A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of BIO89-100 in Subjects With Biopsy-Confirmed Nonalcoholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: 89bio, Inc.

CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy, Safety and Tolerability of BIO89-100 in 
Subjects with Biopsy-Confirmed Nonalcoholic Steatohepatitis 
(NASH) 
Short Title: 
The ENLIVEN Study 
Protocol Number:  
BIO89-100-122 
Compound Number:  
BIO89-100 (Pegozafermin) 
Study Phase:  
Phase 2b 
Sponsor Name: 
89bio, Inc 
Legal Registered Address: 
142 Sansome Street, 2nd Floor 
San Francisco CA 94104, US 
IND Number: 
131934 
Sponsor Representative: 
 
 
Approval Date:  
05 December 2022 
Version: 
Version 4.0 
Amendment: 
Amendment 3 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as 
directed by the provisions of the International Council for Harmonisation (ICH) and with the 
ethical principles contained in the Declaration of Helsinki; United States (US) Code of Federal 
Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; and the Sponsor’s Standard Operating 
Procedures (SOPs). 
CONFIDENTIALITY STATEMENT 
This document contains confidential and proprietary information (including confidential 
commercial information pursuant to 21CFR§20.61) and is a confidential communication of 
89bio, Inc The recipient agrees that no information contained herein may be published or 
disclosed without written approval from the Sponsor. If there is any actual or suspected breach 
of this obligation, the recipient agrees to promptly notify 89bio, Inc. 
© 2021 89bio, Inc All rights reserved 
326
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SIGNATURE PAGE
Sponsor Signatory:
89bio, Inc
Date
Medical Monitor (or designee) Name and Contact Information will be provided separately.

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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy, Safety and Tolerability of BIO89-100 in 
Subjects with Biopsy-Confirmed Nonalcoholic Steatohepatitis 
(NASH) 
Protocol Number 
BIO89-100-122 
Version and Date 
Version 4.0, 05 December 2022 
Amendment No.  
3 
IND Number 
131934 
 
 
I, the undersigned, have read this protocol and agree to personally supervise conduct of this 
protocol in accordance with ethical principles as outlined in the International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice, any applicable laws and 
requirements (including Part 54: Financial Disclosure by Clinical Investigators) and any 
additional conditions mandated by a regulatory authority and/or Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). 
I acknowledge that I am responsible for the overall study conduct; I approve of and will comply 
with all conditions, instructions and restrictions described in this protocol. I am aware that my 
adherence to the above protocol is mandatory and that any changes in the protocol or consent 
form, except those necessary to eliminate apparent immediate hazards to human subjects, must 
first be approved in writing by 89bio, Inc and the respective IRB/IEC. 
I also agree that all information provided to me by the Sponsor, including this document, 
Investigator’s Brochure, case report form, and verbal and written information, will be kept 
strictly confidential and confined to the clinical personnel involved in conducting the study. It is 
recognized that this information may be related in confidence to the IRB/IEC. I also understand 
that reports of information about the study or its progress will not be provided to anyone not 
involved in the study other than to the Principal Investigator, or in confidence to the IRB/IEC or 
to the Food and Drug Administration (FDA) or other legally constituted authority. 
 
 
 
Principal Investigator Signature 
Date 
 
 
Printed Name 
Institution 
City, Country 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Document 
Date 
Version 1.0, Original 
08 April 2021 
Version 2.0, Amendment 1 
01 December 2021 
Version 3.0, Amendment 2 
11 March 2022 
Version 4.0, Amendment 3 
05 December 2022 
Summary of Changes in Protocol Amendment 3, Version 4.0: 
 
 
 
Section Number and 
Heading 
Description of Change 
Brief Rationale 
1.1 Synopsis and  
1.2 Study Schema 
All applicable changes made in the 
corresponding sections in the protocol were 
included in the synopsis and study schema.  
See below for the rationale for 
specific changes. 
1.3 Schedule of Activities 
(SoA) 
x Added visit window of +7 days for the 
Week 26 visit. 
x Specified that all ECG data should be 
provided to the central reader within 72 hours, 
for assessment. 
x Clarified that IP should be dispensed ~ every 
4 weeks and that for QW dosing, every effort 
should be made to take IP on the same day of 
the week and must be at least 5 days between 
2 doses. 
x Removed the requirement for Medical 
Monitor (designee) approval if MRI-PDFF 
and/or DXA assessments are performed out of 
window and widened the window for post-
treatment DXA assessment.  
x Clarified the timepoint(s) at which 
endogenous FGF21 samples will be obtained.  
x Clarifications for study 
procedures. 
x Increased the threshold for screening NSC that 
would require further workup, from > 6.0 to 
> 15 nmol/mL and clarified requirements for 
values >15 nmol/mL on treatment. 
x To align NSC range to better 
monitor cortisol level. 
x Added Table 2 to describe the schedule of 
activities for the immunogenicity follow-up 
period of up to 
 with follow-up visits 
every 12 weeks after the Week 48 visit. 
x Added immunogenicity 
follow-up period to evaluate the 
long-term immunogenicity 
effects of pegozafermin. 
3.1 Main Study 
Objectives and Endpoints 
x Revised the primary endpoints definition to 
the endpoints specified in the original protocol 
and consistent with the primary efficacy 
endpoints outlined in the FDA draft guidance 
on developing drugs for noncirrhotic NASH 
with liver fibrosis. 
x To be consistent with the 
primary efficacy endpoints 
outlined in the FDA draft 
guidance. 
 
 
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Section Number and 
Heading 
Description of Change 
Brief Rationale 
x Moved the primary endpoints with the 
FULWHULRQRIµ-point improvement in NAS 
score’ to exploratory endpoints. 
x Clarified the safety endpoint definition for 
cortisol assessment and BMD assessment 
(main and extension study). 
x Removed the endpoint related to endogenous 
FGF21 in the Main study as there are no 
follow-up assessments during the main study.  
x Removed the redundant exploratory endpoint 
“At least a 2-point improvement in NAS with 
at least a 1-point improvement in ballooning 
or lobular inflammation, and fibrosis 
improvement 1 stage. 
x $GGHG³SHUFHQWDJHRIVXEMHFWVZLWK
decrease in ALT” as an exploratory endpoint 
in both Main and Extension Study. 
x Clarified the endpoint related to FibroScan in 
the Main Study and added the same endpoint 
in Extension Study. 
4.1 Overall Study Design x Included an immunogenicity follow-up period 
after the Week 48 visit, for immunogenicity 
assessment approximately every 3 months for 
up to 
. 
x To evaluate the long-term 
immunogenicity effects of 
pegozafermin. 
4.4 Study Duration 
x The total duration of study participation was 
revised from ~64 weeks to ~ 112 weeks. 
x Defined the Immunogenicity follow-up period 
and specified the duration.  
x To include the duration of the 
immunogenicity follow-up 
period. 
4.5 End of Study 
Definition 
x Clarified the definition of study completion 
and included the definition for end of 
immunogenicity follow-up period. 
x Clarification and additional 
information. 
5.2 Exclusion Criteria 
x # 25: Specified that study participants will not 
be allowed to participate in other 
interventional trials for FGF21 analog or 
FGFR1 activating products, during the 
immunogenicity follow-up period. 
x To avoid confounding factors in 
assessment of immunogenicity. 
6.4.3 Blinding 
x Clarified that specifically-identified Sponsor 
personnel will not be blinded and Sponsor 
personnel responsible for day-to-day study 
operations will remain blinded, including the 
Sponsor and CRO Medical Monitors.  
x Specified that a formal unblinding plan will be 
established prior to the unblinding for 
Week 24. 
x Additional information. 
6.5.1 Guidance for 
Missed Dose(s) 
x Clarified instructions for QW dosing, that 
every effort should be made to take IP on the 
same day of the week and must be at least 
5 days between 2 doses. 
x Clarification. 
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Section Number and 
Heading 
Description of Change 
Brief Rationale 
6.7.1 Prohibited 
Medications/Therapies 
x Included elective bone surgery for bone 
disorders as prohibited therapy. 
x Added that TNF antagonists, adalimumab, 
etanercept, certolizumab, infliximab or 
sulfasalazine for rheumatoid arthritis are 
prohibited during the Main Study but may be 
considered during the Extension Study. 
x For consistency with 
exclusionary criterion for bone 
surgeries. 
x Added that initiation of agents for 
uncontrolled hyperglycemia (but not weight 
loss) may be allowed during the Extension 
Study, with the Medical Monitor’s approval. 
x Additional information. 
x Specified that study participants will not be 
allowed to participate in other interventional 
trials for FGF21 analog or FGFR1 activating 
products, during the immunogenicity 
follow-up period.  
x To avoid confounding factors in 
assessment of immunogenicity. 
7.1 Discontinuation of IP 
and Subject withdrawal 
from the Study 
x Provided additional reasons for 
discontinuation of IP or subject withdrawal 
from the study: (i) evidence of hepatic 
decompensation as assessed by investigator 
(ii) MELD Na+ score (for F4 subjects only).  
x Added as safety measure for 
subjects with cirrhotic (F4) 
NASH. 
x Clarified the assessments to be performed for 
subjects who discontinue IP but do not 
withdraw from the study. 
x Clarification. 
7.1.2 Monitoring and 
Study Continuation of 
Subjects with NASH 
Fibrosis Stage F1 or F4 
(new section) 
x Provided further information on managing 
subjects in the study with NASH fibrosis stage 
F1 or F4. 
x Added as safety measure for 
subjects with cirrhotic (F4) 
NASH. 
x Clarification that F1 will 
continue as an exploratory 
population. 
8.2.5.1 Immunogenicity 
x Revised to specify that subjects who complete 
the Week 48 visit will be asked to return to 
clinic to have blood samples collected 
approximately every 3 months for up to 
 
 
x To evaluate the long-term 
immunogenicity effects of 
pegozafermin.  
 
x Added that the samples for endogenous 
FGF21 level will be collected at the 
immunogenicity follow-up visit(s) and 
clarified that samples will be analyzed only for 
subjects 
. 
x Clarification. 
8.2.5.2 Cortisol 
Assessments 
x Increased the threshold for screening NSC that 
would require further workup, from > 6.0 to > 
15 nmol/mL and clarified requirements for 
values >15 nmol/mL on treatment. 
x Changed threshold based on 
change in methodology and to 
relevant clinical levels for 
establishing hypercortisolism.  
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information 
x Added details on collection of AE and SAE 
information for the immunogenicity follow-up 
period. 
x Additional information based on 
inclusion of the immunogenicity 
follow-up period. 
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Section Number and 
Heading 
Description of Change 
Brief Rationale 
8.4 Pharmacokinetics 
x Specified that PK samples collected from 
subjects during the period when they are 
administered placebo will not be analyzed. 
x Clarification and additional 
information. 
8.5.1 Pharmacodynamics 
x Listed AFP and MELD Na+ score as 
parameters to be evaluated in F4 subjects only. 
x Additional information. 
9.1.1 Estimand 
Framework  
x Specified the primary estimand of interest and 
methods of handling the intercurrent events 
defined for the study. 
x Per ICH guidance for industry 
E9(R1) Statistical Principles for 
Clinical Trials: Addendum: 
Estimand and Sensitivity 
Analysis in Clinical Trials. 
9.2 Sample Size 
Determination 
x Revised the sample size justification and 
assumptions based on the revised primary 
endpoint definition. 
x To update the sample size 
determination section based on 
the revised primary endpoints. 
9.3 Population Analysis 
x Defined the MRI-PDFF analysis set and 
removed the definition of extension analysis 
set.  
x Defined the randomized analysis set.  
x To clarify analysis populations to 
be aligned with the study 
objectives. 
9.4 Statistical Analyses 
x Specified supportive analysis that will 
compare each QW and Q2W treatment arm to 
corresponding QW or Q2W placebo arm (not 
pooled).  
x To add the supportive analysis to 
assess the robustness of the 
primary analysis results. 
9.6 Primary Analysis 
x Specified that the list of Sponsor personnel 
unblinded to the summary results will be 
recorded in a separate document. 
x Additional information. 
9.7 Final Analysis  
x Clarified when the final analysis will be 
performed, as an immunogenicity follow-up 
period was added to the study. 
x Clarification. 
10.2 Clinical Laboratory 
Tests 
x Clarified the collection and follow-up details 
for NSC. 
x Clarified the visits at which full urinalysis 
should be performed. 
x Included AFP assessment as a laboratory 
parameter for F4 patients only.  
x Clarifications. 
10.8 Child-Turcotte- Pugh 
Classification (new) 
x Added the scoring parameters and 
interpretation for CTP score. 
x Additional information for 
guidance. 
Overall 
Editorial and formatting changes, including 
updates to references.  
To clarify and correct any errors 
or inconsistencies across 
sections.  
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Schema .............................................................................................................20 
1.3. 
Schedule of Activities (SoA) ......................................................................................22 
2. 
INTRODUCTION ......................................................................................................30 
2.1. 
Study Rationale ...........................................................................................................30 
2.2. 
Background .................................................................................................................30 
2.3. 
Benefit / Risk Assessment ..........................................................................................32 
2.3.1. 
Risk Assessment .........................................................................................................32 
2.3.2. 
Benefit Assessment .....................................................................................................32 
2.3.3. 
Overall Benefit Risk Assessment ...............................................................................33 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
3.1. 
Main Study Objectives and Endpoints .......................................................................34 
3.2. 
Extension Study Objectives and Endpoints ................................................................39 
4. 
STUDY DESIGN .......................................................................................................43 
4.1. 
Overall Study Design ..................................................................................................43 
4.2. 
Scientific Rationale for Study Design ........................................................................44 
4.3. 
Justification for Dose ..................................................................................................45 
4.4. 
Study Duration ............................................................................................................46 
4.5. 
End of Study and End of Immunogenicity Follow-up Period Definition ...................46 
5. 
ELIGIBILITY CRITERIA .........................................................................................47 
5.1. 
Inclusion Criteria ........................................................................................................47 
5.2. 
Exclusion Criteria .......................................................................................................48 
5.3. 
Lifestyle Considerations .............................................................................................52 
5.4. 
Screen Failures and Rescreening ................................................................................53 
6. 
INVESTIGATIONAL PRODUCT ............................................................................54 
6.1. 
Investigational Product Administered ........................................................................54 
6.2. 
Administration Instructions ........................................................................................55 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................55 
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6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................55 
6.4.1. 
Randomization and Stratification ...............................................................................55 
6.4.2. 
Assignment of Subject Number and Investigational Product .....................................56 
6.4.3. 
Blinding ......................................................................................................................56 
6.4.4. 
Unblinding of an Individual Subject ...........................................................................56 
6.5. 
Investigational Product Compliance ...........................................................................57 
6.5.1. 
Guidance for Missed Dose(s) .....................................................................................57 
6.6. 
Treatment of Overdose ...............................................................................................57 
6.7. 
Concomitant Therapy .................................................................................................58 
6.7.1. 
Prohibited Medications/Therapies ..............................................................................58 
6.8. 
Intervention after the End of Study ............................................................................59 
7. 
DISCONTINUATION OF IP AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................60 
7.1. 
Discontinuation of Investigational Product and Subject Withdrawal from the 
Study ...........................................................................................................................60 
7.1.1. 
Monitoring and Discontinuation for Suspected Drug-induced Liver Injury 
(DILI) ..........................................................................................................................61 
7.1.2. 
Monitoring and Study Continuation of Subjects with NASH Fibrosis Stage 
F1 or F4 .......................................................................................................................63 
7.1.3. 
Pregnancy ...................................................................................................................64 
7.2. 
Lost to Follow-up .......................................................................................................64 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................66 
8.1. 
Efficacy Assessments .................................................................................................66 
8.1.1. 
Liver Biopsy and Scoring ...........................................................................................66 
8.1.2. 
Magnetic Resonance Imaging – Whole Liver Proton Density Fat Fraction 
(MRI-PDFF) ...............................................................................................................67 
8.1.3. 
Transient Elastography (FibroScan®) kPa and CAP scores .......................................69 
8.1.4. 
Anthropometric Measurements ..................................................................................69 
8.1.5. 
Patient Reported Outcome ..........................................................................................69 
8.1.5.1. 
Chronic Liver Disease Questionnaire - NAFLD-NASH (CLDQ NAFLD-
NASH) ........................................................................................................................69 
8.1.5.2. 
Work Productivity and Activity Impairment Questionnaire for NASH 
(WPAI-NASH) ...........................................................................................................70 
8.1.5.3. 
Europe Quality of Life Group 5 Dimension 5 Level Questionnaire (EQ-5D-
5L) ...............................................................................................................................70 
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8.1.5.4. 
Liver-related Pain and Discomfort Questionnaire ......................................................70 
8.1.5.5. 
The Appetite Sensations Visual Analog Scale (VAS) ................................................70 
8.2. 
Safety Assessments .....................................................................................................71 
8.2.1. 
Physical Examinations/Assessment ............................................................................71 
8.2.2. 
Vital Signs ..................................................................................................................71 
8.2.3. 
Electrocardiograms .....................................................................................................71 
8.2.4. 
Bone Mass Density .....................................................................................................71 
8.2.5. 
Clinical Safety Laboratory Assessments ....................................................................71 
8.2.5.1. 
Immunogenicity Assessments ....................................................................................72 
8.2.5.2. 
Bone Marker Assessments ..........................................................................................73 
8.2.5.3. 
Cortisol Assessments ..................................................................................................73 
8.3. 
Adverse Events and Serious Adverse Events .............................................................73 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................74 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................74 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................74 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................75 
8.3.5. 
Pregnancy ...................................................................................................................76 
8.4. 
Pharmacokinetics ........................................................................................................76 
8.5. 
Pharmacodynamics and Biomarkers ...........................................................................76 
8.5.1. 
Pharmacodynamics .....................................................................................................76 
8.5.1.1. 
N-terminal Propeptide of Type III Collagen (Pro-C3) ...............................................77 
8.5.1.2. 
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ........................77 
8.5.1.3. 
Enhanced Liver Fibrosis (ELF) Panel ........................................................................77 
8.5.1.4. 
FIB-4 Index .................................................................................................................77 
8.5.1.5. 
Exploratory Biomarker Assessments ..........................................................................78 
8.6. 
Pharmacogenomics Assessments ................................................................................78 
9. 
STATISTICAL CONSIDERATIONS .......................................................................79 
9.1. 
Statistical Hypotheses .................................................................................................79 
9.1.1. 
Estimand Framework ..................................................................................................79 
9.2. 
Sample Size Determination ........................................................................................80 
9.3. 
Populations for Analyses ............................................................................................81 
9.4. 
Statistical Analyses .....................................................................................................82 
9.4.1. 
Efficacy Analyses .......................................................................................................82 
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9.4.2. 
Safety Analyses ..........................................................................................................83 
9.4.3. 
PK Analyses ................................................................................................................83 
9.5. 
Interim Analyses .........................................................................................................83 
9.6. 
Primary Analysis ........................................................................................................83 
9.7. 
Final Analyses ............................................................................................................83 
9.8. 
Data Monitoring Committee (DMC) ..........................................................................84 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................85 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................85 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................85 
10.1.2. 
Financial Disclosure ...................................................................................................85 
10.1.3. 
Informed Consent Process ..........................................................................................86 
10.1.4. 
Data Protection ...........................................................................................................86 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................86 
10.1.6. 
Data Quality Assurance ..............................................................................................86 
10.1.7. 
Source Documents ......................................................................................................87 
10.1.8. 
Study and Site Closure ................................................................................................88 
10.1.9. 
Publication Policy .......................................................................................................88 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................89 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................92 
10.3.1. 
Definition of AE .........................................................................................................92 
10.3.2. 
Definition of Suspected and Unsuspected Adverse Reaction .....................................93 
10.3.3. 
Definition of Events to Monitor .................................................................................93 
10.3.4. 
Definition of SAE .......................................................................................................93 
10.3.5. 
Recording and Follow-Up of AE and/or SAE ............................................................94 
10.3.6. 
Reporting of SAEs ......................................................................................................96 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................97 
10.5. 
Appendix 5: Pharmacogenomics ................................................................................99 
10.6. 
Appendix 6: Guidance to Address a Pandemic or Other Global Health 
Emergencies and Potential Impact on the Clinical Study ...........................................99 
10.7. 
Appendix 7: Prescreening Criteria for Identifying Potential Subjects with 
NASH and Stage 2 or 3 Fibrosis ...............................................................................104 
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10.8. 
Appendix 8: Child-Turcotte-Pugh Classification for Severity of Liver 
Disease ......................................................................................................................105 
10.9. 
Appendix 9: Glossary ...............................................................................................106 
10.10. 
Appendix 10: Protocol Amendment History ............................................................110 
11. 
REFERENCES .........................................................................................................115 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................22 
Table 2: 
Schedule of Activities (Immunogenicity Follow-up Period) ......................................29 
Table 3: 
Discontinuation Criteria in Subjects with Abnormal Baseline ALT or AST 
Values .........................................................................................................................63 
Table 4: 
Adverse Event Reporting Periods ...............................................................................74 
Table 5: 
Protocol-Required Laboratory Assessments ...............................................................89 
 
LIST OF FIGURES 
Figure 1: 
BIO89-100-122 Study Schema ...................................................................................20 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety and Tolerability of BIO89-100 in Subjects with Biopsy-Confirmed 
Nonalcoholic Steatohepatitis (NASH) 
Short Title: The ENLIVEN Study 
Study Rationale 
BIO89-100 (pegozafermin), developed by 89bio, is a glycoPEGylated analogue of fibroblast 
growth factor 21 (FGF21), an endogenous metabolic hormone secreted by the liver, adipose 
tissue, skeletal muscle, and the pancreas, that is regulated by nutritional status and affects energy 
expenditure and glucose and lipid metabolism (Arner, 2008; Lee, 2014; Park, 2016). 
In patients with nonalcoholic steatohepatitis (NASH), circulating and tissue levels of FGF21 are 
increased, correlate with disease severity, and are normalized by therapeutic interventions 
(Struik, 2019), indicating the presence of FGF21 resistance that is at least in part attributable to 
downregulation of fibroblast growth factor receptor 1 (FGFR1) DQGȕ-Klotho expression in the 
liver (Oh, 2012). 
Administration of exogenous FGF21 is being explored as a method to treat obesity-associated 
insulin-resistance disorders including NASH, the higher-risk variant of nonalcoholic fatty liver 
disease (NAFLD). There are currently no approved pharmaceutical treatments for 
NASH(Friedman, 2018). Several nonclinical and clinical studies have shown that administration 
of various FGF21 analogues had beneficial effects on serum lipids and insulin-resistance as well 
as on liver fat, liver enzymes and liver histology (Gaich, 2013; Zhang, 2014; Sanyal, 2019; 
Kaufman, 2020). 
This randomized, double-blind, placebo-controlled Phase 2b study is designed to assess the 
efficacy, safety, and tolerability of 3 dose regimens of pegozafermin (2 dose levels to be 
administered weekly [QW] and one dose level to be administered once every 2 weeks [Q2W]) in 
subjects with biopsy-FRQILUPHG1$6+1$)/'DFWLYLW\VFRUH>1$6@ILEURVLVVWDJH F2 or F3 
[NASH CRN system]). The study will allow evaluation of the potential histological benefit of 
pegozafermin in the target population. 
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Objectives and Endpoints (Primary, Secondary and Safety) 
Main Study Objectives and Endpoints 
 
1 Resolution of NASH includes the total absence of ballooning (score=0) and absent or mild inflammation (score 0 
to 1).  
:RUVHQLQJRIILEURVLVLVGHILQHGDVSURJUHVVLRQRIILEURVLVVWDJH 
Worsening of NASH is defined as increase in NAS for ballooning, inflammation, or steatosis 
2 UHGXFWLRQ from baseline in liver fat by MRI-PDFF 
3 8/RU reduction from baseline in ALT 
Objectives 
Endpoints 
Primary 
x To evaluate the effect of 
pegozafermin on liver histology after 
24 weeks of treatment 
x Proportion of subjects with NASH 
resolution without worsening of fibrosis1 
at Week 24 compared to baseline.  
x Proportion of subjects achieving 
iPSURYHPHQWRIILEURVLVVWDJHZLWKRXW
worsening of NASH at Week 24 
compared to baseline. 
Key Secondary 
 
x To further evaluate the effect of 
pegozafermin on liver histology after 
24 weeks of treatment 
x Proportion of subjects with at least a 
2-point improvement in NAS and no 
worsening of fibrosis at Week 24 
compared to baseline. 
x Proportion of subjects with NASH 
UHVROXWLRQ$1'ILEURVLVLPSURYHPHQW
stage at Week 24 compared to baseline. 
x 3URSRUWLRQRIVXEMHFWVZLWK 2-point 
improvement in NAS score AND are 
MRI-PDFF responders2 AND ALT 
responders3 at Week 24 compared to 
baseline.  
Secondary 
 
x To evaluate the effects of 
pegozafermin on liver parameters  
x Absolute change and percentage change 
from baseline at Week 12 and Week 24 
in: 
 Hepatic fat fraction by magnetic 
resonance imaging - proton density 
fat fraction (MRI-PDFF) 
 Alanine aminotransferase (ALT) 
 N-terminal type III collagen 
propeptide (Pro-C3) 
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Objectives 
Endpoints 
x To evaluate the metabolic effects of 
pegozafermin  
x Absolute and percent change from 
baseline at Weeks 12 and 24 in: 
 Adiponectin 
 Serum triglycerides 
 High density lipoprotein cholesterol 
(HDL-c) 
 Non-HDL-c 
 Low density lipoprotein-cholesterol 
(LDL-c) 
 Glycated hemoglobin (HbA1c) 
x To characterize pegozafermin 
pharmacokinetics (PK) profile  
x Trough concentration of pegozafermin 
Safety 
x To evaluate the safety and tolerability 
of pegozafermin  
x Frequency and severity of treatment-
emergent adverse events (TEAEs) and 
serious adverse events (SAEs) 
x Number of subjects who discontinued due 
to TEAEs and due to related TEAEs 
x Incidence and shifts of clinically 
significant physical examination findings, 
electrocardiogram (ECG) data and 
laboratory abnormalities; safety 
laboratory evaluations include 
hematology, blood biochemistry and 
urinalysis, serum, salivary, and urinary 
cortisol as appropriate 
x Change from baseline in 
– Insulin-like growth factor 1 (IGF-1) 
– Bone biomarkers: Carboxy-terminal 
collagen crosslinks (CTX), N-
terminal propeptide of type 1 
collagen (P1NP) and osteocalcin 
– Thyroid stimulating hormone (TSH) 
x $EVROXWHDQGFhange from baseline in 
lumbar spine, total hip, and femoral neck 
bone mineral density (BMD) as assessed 
by dual X-ray absorptiometry (DXA) 
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Extension Study Objectives and Endpoints 
 
 
Objectives 
Endpoints 
Primary 
x To evaluate the long-term safety and 
tolerability of pegozafermin 
x Frequency and severity of TEAEs and 
SAEs at Week 48 
Secondary 
 
x To characterize effect of 
pegozafermin on liver parameters 
x Absolute change and percent change from 
baseline at Week 48 in: 
 Hepatic fat fraction by MRI-PDFF 
 ALT 
 Pro-C3 
x To characterize pegozafermin PK 
profile  
x Trough concentration of pegozafermin 
Safety 
x To evaluate additional safety and 
tolerability measures 
x Number of subjects who discontinued due 
to TEAEs and due to related TEAEs 
x Incidence and shifts of clinically 
significant physical examination findings, 
ECG data and laboratory abnormalities; 
safety laboratory evaluations include 
hematology, blood biochemistry and 
urinalysis, serum, salivary, and urinary 
cortisol as appropriate 
x Change from baseline in 
 IGF-1 
Objectives 
Endpoints 
x To evaluate the immunogenicity of 
pegozafermin  
x Incidence and characteristics of antidrug 
antibodies (ADA) and neutralizing 
antibody (NAb) after dosing (e.g., titer 
and binding specificity, to the FGF21 and 
polyethylene glycol [PEG] part of 
pegozafermin) 
x Impact of the presence of ADAs on serum 
pegozafermin concentrations and clinical 
safety 
 
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Objectives 
Endpoints 
 Bone biomarkers: CTX, P1NP and 
osteocalcin 
 TSH 
x $EVROXWHDQGFhange from baseline in 
lumbar spine, total hip, and femoral neck 
BMD as assessed by DXA 
x To evaluate the immunogenicity of 
pegozafermin over time 
x Incidence and characteristics of ADA and 
NAb after dosing (e.g., titer and binding 
specificity, to the FGF21 and PEG part of 
pegozafermin) 
x Impact of the presence of ADAs on serum 
pegozafermin concentrations and clinical 
safety 
x Levels of endogenous FGF21 at 
immunogenicity follow-up visit(s) 
compared to baseline in 
 
subjects 
 
Overall Design 
This is a randomized, double-blind, placebo-controlled, 2-part study to evaluate efficacy, safety, 
tolerability, population PK and pharmacodynamic (PD) profiles and immunogenicity of 
pegozafermin administered subcutaneously (SC) in approximately 184 subjects with biopsy-
FRQILUPHG1$6+1$6ILEURVLVVWDJH F2 or F3 per NASH Clinical Research Network 
(CRN) system). The first part of the study will be double-blind, and the second part of the study 
will be single-blind (specifically-identified Sponsor personnel will not be blinded). Study schema 
is shown in Section 1.2. 
The study will include 2 parts: 
x Main study – a 24-week, double-blind, placebo-controlled study 
x Extension study – an additional 24-week, single-blind, placebo-controlled study 
The entire study will include a Screening period, a Treatment period (Main and Extension), and a 
Follow-up period. Study visits and assessments will be conducted in-clinic and/or remotely as 
shown in the schedule of activities (SoA) in Section 1.3 and described in Section 4.1. 
Throughout the study (Main and Extension), subjects will be evaluated as specified in the SoA. 
All subjects will be followed-up for at least 4 weeks after last dose of investigational product 
(IP). 
For post-treatment immunogenicity assessment, subjects who complete the Week 48 visit will be 
asked to return to clinic to have blood samples collected approximately every 3 months for up to 
 AEs and concomitant medications will also be recorded during the immunogenicity 
follow-up period. Additional testing may be requested in the event of safety-related concerns. 
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The sponsor may elect to terminate participation in the immunogenicity follow-up period based 
on emerging data. Subjects who terminate IP early will not return for immunogenicity follow-up, 
unless asked to return for additional testing(s), at the Medical Monitor’s discretion. 
Main Study 
After signing informed consent, subjects will undergo screening assessments to determine 
eligibility over a period of 12 weeks. In line with the FDA guidance, in instances where COVID-
19 pandemic restrictions or logistical scheduling challenges may be of concern, the screening 
period may be extended beyond 12 weeks with Sponsor approval(FDA, August 2021).  
On Day 1 (baseline), eligible subjects will be randomized 16:8:6:24:15 to Placebo QW, Placebo 
Q2W, pegozafermin 15 mg QW, 30 mg QW and 44 mg Q2W, respectively. The randomization 
will be stratified by Type 2 diabetes mellitus (T2DM) status (yes vs no) and fibrosis stage (F2 vs 
F3). For the purposes of stratification, subjects will be considered to be T2DM status positive if 
any of the following criteria are met: current medical history of T2DM, current use of anti-
glycemic medication(s) for T2DM, or screening laboratory values of for HbA1c RU
mg/dL for fasting plasma glucose. IP will be administered over 24 weeks (includes 24 
administrations in QW dose regimen and 12 administrations in Q2W dose regimen). In the Main 
study, subjects, investigators and site staff, and Sponsor will be blinded to IP (placebo or 
pegozafermin); however, the dose regimen (QW or Q2W) will be known to all parties involved 
in the study. Subjects will undergo a second liver biopsy at the Week 24 visit (window of -7 days 
to +14 days). Liver biopsies will be read centrally by liver pathologists who are blinded to the 
treatment group assignment (refer to Section 6.4.3 for details). 
Extension Study 
Subjects completing the Main study will continue for an additional 24 weeks in the Extension 
study. The Extension study will commence at Main study Week 24 visit. At Week 24, subjects 
randomized to placebo QW in the Main study will be re-randomized 1:1 to pegozafermin 30 mg 
QW (n=21) or placebo QW (n=21) and receive the re-randomized treatment beginning at the 
Week 26 visit (which may be an in-clinic or a remote home visit). All other subjects will 
continue to receive the same treatment regimen in the Extension study that they received during 
the Main study. IP will be administered over 24 additional weeks (includes 24 administrations in 
QW dose regimen and 12 administrations in Q2W dose regimen), for approximately 48 weeks of 
treatment over the entirety of the study (Main and Extension). In the Extension study, 
specifically-identified Sponsor personnel will not be blinded; however, subjects, investigators 
and site staff will remain blinded to IP (placebo or pegozafermin). Dose regimen (QW or Q2W) 
will be known to all parties in the Extension study. 
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Number of Subjects and Intervention Groups 
A total of approximately 184 subjects are planned in the Main study as follows: 
Treatment Group 
Dose 
Frequency 
Route of Administration 
Number of subjects 
Placebo 
- 
QW 
SC 
42*  
Placebo 
- 
Q2W 
SC 
22 
Pegozafermin 
15 mg 
QW 
SC 
16 
Pegozafermin 
30 mg 
QW 
SC 
64 
Pegozafermin 
44 mg 
Q2W 
SC 
40 
Abbreviations: QW, weekly; Q2W, every 2 weeks; SC, subcutaneously 
* At Week 24, subjects randomized to placebo QW in the Main study will be re-randomized 1:1 to pegozafermin 
30 mg QW (n=21) or placebo QW (n=21) 
Study Duration 
For each subject, the total duration of study participation will be up to approximately 112 weeks: 
Screening Period: 
Up to 12 weeks, which may be extended with Sponsor’s approval 
Main Study 
Treatment Period: 
24 weeks (includes 24 administrations in QW dose regimen and 
12 administrations in Q2W dose regimen) 
Extension Study 
Treatment Period: 
24 weeks (includes 24 administrations in QW dose regimen and 
12 administrations in Q2W dose regimen) 
Extension Study 
Follow-up Period: 
 
Approximately 4 weeks from last dose of IP. 
 
Immunogenicity 
Follow-up Period 
Approximately 
 from last dose of IP 
Data Monitoring Committee: Yes 
An independent DMC will periodically review overall unblinded safety data per DMC charter. 
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1.2. 
Study Schema 
Figure 1: 
BIO89-100-122 Study Schema 
 
Notes: The 12-week screening period may be extended with Sponsor’s approval. Subjects, investigators and site staff and Sponsor will be blinded to 
investigational product (placebo or pegozafermin) in the Main study. During the Extension study, the Medical Monitor will remain blinded to treatment 
assignment. Designated members of the unblinded team are specified in the Sponsor Unblinding Plan. Subjects, investigators, and site staff will remain blinded 
to IP. However, the dose regimen (QW or Q2W) will be known to all parties involved in both the Main and Extension study. 
Subject assigned to placebo QW in the Main study will be re-randomized 1:1 to pegozafermin 30 mg QW or placebo QW at the Week 24 visits and will receive 
the re-randomized treatment at the Week 26 visit. 
Treatment duration for Main Study includes 24 administrations in QW dose regimen and 12 administrations in Q2W dose regimen + 1 week for evaluation of 
endpoints (Week 24); treatment duration for Extension includes 24 administrations in QW dose regimen and 12 administrations in Q2W dose regimen + 1 week 
for evaluation of endpoints (Week 48). 
• 
ENiiven 
Consent 
Main Study 
"t/ 
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(.) 
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12 weeks 
E 
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· -
T""" - .. 
ct! -.::t" 
NN 
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0 co 
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C CO 
ct! T""" 
0::: 
(24 Weeks; Double blind) 
LEGEND 
Liver biopsy (central read) 
Screening biopsy (fresh or archival within 6 months of screening) 
Week 24 biopsy (-7 to +14 days of scheduled Week 24 visit) 
I 
MRI-POFF 
Extension Study ---
(24 Weeks; Single blind) 
?/ ·:. ·,, ,: :'i Placebo QW (N=21J,;,:, ;'.,;/;%,,:,1 
EOS 
E 4 weeks 
) 
"t/ 
Week48 
I 
Week 24 
Primary Analysis 
I 
Week 51 
Final Analysis 
Abbreviations: EOS, end of study; QW, weekly; Q2W, every other week; R, Al Week 24, subjects randomized lo placebo QW in the Main study will be re-randomized 1:1 lo pegozafermin 30 mg (n=21) or placebo QW (n=21) 
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The study includes an immunogenicity follow-up period of up to 
 with follow-up visits approximately every 12 weeks after the Week 48 visit.  
Abbreviations: EOS, end of study; QW, weekly; Q2W, every 2 weeks, R, randomization. 
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1.3. 
Schedule of Activities (SoA) 
Table 1: Schedule of Activities 
Subjects will attend clinic visits for Screening, Baseline (Day 1), Week 4, Week 12, Week 24, Week 38 and Week 48/ET.  
Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy 
X a 
 
 
 
 
 
Xb 
 
 
 
 
Xc 
 
Liver biopsies should ideally be done after MRI-PDFF. 
a. Must meet study inclusion criteria. A biopsy performed 
within 6 months of screening is acceptable instead of the 
baseline liver biopsy if the sample is deemed interpretable and 
eligible by the central reader. 
b. To be performed at -7 to +14 days of the Week 24 target visit; 
if biopsy not performed by Week 26 for subjects in QW groups, 
W26 dose to be held until discussion with Sponsor 
c. Applicable for subjects who discontinue IP at or after Week 
16 and before Week 24 of the Main study. 
Histology machine read 
(PathAI) 
X 
 
 
 
 
 
X 
 
 
 
 
Xc 
 
c. Applicable for subjects who discontinue IP at or after Week 
16 and before Week 24 of the Main study. 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
B 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
Complete physical exam 
Xd 
 
 
 
 
 
X 
 
 
 
X 
 
 
d. includes recording height, weight, and calculating BMI. 
Limited physical 
assessmente 
 
B 
X X X 
X 
 
 
X 
X 
 
X 
 
e. if clinically indicated. May be performed by home health 
nurse for remote visits. 
Body weight 
X 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
The Investigator will be requested to further evaluate subjects 
ZLWKZHLJKWORVVRI.0DW:HHNDQG.0DW:HHN
24, from baseline, for the potential cause of weight loss. 
Waist and hip 
circumference 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
Lifestyle counseling 
X 
X 
X X X 
X 
X 
 
X 
X 
 
 
 
Strenuous exercises should be avoided for at least 48 hours prior 
to study visits. 
Fibroscan VCTE and 
CAP 
Xf 
 
 
 
 
 
X 
 
 
 
X 
X 
 
f. Fibroscan should ideally be performed prior to MRI-PDFF. 
At Screening, a historical Fibroscan assessment performed 
within the last 3 months prior to screening may be acceptable. 
12-lead ECG (single)g 
X 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
g. ECGs will be recorded as single bedside measurements. 
Additional ECG may be conducted if clinically indicated. ECG 
should be performed prior to vital signs and laboratory 
assessments. All ECG data should be provided within 72 hours 
to the central reader for assessment. 
Urine drug screen  
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
h. Urine drug screen will be done locally with a standardized kit 
during screening period by Day 1. If cannot be performed 
during screening, test can be performed on Day 1, but must be 
completed before randomization procedures start. Refer to 
Appendix 2 (Section 10.2). 
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Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
Hematology, and 
coagulation factors  
X 
B 
X  
X 
 
X 
 
X 
X 
X 
X 
 
Refer to Appendix 2 (Section 10.2) for laboratory parameters. 
Biochemistry 
Xi 
B 
X X X 
 
X 
 
X 
X 
X 
X 
 
Refer to Appendix 2 (Section 10.2) for laboratory parameters. 
i. For all subjects, ALT and AST will be collected twice during 
the Screening period at least 2 weeks apart between the 1st and 
2nd assessment. A 3rd assessment, if required, will be collected 
via unscheduled visit, and performed at least 1 week apart from 
the 2nd assessment (refer to Exclusion criterion in Section 5.2.) 
FSH  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Only if required to confirm menopausal status in women under 
the age of 45 who have amenorrhea >12 months and are not 
using hormonal contraception or hormone replacement therapy. 
LH, FSH, Estradiol 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Only for WOCBP who are not on hormonal contraception. 
Urinalysis 
X 
B 
X  
X 
 
X 
 
 
X 
X 
X 
 
 
HbA1c 
X 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
HOMA-IR 
X 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
IGF-1 
 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to Appendix 2 (Section 10.2) for laboratory parameters 
(HBsAg, HCV and HIV 1 and 2 antibodies [HCV RNA reflex 
for HCV Ab+ only]). 
Thyroid panel (TSH, 
FT4, TT3) 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
 
 
Pregnancy test in 
WOCBP onlyj 
X (Serum) 
B 
X X X 
X 
X 
 
X 
X 
X 
X 
 
j. Serum pregnancy test will be conducted at Screening; at all 
other timepoints urine pregnancy test will be done. For in-clinic 
visits at the indicated timepoints, a urine pregnancy test will be 
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Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
obtained locally. If the urine test is positive, dosing should be 
withheld, a confirmatory serum pregnancy test should be sent to 
the central laboratory, and the Sponsor should be notified. 
Vital signsk 
(blood pressure, pulse, 
body temperature, and 
respiratory rate) 
X 
B 
X X X 
X 
X 
 
X 
X 
X 
X 
 
k. Vital signs will be measured prior to scheduled blood draws. 
Starting from randomization, blood pressure and pulse will be 
measured in duplicate, the first measurement will be taken up to 
15 minutes before the indicated timepoint. Additional vital signs 
measurement may be done if clinically indicated. Subjects must 
be in a supine or semi-erect/seated position and resting for at 
least 5 minutes prior to measurements. Repeat measurements 
should be performed according to local practice. 
Patient reported 
outcomes 
 
B 
 
 
B 
 
B 
 
 
 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
Xl 
 
 
 
 
 
 
l. for extension study (Placebo QW) 
At Week 24, subjects randomized to placebo QW in the Main 
study will be re-randomized 1:1 to pegozafermin 30 mg QW 
(n=21) or placebo QW (n=21).  
Dispense IP 
 
X 
<=========Xm ==========> 
 
 
 
m. Sponsor-approved courier services may provide IP to 
subjects from Week 4 through EOS. Depending on geography 
this may be direct-to-subject shipment or may require site to-
subject shipment. Instructions for dispensation and IP shipment 
to site and direct-to-subject shipment will be detailed in the 
Pharmacy Manual. IP should be dispensed approximately every 
4 weeks 
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Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
IP administrationn 
 
X 
QW from 
Weeks 1 to 23 
QW from Weeks 
24o to 47 
 
 
 
Dosing window is ±2 days; however for QW dosing, every 
effort should be made to take IP on the same day of the week 
and must be at least 5 days between 2 doses. IP will be 
administered SC to the abdomen by trained and qualified study 
personnel, site staff at clinic visit(s), or at home by healthcare 
professional, or subject’s caregiver for home administration. IP 
may also be self-administered at the subject’s home. 
o. Week 26 may be an in-clinic or a remote/home visit by 
healthcare professional who will administer the IP. 
Q2W from 
Weeks 2 to 22 
Q2W from Weeks 
24 to 46 
 
 
 
PK blood collectionp 
 
B 
B B 
B 
 
B 
 
 
B 
X 
X 
 
p. PK blood samples will be collected predose. Additional blood 
samples for PK analysis may be collected if clinically indicated 
(e.g., in case of SAE). For PK sample collection instruction/ 
procedures, refer to the relevant manual. 
ELF panel, Pro-C3, 
adiponectin, FIB-4 index 
(derived calculation), and 
adipo-IR (fasting free 
fatty acids x fasting 
insulin) 
 
B 
 
 
X 
 
X 
 
 
X 
X 
X 
 
Refer to Appendix 2 (Section 10.2). 
Night-time salivary 
cortisol (NSC)q 
Xq 
 
 
 
X 
 
X 
 
 
X 
X 
X 
 
q. NSC sample will be collected by subject at home between 
8:00pm and 12:00am before submitting the sample for 
processing at the specified visit. If the sample is not collected 
between 8:00pm and 12:00am, the test should be repeated. The 
screening assessment should be performed as early as possible 
during the screening period. Subjects should be provided with 
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Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
NSC collection kit at the first screening visit, when possible, to 
allow sample collection return at the following clinic visit. If 
screening value is >15 nmol/L, Medical Monitor (or designee) 
may request further workup should the value be of clinical 
concern; however, values >15 nmol/L will not be exclusionary. 
The screening NSC is a safety assessment, and not an I/E 
criteria. Refer to Section 10.2 for further requirements for 
values >15 nmol/L on treatment (Section 10.2).  
MRI-PDFF 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
At Screening, MRI-PDFF should ideally be done before liver 
biopsy. At Screening, a historical MRI-PDFF assessment 
performed within the last 3 months prior to screening may be 
acceptable if the images are available and evaluable by the 
central imaging vendor. 
On treatment, MRI-PDFF should ideally be done within ± 7 
days of the target visit date. If out of the window, MRI-PDFF 
should be performed as close to the target visit date. 
cT1 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
Iron-corrected T1 mapping. 
Applicable only at sites capable of conducting cT1 imaging.  
At Screening, a historical cT1 assessment performed within the 
last 3 months prior to screening may be acceptable if the images 
are available and evaluable by the central imaging vendor. 
Liver/Spleen volume and 
pancreatic fat 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
To be done at the same time as MRI-PDFF. 
At Screening, a historical liver/spleen volume and pancreatic fat 
assessment performed within the last 3 months prior to 
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Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, predose; CTX, carboxy-terminal collagen crosslinks; D, Day; 
ECG=electrocardiogram; ELF, enhanced liver fibrosis; EOS, end of study; ET= early termination; FGF21, fibroblast growth factor 21; FIB-4, Fibrosis-4 index; FU, 
Follow-Up; HbA1c= glycated hemoglobin; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HOMA-IR, 
Assessments 
Screening 
Period1 
Treatment Period 
FU Period 
Notes: 
1. Individual assessments may be done remotely as part of tiered 
screening. Screening period may be extended with Sponsor’s 
approval 
2. Clinic visit only (Baseline; Randomization Day) 
3. If a required clinic visit is not possible, contact the Medical 
Monitor (or designee) and refer to Section 10.6 (Appendix 6). 
4. May be a remote (home) visit  
5. May be a remote (home) visit for IP administration  
6. ET assessments to be performed for subjects who withdraw 
from study prematurely 
7. Site staff to contact subject to assess for AEs and concomitant 
medications 
Main Study 
Extension Study 
Study Day 
 
12 
 
 
 
 
 
 
 
 
 
 
 
Study Weeks -12 to 0 
 
43 84 123 164 243 265 304 383 483 ET3,6 517/ 
EOS 
Visit window (days) 
 
 
±2 ±7 ±7 ±7 +7 +7 ±7 ±14 +14 
 
±14 
screening may be acceptable if the images are available and 
evaluable by the central imaging vendor. 
Bone Mineral Density 
(BMD) by Dual X Ray 
Absorptiometry (DXA)r 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
r. DXA should be done within -14/+7 days of the target visit 
date. If out of the window, DXA should be performed as close 
to the target day as possible. 
Plasma for bone 
biomarkers analysis 
 
B 
 
 
X 
 
X 
 
 
 
X 
X 
 
Includes CTX, P1NP, and osteocalcin; refer to Appendix 2 
(Section 10.2). 
Endogenous FGF21s 
 
B 
 
 
 
 
 
 
 
 
 
 
 
s. Baseline samples of endogenous FGF21 will be obtained in 
all subjects; additional samples will be obtained at the 
immunogenicity follow-up visits (See Table 2). Endogenous 
FGF21 samples (baseline and follow-up visit) will be analyzed 
only in subjects with neutralizing ADAs. 
Immunogenicity 
 
B 
X X X 
 
X 
 
 
X 
Xt 
X 
 
t. See Table 2 for immunogenicity follow-up. 
 
Pharmacogenomic 
(DNA) blood sampling 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Optional. 
Blood sample for 
exploratory biomarkers 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
Adverse event 
monitoringu 
X 
X 
<============X =============> 
X 
X 
u. The sites may take non-personally identifying photographs of 
potential injection site reactions (optional). 
Concomitant medications 
X 
X 
<============X =============> 
X 
X 
 
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homeostatic model assessment for insulin resistance; I/E, inclusion/exclusion; IGF-1, insulin-like growth factor 1; IP, investigational product; LH, luteinizing 
hormone; MRI-PDFF, magnetic resonance imaging based proton density fat fraction; NSC, night-time salivary cortisol; P1NP, N-terminal propeptide of type 1 
collagen; PK=pharmacokinetic; Pro-C3, 1ဨWHUPLQDOSURSHSWLde of type III collagen; QW, once weekly; Q2W, every 2 weeks; S, serum; TSH, thyroid stimulating 
hormone; WOCBP=women of child-bearing potential 
Table 2: Schedule of Activities (Immunogenicity Follow-up Period) 
Abbreviations: FGF21 = fibroblast growth factor 21; FU = follow-up; Nab+ = Neutralizing antibody positive 
 
 
 
 
 
 
Assessments 
Immunogenicity Follow-up Period 
Notes: 
1. Informed consent (addendum) for the immunogenicity follow-
up period will be performed at the subject’s next scheduled 
visit from the effective date of Protocol Amendment 3 
informed consent. For subjects who have completed the study 
and  3 months have elapsed since last dose, informed consent 
should be obtained as soon as possible.  
2. Subjects who terminate IP early will not return for 
immunogenicity follow-up, unless asked to return for 
additional testing(s), at the Medical Monitor’s discretion. 
Visit FU Visit 1 
FU Visit 2 
FU Visit 3 
FU Visit 4 
Study Week 
60 
72 
84 
96 
Visit Window (Days) 
± 14 
± 14 
± 14 
± 14 
Immunogenicitya 
X 
X 
X 
X 
a. Subjects who complete the Week 48 visit will be asked to 
return to clinic to have blood samples collected approximately 
every 3 months for up to 
. Additional testing may be 
requested in the event of safety-related concerns. The sponsor 
may elect to terminate participation in the immunogenicity 
follow-up period based on emerging data.  
Endogenous FGF21b 
 
X 
 
X 
b. Endogenous FGF21 samples will only be analyzed for NAb+ 
subjects. 
Adverse event monitoringc 
X 
X 
X 
X 
c. Immunogenicity testing for a longer follow-up may be 
requested in the event of safety-related concerns. 
Concomitant medicationsd 
X 
X 
X 
X 
d. Changes and new concomitant medication will be recorded.  
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
BIO89-100 (hereafter referred to as pegozafermin), developed by 89bio, is a glycoPEGylated 
analogue of fibroblast growth factor 21 (FGF21), an endogenous metabolic hormone secreted by 
the liver, adipose tissue, skeletal muscle, and the pancreas, that is regulated by nutritional status 
and affects energy expenditure and glucose and lipid metabolism (Arner, 2008; Lee, 2014; Park, 
2016). 
In patients with nonalcoholic steatohepatitis (NASH), circulating and tissue levels of FGF21 are 
increased, correlate with disease severity, and are normalized by therapeutic interventions 
(Struik, 2019), indicating the presence of FGF21 resistance that is at least in part attributable to 
downregulation of fibroblast growth factor receptor (FGFR1) DQGȕ-Klotho expression in the 
liver (Oh, 2012). 
Administration of exogenous FGF21 is being explored as a method to treat obesity-associated 
insulin-resistance disorders including NASH, the higher-risk variant of nonalcoholic fatty liver 
disease (NAFLD). There are currently no approved pharmaceutical treatments for NASH 
(Friedman, 2018). Several nonclinical and clinical studies have shown that administration of 
various FGF21 analogues had beneficial effects on serum lipids and insulin-resistance as well as 
on liver fat, liver enzymes and liver histology (Gaich, 2013; Zhang, 2014; Sanyal, 2019; 
Kaufman, 2020). 
This randomized, double-blind, placebo-controlled Phase 2b study is designed to assess the 
efficacy, safety and tolerability of 3 dose regimens of pegozafermin (2 dose levels to be 
administered weekly [QW] and one dose level to be administered once every 2 weeks [Q2W]) in 
subjects with biopsy-FRQILUPHG1$6+1$)/'DFWLYLW\VFRUH>1$6@ILEURVLVVWDJH F2 or F3 
per NASH Clinical Research Network (CRN) system). The study will allow evaluation of the 
potential histological benefit of pegozafermin in the target population. 
2.2. 
Background 
1$6+LVDFKURQLFOLYHUGLVHDVHFKDUDFWHUL]HGKLVWRORJLFDOO\E\KHSDWLFVWHDWRVLV
inflammation and hepatocellular injury (ballooning) (Chalasani, 2012). It is part of the spectrum 
of NAFLD, which is the most common chronic liver disease in North America and Europe. The 
NAFLD spectrum ranges from bland steatosis with or without inflammation (nonalcoholic fatty 
liver) to steatosis plus inflammation and hepatocellular injury, i.e., NASH, fibrosis and cirrhosis 
(Estes, 2018; Chen, 2020). 
The pathophysiologic mechanisms that lead to NAFLD are thought to be similar to those in the 
development of type 2 diabetes mellitus (T2DM), as insulin resistance is a hallmark in both 
disease states. Insulin resistance in adipocytes leads to dysfunction in the normal regulators of 
lipolysis, contributing to elevated circulating free fatty acids, accumulation of triglycerides in the 
liver (Saponaro, 2015) and lipotoxicity, manifested as inflammation and cellular injury (Byrne, 
2015). It is unclear why some patients with NAFLD do not progress to NASH; some genetic 
modifiers of disease progression and severity have been identified (including patatin-like 
phospholipase domain-containing 3 (PNPLA3) (Dongiovanni, 2013). T2DM is associated with a 
greater than 2-fold increase in the risk of developing severe liver disease (Jarvis, 2020). 
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NAFLD is usually asymptomatic unless progression to cirrhosis has occurred. It is often 
diagnosed by demonstration of hepatic steatosis on liver imaging (e.g., ultrasound or magnetic 
resonance imaging [MRI]) in subjects, commonly with features of the metabolic syndrome 
(MetS), in whom no alternative etiology for liver fat accumulation can be identified (e.g., 
alcoholic liver disease, medications). A liver biopsy is the gold standard for assessing the 
presence of NASH and the presence of advanced fibrosis (the most important prognostic 
indicator in subjects with NAFLD) (Dulai, 2017; Balakrishnan, 2020); however, a number of 
non-invasive tools, e.g., clinical risk scores such as the NAFLD fibrosis score (NFS) and 
Fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) score, and vibration-controlled 
transient elastography (VCTE), have been validated and are increasingly used in clinical settings 
for differentiation between subjects with a high vs. low risk of advanced fibrosis (EASL-EASD-
EASO, 2016; Chalasani, 2018; Leoni, 2018). 
The global prevalence of NAFLD in the general adult population has been estimated to be a 
in a large meta-analysis of studies published through 2015 (Younossi 2016). The highest 
prevalence rates were reported in the Middle East and South America, and the lowest were in 
Africa. In North America and Europe, the prevalence of NAFLD is estimated at 21-25 
(Younossi, 2016; Arshad, 2020; Mitra, 2020). The global prevalence of NASH has been 
estimated to range IURPWR (Younossi, 2016; Younossi, 2018). The prevalence of 
NAFLD is on the rise (Younossi, 2016); in the US, the number of NAFLD cases is projected to 
H[SDQGIURPPLOOLRQLQaRIWKHSRSXODWLRQWRPLOOLRQLQ$Q
LQFUHDVHGSURSRUWLRQRIWKHVHFDVHVZLOOEH1$6+ULVLQJIURPWRRIDGults with 
NAFLD during this interval (Estes, 2018). 
There is a high unmet medical need in NASH (Friedman, 2018). The disease progresses to 
ILEURVLVDQGFLUUKRVLVLQDSSUR[LPDWHO\RIaffected patients (Vernon, 2011; Khan, 2015), and 
RIaffected patients with cirrhosis will progress to decompensated cirrhosis within 10 years 
of diagnosis (Rinella, 2015). Eight percent of patients with advanced fibrosis will develop 
hepatocellular carcinoma within 5 years (Hashimoto, 2009), and there is increasing evidence that 
non-cirrhotic subjects with NAFLD may also be at an increased risk of hepatocellular carcinoma 
(Mittal, 2016). Moreover, NASH-related cirrhosis has become one of the leading causes of liver 
transplantation (Charlton, 2011; Golabi, 2018; Noureddin, 2018; Shingina, 2019). 
As of this time, there are no approved therapies for treatment of patients with NASH (Attia, 
2020). A variety of therapeutic agents are being developed for NASH, targeting metabolic 
pathways, inflammatory pathways or fibrosis (Attia, 2020; Dewidar, 2020; Dufour, 2020). 
Positive interim results (reduction of fibrosis) were reported from the ongoing REGENERATE 
Phase 3 study with obeticholic acid in patients with liver fibrosis due to NASH (Younossi, 
2019a). In a Phase 2a proof-of-concept study, positive data were reported in NASH patients 
treated with pharmacological doses of FGF21 for 16 weeks with BMS-986036 (Sanyal, 2019; 
Verzijl, 2020). Furthermore, a beneficial effect of an Fc-FGF21 analog efruxifermin (AKR-001) 
was reported on key NASH parameters, e.g., reduction of liver fat and evaluation of histologic 
changes at 5 months in an ongoing study (BALANCED) in NASH patients (Akero Therapeutics 
Inc, 2020). In a Phase 1b/2a study (BIO89-100-002, Part 1), repeat administration of multiple 
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ascending doses of pegozafermin in subjects with NASH or phenotypic NASH (PNASH4) led to 
robust, significant, and clinically meaningful benefits across key liver parameters observed 
across all dose groups with concurrent metabolic benefits (Loomba, 2020b). Open-label, initial 
assessment of the effect of pegozafermin on histological endpoints in approximately 20 subjects 
with biopsy-proven NASH (F1 with high risk, F2 and F3) is ongoing (BIO89-100-002, Part 2). 
2.3. 
Benefit / Risk Assessment 
Information about the expected benefits and potential risks (adverse events) of pegozafermin can 
be found in the Investigator’s Brochure (IB). 
2.3.1. 
Risk Assessment 
The safety of pegozafermin has been assessed in Phase 1a single ascending dose (dose range 
0.45 to 78 mg) study in healthy volunteers (TV47948-SAD-10122) and Phase 1b/2a multiple 
ascending dose (dose range 3 to 27 mg QW, 18 mg Q2W and 36 mg Q2W) study in subjects 
with NASH, or with NAFLD who are at high risk of NASH (BIO89-100-102 Part 1). 
pegozafermin was generally well tolerated in both studies. 
In a Phase 1b/2a study (BIO89-100-102 Part 1), repeat administration of multiple ascending 
doses of pegozafermin in both NASH and PNASH subjects was generally well tolerated and 
associated with a favorable safety profile per treatment-emergent adverse events (TEAEs), 
laboratory (chemistry, hematology, and urinalysis), vital signs and electrocardiogram (ECG) 
findings. There were no deaths or treatment-related serious adverse events (SAEs); one subject 
discontinued treatment due to a treatment-related TEAE, a Grade 2 drug eruption. The most 
FRPPRQ7($(VRFFXUULQJLQRUPRUHof subjects, were increased appetite, diarrhea, 
headache and nausea. The incidence of gastrointestinal (GI) TEAEs was comparable between 
pooled pegozafermin and placebo with no differences between dose groups in incidence of 
individual GI TEAEs and total TEAEs for the GI system organ class (SOC). There was no clear 
correlation between frequency of TEAEs and dose. No bone or female reproductive tract-related 
adverse events (AEs) were reported (spontaneous reporting). There were no consistent patterns 
of any abnormalities in safety parameters that appeared to be attributable to pegozafermin. 
Overall, no safety concern was identified associated with pegozafermin.  
Information on important identified and potential risks associated with pegozafermin is provided 
in the IB. 
2.3.2. 
Benefit Assessment 
There are currently no approved products for NASH in the US. 
Patients with biopsy-confirmed NASH may derive benefit from treatment with pegozafermin. 
In Part 1 of Study BIO89-100-002, repeat administration of ascending doses of pegozafermin 
(3 mg, 9 mg, 18 mg and 27 mg QW and 18 mg and 36 mg Q2W) for up to 12 weeks in subjects 
with NASH or PNASH led to robust, significant, and clinically meaningful benefits in key liver 
parameters observed across all dose groups, with concurrent metabolic benefits. All dose groups 
 
4 Phenotypic NASH, defined as at least one of the following: 1) obesity with T2DM. 2) Obesity with evidence of 
liver injury (either increased alanine aminotransferase [ALT] and/or vibration-controlled transient elastography 
[VCTE] score  KPa) 
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dePRQVWUDWHGVLJQLILFDQWUHGXFWLRQVLQOLYHUIDWXSWRUHGXFWLRQFRPSDUHGWREDVHOLQHXSWR
UHGXFWLRQFRPSDUHGWRSODFHERDQGOLYHUYROXPHXSWRUHGXFWLRQDVPHDVXUHGE\
magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). A significant 
SURSRUWLRQRIVXEMHFWVUHVSRQGHGWRWKHUDS\ZLWKXSWRDQGRIVXEMHFWVDFKLHYLQJD
RUDUHGXFWLRQLQOLYHUIDWYHUVXVEDVHOLQHUHVSHFWLYHO\7UHDWPHQWZLWK
pegozafermin also resulted in significant improvements in liver transaminases [XSWR
UHGXFWLRQLQDODQLQHDPLQRWUDQVIHUDVH$/7UHGXFWLRQLQDVSDUWDWHDPLQRWUDQVIHUDVH
(AST)], and in N-terminal type III collagen propeptide (Pro-&DPDUNHURIILEURVLVXSWR
reduction) following 12 weeks of treatment. Of note, reduction of liver fat DQG$/7
decrease 17 U/L or KDYHEHHQSUHYLRXVO\UHSRUWHGWREHDVVRFLDWHGZLWKSRVLWLYH
histological outcomes (Harrison, 2020b; Loomba, 2020c). Metabolic benefits of pegozafermin 
incOXGHGDIDYRUDEOHHIIHFWRQOLSLGVZLWKVLJQLILFDQWUHGXFWLRQVLQWULJO\FHULGHVXSWR 
reduction), non-high density lipoprotein (non-HDL) and low density lipoprotein-cholesterol 
(LDL-c) XSWRUHGXFWLRQDQGVLJQLILFDQWLQFUHDVHVLQWKHLQVXOLQVensitizing hormone 
adiponectin XSWR). All these effects were observed in both dose regimens evaluated (QW 
and Q2W) and were most prominent at the 27 mg QW dose and the 36 mg Q2W dose. There 
were no differences between population groups evaluated (biopsy-confirmed NASH or PNASH). 
Based on these findings, it is estimated that 24 weeks of treatment with pegozafermin may have 
a positive impact on liver histology, liver-related (e.g., reduction of hepatic fat) and metabolic 
parameters in subjects with biopsy-confirmed NASH. 
2.3.3. 
Overall Benefit Risk Assessment 
Considering the benefit, potential risks, and risk mitigation measures that have been 
implemented, the Sponsor considers the benefit-risk profile for administering pegozafermin to 
subjects with biopsy-confirmed NASH in study BIO89-100-122 to be favorable. The overall 
benefit-risk associated with administration of pegozafermin will be continually re-assessed with 
the emergence of additional data. 
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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Main Study Objectives and Endpoints 
 
 
Objectives 
Endpoints 
Primary 
x To evaluate the effect of 
pegozafermin on liver histology after 
24 weeks of treatment 
x Proportion of subjects with NASH 
resolution without worsening of fibrosis5 
at Week 24 compared to baseline. 
 
x Proportion of subjects achieving 
LPSURYHPHQWRIILEURVLVVWDJHZLWKRXW
worsening of NASH at Week 24 
compared to baseline. 
Key Secondary 
 
x To further evaluate the effect of 
pegozafermin on liver histology after 
24 weeks of treatment 
x Proportion of subjects with at least a 
2-point improvement in NAS and no 
worsening of fibrosis at Week 24 
compared to baseline. 
x Proportion of subjects with NASH 
resolution $1'ILEURVLVLPSURYHPHQW
stage at Week 24 compared to baseline. 
x 3URSRUWLRQRIVXEMHFWVZLWK 2-point 
improvement in NAS score AND are 
MRI-PDFF responders6 AND ALT 
responders7 at Week 24 compared to 
baseline. 
Secondary 
 
x To evaluate the effects of 
pegozafermin on liver parameters  
x Absolute change and percentage change 
from baseline at Week 12 and Week 24 
in: 
 Hepatic fat fraction by MRI-PDFF 
 ALT 
 Pro-C3 
 
5 Resolution of NASH includes the total absence of ballooning (score=0) and absent or mild inflammation (score 0 
to 1).  
:RUVHQLQJRIILEURVLVLVGHILQHGDVSURJUHVVLRQRIILEURVLVVWDJH 
Worsening of NASH is defined as increase in NAS for ballooning, inflammation, or steatosis 
6 UHGXFWLRQIURPEDVHOLQHLQOLYHUIDWE\05,-PDFF 
7 8/RUUHGXFWLRQIURPEDVHOLQHLQ$/7 
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Objectives 
Endpoints 
x To evaluate the metabolic effects of 
pegozafermin  
x Absolute and percent change from 
baseline at Weeks 12 and 24 in: 
 Adiponectin 
 Serum triglycerides 
 High density lipoprotein cholesterol 
(HDL-c) 
 Non-HDL-c 
 LDL-c 
 Glycated hemoglobin (HbA1c) 
x To characterize pegozafermin 
pharmacokinetics (PK) profile  
x Trough concentration of pegozafermin 
Safety 
x To evaluate the safety and tolerability 
of pegozafermin  
x Frequency and severity of TEAEs and 
SAEs 
x Number of subjects who discontinued due 
to TEAEs and due to related TEAEs 
x Incidence and shifts of clinically 
significant physical examination findings, 
ECG data and laboratory abnormalities; 
safety laboratory evaluations include 
hematology, blood biochemistry and 
urinalysis, serum, salivary, and urinary 
cortisol as appropriate 
x Change from baseline in 
 Insulin-like growth factor 1 (IGF-1) 
 Bone biomarkers: Carboxy-terminal 
collagen crosslinks (CTX), N-
terminal propeptide of type 1 
collagen (P1NP) and osteocalcin 
 Thyroid stimulating hormone (TSH) 
x $EVROXWHDQGFhange from baseline in 
lumbar spine, total hip, and femoral neck 
bone mineral density (BMD) as assessed 
by dual X-ray absorptiometry (DXA) 
x To evaluate the immunogenicity of 
pegozafermin  
x Incidence and characteristics of anti-drug 
antibodies (ADA) and neutralizing 
antibody (NAb) after dosing (e.g., titer 
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Objectives 
Endpoints 
and binding specificity, to the FGF21 and 
polyethylene glycol [PEG] part of 
pegozafermin) 
x Impact of the presence of ADAs on serum 
pegozafermin concentrations and clinical 
safety 
 
Exploratory 
x To evaluate effect of pegozafermin 
on additional clinical parameters 
 
Change from baseline in the following clinical 
parameters: 
Histological assessments 
Proportion of subjects at Week 24 with: 
x )LEURVLVLPSURYHPHQWVWDJHZLWKRXW
worsening of NASH 
x NASH resolution without worsening of 
fibrosis OR improvement of fibrosis 
 stage without worsening of NASH 
x NASH resolution without worsening of 
fibrosis AND improvement of fibrosis 
 stage without worsening of NASH 
x Proportion of subjects with NASH 
resolution without worsening of fibrosis 
DQG 2-point improvement in NAS score 
at Week 24 compared to baseline.  
x Proportion of subjects achieving 
LPSURYHPHQWRIILEURVLVVWDJHZLWKRXW
worsening of 1$6+DQG 2-point 
improvement in NAS score at Week 24 
compared to baseline. 
x At least a 2-point improvement in NAS 
with at least a 1-point improvement in 
ballooning or lobular inflammation, and 
no worsening of fibrosis 
x Decrease >1 stage in fibrosis score 
x At least 2-point improvement in NAS 
score AND are MRI-PDFF responders 
x Fibrosis LPSURYHPHQWVWDJHZLWKRXW
worsening of NASH AND are MRI-PDFF 
responders AND ALT responders  
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Objectives 
Endpoints 
x Fibrosis LPSURYHPHQWVWDJHZLWKRXW
worsening of NASH AND are MRI-PDFF 
responders  
x NASH resolution without worsening of 
fibrosis AND are MRI-PDFF responders 
AND ALT responders  
x NASH resolution without worsening of 
fibrosis AND are MRI-PDFF responders 
 
Mean change from baseline in: 
x NAS score 
x Fibrosis score (categorical) 
In MRI-PDFF responders8: 
Proportion of subjects with: 
 )LEURVLVLPSURYHPHQWVWDJH
without worsening of NASH 
 NASH resolution without worsening 
of fibrosis, OR improvement of 
fibrosis VWDJHZLWKRXWZRUVHQLQJ
of NASH 
 NASH resolution AND fibrosis 
LPSURYHPHQWVWDJH 
 At least a 2-point improvement in 
NAS with at least a 1-point 
improvement in ballooning or lobular 
inflammation, AND no worsening of 
fibrosis 
 At least a 2-point improvement in 
NAS with at least a 1-point 
improvement in ballooning or lobular 
inflammation, AND fibrosis 
LPSURYHPHQWVWDJH 
 Mean change from baseline in NAS 
score 
x Artificial intelligence (AI)-based 
histological analysis (PathAI) 
 
8 UHGXFWLRQIURPEDVHOLQHLQOLYHUIDWE\05,-PDFF  
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Imaging assessments 
x Hepatic fat content 
 Percentage of subjects with 
relative reduction in hepatic fat 
fraction as assessed by MRI-PDFF at 
Weeks 12 and 24 
 Percentage of subject with 
relative reduction in hepatic fat 
fraction as assessed by MRI-PDFF at 
Weeks 12 and 24 
 MRI-3'))at Weeks 12 and 24 
x Change in hepatic fibro-inflammation as 
measured by Iron-corrected T1 (cT1) 
imaging 
x Change in FibroScan VCTE score (liver 
stiffness measurement) and CAP 
(steatosis) 
x Change in liver and spleen volume 
x Change in pancreatic fat percentage 
Anthropometric assessments 
x Body weight 
x Waist circumference 
x Waist/hip ratio 
Laboratory parameters 
x Percentage of subjectVZLWK8/
decrease in ALT 
x Percentage of subjectVZLWK 
decrease in ALT 
x AST 
x Gamma-glutamyl transpeptidase (GGT) 
x Alkaline phosphatase (ALP) 
x Fasting glucose 
x C-peptide 
x Fasting insulin 
x Adipo-IR index (fasting free fatty acids x 
fasting insulin) 
x Homeostatic model assessment for insulin 
resistance (HOMA-IR) 
x ELF score 
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Objectives 
Endpoints 
x FIB-4 index 
 
x To evaluate the effects of 
pegozafermin on patient reported 
outcome (PRO) 
x Change from baseline scores at Weeks 12 
and 24 in: 
 Chronic Liver Disease Questionnaire- 
NAFLD-NASH (CLDQ NAFLD-
NASH) 
 Work Productivity and Activity 
Impairment Questionnaire for NASH 
(WPAI-NASH) 
 Europe Quality of Life Group 
5-dimension 5-level questionnaire 
(EQ-5D-5L) 
 Liver-related pain and discomfort 
questionnaire 
 The appetite sensations VAS 
x To evaluate molecular data (e.g., 
proteomics, genetics) to increase the 
understanding of pegozafermin 
biological activity, and to identify 
potential existing and/or emerging 
biomarkers. 
x To explore pharmacogenomics (PGx) 
x To identify emerging biomarkers from 
RNA/DNA, plasma and serum samples 
collected 
x Effect of naturally occurring genetic 
variation on the efficacy (e.g., clinical 
remission, clinical response), safety, 
and/or PK profile with pegozafermin 
3.2. 
Extension Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
x To evaluate the long-term safety and 
tolerability of pegozafermin 
x Frequency and severity of TEAEs and 
SAEs at Week 48 
Secondary 
 
x To characterize effect of 
pegozafermin on liver parameters 
x Absolute change and percent change from 
baseline at Week 48 in: 
 Hepatic fat fraction by MRI-PDFF 
 ALT 
 Pro-C3 
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Objectives 
Endpoints 
x To characterize pegozafermin PK 
profile  
x Trough concentration of pegozafermin 
Safety 
x To evaluate additional safety and 
tolerability measures 
x Number of subjects who discontinued due 
to TEAEs and due to related TEAEs 
x Incidence and shifts of clinically 
significant physical examination findings, 
ECG data and laboratory abnormalities; 
safety laboratory evaluations include 
hematology, blood biochemistry and 
urinalysis, serum, salivary, and urinary 
cortisol as appropriate 
x Change from baseline in 
 IGF-1 
 Bone biomarkers: CTX, P1NP and 
osteocalcin 
 TSH 
x $EVROXWHDQGFhange from baseline in 
lumbar spine, total hip, and femoral neck 
bone mineral density (BMD) as assessed 
by DXA 
x To evaluate the immunogenicity of 
pegozafermin over time 
x Incidence and characteristics of ADA and 
NAb after dosing (e.g., titer and binding 
specificity, to the FGF21 and PEG part of 
pegozafermin) 
x Impact of the presence of ADAs on serum 
pegozafermin concentrations and clinical 
safety 
x Levels of endogenous FGF21 at the 
immunogenicity follow-up visit(s) 
compared to baseline in 
 
subjects 
Exploratory 
 
x To evaluate pegozafermin on 
additional metabolic parameters 
x Mean and percent change from baseline at 
Weeks 38 and 48 in: 
 Adiponectin 
 Serum triglycerides 
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Objectives 
Endpoints 
 HDL-c 
 Non-HDL-c 
 LDL-c 
 HbA1c 
x To evaluate pegozafermin on 
additional clinical parameters 
Change from baseline in the following clinical 
parameters: 
Imaging assessment 
x Change in hepatic fibro-inflammation as 
measured by cT1 imaging 
x Change in FibroScan VCTE score (liver 
stiffness measurement) and CAP 
(steatosis) 
 
Anthropometric assessments 
x Body weight 
x Waist circumference 
x Waist/hip ratio 
Laboratory parameters 
x Percentage of subjectVZLWK8/
decrease in ALT 
x Percentage of subjectVZLWK 
decrease in ALT 
x AST 
x GGT 
x ALP 
x Fasting glucose 
x C-peptide 
x Fasting insulin 
x Adipo-IR index (fasting free fatty acids x 
fasting insulin) 
x HOMA-IR 
x ELF score 
x FIB-4 index 
x To evaluate the effects of 
pegozafermin on PRO 
x Change from baseline scores at Week 48 
in: 
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Objectives 
Endpoints 
 CLDQ NAFLD-NASH 
 WPAI-NASH 
 EQ-5D-5L 
 Liver-related pain and discomfort 
questionnaire 
 The appetite sensations VAS 
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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, 2-part study to evaluate efficacy, safety, 
tolerability, population PK and pharmacodynamic (PD) profiles and immunogenicity of 
pegozafermin administered subcutaneously (SC) in approximately 184 subjects with biopsy-
FRQILUPHG1$6+1$6ILEURVLVVWDJH)RU) per NASH CRN system). The first part of the 
study will be double-blind, and the second part of the study will be single-blind (specifically-
identified Sponsor personnel will not be blinded). Study schema is shown in Section 1.2. 
The study will include 2 parts: 
x Main study – a 24-week, double-blind, placebo-controlled study 
x Extension study – an additional 24-week, single-blind, placebo-controlled study 
The entire study will include a Screening period, a Treatment period (Main and Extension), and a 
Follow-up period. Study visits and assessments will be conducted in-clinic and/or remotely as 
shown in the schedule of activities (SoA) in Section 1.3. 
Visits at Screening, Baseline (Day 1), Weeks 4, 12, 24, 38, and 48 should be performed in-clinic. 
If circumstances preclude this possibility (e.g., restrictions due to coronavirus disease 2019 
[COVID-19]), the site should contact the Medical Monitor (or designee) to discuss the best way 
to capture appropriate data. Visits at Weeks 8, 16, and 30 may be performed remotely, with 
home health nursing to perform assessments (these visits may be performed in clinic if the 
Investigator feels it is in the best interest of the subject). The Week 26 visit may be an in-clinic 
or a remote (home) visit to administer investigational product (IP), so that placebo subjects who 
are re-randomized to active treatment will be observed the first time they receive IP.  
For immunogenicity assessment, subjects who complete the Week 48 visit will be asked to return 
to clinic to have blood samples collected approximately every 3 months for up to 
. AEs 
and concomitant medication will also be recorded during the immunogenicity follow-up period. 
Additional testing may be requested in the event of safety-related concerns. The sponsor may 
elect to terminate participation in the immunogenicity follow-up period based on emerging data. 
Subjects who terminate IP early will not return for immunogenicity follow-up, unless asked to 
return for additional testing(s), at the Medical Monitor’s discretion. 
A Data Monitoring Committee (DMC) will periodically convene to review unblinded overall 
safety results per DMC charter (Section 9.8). 
Main Study 
After signing informed consent, subjects will undergo screening assessments to determine 
eligibility over a period of 12 weeks. Eligibility period may be extended with Sponsor’s 
approval. Individual screening assessments may be done remotely as part of tiered screening. 
Subjects will either undergo a liver biopsy during Screening or have a recent liver biopsy (within 
6 months prior to consent, available to be evaluated for eligibility by the central reader) that 
meets study inclusion criteria; ideally, the liver biopsy should be done after all non-invasive 
eligibility criteria are met. 
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On Day 1 (baseline), eligible subjects will be randomized to one of the following treatment 
groups: 
x Placebo, N=64; QW (N=42) or Q2W (N=22) 
x Pegozafermin 15 mg, QW subcutaneous (SC), N=16 
x Pegozafermin 30 mg, QW, SC, N=64 
x Pegozafermin 44 mg, Q2W, SC, N=40 
with the randomization 16:8:6:24:15 to Placebo QW, Placebo Q2W, pegozafermin 15 mg QW, 
30 mg QW and 44 mg Q2W, respectively. The randomization will be stratified by T2DM status 
(yes vs. no) and fibrosis stage (F2 vs. F3). For the purposes of stratification, subjects will be 
considered to be T2DM status positive if any of the following criteria are met: current medical 
history of T2DM, current use of anti-glycemic medication(s) for T2DM, or screening laboratory 
YDOXHV+E$FRUIDVWLQJSODVPDJOXFRVHPJG/Subjects will receive IP over 24 
weeks (includes 24 administrations in QW dose regimen and 12 administrations in Q2W dose 
regimen). Subjects, investigators and site staff and Sponsor will be blinded to IP (placebo or 
pegozafermin); however, the dose regimen (QW or Q2W) will be known to all parties involved 
in the study. 
Subjects will undergo a second liver biopsy at the Week 24 visit (window of -7 days to 
+14 days). Liver biopsies will be read centrally by liver pathologists who are blinded to the 
treatment group assignment (refer to Section 6.4.3 for details). 
Extension Study 
Subjects completing the Main study will continue for an additional 24 weeks in the Extension 
study. The Extension study will commence at Main study Week 24 visit. 
At Week 24, subjects randomized to placebo QW in the Main study will be re-randomized 1:1 to 
pegozafermin 30 mg QW (n=21) or placebo QW (n=21) and receive the re-randomized treatment 
at the Week 26 visit (which may be an in-clinic or a remote home visit). All other subjects will 
continue to receive the same treatment regimen in the Extension study that they received during 
the Main study. IP will be administered over 24 additional weeks (includes 24 administrations in 
QW dose regimen and 12 administrations in Q2W dose regimen), for approximately 48 weeks of 
treatment over the entirety of the study (Main and Extension). Specifically-identified Sponsor 
personnel will not be blinded; however, subjects, investigators and site staff will remain blinded 
to IP (placebo or pegozafermin). Dose regimen (QW or Q2W) will be known to all parties in the 
Extension study. 
4.2. 
Scientific Rationale for Study Design 
Data from BIO89-100-002 Part 1 demonstrated favorable safety and tolerability with repeated 
dosing of pegozafermin for 12 weeks. In addition, robust, clinically meaningful reductions in 
liver fat, assessed by MRI-PDFF, and ALT, at thresholds that have been associated with 
histological benefit in subjects with NASH, have been observed. 
This study will further evaluate subjects with biopsy-confirmed NASH and fibrosis (1$6
fibrosis stage F2 or F3 per NASH CRN system), similar to the population that is typically 
enrolled in Phase 2b and pivotal Phase 3 NASH studies, who will be treated with pegozafermin 
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for approximately 48 weeks (with ~24 weeks in the Main study and ~24 weeks in the Extension 
study). The study will be placebo-controlled throughout its duration, double-blinded in the Main 
study and single-blinded in the Extension study. Specifically-identified Sponsor personnel will 
be unblinded after the Main study is completed to evaluate the data and prepare for interactions 
with the FDA. However, subjects, Investigators, site staff, and Sponsor personnel responsible for 
day-to-day study operations including the Sponsor and CRO Medical Monitors, will remain 
blinded to treatment assignment throughout the entire study in order to maintain the integrity of 
the primary endpoint (safety) of the Extension study. 
The primary endpoints of the Main study will further assess the effect of different 
doses/regimens of pegozafermin on improvement in liver histological endpoints compared to 
baseline at Week 24, including, 1) NASH resolution without worsening of fibrosis DQG-point 
improvement in NAS score, 2) LPSURYHPHQWRIILEURVLVVWDJHZLWKRXWZRUVHQLQJRI1$6+ 
DQG-point improvement in NAS score. These modified histological primary endpoints are 
consistent with the FDA guidance on endpoints likely to predict clinical benefit and incorporate 
NAS improvement as a measure that reflects decrease in disease severity, thus is clinically 
meaningful (Neuschwander-Tetri, 2015; Harrison, 2019; FDA Draft Guidance for Industry, 
December 2018). Other Main study secondary efficacy endpoints include changes in liver fat, 
other histological endpoints, and additional liver and metabolic biomarkers. The study will 
contribute to further characterization of the safety profile for pegozafermin. Patient reported 
outcomes and other exploratory endpoints will also be assessed. Efficacy data from this study, in 
particular findings related to the effect of pegozafermin at the studied doses and dose regimens 
on the assessed histological endpoints, will support dose selection and endpoint determination in 
the anticipated Phase 3 program. 
The Extension study will allow long-term safety (including long-term immunogenicity) and 
evaluation of noninvasive biomarker assessments in a single-blinded manner. The re-
randomization of subjects assigned to placebo QW treatment arm in Main study to receive either 
active (pegozafermin 30 mg QW) or placebo QW will allow replication of the pegozafermin 
effects on noninvasive biomarker results observed in the Main study. The two-week delay in 
treatment change for this group will ensure that all biopsies are performed prior to any of these 
subjects being switched from placebo to IP. 
4.3. 
Justification for Dose 
The dose levels and regimens for this study, pegozafermin QW (15 mg or 30 mg) or Q2W 
(44 mg), were selected based on nonclinical safety and pharmacology studies in mice and 
monkeys, safety and pharmacodynamic data from the single ascending dose (SAD) study 
TV47948-SAD-10122, and data from the multiple ascending dose (MAD) study BIO89-100-002 
Part 1. 
In Part 1 of Study BIO89-100-002, exposures to pegozafermin (ascending doses 3 mg, 9 mg, 
18 mg, and 27 mg QW and 18 mg and 36 mg Q2W) in subjects with NASH and PNASH for up 
to 12 weeks were generally dose-proportional following QW or Q2W dosing. Exposures were 
related to the total doses regardless of dosing regimens. Terminal phases of concentration-time 
profiles were parallel, suggesting a dose-proportional PK. AUClast values stratified by regimens 
are also generally dose-proportional. Group tmax occurred between 48 and 72 hours after dosing. 
Accumulation ratios ranged from 1.0 to 1.4. 
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Exposure-response relationship based on Week 
 was established 
using data from Study BIO89-100-002 (Part 1). The data show that higher exposures were 
associated with better response and can be described by an Emax (maximum effect) model. The 
high dose proposed for this study, 30 mg QW, likely approaches full effect. The proposed low 
dose, 15 mg QW, is expected to elicit close to or slightly better than EC50 effect. The 44 mg 
Q2W dose (roughly equivalent to 22 mg, QW) is proposed as a middle dose. 
The predicted AUC(0-dosing interval) for the highest dose in Study BIO89-100-122 was compared to 
exposure at the no observed adverse effect level (NOAEL) 
 in the 26-week chronic 
toxicity study in mice to determine safety margins. Clinical PK parameters obtained from 
BIO89-100-002 were used for prediction. When using the predicted AUC(0-dosing interval) at steady 
state for 30 mg QW and 44 mg Q2W, the highest doses in BIO89-100-122, safety margins were 
calculated to be 
 and 
, respectively. Given that the adverse effects that 
determined the NOAEL at 
 in this study are considered to be secondary to very 
significant body weight reduction in mice that was not observed with pegozafermin in human 
subjects with NASH or PNASH who were treated at a similar dose for up to 
 weeks, and the 
uncertain clinical relevance of the adverse findings in lean mice to mostly overweight or obese 
human subjects, this safety margin is considered acceptable. 
Based on these data, the selected doses and dose regimens are anticipated to be safe, of sufficient 
duration to reach steady state, maintain PD responses over the dosing intervals, and cover the 
dose range where key PD responses are predicted to be associated with important clinical 
outcomes to be assessed in subsequent studies. The results of this study are expected to provide 
valuable information to guide dose selection for future, pivotal pegozafermin studies with 
histological endpoints in NASH. 
4.4. 
Study Duration 
For each subject, the total duration of study participation will be up to approximately 112 weeks: 
Screening Period: 
Up to 12 weeks, which may be extended with Sponsor’s approval 
Main Study 
Treatment Period: 
24 weeks (includes 24 administrations in QW dose regimen and 
12 administrations in Q2W dose regimen) 
Extension Study 
Treatment Period 
24 weeks (includes 24 administrations in QW dose regimen and 
12 administrations in Q2W dose regimen) 
Extension Study 
Follow-up Period 
Approximately 4 weeks from last dose of IP 
Immunogenicity 
Follow-up Period 
Approximately 
 from last dose of IP 
4.5. 
End of Study and End of Immunogenicity Follow-up Period 
Definition 
A subject is considered to have completed the study if he or she has completed the EOS follow-
up visit (Week 51/EOS) or has undergone early termination. The end of the study is defined as 
the date of the last visit (EOS visit) of the last subject in the study. The end of the 
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immunogenicity follow-up period is defined as the last follow-up visit for the immunogenicity 
period.  
5. 
ELIGIBILITY CRITERIA 
The screening process is designed to minimize unnecessary biopsies by identifying subjects at 
high risk for NASH with Stage 2 or 3 fibrosis (per NASH CRN). All efforts should be made to 
ensure that subjects complete the noninvasive assessments prior to the screening biopsy. See 
Appendix 7 (Section 10.7) for Sponsor guidance on prescreening potential subjects that may be 
at high risk for NASH with Stage 2 or 3 fibrosis (NASH CRN). 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Age and Gender 
1. Subjects must be 21 to 75 years of age inclusive, at the time of signing the informed 
consent form (ICF). 
2. Male or female. 
Type of Subject and Disease Characteristics 
3. Biopsy-confirmed NASH with fibrosis stage F2, or F3 per NASH CRN system and NAS 
ZLWKDVFRUHRIDWOHDVWLQHDFKRIVWHDWRVLVEDOORRQLQJGHJHQHUDWLRQDQGOREXODU
inflammation, either through a historical biopsy or a biopsy at screening. A historical 
biopsy should be obtained within 6 months prior to first day of Screening (i.e., day ICF is 
signed) that is deemed suitable for interpretation by a central reader if the subject had no 
significant change in metabolic status (control of diabetes, hyperlipidemia or !weight 
loss or gain).  
Pregnancy and Contraception 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. Refer to Appendix 4 
(Section 10.4) for definitions of women of childbearing potential (WOCBP) and contraception 
guidance. 
4. All subjects (male or female) who are of childbearing potential must agree to use highly 
effective, double contraception (both male and female partners) during the study. Use of 
a condom with spermicide in a male subject who underwent vasectomy is also acceptable 
as double contraception. Use of highly effective, double contraception must continue for 
30 days after the last dose of IP. Female subjects should not donate oocytes during this 
time. Male subjects must not donate sperm during this time. Rhythm methods are not 
considered as highly effective methods of birth control. Subject abstinence for the 
duration of the study and 30 days after the last dose of IP is acceptable if it is the 
subject’s regular practice. 
5. Females of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 1. Females of childbearing 
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potential must agree to undergo a pregnancy test prior to dosing at the timepoints 
specified in the SoA. 
6. Sexually active male subjects whose female partner is pregnant must agree to use a 
condom. 
Informed Consent and Study Requirements 
7. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
8. Subjects must not participate in any other interventional studies throughout the duration 
of this study. COVID-19 protocols may be excepted with Medical Monitor (or designee) 
approval. 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
Liver Disease 
1. History of a liver disorder other than NASH or clinical suspicion of a liver disorder other 
than NASH, including but not limited to hepatitis B and hepatitis C, autoimmune 
hepatitis, hemochromatosis, alcoholic liver disease, primary sclerosing cholangitis, 
primary biliary cirrhosis/cholangitis, alpha-1 antitrypsin deficiency, untreated celiac 
disease, or Wilson’s disease. 
Serology testing will be performed at screening. Subjects positive for hepatitis B surface 
antigen (HBsAg) will be excluded. Subjects positive for hepatitis C virus antibody 
(antiHCV) will undergo reflex polymerase chain reaction (PCR) for HCV RNA, and will 
only be eligible if the following conditions are met: 
a. Subjects with spontaneous clearance of HCV infection (positive serology for HCV 
infection with documented negative PCR for HCV RNA and no history of acute HCV 
infection within 3 years prior to Screening). 
b. Subjects who were previously diagnosed with chronic HCV infection who achieved 
documented sustained viral response (SVR) following treatment at least 2 years prior 
to Screening. 
2. Planned or history of liver transplantation. 
3. History or evidence of cirrhosis (NASH CRN Fibrosis Stage 4 on biopsy) or clinical 
indicators of hepatic decompensation including ascites, hepatic encephalopathy, 
splenomegaly, or variceal bleeding. 
Other Medical Conditions 
4. Presence of any chronic medical condition that, in the opinion of the Investigator, might 
pose additional risk to the subject, make the subject unable to comply with the protocol 
requirements, or confound the results of the study. Individual cases in which the 
Investigator deems the subject appropriate for inclusion despite a clinically significant 
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chronic medical condition should be discussed with and approved by the Medical 
Monitor (or designee). 
5. Hospitalization due to COVID-19 within 3 months prior to Screening. A positive 
COVID-19 test or COVID-19 diagnosis after signing consent is not exclusionary.  
6. Human immunodeficiency virus (HIV)-1 or HIV-2 infection. 
7. Unstable or clinically significant cardiovascular or cerebrovascular disease: 
a. Unstable angina, myocardial infarction, coronary artery bypass graft (CABG) 
surgery, percutaneous coronary intervention (PCI), transient ischemic attack (TIA) or 
cerebrovascular accident (CVA) within 6 months prior to Screening. 
b. Symptomatic valvular or other structural heart disease. 
c. Symptomatic congestive heart failure. 
d. Symptomatic, uncontrolled or high-risk arrhythmia or genetic predisposition to high-
risk arrhythmia in the subject or a first degree relative. 
e. Implanted defibrillator or pacemaker. 
f. High risk abdominal aortic aneurysm, uncontrolled peripheral vascular disease, or 
symptomatic carotid stenosis. 
8. Uncontrolled or newly diagnosed (<2 months since diagnosis at time of Screening) 
hypertension. Subjects with well controlled hypertension who are clinically stable may 
enroll if they have been on a stable dose of antihypertensive medications for at least 
2 months before Screening. 
9. Uncontrolled or newly diagnosed thyroid disease. Subjects with treated thyroid disease 
may be enrolled if they are considered stable on treatment for at least 3 months by the 
Investigator. Modest dose adjustments per standard of care are allowed. 
10. Uncontrolled or newly diagnosed (3 months since diagnosis) T2DM9: 
a. Subjects must have HbA1c level  at screening. 
b. Subjects must have been on a stable antidiabetic regimen for at least 3 months (for 
insulin and dipeptidyl peptidase IV [DPP-IV] antagonists) or 6 months (for glucagon-
like peptide 1 [GLP-1] agonists and sodium glucose co-transporter 2 [SGLT2] 
inhibitors) prior to biopsy (historical or screening) and remains stable up to 
randomization. Stable regimen is defined as no addition or discontinuation of 
antidiabetic medications, but dose adjustments or switching to another medication in 
the same class at the same relative dose per standard of care are allowed. 
Thiazolidinediones are not allowed. Subjects on any other antidiabetic regimen not 
specified above should be on stable treatment for at least 3 months prior to their 
qualifying biopsy. Consult with the Medical Monitor if further clarification is needed.  
11. Type 1 Diabetes Mellitus. 
12. Weight change RIPRUHWKDQZLWKLQPRQWKVSULRUWRon-study screening liver 
biopsy RUPRUHWKDQZLWKLQ months prior to on-study screening liver biopsy or 
planning to start a new weight loss program, training for a marathon, or taking weight 
loss medication (See Section 5.3 Lifestyle Considerations). However, in subjects with a 
 
9 Subjects with newly diagnosed T2DM may be rescreened if considered stable after 3 months. 
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historical biopsy, weight change of no PRUHWKDQis allowed between the historical 
biopsy and first day of Screening.  
13. History of bariatric surgery within the 5 years prior to Screening or plan to have 
bariatric surgery during conduct of study. Reversible procedures, such as lap banding, are 
allowed if they have been removed at least 12 months prior to Screening. Note: Removal 
of intra-gastric balloon or unsuccessful surgery more than 2 years prior to screening is 
acceptable. 
14. History of bone trauma, bone fracture, or bone surgery within 2 months of screening or 
other bone disorders that may have a clinically meaningful impact on bone formation or 
bone remodeling (such as osteoporosis, osteomalacia) or known, untreated severe vitamin 
D deficiency (serum 25-hydroxy-YLWDPLQ'QJP/; severe vitamin D deficiency that 
is being treated is not exclusionary). Joint or connective tissue disorders (such as arthritis) 
are not exclusionary. 
15. History of malignancy diagnosed or treated within 2 years of screening (recent localized 
treatment of squamous or noninvasive basal cell skin cancers is permitted; any carcinoma 
in situ is allowed if appropriately treated within 2 years prior to the Screening biopsy); 
subjects under evaluation for malignancy are not eligible. Any history of hepatocellular 
carcinoma is exclusionary.  
16. Current or history of significant alcohol consumption for a period of more than 
3 consecutive months within 1 year prior to Screening. Defined as more than 
14 units/week for females (>1 drink per day) and more than 21 units/week for males 
(>2 drinks per day) on average, where one unit of alcohol is equivalent to a 12-oz beer, 4-
ounce glass of wine, or 1-ounce shot of hard liquor. 
17. History of substance use disorder, or any other substance dependence (with the 
exception of caffeine or nicotine) as defined by the latest edition of the Diagnostic and 
Statistical Manual of Mental Disorders in the past 2 years prior to Screening. A positive 
urine drug screen is not exclusionary. Subjects who have a positive test during Screening, 
including subjects without a history of substance use disorder or subjects who have been 
prescribed medication (e.g., opiates, benzodiazepines) will be considered for enrollment 
at Investigator’s discretion. Cannabis and cannabidiol (CBD) products are not 
exclusionary.  
Diagnostic Assessments 
18. Clinically significant laboratory abnormality at Screening. Repeat tests may be allowed 
for each laboratory parameter at the discretion of the Investigator. The presence of one or 
more of the following laboratory abnormalities should lead to exclusion of the subject 
from participating in the study: 
a. ALT or AST 50 U/L 
b. Alkaline Phosphatase >2-fold higher than ULN. 
c. Elevation of total bilirubin (TB) > 1.30 mg/dL. Subjects with isolated indirect 
hyperbilirubinemia (normal direct bilirubin) secondary to medically documented 
Gilbert’s syndrome may be enrolled 
d. Triglycerides >1000 mg/dL 
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e. International normalized ratio (INR) > 1.30 unless due to anti-coagulant therapy. 
Subjects on anti-coagulant therapy may require their treatment withheld according to 
local guidelines prior to liver biopsy. 
f. *ORPHUXODUILOWUDWLRQUDWHH*)5
 mL/min/1.73 m2 as estimated by chronic 
kidney disease-epidemiology (CKD-EPI) Creatinine equation (Levey, 2009) 
g. Platelet count <100,000/L 
h. Greater than 40 increase in ALT or AST between 2 screening assessments, to be 
done at least 2 weeks apart between the 1st and 2nd assessment, as per the table below. 
A 3rd assessment, if required, will be collected via unscheduled visit, and performed 
at least 1 week apart from the 2nd assessment: 
ALT and AST Screening Assessments 
Eligibility 
Status 
Assessment 1 
Assessment 2  
Assessment 3 (if applicable) 
Normal 
Normal 
Not applicable 
Eligible 
Normal  
$EQRUPDODQG
increase from 
Assessment 1 
Not applicable 
Eligible 
Normal  
$EQRUPDODQG!
increase from 
Assessment 1 
1RUPDORULQFUHDVHIURP
Assessment 1 
Eligible 
$EQRUPDODQG!LQFUHDVHIURP
Assessment 1 
Excluded 
Abnormal  
LQFUHDVHIURP
Assessment 1 
Not applicable 
Eligible 
Abnormal 
!LQFUHDVHIURP
Assessment 1 
LQFUHDVHIURP$VVHVVPHQW 
Eligible 
!LQFUHDVHIURP$VVHVVPHQW 
Excluded 
1RUPDOLVGHILQHGDV8/1abnormal is defined as > ULN (upper limit of normal). 
Note: Clinical judgment should be used for subjects with isolated AST increases in whom there is suggestion of 
another cause of AST increase (e.g., muscle injury as evident by concurrent creatine phosphokinase elevation). 
19. ECG abnormality by central reader that may, in the opinion of the Investigator, interfere 
ZLWKVWXG\SDUWLFLSDWLRQ5HVWLQJ47F)LQWHUYDORI PVHFIRUPDOHVRU msec for 
females (by central reader). 
20. BMI at Screening <25.0 or >50.0 kg/m2. 
Prior/Concomitant Therapy 
21. Subject report of use of medications historically associated with secondary NAFLD for 
more than 2 consecutive weeks in the 12 months prior to screening (e.g., amiodarone, 
methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens or anabolic 
steroids at doses greater than those used for hormone replacement, valproic acid, and 
other medications with known hepatotoxicity). Inhaled corticosteroids are allowed. 
22. Any prior exposure to a FGF21 analog (e.g., including but not limited to pegozafermin, 
LY2405319, LY3025876, BMS986036, BMS986171, PF05231023, PF-06645849, 
AKR-001) or FGFR1 activating product, if known.  
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23. Any investigational drug small molecule (new chemical entity) within 30 days and large 
molecule (biologics) within 90 days, or 5 half-lives, whichever is longer, prior to Day 1, 
if known. 
24. Subjects taking vitamin E (> 400 IU/day) must be on a stable dose for at least 6 months 
prior to screening. 
Prior/Concurrent Clinical Study Experience 
25. Currently participating in or have participated in a study of an investigational agent or has 
used an investigational device within 30 days prior to the first dose of IP. Note: study 
participants will not be allowed to participate in other interventional trials for FGF21 
analog (e.g., including but not limited to pegozafermin, LY2405319, LY3025876, 
BMS986036, BMS986171, PF05231023, PF-06645849, AKR 001) or FGFR1 activating 
products, during the immunogenicity follow up period.  
Other Exclusions 
26. Inability to undergo a liver biopsy safely for any reason. 
27. Subject who cannot undergo MRI for any reason (e.g., contraindication, claustrophobia 
not controlled by anxiolytic, excessive weight or body size for MRI machine). 
28. Subject who cannot fast for study procedures for any reason. Specifically, subjects with 
T2DM who have a history of clinically significant, symptomatic hypoglycemia or past 
issues with fasting will be excluded. Subjects with T2DM may need to consult their 
treating physician about the optimal timing to take their medications to enable them to 
fast safely for study procedures. 
29. Any abnormality of the skin or abdominal wall that would impede SC administration to 
the abdominal area. 
30. Known hypersensitivity to the components of the IP (refer to pegozafermin IB), or 
history of a severe hypersensitivity reaction that, in the opinion of the Investigator, might 
place the subject at risk to receive IP. 
31. Pregnant or breastfeeding or planning to become pregnant or breastfeed while enrolled in 
the study or within 30 days after last dose of IP. 
32. An employee of the investigational center or has a family member who is involved with 
the conduct of this study. 
33. Any other clinically significant findings (including incidental findings during Screening), 
disorders or prior therapy that, in the opinion of the Investigator or Medical Monitor (or 
designee), would make the subject unsuitable for the study or unable to comply with the 
dosing and protocol requirements. 
5.3. 
Lifestyle Considerations 
At each visit the study staff should discuss diet and exercise, with the goal of lifestyle 
stabilization during the study.  
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To ensure standardization, all sites should provide the same guidance. Subjects should be 
encouraged to limit energy intake from total fats and sugars, increase consumption of fruit and 
vegetables, as well as legumes, whole grains, and nuts, and engage in at least 150 minutes of 
moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of 
vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination 
of moderate- and vigorous-intensity activity. Strenuous exercises should be avoided for at least 
48 hours prior to study visits. Note that per Exclusion Criterion 12, certain physical activities 
such as starting a new weight loss program, training for a marathon, or taking a concomitant 
weight loss medication may have a confounding treatment effect on study drug and are therefore 
exclusionary. The Medical Monitor (or designee) should be contacted if there are any questions 
regarding lifestyle considerations.  
Subjects should also be encouraged to limit alcohol intake to less than approximately 14 drinks 
per week ( 2 drinks per day) for men and 7 drinks per week (1 drink per day) for women. This 
guidance should be documented in the source and electronic case report form (eCRF). Subjects 
will be instructed to maintain the diet and activity level for the duration of the study. As part of 
lifestyle counseling, subjects will be questioned about change in diet or physical activity. 
5.4. 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
If any of the laboratory eligibility criteria, ECG, or vital sign criteria are not met during the 
initial screening, subjects will be allowed to retest at the Investigator’s discretion. If a subject 
fails to meet that laboratory eligibility criteria at the retests, they will remain ineligible. 
Investigator may also request a rerun (i.e., same sample to be analyzed again) at their discretion. 
In these instances, the 12-week screening window may be extended with Sponsor’s (or designee) 
approval.  
Subjects who do not meet all eligibility criteria will be allowed to rescreen with Medical 
Monitor (or designee’s) approval. Subjects who rescreen will be required to sign a new ICF. 
Rescreened subjects whose liver biopsy qualified at their original screening will not repeat the 
biopsy during the rescreening period if the biopsy is still within the 6-month eligibility period 
allowed for historical biopsies. Other imaging assessments, such as MRI and Fibroscan, do not 
need to be repeated for rescreened subjects if those assessments are within the 3-month eligibility 
period respectively allowed for those assessments. Lab assessments will be repeated for 
rescreened subjects.  
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6. 
INVESTIGATIONAL PRODUCT 
IP is defined as pegozafermin or matching placebo, intended to be administered to a study 
subject according to the study protocol. 
6.1. 
Investigational Product Administered 
IP will be administered SC to the abdomen region by qualified personnel in the clinic or in the 
subject’s home, or by the subject/subject’s caregiver following required training on IP 
administration. Some IP administrations will occur at the subject’s home. 
ARM  
Active– liquid formulation 
Placebo (control) 
Investigational product  pegozafermin  
Matching placebo  
Type  
Biologic  
Chemical solution 
Dose Formulation 
Each 1.1 mL vial contains 
 mg of 
pegozafermin in Tris buffer solution 
(containing
 
at a 
concentration of 
 mg/mL  
Each 1.1 mL vial contains Tris 
buffer solution (containing 
 
 
Unit Dose Strength(s) 
mg 
Not applicable 
Dosage Level(s) a 
QW 
15 mg 
30 mg 
QW 
Matching placebo will be injected 
QW. 
Q2W 
44 mg 
Q2W 
Matching placebo will be injected 
Q2W. 
Route of 
Administration 
SC injection 
SC injection 
Administration 
Instructions 
SC injection of the IP will be performed by qualified site staff when the 
subject attends Day 1 visit. Subjects and/or caregivers may also be trained 
on self-administration and thereafter self-administer the IP with staff 
witnessing on Day 1. Further doses will be administered at home by 
subject, subject’s caregiver, or home healthcare services. Details on 
administration at home, including training requirements, are provided in 
the Home Administration Instructions or Pharmacy Manual. 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
Labeling 
IP (pegozafermin and placebo) is supplied as a sterile, preservative-free, 
liquid formulation in a single-use Type 1 clear glass vial for SC injection. 
Each vial will be labeled per country requirement. 
a  7KHDFWXDOGRVHVZLOOEHWKHPJGRVHGXHWRWHFKQLFDOFRQVLGHUDWLRQVUHODWHGWRGUXJZLWKGUDZDOIURPWKHYLDOV
into the syringes for injection. This difference is considered negligible for subject exposure. 
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6.2. 
Administration Instructions 
IP will be administered SC to the abdomen by trained and qualified study personnel/ site staff at 
clinic visit(s). IP will be administered by healthcare professional or trained subject’s caregiver 
for home administration. IP can also be self-administered once a subject is appropriately trained. 
Details on self-administration at home, including training requirements will be provided in the 
Pharmacy Manual. Home healthcare services may be utilized for any subject requiring assistance 
with IP administration.  
Injections will be administered in the abdominal area only. For additional doses in the same 
subject, the injection site should be rotated within the abdominal area by at least 2 inches. 
Injections should be at least 2 inches from the umbilicus (belly button) and should avoid scars or 
tattoos. After administration of the IP, the subject should remain resting for approximately 
15 minutes. 
6.3. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for any IP received and any discrepancies are reported and resolved 
before use of the IP. 
Any IP stored on site, must be kept 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. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
Only subjects enrolled in the study may receive IP. Administration of IP may be performed by 
authorized site staff, home healthcare professionals, or study subjects (or their caregiver) who 
have been appropriately trained.  
Further guidance and information for IP preparation and administration and the final disposition 
of unused IP is provided in the Pharmacy Manual. 
Sponsor-approved courier services may provide IP to subjects from Week 4 through EOS. 
Depending on geography this may be direct-to-subject shipment or may require site-to-subject 
shipment. Instructions for dispensation and IP shipment to site and direct-to-subject shipment 
will be detailed in the Pharmacy Manual.  
Details on preparation, handling, storage, and accountability for at-home visits are provided in 
the Home Administration Instructions or Pharmacy Manual. 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
6.4.1. 
Randomization and Stratification 
Main study: All subjects will be centrally randomized 16:8:6:24:15 to Placebo QW, Placebo 
Q2W, pegozafermin 15 mg QW, 30 mg QW and 44 mg Q2W, respectively. The randomization 
will be stratified by T2DM status (yes vs. no) and fibrosis stage (F2 vs. F3). For the purposes of 
stratification, subjects will be considered to be T2DM status positive if any of the following 
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criteria are met: current medical history of T2DM, current use of anti-glycemic medication(s) for 
T2DM, or screening laboratory values of for HbA1c RUPJG/ for fasting plasma 
glucose. The proportion of subjects enrolled with MRI-3'))PD\EHOLPLWHGDWWKH
Sponsor’s discretion. 
In the Extension study, subjects randomized to placebo QW in the Main study will be 
re-randomized 1:1 to pegozafermin 30 mg QW (n=21) or placebo (n=21). 
All subjects will be centrally assigned to randomized IP using an Interactive Response 
Technology (IRT). 
6.4.2. 
Assignment of Subject Number and Investigational Product 
At the Screening visit, each subject will have a unique subject number assigned for subject 
identification in the study. Subjects who are rescreened will retain the original identification 
number; a new ID will not be assigned. 
IP will be dispensed at the study visits as summarized in the SoA. The IP kit number(s) will be 
assigned by the IRT system upon obtaining the subject’s randomized treatment group. 
For subsequent visits when IP is dispensed, the IRT system will assign IP kits based on the 
subject’s randomized treatment group in the Main study and the Extension study accordingly. 
6.4.3. 
Blinding 
Subjects, investigators, and all site personnel, as well as Sponsor will be blinded to treatment 
assignment and to IP (placebo or pegozafermin) throughout the Main study. In the Extension 
study, specifically-identified Sponsor personnel will not be blinded; however, subjects, 
investigators and site staff will remain blinded to IP (placebo or pegozafermin). However, the 
dose regimen (QW or Q2W) will be known to all parties involved in both the Main and the 
Extension study. Liver biopsies will be read centrally by liver pathologists who are blinded to the 
treatment group assignment and study visit. Results of the following assessments post Study Day 
1, including but not limited to, liver biopsy, MRI, PK and ADA, will be considered as potential 
unblinding information and will remain blinded throughout the study, unless specified otherwise. 
Specifically-identified Sponsor personnel will be unblinded for decision-making purposes and 
interactions with the FDA after all subjects complete the Week 24 assessments in the Main 
study. Sponsor personnel responsible for day-to-day study operations will remain blinded, 
including the Sponsor and CRO Medical Monitors. A formal unblinding plan will be established 
prior to the unblinding for Week 24.  
Other specified personnel or independent vendors may be unblinded based on their study role. 
These individuals include those who analyze PK or immunogenicity samples in the bioanalytical 
laboratories, and manage the unblinded data, manage IP inventory, manage expedited reporting 
of suspected unexpected serious adverse events (SUSARs), and who conduct unblinded analyses 
for the DMC. DMC members will have access to unblinded data for the purposes of reviewing 
unblinded overall safety results (Section 9.8). 
6.4.4. 
Unblinding of an Individual Subject 
The IRT system will be programmed with blind-breaking instructions. In case of a medical 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
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subject’s randomized treatment 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, when possible, should make efforts to contact the Medical Monitor 
(or designee) to discuss unblinding a subject’s treatment assignment before doing so, unless this 
could delay emergency medical treatment of the subject. If a subject’s treatment assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and IRT. 
Appropriate personnel at the Sponsor (or designee) will unblind SUSARs for the purpose of 
regulatory reporting. The Sponsor (or designee) will submit SUSARs to Regulatory Agencies in 
blinded or unblinded fashion according to local law. The Sponsor (or designee) will submit 
SUSARs to Investigators in a blinded fashion. 
Appropriate personnel at the Sponsor (or designee) will have access to unblinded individual 
subject treatment assignments for the purposes of study-required activities including 
management of IP inventory, production of summary tables and figures for DMC review, and 
performance of bioanalytical analysis of PK concentrations. These personnel will not be 
involved in data collection or final analysis of safety and efficacy results. Subjects, investigators, 
and other site personnel who are directly involved in the conduct of the study, collection of the 
data, and analysis of the final safety and efficacy results will remain blinded to treatment 
assignments until after the completion of the study and the database has been locked.  
6.5. 
Investigational Product Compliance 
When subjects are dosed at the site, they will receive IP directly from the Investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of IP and study 
subject identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the IP. 
Details on IP compliance at remote/home visits are provided in the Home Administration 
Instructions or Pharmacy Manual. The allowed time window for dosing is ±2 days. If a subject 
wishes to change their dosing schedule (e.g., to a different day of the week), the Investigator 
should discuss with the Sponsor. 
6.5.1. 
Guidance for Missed Dose(s) 
The IP dosing window is ±2 days however for QW dosing, every effort should be made to take 
IP on the same day of the week and must be at least 5 days between 2 doses. If more than 3 days 
(72 hours) have elapsed from the scheduled dosing for either QW or Q2W, subjects will be 
instructed to skip the missed dose. The Medical Monitor (or designee) should be contacted if 
there are any questions on missed doses. 
6.6. 
Treatment of Overdose 
There is no experience with overdose of pegozafermin in humans. In Study TV47948-SAD-
10122, single doses of pegozafermin at doses up to 78 mg were safe and well tolerated in healthy 
subjects. 
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For this study, any dose of IP greater than the highest protocol-specified dose will be considered 
an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should be notified by the subject and: 
x Contact the Medical Monitor (or designee) immediately. 
x Closely monitor the subject for any AEs and laboratory abnormalities for at least 
30 days. 
x Obtain a serum sample for PK analysis within 2 days from the date of the overdose if 
requested by the Medical Monitor (or designee) (determined on a case-by-case basis). 
x Document the quantity of the excess dose as well as the occurrence of the overdose in 
the eCRF. 
6.7. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and herbal 
supplements) or vaccine that the subject is receiving at the time of enrollment or receives during 
the study must be recorded along with at least the following information: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency and route of administration 
It has previously been reported that NAFLD is associated with reduced CYP3A drug metabolism 
activity in vivo and hepatic CYP3A4 expression in humans (Woolsey, 2015). In addition, based 
on the work by Woolsey et al it is suggested that exogenously administered FGF21 may decrease 
hepatic CYP3A4 activity (Woolsey, 2016). The underlying mechanism has not been fully 
elucidated. 
Subjects receiving concomitant administration of CYP3A4 substrates with narrow therapeutic 
index should be closely monitored for any potentially related safety events, and dose adjustment 
of the CYP3A4 substrate should be considered as needed. 
Short-term use of sliding scale insulin therapy during a medical procedure or hospitalization 
(<5 days) for subjects with T2DM may be performed as needed. 
The Medical Monitor (or designee) should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.7.1. 
Prohibited Medications/Therapies 
Prohibited therapies include: 
x Bariatric surgery 
x Elective bone surgery for any bone disorders  
x Medications historically associated with secondary NAFLD requiring >2 weeks of 
pharmacologic dosing . These include amiodarone, methotrexate, glucocorticoids, 
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tetracyclines, tamoxifen, estrogens or anabolic steroids at doses greater than those 
used for hormone replacement. 
x Other hepatotoxic agents including but not limited to, nefazodone, isoniazid, 
valproate, and carbamazepine.  
x The TNF (tumor necrosis factor) antagonists, adalimumab, etanercept and 
certolizumab, infliximab or sulfasalazine are prohibited during the Main Study but 
may be considered for managing emerging AEs in the Extension Study. 
 Short-term oral steroid bursts with/without taper as well as topical and inhaled 
corticosteroids are allowed. 
x Antidiabetic medications: Thiazolidinediones (e.g., pioglitazone) are prohibited 
throughout study to minimize risk of confounding effect with pegozafermin 
treatment. Dose adjustments or switching from one medication to another within the 
same drug class are allowed after randomization for DPP-IV inhibitors (“gliptins”), 
SGLT2 inhibitors (“gliflozins”) and GLP-1 agonists (“glutides”, including 
semaglutide [Ozempic]); However, initiation of new DPP-IV inhibitors, SGLT2 
inhibitors, or GLP-1 agonists is not allowed during screening and the Main Study 
(e.g., switching from a DPP-IV inhibitor to a GLP-1 agonist is not allowed, but 
switching from one DPP-IV inhibitor to another DPP-IV inhibitor is allowed). 
Initiation of these agents for uncontrolled hyperglycemia (but not for weight loss) 
may be allowed during the Extension Study with the Medical Monitor’s approval. 
x Vitamin E (> 400 IU/day) should not be initiated, or dose increased during the study. 
x Any investigational product, FGF21 analogs (e.g., LY2405319, LY3025876, 
BMS-986036, BMS-986171, PF-05231023, AKR-001, pegozafermin), or FGFR1-
activating products. Note: study participants will not be allowed to participate in other 
interventional trials for FGF21 analog or FGFR1 activating products, during the 
immunogenicity follow up period. 
x Weight loss medications (including GLP-1 agonists specifically for weight loss) 
should not be initiated during the study. 
The Investigator should discuss any questions regarding allowed/prohibited medications with the 
Medical Monitor (or designee). The final decision on any supportive therapy rests with the 
Investigator. However, the decision to continue the subject on IP requires the mutual agreement 
of the Investigator and the Sponsor. 
6.8. 
Intervention after the End of Study 
No additional intervention is planned beyond the end of the study. 
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7. 
DISCONTINUATION OF IP AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Investigational Product and Subject Withdrawal 
from the Study 
In some instances, it may be necessary for a subject to permanently discontinue IP. Temporary 
IP interruption may be allowed if Investigator and Medical Monitor (or designee) assess that IP 
rechallenge is safe and appropriate. 
Permanent discontinuation of IP at any time during the study does not mean withdrawal from the 
study, and the subject will be encouraged to remain in the study, complete the Early Termination 
(ET) visit at the time of IP discontinuation and continue to complete remaining study period 
during the Main Study or the Extension Study as appropriate (i.e., subjects who ET before 
Week 24 may complete study visits through Week 24 and subjects who ET after Week 24 may 
complete visits through Week 48). Procedures for the remaining visits will include assessment of 
AEs and updating concomitant medications. Subjects who permanently discontinue IP at or after 
Week 16 and before Week 24 of the Main study will be requested to provide a liver biopsy at ET 
visit. (Section 1.3). 
Subjects who experience clinically significant TEAEs that are assessed as a potential risk to 
subject safety will be discontinued from IP and undergo an ET visit as specified in the SoA. The 
decision to discontinue IP will be made by the Investigator and should be discussed with the 
Medical Monitor (or designee). If any subject experiences a Grade 3 TEAE that is considered 
related to IP, the Investigator should discuss treatment discontinuation with the Medical Monitor 
(or designee). 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. The reason for 
subject withdrawal from the study will be recorded in the eCRF. At the time of withdrawal from 
the study, the ET visit should be conducted as shown in the SoA. 
A subject may discontinue IP or withdraw from the study for the following reasons: 
x Adverse event 
x Death 
x Lack of efficacy 
x Lost to follow-up 
x Non-compliance with study drug 
x Physician decision 
x Pregnancy 
x Protocol deviation 
x Site terminated by Sponsor 
x Study terminated by Sponsor 
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x Withdrawal by subject 
x Randomized by mistake 
x Evidence of hepatic decompensation including ascites, hepatic encephalopathy, 
splenomegaly, or variceal bleeding as assessed by the Investigator (for F4 subjects 
only). 
x MELD Na+ score >12 (for F4 subjects only) 
For liver chemistry abnormality actions and follow-up assessments, refer to Section 7.1.1. 
Pregnancy is a mandatory criterion for permanent discontinuation of IP (Section 7.1.2). 
7.1.1. 
Monitoring and Discontinuation for Suspected Drug-induced Liver Injury 
(DILI) 
Liver chemistry will be evaluated as specified in the SoA (Section 1.3). 
Per FDA recommendations, the following criteria for elevations in liver transaminases or 
bilirubin will be used for closely monitoring, discontinuing, or temporarily interrupting IP. 
Definition of baseline ALT and AST values 
Baseline value is defined as an average of ALT and AST values performed during Screening and 
the Baseline (Day 1) visit, as follows:  
ALT/AST Screening Assessments 
Day 1 
ALT/AST 
Assessment 
Baseline Value  
Assessment 1 
Assessment 2  
Assessment 3 (if 
applicable) 
Normal 
Normal 
Not applicable 
Any 
Average of 
Assessment 1, 
Assessment 2 and 
Day 1 (3 tests) 
Normal  
Abnormal and 
LQFUHDVH
from Assessment 1 
Not applicable 
Any 
Average of 
Assessment 1, 
Assessment 2 and 
Day 1 (3 tests)  
Normal  
Abnormal and 
!LQFUHDVH
from Assessment 1 
1RUPDORU
increase from 
Assessment 1 
Any 
Average of 
Assessment 1, 
Assessment 2, 
Assessment 3 and 
Day 1 (4 tests) 
$EQRUPDODQG!
increase from 
Assessment 1 
Not applicable, 
subject 
excluded 
Not applicable, 
subject excluded 
Abnormal  
LQFUHDVH
from Assessment 1 
Not applicable 
Any 
Average of 
Assessment 1, 
Assessment 2 and 
Day 1 (3 tests) 
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ALT/AST Screening Assessments 
Day 1 
ALT/AST 
Assessment 
Baseline Value  
Assessment 1 
Assessment 2  
Assessment 3 (if 
applicable) 
Abnormal 
!LQFUHDVH
from Assessment 1 
LQFUHDVHIURP
Assessment 1 
Any 
Average of 
Assessment 1, 
Assessment 2, 
Assessment 3 and 
Day 1 (4 tests) 
!LQFUHDVHIURP
Assessment 1 
Not applicable, 
subject 
excluded 
Not applicable, 
subject excluded 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase  
New transaminase elevations in subjects with baseline value within the normal range: 
For new elevations in transaminases to greater than 2x ULN, repeat measurement should be 
performed within 48-72 hours10 of receipt of laboratory results. If elevations persist, subjects 
should be evaluated for other causes of transaminase elevations and with tests of hepatic 
function. If no other cause is identified, then the subjects need to be monitored closely (see 
below), and discontinuation of the IP should be considered. 
IP should be discontinued, and the subject followed until resolution of symptoms or signs in the 
following situations: 
x ALT or AST >8x ULN 
x ALT or AST >5x ULN for more than 2 weeks 
x ALT or AST >3x ULN and (TB11 >2x ULN or INR >1.5012) 
x ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, jaundice (not attributable to Gilbert’s 
syndrome), and/or eosinophilia (>5.0 
New transaminase elevations in subjects with baseline ALT or AST > ULN 
For new elevations in transaminases to greater than 2x baseline value or total bilirubin >1.5x ULN, 
repeat measurement should be performed within 48-72 hours11 of receipt of laboratory results. If 
elevations persist, subjects should be evaluated for other causes of transaminase elevations and 
with tests of hepatic function. If no other cause is identified, then the subjects need to be 
monitored closely (see below), and discontinuation of the IP should be considered. 
IP should be discontinued, and the subject followed until resolution of symptoms or signs in the 
following situations: 
 
10 In cases of isolated AST elevation to the indicated threshold, with a clear non-hepatic source for AST elevation 
(e.g., evidence of significant concurrent creatine phosphokinase elevation), decision regarding need to proceed with 
DILI work-up will be based on Investigator judgement.  
11 In subjects with Gilbert’s syndrome, Direct bilirubin >2 x ULN. 
12 Subjects on anti-coagulation therapy must be assessed individually, as INR criterion will not apply. 
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Table 3: 
Discontinuation Criteria in Subjects with Abnormal Baseline ALT or AST 
Values 
Baseline Value of ALT/AST 
Criteria to Discontinue IP 
<2× upper limit of normal (ULN) 
if ALT or AST increases to >5× baseline value 
î8/1EXWî8/1 
if ALT or AST increases to >3× baseline value 
î8/1 
if ALT or AST increases to >2× baseline value 
Other 
if ALT or AST increase to >2× baseline value AND the increase is 
accompanied by a concomitant total bilirubin increase to >2× ULN 
OR the INR concomitantly increases by >0.2.  
if ALT or AST increase to >2× baseline value in the presence of 
signs and symptom(s) such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, jaundice (not 
attributable to Gilbert’s syndrome) DQGRUHRVLQRSKLO! 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, normalized ratio; ULN, 
upper limit of normal 
Close Monitoring for Suspected DILI: 
x Repeating liver enzymes, serum bilirubin, hematology panel (for eosinophil count), 
and INR tests two or three times weekly. Frequency of repeat testing can decrease to 
once a week or less if abnormalities stabilize or the IP has been discontinued and the 
subject is asymptomatic. 
x Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
x Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
x Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
x Obtaining a history of exposure to environmental chemical agents. 
x Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
x Considering gastroenterology or hepatology consultations. 
Note: If a visit to the clinic is not feasible, laboratory testing can be performed by home health 
and sent to the central laboratory, or locally and the results should be promptly communicated 
to the Investigator site. 
7.1.2. 
Monitoring and Study Continuation of Subjects with NASH Fibrosis Stage F1 
or F4  
The initial protocol allowed subjects to be included based on the biopsy read by one of the 
2 expert pathologists. Version 3 Amendment #2 (March 11, 2022) changed the biopsy reading 
methodology to a central panel of 3 independent pathologists. This change in methodology 
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resulted in a change in fibrosis stage at baseline for some subjects (from F2 or F3 to either F1 or 
F4). These subjects and subjects evaluated as F4 during the study will be managed as follows: 
1. Subjects with baseline fibrosis stage F1 as determined by a consensus of 3 central 
pathologists  may continue all phases of the study and will be analyzed separately as an 
exploratory population. 
2. Subjects with baseline fibrosis stage F4 (cirrhotic) as determined by a consensus panel of 
3 central pathologists (as described above) will participate in all phases of the study as an 
exploratory population and will be analyzed separately provided: 
a. Their liver disease is considered well compensated as assessed by Child-Pugh 
Class A criteria (See Section 10.8), and 
b. There is no evidence of hepatic decompensation (i.e., hepatic encephalopathy, 
ascites, or bleeding varices) as assessed by the PI according to usual standard of 
care, and  
c. There is no evidence of hepatocellular carcinoma as assessed by local standard of 
care (e.g., ultrasound, CT scan, or MRI imaging methods and/or central AFP 
measurement). Central AFP measurement will be performed at every scheduled 
visit and may be done locally if applicable. 
d. Their MELD Na+ score is 7KHMELD Na+ score can be calculated by the 
Investigator, if applicable. 
3. Subjects who complete the Main Study and have Week 24 biopsy results evaluated as F4 
(cirrhotic) will complete all remaining study periods, provided they continue to meet the 
criteria in 2a-d above. 
4. Consistent with these requirements, subjects who are F4 (cirrhotic) and have evidence of 
decompensation at any time during the study will be discontinued per Section 7.1 
discontinuation criteria above. 
7.1.3. 
Pregnancy 
A female subject must permanently discontinue IP if she becomes pregnant. See Section 10.4 
and Section 8.3.5 for additional details. If a male subject's partner becomes pregnant, the male 
subject must agree to use condoms with spermicide to prevent potential fetal exposure. 
See the SoA (Section 1.3) for data to be collected at the time of IP discontinuation (ET visit). 
7.2. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
x The site must attempt to contact the subject and reschedule the missed 
visit/procedures as soon as possible and counsel the subject on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to or should continue in the study. 
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x 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. 
x Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study (and be labelled as lost to follow-up). 
x Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1 (Section 10.1.8). 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
x Study procedures and their timing are summarized in the SoA (Section 1.3). 
x If multiple assessments are scheduled at the same timepoint, it is recommended that 
procedures be performed in the following sequence: PROs, 12-lead ECGs, vital signs, 
physical examination, sample collection for laboratory and PD biomarker tests, and 
sample collection for PK. 
x The Medical Monitor (or designee) should be notified about immediate safety 
concerns upon occurrence or awareness, as soon as possible. Decisions if the subject 
should continue or discontinue IP will be per Investigator’s discretion, in consultation 
with the Medical Monitor (or designee), if possible. 
x Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
x Any situation at the site level with potential impact on subject safety or study 
conduct, including situations related to COVID-19 infection or control measures 
(Appendix 6, Section 10.6), should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine potential impact on study subject/s or study 
conduct. 
x 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. 
x Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) 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. 
8.1. 
Efficacy Assessments 
Laboratory-associated PD and biomarker assessments are described in Section 8.5. 
8.1.1. 
Liver Biopsy and Scoring 
Liver biopsy remains the gold standard for diagnosing NASH as well as for establishing the 
degree of liver fibrosis as it can reliably assess the various histopathological patterns 
characteristic of NASH (Andronescu, 2018; Arab, 2018; Bedossa, 2018; Gunn, 2018). In 
addition, histopathology scores are used to assess extent of fibrosis before and after treatment. 
The fibrosis stage ranges from F0 (without fibrosis) to F4 (cirrhosis) per NASH CRN system. 
Currently, liver biopsy is required by regulatory authorities as a surrogate endpoint to assess drug 
efficacy in Phase 3 clinical studies. 
Paired liver-biopsy will be performed percutaneously (preferred method) per institution standard, 
at Screening (a recent biopsy within 6 months prior to screening will be acceptable if available 
for central read evaluation in lieu of screening biopsy) and Week 24 (window of -7 days to +14 
days) (as specified in the SoA, Section 1.3). If biopsy is not performed by Week 26 for subjects 
in QW dose groups, further doses should be held until discussion with Sponsor. Subjects who 
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permanently discontinue IP at or after Week 16 and before Week 24 of the Main study will also 
be requested to provide a liver biopsy at ET visit. For any other scenarios of IP discontinuation 
or withdrawal from the study, consult the Medical Monitor (or designee) regarding biopsy 
collection. 
Biopsy assessment for eligibility and endpoints will be based on NASH CRN. The NASH CRN 
adopted the system validated by Kleiner et al. (Kleiner, 2005). The NASH CRN semi-
quantitative scoring of histological features (steatosis, ballooning degeneration, and lobular 
inflammation) which together comprise the unweighted sum to produce the NAFLD Activity 
Score (NAS) and the NASH CRN Fibrosis staging system are as follows: 
 
Steatosis 
Ballooning 
Lobular Inflammation 
Grade 0 
 
None 
No foci 
Grade 1 
!DQG 
Few balloon cells 
<2 foci/200x 
Grade 2 
!DQG 
Many cells/prominent ballooning 
2-4 foci/200x 
Grade 3 
! 
 
>4 foci/200x 
NASH CRN Fibrosis Staging System 
Stage 
Fibrosis 
Stage 0  
None 
Stage 1 
Perisinusoidal or periportal 
Stage 1A 
Mild, zone 3, perisinusoidal 
Stage 1B 
Moderate, zone 3, perisinusoidal 
Stage 1C 
Portal/periportal 
Stage 2 
Perisinusoidal and portal/periportal 
Stage 3 
Bridging fibrosis 
Stage 4 
Cirrhosis 
Transjugular or other biopsy methods may be utilized with Medical Monitor (or designee) 
approval if the Investigator deems it to be a safer option for an individual subject, and if the site 
has extensive experience with obtaining biopsies of adequate size using the technique. Ideally, 
liver biopsies should be done after MRI-PDFF. 
Details on the biopsy procedure, preparation of slides and central read are provided in the Biopsy 
Manual. The procedure will be performed by an experienced hepatologist or radiologist. Biopsies 
will be subject to central read by liver pathologists who are blinded to the treatment group 
assignment. 
In addition to the central read, liver histology will also be quantitatively assessed by an AI-based 
machine-read analysis. 
8.1.2. 
Magnetic Resonance Imaging – Whole Liver Proton Density Fat Fraction 
(MRI-PDFF) 
MRI-PDFF is as a noninvasive, quantitative, and accurate measure of liver fat content (imaging-
based biomarker) to assess treatment response in NASH clinical studies (Caussy, 2018). In this 
study, the MRI-PDFF procedure is used to assess secondary and exploratory endpoints and will 
be performed at timepoints specified in the SoA. 
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PDFF 
The MRI-PDFF is determined using a 6-echo gradient echo pulse sequence covering the liver in 
the axial plane. Analysis is performed by semi-automatic contouring of the liver in every slice 
avoiding major vessels and bile ducts. The method applies multi-peak lipid spectral models and 
simultaneous quantification and correction for T2. The liver fat value (PDFF) is the pooled 
median value of all voxels in the identified volume of interest. For more information, refer to the 
Imaging Manual. 
At Screening, MRI-PDFF should ideally be performed prior to the liver biopsy. A historical 
MRI-PDFF performed within the last 3 months prior to screening may be acceptable if the 
images are available and evaluable by the central imaging vendor. The proportion of subjects 
enrolled with MRI-3'))PD\EHOLPLWHGDWWKH6SRQVRU¶VGLVFUHWLRQ. 
Iron-corrected T1 Mapping (cT1) 
Applicable only at sites capable of conducting cT1 imaging. 
cT1 imaging is an MRI-derived measurement of iron-corrected T1 mapping (cT1). It is a non-
invasive, quantitative and accurate biomarker which correlates with ballooning (Pavlides, 2017; 
Eddowes, 2018), fibrosis (Banerjee, 2014; Pavlides, 2017; Tunnicliffe, 2017; McDonald, 2018), 
and NAS (Eddowes, 2018) and has also been shown to predict clinical outcomes (Pavlides, 
2016). T1 mapping measures longitudinal relaxation time, which can be used as an indication of 
regional tissue water content. 
cT1 is measured by using the LMS MOLLI sequence, which is a multi-slice, multi-breathhold, 
cardiac-gated acquisition performed at end-expiration. It is determined using a five-slice 
transverse acquisition with one breathhold of approximately 10 seconds per slice. This protocol 
uses a ShMOLLI acquisition on GE and Siemens scanners, and a MOLLI acquisition on Philips. 
At Screening, a historical cT1 imaging assessment performed within the last 3 months prior to 
screening may be acceptable if the images are available and evaluable by the central imaging 
vendor. 
Liver and Spleen Volume 
A dedicated axial 3 dimensions (3D) T1-weighted spoiled gradient echo scan with or without fat 
suppression will be positioned to cover the entire liver and spleen. Analysis will be done using a 
semiautomated software to delineate the outer borders of the liver and the liver volume will be 
calculated in liters.  
At Screening, a historical liver and spleen volume assessment performed within the last 3 months 
prior to screening may be acceptable if the images are available and evaluable by the central 
imaging vendor. 
Pancreatic Fat 
An IDEAL (iterative decomposition of water and fat with echo asymmetry and least-squares 
estimation) multi-echo-gradient echo sequence with 6-point gradient echo will be performed in 
the axial plane cantered on the pancreas covering 10 cm of the organ in the feet-head direction. 
7KHSDQFUHDWLFIDWZLOOEHUHSRUWHGLQRISURWRQGHQVLW\IDWfraction. 
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At Screening assessment, a historical pancreatic fat assessment performed within the last 3 
months prior to screening may be acceptable if the images are available and evaluable by the 
central imaging vendor. 
8.1.3. 
Transient Elastography (FibroScan®) kPa and CAP scores 
FibroScan is a validated non-invasive specialized ultrasound assessment of liver fibrosis and 
steatosis (Wong, 2013). Fibrosis and liver stiffness are measured in kilopascals (kPa). 
In this study, both VCTE and CAP will be measured: 
x VCTE has a high negative predictive value to rule out advanced fibrosis; positive 
predictive value when it indicates advanced fibrosis is actually inadequate and 
insufficient to diagnose cirrhosis. VCTE is mostly to differentiate advanced fibrosis 
vs. absence of advanced fibrosis and has limited accuracy in differentiating fibrosis 
stages that are not at the ends of the spectrum. 
x The CAP score is a measurement of fatty change in the liver and is measured in 
decibels per meter (dB/m). 
Specifics for performance of the FibroScan will be in accordance with manufacturer’s standards 
and instructions or manuals. 
FibroScan assessments will be performed at timepoints specified in the SoA. At Screening, a 
historical FibroScan performed within the last 3 months prior to screening may be acceptable. 
8.1.4. 
Anthropometric Measurements 
The following anthropometric measurements will be collected during the study as specified in 
the SoA: 
x Body weight 
x BMI (auto-calculated) 
x Waist circumference 
x Hip circumference 
x Waist/hip ratio (auto-calculated) 
Further information will be provided in the Investigator’s site file. 
8.1.5. 
Patient Reported Outcome 
All PROs should be completed prior to dosing. 
8.1.5.1. 
Chronic Liver Disease Questionnaire - NAFLD-NASH (CLDQ NAFLD-NASH) 
CLDQ NAFLD-NASH is a self-reported 36-item quality of life questionnaire composed of 
6 domains (abdominal symptoms, activity/energy, emotional health, fatigue, systemic symptoms 
and worry). CLDQ-NAFLD/NASH was shown to be reliable and was validated in 1667 patients 
with biopsy-confirmed NASH enrolled in 2 Phase 3 studies (Younossi, 2019b). 
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8.1.5.2. 
Work Productivity and Activity Impairment Questionnaire for NASH 
(WPAI-NASH) 
WPAI-NASH is a well-validated, self-administered instrument measuring impairment of work 
and non-work activities over the prior 7 days in employed subjects. WPAI-NASH includes 
4 VFRUHVRQDVFDOHRIWRDEVHQWHHLVP (the percentage of work time missed because of 
one’s health), presenteeism (the percentage of impairment experienced while at work because of 
one’s health), overall work impairment (a combination of absenteeism and presenteeism) and 
activity impairment (the percentage of impairment in daily activities because of one’s health). 
Higher scores indicate a higher absence from work and impairment (Reilly, 1993). This 
instrument was shown to be valid and reproducible including in subjects with NASH (Balp, 
2019). 
8.1.5.3. 
Europe Quality of Life Group 5 Dimension 5 Level Questionnaire (EQ-5D-5L) 
The EQ-5D-5L was introduced by the EuroQoL Group in 2009 to improve the instrument’s 
sensitivity and to reduce ceiling effects, as compared to the EQ-5D-3L, including in subjects 
with chronic hepatic disease (Janssen, 2013; Scalone, 2013). The EQ-5D-5L essentially consists 
of 2 pages: the EQ-5D descriptive system and the EQ VAS. 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. The subject is asked to 
indicate his/her health state by ticking the box next to the most appropriate statement in each of 
the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for 
that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that 
describes the subject’s health state. 
The EQ VAS records the subject’s self-rated health on a vertical VAS, where the endpoints are 
labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS 
can be used as a quantitative measure of health outcome that reflect the subject’s own judgement. 
The EQ-5D-5L utility score can range between 0 (death) and 1 (perfect health), while VAS score 
ranges from 0 (worst imaginable health) to 100 (best imaginable health). 
8.1.5.4. 
Liver-related Pain and Discomfort Questionnaire 
NAFLD/NASH may be associated with right upper quadrant pain or discomfort. To evaluate the 
effect of treatment with pegozafermin on liver-related pain and discomfort, a targeted 
questionnaire with a graphic that clearly indicates the right upper quadrant, where this pain is 
typically experienced, will be assessed. These questions will be similar to abdominal pain and 
discomfort items in the CLDQ-NAFLD-NASH questionnaire. 
8.1.5.5. 
The Appetite Sensations Visual Analog Scale (VAS) 
VAS measures the intensity or magnitude of sensations and subjective feelings and the relative 
strength of attitudes and opinions about specific stimuli, on a scale of 0 to 10 (Duncan, 1989). 
VAS scores are reliable for appetite research and do not seem to be influenced by prior diet 
standardization (Flint, 2000; Parker, 2004). For this study, VAS will be used to record hunger; 
satiety; fullness; prospective food consumption; and desire to eat something fatty, salty, sweet or 
savory. 
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8.2. 
Safety Assessments 
Safety assessments include AEs (either reported by the subject or observed by the Investigator), 
concomitant medication use, physical examination, ECG, vital signs, and laboratory assessments. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations/Assessment 
x A complete physical examination will include, at a minimum, assessments of the 
skin, respiratory, cardiovascular system, abdomen (liver and spleen) and a 
neurological exam. Height (only collected at Screening) will also be measured and 
recorded. 
x A limited physical assessment will be conducted if clinically indicated and may be 
performed by home health nurse at remote visits; this should include at a minimum, 
assessments of the skin (inspection of injection sites), respiratory, cardiovascular 
system, and abdomen, and any other pertinent system based on prior findings or 
complaints or subject complaint. 
8.2.2. 
Vital Signs 
x Vital signs include blood pressure, pulse, body temperature, and respiratory rate. 
x Planned timepoints for vital signs are provided in the SoA. 
x Starting from randomization, blood pressure and pulse will be measured in duplicate, 
the first measurement will be taken up to 15 minutes before the indicated timepoint 
and repeat measurements should be performed according to local practice. 
x Additional vital signs measurement may be done if clinically indicated. 
x Subjects must be in a supine or semi-erect/seated position and resting for at least 
5 minutes prior to measurements, which should be performed according to local 
practice. 
8.2.3. 
Electrocardiograms 
x 12-lead ECG will be recorded as single bedside measurements using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, and QT (QTcF) 
intervals. 
x Subject to be resting for at least 2 minutes prior to ECG. 
x A central reviewer will be used; instructions will be provided in the imaging manual. 
ECG tracing should be provided to the central reader within 72 hour of assessment. 
8.2.4. 
Bone Mass Density 
BMD will be assessed by DXA, a standard reference test for evaluation of bone loss. 
8.2.5. 
Clinical Safety Laboratory Assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3) for the timing and frequency. Laboratory tests should be performed under 
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fasting conditions (KRXUV). Fasting includes food and all beverages except for non-mineral 
water. It is recommended that subjects abstain from consumption of alcoholic beverages for at 
least 24 hours before laboratory test assessments. It is recommended that subjects refrain from 
strenuous activities. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, 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 28 days after the last dose of IP should be repeated until the values return 
to normal or baseline or are no longer considered clinically significant by the Investigator. 
If such 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. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the relevant study manual and the SoA (Section 1.3). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered clinically 
significant by the Investigator (e.g., SAE or AE or skipping of dose), then the results must be 
recorded in the eCRF and the Sponsor should be notified. 
8.2.5.1. 
Immunogenicity Assessments 
Immunogenicity samples will be collected from all subjects at timepoints designated in the SoA 
(Section 1.3). Antibodies to pegozafermin as well as titer and binding specificity will be 
evaluated in serum samples collected from subjects treated with pegozafermin only. 
For post-treatment immunogenicity assessment, subjects who complete the Week 48 visit will be 
asked to return to clinic to have blood samples collected approximately every 3 months for up to 
. AEs and concomitant medication will also be recorded during the immunogenicity 
follow-up period. Additional testing may be requested in the event of safety-related concerns. 
The sponsor may elect to terminate participation in the immunogenicity follow-up period based 
on emerging data. Subjects who terminate IP early will not return for immunogenicity follow-up, 
unless asked to return for additional testing(s), at the Medical Monitor’s discretion. 
Samples for endogenous FGF21 level will be collected at baseline for all subjects, and at the 
immunogenicity follow-up visit(s). Endogenous FGF21 samples will be analyzed only in 
subjects with 
 to pegozafermin. 
Serum samples will be screened for antibodies binding to pegozafermin and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to pegozafermin and/or further characterize the immunogenicity of 
pegozafermin. The detection and characterization of antibodies to pegozafermin will be 
performed using a validated assay method under the supervision of the Sponsor. Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of the IP(s). 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
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the last subject’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of immune responses to pegozafermin. 
8.2.5.2. 
Bone Marker Assessments 
Plasma samples for potential future assessment of the bone markers CTX and P1NP will be 
obtained at the designated timepoints. 
8.2.5.3. 
Cortisol Assessments 
Saliva samples for measurement of night-time salivary cortisol (NSC) will be obtained at 
timepoints designated in the SoA (Section 1.3) to screen for hypercortisolism (Pappachan, 2017). 
The cortisol screening assessment is performed at screening to obtain baseline values and at 
subsequent visits to assess for hypercortisolism while on treatment. The NSC samples must be 
collected between 8:00pm and 12:00am before submitting the sample for processing at the 
specified visit. If sample is not collected during this time, repeat sample must be collected. 
The screening NSC assessment should be performed as early as possible during the screening 
period to allow sufficient time for samples to be resulted prior to randomization. Subjects should 
be provided with NSC collection kit at the first screening visit, when possible, to allow sample 
collection return at the following clinic visit. Subjects will not be deemed ineligible if screening 
NSC samples have been submitted but have not been resulted by Day 1 and may be randomized. 
Subjects with missing screening values will still have NSC assessments performed at the other 
scheduled visits as designated in the SOA. 
If screening value is >15 nmol/L, Medical Monitor (or designee) may request further workup 
should the value be of clinical concern; however, values >15 nmol/L will not be exclusionary 
The screening NSC is a safety assessment, and not an eligibility criterion.  
For on-treatment values that are >15 nmol/L AND above the screening value, a repeat NSC 
should be performed (sample should be collected at approximately the same time as the 
screening sample). If the repeat assessment is still > 15 nmol/L AND above the screening value, 
an additional screening test for hypercortisolism will be done (either overnight dexamethasone (1 
mg) suppression test [DST] or a 24 h collection for urinary free cortisol [UFC]) level.  
If a screening value is not available, and on-treatment value is >15 nmol/L, a repeat NSC should 
be performed and if the repeat assessment is still >15nmol/L, an additional test for 
hypercortisolism will be done (either a DST or a UFC).  
The Medical Monitor (or designee) will provide guidance on the appropriate assessment based 
on the individual subject for subsequent test values that are also >15nmol/L based on the subject 
profile. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE and SAE can be found in Appendix 3 (Section 10.3). 
AEs will be reported by the subject (or, when appropriate, by a caregiver, 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 AE or SAE and remain responsible for following 
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up AEs that are serious, considered related to the IP or study procedures, or that caused the 
subject to discontinue the study or IP (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be as specified in the SoA (Section 1.3). 
Table 4 below summarizes the different reporting periods for AEs, SAEs, and events to monitor. 
Events to monitor are defined in Section 10.3.3. 
Table 4: 
Adverse Event Reporting Periods 
Type of 
Event 
Adverse Event 
Serious Adverse Event 
Events to monitor with IP 
Reporting 
period 
From consent until 
28 days after last dose of 
IP 
From consent until 28 days 
after the last dose of IP  
From consent until 28 days 
after the last dose of IP 
Reporting 
Timelines to 
the Sponsor  
Entered into the clinical 
database on an ongoing 
basis  
Within 24 hours  
Within 24 hours 
Note: For the immunogenicity follow-up period adverse events and serious adverse events will be collected at every 
visit until subject completes the last immunogenicity follow-up visit. Reporting timelines to the Sponsor for 
adverse events and serious adverse events remains the same as above.  
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
Investigator will submit any updated SAE data to the Sponsor or designee within 24 hours of it 
being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a 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 IP or study participation, the Investigator must promptly notify the Sponsor or 
designee. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs 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 or SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.2). Further 
information on follow-up procedures is given in Appendix 3 (Section 10.3). 
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8.3.4. 
Regulatory Reporting Requirements for SAEs 
x Prompt notification by the Investigator to the Sponsor or designee of an SAE is 
essential so that legal obligations and ethical responsibilities to ensure the safety of 
subjects and the safety profile of IP under clinical investigation are met. 
x The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety profile of IP under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and investigators. 
x Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
x An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
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8.3.5. 
Pregnancy 
x Details of all pregnancies in female subjects and of female partners of male subjects 
will be collected after the start of IP and until 90 days after last dose of IP. 
x If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
x Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4. 
Pharmacokinetics 
Blood samples for analysis of pegozafermin serum levels will be collected predose at the visits 
designated in the SoA (Section 1.3). 
Blood samples will be processed for collection of serum fractions for determination of 
pegozafermin serum concentrations. Serum samples will be shipped to the bioanalytical 
laboratory for analysis. PK samples collected from subjects during the period when they are 
administered placebo will not be analyzed. 
8.5. 
Pharmacodynamics and Biomarkers 
8.5.1. 
Pharmacodynamics 
The following biomarkers/PD parameters will be evaluated at timepoints designated in the SoA 
(Section 1.3): 
Laboratory Parameters 
x Liver function tests: ALT, AST 
x GGT 
x ALP 
x Pro-C3 (see Section 8.5.1.1) 
x Adiponectin 
x Triglycerides 
x HDL-c 
x Non-HDL-c 
x LDL-c 
x Total cholesterol 
x HbA1c 
x C-peptide 
x Fasting glucose 
x Fasting insulin 
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x Adipo-IR index (fasting free fatty acids x fasting insulin) 
x High sensitivity C-reactive protein (hsCRP) 
x ELF panel (Section 8.5.1.2) 
x FIB-4 index (Section 8.5.1.4) 
x AFP (F4 subjects only) 
x MELD Na+ score (F4 subjects only) 
Samples may be stored for a maximum of 15 years after the last subject’s last visit for the study, 
at a facility selected by the Sponsor, to enable further analysis of biomarker responses to 
pegozafermin. 
Residual blood samples will be stored for potential future analysis of biomarkers. 
Additional information will be available in the study-specific laboratory manual. 
8.5.1.1. 
N-terminal Propeptide of Type III Collagen (Pro-C3) 
N-protease cleaved amino-terminal type 3 procollagen peptide (P3NP) neo-epitope (Pro-C3) is 
derived from the synthesis of type 3 collagen. Pro-C3 appears to correlate with liver fibrosis 
stage, fibrosis regression and response to treatment both as a single test and as part of algorithms 
(Nielsen, 2015; Daniels, 2018; Hansen, 2018). 
8.5.1.2. 
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) 
HOMA-IR is a method used to quantify insulin resistance based on the following formula(s) 
(Matthews, 1985): 
Glucose in mmol/L 
 
Glucose in mg/dL 
HOMA-IR = 
Glucose × Insulin 
 
HOMA-IR = 
Glucose × Insulin 
22.5 
 
405 
HOMA-IR will be calculated by the central laboratory based on fasting glucose and insulin. 
8.5.1.3. 
Enhanced Liver Fibrosis (ELF) Panel 
The enhanced liver fibrosis (ELF) blood test has recently been recommended by the National 
Institute for Health and Care Excellence to test for advanced fibrosis in NAFLD. The ELF test 
involves calculating a score from the concentrations of serum biomarkers: tissue inhibitor of 
matrix metalloproteinases-1 (TIMP-1), P3NP, and hyaluronic acid (HA) (Lichtinghagen, 2013). 
The ELF score may be calculated from TIMP-1, P3NP and HA measurements according to the 
following formula: 
ELF Score = 2.278 + 0.851(ln[HA]) + 0.751(ln[P3NP]) + 0.394(ln[TIMP-1]) 
8.5.1.4. 
FIB-4 Index 
The FIB-4 is a simple non-invasive test for liver fibrosis that takes into account age, platelet 
count (PLT), AST, and ALT using the following formula: 
age ([yr] × AST [U/L]) / ((PLT [109/L]) × (ALT [U/L])1/2) 
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6XEMHFWVZLWKDFXWRIIRI!KDYHDSRVLWLYHSUHGLFWLYHYDOXHRIIRUDGYDQFHGILEURVLV
(Sterling, 2006). 
8.5.1.5. 
Exploratory Biomarker Assessments 
Samples for RNA/DNA, as well as plasma and serum samples, will be collected at designated 
timepoints from all subjects who consented from centers in which IRB/IEC approval is granted. 
These samples will be taken for potential future exploratory assessments, to increase 
understanding of pegozafermin biological activity and to identify potential existing and/or 
emerging biomarkers. 
8.6. 
Pharmacogenomics Assessments 
Pharmacogenomics (PGx) analyses may be performed on any bio-sample from subjects who 
have consented for PGx sampling. Subject confidentiality will be maintained. Please also refer to 
Appendix 5 (Section 10.5). 
Suitable bio-samples should be collected from all subjects, where permitted by law and local 
authorities. Subjects who are prohibited from participating in the PGx research by law and/or 
local authorities and subjects providing a written (documented) opt-out may still participate in 
the study. 
A single blood sample will be collected from all enrolled subjects for possible future genetic 
analyses related to pegozafermin, including associations of DNA variations with clinical 
treatment responses to pegozafermin (e.g., PK, tolerability, and safety features or disease 
susceptibility and severity features). Pharmacogenomic assessment may include a sequencing of 
the whole genome, if required. 
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9. 
STATISTICAL CONSIDERATIONS 
This section describes the statistical analysis and intended methodology as foreseen at the time of 
planning the study. Changes, additions, and further details about the analyses will be described in 
the statistical analysis plan (SAP). Any subsequent additional analyses or changes to analyses 
that will be fully disclosed in the clinical study report. Summaries and analyses will be presented 
by dose/treatment group. Before database lock, final statistical and PK analysis plans containing 
full details of all planned analyses will be produced. The analyses presented here represent an 
outline of the intended methodology; Analyses specified in the SAP will take precedence over 
those described herein. All clinical data will be summarized using descriptive statistics: number 
(n), mean, standard deviation (SD), median, minimum, and maximum for continuous 
measurements, and counts and percentages for categorical measurements. 
9.1. 
Statistical Hypotheses 
The primary efficacy endpoints are (1) proportion of subjects with NASH resolution without 
worsening of fibrosis at Week 24 compared to baseline (2) proportion of subjects achieving 
iPSURYHPHQWRIILEURVLVVWDJHZLWKRXWZRUVHQLQJRI1$6+DW:HHN compared to baseline. 
The following hypothesis will be tested for each primary endpoint: 
x The null hypothesis: there is no difference in the proportion of subjects meeting the 
primary endpoint between the placebo and each pegozafermin dose group. 
x The alternative hypothesis: the proportion of subjects meeting the primary endpoint 
between the placebo and each pegozafermin dose group is different. 
The study will be considered successful if a given pegozafermin dose group is demonstrated to 
be superior to the placebo group in either of the two primary endpoints at 0.05 significance level. 
9.1.1. 
Estimand Framework 
As detailed in the ICH E9 (R1) addendum, the following five attributes will define the estimand 
framework in this trial. The primary estimand will be defined as a treatment policy (TP) 
estimand, which compares treatment outcomes in two randomized arms at 24 weeks post-
randomization irrespective of what changes in treatment could have occurred post-randomization 
as a result of various intercurrent events (ICE). To implement TP strategy, it will be important 
that outcomes are collected and recorded after occurrence of ICE’s as close to the 24-week time 
point, regardless of what actual treatment the patient may be receiving. Below are the 5 attributes 
of the primary estimand: 
x Treatment conditions: Randomization to Pegozafermin (15 mg QW or 30 mg QW or 
44 mg Q2W) or Placebo, regardless of ICE’s and deviations from the randomized 
treatment and actual treatment received during or at the end of the treatment period. 
x 3RSXODWLRQ5DQGRPL]HGVXEMHFWVZLWKILEURVLVVWDJHRUDQG1$6DWEDVHOLQH
per 3-panel consensus read. 
x Endpoints: NASH resolution without worsening of fibrosis at Week 24 compared to 
baseline; improvHPHQWRIILEURVLVVWDJHZLWKRXWZRUVHQLQJRI1$6+DW:HHN
compared to baseline  
x Intercurrent events (ICEs): Three types of ICEs are defined below. 
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x Population-level summary: Between treatment group difference expressed in terms of 
the percentage differences in achieving the endpoints. 
The following types of ICEs will be documented in course of the study. 
x ICE-1: Discontinuation of treatment due to lack of efficacy.  
x ICE-2: Discontinuation of treatment due to adverse events (AE).  
x ICE-3: All other events, i.e., protocol deviation, etc. 
The primary analysis will use all observed outcomes at the end of the treatment period, 
regardless of actual treatment. All outcomes collected from patients experiencing this ICE after 
the actual ICE will be used in the analysis and missing values resulting from any ICE will be 
imputed assuming an imputation model informed by observed outcomes from similar patients 
with this type of ICE. The imputation model will include terms for the randomized treatment arm 
and the type of ICE(s) experienced by patients with missing outcomes, i.e., ICE-1,2,3 (as defined 
above) or None. The final inference following multiple imputation (MI) will be conducted using 
Rubin’s combination rules, as detailed in the SAP.  
Although the ICEs’ defined above will be all handled by the same treatment policy strategy for 
the primary estimand, various sensitivity analyses (SA) will be conducted that will incorporate 
different strategies, depending on the type of ICE. For the purposes of sensitivity analysis, 
patients who experienced any of the listed ICEs (ICE-1,2,3), the outcomes for the primary 
efficacy endpoint will be considered missing starting from the occurrence of each ICE (even if 
outcomes are collected following an ICE) and then the missing outcomes will be imputed using 
appropriate imputation strategies.  
For ICE-1, the SA will use the “return to baseline” hypothetical strategy, implying no benefits 
have been received for such patients from randomization until the end of the treatment period. 
The missing outcomes will be imputed using a relevant regression model fitted to the baseline 
data within each treatment arm with relevant patient baseline covariates and stratification factors 
included as covariates.  
For ICE-2, SA will be handled with the “control-based” hypothetical strategy implying that 
patients would have switched to the control treatment (i.e., placebo) starting from the occurrence 
of ICE-2 to the end of the treatment period. The missing outcomes will be imputed from a 
similar regression model fitted to the placebo arm alone with relevant patient baseline covariates 
and stratification factors as covariates.  
For ICE-3, SA will be handled using a hypothetical strategy that assumes that patients would 
have continued their assigned treatment starting from ICE3. The missing outcomes will be 
imputed using the same model as for ICE-2 but fitted to each respective treatment arm. 
Missing data due to reasons unrelated to the intercurrent events (ICE-1, 2, 3), e.g., missingness 
caused by study termination by sponsor, will be imputed using the same model as for ICE-3. 
9.2. 
Sample Size Determination 
The planned sample size is chosen to sufficiently demonstrate the treatment effect in histological 
response at Week 24 and to enable characterization of the treatment effect size and variability 
around the histological response to support planning of statistical analyses and powering for the 
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Phase 3 study and to provide adequate dose response information to support Phase 3 program 
dose selection. 
Approximately 184 subjects will be randomized in a ratio of 16:8:6:24:15 to Placebo QW 
(N=42), Placebo Q2W (N=22), pegozafermin 15 mg QW (N=16), 30 mg QW (N=64) and 44 mg 
Q2W (N=40) in each pegozafermin group, respectively. 
The sample size is selected based on a placebo response rate of  for NASH resolution 
without worsening of fibrosis aQGDSODFHERUHVSRQVHUDWHRIIRULPSURYHPHQWRIILEURVLV
 stage without worsening of NASH. These placebo response rates are supported by a 
comprehensive review on placebo histological response rates in previously reported NASH 
studies and recent meta-analyses (Han, 2019; Rinella, 2019; Drenth, 2020; Mesenbrink, 2020; 
Nikoolenejad, 2020). The anticipated treatment effect is 30IRUERWKKLVWRORJLFDOHQGSRLQWVDQG
is supported by the observed pegozafermin effects on both histological endpoints and in reducing 
MRI-PDFF and ALT in Study BIO89-100-002, the relationship between MRI-PDFF and ALT 
reduction to histological responses (Hoofnagle, 2013; Seko, 2015; Loomba, 2019; Loomba, 
2020a; Loomba, 2020b; Loomba, 2020c), and the observed histological responses in molecules 
with similar mechanism of action with treatment shorter than or close to 24 weeks (Akero 
Therapeutics Inc, 2020; Harrison, 2020a; Harrison, 2020b). Hence, the assumed pegozafermin 
response rates DUH
DQG
IRU1$6+UHVROXWLRQDQGILEURVLVLPSURYHPHQWUHVSHFWLYHO\ 
With these assumptions, the sample size of 64 patients per 30mg QW and placebo group will be 
able to detect the treatment differences with 
 power for 1$6+UHVROXWLRQDQG
IRU
fibrosis improvement at a two-sided nominal 0.05 significance level and accounting for a dropout 
rate of up to 
. For the comparison of the treatment difference between 44mg Q2W group 
(N=40) and placebo group (N=64), the power will be 
for NASH resolution and 
IRU
fibrosis improvement. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 
 
Population 
Description 
Randomized Analysis 
Set 
All enrolled subjects who are assigned a randomization number in the study. 
Full Analysis Set 
(FAS) 
All enrolled subjects ZLWKFRQILUPHGILEURVLVVWDJH)RU)DQG1$6DW
baseline per independent review by a 3-pathologist panel who are eligible and 
assigned a randomization number in the study and received at least 1 dose of 
IP. For analysis purposes, subjects will be analyzed according to the treatment 
they were randomized to regardless of actual treatment received. 
Safety Analysis Set 
All randomized subjects who receive at least 1 dose of IP. In this population, 
subjects will be summarized based upon the IP actually received, regardless of 
the IP to which they were randomized. 
PK Analysis Set 
All subjects in the FAS who have sufficient data to adequately characterize the 
trough serum pegozafermin concentrations and have no other events or 
protocol violations that would adversely affect results, such as not completing 
the full dose. The analysis population for any population PK modeling may be 
defined separately in a population PK data analysis plan. 
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Population 
Description 
MRI-PDFF Analysis 
Set 
All subjects in the Full Analysis Set who have a baseline and at least one 
follow up MRI-PDFF assessment. 
9.4. 
Statistical Analyses 
The SAP will be developed and finalized before the database is unblinded for the Primary 
Analysis and will describe the subject populations to be included in the analyses, and procedures 
for accounting for missing, unused, and spurious data. 
In general, summaries and analyses will be presented by treatment group. Descriptive statistics 
will be presented for demographics and baseline characteristics, efficacy and safety endpoints, 
and PK parameters, when appropriate. 
For analysis purpose, placebo QW and placebo Q2W will be pooled. Supportive analyses of each 
treatment QW arm vs. placebo QW arm and 44 mg Q2W arm vs. placebo Q2W arm will also be 
performed. All statistical tests will be 2-sided and tested at a statistically significant level of 0.05. 
Unadjusted p-values will be reported for all efficacy comparisons. Confidence intervals (CI) will 
be 2-VLGHGXQOHVVVWDWHGRWKHUZLVH 
9.4.1. 
Efficacy Analyses 
The primary analyses of the primary endpoints will be performed using the FAS subjects with 
confirmed fibrosis stage F2 or F3 and NAS  at baseline per a panel of 3 pathologists. To 
evaluate the effect of pegozafermin on liver histology, a stratified Cochran-Mantel-Haenszel 
(CMH) test will be used to compare the differences in proportions of subjects who met 
histological responder criteria at Week 24 between each pegozafermin group and placebo, 
DGMXVWLQJIRUWKHVWUDWLILFDWLRQIDFWRUV7KHSRLQWHVWLPDWHVDQGCI for the differences in 
proportion will be calculated. Different sensitivity analyses to assess the impact of intercurrent 
events as described in Section 9.1.1 will also be explored. The details of how to handle 
intercurrent events, missing 24-week histology data, and the sensitivity analyses will be 
described in the SAP. 
Other binary efficacy endpoints will be analyzed with the methods analogous to those used for 
the histological endpoint. Other continuous efficacy endpoints will be analyzed by analysis of 
variance (ANCOVA) (for single post-baseline measurement), or by a mixed model repeated 
measures (MMRM) method. The model will include treatment group, week and treatment-by-
week interactions as main effects and baseline measurement and stratifications as covariates. An 
unstructured covariance matrix will be used to represent the correlation of the repeated measures 
within each subject whenever the model converges. The model will provide the least square (LS) 
mean, SE and 2-VLGHG&,IRUPHDQFKDQJHRUSHUFHQWFKDQJHIURPEDVHOLQHZLWKLQDQG
between treatments. P-values will be calculated to compare the treatment effect in each 
pegozafermin group to that in the placebo group at specific study weeks. Each treatment group 
comparison will be performed at a 2-sided 0.05 significance level. If the data shows strong 
evidence of a violation of the model assumptions, non-parametric methods will be considered. 
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9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Safety assessments will be 
based on AEs, laboratory values, concomitant medication use, ECG, and vital signs data. 
Summaries will be presented by treatment group. 
Treatment duration and IP received will be summarized by treatment group. Subject incidence of 
TEAEs will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class, MedDRA preferred term, and treatment group. All AEs that started within the first 
dose of IP and the last dose of the IP+28 days or continuing AEs that worsen the grade post IP 
will be considered as TEAEs. For subjects who withdraw consent from the study, the end date of 
the TEAE reporting period will be the earlier of the withdrawal consent date and the date of the 
last dose of the IP + 28 days. All TEAEs, all treatment-related TEAEs, all treatment-emergent 
SAEs, and all treatment-emergent serious related AEs will be summarized. 
7KHQXPEHURIVXEMHFWVZKRIDLOWRFRPSOHWHWKHVWXG\DQGWKHUHDVRQIRUGLVFRQWLQXDWLRQ
DQGWKHQXPEHURIVXEMHFWVZKRIDLOWRFRPSOHWHWKHVWXG\GXHWRUHODWHGTEAEs will be 
summarized and listed. 
Safety laboratory tests, concomitant medication use, vital signs, and ECG measures will be 
summarized by visits and by treatment group. 
Results of immunogenicity assessment will be provided by ADA response (number and percent 
of positive ADA subjects) and immunogenicity profile (e.g., antibody titers, binding specificity), 
when appropriate. 
The effect of ADA on serum pegozafermin concentrations may be evaluated. 
9.4.3. 
PK Analyses 
Serum concentration data will be listed by subject and summarized using descriptive statistics by 
nominal timepoint. 
9.5. 
Interim Analyses 
No interim analysis of the primary endpoint is planned. 
9.6. 
Primary Analysis 
The primary analyses will be conducted according to the SAP after all subjects have completed 
the Week 24 assessments or prematurely discontinued from the study. 
The study blinding will not be broken for the study team (subjects, investigators/site personnel 
and Sponsor) until the final analysis. Specifically-identified Sponsor personnel will be unblinded 
to summary results of the primary analyses for internal decision-making purpose. The list of 
Sponsor personnel unblinded to the summary results will be recorded in a separate document. 
Subjects and investigators/site personnel will remain blinded for the extension safety study. 
9.7. 
Final Analyses 
After all subjects have completed the EOS visit and the data have been cleaned and finalized, the 
study blind will be broken and the final analysis of the data will be performed according to the 
SAP. 
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9.8. 
Data Monitoring Committee (DMC) 
An independent DMC will periodically review overall unblinded safety data. 
Based on these reviews of emerging results, the DMC will recommend continuation, 
modification of the protocol, or termination of the study. 
Composition of the DMC, meeting structure, schedule, and procedures, the content and format of 
DMC reports, and other relevant details will be determined in consultation with DMC members 
and detailed in a separate DMC charter. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 Applicable laws and regulations 
x The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
x 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. 
x The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process 
x The Investigator or his or her representative will explain the nature of the study to the 
subject or his or her legally authorized representative and answer all questions 
regarding the study. 
x 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, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
x 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. 
x Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
x A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
Subjects who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
x 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. 
x The subject must be informed that his or her 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. 
x The subject must be informed that his/her 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. 
10.1.5. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
10.1.6. 
Data Quality Assurance 
x Electronic records and computerized systems used to capture clinical study data will 
be maintained and validated in accordance with ICH and FDA guidelines. 
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x All subject data relating to the study will be recorded on the eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
x The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
x The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
x Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
x The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
x The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
x Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. It may become required that some or all monitoring 
activities will be halted or performed remotely due to the recent COVID-19 
pandemic. In such a case, details of the changes made to the monitoring strategy will 
be described in the Monitoring Plan. 
x Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator per ICH-GCP and local regulations or 
institutional policies. 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, whether within the 
retention period or thereafter. 
10.1.7. 
Source Documents 
x 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. 
x Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
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x Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained. These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
10.1.8. 
Study and Site Closure 
The Sponsor designee 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 to the Sponsor 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: 
x 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 
x Inadequate recruitment of subjects by the Investigator 
x Discontinuation of further IP development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up. 
10.1.9. 
Publication Policy 
x 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. 
x The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
x Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors authorship requirements. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
x The clinical laboratory tests detailed in Table 5 will be performed by a central 
laboratory, except if noted otherwise, at timing/frequency detailed in the SoA 
(Section 1.3). Laboratory tests will be performed under fasting conditions 
 hours). 
x Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5. 
x Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
x Investigators must document their review of each laboratory safety report. 
Table 5: 
Protocol-Required Laboratory Assessments 
Hematology 
 
White blood cell count (WBC) with differential 
(Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils – DEVROXWHDQG 
Red blood cell (RBC) 
RBC Indices: 
Mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH)5HWLFXORF\WHV 
Hemoglobin 
Hematocrit 
Platelet count 
Red cell Distribution Width 
Coagulation factors: prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin time (aPTT) 
Biochemistry 
 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Gamma-glutamyl transferase (GGT) 
Total bilirubin, Indirect/direct bilirubin 
Albumin 
Calcium 
Blood urea nitrogen (BUN) 
Sodium 
Creatinine 
Chloride 
Creatine kinase 
Magnesium 
Bicarbonate 
Potassium 
Lactate dehydrogenase 
Phosphorus/ 
Total protein 
Glucose (fasting) 
Total cholesterol 
 
Uric acid 
Serum lipids: triglycerides, high-density lipoprotein cholesterol (HDL-c), low density lipoprotein 
(LDL-c), non-HDL-c 
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Urinalysis (spot urine) 
 
Basic Urinalysis (dipstick, including macroscopic 
appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, urobilinogen);  
Full urinalysis (dipstick plus microscopic 
evaluation) to be performed only at the Screening 
and Week 48/ET visits). A reflex microscopic 
urinalysis should be performed if the result of the 
urinalysis is abnormal or at the discretion of the 
Investigator or delegate. 
Other Study-Specific Laboratory Assessments 
 
Pegozafermin (to be evaluated by bioanalytical 
laboratory) 
Insulin 
High-sensitivity C-reactive protein (hsCRP) 
Hemoglobin A1c (HbA1c) 
Insulin-like growth factor-1 (IGF-1), total 
Adiponectin, total 
C-peptide 
Enhanced liver fibrosis (ELF) panel including 
concentrations of serum biomarkers: tissue 
inhibitor of matrix metalloproteinases-1 (TIMP-1), 
amino-terminal type 3 procollagen peptide (P3NP), 
and hyaluronic acid (HA) 
N-terminal type 3 propeptide of collagen (Pro-C3) 
Fasting free fatty acids (FFA) and Adipo-IR index 
(fasting FFA x fasting insulin)a 
FIB-4 index (derived calculation) 
Alpha feto-protein (AFP) (for F4 patients only) 
MELD Na+ (for F4 patients only) 
Serum and urine human chorionic gonadotropin 
(hCG) pregnancy test for women of childbearing 
potential 
FSH (for confirmation of menopausal status in 
women under the age of 45 with >12 months 
amenorrhea not using hormonal contraception or 
hormone replacement therapy) 
Luteinizing hormone (LH), FSH and estradiol 
(only for WOCBP who are not on hormonal 
contraception) 
Thyroid panel: TSH, FT4 and TT3 
Night-time salivary cortisol (NSC)* 
* NSC samples must be collected between 8:00pm 
and 12:00am before submitting the sample for 
processing at the specified visit. If sample is not 
collected during this time, repeat sample must be 
collected. If screening value is >15 nmol/L, Medical 
Monitor (or designee) may request further workup 
should the value be of clinical concern; however, 
values > 15 nmol/L will not be exclusionary. The 
screening NSC is a safety assessment, and not an 
eligibility criteria. The screening assessment should 
be performed as early as possible during the 
screening period. Subjects should be provided with 
NSC collection kit at the first screening visit, when 
possible, to allow sample collection return at the 
following clinic visit.  
 
For on-treatment values that are >15.0 nmol/L AND 
above the screening value, a repeat NSC should be 
performed (sample should be collected at 
approximately the same time as the screening 
sample). If this repeat assessment is still > 15.0 
nmol/L AND above the screening value, an 
additional screening test for hypercortisolism will 
be done (either overnight dexamethasone (1 mg) 
suppression test or a 24 h collection for urinary free 
cortisol).  
Medical Monitor (or designee) will provide 
guidance on the appropriate assessment based on 
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the individual subject for subsequent test values that 
are also >15 nmol/L based on the subject profile. 
Urine drug screen including amphetamines, 
barbiturates, cocaine metabolites, opiates, 
benzodiazepines and cannabinoids will be done 
at local laboratory using a standardized kit 
during screening period by Day 1. If cannot be 
performed during screening, test can be 
performed on Day 1, but must be completed 
before randomization procedures start. 
Serology: HIV 1 and 2 antibodies, hepatitis B 
surface antigen (HBsAg), hepatitis C virus 
antibody, and HCV RNA (only if HCV antibody-
positive) 
 
Immunogenicity: 
Antibody to pegozafermin and NAb 
Endogenous FGF21 
Bone markers: carboxy-terminal collagen 
crosslinks (CTX), N-terminal propeptide of type 
1 collagen (P1NP), osteocalcin 
Plasma and serum samples for exploratory 
biomarkers 
Biomarkers from RNA/DNA 
Pharmacogenomics sample 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
x 
An AE is any untoward medical occurrence in a clinical study subject, temporally associated with 
the use of IP, whether or not considered related to the IP. 
x 
NOTE: An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of IP. 
 
Events Meeting the AE Definition  
x 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
Investigator (i.e., not related to progression of underlying disease). A clinically significant 
abnormality is a confirmed abnormality (by repeat testing) that is changed sufficiently from 
Baseline so that in the judgment of the Investigator a change in management is warranted. This 
alteration may include: monitoring the laboratory test further, initiating other diagnostic tests or 
procedures, changing ongoing treatment, or administering new treatment. 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
x 
New conditions detected or diagnosed after IP administration even though it may have been present 
before the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a concomitant 
medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose 
taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 
Events NOT Meeting the AE Definition  
1. Any clinically significant abnormal laboratory findings or other abnormal safety assessments which 
are associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
2. The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
3. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
4. Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
5. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
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10.3.2. 
Definition of Suspected and Unsuspected Adverse Reaction 
Suspected adverse reactions are defined as: 
x 
Any AE for which there is a reasonable possibility that the IP caused the AE. For the purposes of 
Sponsor regulatory safety reporting, “reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by an IP. 
Unexpected AEs are defined as: 
x 
AE which is not listed in the IB of the IP or is not listed at the specificity or severity that has been 
observed. 
10.3.3. 
Definition of Events to Monitor 
Sponsor-defined Events to Monitor for Pegozafermin: 
Events to Monitor include immunogenicity and hypersensitivity reactions occurring after the first 
administration of study agent(s) in subjects participating in this clinical study. These events must be 
reported by the Investigator to the Sponsor within 24 hours and are to be considered serious (for 
regulatory reporting purposes) only if they meet the definition of an SAE. These events are to be 
reported on an SAE form. 
10.3.4. 
Definition of SAE 
If an event is not an AE per definition in Section 10.3.1, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an SAE. Treatment or observation on an emergency outpatient basis not resulting in 
hospital admission is not considered an SAE. 
4. Results in persistent disability/incapacity 
x 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
x 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
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An SAE is defined as any untoward medical occurrence that, at any dose: 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
x 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
x 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
10.3.5. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
x 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
x 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
x 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to the 
Medical Monitor (or designee) in lieu of completion of the AE/SAE eCRF page. 
x 
There may be instances when copies of medical records for certain cases are requested by the 
Medical Monitor (or designee). In this case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before submission to the 
Medical Monitor (or designee). 
x 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The severity of each AE will be assessed at onset by a nurse and/or physician. When recording the 
outcome of the AE the maximum severity of the AE experienced will also be recorded. The severity of 
the AE will be graded according to the CTCAE v5.0: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL)*. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
ADL: 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
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AE and SAE Recording 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between IP and each occurrence of each 
AE/SAE. 
x 
A “"reasonable possibility”" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
x 
The Investigator will use clinical judgment to determine the relationship. 
x 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to IP administration will be considered and 
investigated. 
x 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
x 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
x 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Medical Monitor (or designee). However, it is 
very important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Medical Monitor (or 
designee). 
x 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
x 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Causality Categories: 
x 
Related – The AE is known to occur with the IP, there is a reasonable possibility that the IP 
caused the AE, or there is a temporal relationship between the IP and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the IP and the 
AE. 
x 
Not Related – There is not a reasonable possibility that the administration of the IP caused the 
event, there is no temporal relationship between the IP and event onset, or an alternative 
etiology has been established. 
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AE and SAE Recording 
Follow-up of AEs and SAEs 
x 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical Monitor 
(or designee) to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
x 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Medical Monitor (or designee) with a copy of any post-mortem 
findings including histopathology. 
x 
New or updated information will be recorded in the originally completed eCRF. 
x 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
10.3.6. 
Reporting of SAEs 
Reporting of SAEs will be done using paper methods. 
SAE Reporting to the Medical Monitor (or designee) via Paper CRF 
x 
Facsimile or email transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Medical Monitor (or designee). 
x 
In rare circumstances and in the absence of facsimile or email equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service. 
x 
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
x 
Contacts for SAE reporting can be found in the relevant manual. 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women who do not meet criteria for “females not of childbearing potential” (see below) and are 
post-menarche are considered to be “females of childbearing potential” in this study. 
Women NOT of childbearing potential 
1. Pre-menarchal 
2. Surgically sterile (hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy, 
or bilateral tubal occlusion) 
3. Postmenopausal (defined as cessation of regular menstrual periods for at least 12 months 
without an alternative medical cause in women over the age of 45).  
a. In women under the age of 45 who have amenorrhea >12 months, menopausal status 
may be confirmed by follicle stimulating hormone (FSH) level of 30.0 mIU/mL in 
women not using hormonal contraception or hormone replacement therapy. Note that 
FSH levels can be normal or in the postmenopausal range depending on degree of 
ovarian dysfunction in women under 45 years of age with <12 months amenorrhea. 
Consult with the Medical Monitor (or designee) regarding subjects whose 
menopausal status may be in transition or unclear. 
4.  For individuals with permanent infertility due to an alternative medical cause (e.g., 
Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Male subjects 
Men will not be required to use contraception when sexually active with a woman who is not of 
childbearing potential. 
Men who are sexually active with WOCBP need to confirm that they will use 2 forms of 
contraception as per protocol. 
Men who are sexually active with a partner who is pregnant are required to use a condom. 
Contraception Guidance: 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Subjects should use highly effective, double contraception (both male and female partners) 
during the study and 30 days after the last dose of IP. 
Double contraception is defined as a condom with one of any of the following: 
x Oral contraceptive pills 
x Depot or injectable birth control 
x Intrauterine device (IUD) 
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x Contraceptive patch (e.g., Xulane®) or NuvaRing® 
x Vasectomy 
Subjects may not donate sperm or oocytes during the study and for 30 days or 5 half-lives 
(whichever is longer) after last dose of IP. 
Rhythm methods are not considered as highly effective methods of birth control. Subject 
abstinence for the duration of the study and 30 days or 5 half-lives (whichever is longer) after 
last dose of IP is acceptable if it is the subject’s regular practice. 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
x The Investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. 
x After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female subjects who become pregnant 
x Female subjects who become pregnant should discontinue treatment and be 
withdrawn from the study. 
x The Investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
subject's pregnancy. 
x The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
IP by the Investigator will be reported to the Sponsor as described in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former 
study subjects, he or she may learn of an SAE through spontaneous reporting. 
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10.5. 
Appendix 5: Pharmacogenomics 
Use and Analysis of DNA 
x Germ line variation may impact a subject’s response to IP, susceptibility to, and 
severity and progression of disease. Variable response to IP may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the 
disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
bio-sample may be collected for analysis from subjects. 
x Samples may be analyzed for genetic variations in genes that significantly affect the 
PK of pegozafermin, the safety, and/or efficacy profile. Often times, a large 
variability in the plasma concentration–time profiles of any medicine can be linked to 
loss of function mutations in the drug metabolizing enzymes and/or transporters. 
x If analyzed, the results of these analyses may be reported in a separate study 
summary. 
x The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
x The samples will be retained while research on pegozafermin continues but no longer 
than 8 years or other period as per local requirements. 
10.6. 
Appendix 6: Guidance to Address a Pandemic or Other Global 
Health Emergencies and Potential Impact on the Clinical Study 
In the occurrence of a global health emergency affecting the conduct of the ongoing study, such 
as the coronavirus disease 2019 (COVID-19) pandemic, study conduct may be adjusted due to 
subjects being in self-isolation/quarantine, limited access to public places (including hospitals) 
due to the risk of spreading infections, and health care professionals being committed to critical 
tasks. Study conduct and/or assessments may also be impacted by secondary factors as a result of 
the pandemic, such as supply chain issues and logistical challenges. In instances where 
COVID-19 pandemic restrictions or logistical scheduling challenges may be of concern, 
adjustments to the study conduct may be necessary (e.g., the screening period may be extended 
beyond 12 weeks with Sponsor approval, study visit windows may also extended etc.) (FDA, 
August 2021). 
Adjustments to the this protocol may be made as described below, in line with global regulatory 
authorities’ guidance to ensure the safety of study subjects, maintain compliance with Good 
Clinical Practice (GCP), and minimize the risks to study integrity during the COVID-19 
pandemic (Health Canada, 03 April 2020; MHRA, 22 April 2020; EMA, April 2020; FDA, 
March 2020). Other countries may issue their own guidance requiring country-specific 
recommendations to be followed. 
Informed Consent 
x If written consent by the study subject is not possible (e.g., because of physical 
isolation due to COVID-19 or other global health emergencies), consent could be 
given orally by the study subject and documented according to regulatory guidance. 
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x Study subjects and the person obtaining consent could sign and date separate 
Informed Consent Forms (ICF). 
x In case written informed consent cannot be obtained at the clinical site, electronic 
informed consent can be obtained remotely. Alternatively, the consent form may be 
sent to the subject or the subject’s legally authorized representative by facsimile or 
email, and the consent interview may then be conducted by telephone/teleconference 
when the subject or subject’s legally authorized representative can read the consent 
form during the discussion; the subject or subject’s legally authorized representative 
will be requested to sign and date a blank piece of paper with a written statement 
affirming that they agree to participate in the study and documented according to 
regulatory guidance. 
x If re-consent is necessary for the implementation of new urgent changes in study 
conduct (mainly expected for reasons related to global health emergencies or 
important safety issues for other studies), alternative ways of obtaining consent may 
include contacting the study subject via phone or video-calls and obtaining verbal 
consent, to be documented in the study subjects’ medical records, supplemented with 
e-mail confirmation. 
x The informed consent procedure is to remain compliant with the study protocol as 
well as local regulatory requirements. All relevant records should be archived in the 
Investigator's site master file. A correctly signed and dated ICF should be obtained 
from the study subjects later, as soon as possible. 
Study Visits and Procedures 
x COVID-19 screening procedures that may be mandated by the health care system in 
which a clinical study is being conducted do not need to be reported as an amendment 
to the protocol even if done during clinical study visits. The Investigator in 
consultation with the Sponsor will decide if it is in the best interest of 
COVID19positive subjects to remain in the study. 
x In the case of missed visits due to global health emergencies (or other pandemic-
related reasons): 
 The site should make every effort to contact the study subject to confirm and 
document the reason for the missed visit and at minimum, evaluate Adverse Event 
(AEs)/Serious Adverse Events (SAEs), and concomitant medications to assess 
subject safety. 
 Upon resumption of visits, the subject will continue at the next planned visit 
relative to the last visit performed prior to study interruption. 
x Changes in study visit schedules, missed visits, or subject discontinuations may lead 
to missing information (e.g., for protocol-specified procedures). Specific information 
will be captured in the case report form that explains the basis of the missing data, 
including the relationship to COVID19 for missing protocol-specified information 
(e.g., from missed study visits or study discontinuations due to COVID-19). 
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x To maintain the integrity of the study, alternative methods of collecting study 
procedures may be considered where possible: 
 In cases where global health emergencies-related circumstances preclude a visit to 
the investigative site, remote visits (e.g., by telemedicine or phone contact) will be 
allowed for relevant study procedures. 
 In certain situations, with Sponsor approval, and according to site business 
continuity plans, remote/home visits may be used, e.g., to collect laboratory 
samples and assessments as required by the protocol. 
 Study assessments will be conducted in a remote manner if they can be done 
without affecting the well-being of the subject during the study. 
 Remote study assessments can be completed via online technology. The subject 
may interact with study personnel using online communication tools that 
incorporate telemedicine. 
 In cases where a subject is continuing to receive IP but cannot obtain laboratory 
tests at the investigative site, local laboratory tests may be obtained at a certified 
laboratory. The site should inform the Sponsor about such cases. Local analysis 
can be used for safety decisions. In addition, local labs can be used for trial 
endpoints if samples drawn at the local laboratory cannot be shipped to the central 
laboratory. 
 Urine pregnancy tests can be performed if serum pregnancy tests cannot be 
performed. 
Investigational Product and/or Study Interruption Due to Global Pandemic 
x Interruption in IP administration and other study procedures, including MRI-PDFF 
and liver biopsy (collectively “study interruption”) will be allowed for up to 4 weeks 
GD\V$Q\LQWHUUXSWLRQODVWLQJ weeks will be considered a study interruption. 
x For subjects who have a study interruption, prior to resuming dosing, the Investigator 
will assess whether the subject is clinically stable to continue participation in the 
study. This assessment will include limited physical examination, vital signs, 
pregnancy test (local) in WOCBP, and laboratory tests (hematology and clinical 
biochemistry) to be done locally. If clinical laboratory tests are not part of the 
protocol-defined procedures for the first dosing visit after study interruption, 
hematology and clinical biochemistry panels will be obtained prior to dosing and sent 
to the central laboratory. Results from both the local and central labs should be 
documented in electronic case report form. Upon resumption of dosing, the subject 
will continue at the next planned visit relative to the last visit performed prior to study 
interruption and will be administered all remaining planned doses. 
x End of Treatment may be considered for the following scenarios: 
 For subjects who have reached the Week 24 (Main study) or Week 48 (Extension 
study), an End of Treatment visit may be considered instead of the study 
interruption. The Investigator should discuss with the Sponsor about the 
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feasibility of these two options based on the potential impact from COVID-19 
and/or the control measures in place in their location. 
 Study interruptions longer than 4 weeks will lead to IP discontinuation and the 
subject’s withdrawal from the study. 
x Efforts should be made to obtain End of Treatment assessments in subjects who are 
not willing to return to the study after study interruption, who are deemed not 
clinically stable to continue participation by the Investigator, or who are lost to the 
study due to disruptions because of COVID-19 pandemic. The End of Treatment visit 
should be scheduled as soon as possible in these scenarios. 
x )RUGRVHLQWHUUXSWLRQVODVWLQJZHHNVFRQWDFWZLOOEHHVWDEOLVKHGZLWKWKHVWXG\
subject remotely (e.g., by phone) to obtain information about AEs, concomitant 
medications, or any other update related to the subjects’ safety. 
x Study interruption will be allowed as long as COVID-19 pandemic-related 
circumstances are ongoing and will not be allowed when these circumstances are no 
longer applicable, as determined by the Sponsor. 
x For newly randomized subjects who have not yet received their first dose at a site that 
can foresee near-term disruption by COVID-19 pandemic, the Investigator should 
discuss with the Sponsor whether the initiation of dosing should be postponed. In this 
situation, study interruption should not apply, and the subject will initiate and finish 
all planned doses when the Investigator deems it is safe to start dosing. 
Supply of Investigational Product 
x IP supply will be provided for home administration as planned in the protocol. 
x Sponsor approved IP supply options will be specified in the Pharmacy Manual. 
Direct-to-patient shipment may be available, where possible. Direct-to-patient IP 
shipment will require consent to provide name and address to courier. 
Monitoring and Audits 
x Certain Sponsor oversight responsibilities, such as monitoring and quality assurance 
activities, may need to be re-assessed and temporary, alternative proportionate 
mechanisms of oversight may be required. On-site audits will be avoided or 
postponed, and if permitted under local regulations, social distancing restrictions 
should apply. 
x Canceling or postponing on-site monitoring visits and extending the period between 
monitoring visits will be allowed. 
x To the extent on-site monitoring remains feasible, it should take into account national, 
local, and/or organizational social distancing restrictions. 
x Centralized monitoring can be considered for data acquired by electronic data capture 
systems (e.g., electronic case report forms [eCRFs], central laboratory or 
electrocardiogram [ECG] data, electronic patient reported outcomes) that are in place 
or could be put in place, providing additional monitoring capabilities that can 
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supplement and temporarily replace on-site monitoring through remote evaluation of 
ongoing and/or cumulative data collected from study sites, in a timely manner. 
x Off-site monitoring can be conducted and will include phone calls, video visits, 
e-mail, or other online tools to discuss the study with the Investigator and site staff. 
Remote monitoring should be focused on review of critical study site documentation 
and source data. These activities could be used to get information on the clinical 
study progress, to exchange information on the resolution of problems, review of 
procedures, study subject status, as well as to facilitate remote site selection and 
Investigator training for critical study procedures. 
Risk Mitigation 
The Sponsor will continually assess whether the limitations imposed by the COVID-19 public 
health emergency on protocol implementation pose new safety risks to study subjects, and 
whether it is feasible to mitigate these risks by amending study processes and/or procedures. 
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10.7. 
Appendix 7: Prescreening Criteria for Identifying Potential Subjects 
with NASH and Stage 2 or 3 Fibrosis  
To minimize unnecessary biopsies and help sites identify subjects at high risk for NASH with 
Stage 2 or 3 fibrosis (per NASH CRN system), the Sponsor recommends that screening liver 
biopsy decisions be based on the following prescreening criteria.  
These guidelines are not inclusionary protocol requirements but are recommendations that 
Investigators can use when considering whether a potential subject should be screened for the 
study. All efforts should be made to ensure that noninvasive procedures are performed prior to 
the liver biopsy.  
Consult with the Medical Monitor (or designee) if clarification is needed on whether a potential 
subject should be considered for the study.  
1. 
Increased metabolic risk: potential subjects with at least 2 of the criteria as part of 
their medical history are at increased metabolic risk: 
a. 
Central obesity: Waist circumference of >102.0 cm for males, >88.0 cm for 
females, or body mass index (BMI) >25.0 kg/m2. BMI should not exceed 50.0 
kg/m2. 
b. 
Type 2 diabetes mellitus (T2DM; as determined by medical history PRQWKV
before Screening); or fasting glucose 00 mg/dL 
c. 
Increased fasting triglycerides (150 mg/dL) or on treatment for 
hypertriglyceridemia 
d. 
Reduced fasting HDL-c (<40 mg/dL for males and <50 mg/dL for females) 
e. 
Hypertension or on treatment for hypertensionRUPP+JV\VWROLFEORRG
SUHVVXUHRUPP+JGLDVWROLFEORRGSUHVVXUH 
2. 
Increased risk for Stage 2 or 3 fibrosis:  potential subjects meeting one of the 
following criteria have a high likelihood of having Stage 2 or 3 fibrosis:  
a. 
)LEURVFDQ9&7(VFRUH7.0 kPa.  
b. 
A historical liver biopsy that was performed more than 6 months but less than 
2 years before Screening that indicated Stage 1, 2 or 3 fibrosis. While this 
historical biopsy would not be eligible for the study, there is high likelihood 
that a new screening biopsy would indicate Stage 2 or 3 fibrosis. 
c. 
AST value >30 U/L    
3. 
Increased risk for steatosis:  potential subjects meeting one of the following criteria 
have a high likelihood of having steatosis: 
f. 
MRI-PDFF .0 
a. 
Where available, sites may perform Fibroscan controlled attenuation parameter 
(CAP) measurements to estimate the risk for steatosis, as CAP is correlated 
with fat content3RWHQWLDOVXEMHFWVZLWK&$3YDOXHVG%PDUHOLNHO\WREH
at high risk for steatosis. To ensure accuracy, Fibroscan assessments should 
always be performed with a subject-appropriate probe and according to 
manufacturer’s instructions. 
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10.8. 
Appendix 8: Child-Turcotte-Pugh Classification for Severity of Liver 
Disease 
Points: 
1 
2 
3 
Encephalopathy 
None 
Grade 1 or Grade 2 
Grade 3 or Grade 4 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin (mg/dL) 
<2 
2 to 3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prothrombin Time (INR) 
<1.7 
1.7 to 2.3 
>2.3 
Note: CTP Score is obtained by adding the score for each parameter. CTP Score interpretation is as follows:  
o 5 to 6 points: Child class A 
o 7 to 9 points: Child class B 
o 10 to 15 points: Child class C 
References: 
1. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. 
Br J Surg. 1973; 60:646 
2. Child CG, Turcotte JG. The Liver and Portal Hypertension. Philadelphia, WB Saunders Co. 1964.  
3. Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. NEJM. 1966; 
274:473 
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10.9. 
Appendix 9: Glossary 
Abbreviation Term 
Description 
ADA 
Antidrug antibodies  
ADL 
Activities of Daily Living  
AE 
Adverse event 
AFP 
Alpha feto-protein 
AI 
Artificial intelligence 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase  
ANCOVA 
Analysis of variance 
AST 
Aspartate transaminase  
AUC 
Area under the curve 
BMD 
Bone mineral density  
BMI 
Body mass index  
CAP 
Controlled Attenuation Parameter  
CFR 
Code of Federal Regulations  
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences  
CKD-EPI 
Chronic kidney disease-epidemiology 
CLDQ-NAFLD-NASH 
Chronic Liver Disease Questionnaire - NAFLD-NASH 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
CRN 
Clinical Research Network 
cT1 
Iron-corrected T1 mapping 
CTCAE 
Common terminology criteria for adverse events 
CTP 
Child-Turcotte-Pugh 
CTX 
Carboxy-terminal collagen crosslinks 
DILI 
Drug-induced liver injury 
DMC 
Data Monitoring Committee  
DNA 
Deoxyribonucleic acid 
DXA 
Dual X-ray absorptiometry 
DST 
Dexamethasone suppression test 
ECG 
Electrocardiogram  
eCRF 
Electronic case report form 
ELF 
Enhanced liver fibrosis  
EOS 
End of study 
EQ-5D-5L 
Europe Quality of Life Group 5-dimension 5-level questionnaire 
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Abbreviation Term 
Description 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FGF21 
Fibroblast growth factor 21 
FGFR 
Fibroblast growth factor receptor 
FIB-4 
Fibrosis-4 
FSH 
Follicle stimulating hormone  
FU 
Follow up  
GCP 
Good Clinical Practice  
GGT 
Gamma-glutamyl transferase  
GI  
Gastrointestinal 
HA 
Hyaluronic acid  
HbA1c 
Glycated hemoglobin 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HDL-c 
High density lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus  
HOMA-IR 
Homeostatic model assessment for insulin resistance 
IB 
Investigator’s Brochure  
ICE 
Intercurrent event 
ICF 
Informed consent form  
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee  
IGF-1 
Insulin-like growth factor-1 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board  
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
kPa 
Kilopascal 
LDL-c 
Low density lipoprotein cholesterol 
LS 
Least square 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging  
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Abbreviation Term 
Description 
n 
Number 
NAb 
Neutralizing antibodies 
NAFLD 
Nonalcoholic fatty liver disease  
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic steatohepatitis  
NFS 
NAFLD fibrosis score  
NOAEL 
No observed adverse effect level  
NSC 
Night-time salivary cortisol 
P1NP 
N-terminal propeptide of type 1 collagen 
P3NP 
Amino-terminal type 3 procollagen peptide 
PD 
Pharmacodynamic  
PDFF 
Proton density fat fraction 
PEG 
Polyethylene glycol 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetic  
PLT 
Platelet 
PNASH 
Phenotypic NASH, defined as at least one of the following: 1) obesity with 
T2DM. 2) Obesity with evidence of liver injury (either increased alanine 
aminotransferase [ALT] and/or vibration-controlled transient elastography 
[VCTE] score  KPa) 
PRO 
Patient reported outcome  
Pro-C3 
1ဨWHUPLQDOSURSHSWLGHRIW\SH3 collagen 
Q2W 
Every 2 weeks 
QRS 
Complex in ECG representing ventricular depolarization 
QTcF 
Fredericia corrected QT interval in ECG 
QW 
Weekly  
RNA 
Ribonucleic acid  
SAD 
Single ascending doses  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan  
SC 
Subcutaneous  
SD 
Standard deviation 
SE 
Standard error 
SoA 
Schedule of activities  
SUSAR 
Suspected unexpected serious adverse event 
T2DM 
Type 2 diabetes mellitus 
TB 
Total bilirubin  
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Abbreviation Term 
Description 
TEAE 
Treatment-emergent adverse event 
tmax  
Time to achieve maximal observed serum concentrations (Cmax) 
TSH 
Thyroid stimulating hormone 
UFC 
Urinary free cortisol 
ULN 
Upper limit of normal  
US 
United States  
VAS 
Visual analog scale 
VCTE 
Vibration-controlled transient elastography 
WOCBP 
Woman of childbearing potential  
WPAI-NASH 
Work Productivity and Activity Impairment Questionnaire for NASH 
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10.10. 
Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes for the current amendment is located directly 
before the Table of Contents. The Summary of Changes for prior protocol amendments are 
presented in this appendix. 
Amendment 2: Version 3.0 (11 March 2022) 
Section Number 
and Heading 
Description of Change 
Brief Rationale 
1.1 Synopsis and  
1.2 Study Schema 
All applicable changes made in the corresponding 
sections in the protocol were included in the synopsis 
and study schema.  
See below for the rationale for 
specific changes. 
3.1 Main Study 
Objectives and 
Endpoints 
9.1 Statistical 
Hypotheses 
x Primary endpoint has been modified by the addition of 
-point reduction in NAS score: (i.e., Proportion of 
subjects with NASH resolution without worsening of 
ILEURVLVDQG-point improvement in NAS score at 
Week 24 compared to baseline OR Proportion of 
VXEMHFWVDFKLHYLQJLPSURYHPHQWRIILEURVLVVWDJH
ZLWKRXWZRUVHQLQJRI1$6+DQG-point 
improvement in NAS score at Week 24 compared to 
baseline) 
x Additional Key secondary endpoint: (i.e., Proportion 
RIVXEMHFWVZLWK 2-point improvement in NAS score 
AND are MRI-PDFF responders AND ALT 
responders at Week 24 compared to baseline) and 
additional exploratory endpoints that include histology 
and/or MRI-PDFF responders, and/or ALT responders 
to the composite  
x The modified Primary endpoint 
allows for stabilization of 
placebo response to improve 
ability to determine treatment 
effect with pegozafermin 
x -point reduction in NAS 
components reflect decrease in 
disease severity thus are 
clinically meaningful  
x Responses in MRI-PDFF (i.e., 
reduction by DQG$/7
(i.e., reduction by 8/RU
are clinically meaningful 
and have been previously 
associated with positive 
histological outcomes 
4 Study Design 
9.2 Sample Size 
Determination 
 
x Overall sample size reduction (from 216 to 184) and 
redistribution among arms 
x Preliminary data from Part 2 of 
the Phase 1b/2a study suggest 
that 30 mg QW pegozafermin 
dose may be highly active, thus 
subject numbers have been 
increased in both the 30 mg QW 
active and placebo QW arms 
x Sample sizes at the 15 mg QW 
and 44 mg Q2W pegozafermin 
have been reduced to 
accommodate increases to the 30 
mg QW arms, yet remain at 
sufficient levels to generate 
meaningful data at these lower 
doses  
5.2 Exclusion 
Criteria 
x Added clarification to the language for Exclusion 
Criteria # 1, #16, # 17, and # 21. 
x Added alkaline phosphatase >2-fold higher than ULN  
and triglycerides > 1000 mg/dL  as exclusionary 
laboratory abnormalities in EC #18. 
x Clarification 
x Added limits on allowable ULN 
for alkaline phosphatase and 
triglycerides to exclude subjects 
at risk for other  possibly 
confounding comorbidities and 
safety events 
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Section Number 
and Heading 
Description of Change 
Brief Rationale 
8.2.5.3 Cortisol 
Assessments 
(new) 
x Added further details on the instructions for NSC 
collection and assessment. 
x Clarification 
Overall 
x Editorial and formatting changes, including updates to 
references.  
x The term BIO89-100 was replaced with the USAN 
‘pegozafermin’ throughout the protocol, as applicable. 
x Change in Sponsor signatory. 
x To clarify and correct any errors 
or inconsistencies across 
sections. 
x Update 
x Personnel update 
Amendment 1: Version 2.0 (01 December 2021) 
Section Number 
and Heading 
Description of Change 
Brief Rationale 
1.1 Synopsis and  
1.2 Study Schema 
All applicable changes made in the corresponding sections 
in the protocol were included in the synopsis and study 
schema.  
See below for the rationale 
for specific changes. 
1.3 Schedule of 
Activities (SoA) 
x Added blood sample collection for exploratory biomarkers 
at Day 1, Week 24, Week 48/ ET visits. 
x Removed the requirement to perform assessments predose 
for several assessments at specific visits as shown in the 
SoA. 
x Revised Week 26 visit to be either in clinic or remote visit, 
rather than remote only. 
x Clarified the language on process, timing, requirements, or 
description for the following assessments: NSC, urine drug 
screen, serology, biochemistry, FSH, vital signs, liver 
biopsy, MRI-PDFF, and immunogenicity. 
x Specified that the screening window may be extended with 
Sponsor’s approval and certain assessments (MRI-PDFF, 
DXA) if needed to be performed out of specified window, 
should be done with the Medical Monitor (or designee’s) 
approval. 
x Specified that strenuous exercises should be avoided for at 
least 48 hours prior to study visits. 
x Inadvertently omitted 
from the SoA. 
x To provide flexibility in 
the sequence of 
assessments. 
x To provide visit 
flexibility to sites and 
subjects. 
x To clarify and provide 
further guidance on 
operational and logistics 
aspects of assessments. 
x To provide flexibility in 
scheduling for the various 
assessments at screening 
and other visits. 
x To avoid potential 
confounding effect on 
study assessments. 
2.3.1 Risk 
Assessment 
Removed the detailed information on risk assessment 
including Table 2 and cross-referenced the IB for this 
information.  
For consistency and 
reference to most current 
information on 
BIO89-100. 
4. Study Design
x Specified that the Extension study will be single-blind, i.e., 
the investigator (including site staff) and subject will be 
blinded but the Sponsor will not be blinded.  
x Added that the screening period may be extended with 
Sponsor’s approval. 
x For continued planning of 
the development program 
for BIO89100 and 
Sponsor interactions with 
the Agency. 
x To provide flexibility. 
5.1 Inclusion Criteria 
IC 3: Simplified criterion for eligibility with biopsy and 
listed the specific parameters (revised 3.b.1 and 3.b.2) 
to consider prior to biopsy as guidance for 
prescreening criteria in Appendix 7.  
To clarify criteria and 
loosen the otherwise 
stringent criteria, to 
facilitate enrolment. 
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Section Number 
and Heading 
Description of Change 
Brief Rationale 
IC 4: Removed as a protocol IC and listed as a prescreening 
criterion (Appendix 7) for identifying subjects with 
increased risk for steatosis, with revised thresholds for 
MRI-PDFF and CAP scores. 
5.2 Exclusion 
Criteria 
EC 1: Provided additional guidance on eligibility criterion 
for subjects with prior HCV infection. 
EC 2: Added planned liver transplantation to EC. 
EC 3: Revised the parameters to consider as evidence of 
cirrhosis. 
EC 5: Specified that a positive COVID-19 test, or COVID-
19 diagnosis is not exclusionary. 
EC 8: Revised timeframe for the definition of newly 
diagnosed hypertension from ‘< 3’ to ‘< 2’ months 
since screening and removed the provision for 
allowing newly diagnosed subjects who had already 
initiated treatment or subjects on more than 2 
antihypertensives.  
EC 10: Clarified language regarding stable antidiabetic 
regimen for T2DM. 
EC 12: Clarified language regarding weight loss plan to 
include initiation of weight loss program, training for 
marathon, and weight loss medication during the 
study. 
EC 14: Provided additional details on other bone disorders. 
EC 15: Clarified language around history of malignancy 
and the timeframe for exclusion. 
EC 16: Further clarification provided on definition of 
significant alcohol consumption. 
EC 17: Clarified criterion on substance use disorder and the 
version of DSM used to define disorder.  
EC 18: Revised language to allow for more than one repeat 
test, removed alkaline phosphatase test from the list of 
exclusionary lab abnormalities, and specified the 
interval between 2nd and 3rd ALT and AST screening 
assessments.  
EC 22 (old): Removed the exclusionary criterion as it is 
difficult to quantify cannabis use. 
EC 24 (new): specified the dose for Vitamin E and clarified 
timeframe for stable dose. 
The changes specified for 
the various EC were made 
to either clarify criteria, 
provide additional 
information, or to loosen 
the otherwise stringent 
criteria, in order to 
facilitate enrolment. 
5.3 Lifestyle 
Considerations 
x Clarified the recommended guidelines for alcohol intake. 
x Specified that strenuous exercises should be avoided for at 
least 48 hours prior to study visits.  
x Added that activities such as starting a new weight loss 
program, training for a marathon, or taking a concomitant 
weight loss medication are exclusionary (EC # 12). 
For clarification and 
additional information. 
5.4 Screen Failures 
and Rescreening 
Included information on when retests are allowed during 
the screening period and added criteria and details for when 
a subject can be rescreened. 
For clarification and 
additional information. 
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Section Number 
and Heading 
Description of Change 
Brief Rationale 
6. Investigational 
Product 
x Clarified that a subject’s caregiver may administer IP 
following training. 
For clarification and 
additional information. 
6.4 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
x Specified that the proportion of subjects enrolled with 
MRIPDFF PD\EHOLPLWHGDWWKH6SRQVRU¶V
discretion. 
x Added that subjects who are rescreened will retain their 
original ID number; a new ID number will not be assigned. 
x Specified that the Extension study will be single blind and 
removed reference to a study-data integrity plan that was 
to be created for selected unblinding.  
x Clarified that the DMC will have access to unblinded 
safety data (not emerging efficacy results) for review 
purposes. 
For clarification and 
additional information. 
6.7 Concomitant 
Therapy 
Added that short-term use of sliding scale insulin therapy 
during a medical procedure or hospitalization (<5 days) for 
subjects with T2DM may be performed as needed. 
For clarification and 
additional information. 
6.7.1 Prohibited 
Medications/ 
Therapies 
x Clarified the prohibited and acceptable criteria for 
antidiabetic medications. 
x Specified the dose for Vitamin E that is prohibited. 
x Added that weight loss medication should not be initiated 
during the study.  
For clarification. 
7.1 Discontinuation 
of IP and Subject 
Withdrawal 
Added that for any subject experiencing a Grade 3 TEAE 
that is considered related to IP, the Investigator should 
discuss treatment discontinuation with the Medical Monitor 
(or designee). 
For additional guidance on 
handling of 
discontinuations. 
8.1.1 Liver Biopsy 
and Scoring 
x Provided further guidance on when to perform biopsy and 
if not performed within the given window. 
x Included information on the NASH CRN scoring of 
histological features with reference. 
For clarification and 
additional information. 
8.1.2 MRI-PDFF  
x Specified that a historical MRI-PDFF assessment 
performed within the last 3 months prior to screening may 
be acceptable if the images are available and evaluable by 
the central imaging vendor. This also applies to cT1, 
pancreatic fat, liver-volume, and spleen-volume 
assessments.  
x Specified that the proportion of subjects enrolled with 
MRI-3')) may be limited at the Sponsor’s 
discretion. 
To provide flexibility and 
facilitate enrolment. 
8.1.3 Transient 
Elastography kPa 
and CAP scores 
Specified that a historical Fibroscan assessment performed 
within the last 3 months prior to screening may be 
acceptable. 
To provide flexibility and 
facilitate enrolment. 
9.4.2 Safety 
Analyses 
Specified the TEAE reporting period for subjects who 
withdraw consent from the study. 
For clarification. 
9.6 Primary Analysis 
Removed the reference to a study data integrity plan for 
unblinding required for unblinding select sponsor 
personnel. 
Sponsor will be unblinded 
for the Extension study. 
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Section Number 
and Heading 
Description of Change 
Brief Rationale 
9.7 DMC 
Revised to specify that DMC will review unblinded safety 
data and not emerging efficacy results. 
Correction. 
10.2 Appendix 2 
Clarified the specifications for FSH, NSC, urine drug 
screen, and serology assessments. 
For clarification and 
further guidance on 
assessments. 
10.8 Appendix 7 
(new) 
Included prescreening criteria as guidelines and 
recommendations for identifying potential subjects for the 
study. These are adapted (with revisions) from IC 3.b.1., 
3.b.2, and 4 in the original protocol (v1.0).  
To facilitate recruitment 
and enrolment. 
Overall 
Editorial and formatting changes, including updates to 
references.  
To clarify and correct any 
errors or inconsistencies 
across sections.  
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11. 
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