follows: 
Full health = 1 
Minus N2: -0.081 
Minus N3: -0.269 
Minus mobility level 1: 0 
Minus self-care level 1: 0 
Minus usual activities level 2: -0.036 
Minus pain/discomfort level 2: -0.123 
Minus anxiety/depression level 3: -0.236 
where level 1 corresponds to no problems, level 2 to some problems and level 3 to extreme 
problems. 
DLQI10 
DLQI measures the health-related quality of life of adult patients suffering from a skin 
disease. It comprises 10 items arranged in six categories: symptoms and feelings (questions 1 
and 2), daily activity (3 and 4), leisure (5 and 6), work or study (7), interpersonal relationships 
(8 and 9), and treatment (10). The total score can vary from 0 (no impact) to 30 (maximum 
impact). The DLQI score is calculated by summing the score of each question resulting in a 
maximum of 30 and a minimum of 0. The highest score represents the highest impairment of 
the health-related quality of life.  


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The scoring of each question is as follows:  
• 
Very much  
• 
A lot  
• 
A little  
• 
Not at all  
• 
Not relevant  
• 
Question unanswered or missing 
• 
If leading Question 7 response is Yes*  
• 
If leading Question 7 response is not Yes*  
Scored 3  
Scored 2  
Scored 1  
Scored 0  
Scored 0  
Scored 0  
Scored 3  
Scored as above using follow-
up Question 7  
* Questions 7 and 7a substitute each other. Only 1 of them may contribute to overall DLQI both in 
terms of score and number of questions. I.e. if Q7 = “Yes” and Q7a = “A little” – only Q7 is scored 
as “3” and +1 non missing-question, while Q7a is completely ignored. 
DLQI = sum(non-missing question score) / (number of non-missing questions) × 10. If the 
number of questions with a missing answer is ≥ 5 (≥ 50%) then DLQI is missing. 
HADS11 
The HADS is a self-report rating scale of 14 items on a 4-point Likert scale (range 0–3, with 
0 least severe and 3 most severe). It is designed to measure anxiety and depression (7 items 
for each subscale). The total score is the sum of the 14 items, and for each subscale, the score 
is the sum of the respective seven items (ranging from 0–21). HADS-Anxiety includes 
questions 1, 3, 5, 7, 9, 11, and 13. HADS-Depression includes questions 2, 4, 6, 8, 10, 12, and 
14. 
HADS will be present as anxiety, depression, and overall respectively. If the number of 
questions with a missing answer is ≥ 4, ≥ 4, and ≥ 7 (≥ 50%) for anxiety, depression, and 
overall respectively, then the score is missing. 
Erythema Score 
At every visit, for each anatomic region affected by HS, the investigator will assess the overall 
degree of erythema using a four-point ordinal scale ranging between 0 and 3. 
• Left axilla 
• Right axilla 
• Left sub/inframammary area 
• Right sub/inframammary area 
• Intermammary area 
• Left buttock 


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• Right buttock 
• Left inguino-crural fold 
• Right inguino-crural fold 
• Perianal 
• Perineal 
• Upper Back and Neck 
• Other 
The scoring rule as following: 
• 0 = no redness  
• 1 = faint but discernible pink coloration  
• 2 = moderate red coloration  
• 3 = very red or bright red coloration 
 
Erythema score = 12 × {sum (non-missing score of each region [total 12 regions + Other 
regions])/ (number of non-missing region)}. The multiplier of 12 will not change even if the 
number of non-missing + Other regions changes. If the number of questions with a missing 
answer is ≥ 6 (≥ 50%) then the Erythema score is missing. 
A region is considered “affected” if it has a > 0 abscess/nodule/fistula count or a non-zero 
response to any of the other quantitative questions on the Lesion Count/Hurley Stage eCRF 
form for the region or “intervening normal appearance tissue” = “No” or Hurley Stage not 
equal to “Not Applicable”. 
SF-12v2 
The SF-12v212 is a self-reported outcome measure assessing the impact of health on an 
individual's everyday life. Two component scores are derived from the SF-12 including the  
SF-12 Physical Component Score  and the SF-12 Mental Component Score. SF-12 summary 
score can be calculated only when all components are non-missing (i.e. all answers provided), 
otherwise should be set to missing. If all answers are available then calculate as per following 
steps. 
The instructions for computing the component scores are as follows:  
1. Compute raw scale scores based on the table from precoded item value to final item 
value.  
2. Transform raw scale scores to 0-100 scale. 
3. Standardization of SF-12v2 scales (Z-scores), Standard Form 
4. Norm-Based Transformation of SF-12v2 scales Z-scores, Standard Form 
5. Norm-Based Scoring SF-12v2 Physical and Mental Summary Measures  
 


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1. Precoded and final values by items: 
Item: 1 
Response choices 
Precoded Item Value 
Final Item Value 
Excellent 
1 
5.0 
Very good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.0 
Poor 
5 
1.0 
 
Items: 2a, 2b 
Response choices 
Precoded Item Value 
Final Item Value 
Yes, limited a lot 
1 
1 
Yes, limited a little 
 2 
2 
No, not limited at all 
3 
3 
 
Items: 3a, 3b, 4a, 4b, 7 
Response choices 
Precoded Item Value 
Final Item Value 
All of the time 
1 
1 
Most of the time 
2 
2 
Some of the time 
3 
3 
A little of the time 
4 
4 
None of the time 
5 
5 
 
Item: 5 
Response choices 
Precoded Item Value 
Final Item Value 
Not at all 
1 
5 
A little bit 
2 
4 
Moderately 
3 
3 
Quite a bit 
4 
2 
Extremely 
5 
1 
 
Items: 6a, 6b 
Response choices 
Precoded Item Value 
Final Item Value 
All of the time 
1 
5 
Most of the time 
2 
4 
Some of the time 
3 
3 
A little of the time 
4 
2 
None of the time 
5 
1 
 
Items: 6c 
Response choices 
Precoded Item Value 
Final Item Value 
All of the time 
1 
1 
Most of the time 
2 
2 


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Some of the time 
3 
3 
A little of the time 
4 
4 
None of the time 
5 
5 
 
2. Transformation of scale scores: 
The next step involves transforming each raw score to 0-100 scale using the formula shown 
below: 
𝑇𝑟𝑎𝑛𝑠𝑓𝑜𝑟𝑚𝑒𝑑 𝑠𝑐𝑎𝑙𝑒
= [
(𝐴𝑐𝑡𝑢𝑎𝑙 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−𝑙𝑜𝑤𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒)𝑃𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒]
×  100 
This transformation converts the lowest and highest possible scores to zero and 100, 
respectively. Scores between these values represent the percentage of the total possible score 
achieved. 
Scale items aggregated and range of possible scores: 
SF-12v2 scale 
Sum final Item 
Values (after 
recoding items) 
Lowest and highest 
possible raw scores 
Possible raw 
score range 
Physical Functioning 
(PF) 
Items 2a + 2b 
2, 6 
4 
Role Physical (RP) 
Items 3a + 3b 
2, 10 
8 
Bodily Pain (BP) 
Item 5 
1, 5 
4 
General Health (GH) 
Item 1 
1, 5 
4 
Vitality (VT) 
Item 6b 
1, 5 
4 
Social Functioning (SF) 
Item 7 
1, 5 
4 
Role Emotional (RE) 
Items 4a + 4b 
2, 10 
8 
Mental Health (MH) 
Items 6a + 6c 
2, 10 
8 
 
1. Standardization of SF-12v2 scales (Z-scores), Standard Form: 
Formulas for z-score standardization of SF-12v2 scales, Standard Form: 
SF-12v2 
Z-scores 
Physical Functioning (PF_Z) 
PF_Z = (PF – 81.18122) / 29.10558 
Role Physical (RP_Z) 
RP_Z = (RP – 80.52856) / 27.13526 
Bodily Pain (BP_Z) 
BP_Z = (BP – 81.74015) / 24.53019 
General Health (GH_Z) 
GH_Z = (GH – 72.19795) / 23.19041 
Vitality (VT Z) 
VT Z = (VT – 55.59090) / 24.84380 
Social Functioning (SF_Z) 
SF_Z = (SF – 83.73973) / 24.75775 
Role Emotional (RE_Z) 
RE_Z = (RE – 86.41051) / 22.35543 


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Mental Health (MH_Z) 
MH_Z = (MH – 70.18217) / 
20.50597 
 
Norm-Based Transformation of SF-12v2 scales Z-scores, Standard Form: 
 
SF-12v2  
Norm-Based scores 
Physical Functioning (Norm-Based PF) 
Norm-Based PF = 50 + (PF_Z * 10) 
Role Physical (Norm-Based RP) 
Norm-Based RP = 50 + (RP_Z * 10) 
Bodily Pain (Norm-Based BP) 
Norm-Based BP = 50 + (BP_Z * 10) 
General Health (Norm-Based GH) 
Norm-Based GH = 50 + (GH_Z * 
10) 
Vitality (Norm-Based VT) 
Norm-Based VT = 50 + (VT Z * 10) 
Social Functioning (Norm-Based SF) 
Norm-Based SF = 50 + (SF_Z * 10) 
Role Emotional (Norm-Based RE) 
Norm-Based RE = 50 + (RE Z * 10) 
Mental Health (Norm-Based MH) 
Norm-Based MH = 50 + (MH_Z * 
10) 
 
3. Norm-Based Scoring SF-12v2 Physical and Mental Summary Measures (Standard 4-
week recall) 
 
SF-12v2  
Aggregated scores 
Aggregate Physical Summary 
Score (AGG_PHYS) 
AGG_PHYS = (PF_Z * 0.42402) + (RP_Z * 0.35119) + 
(BP_Z * 0.31754) + (GH_Z * 0.24954) + (VT_Z * 0.02877) 
+ (SF_Z * -0.00753) + (RE_Z * -0.19206) + (MH_Z * -
0.22069) 
Aggregate Mental Summary 
Score (AGG_MENT) 
AGG_MENT = (PF_Z * -0.22999) + (RP_Z * -0.12329) + 
(BP_Z * -0.09731) + (GH_Z * -0.01571) + (VT_Z * 
0.23534) + (SF_Z * 0.26876) + (RE_Z * 0.43407) + (MH_Z 
* 0.48581) 
 
4. Transformation of Summary Scores (Standard Form) 
 
SF-12v2  
Z-scores 
Transformed Physical 
Component Score (PCS) 
50 + (AGG_PHYS * 10) 
Transformed Mental 
Component Score (MCS) 
50 + (AGG_MENT * 10) 
 
 
 


Statistical Analysis Plan 
 
CONFIDENTIAL 
 
 
Protocol Reference: 21102 
Final, Version 3.0, 03APR2024 
Page 75 of 75 
 
 
ST-AD-008 version 06 
 
8. References 
 
 
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. 
 
6 Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley & Sons. 
 
 
 
8 Sartorius K, Emtestam L, Jemec GB et al. Objective scoring of hidradenitis suppurativa 
reflecting the role of tobacco smoking and obesity. Br J Dermatol 2009; 161: 831–839. 
 
9 The EuroQol Group. EuroQoL-a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199−208. 
 
10 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clinical and Experimental Dermatology 1994;19:210−16. 
 
11 Zigmond AS Snaith RP . The Hospital Anxiety and Depression Scale. Acta Psychiatr 
Scand 1983;67:361–370. 
 
12 Ware, J. E., Jr., Kosinski, M., Turner-Bowker, D. M., & Gandek, B. (2002). How to score 
version 2 of the SF-12® health survey (with a supplement documenting version 1). Lincoln, 
RI: QualityMetric Incorporated. 


Signature Page for VV-CLIN-000197 v1.0
Signature Page for VV-CLIN-000197 v1.0
Approval Task Task
Verdict: Approved
03-Apr-2024 21:49:48 GMT+0000
Approval Task Task
Verdict: Approved
04-Apr-2024 16:01:50 GMT+0000

Prot_000.pdf: 
Document Type:  
Final Protocol 
Document Date:  
13 December 2023 
Study Title:  
A Phase 2b Pivotal Study to Evaluate the Efficacy and Safety of 
Izokibep in Subjects with Moderate to Severe Hidradenitis Suppurativa 
Protocol Reference Number: 21102 
NCT Number:  
NCT05355805 
 
 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
1 
Title Page 
Protocol Title: 
A Phase 2b Pivotal Study to Evaluate the Efficacy and Safety of Izokibep in Subjects with 
Moderate to Severe Hidradenitis Suppurativa 
Protocol Number: 21102 
Protocol Version: 4.0 
Protocol Date: 13 December 2023 
Compound: Izokibep 
Brief Title: Hidradenitis Suppurativa Phase 2b Pivotal Study of Izokibep 
Study Phase: Phase 2b 
Sponsor Name: ACELYRIN, INC. 
Legal Registered Address: 
4149 Liberty Canyon Rd, Agoura Hills, CA 91301 
United States of America 
 
The medical monitor’s name and contact information will be provided separately. 
Regulatory Agency Identifier Number(s): 
EudraCT number: 2021-005713-13 
 
 
Previous versions 
Date 
1.0 
04 November 2021 
2.0 
28 July 2022 
3.0 
26 April 2023 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
2 
Amendment 3 (11 December 2023) 
This amendment is considered nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study. 
Overall Rationale for the Amendment: 
The main purpose of this amendment is to improve the method of handling missing data for the 
secondary endpoint of percentage of subjects who experience flare; align the power calculation 
with the primary endpoint of hidradenitis suppurativa clinical response with at least a 75% 
reduction from baseline in the total abscess and inflammatory nodule count, with no increase 
from baseline in abscess or draining fistula count (ie, HiSCR75); and better define the adverse 
events of special interest.  A tabular summary of the changes is provided on the next page. 
 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
3 
Protocol Amendment Summary of Changes Table 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
Removed sponsor signatory. 
Sponsor approval is provided and maintained 
within the regulatory information 
management system. 
2.3.1 Risks 
Removed 2 examples of potential 
risks of IL-17 inhibitors and added 
cross reference to Section 8.3.6 
Events of Special Interest for the full 
list. 
The previous list of potential risks was 
incomplete. To reduce redundancy, a cross 
reference to the appropriate section was 
added. 
8.3.6 Events 
of Special 
Interest 
• 
Clarified that major adverse 
cardiovascular and cerebrovascular 
events includes cerebrovascular 
accident and transient ischemic 
attack, non-fatal myocardial 
infarction or unstable angina, 
cardiovascular death. 
• 
Clarified that for infections, 
only those that are serious, 
opportunistic, or fungal are included 
as adverse events of interest. 
Improved the clarity of the definitions for 
events that qualify as adverse events of 
special interest. 
 
9.3.3 
Secondary 
Endpoints and 
Estimands 
Updated the method of handling 
missing data for the secondary 
endpoint of percentage of subjects 
who experience flare from 
non-response imputation (NRI) to 
multiple imputation. 
The multiple imputation analysis method 
better represents missing data than NRI. The 
number of subjects with missing data may be 
larger than the number of subjects who 
experience a flare, so using NRI may result in 
an analysis dominated by missing data.  
9.5 Sample 
Size 
Determination 
Updated the power calculation for 
Part B to align with the primary 
endpoint of HiSCR75. 
Corrected power calculation in Part B in line 
with HiSCR75, which was inadvertently 
missed in the previous amendment when the 
primary endpoint was updated from HiSCR to 
HiSCR75. 
Global 
Minor editorial and document 
formatting revisions. 
Administrative change. 
Global 
Version and date were revised on the 
title page and in the header 
throughout the document. 
Administrative change. 
 
 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
4 
Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities for Part A and Part B ..................................................................14 
2. 
Introduction ...................................................................................................................19 
2.1. 
Study Rationale ...............................................................................................................19 
2.2. 
Background .....................................................................................................................19 
2.2.1. 
Disease Background........................................................................................................19 
2.2.2. 
IL-17 ...............................................................................................................................20 
2.2.3. 
Izokibep Background ......................................................................................................20 
2.3. 
Benefit/Risk Assessment ................................................................................................23 
2.3.1. 
Risk Assessment .............................................................................................................23 
2.3.2. 
Benefit Assessment .........................................................................................................24 
2.3.3. 
Overall Benefit-Risk Conclusion ....................................................................................24 
2.3.4. 
COVID-19 Benefit/Risk Assessment .............................................................................25 
3. 
Objectives, Endpoints, and Estimands .......................................................................26 
4. 
Study Design ..................................................................................................................29 
4.1. 
Overall Design ................................................................................................................29 
4.1.1. 
Part A: Single-arm, Open-label.......................................................................................29 
4.1.2. 
Part B: Randomized, Double-blind, Dose-finding ..........................................................29 
4.1.3. 
Independent Data Monitoring Committee ......................................................................30 
4.1.4. 
Number of Sites ..............................................................................................................31 
4.1.5. 
Number of Subjects.........................................................................................................31 
4.1.6. 
Study Duration for Subjects ............................................................................................31 
4.1.7. 
Scientific Rationale for Study Design.............................................................................31 
4.2. 
Justification for Dose ......................................................................................................31 
4.3. 
End of Study Definition ..................................................................................................33 
5. 
Study Population ...........................................................................................................35 
5.1. 
Inclusion Criteria ............................................................................................................35 
5.2. 
Exclusion Criteria ...........................................................................................................37 
5.3. 
Lifestyle Considerations .................................................................................................40 
5.4. 
Screen Failures ................................................................................................................40 
5.5. 
Criteria for Temporarily Delaying ..................................................................................40 
5.6. 
COVID-19 Related Precautions......................................................................................40 
6. 
Study Drug(s) and Concomitant Therapy ..................................................................42 
6.1. 
Study Drug(s) Administered ...........................................................................................42 
6.1.1. 
Dosage, Administration and Schedule ............................................................................42 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................43 
6.3.1. 
Subject Enrollment..........................................................................................................43 
6.3.2. 
Rescreening .....................................................................................................................44 
6.3.3. 
Treatment Assignment/Randomization ..........................................................................45 
6.3.4. 
Site Personnel Access to Individual Treatment Assignments.........................................45 


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ACELYRIN Izokibep Protocol 21102 
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5 
6.4. 
Study Drug Compliance..................................................................................................46 
6.5. 
Dose Modification ..........................................................................................................46 
6.6. 
Continued Access to Study Drug After the End of the Study ........................................46 
6.7. 
Overdose .........................................................................................................................46 
6.8. 
Prior and Concomitant Therapy ......................................................................................46 
6.8.1. 
Prior Therapies ................................................................................................................47 
6.8.2. 
Concomitant Therapies ...................................................................................................47 
6.8.3. 
Rescue Medicine .............................................................................................................49 
6.8.4. 
Prohibited Medications ...................................................................................................49 
7. 
Discontinuation of Study Drug and Subject 
Discontinuation/Withdrawal........................................................................................51 
7.1. 
Discontinuation of Study Drug .......................................................................................51 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................52 
7.1.2. 
Study Drug Restart or Rechallenge After Liver Stopping Criteria 
Are Met ...........................................................................................................................53 
7.2. 
Subject Discontinuation/Withdrawal from the Study .....................................................54 
7.3. 
Lost to Follow-up............................................................................................................54 
8. 
Study Assessments and Procedures.............................................................................55 
8.1. 
Efficacy Assessments .....................................................................................................55 
8.1.1. 
Lesion Count ...................................................................................................................56 
8.1.2. 
Erythema Score ...............................................................................................................57 
8.1.3. 
Hurley Stage....................................................................................................................57 
8.1.4. 
Hidradenitis Suppurativa-Physician’s Global Assessment .............................................57 
8.1.5. 
Numeric Rating Scale Patient Global Assessment of Skin Pain.....................................57 
8.1.6. 
Dermatology Life Quality Index .....................................................................................58 
8.1.7. 
Short Form 12 .................................................................................................................58 
8.1.8. 
European Quality of Life-5 Dimensions .........................................................................58 
8.1.9. 
Hidradenitis Suppurativa Patient Global Impression of Change ....................................59 
8.1.10. Hospital Anxiety and Depression Scale ..........................................................................59 
8.1.11. Photography (Optional Substudy)...................................................................................59 
8.2. 
Safety Assessments .........................................................................................................59 
8.2.1. 
Physical Examination......................................................................................................59 
8.2.2. 
Physical Measurements ...................................................................................................59 
8.2.3. 
Vital Signs .......................................................................................................................59 
8.2.4. 
Electrocardiograms .........................................................................................................60 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................60 
8.2.6. 
Pregnancy Testing ...........................................................................................................60 
8.2.7. 
Hepatitis Testing .............................................................................................................61 
8.2.8. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................61 
8.2.9. 
Home Study Drug Administration Diary ........................................................................61 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................................61 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................62 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................62 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................62 


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ACELYRIN Izokibep Protocol 21102 
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6 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................62 
8.3.5. 
Pregnancy ........................................................................................................................63 
8.3.6. 
Events of Special Interest................................................................................................63 
8.4. 
Pharmacokinetic Assessments ........................................................................................64 
8.5. 
Genetics ..........................................................................................................................64 
8.6. 
Biomarker Assessments (USA Only) .............................................................................65 
8.7. 
Immunogenicity Assessments.........................................................................................65 
8.8. 
Health Economics ...........................................................................................................65 
9. 
Statistical Considerations .............................................................................................66 
9.1. 
Statistical Hypotheses .....................................................................................................66 
9.1.1. 
Multiplicity Adjustment and Type I Error Rate ..............................................................66 
9.2. 
Analysis Sets ...................................................................................................................68 
9.3. 
Statistical Analyses .........................................................................................................68 
9.3.1. 
General Considerations ...................................................................................................68 
9.3.2. 
Primary Endpoint and Estimand .....................................................................................69 
9.3.3. 
Secondary Endpoints and Estimands ..............................................................................70 
9.3.4. 
Exploratory Endpoints ....................................................................................................71 
9.3.5. 
Safety Analyses ...............................................................................................................71 
9.4. 
Interim Analysis and Early Stopping Rules ....................................................................71 
9.5. 
Sample Size Determination ............................................................................................72 
10. 
Supporting Documentation and Operational Considerations ..................................73 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .............................................73 
10.1.1. Regulatory and Ethical Considerations ...........................................................................73 
10.1.2. Financial Disclosure........................................................................................................73 
10.1.3. Informed Consent Process ..............................................................................................74 
10.1.4. Data Protection................................................................................................................74 
10.1.5. Dissemination of Clinical Study Data.............................................................................75 
10.1.6. Monitoring and Data Quality Assurance ........................................................................75 
10.1.7. Source Documents ..........................................................................................................76 
10.1.8. Study and Site Start and Closure ....................................................................................77 
10.1.9. Publication Policy ...........................................................................................................78 
10.2. 
Clinical Laboratory Tests................................................................................................79 
10.3. 
AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................81 
10.3.1. Definition of AE .............................................................................................................81 
10.3.2. Definition of SAE ...........................................................................................................82 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................83 
10.3.4. Reporting of SAEs ..........................................................................................................85 
10.4. 
Contraceptive and Barrier Guidance ...............................................................................86 
10.4.1. Definitions.......................................................................................................................86 
10.4.2. Contraception Guidance..................................................................................................87 
10.5. 
Liver Safety: Required Actions and Follow-up Assessments and 
Study Drug Restart/Rechallenge Guidelines ..................................................................89 
10.6. 
Abbreviations and Definitions ........................................................................................92 
10.7. 
Lesion Count ...................................................................................................................95 
10.8. 
Erythema Score ...............................................................................................................96 


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ACELYRIN Izokibep Protocol 21102 
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7 
10.9. 
Numeric Rating Scale Patient Global Assessment of Skin Pain ....................................97 
10.10. 
Daily Subject Analgesic (Pain) Use Diary – Example ...................................................98 
10.11. 
Hidradenitis Suppurativa Patient Global Impression of Change ....................................99 
11. 
References ....................................................................................................................100 
 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
8 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2b Pivotal Study to Evaluate the Efficacy and Safety of Izokibep in 
Subjects with Moderate to Severe Hidradenitis Suppurativa 
Brief Title: Hidradenitis Suppurativa Phase 2b Pivotal Study of Izokibep 
Rationale: 
Izokibep is a small protein molecule that acts as a selective, potent inhibitor of interleukin 17A 
(IL-17A), to which it binds with high affinity. This study investigates izokibep in subjects with 
moderate to severe hidradenitis suppurativa (HS) and is intended to be one of 2 adequate and 
well-controlled studies to support a claim of efficacy of izokibep in subjects with HS. 
Overall Design: 
This is a phase 2b pivotal, multi-center, dose-finding study to evaluate the efficacy, safety, and 
immunogenicity of izokibep in subjects with moderate to severe HS. Subjects must have HS 
lesions present in ≥ 2 distinct anatomic areas, one of which is Hurley Stage II or Hurley Stage III 
and a total abscess and inflammatory nodule count of ≥ 5. Subjects with draining fistula count of 
> 20 at screening will be excluded. 
This study consists of 2 parts. Part A is an exploratory open-label, single-arm investigation in 
which a minimum of 20 and up to 30 subjects will be enrolled. Once Part A is fully enrolled, 
subsequent subjects will be enrolled into Part B. Part B is a randomized, double-blind, 
placebo-controlled, parallel-group, dose-finding investigation in which approximately 
170 subjects will be enrolled. 
This study will be conducted at study sites in North America and Europe. Additional sites and 
regions may be added. 




CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
10 
Objectives 
Endpoints 
• Percentage of subjects achieving at least 
3-point reduction from baseline in NRS 
in Patient Global Assessment of Skin 
Pain at its worst at Week 16 among 
subjects with baseline NRS ≥4 
• NRS in Patient Global Assessment 
of Skin Pain at its worst at 
Week 16 
To assess the safety and tolerability of izokibep 
as measured by the incidence of TEAEs, events 
of interest, SAEs, and clinically significant 
laboratory values and vital signs  
• TEAEs, events of interest, and 
SAEs 
• Laboratory values and vital signs 
at collected timepoints 
To assess the immunogenicity of izokibep as 
measured by the presence of ADAs  
• ADAs 
ADAs = anti-drug antibodies; AN = abscess and inflammatory nodule; HiSCR = hidradenitis suppurativa clinical 
response; HS = hidradenitis suppurativa; IHS4 = International Hidradenitis Suppurativa Severity Score; 
NRS = numeric rating scale; SAE = Serious Adverse Event; TEAE = treatment-emergent adverse event 
1 HiSCR50/75/90/100 is defined as at least a 50%, 75%, 90%, or 100% reduction from baseline in the total AN 
count, with no increase from baseline in abscess or draining fistula count. 
2 Flare is defined as ≥ 25% increase in AN count with a minimum increase of 2 AN relative to baseline. 
 
Brief Summary: 
Overall, approximately 200 subjects with moderate to severe HS will be enrolled. 
Part A is an open-label, single-arm, investigation consisting of up to a 28-day screening period, a 
31-week treatment period and a follow-up period that includes 2 visits to be completed by all 
subjects at Week 39 and Week 45. For subjects who early terminate, the follow-up visits should 
be completed 8 weeks (± 5 days) and 14 weeks (± 5 days) after the last dose of study drug. A 
minimum of 20 subjects and up to 30 subjects meeting eligibility criteria will be enrolled into 
Part A (Group 0). Subjects will be assigned to treatment with open-label izokibep subcutaneous 
(SC) 160 mg every week (QW) from Day 1/Week 0 to Week 31. Once enrollment in Part A has 
finished, enrollment will begin into Part B. 
Part B is a randomized, double-blind, placebo-controlled, parallel-group, dose-finding 
investigation to evaluate the efficacy, safety, and immunogenicity of izokibep in subjects with 
moderate to severe HS. Subjects will complete up to a 28-day screening period, followed by a 
16-week double-blind treatment period. At completion of the Week 16 visit procedures, subjects 
randomized to placebo will be switched to active treatment in a blinded manner for the Week 16 
dose through Week 30 (Q2W dose group) or Week 31 (QW dose group). Subjects randomized to 
izokibep will remain on the same dose through Week 30 (Q2W dose group) or Week 31 (QW 
dose group). After their respective treatment periods, all subjects will enter a follow-up period 
that includes 2 visits to be completed at Week 39 and Week 45. For subjects who early 
terminate, the follow-up visits should be completed 8 weeks (± 5 days) and 14 weeks (± 5 days) 
after the last dose of study drug. 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
11 
In Part B, approximately 170 subjects will be randomized into 1 of 4 groups in a 1:1:2:2 ratio as 
follows: 
• Group 1 (n = 28-29): placebo SC QW from Day 1 (Week 0) to Week 15, then izokibep 
SC 160 mg QW from Week 16 to Week 31. 
• Group 2 (n = 28-29): placebo SC every other week (Q2W) from Day 1 (Week 0) to 
Week 14, then izokibep SC 160 mg Q2W from Week 16 to Week 30. 
• Group 3 (n = 56-57): izokibep SC 160 mg QW from Day 1 (Week 0) to Week 31. 
• Group 4 (n = 56-57): izokibep SC 160 mg Q2W from Day 1 (Week 0) to Week 30. 
Randomization will be stratified by any prior biologic/Janus Kinase (JAK) inhibitor use for HS 
(Yes/No) and Hurley Stage (II or III). 
Subjects will complete study assessments according to the study visits outlined in the Schedule 
of Assessments. Day 1 corresponds to the first dose of study drug. All visits will be scheduled 
based on the Day 1 visit. 
The primary endpoint will be assessed at Week 16 in Part B only. The last dose of study drug 
will be administered on Week 31 for QW dosing groups and at Week 30 for Q2W dosing groups. 
Number of Subjects: 
Approximately 200 subjects will be enrolled in the study. 
Study Drug Groups and Duration: 
• Group 0 (n = minimum 20 subjects and up to 30 subjects): izokibep SC 160 mg QW from 
Day 1/Week 0 to Week 31. 
• Group 1 (n = 28-29): placebo SC QW from Day 1 (Week 0) to Week 15, then izokibep 
SC 160 mg QW from Week 16 to Week 31. 
• Group 2 (n = 28-29): placebo SC every other week (Q2W) from Day 1 (Week 0) to 
Week 14, then izokibep SC 160 mg Q2W from Week 16 to Week 30. 
• Group 3 (n = 56-57): izokibep SC 160 mg QW from Day 1 (Week 0) to Week 31. 
• Group 4 (n = 56-57): izokibep SC 160 mg Q2W from Day 1 (Week 0) to Week 30. 
Study drug doses are fixed and will not be adjusted for individual subjects during the study. 
Subjects assigned to placebo SC QW and placebo SC Q2W will be grouped together into a single 
placebo group for comparison to each dosing regimen of izokibep for Part B. 
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. 
The DMC will consist of at least one medical expert with the relevant therapeutic area expertise 
and at least one statistician. The DMC will also have a minimum of 3 members, one of whom 
will serve as the Chair. 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. 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
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12 
Part A 
The DMC will review data in Part A, after all subjects have had the opportunity to complete the 
Week 8 visit (or discontinued the study early). Based on this review, the DMC may recommend 
continuing, stopping, or altering Part B. 
Part B 
In Part B, no formal interim analysis is planned for the purpose of stopping or altering this study. 
The DMC will review unblinded data when the first approximately 105 subjects randomized into 
Part B have had the opportunity to complete the Week 8 visit to make a recommendation on 
further development activities for izokibep. The DMC will not be empowered to recommend 
stopping this study or changing the sample size due to a demonstration of positive efficacy. The 
type I error rate for hypothesis tests at the end of the study will be decreased by 0.0001 to 
account for this interim summary of unblinded data. The study team and the investigators will 
remain blinded to these interim results until after the study is completed. After all subjects have 
had the opportunity to complete the Week 16 assessment in Part B, the analysis of the primary 
endpoint may be completed. Site staff and all members of the study team who interact with site 
staff will remain blinded to individual subject treatment assignment until all subjects have 
completed all visits in the study. 
Statistical Considerations 
Data from Parts A and B will be summarized separately. Objectives and statistical hypotheses 
will be addressed using data from Part B only. The treatment policy estimand will be used in 
general for efficacy data, with all treated subjects contributing to Part A and all randomized 
subjects contributing to Part B. All treated subjects will contribute to safety analyses in both 
Parts A and B. 
For comparisons of izokibep to placebo in Part B, the 2 dosing regimens of izokibep (QW and 
Q2W) will be compared separately to placebo. The 2 placebo dosing regimens (QW and Q2W) 
will be combined for comparison to each izokibep dosing regimen. Binary endpoints including 
the primary endpoint of HiSCR rate will be compared with a stratified test of risk difference. 
Continuous endpoints will be compared with a repeated measures mixed model. 
Safety data will be summarized separately for Part A and Part B. Adverse events, serious adverse 
events, and laboratory data will be summarized. 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
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13 
1.2. 
Schema 
 
 
EOS = end of study; FU = follow-up; QW = once weekly; Q2W = every other week 
a Randomization will be stratified by any prior biologic/Janus Kinase (JAK) inhibitor use for hidradenitis suppurativa (Yes/No) and Hurley Stage (II or III). 
b Two follow-up visits will be completed by all subjects at Week 39 (± 5 days) and Week 45 (± 5 days). For subjects who early terminate, the follow-up visits 
should be completed at 8 weeks (± 5 days) and 14 weeks (± 5 days) after the last dose of study drug. 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
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14 
1.3. 
Schedule of Activities for Part A and Part B 
 
 
 
Follow-upb 
Procedures 
Screen 
Treatment Period (weeks)a 
8 weeks 
after 
last 
dose 
14 weeks 
after last 
dose/EOS 
 
≤ 28 d 
prior 
to d1 
0 
(d1)  1 
2 
3a 
4 
8 
12 
13a 
14 
15a 
16  
17a 
18 
20 
24 
28 
32 
or 
ETp 
39 
45 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hurley staging 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication 
history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and nicotine use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
AE reportingf (through 
4 weeks after last dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE reportingf (through 
8 weeks after last dose) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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ET = early termination; HADS = Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus; HS-PGIC = HS Patient 
Global Impression of Change; NRS = Numeric Rating Scale; PGA = Physician’s Global Assessment; PK = pharmacokinetic; PPD = purified protein derivative; 
Q2W = every other week; QW = once weekly; SAE = serious adverse event; SF-12 = 12-Item Short Form Survey; TB = tuberculosis; WOCBP = women of 
childbearing potential. 
a Visit/dosing windows of ±3 days on either side of the scheduled visits/dosing are permitted; however, the investigator should try to keep the subjects on the 
original visit/dosing schedule. 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. For QW dosing, the time between doses 
should be no less than 4 days and no more than 10 days. For Q2W dosing, the time between doses should be no less than 11 days and no more than 17 days. 
Study visits for QW dosing are not required at Weeks 5 to 7, 9 to 11, 18, 19, 21 to 23,25 to 27, or 29 to 31 if subject/caregiver completes study drug 
administration at home. Subjects randomized to Q2W arms are not required to complete visits on Weeks 1, 3, 13, 15, and 17. Study visits for Q2W dosing not 
required at Weeks 6, 10, 22, 26, or 30 if subject/caregiver completes study drug administration at home. See footnotes n and o below. 
b The follow-up period consists of 2 visits to be completed by all subjects at Week 39 and Week 45. For subjects who early terminate, the follow-up visits should 
be completed 8 weeks (± 5 days) and 14 weeks (± 5 days) after the last dose of study drug. 
c 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 of rest. 
d Electrocardiograms in triplicate will be recorded after subject has been supine for at least 5 minutes. 
e Chest x-ray (posterior/anterior or anterior/posterior) will be performed at screening for subjects who do not have a chest x-ray available within 3 months of 
screening. Women of childbearing potential must have negative pregnancy test before x-ray is performed. 
f Serious adverse events will be recorded from the signing of informed consent through the 8-week 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. 
g Confirm ongoing antiseptic wash requirement at every visit. From Screening through Week 16, subjects will complete a daily diary of their analgesic use. From 
Week 16 through Week 32, subjects will be required to tell site staff if they took any analgesics within 24 hours of their site visit. See Section 10.10. Subjects 
will refrain from taking analgesics 12 hours before the site visit, if possible. 
h Lesion count will be performed at every study visit marked in the Schedule of Activities and must address all relevant anatomical regions in each subject. The 
AN count includes counts of draining tunnels (fistulas and sinuses). See Section 8.1.1 for more details. Any unscheduled visit for disease worsening based on the 
investigator judgment will include AN count and will be recorded in the appropriate CRF. 
i From screening through Week 16, subjects will complete a daily diary of their skin pain. See Section 8.1.5. No in-site assessment of skin pain will be completed 
at the Week 16 visit. From Week 16 through Week 32, subjects will complete skin pain assessments at the site. Note: subjects may not be randomized if pain 
diaries are not completed for ≥ 3 out of 7 days (at a minimum) prior to the Day 1 visit. 
j For subjects who consent to the optional photography substudy at selected sites, photographs will be taken. 
k QuantiFERON® test or PPD test 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 women of childbearing potential. 
m Pharmacokinetic and ADA blood sampling will be taken prior to administration of study drug (pre-dose) on dosing days. 
n Administration of study drug should be done last after all study procedures unless indicated otherwise. Subjects will be monitored at the study site for at least 
one hour after study drug administrations at the following visits: for subjects enrolled to QW arms, on Day 1 and Weeks 1, 16, and 17; for subjects enrolled to 
Q2W arms, on Day 1 and Weeks 2, 16, and 18. After Week 4, qualified 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 (QW dosing) or 
Week 6 (Q2W dosing). Subjects will be trained on study drug handling and self-administration of study drug at the study visits prior to beginning 
self-administration. A subject’s caregiver or designee can also be trained on home dosing based on the subject’s preference. Study-site staff will administer study 
drug at the first 2 visits. Thereafter, if home dosing is a consideration, the subject or subject's caregiver or designee must administer and demonstrate competency 


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for at least 2 visits prior to being allowed to dose at home. Otherwise, the subject will need to return to the site for all injections. The last dose of study drug for 
subjects dosed QW is Week 31 and for subjects dosed Q2W is Week 30. 
o A dosing diary will be completed for every home dosing administration. 
p Subjects who end the study early will complete an early termination visit and complete the procedures described at the Week 32 visit within 2 weeks of the last 
dose of study drug. 
 


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2. 
Introduction 
Izokibep is a potent and selective inhibitor of interleukin 17A (IL-17A) that is being developed 
for treatment of hidradenitis suppurativa (HS). 
2.1. 
Study Rationale 
Izokibep is a small protein molecule that acts as a selective, potent inhibitor of IL-17A, to which 
it binds with high affinity. Izokibep has been investigated in non-clinical and clinical studies 
including healthy volunteers and subjects with psoriasis and psoriatic arthritis (PsA) and is 
currently being studied in uveitis, PsA and axial spondyloarthritis. The current phase 2b, 
double-blind, randomized, placebo-controlled, dose-finding study will evaluate the efficacy, 
safety, and immunogenicity of izokibep administered subcutaneously (SC) in adult subjects with 
moderate to severe HS. This is intended to be one of 2 adequate and well-controlled studies to 
support a claim of efficacy of izokibep in subjects with HS. 
2.2. 
Background 
2.2.1. 
Disease Background 
Hidradenitis suppurativa is a chronic inflammatory skin disease characterized by occlusion of 
hair follicles as a primary pathogenic factor associated with a chronic cycle of inflammation, 
healing, and scarring (Sabat et al, 2020). A recent meta-regression analysis found an overall HS 
prevalence of 0.40% (95% confidence interval [CI]: 0.26%-0.63%) among the populations 
studied around the world (Jfri et al, 2021). In a population-based analysis, the overall point 
prevalence of HS in the United States (US) was 0.10%, or 98 per 100 000 persons. Prevalence 
was highest among women (137 per 100 000), those aged 30 to 39 years (172 per 100 000), and 
African American (296 per 100 000) and biracial (218 per 100 000) patient groups (Garg et al, 
2017). Patients with HS develop painful inflamed nodules, abscesses, and pus-discharging tracts 
and fistulas, which typically occur in skin folds of axillary (armpits), inguinal (groin), gluteal and 
perianal areas of the body. Hidradenitis suppurativa causes severe pain, purulent secretions that 
smell bad, and movement restrictions that have a profound negative influence on patients’ lives 
(Sabat et al, 2020). 
A genetic predisposition, smoking, obesity, and hormonal factors are established etiological 
factors for HS. Cutaneous changes begin around hair follicles and involve activation of cells of 
the innate and adaptive immune systems, with pivotal roles for proinflammatory cytokines such 
as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17 (Sabat et al, 2020). 
Clinical management of HS is challenging and consists of both medical and surgical approaches. 
Topical therapies, systemic antibiotics, hormonal therapies, and immunosuppressant medications 
have been used. However, there are patients where HS remains resistant to conventional 
treatment particularly those with moderate to severe disease (Alikhan et al, 2019). The TNF-α 
inhibitor, adalimumab is currently the only approved biologic immunomodulator by the US Food 
and Drug Administration for treating moderate to severe HS (HUMIRA® USPI 2021). Only 
around 50% of subjects achieved a clinical response at Week 12 in the 2 randomized, 
double-blind, placebo-controlled studies of adalimumab in a total of 633 adult subjects with 


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moderate to severe HS. During the second part of both studies (up to 36-week treatment 
duration), approximately 40% of subjects who initially responded to adalimumab weekly therapy 
continued to benefit from this drug (Kimball et al, 2016a). 
In summary, there continues to be a significant unmet medical need for additional therapies to 
treat patients with HS. Additional therapies are needed to manage pain, abscess formation, and 
disease progression. In addition, given the significant reduction in quality of life and functional 
impairment experienced by patients diagnosed with HS, there is an unmet need for medical 
therapies that can have a substantial impact on improving a patient’s quality of life. 
2.2.2. 
IL-17 
A broad range of immune mediators are highly expressed in established HS lesions compared 
with healthy control skin. Patients with HS have imbalances in the T-helper 17 cell (Th17) axis 
that are similar to those in patients with psoriasis (Wolk et al, 2020). They have high serum 
levels of the proinflammatory cytokine IL-17A, which leads to neutrophil recruitment and 
provides positive feedback to maintain the population of proinflammatory Th17 cells 
(Matusiak et al, 2017). These imbalances improved in patients treated with TNF-α inhibitors. It 
is hypothesized that by reducing circulating IL-17A, anti-IL-17A inhibitors like izokibep may 
also provide benefit for patients with HS. Clinical evidence for this benefit comes from 
2 open-label trials with secukinumab 300 mg and brodalumab 270 mg, where 70% of 20 patients 
and 100% of 10 patients responded at 24 weeks based on the Hidradenitis suppurativa Clinical 
Response (HiSCR) (Casseres et al, 2020; Frew et al, 2020). In addition, bimekizumab 320 mg 
dosed every 2 weeks appeared to deliver greater efficacy than adalimumab dosed based on the 
prescribing information, at 12 weeks based on the HiSCR75 and HiSCR90 responses (Glatt et al, 
2021). Phase 3 trials in patients with HS for secukinumab and bimekizumab are underway. 
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 (Affibody® molecule) binding to and blocking the biological 
effect of the cytokine IL-17A. The izokibep protein molecule also contains an albumin binding 
domain, which confers specific binding to a single site on endogenous serum albumin and 
thereby a prolonged half-life 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 and PsA. These include secukinumab (Cosentyx®) 
and ixekizumab (Taltz®) in the US, Canada, and the European Union. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of izokibep is 
provided in the investigator’s brochure. 


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2.2.3.1. 
Non-clinical 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 pharmacodynamics 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. 
Pharmacokinetic (PK) data for intravenously (IV) and 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 day to 3 month) SC or IV administration of izokibep to cynomolgus monkeys was 
well tolerated with no observed adverse effect levels (NOAELs) of 40 mg/kg/dose (IV, 28-day 
study) and 20 mg/dose (SC, 28-day study) and 20 mg/kg/week (SC, 3-month study), being the 
highest dose levels tested in the respective studies. 
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 one 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 post-natal 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 No. 2015-004531-13, 
NCT02690142) has been conducted with the parenteral formulation of izokibep. Izokibep was 
administered IV and SC to healthy subjects and subjects with plaque psoriasis, in doses ranging 
from 2 to 40 mg in a single or multiple dose regimen. 
A phase 2 clinical trial in 108 randomized and treated subjects with moderate to severe plaque 
psoriasis is ongoing (Study ABY-035-002, EudraCT No. 2017-001615-36, NCT03591887). 
Study ABY-035-002 is a dose-finding trial comparing 2-, 20-, 80- and 160-mg dose SC izokibep 
groups to placebo for 48 weeks of treatment (52-week core study). The 52-week core study has 
been completed and results are summarized in the investigator’s brochure. The primary endpoint 
of the study was the proportion of subjects that achieved a Psoriasis Area and Severity Index 
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 every other week (Q2W) of izokibep 
respectively. In the lower dose groups, 2 mg and 20 mg izokibep, only 5.0% and 19.0% of 


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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- and 160-mg treatment groups. Safety and efficacy data obtained from this 52-week 
core study izokibep suggest a favorable benefit-risk profile in plaque psoriasis (investigator’s 
brochure). 
In HS, data from adalimumab and bimekizumab clinical studies demonstrate that exposures are 
lower for HS as compared to other indications, such as plaque psoriasis (Kimball et al, 2016a; 
Glatt et al, 2021). In addition, there is evidence that clinical responses do increase as the dose of 
adalimumab is increased to double the approved dose (Zouboulis et al, 2020). This suggests 
higher exposures are important to optimize clinical benefit in patients with HS. As reviewed 
below, there is no dose-limiting adverse events (AEs) for izokibep which supports 160 mg once 
weekly (QW) and 160 mg Q2W dosing (see Section 4.2). 
2.2.3.3. 
Safety Overview 
In the first in human clinical 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) was well tolerated, 
with no deaths or treatment related serious adverse events (SAE). 
Intravenous administration (single doses up to 40 mg in 46 subjects in total) resulted in the 
following TEAEs by preferred term: oropharyngeal pain (10.9%), nasopharyngitis (6.5%), 
diarrhea (4.3%), and headache (4.3%). A further 9 TEAEs were reported, affecting one subject 
each (2.2% each). Subcutaneous administration (single and multiples 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, affecting one 
subject each (5.2% each). The majority of the injection site reactions were of mild intensity. 
In the phase 2, 52-week core period in subjects with plaque psoriasis (ABY-035-002), multiple 
doses of up to 160 mg SC of izokibep (n = 108) were well tolerated with no deaths or 
treatment-related SAE. A total of 65 subjects (60.2%) experience at least 1 izokibep-related 
TEAE. The most common izokibep-related TEAEs (n/%) were injection site reaction 
(42/38.9%), nasopharyngitis (13/12%), diarrhea (7/6.5%), and fatigue (6/5.6%) consistent with 
the first in human study. 
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, 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 bi-phasic 
manner with the geometric mean half-life (t½) being 278 hours which was similar to that after IV 
administration (288 hours). Individual t½ estimates ranged from 199 to 464 hours and 220 to 
340 hours for SC and IV treatments, respectively. In general, as assessed by the geometric 
percent coefficient of variation (CV%) low between-subject variability was noted for area under 
the plasma concentration-time curve from time zero to infinity (AUC0-∞) and Cmax for both dose 
routes, with values ranging from 19.7% to 21.6% and 13.6% to 15.4%, respectively. 


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Following 40 mg SC repeated doses, maximum plasma concentrations occurred at a median tmax 
of 48.0 hours post dose on Days 1 and 29 (individual range: 24.0 to 71.0 hours post dose). On 
Day 85, median tmax was slightly later at 71.6 hours post dose (individual range: 66.6 to 
73.1 hours post dose). After reaching Cmax on Day 85, plasma concentrations of izokibep 
declined in an apparent mono- or bi-phasic manner with a geometric mean t½ of 279 hours with 
individual subjects ranging from 229 to 423 hours. Pre-dose 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 area under the plasma concentration-time 
curve over a dosing interval (AUC0-τ), of 1.95, and individual subjects ranging from 1.35 to 5.09. 
Between-subject variability, based on geometric CV%, was moderate on all trial 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 and ixekizumab as well as izokibep 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 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 inflammatory bowel disease (IBD). 
See Section 8.3.6 for the list of potential risks of IL-17 inhibitors. 
• 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: 
o 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 trial 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. 


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2.3.2. 
Benefit Assessment 
The potential benefit of izokibep is that it is designed to demonstrate whether treatment is 
associated with a reduction in the extent of inflammation in patients with moderate to severe HS, 
manifested as a specific reduction in the number of inflammatory nodules and abscesses. As 
these inflammatory lesions are associated with considerable pain and impairment in quality of 
life, a reduction in the number of such lesions could directly benefit patients. 
Safety, efficacy, and PK data obtained in clinical trials with izokibep in healthy volunteers and in 
subjects with psoriasis and PsA suggest a favorable benefit-risk profile in HS. Based on 
published data showing efficacy and safety for other IL-17 inhibitors, including in patients with 
HS, the benefit-risk relationship also in patients with HS appears favorable and justifies clinical 
development of izokibep in HS as well. Due to its small molecular size as compared to 
monoclonal antibodies and its binding to albumin, izokibep may have the potential to better 
reach inflamed tissues and may provide higher exposure relative to monoclonal antibodies. 
A 16-week placebo-controlled period does not entail any additional risk of irreversible harm to 
subjects. Specified analgesics are permitted for HS-associated pain, and for subjects with 
increases in abscess and inflammatory node counts (≥ 150% of Day 1 abscess and inflammatory 
nodule [AN] count), investigators may provide permitted oral antibiotic rescue therapy. 
Additionally, subjects with a draining fistula count > 20 at the baseline visit are excluded from 
enrolling in the study to exclude the most severe forms of the disease that may place subjects at a 
higher risk of disease-related complications. 
The investigator is referred to the current investigator's brochure where additional and more 
detailed information (including non-clinical 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 moderate to severe HS will be enrolled. Subjects must have HS 
lesions present in at least 2 distinct anatomic areas, one of which is Hurley Stage II or 
Hurley Stage III and AN count of ≥ 5. However, subjects with draining fistula count of 
> 20 at screening will be excluded. 
• 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 or with a history of 
autoimmune, chronic inflammatory, or connective tissue disease will be excluded from 
participating in the study. 
• Subjects will be monitored at the study site for at least one hour after the first 2 study 
drug administrations of izokibep. 
• After enrollment and through the end of the study if the subject’s AN count is ≥ 150% of 
Day 1 AN count, antibiotic rescue medication is permitted. 


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• In Part B of the study, placebo treatment will be limited to 16 weeks. After Week 16, 
subjects randomized to placebo will begin blinded active treatment (izokibep 160 mg) in 
order to potentially derive benefit from the disease-relevant effect of IL-17 inhibition. 
• Participation in the trial is voluntary. Each subject may refuse to participate or withdraw 
from the trial, 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, 
and the lack of clear dose-limiting AEs associated with izokibep, the pre-existing data on the 
effects of IL-17 inhibitors in hidradenitis, the potential risks identified in association with 
izokibep are justified by the anticipated benefits that may be afforded to subjects with HS. 
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 risk-benefit 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 
• IHS4, after 4, 8, 12, 16, 24, and 32 
weeks of treatment 
• IHS4 scores at Weeks 4, 8, 12, 16, 
24, and 32 
• Hidradenitis Suppurativa-Physician’s 
Global Assessment (HS-PGA) 
• Change from baseline to Week 16 
in HS-PGA 
To explore the effect of izokibep on PROs as 
measured by change from baseline over time in: 
• EQ-5D 
 
• Change from baseline to Week 16 
in EQ-5D 
• DLQI  
• Change from baseline to Week 16 
in DLQI 
• HADS 
• Change from baseline to Week 16 
in HADS, HADS-anxiety and 
HADS-depression  
To evaluate the pharmacokinetics of izokibep in 
subjects with HS 
• Trough plasma concentrations of 
izokibep at collected timepoints 
ADAs = anti-drug antibodies; AN = abscess and inflammatory nodule; DLQI = Dermatology Life Quality Index; 
EQ-5D = European Quality of Life-5 Dimensions; HADS = Hospital Anxiety and Depression Scale; 
HiSCR = hidradenitis suppurativa clinical response; HS = hidradenitis suppurativa; IHS4 = International 
Hidradenitis Suppurativa Severity Score; NRS = numeric rating scale; PRO = patient-reported outcomes; 
SAE = Serious Adverse Event; TEAE = treatment-emergent adverse event. 
1 HiSCR50/75/90/100 is defined as at least a 50%, 75%, 90%, or 100% reduction from baseline in the total abscess 
and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count. 
2 Flare is defined as ≥ 25% increase in AN count with a minimum increase of 2 AN relative to baseline. 
 
Primary estimand 
Please refer to Section 9.3.2. 
Secondary estimand(s) 
Please refer to Section 9.3.3. 


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4. 
Study Design 
4.1. 
Overall Design 
This is a phase 2b pivotal, multi-center, dose-finding study to evaluate the efficacy, safety, and 
immunogenicity of izokibep in subjects with moderate to severe HS. 
This study consists of 2 parts, Part A and Part B as described below. 
4.1.1. 
Part A: Single-arm, Open-label 
Part A is a single-arm, open-label, proof-of-concept investigation to explore preliminary efficacy 
and safety of izokibep in adult subjects with moderate to severe HS. Part A consists of up to a 
28-day screening period, a 31-week treatment period and a follow-up period that includes 2 visits 
to be completed by all subjects at Week 39 and Week 45. For subjects who early terminate, the 
follow-up visits should be completed 8 weeks (± 5 days) and 14 weeks (± 5 days) after the last 
dose of study drug. A minimum of 20 subjects and up to 30 subjects will be enrolled into Part A 
and treated with izokibep SC 160 mg QW (Group 0). 
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. 
After enrollment and through the end of the study if the subject’s AN count is ≥ 150% of Day 1 
AN count, antibiotic rescue medication is permitted (Section 6.8.3). 
Once Part A is fully enrolled, subsequent subjects will be enrolled into Part B. 
4.1.2. 
Part B: Randomized, Double-blind, Dose-finding 
Part B is a randomized, double-blind, placebo-controlled, parallel-group, dose-finding 
investigation to evaluate the efficacy, safety, and immunogenicity of izokibep in subjects with 
moderate to severe HS. Subjects will complete up to a 28-day screening period, followed by a 
16-week double-blind treatment period. At completion of the Week 16 visit procedures, subjects 
randomized to placebo will be switched to active treatment in a blinded manner for the Week 16 
dose through Week 30 (Q2W dose group) or Week 31 (QW dose group). Subjects randomized to 
izokibep will remain on the same dose through Week 30 (Q2W dose group) or Week 31 (QW 
dose group). After their respective treatment periods, all subjects will enter a follow-up period 
that includes 2 visits to be completed at Week 39 and Week 45. For subjects who early 
terminate, the follow-up visits should be completed 8 weeks (± 5 days) and 14 weeks (± 5 days) 
after the last dose of study drug. 
Approximately 170 subjects will be randomized into 1 of 4 groups in a 1:1:2:2 ratio as follows: 
• Group 1 (n = 28-29): placebo SC QW from Day 1 (Week 0) to Week 15, then izokibep 
SC 160 mg QW from Week 16 to Week 31. 
• Group 2 (n = 28-29): placebo SC Q2W from Day 1 (Week 0) to Week 14, then izokibep 
SC 160 mg Q2W from Week 16 to Week 30. 
• Group 3 (n = 56-57): izokibep SC 160 mg QW from Day 1 (Week 0) to Week 31. 
• Group 4 (n = 56-57): izokibep SC 160 mg Q2W from Day 1 (Week 0) to Week 30. 


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Randomization will be stratified by any prior biologic/Janus Kinase (JAK) inhibitor use for HS 
(Yes/No) and Hurley Stage (II or III). 
Subjects will complete study assessments according to the study visits outlined in the SoA. 
Subjects in the QW dosing groups (Group 0 [Part A], Groups 1 and 3 [Part B]) will have study 
visits at screening, Day 1 (Week 0), and at Weeks 1, 2, 3, 4, 8, 12, 13, 14, 15, 16, 17, 20, 24, 28, 
and 32 as well as at the follow-up visits. 
Subjects in the Q2W dosing regimens (Groups 2 and 4 in Part B) will have study visits at 
screening, Day 1 (Week 0), and at Weeks 2, 4, 8, 12, 14, 16, 18, 20, 24, 28, and 32 as well as at 
the follow-up visits. 
Subjects assigned to placebo SC QW and placebo SC Q2W will be grouped together into a single 
placebo group for comparison to each dosing regimen of izokibep for Part B. The primary 
endpoint will be assessed at Week 16. 
After randomization and through the end of the study if the AN count is ≥ 150% of Day 1 AN 
count, antibiotic rescue medication is permitted (Section 6.8.3). 
4.1.3. 
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. 
The DMC will consist of at least one medical expert with the relevant therapeutic area expertise 
and at least one statistician. The DMC will also have a minimum of 3 members, one of whom 
will serve as the Chair. The DMC responsibilities, authorities, and procedure will be documented 
in the DMC charter. Over the course of the study the DMC will meet every 6 months to review 
interim data. After each review, the DMC will make recommendations regarding the 
continuation of the study based on safety. In addition, the DMC will meet as indicated below to 
review data from Part A and Part B. 
Part A 
The DMC will review data in Part A, after all subjects have had the opportunity to complete the 
Week 8 visit (or discontinued the study early). Based on this review, the DMC may recommend 
continuing, stopping, or altering Part B (Section 9.4). 
Part B 
In Part B, no formal interim analysis is planned for purposes of stopping or altering this study 
(Section 9.4). The DMC will review unblinded data when the first approximately 105 subjects 
randomized into Part B have had the opportunity to complete the Week 8 visit to make a 
recommendation on further development activities for izokibep. The DMC will not be 
empowered to recommend stopping this study or changing the sample size due to a 
demonstration of positive efficacy. The type I error rate for hypothesis tests at the end of the 
study will be decreased by 0.0001 to account for this interim summary of unblinded data. The 
study team and the investigators will remain blinded to these interim results until after the study 
is completed. 


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4.1.4. 
Number of Sites 
Approximately 50 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. 
4.1.5. 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.” A minimum of 
20 subjects and up to 30 subjects will be enrolled into Part A and approximately 170 subjects 
will be enrolled/randomized into Part B. Subjects who are withdrawn or removed from 
treatment, or the study will not be replaced. 
4.1.6. 
Study Duration for Subjects 
The maximum planned length of participation in the study for an individual subject is up to 
49 weeks, which includes the following: 
• 
Screening period of up to 28 days (4 weeks) 
• 
31-week treatment period 
• 
Follow-up visit at Week 45 
4.1.7. 
Scientific Rationale for Study Design 
The design of this clinical trial was chosen to evaluate izokibep in subjects with moderate to 
severe HS. Part A is a proof-of-concept, single-arm, open-label part to generate preliminary data 
on the efficacy and safety of izokibep. The purpose of Part B (Weeks 0 to 16) is to provide 
16-week placebo-controlled data demonstrating the safety and efficacy of izokibep administered 
SC at a dose of 160 mg QW and 160 mg Q2W for the treatment of HS. After Week 16, subjects 
randomized to izokibep will continue on the same blinded dosing regimen and subjects 
randomized to placebo will receive blinded active treatment (izokibep 160 mg QW or 160 mg 
Q2W) until Week 31. Long term safety and efficacy beyond Week 16 will be explored from 
Week 16 to Week 32 and will provide information on flares for subjects who achieved HiSCR on 
izokibep during the first 16 weeks of treatment. 
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 moderate to severe HS. 
All clinical and laboratory procedures in this study are standard and generally accepted. 
Males and females ≥ 18 years and ≤ 75 years with moderate to severe HS (AN count of ≥ 5) 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. 
4.2. 
Justification for Dose 
The dose of izokibep in Part A is 160 mg SC QW administered from Day 1 through Week 31. 
The doses of izokibep in Part B are: 160 mg SC QW and 160 mg SC Q2W administered from 
Day 1 through Week 30 (Q2W dosing) and Week 31(QW dosing) in subjects randomized to 


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izokibep. Subjects randomized to placebo will switch to active treatment at Week 16 and will 
receive either izokibep 160 mg QW or 160 mg Q2W until Week 31 or Week 30, respectively. 
The selection of the doses in Part A and Part B is informed by the following facts. Izokibep has 
not demonstrated dose-limiting toxicity up to 160 mg Q2W with multiple doses. A dose of 
160 mg QW has 10-fold margin for Cmax and 9-fold margin for AUCtau based on the NOAEL 
from non-clinical cynomolgus studies (Table 1). Hidradenitis suppurativa patients have achieved 
lower drug exposures compared to patients with other diseases, such as psoriasis, as 
demonstrated for both adalimumab and bimekizumab (Kimball et al, 2016; Glatt et al, 2021). In 
addition, higher doses of adalimumab have been shown to provide greater clinical benefits, 
including on pain, quality of life, and the International Hidradenitis Suppurativa Severity Score 
(IHS4) (Zouboulis et al, 2020). Further it is evident that doses of secukinumab 10 mg/kg 
(approximately 800 mg) IV and 30 mg/kg (2400 mg) IV dosed Q2W for 4 and 2 doses 
respectively in patients with uveitis disclosed no dose related toxicity (Letko et al, 2015). 
Furthermore, based on PK modeling of the izokibep psoriasis data against the available data with 
secukinumab in uveitis, we can approximate the 10 mg/kg exposures seen with secukinumab 
with a weekly injection of izokibep 160 mg as shown in Figure 1 and Table 2 (internal data to 
ACELYRIN). 
Table 1. Cmax and AUCtau at NOAEL in Cynomolgus Monkey vs. Predicted Exposure Levels in 
Humans and Respective Margins 
Parameter 
NOAEL  
in Cynomolgus 
Predicted in Subjects  
at Steady State (QW) 
Margin 
Cmax  
409 µg/mL 
40.8 µg/mL 
10 
AUCtau 
52500 h·µg/mL 
5850 h·µg/mL 
9.0 
AUCtau = area under the curve over a dosing interval; Cmax= maximum observed plasma concentration; h = hour; 
NOAEL = no observed adverse effect level. 
 




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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 (ie, final follow-up visit (ie, 
Week 45). 
 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are 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. Diagnosis of HS for ≥ 1 year prior to first dose of study drug. 
4. Hidradenitis suppurativa lesions present in ≥ 2 distinct anatomic areas (eg, left and 
right axilla; or left axilla and left inguino-crural fold), one of which is Hurley Stage II 
or Hurley Stage III at screening and Day 1 prior to enrollment/randomization. 
5. A total AN count of ≥ 5 at screening and Day 1 prior to enrollment/randomization. 
6. Subject must have had an inadequate response to oral antibiotics (defined as ≥ 3-month 
treatment with an oral antibiotic for treatment of HS) OR exhibited recurrence after 
discontinuation to, OR demonstrated intolerance to, OR have a contraindication to oral 
antibiotics for treatment of their HS as assessed by the investigator through subject 
interview and review of medical history. 
7. Must agree to use daily (throughout the duration of the study) one of the following 
over-the-counter topical antiseptics on their body areas affected with HS suppurativa 
lesions: chlorhexidine gluconate, triclosan, benzoyl peroxide, or diluted bleach in 
bathwater. 
8. Subject must be willing to complete a daily skin pain diary 7 consecutive days prior to 
Day 1; if skin pain diaries are not completed for at least 3 of the 7 consecutive days 
prior to the Day 1 visit, the subject may not be enrolled/randomized.  
Other Inclusions 
9. No known history of active tuberculosis. 
10. Subject has a negative tuberculosis test at screening, as defined by1: 
o Negative QuantiFERON test OR 
o Negative purified protein derivative (PPD) test (< 5 mm of induration at 48 to 
72 hours after test is placed). 


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- Subjects with a positive PPD test and a history of Bacillus 
Calmette-Guerin vaccination will be allowed with a negative 
QuantiFERON test. 
- Subjects with a positive or indeterminate QuantiFERON test are 
allowed if all of the following is satisfied: 
• No symptoms of tuberculosis as determined by investigator. 
• Documented history of adequate prophylaxis initiation prior to 
receiving first dose of study drug. 
• No known exposure to a case of active tuberculosis after most 
recent prophylaxis. 
• No evidence of active tuberculosis on chest radiograph within 
3 months prior first dose of study drug. 
1 T-SPOT® tuberculosis test may be used to establish eligibility if agreed upon with the medical 
monitor. 
Sex and Contraceptive/Barrier Requirements 
11. Male and Female 
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: 
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 fresh unwashed 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 who is not currently pregnant. 
b. Female subjects: 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
o Is a woman of nonchildbearing potential as defined in Section 10.4 (Contraceptive 
and Barrier Guidance) 


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ACELYRIN Izokibep Protocol 21102 
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OR 
o Is a woman of childbearing potential (WOCBP) and using 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 negative urine pregnancy test on Day 1 prior to the first dose of study drug, see 
Section 8.2.5.  
 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Draining fistula count of > 20 at screening or Day 1 prior to enrollment/randomization. 
2. Outpatient surgery ≤ 8 weeks prior or inpatient surgery ≤ 12 weeks prior to 
enrollment/randomization. 
3. Other active skin disease or condition (eg, bacterial, fungal or viral infection) that 
could interfere with study assessments. 
4. Active IBD within 3 years prior to enrollment. 
5. Chronic pain not associated with HS (eg, fibromyalgia). 
6. Uncontrolled, clinically significant system disease such as diabetes mellitus, 
cardiovascular disease including moderate to severe heart failure (New York Heart 
Association class III/IV), moderate to severe renal disease, moderate to severe liver 
disease or hypertension, as determined by investigator. 
7. History of demyelinating disease (including myelitis) or neurological symptoms 
suggestive of demyelinating disease. 
8. 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. 
9. The subject is at risk of self-harm or harm to others as evidenced by past suicidal 
behavior or endorsing items 4 or 5 on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) assessed at screening. Subjects with major depressive disorder are permitted 
in the study if they are considered by the investigator to be stable and are taking no 
more than 1 medication. Subjects must have been on a stable dose within the 3 months 
prior to the first dose of study drug. 
10. 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. 


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11. Exclusion criterion removed with Amendment 1 because it was a duplicate with 
Exclusion criterion 9. 
12. Do not capture Exclusion 12, please select from 13, 14, or 15. Active infection or 
history of infection as follows: 
13. Any active infection for which oral anti-infectives (antibiotics, antivirals, antifungals) 
were used ≤ 14 days prior to first dose of study drug (except for the use of a stable dose 
allowable antibiotics [doxycycline or minocycline only] for HS). 
14. A serious infection requiring hospitalization or IV anti-infectives (antibiotics, 
antivirals, antifungals) ≤ 30 days prior to first dose of study drug. 
15. 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. 
16. Candida infection requiring systemic treatment ≤ 3 months prior to first dose of study 
drug. 
17. Tuberculosis or fungal infection seen on available chest x-ray taken ≤ 3 months of 
screening or at screening (Exception: documented evidence of completed treatment and 
clinically resolved). 
18. Known history of human immunodeficiency virus (HIV). 
 Prior/Concomitant Therapy 
19. Previous exposure to izokibep or any other IL-17 receptor inhibitors (eg, secukinumab, 
ixekizumab, bimekizumab, brodalumab). 
20. Prior exposure to biologics that have a potential for or known association with 
progressive multifocal leukoencephalopathy (ie, natalizumab [Tysabri®], rituximab 
[Rituxan®], or efalizumab [Raptiva®]). 
21. Exposure to TNF-α inhibitors, IL-1, IL-12, IL-23, or IL-12/23 receptor inhibitors 
within 5 half-lives prior to first dose of study drug. 
22. Exposure to any of the following: 
• Exposure to the following ≤ 12 weeks prior to first dose of study drug 
o Other experimental or commercially available biologic or biosimilar therapies 
(within 12 weeks or 5 half-lives, whichever is longer). 
o IV gamma-globulin or Prosorba column therapy. 
• Exposure to the following ≤ 4 weeks prior to first dose of study drug 
o JAK inhibitors (eg, tofacitinib, upadacitinib) 
o Oral or injectable corticosteroids (including intralesional injections) 
o Cyclosporine, azathioprine, tacrolimus 
o Other systemic treatments for autoimmune/inflammatory conditions not listed 
above or below (eg, mycophenolate mofetil, retinoids, fumarates, apremilast, or 
phototherapy [eg, PUVA, UVA, UVB]), except for allowable stable dose 
antibiotics (doxycycline or minocycline) 
o Laser or intense pulse light therapy in anatomic areas of HS lesions 


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ACELYRIN Izokibep Protocol 21102 
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23. Exposure of the following ≤ 2 weeks prior to first dose of study drug: 
• Prescription topical therapies 
• Opioid analgesics 
• Non-oral concomitant analgesics (eg, IV, SC). 
24. For subjects entering study with a permitted oral antibiotic treatment (doxycycline or 
minocycline only) for HS: not on a stable dose for ≥ 4 weeks prior to first dose of study 
drug. 
25. For subjects entering study with oral, non-opioid analgesics: not on a stable dose for 
≥ 5 days prior to first dose of study drug. Exception is acetaminophen is allowed ≤ 2 g 
per day. 
26. Required or is expected to require, opioid analgesics for any reason (excluding 
tramadol) during the study. 
27. History of hypersensitivity or allergy to izokibep or its excipients. 
28. Received live vaccination ≤ 12 weeks prior to dosing or scheduled to receive a live 
vaccine ≤ 12 weeks following the last dose of study drug. 
29. Participating in another clinical study or participated in a clinical study involving 
administration of an investigational medicinal product (IMP) within the following time 
period prior to dosing: 12 weeks, 5 half-lives, or twice the duration of the biological 
effect of the IMP (whichever is longer). 
Diagnostic Assessments 
Laboratory abnormalities and measurements 
30. Positive hepatitis B surface antigen (HBsAg) or detected sensitivity on the hepatitis B 
virus DNA polymerase chain reaction (PCR) qualitative test for hepatitis B core 
antibodies (HBcAb)/Hepatitis B surface antibodies (HBsAb) positive subjects OR 
positive Hepatitis C virus antibody test at screening. 
31. Laboratory abnormalities at screening: 
• Hemoglobin < 9 g/dL 
• Platelet count < 100 000/mm3 
• White blood cell count < 3000 cells/mm3 
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 2.5 times 
the upper limit of normal 
• Moderate or severe renal impairment (ie, CrCL < 60 mL/min) (Modification of Diet in 
Renal Disease [MDRD] formula) 
Note: Laboratory assessments due to value(s) out of range due to sampling error or that could 
be within range with repeat sampling may be repeated up to 2 times. 
32. 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. 


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ACELYRIN Izokibep Protocol 21102 
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40 
Other Exclusions 
33. Previously enrolled, randomized to or withdrawn from this study. 
34. Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study 
drug, as determined by the investigator. 
35. Any condition that compromises the ability of the subject to give written informed 
consent, or the subject’s unwillingness or inability to comply with study procedures. 
 
 
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 (177 mL) glass of wine, a 1 oz (30 mL) 
glass of hard liquor (eg, whiskey) or an 8 oz (237 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 
Subjects 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 case report form (CRF). 


CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
41 
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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CONFIDENTIAL 
ACELYRIN Izokibep Protocol 21102 
Version 4.0 (13 December 2023)
 
 
43 
Please see the Pharmacy Manual for further details on study drug. 
6.1.1.1. 
Part A: Open-label, Single-arm 
• Group 0: open-label izokibep 160 mg QW from Day 1/Week 0 to Week 31 
6.1.1.2. 
Part B: Randomized, Double-blind 
• Group 1: placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg QW from 
Week 16 to Week 31 
• Group 2: placebo Q2W from Day 1/Week 0 to Week 14, then izokibep 160 mg Q2W 
from Week 16 to Week 30 
• Group 3: izokibep 160 mg QW from Day 1/Week 0 to Week 31 
• Group 4: izokibep 160 mg Q2W from Day 1/Week 0 to Week 30 
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 enrolled 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 the 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 
Voice/Web Response System (IXRS). 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 
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 


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assessments due to value(s) out of range due to potential sampling error or that could be within 
range with repeat sampling. 
All subjects who enter the screening period for the study receive a unique subject identification 
number assigned by the IXRS. 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) 
o First 3 digits correspond to the last 3 digits of the study protocol number (ie, 102) 
o 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) 
o Last 3 digits are sequential numbers given to sites within a country (eg, For a US 
site =102840001) 
• Sequential numbering of subjects within a site (last 3 digits) 
o The last 3 digits are sequential numbers assigned by IXRS within a site (eg, For 
US Site 102840001, their first subject = 102840001001) 
A subject who is determined to be ineligible must be registered as a screen fail in the IXRS. 
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; or 
• 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 
other reasons. 
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, 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 
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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, tuberculosis, 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. 
Treatment Assignment/Randomization 
Once a subject is enrolled, the IXRS will assign the subject to either Part A or Part B. Once 
Part A is fully enrolled the IXRS will begin assigning subjects to Part B. 
6.3.3.1. 
Treatment Assignment Part A 
Part A is a single-arm investigation. Subjects will be assigned to open-label study drug (QW) on 
Day 1 by IXRS. 
6.3.3.2. 
Treatment Assignment Part B 
Part B is a double-blind, randomized investigation. Subjects will be randomized to the study drug 
(QW or Q2W) on Day 1 by IXRS. 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. 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) but not to the dosing schedule (QW or Q2W). The randomization dates are 
to be documented in the subject’s medical record. 
Randomization will be stratified by any prior biologic and/or JAK inhibitor use for HS (Yes/No) 
as well as by Hurley Stage (II or III). 
Izokibep and matching placebo will be visually indistinguishable to prevent unblinding during 
preparation or administration of study material. 
Subjects assigned to receive placebo will be randomized in a 1:1 ratio to receive placebo 
administered QW or Q2W. This will allow for blinding of test material, while the treatment 
schedule (QW or Q2W) will not be blinded from the subject or site personnel, and also will not 
be blinded from sponsor staff or designee who have access to administration logs. 
6.3.4. 
Site Personnel Access to Individual Treatment Assignments 
In Part B, a 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. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a subjects’ 
intervention assignment is warranted. Subject safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator is strongly encouraged to contact the sponsor to discuss the situation prior to 
unblinding a subject’s intervention assignment unless this could delay emergency treatment for 
the subject. If a subject’s intervention assignment is unblinded, the sponsor must be notified 
within 24 hours of this occurrence. The date and reason for the unblinding must be recorded. 


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If an SAE requires an expedited regulatory report to be sent to one or more regulatory agencies, 
sponsor/designee’s safety staff may unblind the study drug assignment for the subject. A copy of 
the report, identifying the subject’s study drug assignment, may be sent to that regulatory agency 
in accordance with local regulations. 
Please refer to the Study Pharmacy Manual for details. 
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. 
When study drug(s) is 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. 
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. Study drug dose dates, 
including study drug 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 HS at the end of the clinical trial depends on the subject's individual needs and is left 
at the physician's discretion. 
6.7. 
Overdose 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the CRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. 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: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including route, dose, and frequency 


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Concomitant medications should be used in alignment with the approved label in the respective 
country, and per doses as outlined below. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1. 
Prior Therapies 
Any treatments for HS 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 CRF, along with the reason for discontinuation. 
A detailed history of prior antibiotic and biologic (including but not limited to TNF-α inhibitors, 
IL-1, IL-12, IL-23, or IL-12/23 receptor inhibitors) use, response and reason for discontinuation 
will be collected. 
6.8.2. 
Concomitant Therapies 
Upon initiation or discontinuation of investigational product, investigators should consider 
potential effects on metabolism of cytochrome P450 substrates with narrow therapeutic indexes 
such as methotrexate, tacrolimus, cyclosporine, certain tricyclic antidepressants (including 
amitriptyline and nortriptyline), baricitinib, warfarin and tamoxifen. The concomitant 
medications/treatments in the following sections are permitted during the study. 
6.8.2.1. 
Antiseptic Therapy 
Subjects are required to use an antiseptic wash on their HS lesions daily or at a minimum of 
3 days a week. Antiseptic wash use should be consistent during the study. Allowable antiseptic 
washes are limited to one of the following: chlorhexidine gluconate, triclosan, benzoyl peroxide, 
or dilute bleach in bathwater. If a different antiseptic wash is required during the study, the 
medical monitor should be consulted. 
6.8.2.2. 
Wound Care 
Concomitant use of wound care dressings on HS wounds is allowed; however, options are 
limited to alginates, hydrocolloids, and hydrogels. If a different option for wound care is required 
during the study, the medical monitor should be consulted. 
6.8.2.3. 
Analgesic Therapy 
For subjects entering the study on oral non-opioid analgesic the dose must be stable for ≥ 5 days. 
For a non-HS medical condition (eg, osteoarthritis), the subject may continue the analgesic, 
provided the dose is stable for 5 days prior to the first dose of study drug and is anticipated to 
remain stable throughout study participation. 
If a subject's pain (HS-related or non-HS-related) worsens after Day 1, they may initiate 
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For HS-related pain, permitted analgesics are limited to: 
• Ibuprofen (at a dose of up to 800 mg po every 6 hours) not to exceed 3.2 grams/per 
24 hours; AND/OR acetaminophen/paracetamol as per local labeling. 
• If HS-related pain is uncontrolled with ibuprofen or acetaminophen/paracetamol at the 
above dosing regimens after the Day 1 visit, subjects can be prescribed tramadol (at a 
dose of up to 100 mg po every 4 hours), not to exceed 400 mg per 24 hours. 
• From screening through Week 16, subjects will complete a daily diary of their analgesic 
use (Section 10.10). From Week 16 through Week 32, subjects will be required to tell site 
staff if they took any analgesics within 24 hours of their study-site visit. All analgesics 
and dose adjustments will be captured in the source and on the appropriate CRF. 
• Subjects will be encouraged not to take analgesics 12 hours prior to a study visit. 
For non-HS-related Pain: 
• Opioid analgesics are prohibited. 
• All other analgesics (including tramadol) are allowed at the recommended or prescribed 
dose. 
6.8.2.4. 
Antibiotic Therapy 
In approximately 30% of subjects, concomitant antibiotic use is permitted if dosing regimen has 
been stable for ≥4 weeks prior to first dose of study drug, and dosing regimen is maintained 
through the placebo-controlled period (Week 16 assessment). Antibiotics taken on a PRN basis 
are not considered a stable dose. 
Permitted oral concomitant antibiotics include: 
• Oral: doxycycline (at a dose of up to 100 mg twice daily [BID]); minocycline (at a dose 
of up to 100 mg, BID). 
• If another oral concomitant antibiotic for HS is medically necessary at the time of 
enrollment/randomization, the medical monitor must be contacted for approval. If 
systemic antibiotics are used concomitantly, the dose should remain stable and constant. 
6.8.2.5. 
Lesion Intervention 
In the event that an acutely painful lesion occurs that requires an immediate intervention, the 
investigator will have the option to perform protocol-allowed interventions. Only 2 types of 
interventions are allowed: injection with intralesional triamcinolone acetonide suspension (at a 
concentration of up to 5 mg/mL, up to 1 cc) and incision and drainage. 
If incision and drainage is performed, the required over-the-counter antiseptic wash should 
continue to be used. New systemic and topical therapies following incision and drainage 
(including antibiotics), are prohibited. Concomitant use of wound care dressings is allowed 
however, options are limited to alginates, hydrocolloids, and hydrogels. 
Subjects should continue using any ongoing oral and topical therapies (including antibiotics, 
with the constraints as described in Section 6.8.2.4) during the study. 


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Concomitant medications associated with the lesion intervention(s) must be captured in the 
source and on the appropriate CRF. 
A total of 2 protocol-allowed interventions are permissible up until Week 16 visit. An 
intervention can occur on maximally 2 different lesions at the same visit or on the same lesion at 
2 different study visits. The same lesion cannot be treated 2 times at the same visit. If a subject 
requires more than 2 interventions within the first 16 weeks, then they must be discontinued from 
study drug. After Week 16, maximally 2 interventions every 4 weeks are permitted. If a subject 
requires more than 2 interventions within a 4-week period or has 2 of the same interventions on 
the same lesion within that period, then he or she must be discontinued from the study 
intervention. 
All study visit evaluations must occur before any interventions are performed. Any lesion that 
undergoes an intervention will be documented in the source documents. The site will be required 
to count any lesion that undergoes an intervention as permanently present from the date of the 
intervention and must account for it in the source documents and on the appropriate CRF. 
6.8.3. 
Rescue Medicine 
If a subject experiences an increase in their AN count such that the total count is ≥ 150% of their 
Day 1 AN count, antibiotic rescue medication may be initiated. 
Subjects who qualify may initiate treatment with minocycline or doxycycline up to 100 mg BID. 
The dosing regimen must remain stable throughout study participation. In the case that a subject 
was previously intolerant or has a contraindication to both minocycline and doxycycline for the 
treatment of HS, the medical monitor should review to determine whether another rescue 
medication would be more appropriate. Rescue antibiotic therapy should be captured in the 
source and on the appropriate electronic CRF. 
6.8.4. 
Prohibited Medications 
The following medications are prohibited from enrollment through 2 weeks after the last dose of 
study drug: 
• All other biologic therapies with a potential therapeutic impact on HS including but not 
limited to TNF-α inhibitors, IL-1, IL-12, IL-17, IL-23, or IL-12/23 inhibitors 
• Any other immunomodulatory therapy (eg, cyclosporine, azathioprine, tacrolimus, IV 
gamma-globulin or Prosorba column therapy) 
• JAK inhibitors (eg, tofacitinib, upadacitinib) 
• Other systemic treatments for HS including but not limited to antibiotics (except as 
specified in Section 6.8.2.4 or Section 6.8.3), methotrexate, cyclosporine, retinoids, and 
fumaric acid esters 
• Prescription topical therapies 
• Oral analgesics for HS not listed in Section 6.8.2.3 
• Oral opioid analgesics 
• Non-oral concomitant analgesics (eg, IV, SC) 


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• Live vaccines (during the study and for 2 months after the last dose of study drug) 
• Oral or injectable corticosteroids (except as allowed per Section 6.8.2.5) 
• Phototherapy 
• Any investigational agents 
• Over-the-counter topical antiseptic washes, creams, soaps, ointments, gels, and liquids 
containing antibacterial agents to treat HS not listed in Section 6.8.2.1 
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7. 
Discontinuation of Study Drug and Subject 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole is 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 the permanent discontinuation of study drug will be documented. If study drug is 
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 where possible, with the exception of study drug administration. Reasons for removal 
from study drug include any of the following: 
• subject request 
• safety concern (eg, due to an AE, ineligibility determined, protocol deviation, 
non-compliance, pregnancy, hepatotoxicity) 
• death 
• lost to follow-up 
• decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• protocol-specified reasons: 
o A subject who requires more than 2 lesion interventions within the first 16 weeks 
of the study must be discontinued from study drug 
o After Week 16, a subject who requires more than 2 lesion interventions within a 
4-week period or has 2 of the same interventions on the same lesion within that 
period must be discontinued from study drug 
Additionally, subjects experiencing any of the following AEs must be discontinued from study 
drug, but continued in the study and followed until resolution of the AE: 
• Hematologic AE of moderate or severe intensity (refer to Section 10.3.3 for description 
of intensity assessment) 
• Cardiovascular AE of moderate or severe intensity 
Note: Exceptions to this requirement include the following specific cardiovascular events 
that represent asymptomatic findings discovered as part of testing that may have been 
done for other reasons most likely unrelated to the drug product or the trial itself. 
Cardiovascular AEs that do not meet study drug discontinuation criteria include the 
following AEs related to asymptomatic valvular findings and asymptomatic arrythmia 
findings: 
o Valvular asymptomatic findings: 
▪ Aortic valve: Asymptomatic valvular thickening with or without 
mild valvular regurgitation or stenosis by imaging 
▪ Mitral valve disease: Asymptomatic; moderate regurgitation or 
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▪ Pulmonary valve disease: Asymptomatic; moderate regurgitation 
or stenosis by imaging 
▪ Tricuspid valvular disease: Asymptomatic; moderate regurgitation 
or stenosis by imaging 
o Arrythmia findings of a non-urgent medical nature: 
▪ Atrial fibrillation: non-urgent medical intervention indicated 
▪ Atrial flutter: non-urgent medical intervention indicated 
▪ Atrioventricular block: non-urgent medical intervention indicated 
▪ Conduction disorder: non-urgent medical intervention indicated 
▪ Paroxysmal atrial tachycardia: non-urgent medical intervention 
indicated 
▪ Supraventricular tachycardia: non-urgent medical intervention 
indicated 
• AEs of severe intensity in any other organ system 
Subjects with newly diagnosed IBD or with IBD flares during the study must: 
• Discontinue study drug and be followed-up until resolution of active IBD symptoms 
• Be referred, as appropriate, to a healthcare professional treating IBD, such as a 
gastroenterologist 
- If IBD flares increase in severity or frequency during the study, the investigator 
should use clinical judgment in deciding whether the subject should continue in 
the study and contact the medical monitor to confirm the subject’s suitability for 
continued participation in the study. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study drug for abnormal liver tests is required by the investigator when a 
subject meets one 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 
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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 early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• 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/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 telephone calls, 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 to have 
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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; however, the investigator should try to keep the subjects on the original 
visit/dosing schedule. The window of ± 3 days is relative to Day 1 and applicable for all 
subsequent visits/dosing. For QW dosing, the time between doses should be no less than 
4 days and no more than 10 days. For Q2W dosing, the time between doses should be no 
less than 11 days and no more than 17 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. 
• 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, 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, 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. 
• 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. 
Lesion Count 
The number of inflammatory and non-inflammatory nodules, abscesses, draining and 
non-draining fistulas, and hypertrophic scars, as well as the physical location (right/left axilla, 
right/left inframammary, intermammary, right/left buttock, right/left inguino-crural fold, 
perianal, perineal, other) will be recorded (Section 10.7) at the designated study visits listed in 
SoA (Section 1.3). In addition, lesions counts will be performed at any time if the subject 
experiences a disease flare. The longest distance between 2 relevant lesions (if only one lesion, 
measure diameter of lesion) and whether the lesions are clearly separated by normal-appearing 
skin (yes or no) will be measured. The calculation of the HiSCR, IHS4, and modified Sartorius 
score will be performed by the sponsor or designee based on the lesion counts entered by the 
study investigator(s) on the appropriate CRFs. In addition, the sponsor or designee will utilize 
the lesions counts entered by the investigator on the CRF to establish the rate of flares (See 
Section 3). 
Treatment decisions made during the conduct of the study will not be based on the HiSCR. 
8.1.1.1. 
Hidradenitis Suppurativa Clinical Response 
The HiSCR was developed to address issues with available HS scoring systems and is a 
validated measure that is responsive to improvement in disease activity, simplifies the scoring 
process, and increases the sensitivity to detect HS-specific lesions (Kimball et al, 2014; 
Kimball et al, 2016b). The HiSCR is defined as at least a 50% reduction from baseline in the 
total AN count, with no increase from baseline in abscess or draining fistula count. HiSCR50, 
HiSCR75, HiSCR90, and HiSCR100 are defined as at least 50%, 75%, 90%, or 100% reduction 
respectively from baseline in the total AN count, with no increase from baseline in abscess or 
draining fistula count. 
8.1.1.2. 
International Hidradenitis Suppurativa Severity Score System 
The IHS4 is a validated tool to dynamically assess HS severity to be used both in real-life and 
clinical trials setting. The determination of IHS4 requires counting the nodules, abscesses, and 
draining fistulas/sinus tracts. The IHS4 score (points) = (number of nodules x 1) + (number of 
abscesses x 2) + (number of draining tunnels [fistulae/sinuses] x 4). A score of ≤ 3 signifies mild 
HS, a score of 4 to 10 signifies moderate HS and a score of ≥ 11 signifies severe (Zouboulis et al, 
2017). 
8.1.1.3. 
Modified Sartorius score 
The Sartorius scale was created as a more detailed and dynamic HS severity scale and was 
modified in order to further develop and simplify this assessment for the clinical setting 
(Sartorius et al, 2009; Sartorius et al, 2010). The modified Sartorius score was the first 
disease-specific instrument for dynamically measuring clinical severity. The main parameter in 
the modified Sartorius score is the counting of individual nodules and fistulas. The modified 
Sartorius score includes an assessment of the anatomical regions involved, the numbers and 
scores of lesions for each region, the longest distance between 2 relevant regions (or size of a 
single lesion), and whether all lesions are separated by normal skin (yes or no). 


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8.1.2. 
Erythema Score 
The erythema score is a scoring system used by the physician to assess the overall degree of 
erythema in the HS lesions. This assessment uses a 4-point ordinal scale ranging between 0 (no 
redness) for no erythema and 3 (very red or bright red coloration) for severe erythema. A score 
of 1 (faint but discernible pink coloration) or 2 (moderate red coloration) indicates a moderate 
degree of erythema. Refer to Section 10.8. 
8.1.3. 
Hurley Stage 
The Hurley Stage is a severity classification for HS that was developed in 1989 and is widely 
used for the determination of the severity of HS (Hurley, 1989). The Hurley Stage is defined by 
the following criteria: 
• Stage I: Abscess formation, single or multiple, without sinus tracts and cicatrization 
(scarring). 
• Stage II: Recurrent abscesses with tract formation and cicatrization, single or multiple, 
widely separated lesions. 
• Stage III: Diffuse or near-diffuse involvement, or multiple interconnected tracts and 
abscesses across the entire area. 
The study investigator will determine the Hurley Stage in each affected anatomical region at the 
designated study visits listed in the SoA (Section 1.3). If more than one stage is present in a 
region, the worst state in each region should be entered. 
8.1.4. 
Hidradenitis Suppurativa-Physician’s Global Assessment 
The HS-Physician’s Global Assessment is a validated 6-point scale that is used to measure 
improvement in inflammatory nodules, abscesses, and draining fistulas (Kimball et al, 2012; 
Zouboulis et al, 2015). The HS-Physician’s Global Assessment scale is defined by the following: 
• Clear: No inflammatory or non-inflammatory nodules 
• Minimal: Only the presence of non-inflammatory nodules 
• Mild: < 5 inflammatory nodules or 1 abscess or draining fistula and no inflammatory 
nodules 
• Moderate: ≥ 5 inflammatory nodules or 1 abscess or draining fistula and 
≥ 1 inflammatory nodule or 2 to 5 abscesses or draining fistulas and < 10 inflammatory 
nodules 
• Severe: 2 to 5 abscesses or draining fistulas and ≥ 10 or more inflammatory nodules 
• Very severe: > 5 abscesses or draining fistulas 
8.1.5. 
Numeric Rating Scale Patient Global Assessment of Skin Pain 
The numeric rating scale (NRS) Patient Global Assessment of Skin Pain (Section 10.9) will be 
completed on a daily diary by subjects from screening through Week 16, and at the designated 
study visits after Week 16, listed in SoA (Section 1.3). If pain diaries are not completed for at 
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The Patient Global Assessment of Skin Pain is a unidimensional NRS that allows for rapid (often 
1 item) measures of pain that can be administered multiple times with minimal administrative 
burden. The NRS consists of scores from 0 to 10 with 0 indicating “no skin pain” and 10 
indicating “pain as bad as you can imagine”. The pain will be described as “skin pain at its worst 
in the last 24 hours” and “skin pain on average in the last 24 hours.” 
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. 
8.1.6. 
Dermatology Life Quality Index 
Subjects will complete the Dermatology Life Quality Index (DLQI) questionnaire at the 
designated study visits listed in SoA (Section 1.3). The DLQI will be used to assess the 
symptoms and the impact of skin problems on quality of life. The DLQI can be used to evaluate 
6 areas: symptoms and feelings, daily activities, leisure, work and school, personal relationships, 
and treatment (Finlay et al, 1994). Subjects will be asked to respond to the 10 items of the DLQI 
based on a recall period of 'the last week.' Decreased scores indicate improved health-related 
quality of life. 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. 
8.1.7. 
Short Form 12 
The acute Short Form-12v2™ Health Survey (SF-12v2) is a 7-day recall, 12-item subset of the 
Short Form-36v2™ questionnaire that measures the same 8 domains of health including physical 
functioning, role-function, bodily pain, general health, vitality, social functioning, 
role-emotional, and mental health. The SF-12 is a brief, reliable measure of overall health status 
with scores general for physical component and mental components. Each item on the SF-12 is 
score on 3- or 5-item Likert scales and the domains scales are standardized to 0 to 100 scale 
where 0 represents lower quality of life and 100 represents higher quality of life. The subject 
should complete the questionnaire before site personnel performs any clinic assessments and 
before any interaction with the site personnel has occurred to avoid biasing the subject's 
response. 
8.1.8. 
European Quality of Life-5 Dimensions 
The European Quality of Life-5 Dimensions (EQ-5D) comprises 5 questions on mobility, 
self-care, pain, usual activities, and psychological status with 3 possible answers for each item 
(1=no problem, 2=moderate problem, 3=severe problem). A summary index with a maximum 
score of 1 can be derived from these 5 dimensions by conversion with a table of scores. The 
maximum score of 1 indicates the best health state, by contrast with the scores of individual 
questions, where higher scores indicate more severe or frequent problems. In addition, there is a 
visual analog scale to indicate the general health status with 100 indicating the best health status. 


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8.1.9. 
Hidradenitis Suppurativa Patient Global Impression of Change 
Subjects will complete the HS Patient Global Impression of Change (PGIC) (Section 10.11) 
questionnaire at the designated study visits listed in SoA (Section 1.3). The PGIC consists of one 
self-administered item that assesses change in the severity of skin pain due to HS. Subjects are 
asked to indicate their impression of change compared with their last visit, except at Week 16, 
when the subject will also be asked about their pain since treatment began during this study. 
8.1.10. 
Hospital Anxiety and Depression Scale 
In addition, 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 
≥ 15 and above is considered severe (Snaith and Zigmond, 1994). 
8.1.11. 
Photography (Optional Substudy) 
Subjects at a subset of selected sites will be invited to participate in an optional substudy to have 
photographs taken of their disease response during the study. Subjects who consent to this 
optional substudy will have photographs taken at the designated study visits listed in the SoA 
(Section 1.3). Sites participating in the photography substudy will be trained and receive 
standardized photographic equipment from the central photography vendor. Sites will submit the 
digital images to the central photography vendor. Photographs will be anonymized. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
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 the first dose of study drug should be listed as 
medical history in the CRF and reported as AEs if observed after first dose of study drug. 
8.2.2. 
Physical Measurements 
Height and weight measurements are to be performed at the timepoints indicated in the SoA and 
data will be recorded in centimeters and kilograms respectively. Height and weight are to be 
measured without shoes. 
8.2.3. 
Vital Signs 
Vital signs will be measured in a sitting position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate. 


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8.2.4. 
Electrocardiograms 
Triple 12-lead ECGs will be obtained 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. 
8.2.5. 
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 10.3, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
c. If laboratory values from non-protocol-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. 
8.2.6. 
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. 
• The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 


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8.2.7. 
Hepatitis Testing 
All subjects will be tested for the presence of the hepatitis B virus (HBV) and hepatitis C virus at 
screening. A positive result for the HBsAg will be exclusionary. Samples negative for HBsAg 
will be tested for surface antibodies (HBsAb) and core antibodies (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. 
8.2.8. 
Suicidal Ideation and Behavior Risk Monitoring 
Subjects with HS may occasionally develop suicidal ideation or behavior. Furthermore, suicidal 
ideation and behavior has been identified as a potential risk with other IL-17 class products. 
Suicidal ideation and behavior will be assessed during the study by trained study personnel using 
the C-SSRS. The visits at which the C-SSRS assessments will be performed are specified in the 
SoA (Section 1.3). The C-SSRS is a standardized and validated instrument developed for the 
assessment of the severity and frequency of suicidal ideation and behavior (Posner et al, 2011). 
Subjects respond to standardized clinical questions that are presented in a uniform fashion. The 
C-SSRS defines 5 subtypes of suicidal ideation and behavior in addition to self-injurious 
behavior with no suicidal intent. The C-SSRS takes approximately 3 to 10 minutes to complete. 
Subjects should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of study drug. Subjects who experience signs of suicidal ideation and behavior should 
undergo a risk assessment which may or may not include examination by another mental health 
care professional. All factors contributing to suicidal ideation and behavior should be evaluated 
and consideration should be given to discontinuation of the study drug. 
8.2.9. 
Home Study Drug Administration Diary 
Study-site staff will administer study drug at the first 2 visits. Thereafter, if home dosing is a 
consideration, the subject or subject's caregiver or designee must administer and demonstrate 
competency for at least 2 visits prior to being allowed to dose at home. Otherwise, the subject 
will need to return to the site for all injections. 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 on 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 caregiver, surrogate, 
or the subject’s legally authorized representative). 


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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 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 (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 AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the 8-week follow-up visit as 
specified in the SoA (Section 1.3). 
All AEs will be collected from the first dose of study drug until 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 the conclusion 
of the study participation. However, if the investigator learns of any SAE, including death, at any 
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/designee (see Section 10.3.4). 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
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 SAEs 
• Prompt notification by the investigator to the sponsor or designee of an SAE is essential 
so that legal obligations and ethical responsibilities toward 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. 


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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 according to local regulatory requirements and sponsor or designee policy and 
forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of study drug and until 8 weeks after the last dose 
of study drug. 
• 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 
the female subject or female partner of male subject (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy 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. 
• 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 or 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 will be monitored: 
• Candida infection 
• IBD 


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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 adverse cardiovascular and cerebrovascular events (cerebrovascular accident and 
transient ischemic attack, non-fatal myocardial infarction or unstable angina, and 
cardiovascular death) 
• Tuberculosis 
• Infections (opportunistic, serious, or fungal only) 
• Cytopenias 
• Systemic hypersensitivity reactions 
8.4. 
Pharmacokinetic Assessments 
• 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 may 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 collected may be used for assay validation and related assay 
development purposes. 
• 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 samples will be retained while research on izokibep or study drugs of this class 
or HS continues but no longer than 20 years or other period as per local requirements. 
8.5. 
Genetics 
Not applicable. 


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8.6. 
Biomarker Assessments (USA Only) 
• Serum and blood (PAXgene) samples will be collected for exploratory biomarker 
analysis as specified in the SoA (Section 1.3). 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 will be used to assess biomarkers of anti-IL-17A treatment and biomarkers 
associated with HS efficacy. mRNA transcriptomic analyses will be performed on the 
whole blood PAXgene samples. 
• Exploratory biomarker samples will be shipped frozen from clinical sites to the central 
laboratory and later shipped from central laboratory to the laboratory for analysis. The 
samples will be stored in a secure storage space with adequate measures to protect 
confidentiality. 
• The exploratory samples will be retained while research on izokibep or study drugs of 
this class or HS continues but no longer than 5 years as specified in the future use consent 
form or other period as per local requirements. 
• Biomarker analyses will only be performed on subject samples where future use consent 
for such analyses has been obtained.  
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. 
• Antibody samples collected may be used for assay validation and related assay 
development purposes. 
• Anti-drug antibodies (ADA) serum samples will be shipped frozen from clinical sites to 
the central laboratory and later shipped from the central laboratory to the ADA laboratory 
for analysis. The ADA serum samples will be stored in a secure storage space with 
adequate measures to protect confidentiality. 
• Samples will be retained while research on izokibep or study drugs of this class or HS 
continues but no longer than 20 years or other period as per local requirements. 
8.8. 
Health Economics 
Refer to Section 8.1.7 Short Form 12 and Section 8.1.8 EQ-5D. 


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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 
No statistical hypotheses will be tested in Part A of this study. 
The primary objective of Part B of this study is to demonstrate that izokibep is superior to 
placebo in the proportion of subjects achieving HiSCR 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 achieving HiSCR at Week 16 among subjects randomly 
assigned to receive izokibep and placebo, respectively. One set of hypotheses will be tested for 
each dosing frequency of izokibep. 
Analogous statistical hypotheses will be used for the secondary objective of assessing the 
percentage of subjects who experience a flare through Week 16 and the percentage of subjects 
who achieve AN count of 0, 1, or 2 at Week 16. 
Hypotheses to assess the change in pain score are: 
H0: µABY – µPBO = 0 
HA: µABY – µPBO ≠ 0 
where µABY and µPBO are the mean change in Skin Pain NRS from baseline to Week 16. 
9.1.1. 
Multiplicity Adjustment and Type I Error Rate 
No alpha-controlled testing will be reported using any data from Part A of the study. Hypotheses 
tested using data from Part B will be adjusted to control the familywise error rate in the strong 
sense at α = 0.050, two-sided. 
As described in Section 9.4, an adjustment of 0.0001 will be made to account for the unblinded 
data summaries reviewed by the DMC. The hypotheses will therefore be tested at α = 0.0499. 
The statistical comparisons in Part B 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 dosed QW or Q2W, will be tested first, with 
significance concluded if p < 0.0499. If significant, the primary endpoint, comparing izokibep 
dosed Q2W to placebo dosed QW or Q2W will be tested next, with significance concluded if 
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Testing of secondary endpoints will only be carried out if all prior tests, including both tests of 
the primary endpoint, first show significance with p < 0.0499. As long as all prior tests are 
significant, testing will proceed in the following order: 
• The first secondary endpoint, HiSCR90 at Week 16, comparing izokibep dosed QW to 
placebo dosed QW or Q2W. 
• The first secondary endpoint, HiSCR90 at Week 16, comparing izokibep dosed Q2W to 
placebo dosed QW or Q2W. 
• The second secondary endpoint, HiSCR100 at Week 16, comparing izokibep dosed QW 
to placebo dosed QW or Q2W. 
• The second secondary endpoint, HiSCR100 at Week 16, comparing izokibep dosed Q2W 
to placebo dosed QW or Q2W. 
• The third secondary endpoint, HiSCR50 at Week 16, comparing izokibep dosed QW to 
placebo dosed QW or Q2W. 
• The third secondary endpoint, HiSCR50 at Week 16, comparing izokibep dosed Q2W to 
placebo dosed QW or Q2W. 
• The fourth secondary endpoint, proportion of subjects who experience flare, comparing 
izokibep dosed QW to placebo dosed QW or Q2W. 
• The fourth secondary endpoint, proportion of subjects who experience flare, comparing 
izokibep dosed Q2W to placebo dosed QW or Q2W. 
• The fifth secondary endpoint, achieving AN count of 0, 1 or 2 among subjects with 
baseline Hurley Stage II, comparing izokibep dosed QW to placebo dosed QW or Q2W. 
• The fifth secondary endpoint, achieving AN count of 0, 1 or 2 among subjects with 
baseline Hurley Stage II, comparing izokibep dosed Q2W to placebo dosed QW or Q2W. 
• The sixth secondary endpoint, change in pain score, comparing izokibep dosed QW to 
placebo dosed QW or Q2W. 
• The sixth secondary endpoint, change in pain score, comparing izokibep dosed Q2W to 
placebo dosed QW or Q2W. 
If a null hypothesis is not rejected, p-values for subsequent hypotheses in the sequence will be 
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9.2. 
Analysis Sets 
Analysis sets will be created separately for subjects enrolled in Part A and Part B. Hypotheses 
will be tested using only data from Part B. 
Full Analysis Set 
Part A 
For assessing efficacy in Part A, the full analysis set (FAS) will include all subjects who receive 
at least one administration of study drug. 
Part B 
For assessing the primary and secondary efficacy objectives, all subjects randomized in Part B 
will be included in the analyses as 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 9.3. Subjects will be included according to randomized 
treatment. 
For assessment of the third secondary endpoint, the proportion of subjects who achieve AN of 0, 
1, or 2 at Week 16, only the subset of subjects in the FAS who have Hurley Stage II at baseline 
will be included in the assessment. This will be called the FAS for reporting purposes. 
Safety Analysis Set 
Part A 
The safety analysis set for subjects in Part A will include all subjects who received at least one 
administration of test material. 
Part B 
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 treatment, that subject will be grouped according to treatment 
received. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Data from Part A and Part B will be summarized separately. 
All data collected will be summarized by planned timepoint without imputation. Continuous data 
will be summarized with count, mean, median, 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. Placebo subjects assigned to receive doses QW or Q2W will 
be summarized both separately and combined, with hypotheses tested using both placebo dosing 
frequencies combined. 
All hypothesis tests will use only data from Part B and will be reported with two-sided p-values. 
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placebo; comparison of Q2W dosing to placebo will use only subjects assigned to receive 
izokibep Q2W or placebo. All CIs will be two-sided with nominal 95% coverage. 
Data will be summarized by part and planned timepoint, using data collected at the visit. Study 
day will be calculated as post-baseline 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 
post-baseline value minus baseline value. 
For testing purposes, subjects randomly assigned to placebo QW and placebo Q2W will be 
grouped together into a single placebo group for comparison to each dosing regimen of izokibep. 
This assumes that dosing with placebo QW or Q2W does not affect efficacy, an assumption 
which will be explored with simple summary statistics. Stratified tests will use the 4 strata from 
the randomization process. If a subject is incorrectly classified during the randomization process, 
the analysis will use the correct classification, not the classification used during randomization. 
9.3.2. 
Primary Endpoint and Estimand 
The primary endpoint in Part A is HiSCR75, the proportion of subjects who achieve at least a 
75% reduction from baseline in the total AN count, with no increase from baseline in abscess or 
draining fistula count, as defined in Section 8.1.1.1. The primary timepoint for analysis is 
Week 12 for Part A. 
HiSCR75 is defined as meeting all 3 criteria below: 
• AN count at baseline minus AN count at current visit)/AN count at baseline × 100% ± 
75% 
• Abscess count at baseline ≥ abscess count at the current visit 
• Draining fistula count at baseline ≥ draining fistula count at the current visit 
Where AN count is abscess count plus inflammatory nodule count, including all abscesses and 
inflammatory nodules that have previously undergone localized surgical or medical intervention 
and are no longer present. 
The primary endpoint for Part B is HiSCR75, which is defined as at least a 75% reduction from 
baseline in the total AN count with no increase from baseline in abscess or draining fistula count. 
The primary timepoint for analysis is Week 16 for Part B. 
The treatment policy strategy approach for the estimand will be used in general, so subjects will 
be included using observed data at the primary timepoint regardless of treatment compliance, use 
of rescue medications except as noted below, or any other protocol deviations. Subjects with 
missing HiSCR assessments at the primary timepoint will be imputed as non-responders 
(non-response imputation or NRI). A composite strategy will be used for intercurrent events of 
receiving oral antibiotic therapy that could affect HS: a list of all oral antibiotic therapy that 
results in such imputation will be finalized after review of all oral antibiotic therapy received by 
any subject and before unblinding of the study, and will include tetracycline, clindamycin, and 
possibly other products. Such subjects will be imputed using NRI. The number of subjects 
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The null hypothesis of equal response rates will compare each dosing regimen of izokibep to the 
combined placebo group. A stratified test of response rates will be used. Within each of the 
4 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 4 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 HiSCR 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. 
Supportive analyses using other assumptions about ICEs will also be reported. These will be 
defined before the database is locked and treatment assignments are unblinded. 
9.3.3. 
Secondary Endpoints and Estimands 
In Part B, the secondary endpoints are percentage of subjects achieving HiSCR90/100/50 at 
Week 16, change in pain score, percentage of subjects who experience flare through Week 16 
and percentage of subjects with baseline Hurley Stage II who achieved AN count of 0, 1, or 2. 
The treatment policy strategy will be used to construct estimands for each secondary endpoint. 
HiSCR90/100/50 is defined as at least a 90%, 100%, or 50% reduction from baseline in the total 
AN count with no increase from baseline in abscess or draining fistula count. 
The secondary endpoint of percentage of subjects achieving at least a 3-point reduction from 
baseline in NRS in Patient Global Assessment of Skin Pain at its worst at Week 16 among 
subjects with baseline NRS ≥ 4 will be analyzed analogously to the primary endpoint. A hybrid 
estimand will be used, with treatment policy strategy used for most intercurrent events and 
hypothetical strategy used to account for use of prohibited pain medications. All pain scores after 
the use of prohibited pain medication will be omitted from the dataset and replaced via non-
response imputation. Mean pain from the 7 days prior to an actual visit will be used for analysis, 
with missing data used at a given visit if fewer than 3 days of observed data are available for that 
visit. Sensitivity analyses will include a nonlinear mixed effects model with repeated measures 
(MMRM), using observed change in pain score at all scheduled post-baseline assessments. 
The secondary endpoint of percentage of subjects who experience flare will be analyzed 
analogously to the primary endpoint. Multiple imputation will be used to impute data for subjects 
with missing data. Subjects with missing AN counts at any scheduled visit (Week 4, Week 8, 
Week 12 and/or Week 16) will have their AN counts imputed (separately) for each visit with 
missing data. The imputed counts will be summed and compared to criteria for flare. If the 
observed or imputed value at any visit meets the definition of flare, the subject will be counted as 
having a flare; otherwise, the subject will be counted as not having a flare. A total of 100 
imputations will be imputed to form the complete data set with a pre-specified seed (3617627) to 
ensure reproducibility. The final inference on treatment difference is conducted from the 
multiple datasets using Rubin’s combining rules. Other imputation, fully conditional 
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The secondary endpoint of percentage of subjects with baseline Hurley Stage II who achieved 
AN count of 0, 1, or 2 will be analyzed analogously to the primary endpoint. Subjects who have 
missing data at Week 16 or who received an oral antibiotic that could impact HS will be included 
in the analysis with NRI (did not achieve AN count of 0, 1, or 2). Only subjects with Hurley 
Stage II at baseline will be included in the hypothesis test for AN count, while other subjects will 
be summarized, and a p-value reported for descriptive use only. 
9.3.4. 
Exploratory Endpoints 
Exploratory endpoints will be analyzed analogously to primary and secondary endpoints with the 
same strategies for ICEs. Binary endpoints will be analyzed with a stratified test of risk 
difference and continuous endpoints will be analyzed with an MMRM model. Continuous data at 
timepoints before and including the primary timepoint will use all data from planned assessments 
up to and including the primary timepoint; continuous data after the primary timepoint will use 
all data from all planned assessments. 
Pharmacokinetic concentration data will be summarized at all planned collections with mean, 
geometric mean, minimum, and maximum. Pharmacokinetic data collected from this study may 
also be combined with PK data collected from other studies for comprehensive modeling of drug 
concentrations. 
9.3.5. 
Safety Analyses 
Safety data will include summaries of exposure, AEs, SAEs, and laboratory data. Safety will be 
reported separately for Parts A and B of the study. In Part B, subjects who received placebo QW 
and placebo Q2W will be combined for summaries during the placebo-controlled portion of the 
study. 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. 
Adverse events and SAEs reported before first administration of study drug will be listed. All 
summaries will include only treatment-emergent events. The number of subjects who report one 
or more AEs, the number who report one or more severe AEs, the number who report one or 
more SAEs, and the number who report one or more AEs that leads to discontinuation of study 
drug will be summarized by treatment during the primary phase of the study and overall. 
Subjects who receive placebo during the primary phase will additionally be summarized by 
phase (placebo-controlled and after crossing over to active). 
Laboratory data will be summarized at each planned collection timepoint. Subjects with positive 
ADA results will be summarized by timepoint. 
9.4. 
Interim Analysis and Early Stopping Rules 
After all subjects in Part A have had the opportunity to complete the Week 8 visit (or 
discontinued the study early), data at Week 8 will be summarized. The DMC will review the data 
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No formal interim analysis of data from Part B is planned for purposes of stopping or altering 
this study. Two summaries of primary endpoint data are planned before the last subject 
completes the study: 
• After the first 105 subjects have had the opportunity to complete the Week 8 visit, the 
DMC will review unblinded data to make a recommendation on further development 
activities of izokibep. The DMC will not be empowered to recommend stopping this 
study or changing the sample size due to a demonstration of positive efficacy. The type I 
error rate for hypothesis tests at the end of the study will be decreased by 0.0001 to 
account for this interim summary of unblinded data. The study team and the investigators 
will remain blinded to these interim results until after the study is completed. 
• After all subjects have had an opportunity to complete the Week 16 visit (complete the 
visit, or complete a subsequent visit, or permanently discontinue the study), the primary 
endpoint analyses may be conducted. These will be the final analyses for the primary 
endpoint, so no adjustment of the type I error will be applied. Site staff, and all sponsor 
staff who interact with site staff, will remain blinded to individual subject treatment 
assignment until the final subject has completed the final visit. 
9.5. 
Sample Size Determination 
In Part A, a minimum of 20 subjects and up to 30 subjects will be enrolled. With the minimum of 
20 subjects enrolled if the true HiSCR response rate is 50%, an observed rate of 30% to 70% will 
be observed with 95% probability. Conversely, an observed response rate of 25% or lower 
suggests that the true rate is < 50% and an observed rate of 75% or higher suggests that the true 
rate is > 50%, based on limits of a two-sided 95% CI. 
In Part B, comparisons will have approximately 55 subjects in each izokibep regimen compared 
to approximately 55 subjects on placebo (QW and Q2W combined). In prior studies of 
adalimumab in a similar patient population (Kimball, 2016a), HiSCR75 response rates of 10% to 
15% were observed with placebo compared with response rates of 25% to 35% with 
adalimumab. If true response rates with placebo and izokibep are 15% and 40%, respectively, 
this study will have approximately 80% power to reject the null hypothesis of equal response 
rates. This calculation was made in SAS® using the POWER procedure on an unstratified test of 
binomial proportions. 


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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: 
o 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 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o 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 a 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 the nature of the study, including 
the risks and benefits, to the subject and answer all questions regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be required 
to sign 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 the ICF. 
• 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 
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 


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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 CRF 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’s 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 
study documents. 
• All subject data relating to the study will be recorded on CRFs 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 CRF. 
• Guidance on completion of CRFs 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 
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• 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 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 
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 CRF 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. 
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• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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 
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 
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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 trial 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 multi-center 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. 
 
 
















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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): 
1. 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 (FSH) 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 one FSH measurement is required. 
o Females on HRT and whose menopausal status is in doubt will be required to use one 
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 woman of childbearing potential 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 
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• 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. 
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 method are not acceptable methods of contraception. Male 
condoms and female condoms should not be used together (due to risk of failure from friction). 
 
 


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10.5. 
Liver Safety: Required 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 European Association for 
the Study of the Liver Clinical Practice Guidelines: Drug-induced Liver Injury. (2019) and FDA 
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 Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST)  5 x upper limit of normal (ULN) 
ALT or AST Increase ALT or AST  3 x ULN persists for  4 weeks 
Bilirubin1,2 
ALT or AST  3 x ULN and total bilirubin  2 x ULN (> 35% 
direct bilirubin) 
INR2 
ALT or AST  3 x ULN and international normalized ratio (INR) 
> 1.5 
Cannot Monitor 
ALT or AST  3 x ULN and cannot be monitored twice weekly for 
4 weeks 
Symptomatic3 
ALT or AST  3 x ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
 
Required 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) CRF 
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, normalize, or return to 
baseline. 
• Viral hepatitis serology4 
• Obtain blood sample for 
pharmacokinetic (PK) analysis after 
the most recent dose5. 
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyltransferase [GGT], 
glutamate dehydrogenase [GLDH], 
and serum albumin. 
• Fractionate bilirubin, if total bilirubin 
 2 x ULN. 


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MONITORING: 
If ALT or AST  3 x ULN AND total bilirubin 
 2 x ULN or INR > 1.5 (with or without 
symptoms of liver injury or hypersensitivity): 
• 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, 
normalize, or return to baseline. 
• A hepatology consultation is recommended. 
• Additional monitoring may be done at the 
investigator’s discretion. 
• See additional follow-up tests in this section. 
 
If ALT or AST  3 x ULN AND total bilirubin 
< 2 x ULN and INR  1.5 (with or without 
symptoms of liver injury or hypersensitivity): 
• 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, normalize, or 
return to baseline. 
• Additional monitoring may be done at the 
investigator’s discretion. 
• Once abnormalities stabilize or the trial drug 
has been discontinued and the subject is 
asymptomatic, frequency of retesting can 
decrease to once a week 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 CRF. 
• Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, and 
other over-the-counter medications) 
on the concomitant medications CRF. 
• Record alcohol use on the alcohol and 
nicotine use CRF. 
If ALT or AST  3 x ULN AND total 
bilirubin  2 x ULN or INR > 1.5 
obtain the following in addition to the 
assessments listed above: 
• Antinuclear antibody, antismooth 
muscle antibody, Type 1 antiliver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG), 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 (AIH) 
o In subjects when suspected 
drug-induced liver injury 


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progresses or fails to resolve on 
withdrawal of study drug 
o In subjects with acute or chronic 
atypical presentation 
• If liver biopsy conducted provide 
biopsy information. 
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 x ULN and total bilirubin  2 x ULN (> 35% direct bilirubin) or ALT or AST 
 3 x 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 if SAE criteria met (excluding studies of hepatic 
impairment or cirrhosis). 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 CRF. If the date or 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 
ADA 
anti-drug antibody 
AE  
adverse event 
ALT  
alanine aminotransferase 
AN 
abscess and inflammatory nodule 
AST  
aspartate aminotransferase 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to 
infinity 
AUC0-τ 
area under the plasma concentration-time curve over a dosing 
interval 
BID 
twice daily 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
COVID-19  
coronavirus disease of 2019 
CRF  
case report form 
CRO  
contract research organization 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
CV% 
percent coefficient of variation 
DLQI  
Dermatology Life Quality Index 
DMC  
Data Monitoring Committee 
ECG  
electrocardiogram 
EQ-5D 
European Quality of Life-5 Dimensions 
EudraCT  
European Union Drug Regulating Authorities Clinical Trials 
FAS  
Full Analysis Set 
FSH  
follicle-stimulating hormone 
GCP  
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression scale 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibodies 
HBsAb 
hepatitis B surface antibodies 
HbsAg 
hepatitis B surface antigen 


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Abbreviation 
Definition 
HiSCR  
hidradenitis suppurativa clinical response defined as at least a 50% 
reduction from baseline in the total abscess and inflammatory nodule 
count, with no increase from baseline in abscess or draining fistula 
count 
HiSCR50  
HiSCR defined as at least a 50% reduction from baseline in the total 
abscess and inflammatory nodule count, with no increase from 
baseline in abscess or draining fistula count 
HiSCR75  
HiSCR defined as at least a 75% reduction from baseline in the total 
abscess and inflammatory nodule count, with no increase from 
baseline in abscess or draining fistula count 
HiSCR90  
HiSCR defined as at least a 90% reduction from baseline in the total 
abscess and inflammatory nodule count, with no increase from 
baseline in abscess or draining fistula count 
HiSCR100 
HiSCR defined as at least a 100% reduction from baseline in the 
total abscess and inflammatory nodule count, with no increase from 
baseline in abscess or draining fistula count 
HIV  
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
HS 
hidradenitis suppurativa 
HS-PGA 
Hidradenitis Suppurativa-Physician’s Global Assessment 
IBD  
inflammatory bowel disease 
ICE 
Intercurrent event 
ICH  
International Council for Harmonisation 
ICF  
Informed Consent Form 
IEC  
Independent Ethics Committee 
IHS4  
International Hidradenitis Suppurativa Severity Score System 
IL  
interleukin 
IMP  
investigational medicinal product 
IRB  
Institutional Review Board 
IXRS  
Interactive Voice/Web Response System 
IV 
intravenous(ly) 
JAK 
Janus kinase 
MMRM 
nonlinear mixed effects model with repeated measures 
NOAEL 
no observed adverse effect level 
NRI 
non-response imputation 
NRS  
numeric rating scale 
PASI 
Psoriasis Area and Severity Index  


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Abbreviation 
Definition 
PCR 
polymerase chain reaction 
PGIC 
Patient Global Impression of Change 
PK  
pharmacokinetics 
PPD 
purified protein derivative 
PRN 
as needed 
QW 
every week 
Q2W 
every other week 
SAE  
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 
SC 
subcutaneous(ly) 
SF-12v2 
12-Item Short Form Survey version 2 
SoA 
Schedule of Activities 
t½ 
half-life 
TEAE  
treatment-emergent adverse events 
Th17  
IL-17-producing T-helper cells 
tmax 
time to maximum observed concentration 
TNF-α  
tumor necrosis factor-α 
ULN  
upper limit of normal 
US  
United States 
USPI 
United States prescribing information 
WOCBP 
women of childbearing potential 
 


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10.7. 
Lesion Count 
 
Lesion countsa 
Abscess 
Non-
draining 
fistula 
Draining 
fistula 
Non-
inflammatory 
nodule 
Inflammatory 
nodule 
Hypertrophic 
scar 
Longest distance 
(mm) between 2 
relevant lesionsb 
Intervening 
normal 
appearance tissue 
(yes or no)c 
Left axilla  
 
 
 
 
 
 
 
 
Right axilla 
 
 
 
 
 
 
 
 
Left sub/inframammary 
Area  
 
 
 
 
 
 
 
 
Right 
sub/inframammary area  
 
 
 
 
 
 
 
 
Intermammary area 
 
 
 
 
 
 
 
 
Left buttock 
 
 
 
 
 
 
 
 
Right buttock 
 
 
 
 
 
 
 
 
Left inguino-crural foldd 
 
 
 
 
 
 
 
 
Right inguino-crural 
foldd 
 
 
 
 
 
 
 
 
Perianal 
 
 
 
 
 
 
 
 
Perineal 
 
 
 
 
 
 
 
 
Upper back and neck 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
Totals 
 
 
 
 
 
 
 
 
a Lesion counts are to be recorded every study visit. 
b If only 1 lesion, record diameter of that single lesion. 
c Are all lesions in this area clearing and separated by normal-appearing tissues? Answer: yes or no. 
d Includes the immediate adjacent area. 


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10.8. 
Erythema Score 
Example 
At every visit, for each anatomic region affected by HS, the investigator will assess the overall 
degree of erythema using a four-point ordinal scale ranging between 0 and 3. 
Region (to be assessed at every visit) 
Degree of Erythema 
Left axilla  
 
Right axilla 
 
Left sub/inframammary area  
 
Right sub/inframammary area  
 
Intermammary area 
 
Left buttock 
 
Right buttock 
 
Left inguino-crural fold 
 
Right inguino-crural fold 
 
Perianal 
 
Perineal 
 
Upper back and neck 
 
Other 
 
0 = no redness; 1 = faint but discernible pink coloration; 2 = moderate red coloration; 3 = very red or bright red 
coloration. 




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10.10. Daily Subject Analgesic (Pain) Use Diary – Example 
Please answer the questions below before you go to bed. Provide your response based on the past 
24 hours. 
Did you take any pain medication in the past 24 hours?  Yes  No 
If YES: 
Fill in the chart with the information about the pain medication you took. If "Other" write in the 
name of the pain medication you took. 
 
Type of Pain 
Medication Taken 
(check box) 
Was the Pain 
Medication for HS? 
Dose and Unit 
(example 325 mg 
pill) 
Number of Pills 
Taken (example: 
2 pills) 
Pain Medication 
□ 
□ Yes 
□ No 
 
 
Ibuprofen 
□ 
□ Yes 
□ No 
 
 
Acetaminophen 
□ 
□ Yes 
□ No 
 
 
Tramadol 
□ 
□ Yes 
□ No 
 
 
Other pain 
medication: 
 
□ 
□ Yes 
□ No 
 
 
Other pain 
medication: 
 
□ 
□ Yes 
□ No 
 
 
Other pain 
medication: 
 
□ 
□ Yes 
□ No 
 
 


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10.11. Hidradenitis Suppurativa Patient Global Impression of Change 
Example 
 
1. Since your last visit, how would you rate your pain due to your Hidradenitis Suppurativa 
(HS)? 
 
□ Very much worse 
□ Much worse 
□ A little worse 
□ No change 
□ A little better 
□ Much better 
□ Very much better 
Note, at Week 16 an additional question with the same response options will be as follows: Since 
the start of study treatment, how would you rate your skin pain due to your Hidradenitis 
Suppurativa (HS)? 


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11. 
References 
ACELYRIN Inc, Izokibep Investigator’s Brochure 
Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for 
hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis 
Suppurativa Foundations: Part II: Topical, intralesional, and systemic medical management. 
J Am Acad Dermatol. 2019;81(1):91-101. 
Casseres RG, Prussick L, Zancanaro P, et al. Secukinumab in the treatment of moderate to severe 
hidradenitis suppurativa: Results of an open-label trial. J Am Acad Dermatol. 
2020;82(6):1524-1526. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)-a simple practical measure for 
routine clinical use. In Clin Exp Dermatol. 1994;19(3):210-216. 
Frew JW, Navrazhina K, Grand D, et al. The effect of subcutaneous brodalumab on clinical 
disease activity in hidradenitis suppurativa: An open-label cohort study. J Am Acad Dermatol. 
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Garg A, Kirby JS, Lavian J, Lin G, Strunk A. Sex- and age-adjusted population analysis of 
prevalence estimates for hidradenitis suppurativa in the United States. J Am Acad Dermatol. 
2017;153(8):760-764. 
Glatt S, Jemec GBE, Forman S, Sayed C, et al. Efficacy and safety of bimekizumab in moderate 
to severe hidradenitis suppurativa. J Am Acad Dermatol. 2021;157(11):1279-1288. 
Humira USPI. (n.d.). Highlights of prescribing information. www.fda.gov/medwatch 
Hurley H. Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial l 
benign pemphigus: Surgical approach. In Roenigk RK, Roenigk HH, eds. Dermatological 
Surgery. New York: Marcel Dekker;1989:729-739. 
Jfri A, Nassim D, O’Brien E, Gulliver W, Nikolakis G, Zouboulis CC. Prevalence of 
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Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the Treatment of Moderate to Severe 
Hidradenitis Suppurativa. Ann Intern Med. 2012;157(12):846-855. 
Kimball AB, Jemec GBE, Yang M, et al. Assessing the validity, responsiveness, and 
meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical 
endpoint in hidradenitis suppurativa. Br J Dermatol. 2014;171(6):1434-1442. 
Kimball AB, Okun MM, Williams DA, et al. Two phase 3 trials of adalimumab for hidradenitis 
suppurativa. N Engl J Med. 2016a;375(5):422-434. 
Kimball AB, Sobell JM, Zouboulis CC, et al. HiSCR (Hidradenitis Suppurativa Clinical 
Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with 
hidradenitis suppurativa from the placebo-controlled portion of a Phase 2 adalimumab study. 
J Eur Acad of Dermatol Venereol. 2016b;30(6):989-994. 


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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 
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validity and internal consistency findings from three multisite studies with adolescents and 
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Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. 
Nat Rev Dis Primers. 2020;6(1):18. 
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Sartorius K, Killasli H, Heilborn J, Jemec GBE, Lapins J, Emtestam L. Interobserver variability 
of clinical scores in hidradenitis suppurativa is low. Br J Dermatol. 2010;162(6):1261-1268. 
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Wolk K, Join-Lambert O, Sabat R. Aetiology and pathogenesis of hidradenitis suppurativa. 
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Suppurativa/Acne Inversa: Criteria for Diagnosis, Severity Assessment, Classification and 
Disease Evaluation. Dermatology. 2015;231(2):184-90. 
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recalcitrant hidradenitis suppurativa/Acne inversa. Dermatology. 2020;236(1):25-30. 
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