A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study to Evaluate the Efficacy, Safety, and Tolerability of Three Doses of NGM282 Administered for 24 Weeks for the Treatment of Histologically Confirmed Nonalcoholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: NASH - Nonalcoholic Steatohepatitis
Sponsor: NGM Biopharmaceuticals, Inc

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Aldafermin (NGM282) Clinical Protocol, Study 18-0108 (ALPINE 2/3) 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study to 
Evaluate the Efficacy, Safety, and Tolerability of Three Doses of Aldafermin 
Administered for 24 Weeks for the Treatment of Histologically Confirmed 
Nonalcoholic Steatohepatitis (NASH) 
for 
NGM Biopharmaceuticals, Inc. 
333 Oyster Point Boulevard 
South San Francisco, CA 94080 
Original Protocol: 08 August 2018 
Amendment 1: 21 January 2019 
Amendment 2: 03 July 2019 
Amendment 3: 31 October 2019 
Amendment 4: 15 January 2020 
This document contains proprietary and confidential information of NGM Biopharmaceuticals, Inc. 
Acceptance of this document constitutes agreement by the recipient that no previously unpublished 
information contained herein will be published or disclosed without the prior written approval of 
NGM Biopharmaceuticals, Inc., with the exception that this document may be disclosed to study personnel 
under your supervision who need to know the contents for conducting the study and appropriate Institutional 
Review Boards/Human Research Ethics Committees under the condition that the personnel have agreed to 
keep this information confidential. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, NGM Biopharmaceuticals, Inc. shall be promptly notified of any such 
disclosure. 
NCT03912532

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1 
Study Identification 
Sponsor: 
NGM Biopharmaceuticals, Inc. 
333 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Phone: +1 (650) 243-5555 
Fax: 
+1 (650) 583-1646 
Sponsor Study Contact: 
 
Executive Director, Clinical Operations 
NGM Biopharmaceuticals, Inc. 
333 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Phone: 
  
Fax: 
 
Sponsor Medical Monitor: 
 
Sr. Director, Clinical Development  
NGM Biopharmaceuticals, Inc. 
333 Oyster Point Boulevard 
South San Francisco, CA 94080, USA 
Phone:
 
Mobile:
  
Fax: 
  
 
 
 

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2 
Summary of Changes 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  

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Protocol 
Section 
Modification 
Justification for Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 

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Protocol 
Section 
Modification 
Justification for Change 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
. 

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3 
Table of Contents 
Title Page ................................................................................................................................................................ 1 
1 
Study Identification ....................................................................................................................................... 2 
2 
Summary of Changes .................................................................................................................................... 3 
3 
Table of Contents .......................................................................................................................................... 6 
3.1 
List of Tables .................................................................................................................................... 8 
3.2 
List of Appendices ............................................................................................................................ 8 
3.3 
List of Abbreviations ........................................................................................................................ 8 
4 
Synopsis....................................................................................................................................................... 11 
Exclusion Criteria ............................................................................................................................................ 14 
5 
Introduction ................................................................................................................................................. 21 
5.1 
Background ..................................................................................................................................... 21 
5.1.1 
Nonalcoholic Steatohepatitis (NASH) ....................................................................................... 21 
5.1.2 
Treatment of NASH ................................................................................................................... 22 
5.2 
Nonclinical Studies ......................................................................................................................... 23 
5.2.1 
Nonclinical Safety Assessment .................................................................................................. 23 
5.2.2 
Therapeutic Rationale for Aldafermin in NASH ....................................................................... 24 
5.3 
Clinical Studies ............................................................................................................................... 27 
5.4 
Study Rationale............................................................................................................................... 27 
6 
Study Objectives .......................................................................................................................................... 29 
6.1 
Primary Objectives and Endpoints: ................................................................................................ 29 
6.2 
Secondary Objectives and Endpoints ............................................................................................. 29 
6.3 
Exploratory Objectives and Endpoints: .......................................................................................... 30 
7 
Study Design ............................................................................................................................................... 31 
7.1 
Study-Stop Criteria ......................................................................................................................... 33 
8 
Enrollment Criteria ...................................................................................................................................... 34 
8.1 
Inclusion Criteria ............................................................................................................................ 34 
8.2 
Exclusion Criteria ........................................................................................................................... 36 
8.3 
Study Treatment Discontinuation, Interruption, or Dose Reduction for an Individual Subject ...... 39 
8.4 
Discontinuation of Subjects from Study Participation .................................................................... 41 
9 
Study Methods ............................................................................................................................................. 43 
9.1 
Schedule of Study Procedures ........................................................................................................ 43 
9.2 
Study Visit Procedures ................................................................................................................... 47 
9.2.1 
Day –42 (Screening) Procedures ................................................................................................ 47 
9.2.2 
Day –28 to Day -1 (Screening) Procedures ................................................................................ 48 
9.2.3 
Day 1 Procedures ....................................................................................................................... 48 
9.2.4 
Week 2 Procedures .................................................................................................................... 50 
9.2.5 
Week 4 Procedures .................................................................................................................... 51 
9.2.6 
Week 8 Procedures .................................................................................................................... 52 
9.2.7 
Week 12 Procedures .................................................................................................................. 54 
9.2.8 
Week 18 Procedures .................................................................................................................. 56 
9.2.9 
Week 24 / Early Withdrawal (End of Treatment) Procedures ................................................... 57 
9.2.10 
Week 25 (Post-Treatment Response) Procedures ...................................................................... 59 
9.2.11 
Week 30 (End of Study) Procedures .......................................................................................... 60 
9.2.12 
Lipid Monitoring Assessment 4 Week Follow up Visit Procedures .......................................... 61 
9.2.13 
Monitoring of Anti-Drug Antibody Response ........................................................................... 62 
9.3 
Concomitant Medications ............................................................................................................... 62 
9.3.1 
Prohibited Medications .............................................................................................................. 62 
9.3.2 
Restricted Concomitant Medications/Treatments: ..................................................................... 63 
9.4 
Clinical Evaluations ........................................................................................................................ 64 
9.4.1 
Alcohol Consumption ................................................................................................................ 64 
9.4.1.1 
AUDIT-C ........................................................................................................................... 64 

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9.4.1.2 
History of Alcohol Consumption ....................................................................................... 64 
9.4.1.3 
PEth Screen ....................................................................................................................... 64 
9.4.2 
Liver Biopsy .............................................................................................................................. 64 
9.4.3 
Magnetic Resonance Imaging (MRI) ......................................................................................... 65 
9.4.4 
Pharmacokinetic Blood Sample Collection and Processing ....................................................... 66 
9.4.5 
C4 and Bile Acid Testing ........................................................................................................... 66 
9.4.6 
Biomarkers ................................................................................................................................. 66 
9.4.7 
Insulin/HOMA-IR ...................................................................................................................... 66 
9.4.8 
Lipoprotein Particles .................................................................................................................. 66 
9.4.9 
Clinical Laboratory Evaluations ................................................................................................ 67 
9.4.10 
12-Lead Electrocardiograms ...................................................................................................... 67 
9.4.11 
Vital Signs ................................................................................................................................. 67 
9.4.12 
Physical Examinations and RUQ Pain Assessment ................................................................... 67 
9.4.13 
Local Injection-Site Symptom Assessments (LISSA) ............................................................... 68 
9.4.14 
Lipid-Lowering Therapy Assessment ........................................................................................ 68 
9.4.15 
Diet and Activity Control ........................................................................................................... 69 
10 
Study Drug .................................................................................................................................................. 70 
10.1 
Clinical Supplies ............................................................................................................................. 70 
10.1.1 
Aldafermin ................................................................................................................................. 70 
10.1.2 
Aldafermin-matched Placebo ..................................................................................................... 70 
10.1.3 
Rosuvastatin ............................................................................................................................... 70 
10.2 
Study-Drug Accountability ............................................................................................................. 70 
10.3 
Study-Drug Storage ........................................................................................................................ 71 
10.4 
Dose Preparation and Administration ............................................................................................. 71 
10.4.1 
Aldafermin ................................................................................................................................. 71 
10.4.2 
Rosuvastatin ............................................................................................................................... 71 
10.5 
Removal of Study Blind ................................................................................................................. 72 
11 
Adverse Events ............................................................................................................................................ 73 
11.1 
Definition and Grading Intensity of Adverse Events ...................................................................... 73 
11.2 
Criteria for Determining Relationship to Study Drug ..................................................................... 74 
11.3 
Reporting ........................................................................................................................................ 74 
11.4 
Cardiovascular Adjudication .......................................................................................................... 75 
12 
Statistical Considerations ............................................................................................................................ 76 
12.1 
Sample Size Determination ............................................................................................................ 76 
12.2 
Randomization ................................................................................................................................ 76 
12.3 
Analysis Populations ...................................................................................................................... 77 
12.4 
Demographics and Other Baseline Characteristics ......................................................................... 77 
12.5 
Efficacy Analyses ........................................................................................................................... 78 
12.5.1 
Primary Efficacy Analysis ......................................................................................................... 78 
12.5.2 
Secondary Efficacy Analyses..................................................................................................... 78 
12.5.3 
Other Efficacy/Pharmacodynamic Analyses .............................................................................. 79 
12.6 
Safety .............................................................................................................................................. 79 
13 
Administrative Aspects ............................................................................................................................... 80 
13.1 
Protocol Adherence ........................................................................................................................ 80 
13.2 
Disclosure ....................................................................................................................................... 80 
13.3 
Monitoring ...................................................................................................................................... 80 
13.4 
Institutional Review Board/Ethics Committee ............................................................................... 80 
13.5 
Informed Consent ........................................................................................................................... 81 
13.6 
Records ........................................................................................................................................... 81 
13.7 
Financing and Insurance ................................................................................................................. 81 
13.8 
Publication Policy ........................................................................................................................... 81 
Investigator Protocol Review and Signature Form ............................................................................................... 82 
Sponsor Protocol Approval and Signature Page ................................................................................................... 83 
14 
References ................................................................................................................................................... 84 

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14.1 
Clinical Study References ............................................................................................................... 84 
14.2 
Nonclinical Study References ......................................................................................................... 84 
14.3 
Literature References ...................................................................................................................... 84 
15 
Appendices .................................................................................................................................................. 88 
Appendix 1. NASH Clinical Research Network NAFLD Activity Score and Fibrosis Score ........................ 88 
Appendix 2. Food and Drug Administration Toxicity Grading Scale: Clinical Abnormalities in Local 
Injection Site Symptom Assessments ........................................................................................ 89 
Appendix 3. Lipid Lowering Algorithm ......................................................................................................... 90 
Appendix 4. Rosuvastatin Dose Reduction Algorithm ................................................................................... 91 
Appendix 5. Statin-Related Muscle Symptoms or Creatine Kinase (CK) Elevation ...................................... 92 
Appendix 6. Rosuvastatin Package Insert ...................................................................................................... 93 
Appendix 7. Ezetimibe Package Insert ........................................................................................................... 94 
Appendix 8. AUDIT-C Alcohol Consumption Questionnaire ....................................................................... 95 
Appendix 9. Prohibited Hepatotoxic Agents .................................................................................................. 97 
 
3.1 
List of Tables 
Table 1. 
Estimated Safety Exposure Margin of Aldafermin .................................................................. 24 
Table 2. 
Change from Baseline to Week 12 in MRI-PDFF in NASH Subjects ..................................... 26 
Table 3. 
Study Design ............................................................................................................................ 31 
Table 4. 
Schedule of Study Procedures.................................................................................................. 44 
Table 5. 
Power Simulations for the Primary Efficacy Analysis ............................................................. 76 
 
3.2 
List of Appendices 
Appendix 1. 
NASH Clinical Research Network NAFLD Activity Score and Fibrosis Score ...................... 88 
Appendix 2. 
Food and Drug Administration Toxicity Grading Scale: Clinical Abnormalities in Local 
Injection Site Symptom Assessments ...................................................................................... 89 
Appendix 3. 
Lipid Lowering Algorithm ....................................................................................................... 90 
Appendix 4. 
Rosuvastatin Dose Reduction Algorithm ................................................................................. 91 
Appendix 5. 
Statin-Related Muscle Symptoms or Creatine Kinase (CK) Elevation .................................... 92 
Appendix 6. 
Rosuvastatin Package Insert .................................................................................................... 93 
Appendix 7. 
Ezetimibe Package Insert ......................................................................................................... 94 
Appendix 8. 
AUDIT-C Alcohol Consumption Questionnaire ..................................................................... 95 
Appendix 9. 
Prohibited Hepatotoxic Agents ................................................................................................ 97 
 
3.3 
List of Abbreviations 
Abbreviation 
Definition/Explanation 
AAV 
Adeno-associated virus 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AFP 
Alpha fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
ApoB 
Alanine aminotransferase 
Apolipoprotein B 
ANCOVA  
Analysis of covariance  
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration–time curve 
BMI 
Body mass index 
C2h 
Concentration at 2 hours post-dose 

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Abbreviation 
Definition/Explanation 
C4 
7-alpha-hydroxy-4-cholesten-3-one 
CBC 
Complete blood count (hematology clinical laboratory evaluations) 
CHMP 
Committee for Medicinal Products for Human Use (European Medicines Agency) 
CI 
Confidence interval 
CL/F 
Clearance divided by the bioavailable fraction 
Cmax 
Maximum drug concentration 
CMH 
Cochran-Mantel-Haenszel 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cmin 
Minimal observed concentration during a dosing interval 
D 
Day 
DILI 
Drug-Induced Liver Injury 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ELF 
Enhanced liver fibrosis 
EOS 
End of Study 
EOT 
End of Treatment 
ER 
Emergency room 
FDA 
Food and Drug Administration 
FGF19 
Fibroblast growth factor 19 
FXR 
Farnesoid X receptor 
GGT 
Gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GLP1 
Glucagon-like peptide-1 
GRE 
Gradient recalled echo 
HbA1C 
Hemoglobin A1C 
HBsAg 
Hepatitis B virus surface antigen 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein-cholesterol 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostasis model assessment–estimated insulin resistance 
H 
Hour(s) 
hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
ISR 
Injection-site reaction 
ITT 
Intent-to-treat 
 
 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein-cholesterol 
LFC 
Liver fat content 
LISSA 
LLN 
Local injection-site symptom assessment 
Lower Limit of Normal 
LLT 
Lowest Level Term (MedDRA) 
MAD 
Multiple ascending dose 
Max 
Maximum 
MCP-Mod 
Multiple Comparison Procedure – Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model of end-stage liver disease 
MI 
Multiple imputation 
Min 
Minimum 
MMRM 
Mixed model for repeated measures 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging–proton density fat fraction 

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Abbreviation 
Definition/Explanation 
n 
Number / number of non-missing observations  
Nab 
Neutralizing antibody 
NAFLD 
Nonalcoholic fatty liver disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic steatohepatitis 
NGM 
NGM Biopharmaceuticals, Inc. 
Aldafermin/NGM282 A Recombinant protein of 190 amino acids; engineered variant of humanized FGF19  
NIH 
National Institutes of Health 
No. 
Number 
NOAEL 
No-observed-adverse-effect level 
NPO 
Nothing by mouth  
NRS 
Numeric Rating Scale 
NZW 
New Zealand White 
OCA 
Obeticholic acid 
PBC 
Primary biliary cholangitis 
PD 
Pharmacodynamics; pharmacodynamic 
PDFF 
Proton density fat fraction 
PI 
Principal Investigator 
Peth 
Phosphatidylethanol 
PIIINP 
Propeptide of type III procollagen 
PK 
Pharmacokinetics; pharmacokinetic 
PNPLA3 
Patatin-like phospholipase domain-containing protein 3 
PP 
Per protocol 
Pro-C3 
N-terminal type III collagen 
PSC 
Primary sclerosing cholangitis 
PT 
Preferred term 
REML 
Restricted maximum likelihood 
 
 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
t1/2 
Apparent terminal elimination half-life 
T2D 
Type 2 diabetes 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TIMP-1 
Tissue inhibitor of metalloproteinase 1 
Tmax 
Time to maximum concentration 
TNF 
Tissue necrosis factor 
Tx 
Treatment 
ULN 
Upper limit of normal 
US/U.S. 
United States 
Vz/F 
Volume of distribution based on the terminal portion of the concentration–time curve divided by the 
bioavailable fraction 
W 
Week 

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4 
Synopsis 
Title of Study: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Study to 
Evaluate the Efficacy, Safety, and Tolerability of Three Doses of NGM282 Administered 
for 24 Weeks for the Treatment of Histologically Confirmed Nonalcoholic Steatohepatitis 
(NASH) 
Protocol 
Number: 
18-0108 
Phase: 
2b 
Investigational 
Product: 
NGM282, henceforth aldafermin  
Study Objectives 
and Endpoints: 
Primary Objectives and Endpoints:  
The primary objectives are to evaluate the efficacy, safety and tolerability of aldafermin 
based on liver histology at 24 weeks versus placebo. 
1. The primary efficacy endpoint is the histologic response defined as an improvement 
in liver fibrosis by ≥ 1 stage by NASH Clinical Research Network (CRN) criteria 
with no worsening of steatohepatitis at Week 24 compared with baseline. 
2. The primary safety endpoint is frequency, severity, and timing of adverse events 
(AEs) and serious adverse events (SAEs). Safety and tolerability of aldafermin in 
subjects with NASH as a function of dose level after up to 24 weeks of treatment 
with aldafermin will be assessed.  
Secondary Objectives and Endpoints:  
The secondary objectives of this study are to evaluate the effect of aldafermin on 
pharmacokinetics, biomarkers of target engagement, fibrogenesis, and imaging. 
The secondary endpoints are as follows:  
1. Resolution of NASH (defined as an NAS score of 0 or 1 for inflammation and 0 for 
ballooning) with no worsening of fibrosis as determined by the NASH CRN criteria 
at Week 24 compared with baseline. 
2. Subjects with improvement in liver fibrosis by > 1 stage by CRN criteria with no 
worsening of steatohepatitis and resolution of NASH with no worsening of fibrosis 
as determined by the NASH CRN criteria at Week 24. 
3. Subjects with improved, no change, and worsening of fibrosis and NAS (total score 
and individual components) at 24 weeks compared to baseline 
4. Subjects with the following changes in liver fat content (LFC) by MRI-PDFF at 
Week 24  
o 
Normalization for LFC (defined as < 5% absolute LFC)  
o 
≥ 5% decrease in absolute LFC  
o 
≥ 30% relative decrease in LFC  
5. Absolute and percentage changes from Baseline to Week 24 of the following: 
o 
ALT, AST, total bilirubin, ALP and gamma glutamyl transpeptidase (GGT) 
o 
Total cholesterol, high-density lipoprotein-cholesterol (HDL-C), LDL-C, 
triglycerides 

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o 
Lipoprotein particles 
 
o 
Homeostasis model assessment–estimated insulin resistance (HOMA-IR) 
o 
N-terminal Type III collagen (Pro-C3)  
o 
Total ELF Score and individual components (i.e., hyaluronic acid, PIIINP, 
TIMP-1) 
o 
7-alpha-hydroxy-4-cholesten-3-one (C4) and serum bile acids (total and 
individual bile acids) 
o 
 
6. Subjects with normalization of ALT and AST at Week 24 
Exploratory Objectives and Endpoints:  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
Study Population Inclusion Criteria: 
Subjects who meet the following criteria may be included in the study: 
1. 
Males and females 18 to 75 years of age (inclusive) who are able to comprehend 
and willing to sign an Informed Consent Form (ICF) 
2. 
Histologically confirmed NASH diagnosis as defined by the NIH NASH CRN 
(see Appendix 1, Kleiner 2005) and liver biopsy criteria outlined below. 
A historical biopsy is acceptable if performed within the required 6-months of 
Screening and tissue slides are available for a qualified central pathologist 
reader:  
 
NAS ≥ 4 with a minimum of 1 point in each component 
 
Histologic evidence of Stage 2 or Stage 3 fibrosis without cirrhosis 
3. 
Total liver fat content of ≥ 8% as measured by MRI-PDFF 
4. 
Subjects with T2D or insulin resistance are permitted as long as diabetic 
medications are stable as outlined in Section 9.3 Concomitant Medications and 
subject attempts to maintain a stable regimen during the study period.  
5. 
Other concomitant medications/therapies for NAFLD or NASH: requires a 
stable regimen for at least 3 months prior to the Screening biopsy of record and 
throughout the study (Refer to Section 9.3 Concomitant Medications).  
6. 
Statin use based on the following criteria for statin-naïve or statin-experienced at 
Screening: 
 
Statin naïve is defined as no administration of statins within 3 months prior 
to Screening. 

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 
Statin experienced is defined as administration of the following stable 
daily doses of approved statin therapies taken for at least 3 months prior to 
Screening through Week 2: 
o 
Atorvastatin: ≤ 40 mg/day 
o 
Fluvastatin: ≤ 40 mg/day 
o 
Lovastatin: ≤ 40 mg/day (immediate release), ≤ 30 mg/day 
(extended release) 
o 
Pitavastatin: ≤ 2 mg/day 
o 
Pravastatin: ≤ 40 mg/day 
o 
Simvastatin: ≤ 40 mg/day 
o 
Rosuvastatin: ≤ 20 mg/day   
7. 
The following laboratory parameters must be met at Screening: 
 
Total bilirubin ≤ULN (Upper Limit of Normal) based on the Day -42 value 
or average of at least 2 Screening values obtained during the Screening 
Period, except for subjects with an established diagnosis of Gilbert’s 
Syndrome provided the direct bilirubin level is ≤ULN and hemoglobin and 
reticulocyte count are normal. 
 
Aspartate aminotransferase (AST) ≥ 30 IU/L and ≤ 250 IU/L in all subjects, 
based on the Day -42 value or average of at least 2 screening values 
obtained during the Screening Period  
i. Exception: subjects with an average AST ≥ 20 and < 30 IU/L will be 
permitted provided that at least one of the following criteria are met: 
1. Local historical biopsy within 6 months with a NAS of 4 with at least 
1 point in each component and fibrosis Stage 2 or 3. Subjects with a 
historical biopsy will have their slides evaluated by the central reader 
prior to undergoing MRI-PDFF.  
2. Vibration-controlled transient elastography (VCTE® by Fibroscan) 
≥ 9.5 kPa within 6 months of Screening. If no historical Fibroscan is 
available, it may be conducted and evaluated as per local “standard-
of-care” prior to Day -28. 
 
Hemoglobin A1c (HbA1c) ≤ 9.5%  
 
Platelet count ≥ Lower Limit of Normal (LLN) (i.e., 140,000/mm3) 
 
Creatinine clearance ≥ 60 mL/min as calculated by Cockcroft-Gault 
equation  
 
Alpha fetoprotein (AFP) < 100 ng/mL  
8. 
Female subjects who are of non-childbearing potential must have had a 
hysterectomy, bilateral oophorectomy, medically documented ovarian failure, 
are documented postmenopausal, OR a follicle stimulating hormone 
> 40 mIU/mL  
9. 
Female subjects of child-bearing potential must not be pregnant or nursing. 
Female subjects of childbearing potential are defined as women < 55 years of 
age with ≤ 2 years of amenorrhea and who meet both of the following criteria: 
i. A negative serum pregnancy test at Screening and urine pregnancy test 
prior to randomization 

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ii. Correct and consistent use of one of the following methods of birth 
control in addition to a male partner using a condom from Screening to 
30 days after the last dose of study drug: 
1. hormone containing contraceptive 
2. intrauterine device with a failure rate < 1% per year 
3. cervical cap or diaphragm with spermicidal agent 
4. tubal sterilization 
5. vasectomy in male partner 
6. complete abstinence of sexual intercourse 
10. 
Male subjects are eligible for the study if they meet the following criteria: 
a. Male subjects must agree to consistently and correctly use a condom in 
combination with one of the following from the date of consent to 30 days 
after the last dose of study drug: 
ii. Condom with spermicide 
iii. Vasectomy 
iv. Complete abstinence of sexual intercourse. 
AND 
a. Female partner(s) must use any of the approved methods of birth control in 
inclusion criterion #9. 
11. 
Able and willing to comply with the dosing instructions for study-drug 
administration and able to complete the study schedule of assessments 
12. 
BMI ≥ 25 kg/m2 for subjects self-identified of Asian descent only 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. 
Clinically significant acute or chronic liver disease of an etiology other than 
NASH 
2. 
Evidence of drug-induced steatohepatitis secondary to amiodarone, 
corticosteroids, estrogens, methotrexate, tetracycline, or other medications 
known to cause hepatic steatosis 
3. 
History or presence of cirrhosis (compensated or decompensated) as determined 
by histology and/or relevant medical complications and/or laboratory parameters 
4. 
Prior or pending liver transplantation 
5. 
Model of end-stage liver disease (MELD) score ≥ 12 (except for subjects with 
established Gilbert’s syndrome) 
6. 
Evidence of worsening liver disease (defined below) between Screening visits 
(i.e., Day -42 and Day -28) including measures of AST, ALT, TBL, and ALP: 
 
For subjects with AST, ALT, TBL or ALP baseline levels > ULN on 
Day -28, the Day -28 assessment should not exceed an increase of 35% over 
the Day -42 assessment. 
 
For subjects with Gilbert’s syndrome and a total bilirubin > ULN at the 
Day -42 assessment, the total bilirubin assessment at Day -28 should not 
exceed an increase of 50% over the Day -42 assessment. 
Note: For AST, ALT, TBL and ALP, if the percent increase in laboratory 
values between Day -42 and Day -28 is > 35%, repeat blood samples will be 
collected at an unscheduled visit at a minimum of two weeks from the 
Day - 28 visit. The average of Day -42 and Day -28 values will be compared 

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to the 3rd value to determine if eligibility ranges (i.e., % agreement ≤ 35%) 
are met.  
7. 
Clinically significant cardiovascular or cerebrovascular event or new diagnosis 
within 6 months of Screening, including but not limited to congestive heart 
failure, myocardial infarction, acute coronary syndrome, revascularization, 
stroke (hemorrhagic or ischemic), transient ischemic attack (TIA), or implanted 
defibrillator or pacemaker (except for uncomplicated elective pacemaker 
procedure, 3 months post procedure will be allowed).  
8. 
History of gastric bypass or bariatric surgery or planned procedure during the 
study period. Removal of a gastric balloon or lap band is permitted if surgery 
performed within 6 months prior to Day 1. 
9. 
Type 1 diabetes 
10. 
History of clinically significant unstable or untreated illness or any other major 
medical disorder that may interfere with patient treatment, assessment, or 
compliance with the protocol 
11. 
Any contraindication or inability to obtain an MRI  
12. 
Inability to obtain or any contraindication to liver biopsy (if a historical biopsy 
with viable tissue slides are not available within the required time period) 
13. 
Screening ECG with clinically significant abnormalities or unexplained findings 
that the investigator feels needs further evaluation and treatment  
14. 
Positive for HBsAg, anti-HIV, or anti-HCV plus HCV-RNA. Subjects who are 
anti-HCV- positive but HCV-RNA negative (secondary to treatment or viral 
clearance) are eligible with at least a 1-year period since documented sustained 
viral response at Week 12 post-treatment 
15. 
History of malignancy diagnosed or treated within 2 years (recent localized 
treatment of squamous or non-invasive basal cell skin cancers is permitted; 
cervical carcinoma in situ is allowed if appropriately treated prior to Screening); 
subjects under evaluation for malignancy are not eligible 
16. 
Clinically-relevant drug use within 12 months of Screening. A positive drug 
screen will exclude subjects unless it can be clearly explained by a prescribed 
medication. The diagnosis and prescription must be approved by the Investigator 
and the Sponsor Medical Monitor or designee. Marijuana is not part of the drug 
screen.  
17. 
Significant alcohol intake as measured by a phosphatidylethanol (PEth) level 
≥ 200 ng/mL AND positive results from AUDIT-C alcohol consumption 
questionnaire (Appendix 8) 
18. 
Criterion eliminated per protocol amendment 3  
19. 
Consumption of ≥ 21 units of alcohol per week in males and ≥ 14 units of 
alcohol per week in females for two years prior to enrollment, where a “unit” of 
alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot 
of hard liquor 
20. 
Use of any prohibited concomitant medications as described in Section 9.3 from 
Day -42 to the end of the study including: 
 
Investigational agents, other than aldafermin, or devices for any indication 
 
Combination preparations of statins and other lipid-lowering agents (other than 
approved statin therapies listed in inclusion criterion #6) 
 
Weight loss medications 
 
Any medication that is contraindicated according to the rosuvastatin package 
insert (Appendix 6) or if subject has a known hypersensitivity to rosuvastatin 
product components (Section 10.1.3). 

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 
Any medication that is contraindicated according to the ezetimibe package insert 
(Appendix 7) or if subject has a known hypersensitivity to ezetimibe product 
components. 
 
Hepatotoxic medications (Appendix 9). For subjects who have been on stable 
therapy with no related hepatotoxicity, the MM may be contacted to assess the 
medical context and eligibility of the subject. Allopurinol to treat gout is 
permitted provided there is no prior history of intolerability.  
 
Anabolic steroids; Low levels of estrogen or testosterone as replacement therapy 
are allowed per Medical Monitor approval. 
21. 
History of statin intolerance as evidenced by presence of ALT elevations, 
adverse event(s), or other significant side effects attributed to statins 
22. 
Prior participation in a clinical trial of aldafermin is excluded unless previously 
enrolled into a placebo treatment group of the trial.  
23. 
Subject with severe allergic or anaphylactic reactions to recombinant therapeutic 
proteins, fusion proteins, or chimeric, human, or humanized antibodies 
24. 
Participation in a study of another investigational agent: 
 
NASH investigational agents: < 3 months prior to Screening if treated with 
active study drug or < 28 days if treated with placebo) 
 
All other investigational agents: within 28 days or five half-lives of the drug 
(whichever is longer) prior to Screening 
25. 
Any acute or chronic condition that, in the opinion of the Investigator or the 
Sponsor Medical Monitor, would limit the subject’s ability to complete and/or 
participate in this clinical study 
26. 
Pregnancy or lactation 
27. 
Criterion eliminated per protocol amendment 4  
Methodology/ 
Study Design: 
This is a multiple-center evaluation of aldafermin in a randomized, double-blind, 
placebo-controlled study, when administered for 24 weeks as a daily subcutaneous (SC) 
injection in patients with histologically confirmed NASH. 
Approximately 152 subjects, of which no more than 15% (approximately 22 subjects) 
will be self-identified Asian subjects, will be randomized at approximately 40 sites in the 
US. Depending on the overall enrollment rate and the proportion of subjects enrolled with 
F2 or F3, the sponsor may limit the enrollment of F2 subjects to be no greater than 
approximately 65% (99/152 subjects).   
Subjects to be studied will have histologically confirmed NASH as defined by the NIH 
NASH CRN (Kleiner 2005) and determined by a qualified central pathologist’s reading 
(see Appendix 1). Historical biopsy results within 6 months of the first Screening visit 
may be used for inclusion into the study; otherwise, a liver biopsy must be obtained for 
assessment. Subjects must have a NAS of at least 4, with a minimum of 1 point in each of 
the three components, along with the presence of either Stage 2 or 3 fibrosis. 
Subjects with no (Stage 0) or minimal (Stage 1) fibrosis and cirrhosis (Stage 4) will be 
excluded from this study. Subjects will undergo MRI during the Screening period, which 
must demonstrate ≥8% total liver fat content (LFC) by MRI-PDFF. 
Subjects may be rescreened once with Medical Monitor approval. Note: certain laboratory 
parameters of interest (e.g., AST, TBL, creatinine clearance) may be retested at the 
investigators' discretion after discussing with the Medical Monitor.  
On Day 1, eligible subjects will be randomized into one of the four treatment groups 
(0.3 mg aldafermin, 1 mg aldafermin, 3 mg aldafermin, or placebo) in a 1:1:1:1 ratio 

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(Table 3). Randomization will be stratified by baseline stage of fibrosis (Stage 2 versus 3) 
on the qualification liver biopsy as determined by the Central Pathologist. Treatment 
assignment will be blinded to the investigational sites, study subjects, and sponsor (both 
Study Team and sponsor Medical Monitor or designee) throughout the study period and 
managed through the 
 Study-drug 
self-administration instructions and training will be provided to the subjects and 
study-drug kits will be dispensed.  
The first dose of aldafermin (Day 1) and doses at Weeks 2, 4, 8, 12, 18, and 24 study 
visits will be self-administered in the clinic, with all other daily doses through Week 24 
self-administered at home. Self-administration should occur daily at a similar time at 
home. Subjects will return to the clinic on Weeks 2, 4, 8, 12, and 18 for on-treatment 
assessments and to receive aldafermin study-drug kits.  
LDL-C will be evaluated at Weeks 2, 4, 8, 12 and 18 in all subjects for possible increases 
in lipid levels associated with aldafermin administration. Rosuvastatin will be started in 
subjects meeting specific LDL-C level criteria at Week 2. Rosuvastatin and matched 
placebo are over-encapsulated to maintain the blind at the sites and with the sponsor 
study teams. Initiation and ongoing dose adjustments of rosuvastatin/matched placebo 
will be managed by an unblinded third-party medical monitor and through the 
. 
The sponsor and study sites will be blinded to LDL-C values and the specific rosuvastatin 
dosing decisions as outlined in Section 9.4.14. Subjects who have not achieved an 
adequate response or cannot tolerate rosuvastatin as defined in Section 9.4.14 will be 
considered for the addition of ezetimibe as second-line lipid management therapy. 
Ezetimibe 10 mg tablets can be administered with or without food at the same time as 
rosuvastatin and aldafermin.  Subjects whose LDL-C values are not adequately managed 
by their maximum tolerated rosuvastatin dose plus ezetimibe will be discontinued from 
study and an early withdrawal study visit will be completed. The follow-up visit/EOS 
should be scheduled for 6 weeks after the early withdrawal study visit. The specific 
rosuvastatin dosing algorithm is outlined in detail in Appendix 3.  
Rosuvastatin or matching placebo will be dispensed at each study visit through Week 18 
(statin-naïve) or Week 24 (statin-experienced).  If the subject is taking statins, evaluate 
tolerability and continue therapy to Week 24 if statin naïve or Week 30 if statin 
experienced. 
All subjects will return to the clinic at Week 25 for post-treatment LDL-C assessment. 
Subjects who have an LDL-C value of >100 mg/dL and > 15 mg/dL above their Day 1 
value at Week 25 will be re-assessed at Week 30. Subjects who have an LDL-C value of 
> 100 mg/dL and >15 mg/dL above their Day 1 value at Week 30 will have an additional 
4-week follow-up visit to confirm their LDL-C value is ≤ 100 mg/dL or ≤ 15 mg/dL 
above their Day 1 value.  
The study visit at Week 24 will be the aldafermin EOT clinic visit and subjects will return 
to the clinic at Weeks 25 and 30 (or at 1 and 6 weeks after last dose of aldafermin) for a 
post- treatment response and EOS follow-up visits. Subjects are required to undergo MRI 
performed during Screening Day -28 and at Weeks 12, 24 / Early Withdrawal (EOT), and 
30 (EOS) visits.  

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All subjects will have blood samples drawn for 
 
 
 
 
 
 
 
Number of 
Subjects: 
A total of approximately 152 subjects (38 per treatment group) will be randomized.   
Number of Study 
Sites: 
Approximately 40 sites in the United States 
Test Product(s), 
Dose, and Mode 
of 
Administration: 
Aldafermin final product will be supplied in pre-filled syringes intended to deliver 
0.3 mL containing 0.3 mg, 1 mg, or 3 mg aldafermin for SC injection. Placebo will be 
provided in volume-matched syringes. Subjects will be instructed to dose aldafermin at 
home at a similar time each day; however, study drug will be taken in the clinic on study 
visit days. 
Rosuvastatin will be administered for subjects meeting pre-specified LDL-C criteria 
(statin-naïve subjects) or automatically at Week 2 (statin-experienced). Study-labeled 
rosuvastatin/matching placebo is over-encapsulated and will be supplied in 5 mg, 10 mg, 
20 mg, or 40 mg total daily doses as outlined in Section 10.1.3 of the protocol to manage 
possible LDL-C increase during aldafermin treatment.  
Duration of 
Treatment: 
Subjects will sign the Informed Consent Form at the Day -42 Screening Visit and will 
undergo screening assessments to determine study eligibility. All subjects will be treated 
with aldafermin or matched placebo for 24 weeks and will be monitored for 6 weeks after 
completing their final dose of aldafermin or placebo. The total duration of individual 
subject participation will be approximately 36 weeks. 
Statistical 
Methods: 
Analysis Populations: 
Subjects will be analyzed using the following analysis populations:  
 
Intent-to-Treat Population 
All randomized subjects will be included in the Intent-to-Treat (ITT) population. The ITT 
population will be based on randomized treatment if this differs from actual treatment 
received. 
 
Safety Population 
All subjects who receive at least one dose (full or partial) of study drug will be included 
in the Safety population. All safety endpoints will be summarized using the Safety 
population and will be based on actual treatment received if this differs from the 
randomized/enrolled treatment. 
 
Full Analysis Population 
All randomized/enrolled subjects who receive at least one dose (full or partial) of study 
drug and have at least one valid, non-missing post-dose efficacy/PD parameter value will 
be included in the Full Analysis population. The Full Analysis population will be based 
on randomized/enrolled treatment if this differs from actual treatment received.  
 
Per Protocol (PP) Population  
The Per Protocol (PP) population will constitute a subset of the Full Analysis population 
and will include subjects that have at least one valid, non-missing baseline and post-dose 

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liver biopsy results and do not have protocol deviations that impact the liver biopsy 
assessments.  
 
 
 
 
 
 
 
 
General Statistical Considerations: 
In general, descriptive statistics including the number of non-missing observations (n), 
arithmetic mean (mean), standard deviation (SD), median, minimum (min), and 
maximum (max) will be presented for continuous variables, frequency and percentage 
distribution for categorical variables, and Kaplan–Meier estimates for time-to-event 
variables.  
Primary Efficacy Analysis: 
The primary efficacy endpoint for this study is the histologic response at Week 24, 
defined as a subject achieving an improvement in liver fibrosis greater than or equal to 
one stage (NASH CRN fibrosis score) with no worsening of steatohepatitis (defined as no 
increase in NAS for ballooning, inflammation, or steatosis) after 24 weeks of treatment. 
Subjects with two biopsies (baseline and post-baseline) will be considered for this 
analysis only if the second biopsy is taken after at least 12 weeks (i.e., 50% of the 
intended duration of 24-week treatment period) of treatment on the study drug. For the 
primary efficacy analysis, missing histologic responses at Week 24 will be imputed using 
a multiple imputation (MI) method under the assumption of missing at random. The 
details of the MI method will be provided in the SAP. 
The primary efficacy endpoint will be analyzed using the MCP-Mod (Multiple 
Comparison Procedure – Modelling) approach to assess the dose-response relationship. 
Within the framework of the MCP-Mod procedure, the null hypothesis of no dose-
response will be tested at the 5% significance level against the alternative hypothesis that 
there is a dose-response. The details of the MCP-Mod approach will be provided in the 
SAP. 
Sensitivity analyses will include imputations with missing histologic responses as both 
responders and non-responders, and analysis with the assumption of missing not at 
random (e.g., pattern mixture models).  
The primary efficacy analyses will be performed using the ITT population. The Full-
Analysis and PP populations will be used as sensitivity analyses.  
Secondary Efficacy Analyses: 
Secondary efficacy analyses include the analyses of the primary efficacy endpoint 
(i.e., histologic response at Week 24) based on pair-wise comparisons between treatment 
groups and the analyses of the secondary efficacy endpoints.  

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All binary efficacy endpoints (i.e., responders) will be analyzed using a Cochran-Mantel-
Haenszel (CMH) test stratified by baseline fibrosis stage. 
All continuous efficacy endpoints will be analyzed using an analysis of covariance 
(ANCOVA) model with effects for treatment, baseline fibrosis stage and baseline 
outcome value as a covariate.  
All secondary efficacy analyses will be performed using the ITT population. Full-
Analysis, and PP populations will be used as sensitivity analyses. 
No multiplicity adjustment will be made between the primary and secondary efficacy 
analyses to control the experiment-wise type I error rate, and thus all secondary efficacy 
analyses are exploratory in nature. 
Safety Analyses:  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment emergent adverse events (TEAEs) will be summarized by primary 
system organ class and preferred term. Actual values and change from baseline values for 
vital signs, ECGs, clinical laboratory (hematology and chemistry) tests, and other 
continuous safety variables will be summarized with descriptive statistics. Concomitant 
medications, injection site reactions, and other categorical safety variables will be 
summarized with frequency and percentage distribution.  
All safety analyses will be performed using the Safety population. 
Interim Analysis No Interim Analysis is planned for this study.  
 

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5 
Introduction 
5.1 
Background 
5.1.1 
Nonalcoholic Steatohepatitis (NASH) 
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease ranging from 
simple steatosis to inflammatory steatohepatitis (NASH). The estimated global prevalence of 
NASH has risen rapidly in parallel with the dramatic rise in population levels of obesity and 
diabetes, resulting in NAFLD now representing the most common cause of liver disease in 
the Western world (Swinburn 2011, Centers for Disease Control US Obesity Trends 2014). 
The prevalence of NASH is estimated to be between 2% and 5% in Western adults, rising to 
as high as 40%–50% in the morbidly obese patients with type 2 diabetes (T2D) (Argo 2009, 
Williams 2011). The histologic criteria for the diagnosis of adult NASH include 
macrovesicular steatosis, hepatocyte ballooning, and mild lobular inflammation 
(Kleiner 2005, Brunt 2009). Portal and periportal fibrosis followed by bridging fibrosis and 
cirrhosis are seen in patients with the progression of NASH. Steatosis may be absent in cases 
of bridging fibrosis or cirrhosis (“burnt-out NASH”) and is often misdiagnosed as 
cryptogenic cirrhosis (Caldwell 2004). The NAFLD Activity Score (NAS) is a validated 
score used to grade disease activity in patients with NAFLD and NASH (Appendix 1). 
The NAS is the sum of the biopsy's individual scores for steatosis (0–3), lobular 
inflammation (0–2), and hepatocellular ballooning (0–2). Fibrosis staging is assessed using a 
separate (0–4) scoring system from the NAS (Kleiner 2005).  
Most patients with NASH are asymptomatic, although some patients may present with 
fatigue, malaise, and vague right-upper abdominal discomfort. Patients are more likely to 
initially be identified by elevated liver aminotransferases on routine exams or hepatic 
steatosis detected incidentally on abdominal imaging. Patients with NASH often have one or 
more components of the metabolic syndrome such as obesity, hypertension, dyslipidemia, 
and insulin resistance or T2D, with NASH considered to be the hepatic manifestation of 
metabolic syndrome (Torres 2012). Most patients are diagnosed with NASH in their forties 
or fifties. Studies vary with regard to the sex distribution of NASH, with some studies 
suggesting it is more common in women while others suggest it is more common in men 
(Pan 2014). There appear to be ethnic differences in the prevalence of NASH, with a higher 
prevalence of hepatic steatosis in Hispanics compared with whites or blacks (Pan 2014).  
The pathogenesis of NASH and progression to fibrosis/cirrhosis is not yet fully understood, 
despite recent advances in understanding complex metabolic and inflammatory pathways that 
are likely involved in disease progression. The most widely supported theory implicates 
insulin resistance as the key mechanism leading to hepatic steatosis and subsequent NASH 
(Cusi 2012). This is likely followed by oxidative injury resulting in the necroinflammatory 
component of NASH (Cusi 2012). Hepatic iron, antioxidant deficiency, and intestinal 
bacteria have all been suggested as potential oxidative stressors (Cusi 2012). Several other 
factors known to be involved in the progression of NASH include inflammatory cytokines, 

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adipokines, lipotoxicity, autophagy, and mitochondrial dysfunction (Tsochatzis 2009). 
There is also growing evidence of a genetic component for the progression of NAFLD to 
NASH as well as fibrogenesis in patients with NASH (Mehta 2014). 
The natural history of NASH is variable from patient to patient and the NAS does not appear 
to be predictive of disease progression. The presence of fibrosis has been the only highly 
predictive factor of patients who will progress to cirrhosis. Approximately 10%–20% of 
patients with NAFLD will progress to NASH over a 7-year period (Argo 2009, Bhala 2013). 
Of these patients, roughly 20% will progress to cirrhosis over a 20-year period (Bhala 2013). 
A recent meta-analysis of paired biopsy studies in NASH patients demonstrated an annual 
fibrosis progression rate of 0.14 fibrosis stages in patients with NASH and 1 stage of 
progression over 7.1 years for patients with NASH (Singh 2015). The mortality rate of 
patients with NASH has been estimated at 1%–2% per year in patients with fibrosis, largely 
due to cardiovascular disease followed by liver-related causes (Kim 2013). Patients with 
NASH-related cirrhosis can progress to decompensated liver disease, complications of portal 
hypertension, and hepatocellular carcinoma (HCC). Recently, a growing number of cases of 
HCC in NASH patients have been reported without bridging fibrosis or cirrhosis, suggesting 
an independent pathogenic mechanism in this population (Paradis 2009). NASH is rapidly 
growing as the primary cause of end-stage liver disease in the U.S. and European populations 
and is expected to be the primary indication for liver transplantation by 2020 (Charlton 2011, 
Afzali 2012). 
5.1.2 
Treatment of NASH 
The identification of a single therapeutic target has been complicated by the complexity of 
the pathogenesis of NASH. The treatment goals for NASH have focused on the prevention or 
reversal of liver injury either by treating the underlying metabolic and inflammatory 
conditions or through directly targeting fibrogenic pathways. Early-stage disease treatments 
have focused on insulin sensitization, decreasing lipids, and antioxidant activity. The 
endpoints for these treatments have been both improvements in biochemical parameters and 
histologic improvement in the components of NAS with no worsening or improvement of 
fibrosis. More recently, the resolution of NASH on biopsy has been considered a more 
clinically meaningful treatment endpoint. Antifibrotic agents have targeted the advanced 
fibrosis and cirrhotic populations but have little activity on the underlying disease causing the 
chronic hepatic injury. 
Weight loss through lifestyle management is considered the first-line treatment strategy for 
NASH and is associated with improvement in liver histology and a reduction in 
cardiovascular and metabolic complications (Promrat 2010, Glass 2015). However, the 
majority of patients are unsuccessful in achieving or maintaining adequate weight loss and 
require other interventions. In cases of morbid obesity, bariatric surgery has been successful 
in reversing the metabolic and hepatic injury associated with NASH (Cazzo 2015). 
Currently, no agents have been approved by regulatory authorities for the treatment of 
NASH; the majority of interventions have utilized agents approved for other indications. 

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However, the interpretation of the data with many of these agents has been complicated by 
the study designs and endpoints. The majority of studies are uncontrolled or retrospective 
cohorts, have small sample sizes and/or are insufficiently powered, were comprised of 
heterogeneous populations, have treatment durations too short (< 12 months) to demonstrate 
a treatment effect, and lack consistent definitions of response. Evaluated agents including 
metformin, fibrates, ursodeoxycholic acid, and orlistat have failed to show a significant 
histologic benefit in NASH (Torres 2012). Pilot studies with PPAR agonists (pioglitazone, 
rosiglitazone) have been undertaken based on their effects on insulin resistance, 
inflammatory signaling, and fibrogenesis. Both agents have demonstrated improvements in 
alanine aminotransferase (ALT) and steatosis with pioglitazone having a marginally better 
anti-inflammatory and anti-fibrotic activity (Belfort 2006, Neuschwander-Tetri 2003). 
Vitamin E has also been evaluated in NASH patients based on its antioxidant properties. 
Small pilot studies have demonstrated histologic improvement with daily doses of 
400-800 IU (Harrison 2003). The PIVENS trial comparing pioglitazone or vitamin E to 
placebo was the first well-controlled study to show an impact on steatosis, inflammation, 
hepatocyte ballooning, and fibrosis, with vitamin E having slightly better improvements in 
fibrosis (Sanyal 2010). Although a treatment benefit was demonstrated in this study, the 
improvements in fibrosis were modest. Additionally, near- and long-term safety and 
tolerability concerns were observed with both pioglitazone (weight gain, edema, bone 
fractures, malignancy) and vitamin E (hemorrhagic stroke, inhibition of platelet aggregation, 
malignancy). More recently, the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) 
was evaluated in the FLINT trial in a population similar to that in the PIVENS study with 
comparable primary and secondary endpoints (Neuschwander-Tetri 2015). OCA 
demonstrated results comparable to vitamin E versus placebo in terms of improvements in 
NAS and fibrosis whereas vitamin E and pioglitazone demonstrated better results compared 
to OCA in terms of resolution of NASH. Additionally, significant increases in pruritus and 
lipids (requiring treatment on study) were associated with OCA. Although these agents have 
demonstrated some histologic improvement in NASH, a significant medical need for new 
effective therapies with favorable safety and tolerability profiles remains. 
5.2 
Nonclinical Studies 
Aldafermin has been evaluated in a series of in vitro and in vivo nonclinical studies to 
support its clinical development in patients with NASH. Please refer to the Investigator’s 
Brochure (IB) for additional information on these studies. 
5.2.1 
Nonclinical Safety Assessment 
The nonclinical safety of aldafermin has been assessed in general toxicity studies in 
CD-1 mice, Sprague-Dawley rats, and cynomolgus monkeys (Macaca fascicularis) for up to 
26 weeks of treatment and in embryo–fetal toxicity studies in CD-1 mice and New Zealand 
White (NZW) rabbits. Aldafermin is pharmacologically active in the mouse and monkey for 
up to 26 weeks of treatment. Aldafermin was generally well tolerated in animals. 

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Based on the cumulative nonclinical safety profile of aldafermin for up to 26 weeks of 
treatment, the NOAELs in the mouse, rat, and monkey were determined to be 3, 3, and 
1 mg/kg, respectively. A sufficient safety margin exists for aldafermin at the proposed 
maximal clinical dose of 3 mg (0.0864 mg/kg) where estimated exposure is estimated to be 
5- or 28-fold below that at the NOAELs in the mouse or monkey, respectively (see Table 1). 
Table 1. 
Estimated Safety Exposure Margin of Aldafermin 
Nonclinical 
Species 
NOAEL 
(mg/kg) a 
Plasma AUC 
(hr  ng/mL) b 
Exposure Margin Relative to 
Maximum Human Therapeutic Dose c 
Monkey 
1 
6610 
28X 
Mouse 
3 
1062 
5X 
Rat 
3 
6580 
28X 
AUC = area under the concentration–time curve; hr = hour; NOAEL = no-observed-adverse-effect level. 
a Determined from the 6-month chronic toxicity studies. 
b Systemic exposure at Day 1 after a single dose was used as the most conservative estimate of exposure given 
the presence of anti-drug antibody formation with repeat dosing in animals leading to drug accumulation 
(plasma AUC 7-fold above Day 1 levels).  
c Based on a maximal therapeutic dose of 3 mg (0.033 mg/kg based on a 90-kg patient) where plasma AUC is 
projected to be 233 hr  ng/mL (Study 12-0101). 
5.2.2 
Therapeutic Rationale for Aldafermin in NASH 
Aldafermin (also known as NGM282 or M70) is a recombinant protein with an amino acid 
sequence 95.4% identical to that of human FGF19. Aldafermin was engineered to retain the 
beneficial functions of FGF19 including improved metabolic parameters and regulation of 
hepatic bile acid synthesis (Zhou 2014, Luo 2014, DePaoli 2019).  
The pathogenesis of NASH involves complex interactions of insulin resistance, dysregulation 
of lipid and triglyceride metabolism, and bile acid synthesis that leads to steatohepatitis and 
fibrogenic activity. Interestingly, decreased FGF19 serum levels are inversely correlated with 
severity of fibrosis/cirrhosis in NASH related liver disease (Alisi 2013). Moreover, patients 
with biopsy-proven NAFLD and NASH have decreased serum levels of FGF19 (Eren 2012, 
Bechmann 2013), which correlates with a reduced hepatic response to FGF19. These changes 
in FGF19 levels also correlate to increased hepatocyte ballooning (Schreuder 2010, 
Wojcik 2012). 
The potential role of reduced FGF19 activity in the pathogenesis of NASH is not fully 
elucidated but may, in part, be due to accumulation of hepatic bile acids. For example, 
increased bile acid synthesis as well as serum bile acid 7-alpha-hydroxy-4-cholesten-3-one 
(C4) concentrations, a key marker of CYP7A1 activity, correlate with NASH disease severity 
and fibrotic activity (Bechmann 2013). Altered bile acid composition has been observed in 
patients with NASH, with a compensatory transition from CYP7A1-mediated classic 
pathway (toxic bile acids) to the less toxic alternative pathway (Lake 2013). Increased 
hepatic concentrations of bile acids are also associated with increased apoptosis, Fas, and 

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tissue necrosis factor (TNF) R1 activity resulting in hepatocyte injury and stellate cell 
activation (Faubion 1999, Higuchi 2003). A significant correlation also exists between 
increases in specific bile acids and severity of NASH-related hepatic injury (Aranha 2008). 
FGF19 levels are also decreased in subjects with T2D or metabolic syndrome and return to 
normal levels after bariatric surgery in diabetic subjects (Mingrone 2012). 
The potential therapeutic benefits of increased FGF19 pathway activity in metabolic disease 
and NASH is well documented in various animal models of disease. For example, aldafermin 
has been evaluated in various mouse animal models of NASH, and has demonstrated 
improvement in the histologic, biochemical, and fibrogenic biomarkers associated with 
NASH-related hepatic injury (Study 13-PD-NGM282-1007). Furthermore, aldafermin 
produced significant reduction in steatosis, inflammation, and ballooning in mouse models of 
NASH (Zhou 2017). Importantly, aldafermin is devoid of proliferative activity based on 
chronic evaluation in rodents and non-human primates that is a potential limitation of FGF19 
as a therapeutic agent (Zhou 2014). Aldafermin was selected from more than 160 variants of 
human FGF19 that were screened to retain robust efficacy while lacking evidence of 
proliferative activity in db/db mice (Luo 2014, Zhou 2014, DePaoli 2019). 
The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of aldafermin 
have been studied in a blinded, placebo-controlled, single-ascending-dose (SAD) and 
multiple-ascending-dose (MAD) study in normal subjects (Study 12-0101) and in subjects 
with T2D (Study 13-0102). Aldafermin was safe and generally well tolerated with 
dose-dependent mild to moderate injection-site reactions (ISRs), increases in total cholesterol 
and gastrointestinal (GI) symptoms (loose stools, abdominal cramping, nausea) the most 
common drug-related adverse events (AEs), which were observed mainly with higher doses. 
Dose-dependent significant reductions in serum C4 levels were also observed after 
administration of aldafermin in both populations supported target engagement and 
suppression of CYP7A1. 
Aldafermin is being evaluated in an ongoing 3-Part Phase 2 trial in patients with 
biopsy-confirmed NASH (Study 15-0105). In the now complete Part 1, the randomized, 
placebo-controlled, double-blind cohort, patients with biopsy-confirmed non-cirrhotic 
NAS H had decreased absolute LFC by -9.7% and -11.9% upon treatment with aldafermin 
doses of 3 mg and 6 mg (p<0.001), respectively, versus -0.9% with placebo (Table 2). 
74% (20/27) of patients receiving aldafermin at 3 mg and 85% (22/26) of patients receiving 
aldafermin at 6 mg met the primary endpoint of decrease in absolute LFC of ≥ 5%, while 
only 7% (2/27) of patients in the placebo group met this criteria (Table 2). There were no 
significant differences between the two aldafermin doses in either absolute or relative LFC 
reductions. Patients receiving aldafermin had a mean relative change in LFC from Baseline 
to Week 12 of -47% and -61% with the 3 mg and 6 mg doses, respectively, versus -1% with 
placebo (p < 0.001) (Table 2). Overall, 89% (47/53) of patients receiving aldafermin for 
12 weeks achieved a clinically meaningful change (≥ 30% relative change) in LFC, with 

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normalization (below a threshold of < 5% absolute LFC) observed in 34% of patients of 
aldafermin-treated subjects versus none in the placebo group.  
Table 2. 
Change from Baseline to Week 12 in MRI-PDFF in NASH Subjects  
 
Aldafermin 
Placebo 
(N=27) 
3 mg 
(N=27) 
6 mg 
(N=26) 
MRI-PDFF, Absolute % (Wk 12) 
-0.9% 
-9.7% 
-11.9% 
Absolute ≥5% (% pts.) 
7% 
74% 
85% 
MRI-PDFF, Relative % (Wk 12) 
-1% 
-47% 
-61% 
Relative ≥30% (% pts.) 
7% 
85% 
92% 
ALT, Absolute IU (Wk 12) 
-2 
-35 
-32 
ALT Normalization 
(female <19 IU, male < 30 IU) 
3.8% 
37.0% 
35.7% 
ALT, Relative % (Wk 12) 
1% 
-43% 
-44% 
pts=patients 
Greater reductions from Baseline in mean absolute ALT levels were observed for both 
aldafermin 3 mg (−35 IU, p<0.0001) and 6 mg (−33 IU, p<0.0001) at Week 12 compared 
with placebo. The reductions achieved statistical significance as early as 1 week with a 
sustained reduction throughout the entire 12-week study treatment period. The mean relative 
percentage decreases in ALT levels from Baseline to Week 12 were also significant in both 
the doses, ranging from -45% to -47% (p<0.001). ALT levels achieved normalization 
(defined as <19 IU in females and < 30 IU in males) in 24% of aldafermin -treated patients 
by Week 2 and 36% of treated subjects by Week 12. Similarly, treatment with aldafermin 
resulted in significant mean absolute reductions in AST levels from Baseline to Week 12 
compared with placebo with the majority of subjects decreasing below the clinically 
meaningful threshold of 40 IU as soon as 2 weeks after starting treatment.  
In the completed Part 2, the single-blind cohort evaluating 3 doses aldafermin (0.3 mg, 1 mg, 
3 mg) in patients with biopsy-confirmed non-cirrhotic NASH, the primary endpoint (≥ 5% 
decrease in absolute LFC) was met in 57%, 90% and 100% of the 0.3 mg, 1 mg and 3 mg 
doses, respectively, at week 12. LFC normalization was achieved in 17%, 24% and 69% of 
the 0.3 mg, 1 mg and 3 mg doses, respectively and was highly dependent on the Baseline 
MRI-PDFF for the 0.3 mg dose.  
Importantly, similar to the LFC, by Week 12, ALT levels decreased to a similar magnitude in 
the 1 mg and 3 mg dose groups, whereas in the 0.3 mg dose group, the ALT levels decreased 
in a lesser magnitude plateauing above the ULN in the majority of subjects. The 1 mg and 
3 mg dose groups show similar reductions of LFC and levels of ALT to those observed with 
the 3 mg dose in Part 1. 
Liver histology was evaluated at 12 weeks in the 1 mg and 3 mg dosing groups in Part 2 in a 
total of 44 subjects. Based on the data, fibrosis improved by at least 1 stage without NASH 

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worsening in 25% and 42% of subjects in the 1 mg and 3 mg groups, respectively, with 
3 subjects improving by 2 stages from Stage 3 to Stage 1 in the 3 mg group; 12% and 10% of 
subjects in the 1 mg and 3 mg groups, respectively, had resolution of NASH as currently 
defined by the FDA with no worsening in fibrosis; and NAS was decreased by ≥2 points 
(including inflammation and/or ballooning) without fibrosis worsening in 50% and 63% of 
subjects in the 1 mg and 3 mg groups, respectively. 
Overall, aldafermin has demonstrated robust activity in reducing liver fat content, 
transaminase and serum markers of fibrogenesis, leading to improvement in liver fibrosis and 
histology in patients with biopsy-confirmed, non-cirrhotic NASH. 
Thus, based on the favorable safety and tolerability profiles in normal volunteers as well as 
T2D and NASH patients as well as the potent treatment effects as measured by imaging, 
laboratory markers, and histology, aldafermin represents a potentially important therapeutic 
option for the treatment of NASH. 
5.3 
Clinical Studies 
NGM has completed a Phase 1 clinical study in healthy volunteers and Phase 2 clinical 
studies in T2D, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), 
in addition to the interim analyses from the ongoing NASH study, to further support the 
clinical development of aldafermin in patients with NASH. Please refer to Section 5.2.2 and 
the current version of the NASH IB for additional detailed information on these studies. 
5.4 
Study Rationale 
This is a Phase 2b study being conducted to evaluate the efficacy and safety and tolerability 
of aldafermin in patients with histologically confirmed NASH upon treatment for 24 weeks. 
The doses selected are supported by both the nonclinical and clinical data generated to date 
and are within the current safety margins in both monkeys and mice obtained in the GLP 
26-week toxicology program. Based on efficacy of aldafermin observed NASH patients 
(Study 15-0105 Section 5.2.2), the selected doses of 0.3 mg, 1 mg, and 3 mg of aldafermin 
are expected allow a balance of optimizing biologic activity versus safety and tolerability in 
the studied population.  
Additionally, while the efficacy obtained with 12 weeks of aldafermin treatment in Study 15-
105, as measured by non-invasive assessment and liver histology, equals or exceeds the 
effects seen with available treatments per the current clinical guidelines and mid- and late-
stage investigational agents that have been studied in Phase 2 and is encouraging, longer 
exposures are desirable in the further development of the molecule. Recent publications 
endorsed by the FDA have supported that 24 weeks is a sufficient duration to determine 
histologic response, depending on the mechanism of action of the drug being tested. 
Therefore, this study will evaluate the efficacy of aldafermin at 24 weeks. 
Moreover, given that aldafermin has been shown to cause as increase serum levels of total 
and LDL-C cholesterol in normal volunteers (Study 12-0101) and T2D patients (Study 13-

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0102), 5, 10, 20, and 40 mg of rosuvastatin will be studied in this study to further evaluate 
co-administration of a statin on lipid levels, safety, and tolerability in a larger population of 
aldafermin-treated subjects.  
 
 
  

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6 
Study Objectives 
6.1 
Primary Objectives and Endpoints: 
The primary objectives are to evaluate the efficacy, safety and tolerability of aldafermin 
based on liver histology at 24 weeks versus placebo. 
1. The primary efficacy endpoint is the histologic response defined as an improvement in 
liver fibrosis by ≥ 1 stage by NASH Clinical Research Network (CRN) criteria with no 
worsening of steatohepatitis at Week 24 compared with baseline. 
2. The primary safety endpoint is frequency, severity, and timing of adverse events (AEs) 
and serious adverse events (SAEs). Safety and tolerability of aldafermin in subjects with 
NASH as a function of dose level after up to 24 weeks of treatment with aldafermin will 
be assessed.  
6.2 
Secondary Objectives and Endpoints  
The secondary objectives of this study are to evaluate the effect of aldafermin 2 on 
pharmacokinetics, biomarkers of target engagement, fibrogenesis, and imaging. 
The secondary endpoints are as follows:  
1. Resolution of NASH (defined as an NAS score of 0 or 1 for inflammation and 0 for 
ballooning) with no worsening of fibrosis as determined by the NASH CRN criteria at 
Week 24 compared with baseline. 
2. Subjects with improvement in liver fibrosis by > 1 stage by CRN criteria with no 
worsening of steatohepatitis and resolution of NASH with no worsening of fibrosis as 
determined by the NASH CRN criteria at Week 24. 
3. Subjects with improved, no change, and worsening of fibrosis and NAS (total score and 
individual components) at 24 weeks compared to baseline 
4. Subjects with the following changes in liver fat content (LFC) by MRI-PDFF at Week 24  
o Normalization for LFC (defined as < 5% absolute LFC)  
o ≥ 5% decrease in absolute LFC  
o ≥ 30% relative decrease in LFC  
5. Absolute and percentage changes from Baseline to Week 24 of the following: 
o ALT, AST, total bilirubin, ALP and gamma glutamyl transpeptidase (GGT) 
o Total cholesterol, high-density lipoprotein-cholesterol (HDL-C), LDL-C, 
triglycerides  
o Lipoprotein particles (including ApoB) 
o Homeostasis model assessment–estimated insulin resistance (HOMA-IR) 
o N-terminal type III collagen (Pro-C3)  
o Total ELF Score and individual components (i.e., hyaluronic acid, PIIINP, TIMP-1) 

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o 7-alpha-hydroxy-4-cholesten-3-one (C4) and serum bile acids (total and individual 
bile acids) 
o High-sensitivity C-reactive protein (hs-CRP) 
6. Subjects with normalization of ALT and AST at Week 24 
6.3 
Exploratory Objectives and Endpoints: 
 
 
  
 
 
 
 
 
 
 
  
 
 
    
 
 

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The first dose of aldafermin (Day 1) and doses at Weeks 2, 4, 8, 12, 18, and 24 study visits 
will be self-administered in the clinic, with all other daily doses through Week 24 
self-administered at home. Self-administration should occur daily at a similar time at home.  
Subjects will return to the clinic on Weeks 2, 4, 8, 12, and 18 for on-treatment assessments 
and to receive aldafermin study-drug kits.  
LDL-C will be evaluated at Weeks 2, 4, 8, 12, and 18 in all subjects for possible increases in 
lipid levels associated with aldafermin administration. Rosuvastatin will be started in subjects 
meeting specific LDL-C level criteria at Week 2. Rosuvastatin and matched placebo are 
over-encapsulated to maintain the blind at the sites and with the sponsor study teams. 
Initiation and ongoing dose adjustments of rosuvastatin/matched placebo will be managed by 
an unblinded third-party medical monitor and through the 
 The sponsor and study sites 
will be blinded to LDL-C values and the specific rosuvastatin dosing decisions as outlined in 
Section 9.4.14. Subjects who have not achieved an adequate response or cannot tolerate 
rosuvastatin as defined in Section 9.4.14 will be considered for the addition of ezetimibe as 
second-line lipid management therapy. Ezetimibe 10 mg tablets can be administered with or 
without food at the same time as rosuvastatin and aldafermin. Subjects whose LDL-C values 
are not adequately managed by their maximum tolerated rosuvastatin dose plus ezetimibe 
will be discontinued from study and an early withdrawal study visit will be completed. 
The follow-up visit/EOS should be scheduled for 6 weeks after the early withdrawal study 
visit. The specific rosuvastatin dosing algorithm is outlined in detail in Appendix 3.  
Rosuvastatin or matching placebo will be dispensed at each study visit through Week 18 
(statin-naïve) or Week 24 (statin-experienced). If the subject is taking statins, evaluate 
tolerability and continue therapy to Week 24 if statin naïve or Week 30 if statin experienced.  
All subjects will return to the clinic at Week 25 for post-treatment LDL-C assessment. 
Subjects who have an LDL-C value of >100 mg/dL and >15 mg/dL above their Day 1 value 
at Week 25 will be re-assessed at Week 30. Subjects who have an LDL-C value of 
> 100 mg/dL and > 15 mg/dL above their Day 1 value at Week 30 will have an additional 
4- week follow-up visit to confirm their LDL-C value is ≤ 100 mg/dL or ≤ 15 mg/dL above 
their Day 1 value.  
The study visit at Week 24 will be the aldafermin EOT clinic visit and subjects will return to 
the clinic at Weeks 25 and 30 (or at 1 and 6 weeks after last dose of aldafermin) for a post- 
treatment response and EOS follow-up visits. Subjects are required to undergo MRI 
performed during Screening Day -28 and at Weeks 12, 24 / Early Withdrawal (EOT), and 
30 (EOS) visits.  
All subjects will have blood samples drawn for 
 
 
 
 

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7.1 
Study-Stop Criteria 
The entire study may be discontinued at the discretion of the Sponsor based on the 
occurrence of the following: 
 AEs with respect to their frequency, severity, and/or duration 
 Medical or ethical reasons affecting the continued performance of the study 
 Difficulties in the recruitment of subjects 
 Cancellation of drug development 
 
 

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8 
Enrollment Criteria 
8.1 
Inclusion Criteria 
Subjects who meet the following criteria may be included in the study: 
1. 
Males and females 18 to 75 years of age (inclusive) who are able to comprehend and 
willing to sign an Informed Consent Form (ICF) 
2. 
Histologically confirmed NASH diagnosis as defined by the NIH NASH CRN 
(see Appendix 1, Kleiner 2005) and liver biopsy criteria outlined below. A historical 
biopsy is acceptable if performed within the required 6-months of Screening and 
tissue slides are available for a qualified central pathologist reader:  
 NAS ≥ 4 with a minimum of 1 point in each component 
 Histologic evidence of Stage 2 or Stage 3 fibrosis without cirrhosis  
3. 
Total liver fat content of ≥ 8% as measured by MRI-PDFF 
4. 
Subjects with T2D or insulin resistance are permitted as long as diabetic medications 
are stable as outlined in Section 9.3 Concomitant Medications and subject attempts to 
maintain a stable regimen during the study period.  
5. 
Other concomitant medications/therapies for NAFLD or NASH: requires a stable 
regimen for at least 3 months prior to the Screening biopsy of record and throughout 
the study (Refer to Section 9.3 Concomitant Medications).  
6. 
Statin use based on the following criteria for statin-naïve or statin-experienced at 
Screening: 
 Statin naïve is defined as no administration of statins within 3 months prior to 
Screening. 
 Statin experienced is defined as administration of the following stable daily 
doses of approved statin therapies taken for at least 3 months prior to Screening 
through Week 2 
o Atorvastatin: ≤ 40 mg/day 
o Fluvastatin: ≤ 40 mg/day 
o Lovastatin: ≤ 40 mg/day (immediate release), ≤ 30 mg/day (extended release) 
o Pitavastatin: ≤ 2 mg/day 
o Pravastatin: ≤ 40 mg/day 
o Simvastatin: ≤ 40 mg/day 
o Rosuvastatin: ≤ 20 mg/day   

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7. 
The following laboratory parameters must be met at Screening: 
 Total bilirubin ≤ULN (Upper Limit of Normal) based on the Day -42 value or 
average of at least 2 Screening values obtained during the Screening Period, 
except for subjects with an established diagnosis of Gilbert’s Syndrome provided 
the direct bilirubin level is ≤ULN and hemoglobin and reticulocyte count are 
normal. 
 Aspartate aminotransferase (AST) ≥ 30 IU/L and ≤ 250 IU/L in all subjects, based 
on the Day -42 value or average of at least 2 screening values obtained during the 
Screening Period  
i. Exception: subjects with an average AST ≥ 20 and < 30 IU/L will be permitted 
provided that at least one of the following criteria are met: 
1. Local historical biopsy within 6 months with a NAS of 4 with at least 
1 point in each component and fibrosis Stage 2 or 3. Subjects with a 
historical biopsy will have their slides evaluated by the central reader prior 
to undergoing MRI-PDFF.  
2. Vibration-controlled transient elastography (VCTE® by Fibroscan) ≥ 9.5 kPa 
within 6 months of Screening. If no historical Fibroscan is available, it may 
be conducted and evaluated as per local “standard-of-care” prior to Day -28. 
 Hemoglobin A1c (HbA1c) ≤ 9.5%  
 Platelet count ≥ Lower Limit of Normal (LLN) (i.e., 140,000/mm3) 
 Creatinine clearance ≥ 60 mL/min as calculated by Cockcroft-Gault equation  
 Alpha fetoprotein (AFP) < 100 ng/mL  
8. 
Female subjects who are of non-childbearing potential must have had a hysterectomy, 
bilateral oophorectomy, medically documented ovarian failure, are documented 
postmenopausal, OR a follicle stimulating hormone > 40 mIU/mL  
9. 
Female subjects of child-bearing potential must not be pregnant or nursing. 
Female subjects of childbearing potential are defined as women < 55 years of age 
with ≤ 2 years of amenorrhea and who meet both of the following criteria: 
i. A negative serum pregnancy test at Screening and urine pregnancy test prior to 
randomization 
ii. Correct and consistent use of one of the following methods of birth control in 
addition to a male partner using a condom from Screening to 30 days after the 
last dose of study drug: 
1. hormone containing contraceptive 
2. intrauterine device with a failure rate < 1% per year 
3. cervical cap or diaphragm with spermicidal agent 
4. tubal sterilization 
5. vasectomy in male partner 

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6. complete abstinence of sexual intercourse 
10. 
Male subjects are eligible for the study if they meet the following criteria: 
a. Male subjects must agree to consistently and correctly use a condom in 
combination with one of the following from the date of consent to 30 days after 
the last dose of study drug: 
i. 
Condom with spermicide 
ii. 
Vasectomy 
iii. 
Complete abstinence of sexual intercourse. 
AND 
b. Female partner(s) must use any of the approved methods of birth control in 
inclusion criterion #9. 
11. 
Able and willing to comply with the dosing instructions for study-drug administration 
and able to complete the study schedule of assessments  
12. 
BMI ≥25 kg/m2 for subjects self-identified of Asian descent only 
 
8.2 
Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. 
Clinically significant acute or chronic liver disease of an etiology other than NASH 
2. 
Evidence of drug-induced steatohepatitis secondary to amiodarone, corticosteroids, 
estrogens, methotrexate, tetracycline, or other medications known to cause hepatic 
steatosis 
3. 
History or presence of cirrhosis (compensated or decompensated) as determined by 
histology and/or relevant medical complications and/or laboratory parameters 
4. 
Prior or pending liver transplantation 
5. 
Model of end-stage liver disease (MELD) score ≥ 12 (except for subjects with 
established Gilbert’s syndrome)  
6. 
Evidence of worsening liver disease (defined below) between Screening visits 
(i.e., Day -42 and Day -28) including measures of AST, ALT, TBL, and ALP: 
 For subjects with AST, ALT, TBL, or ALP baseline levels > ULN on Day -28, 
the Day -28 assessment should not exceed an increase of 35% over the Day -42 
assessment. 
 For subjects with Gilbert’s syndrome and a total bilirubin > ULN at the Day -42 
assessment, the total bilirubin assessment at Day -28 should not exceed an 
increase of 50% over the Day -42 assessment. 
Note: For AST, ALT, TBL, and ALP, if the percent increase in laboratory values 
between Day -42 and Day -28 is > 35%, repeat blood samples will be 

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collected at an unscheduled visit at a minimum of two weeks from the 
Day -28 visit. The average of Day -42 and Day -28 values will be 
compared to the 3rd value to determine if eligibility ranges 
(i.e., % agreement ≤ 35%) are met.  
7. 
Clinically significant cardiovascular or cerebrovascular event or new diagnosis within 
6 months of Screening, including but not limited to congestive heart failure, 
myocardial infarction, acute coronary syndrome, revascularization, stroke 
(hemorrhagic or ischemic), transient ischemic attack (TIA), or implanted defibrillator 
or pacemaker (except for uncomplicated elective pacemaker procedure, 3 months post 
procedure will be allowed).  
8. 
History of gastric bypass or bariatric surgery or planned procedure during the study 
period. Removal of a gastric balloon or lap band is permitted if surgery performed 
within 6 months prior to Day 1. 
9. 
Type 1 diabetes 
10. 
History of clinically significant unstable or untreated illness or any other major 
medical disorder that may interfere with patient treatment, assessment, or compliance 
with the protocol 
11. 
Any contraindication or inability to obtain an MRI  
12. 
Inability to obtain or any contraindication to liver biopsy (if a historical biopsy with 
viable tissue slides are not available within the required time period) 
13. 
Screening ECG with clinically significant abnormalities or unexplained findings that 
the investigator feels needs further evaluation and treatment  
14. 
Positive for HBsAg, anti-HIV, or anti-HCV plus HCV-RNA. Subjects who are anti-
HCV- positive but HCV-RNA negative (secondary to treatment or viral clearance) 
are eligible with at least a 1-year period since documented sustained viral response at 
Week 12 post-treatment 
15. 
History of malignancy diagnosed or treated within 2 years (recent localized treatment 
of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma 
in situ is allowed if appropriately treated prior to Screening); subjects under 
evaluation for malignancy are not eligible 
16. 
Clinically-relevant drug use within 12 months of Screening. A positive drug screen 
will exclude subjects unless it can be clearly explained by a prescribed medication. 
The diagnosis and prescription must be approved by the Investigator and the Sponsor 
Medical Monitor or designee. Marijuana is not part of the drug screen.  
17. 
Significant alcohol intake as measured by a phosphatidylethanol (PEth) level 
≥ 200 ng/mL AND positive results from AUDIT-C alcohol consumption 
questionnaire (Appendix 8) 

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18. 
Criterion eliminated per protocol amendment 3  
19. 
Consumption of ≥ 21 units of alcohol per week in males and ≥ 14 units of alcohol per 
week in females for two years prior to enrollment, where a “unit” of alcohol is 
equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor 
20. 
Use of any prohibited concomitant medications as described in Section 9.3 from 
Day -42 to the end of the study including: 
 Investigational agents, other than aldafermin, or devices for any indication. 
These agents must also have been discontinued prior to Screening 
 Combination preparations of statins and other lipid-lowering agents (other than 
approved statin therapies listed in inclusion criterion #6) 
 Weight loss medications 
 Any medication that is contraindicated according to the rosuvastatin package 
insert (Appendix 6) or if subject has a known hypersensitivity to rosuvastatin 
product components (Section 10.1.3). 
 Any medication that is contraindicated according to the ezetimibe package insert 
(Appendix 7) or if subject has a known hypersensitivity to ezetimibe product 
components. 
 Hepatotoxic medications (Appendix 9). For subjects who have been on stable therapy 
with no related hepatotoxicity, the MM may be contacted to assess the medical context 
and eligibility of the subject.  Allopurinol to treat gout is permitted provided there is 
no prior history of intolerability. 
 Anabolic steroids; Low levels of estrogen or testosterone as replacement therapy 
are allowed per Medical Monitor approval.  
21. 
History of statin intolerance as evidenced by presence of ALT elevations, adverse 
event(s), or other significant side effects attributed to statins 
22. 
Prior participation in a clinical trial of aldafermin is excluded unless previously 
enrolled into a placebo treatment group of the trial.  
23. 
Subject with severe allergic or anaphylactic reactions to recombinant therapeutic 
proteins, fusion proteins, or chimeric, human, or humanized antibodies 
24. 
Participation in a study of another investigational agent: 
 NASH investigational agents: < 3 months prior to Screening if treated with active 
study drug or < 28 days if treated with placebo 
 All other investigational agents: within 28 days or five half-lives of the drug 
(whichever is longer) prior to Screening 
25. 
Any acute or chronic condition that, in the opinion of the Investigator or the Sponsor 
Medical Monitor, would limit the subject’s ability to complete and/or participate in 
this clinical study 

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26. 
Pregnancy or lactation 
27. 
Criterion eliminated per protocol amendment 4 
8.3 
Study Treatment Discontinuation, Interruption, or Dose Reduction for an 
Individual Subject 
Study treatment discontinuation, interruption or dose reduction will be considered if the 
subject experience any of the following: 
i. 
Treatment emergent adverse event (TEAE) of grade 3 or 4 (CTCAE V5.0) severity 
ii. 
Any suspected statin-related adverse event related to muscle symptoms (Appendix 5) 
iii. 
Adverse event of muscle symptoms (e.g., myalgia, pain, or weakness) or elevated 
creatine kinase  
iv. 
Laboratory value(s) indicative of drug induced liver disease (DILI) 
 
Specific actions taken will be as follows: 
i. 
TEAE of Grade 3 or grade 4 (CTCAE V5.0): 
 Any possibly or probably related Grade 3 TEAE 
 Any Grade 4 or higher TEAE  
 
Aldafermin and statin will be discontinued 
ii. 
Any suspected statin-related adverse event (other than muscle symptoms): 
Subjects will be allowed a one-time rosuvastatin dose adjustment if the subject 
experiences a statin-related adverse event (as determined by the PI) which would 
compromise the subject continuing in the study. The third-party Medical Monitor will be 
contacted by the study site to report a possible statin-related AE requiring intervention. 
Information will be collected on the AE including the specific description, history, and 
severity based on CTCAE grading and forwarded to the Sponsor Medical Monitor or 
designee for approval of the rosuvastatin/placebo dose reduction. The study team should 
instruct the subject to refrain from administering the rosuvastatin/placebo therapy and to 
repeat safety laboratory examinations as indicated by the specific AE within 72 hours. 
If the subject is < 2 weeks from their next visit, they should not dose the 
rosuvastatin/placebo therapy until the next scheduled visit. If they are ≥ 2 weeks from 
their next study visit, an unscheduled visit should be made to repeat laboratory 
examinations and dispense 2 bottles (10 mg and placebo). If the AE resolves, rosuvastatin 
may be restarted. Subjects on rosuvastatin 20 mg or 40 mg will be restarted on 
rosuvastatin 10 mg. If the AE reoccurs following administration of the new dose of 
rosuvastatin, rosuvastatin/placebo should not be restarted and second-line lipid-lowering 
therapy (ezetimibe) will be considered with third party unblinded Medical Monitor 
approval. Aldafermin dosing will not be interrupted. Rosuvastatin Dose Reduction 
Algorithm also presented in Appendix 4. 

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iii. 
Adverse event of muscle symptoms (e.g., myalgia, pain, or weakness) or elevated 
creatine kinase:  
A sample will be collected for assessment of CK within 48-72 hours, and CK assessment 
will be repeated if needed (refer to Appendix 5). At Weeks 12 and 24, the creatine kinase 
(CK) level will be compared to the subject’s baseline level.  
 If CK level is ≤ 3x baseline, subject will continue on aldafermin and over-
encapsulated rosuvastatin. 
 If CK level is > 3x baseline, CK will be repeated within 48 - 72 hours and aldafermin 
and rosuvastatin will be held: 
o If CK is ≤ 3x baseline, subject can re-start on aldafermin and rosuvastatin based 
on the investigator’s judgement. 
o If CK is > 3x and < 5x baseline, repeat CK levels within 48 - 72 hours while 
aldafermin and rosuvastatin on hold.  
o  If CK is ≥ 5x baseline, aldafermin and rosuvastatin will be discontinued.  
Upon repeat testing for subjects previously with CK > 3x but < 5x baseline: 
 If CK is ≤ 3x baseline, subject can re-start on aldafermin and rosuvastatin 
based on the investigator’s judgement.  
 If CK level is > 3x baseline, subject will discontinue aldafermin and 
rosuvastatin.  
iv. 
Laboratory value(s) indicative of DILI:  
a) Elevation of AST or ALT > 2x above subject-specific baseline value (calculated 
using the average of the Day -42, Day -28 and the Day 1 values) and total bilirubin 
> 1.5 x subject-specific baseline value, repeat testing of ALT, AST, and bilirubin 
must be performed within 48 - 72 hours. If there are persistent elevations (AST or 
ALT > 2x baseline or TBL > 1.5x baseline values) upon repeat testing, then close 
observation (testing and physical examination 2 - 3 times per week) should be 
implemented and discontinuation of aldafermin and rosuvastatin should be 
considered (see b below). 
b) A decision to discontinue or temporarily interrupt the study drug will be 
considered based on factors that include how much higher than baseline ALT and 
AST were relative to the upper limit of normal (ULN) and how much the on study 
ALT and AST levels have increased relative to baseline, in addition to whether 
there is concomitant elevation of bilirubin or INR. Aldafermin and rosuvastatin 
will be discontinued or temporarily interrupted as follows: 
 
 If baseline measurements (BLM) were < 2x ULN, discontinue if ALT or AST 
increases to > 5x BLM 
 If BLM ≥ 2x ULN but < 5x ULN, discontinue if ALT or AST increases to > 3x 
BLM 

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 If BLM ≥ 5x ULN, discontinue if ALT or AST increases to > 2x BLM 
 Discontinue if ALT or AST increase > 2x BLM AND the increase is 
accompanied by a concomitant increase in TBL to > 2x BLM OR the INR 
concomitantly increases by > 0.2 
 In any subjects with signs and symptoms of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
c) If the subject lives in a remote area, laboratory testing can be performed locally 
and the results should be promptly communicated to the investigator site. 
d) Close observation for suspected DILI will include:  
 Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of repeat testing can decrease to once a week or less if abnormalities 
stabilize or the study drug has been discontinued and the subject is 
asymptomatic. 
 Obtaining or re-confirming a detailed history of symptoms and prior or 
concurrent diseases. 
 Obtaining or re-confirming the history of concomitant drug use (including 
nonprescription medications and herbal and dietary supplement preparations), 
alcohol use, recreational drug use, and special diets. 
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; NASH hypoxic/ischemic hepatopathy; and biliary tract 
disease. 
 Obtaining a history of exposure to environmental chemical agents 
Outside of situations listed above no aldafermin /matched placebo dose reductions will be 
allowed. Temporary drug holidays from aldafermin dosing ≤ 5 days will be allowed on a case 
by case basis for subjects for safety or tolerability but must be approved by the Sponsor 
Medical Monitor or designee. If drug is restarted and is still not tolerated, the subject should 
stop the medication as multiple drug holidays will not be allowed.  
8.4 
Discontinuation of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Principal Investigator (PI) may remove a subject from the study if, in the 
PI’s opinion, it is not in the best interest of the subject to continue the study. Subjects may be 
discontinued due to a change in compliance with an inclusion/exclusion criterion that is 
clinically relevant and affects subject safety, occurrence of AEs, occurrence of pregnancy, or 
administration of non-permitted concomitant medication that might affect subject safety or 
study assessments/objectives. Notification of discontinuation will be made immediately to 
the Sponsor Medical Monitor or designee. In case of premature discontinuation of study 
participation, efforts will be made to perform all final EOT and EOS visits/assessments. 
The date the subject is withdrawn from the study and the reason for discontinuation will be 
recorded on the subject’s Case Report Form (CRF). All withdrawn subjects will be followed 

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until resolution of any AEs or until any unresolved AEs are judged by the PI to have 
stabilized. 

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9 
Study Methods 
9.1 
Schedule of Study Procedures 
The Schedule of Study Procedures is shown in Table 4. The visits should occur as close to 
the intended dates as possible. However, Weeks 2 and 4 will have a visit window of ±3 days. 
Weeks 8, 12, 18, and 24 will have a visit window of ±7 days. Week 25 will have a visit 
window of +3 days, and Week 30 will have a visit window of ±7 days. Subjects attending 
any visits out of windows from Day 1 to Week 24/Early Withdrawal (EOT) visit should be 
brought back into compliance with the overall study-visit schedule as soon as possible 
thereafter. Subjects will return to the clinic at Week 25 and Week 30 (1 and 6 weeks after last 
dose) for a post-treatment response and EOS follow-up visits, respectively.  
Subjects who have an LDL-C value of > 100 mg/dL and > 15 mg/dL above their Day 1 value 
at Week 25 will need to be re-assessed at Week 30. Subjects who have an LDL-C value of 
> 100 mg/dL and > 15 mg/dL above their Day 1 value at Week 30 will have am additional 
4- week follow up visit to confirm their LDL-C value is ≤ 100 mg/dL or ≤ 15 mg/dL above 
their Day 1 value. Subjects will continue to be followed until their LDL-C value is 
≤ 100 mg/dL or ≤ 15 mg/dL above their Day 1 value. Subjects whose LDL-C values are not 
adequately managed by their maximum tolerated rosuvastatin dose plus ezetimibe will be 
discontinued from study and an early withdrawal study visit will be completed. The follow 
up/EOS visit should be scheduled for 6 weeks after the early withdrawal study visit. 
 

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PEth alcohol screen  
X 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel  
X 
 
X g 
X g 
X g 
X g 
X g 
X g 
X g 
X g 
X g 
Lipoprotein particles 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Lipase 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C4 and serum bile acids k 
 
 
X k 
X 
X 
X 
X 
X 
X k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
  
Anti-drug antibodies & NAb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ELF Panel/ PRO-C3 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic biomarker sample, including PNPLA3 n 
 
 
X 
 
 
 
 
 
 
 
 
aldafermin /matched placebo in-clinic 
self-administration o 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense aldafermin /matched placebo 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense rosuvastatin p  
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Medication compliance 
 
 
 
X 
X 
X 
X 
X 
X 
 
Xq  
Lipid-Lowering Therapy Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
Xq 
Xr 
BMI = body mass index; C4 = 7-alpha-hydroxy-4-cholesten-3-one; D = Day; ECG = electrocardiogram; ELF = enhanced liver fibrosis; EOS = End of Study; EOT = End of 
Treatment; EW = Early Withdrawal; HIV = human immunodeficiency virus; HOMA-IR = homeostasis model assessment–estimated insulin resistance; hr. = hour; 
 
 
; LISSA = local injection-site symptom assessment; MRI = magnetic resonance imaging; PEth = 
phosphatidylethanol, PRO-C3 = N-terminal Type III collagen; PK = pharmacokinetic; 
; Tx = treatment; W = week 
a Weeks 2 and 4 will have a visit window of ±3 days. Weeks 8, 12, 18, and 24 will have a visit window of ±7 days.  Week 25 will have a visit window of +3 days. Week 30 will have a 
visit window of ±7 days. 
b There must be a minimum of 14 days (2 weeks) between Day -42 and Day -28 Screening Visits to allow for adequate separation of baseline liver function tests. If baseline liver 
function tests are repeated to verify eligibility criteria have been met, there must be a minimum of 14 days (2 weeks) between the Day -28 visit and the repeat liver function tests, and 
Screening Day -28 to -1 will be extended an additional 14 days (2 weeks). Subjects who have completed all Screening assessments, including liver biopsy, and are eligible to 
participate in the study may have their Screening window extended with Sponsor approval for up to 2 additional weeks if the delay is due to scheduling conflicts. 
c During screening, sites will complete; i) AUDIT-C alcohol consumption questionnaire and, ii) document subject- reported alcohol consumption to confirm whether amounts are 
within protocol defined limits (refer to exclusion criterion #19)  
d Screening Day -28 MRI-PDFF (includes 
) will serve as baseline for efficacy endpoint analysis. The Screening MRI result is valid for up to 8 weeks and 
may be used for a subject who is re-screened within that time frame. 
 
 
e All subjects are required to have a liver biopsy result at Screening and additional liver biopsy at Week 24. A Screening liver biopsy will be performed only in subjects who do not 
have a historical biopsy available within 6 months of Screening. 
f Adverse events will be monitored and recorded from subject signing informed consent through follow-up. 
g Serum chemistry will include ALT, AST, ALP, bicarbonate, bilirubin (direct and total), BUN, calcium, chloride, creatinine, CK, GGT, glucose, HDL, LDL, lipase, phosphate, 
potassium, proteins (albumin, total protein), sodium, total cholesterol, and TG. Lab results for ALT, AST, total cholesterol, LDL, HDL, and triglycerides are blinded to the site and 
sponsor from Week 2 onward. 
h Creatine Kinase will be collected at Day -42, Day 1 and Week 12, and Week 24. 
i A serum pregnancy test will be performed on all female subjects of childbearing potential at Day -42, -28 Screening visits and Day 1 (pre-dose), A urine pregnancy test will be 
performed on all female subjects of childbearing potential at Weeks 4, 12, 24, and 30. If the urine pregnancy test is positive, a serum pregnancy test will be performed to confirm 

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results.  
j Urine drug and alcohol screens may be repeated during treatment for subjects suspected of excessive alcohol intake or to rule out association with a safety event  
k C4 and bile acid testing will be collected at Day 1 and Weeks 2, 4, 8, 12, 18, 24, 25 and 30. In addition, for subjects participating in the optional PK sub-study, additional C4 will be 
tested at the same timepoints as the PK blood sample collections: Day 1 and Week 24 at pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. 
l PK blood samples will be collected in all subjects before dosing themselves in the clinic (pre-dose) on Day 1, and Weeks 2, 4, 8, 12, 18, 24, and 25. On Day 1, and Week 24, a 2-hour 
post-dose sample will be collected. Week 24 PK testing should be done at the 2-hour post time point after the subject has injected their last dose of aldafermin /matched placebo. 
m For subjects participating in the optional PK sub-study, blood samples will be collected when the subjects dose themselves in the clinic on Day 1, and Week 24 at pre-dose, and post-
dose at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. The window for sample collection for the pre-dose through 8-hour time points is ±5 minutes. The window for sample collection for the 
12- through 24-hour time points is ±30 minutes 
n A blood sample for genetic biomarker testing will be collected predose on Day 1 
o Subjects will be instructed to self-inject aldafermin daily at the same time each day in the abdomen. Subjects will not self-inject aldafermin at home on clinic visit. 
p Rosuvastatin will be dispensed at Weeks 2, 4, 8, 12, and 18 visits and subjects will be provided further dosing instruction based on their LDL-C levels and whether they are 
statin-naïve versus statin experienced. Subjects on a statin at screening will switch from their current statin to 5 mg (Asian subjects) or 10 mg (non-Asian subjects) rosuvastatin at 
Week 2 and will be dispensed additional rosuvastatin at Week 24 and continue through Week 30. 
q Medication compliance will be assessed at Week 30 only in subjects who were statin experienced at Baseline. 
r Subjects who have an LDL-C value of > 100 mg/dL and > 15 mg/dL above their Day 1 value at Week 25 will need to be re-assessed at Week 30. Subjects who have an LDL-C value 
of > 100 mg/dL and > 15 mg/dL above their Day 1 value at Week 30 will have a 4-week follow-up visit to confirm their LDL-C value is ≤ 100 mg/dL or ≤ 15 mg/dL above their 
Day 1 value.  
 

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9.2 
Study Visit Procedures 
9.2.1 
Day –42 (Screening) Procedures 
Subjects will report to clinic fasted. The Screening procedures should be all be completed 
within 42 days from consent in order to randomize the subject.  
 Obtain informed consent 
 Collect demographic data 
 Ascertain medical history 
 Collect smoking history 
 Assess inclusion/exclusion criteria 
 Measure height 
 Measure body weight, BMI, waist circumference 
 
 
  
 Complete AUDIT-C alcohol consumption questionnaire 
 Obtain 12-lead ECG (after subject has been supine for at least 5 minutes) 
 Measure vital signs (including temperature, respiratory rate, and seated blood pressure 
and pulse) 
 Register screened subject  
 
 Record prior and concomitant medications 
 Record AEs (starting from the when the subject signs informed consent) 
 Obtain blood for 10-hour fasted laboratory sample collection for: 
o Chemistry 
o CBC 
o HbA1c 
o Insulin level 
o HOMA-IR calculation 
o INR 
o Alfa fetoprotein (AFP)  
o Serum pregnancy test (all female subjects of childbearing potential) 
o Hepatitis and HIV screen 
o PEth alcohol screen  
o Lipid panel 
 Obtain urine for 10-hour fasted laboratory sample collection for: 
o Urinalysis 
o Urine drug screen 

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 Subjects with a local historical biopsy will have their slides evaluated and read by the 
central pathologists to ensure eligibility prior to undergoing MRI-PDFF 
9.2.2 
Day –28 to Day -1 (Screening) Procedures 
Subjects will report to clinic fasted. Day -28 Screening procedures must be completed no 
sooner than 14 days (2 weeks) +3 days after the Day -42 Screening visit to allow for 
adequate separation of liver function tests.  
 Obtain blood for 10-hour fasted laboratory sample collection for: 
o Chemistry 
 Obtain urine for 10-hour fasted laboratory sample collection for: 
o Pre-dose serum pregnancy in all females of childbearing potential  
 Obtain an MRI-PDFF assessment (preferably prior to any histologic evaluation unless a 
historical biopsy is available) 
 Obtain viable tissue slides from eligible historical liver biopsy or undergo a liver biopsy 
procedure to obtain new tissue 
 Record concomitant medications 
 Record AEs  
9.2.3 
Day 1 Procedures 
Subjects will report to clinic fasted. The following procedures will be performed at the Day 1 
Visit: 
Pre-dose: 
 Reassess inclusion/exclusion criteria 
 Measure body weight, BMI, and waist circumference 
 
 
 Obtain 12-lead ECG (after subject has been supine for at least 5 minutes) 
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Randomize subject  
 for aldafermin/matched placebo study-drug kit 
assignment  
 Record concomitant medications 
 Record new and/or changes to AEs  
 Obtain 10-hour fasted clinical laboratory samples for the following:  
o Chemistry 

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o CBC 
o HbA1c 
o Insulin level 
o HOMA-IR calculation 
o 
 
o INR 
o Lipid panel  
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids 
o PK (pre-dose)  
o Anti-drug antibodies (ADAs) 
o Neutralizing antibodies (NAbs) 
o ELF panel 
o Pro-C3 
 
 
 
 
 
 
o Blood sample (pre-dose) for genetic biomarker testing  
o pre-dose serum pregnancy in all females of childbearing potential  
 Obtain urine for 10-hour fasted laboratory sample collection for:   
o urinalysis 
o urine drug screen 
In-clinic dosing and assessments: 
 
Dispense initial aldafermin/matched placebo study-drug kit and home diary  
 
Provide aldafermin/matched placebo study-drug self-administration training.  
 
Oversee subject’s aldafermin/matched placebo study-drug self-administration. 
 
Perform local injection-site symptom assessment (LISSA) evaluation. 
Before clinic discharge: 
 
Obtain 2-hour post-dose PK sample  

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 
Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
 
Schedule Week 2 visit 
For Optional PK Sub-study Subjects: 
For those subjects participating in the optional PK sub-study, PK samples will be collected 
before subjects dose themselves in the clinic and post-dose at 0.5, 1, 2, 4, 6, 8, 12, and 
24 hours. The 24-hour post-dose sample will be collected prior to dosing themselves with 
aldafermin/matched placebo on Day 2. Additional samples will be collected for C4 testing at 
the same timepoints as the PK blood sample collections. The window for sample collection 
for the pre-dose through 8-hour time points is ±5 minutes. The window for sample collection 
for the 12- through 24-hour time points is ±30 minutes.  
9.2.4 
Week 2 Procedures 
Subjects will report to clinic fasted and not dosed with aldafermin/matched placebo. 
The following procedures will be performed: 
Pre-dose: 
 
Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 
Record concomitant medications 
 Record AEs 
 Obtain blood for 10-hour fasted clinical laboratory samples  
o Chemistry 
o CBC 
o INR 
o Lipid panel  
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids 
o PK (pre-dose) 
o ADAs 
o NAbs 
 
 
 
 
 
 

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Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
In-clinic dosing and dispensing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation 
 Dispense new aldafermin/matched placebo study-drug kit/diary 
 Dispense rosuvastatin medication/diary  
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
new kit).  
 Perform LISSA evaluation 
 
Before clinic discharge: 
 Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
 Schedule Week 4 visit 
Lipid-Lowering Therapy Assessment: 
The third-party Medical Monitor will evaluate LDL-C results to assess the need for 
lipid-lowering therapy (refer to Section 9.4.14). 
9.2.5 
Week 4 Procedures 
Subjects will report to clinic fasted and not dosed with aldafermin/matched placebo. 
The following procedures will be performed: 
Pre-dose: 
 
 
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Record concomitant medications 
 Record AEs  
 Obtain blood for 10-hour fasted clinical laboratory samples:  
o Chemistry 
o CBC 
o INR 
o Lipid panel  
o Lipoprotein particles 

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o Lipase 
o C4 and serum bile acids 
o PK (pre-dose) 
o ADAs 
o NAbs 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
 Obtain urine for 10-hour fasted laboratory sample collection for: 
o Pre-dose urine pregnancy in all females of childbearing potential 
In-clinic dosing and dispensing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation 
 Dispense new aldafermin/matched placebo study-drug kit/diary 
 Dispense rosuvastatin medication/diary 
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
new kit)  
 Perform LISSA evaluation 
Before clinic discharge: 
 Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
 Schedule Week 8 visit 
Lipid-Lowering Therapy Assessment: 
The third-party Medical Monitor will evaluate LDL-C results to assess the need for 
lipid-lowering therapy (refer to Section 9.4.14). 
9.2.6 
Week 8 Procedures 
Subjects will report to clinic fasted and not dosed with aldafermin/matched placebo. 
The following procedures will be performed: 
Pre-dose: 
 
 

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 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Record concomitant medications 
 Record AEs  
 Obtain blood for 10-hour fasted clinical laboratory samples:  
o Chemistry 
o CBC 
o INR 
o Lipid panel  
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids 
o PK (pre-dose) 
o ADAs 
o NAbs 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
In-clinic dosing and dispensing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation. 
 Dispense new aldafermin/matched placebo study-drug kit/diary 
 Dispense rosuvastatin medication/diary 
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
new kit)  
 Perform LISSA evaluation 
Before clinic discharge: 
 Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
  Schedule Week 12 visit 

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Lipid-Lowering Therapy Assessment: 
The third-party Medical Monitor will evaluate LDL-C results to assess the need for 
lipid-lowering therapy (refer to Section 9.4.14). 
9.2.7 
Week 12 Procedures 
Subjects will report clinic fasted and not dosed with aldafermin/matched placebo. 
The following procedures will be performed: 
Pre-dose: 
 Measure body weight, BMI, and waist circumference 
 
  
 Obtain 12-lead ECG (after subject has been supine for at least 5 minutes) 
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Obtain an MRI-PDFF assessment 
 Record prior and concomitant medications 
 Record AEs (starting from the when the subject signs informed consent) 
 Obtain blood for 10-hour fasted laboratory sample collection for: 
o Chemistry 
o CBC 
o HbA1c 
o Insulin level 
o HOMA-IR calculation 
o 
 
o INR 
o Lipid panel 
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids  
o PK (pre-dose) 
o ADAs 
o NAbs 

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o ELF panel 
o Pro-C3 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
 Obtain urine for 10-hour fasted laboratory sample collection for: 
o Pre-dose urine pregnancy in all females of childbearing potential 
o Urinalysis 
o Urine drug screen 
In-clinic dosing and dispensing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation 
 Dispense new aldafermin/matched placebo study-drug kit/diary 
 Dispense rosuvastatin medication/diary 
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
new kit)  
 Perform LISSA evaluation 
Before clinic discharge: 
 Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
 Schedule Week 18 visit 
Lipid-Lowering Therapy Assessment: 
The third-party Medical Monitor will evaluate LDL-C results to assess the need for 
lipid-lowering therapy (refer to Section 9.4.14). 

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9.2.8 
Week 18 Procedures 
Subjects will report to clinic fasted and not dosed with aldafermin/matched placebo. 
The following procedures will be performed: 
Pre-dose: 
 
  
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Record concomitant medications 
 Record AEs 
 Obtain blood for 10-hour fasted laboratory sample collection for: 
o Chemistry 
o CBC 
o INR 
o Lipid panel 
o Lipoproteins 
o Lipase 
o C4 and serum bile acids  
o PK (pre-dose) 
o ADAs 
o NAbs 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
In-clinic dosing and dispensing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation 
 Collect old rosuvastatin medication bottle/diary and conduct reconciliation 
 Dispense new aldafermin/matched placebo study-drug kit/diary 

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 Dispense new rosuvastatin medication/diary 
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
new kit) 
 Perform LISSA evaluation  
Before clinic discharge: 
 If subject is taking statins, evaluate tolerability and continue therapy to Week 24 for 
statin naïve or Week 30 for statin experienced 
 Record new and/or changes to AEs after aldafermin/matched placebo dosing 
 Remind subject to bring study-drug kit/diary and to not self-inject 
aldafermin/matched placebo on clinic visit days 
 Schedule Week 24 (End of Treatment) visit 
Lipid-Lowering Therapy Assessment: 
The third-party Medical Monitor will evaluate LDL-C results to assess the need for 
lipid-lowering therapy (refer to Section 9.4.14). 
9.2.9 
Week 24 / Early Withdrawal (End of Treatment) Procedures 
Subjects will report to this visit fasted and not dosed with aldafermin/matched placebo.  
The following procedures will be performed at the Week 24/Early Withdrawal visit: 
Pre-dose: 
 Measure body weight, BMI, and waist circumference 
 
 
 Obtain 12-lead ECG (after subject has been supine for at least 5 minutes) 
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Obtain an MRI-PDFF assessment.  
 Undergo a liver biopsy procedure to obtain new tissue  
 Record concomitant medications 
 Record AEs 
 Obtain 10-hour fasted clinical laboratory samples for the following:  
o Chemistry 
o CBC 
o HbA1c 
o Insulin level 
o HOMA-IR calculation 

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o 
 
o INR 
o Lipid panel  
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids 
o PK (pre-dose) collect for all subjects other than those participating in the 
Optional PK sub-study 
o ADAs 
o NAbs 
o ELF panel 
o Pro-C3 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to 
the site and sponsor. 
Obtain 10-hour fasted clinical laboratory samples for the following:  
 Urine pregnancy test (all female subjects of childbearing potential) 
 Urinalysis 
 Urine drug screen 
In-clinic dosing: 
 Collect old aldafermin/matched placebo study-drug kit/diary and conduct 
reconciliation 
 Collect old rosuvastatin bottle and conduct reconciliation 
 Dispense new rosuvastatin study-drug/diary (only for subjects who were statin 
experienced at Baseline) 
 Oversee subject’s aldafermin/matched placebo study-drug self-administration (from 
old kit) (not applicable for Early Withdrawal subjects)  
 Perform LISSA evaluation 

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Before clinic discharge: 
(NOTE: PK sampling before-clinic-discharge is not applicable for Early Withdrawal 
subjects; however, Early Withdrawal subjects should be scheduled for a 6-week Follow-up 
visit.)  
 Obtain 2-hour post-dose PK blood sample 
 Schedule subject for Week 25 Post-Treatment Response Visit 
Lipid-Lowering Therapy Assessment: 
 
The third-party Medical Monitor will evaluate LDL-C results to assess the need 
for lipid-lowering therapy (refer to Section 9.4.14). 
For Optional PK Sub-study Subjects: 
For those subjects participating in the optional PK sub-study, PK samples will be collected 
pre-dose before subjects dose themselves in the clinic and post-dose at 0.5, 1, 2, 4, 6, 8, 12, 
and 24 hours. The 24-hour post-dose sample will be collected prior to dosing themselves 
with aldafermin/matched placebo on Day 2. Additional samples will be collected for C4 
testing at the same timepoints as the PK blood sample collections. The window for sample 
collection for the pre-dose through 8-hour time points is ±5 minutes. The window for sample 
collection for the 12- through 24-hour time points is ±30 minutes.  
9.2.10 
Week 25 (Post-Treatment Response) Procedures 
Subjects will report to this visit fasted. The following procedures will be performed at the 
Week 25 visit: 
 
 
 Record concomitant medications 
 Record new and/or changes to AEs 
 Obtain 10-hour fasted clinical laboratory samples for the following:  
o Chemistry 
o INR 
o Lipid panel 
o Lipase 
o C4 and serum bile acids 
o PK sample 
o ADAs  
o NAbs 
o ELF panel 

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o Pro-C3 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
Before clinic discharge: 
 Schedule Week 30 (End of Study) visit 
Lipid-Monitoring Assessment: 
The third-party Medical Monitor will evaluate LDL-C (refer to Section 9.4.14). Subjects who 
have an LDL-C value of > 100 mg/dL, and > 15 mg/dL above their Day 1 value at Week 25 
will be re-assessed at Week 30.  
9.2.11 
Week 30 (End of Study) Procedures 
This visit will be performed 6 weeks after the EOT visit. Subjects will report to this visit 
fasted. 
 Measure body weight, BMI, and waist circumference 
 
 
 Obtain 12-lead ECG (after subject has been supine for at least 5 minutes) 
 Measure vital signs (including temperature, respiratory rate, and seated blood 
pressure and pulse) 
 Obtain an MRI-PDFF assessment 
 Record concomitant medications 
 Record new and/or changes to AEs 
 Obtain 10-hour fasted clinical laboratory samples for the following:  
o Chemistry 
o CBC 
o HbA1c 
o Insulin level 
o HOMA-IR calculation 
o 
 
o INR 

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o PK Sample  
o Lipid panel  
o Lipoprotein particles 
o Lipase 
o C4 and serum bile acids 
o ADAs 
o NAbs 
o ELF panel 
o Pro-C3 
 
 
 
 
 
 
Results for ALT, AST, Total Cholesterol, LDL, HDL, and triglycerides are blinded to the 
site and sponsor. 
 Urine pregnancy test (all female subjects of childbearing potential).  
 Obtain urine sample for urinalysis 
 Collect old rosuvastatin bottles/diary and conduct reconciliation (only for subjects 
who were on statin therapy at Baseline and continued on rosuvastatin after EOT 
visit) 
Lipid-Monitoring Assessment: 
For subjects who were identified at Week 25 as needing re-assessment of LDL-C at 
Week 30, the third-party Medical Monitor will evaluate LDL-C results to assess the need to 
schedule a 4 week LDL-C safety follow up visit to confirm their LDL-C value has returned 
≤ 100 mg/dL or ≤ 15 mg/dL above their Day 1 value (refer to Section 9.4.14).  
9.2.12 
Lipid Monitoring Assessment 4 Week Follow up Visit Procedures 
This visit will be performed 4 weeks after the EOS visit. The following procedures will be 
performed at this visit: 
 Record concomitant medications 
 Record AEs  

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 Obtain blood for 10-hour fasted laboratory sample collection for: 
o Chemistry 
o Lipid panel 
9.2.13 
Monitoring of Anti-Drug Antibody Response 
Subjects maybe contacted to participate in additional optional follow-up visits, if necessary, 
to monitor anti-drug antibody (ADA) responses.  
9.3 
Concomitant Medications 
Any medication taken at least once within 42 days prior to Screening Visit and during the 
study period as well as the reason for use will be recorded in the source documents and the 
CRFs. Subjects should refrain from the use of any new prescription medications or products 
or changes in the dose or frequency of existing therapies from Screening to Day 1 until EOS.  
The Sponsor Medical Monitor or designee should be informed of any changes or addition of 
prohibited medications during this time period.  
9.3.1 Prohibited Medications  
 
Investigational agents, other than aldafermin/matched placebo, or devices for any 
indication.  These agents must also have been discontinued prior to Screening per 
exclusion criterion #24. 
 
Any other lipid lowering agents or combination preparation of statins (other than 
ezetimibe when used as a second-line lipid management therapy per 
Section 9.4.14, or one of the approved statin therapies listed in inclusion criterion 
#6) including: 
o Cholestyramine, colesevelam, PCSK9 inhibitors (evolocumab or 
alirocumab), colestid, niacin, fibrates, fenofibrates, fish oil from Day -42 
onward through the end of the study.  
 
Agents used for the treatment of any condition listed in the exclusionary 
enrollment criteria (see Section 8.2) from Day -42 onward through the end of the 
study.  
 
Weight loss medications, including orlistat, phentermine, topiramate, qsymia, 
lorcaserin hydrochloride, naltrexone hydrochloride, liraglutide, benzphentamine, 
diethylpropion, phendimetrazine from Day -42 onward through the end of the 
study.  
 
Contraindicated medications according to the rosuvastatin package insert, 
Appendix 6 including; cyclosporine, gemfibrozil, protease inhibitors (atazanavir, 
ritonavir, lopinavir, simeprevir), coumarin anticoagulants, fenofibrates, niacin, 
colchicine, from Day -42 onward through the end of the study.   

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 
Contraindicated medications according to the ezetimibe package insert, 
Appendix 7 including; cyclosporine, fenofibrate, cholestyramine, coumarin 
anticoagulants, from Day -42 onward through the end of the study. 
 
Known hepatotoxic agents (refer to Appendix 9) For subjects who have been on 
stable therapy with no related hepatotoxicity, the MM may be contacted to assess the 
medical context and eligibility of the subject, from Day -42 onward through the end 
of the study. 
 
 This list of prohibited medications along with Appendix 6, Appendix 7, and 
Appendix 9 are not an inclusive list. Investigator judgement must be used to 
justify initiating any study medication during the study. Use of allopurinol to treat 
gout is allowed if there is no history of intolerance. 
 
9.3.2 Restricted Concomitant Medications/Treatments:  
 
Statin Therapies: For statin experienced subjects only, the following daily dose of 
approved statin therapies are allowed if dosing is stable at least 3 months prior to 
Screening through Week 2: 
o Atorvastatin: ≤ 40 mg/day 
o Fluvastatin: ≤ 40 mg/day 
o Lovastatin: ≤ 40 mg/day (immediate release), ≤ 30 mg/day (extended 
release) 
o Pitavastatin: ≤ 2 mg/day 
o Pravastatin: ≤ 40 mg/day 
o Simvastatin: ≤ 40 mg/day 
o Rosuvastatin: ≤ 20 mg/day   
 
Other therapies for NAFLD or NASH require a stable regimen for at least 
3 months prior to the Screening biopsy of record and throughout the study 
including: 
o Standard vitamin supplements 
o Vitamin E (>400 IU) 
o Pentoxifylline 
 
Diabetic medications: 
o Insulin: require stable dosing, defined as reasonable dose adjustments to 
maintain glucose control, for at least 3 months prior to Day 1  
o All other diabetic medications (except liraglutide which is prohibited): 
require a stable dose for at least 3 months prior to Day 1. The investigator 
may adjust diabetic medications as warranted based on clinical 
response/glucose control parameters throughout the study. 

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 
Antibiotics (not listed in Appendix 9) use will be at the discretion of the principal 
investigator 
 
Procedural Medications including anti-anxiety medication for MRI scan, 
anesthetic or sedation (e.g., a benzodiazepine) for liver biopsy or for other minor 
(outpatient) procedures will be used at the discretion of the principal investigator 
 
Anabolic steroids; low levels of estrogen or testosterone as replacement therapies 
are allowed.   
 
9.4 
Clinical Evaluations 
9.4.1 
Alcohol Consumption 
9.4.1.1 
AUDIT-C 
During Screening, clinical sites will implement the AUDIT-C, a 3-item alcohol screen that 
can help identify persons who are hazardous drinkers or have active alcohol use disorders 
(see Appendix 8). The AUDIT-C is scored on a scale of 0-12. Each AUDIT-C question has 
5 answer choices. Points allotted are a = 0 points, b = 1 point, c = 2 points, d = 3 points, e = 4 
points. In men a score of 4 or more is considered positive, optimal for identifying hazardous 
drinking or active alcohol use disorders. In women a score of 3 or more is considered 
positive.  
9.4.1.2 
History of Alcohol Consumption 
Subjects will also be asked to report their history of alcohol consumption and will be 
excluded from study participation if they consume ≥ 21 units per week (males) or ≥ 14 units 
per week (females) for two years prior to enrollment and where a unit of alcohol is equivalent 
to a 12-ounce beer, 4-ounce glass of wine, or a 1-ounce shot of hard liquor.  
9.4.1.3 
PEth Screen 
Subjects that present with a significant alcohol intake as measured by a phosphatidylethanol 
(PEth) level ≥ 200 ng/mL AND also have a positive AUDIT-C score (Section 9.4.1.1) will be 
excluded from the study at Screening.  
9.4.2 
Liver Biopsy 
Subjects who meet the Screening criteria of an available liver biopsy tissue specimen within 
6 months of Screening will not be required to undergo a new liver biopsy. For subjects who 
have participated in a prior study involving an investigational agent for NASH, the prior liver 
biopsy obtained within 6 months may be used only if the subject was treated with placebo. 
All other subjects will be required to undergo a liver biopsy per the study site’s local 
standard-of-care procedure during the Screening period and prior to randomization. 
Sites should not perform a local reporting of the NAS or fibrosis score at either Screening or 

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Week 24 to the site in order to maintain the blinding of the primary endpoint. Tissue from all 
subjects will be collected, prepped and sent to the Central Study Pathologist for review for 
the absence/presence of NASH as defined in the Biopsy Manual. Liver biopsies with 
histologically confirmed NASH will be further assessed using the NAS established and 
validated by the NASH CRN (see Appendix 1). Liver biopsies will be assessed for degree of 
steatosis (0 – 3), lobular inflammation (0 – 3), hepatocellular ballooning (0 – 2), and fibrosis 
(0 – 4). The first three components will be added together to determine the NAS that ranges 
from 0 to 8. Liver biopsies with an NAS of < 4 will be considered exclusionary. Subjects 
with liver biopsies with Stage 4 fibrosis, consistent with cirrhosis, will be excluded from this 
study. The Week 24 biopsy should be obtained ≤ 7 days before last dose of 
aldafermin/matched placebo. 
9.4.3 
Magnetic Resonance Imaging (MRI) 
All enrolled subjects will have a Baseline (from the Screening result) and EOT MRI of the 
liver to evaluate 
 liver fat. Subjects will have an MRI performed at 
Screening Day -28 and at Weeks 12, 24 (EOT), and 30 (EOS). MRI-PDFF will be reported 
on all MRI imaging scans. Scans should be performed at high field strength (3T preferred, 
1.5T acceptable), without the administration of oral or intravenous contrast material. MRI 
examinations will include a six-echo gradient recalled 
 
 
 
The initial study MRI examination will be performed during the Screening period prior to 
randomization. An MRI-PDFF value of ≥ 8% at Screening as assessed by the central 
radiology core is one of the inclusion criteria for the study. Therefore, for subjects who 
require a liver biopsy as part of the trial (for whom no recent liver biopsy is available), it is 
recommended that the liver biopsy be scheduled no sooner than 7 business days after 
(electronic) transmission of the screening MRI examination to the central radiology core to 
allow adequate time for processing and reporting of the result. The screening MRI-PDFF 
results will be reported to the individual site no more than 5 business days after the MRI 
examination is received. The Screening MRI result is valid for up to 8 weeks and may be 
used for a subject who is re-screened within that time frame. None of the on treatment or post 
treatment MRI results (other than incidental findings) will be provided to the sites. 
Week 24/EW/EOT MRI-PDFF should be performed before the last dose of 
aldafermin/matched placebo. 
For both Screening and EOT/Early Withdrawal MRI examinations, subjects should consume 
nothing by mouth (NPO) for 4 hours prior to their MRI appointment. Medications and small 
amounts of water are acceptable. 
Prior to MRI, all subjects should undergo safety assessment per institutional protocols and 
per the guidelines of the local Institutional Review Board. Subjects should be questioned 
regarding claustrophobia, pregnancy or potential pregnancy, size or weight exceeding the 
capabilities of the MRI system, metal implants, and other potential safety issues.  

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Detailed instructions for MRI procedures and provision of examination to a central reader 
will be presented in a separate MRI Manual.  
9.4.4 
Pharmacokinetic Blood Sample Collection and Processing 
In all subjects, blood samples for PK analysis of aldafermin levels will be collected before 
dosing at study visits at 
 
  
The 
 
 
The window for sample collection for the pre-dose and 2-hour time points is ±5 minutes. 
 at the 
Day 1 and Week 24 visits at the following time points: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 
24 hours post-dose. The window for sample collection for the 0.5-hr through 8-hour time 
points is ±5 minutes. The window for sample collection for the 12- through 24-hour time 
points is ±30 minutes. 
Processing, storage, and shipping instructions for these PK blood samples will be presented 
in the study Lab Manual. 
9.4.5 
C4 and Bile Acid Testing  
C4 and bile acid testing will be collected at Day 1 and Weeks 2, 4, 8, 12, 18, 24, 25, and 30. 
In addition, for subjects participating in the optional PK sub-study, additional C4 will be 
tested at the same timepoints as the PK blood sample collections: Day 1 and Week 24 at pre-
dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. 
9.4.6 
Biomarkers  
Blood samples will be collected for ELF score, Pro-C3, 
 
genetic biomarker including PNPLA3 will be collected as outlined in Table 4. 
9.4.7 
Insulin/HOMA-IR 
Insulin level and HOMA-IR will be evaluated at Day -42 (Screening), Day 1, Week 12, 
Week 24 and Week 30. Subjects will have fasted 10 hours.  
9.4.8 
Lipoprotein Particles  
Lipoprotein particles, 
 will be tested on scheduled visits on Day 1 through 
Week 24 and on Week 30. Subjects will have fasted 10 hours (Table 4).  

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Subjects will be weighed, BMI calculated, and waist circumference measured at Screening 
Day -42, Day 1, and Weeks 12, 24, and 30. Formal instructions for recording weight and 
measuring waist circumference will be provided to sites. 
9.4.13 
Local Injection-Site Symptom Assessments (LISSA) 
Injection-site evaluation will be made and documented by the PI or clinic staff using a 
LISSA (Appendix 2). 
LISSA evaluations are to be performed at each clinic visit from Day 1 through Week 24. 
The LISSA is intended to be a “snapshot” of the ISRs at the time of clinic assessment. 
The LISSA is not intended to capture ISR data (frequency, severity, duration, etc.) in 
between clinic visits. As with any other potential AE, Investigator judgment should be used 
as to whether any ISR is recorded as an AE. Mild to Severe Reactions (LISSA Grades 1–3) 
are reported as AEs at the discretion of the investigator unless standard SAE criteria are met 
and then must be reported as an SAE. Life-threatening (LISSA Grade 4) meet SAE criteria 
and must be reported as such. 
LISSAs may be performed if necessary and as clinically indicated by the PI to capture ISRs 
outside of the routine scheduled assessment time points. 
The 2007 FDA Toxicity Grading Scale (Appendix 2) will be used to assess any ISRs (U.S. 
Department of Health and Human Services 2007). The documented record will include all of 
the symptoms, severity, and any local reaction (including pain, tenderness, redness, and 
swelling) and size of injection-site skin reactions identified and observed by the subject or 
clinic personnel. LISSA scores will be documented on the subject’s CRF. 
9.4.14 
Lipid-Lowering Therapy Assessment 
LDL-C will be evaluated at all study visits for possible increases in lipid levels associated 
with aldafermin administration. Rosuvastatin will be started in subjects meeting specific 
LDL-C level criteria at Week 2. Rosuvastatin and matched placebo are over-encapsulated in 
bottles of 35 capsules (Section 10.4.2). Initiation and ongoing dose adjustments of 
rosuvastatin will be managed by an unblinded third-party Medical Monitor and through the 
. Lipid levels will be blinded to the sponsor and site. Initiation and dose adjustments 
will be determined by the lipid levels collected at Weeks 2, 4, 8, 12, and 18. LDL-C samples 
will be analyzed and reported to the third-party Medical Monitor. Bottles of rosuvastatin 
and/or matching placebo will be dispensed at each study visit through Week 18 (statin naïve) 
or Week 24 (statin experienced) as instructed through 
 
 
. The subject will be 
sent home from their clinic visit with the IVRS assigned bottle(s) and instructed to refrain 
from dosing until told from which bottle or bottles to dose by the study site. The third-party 
Medical Monitor will review the LDL-C level and assign the dose of rosuvastatin  
 
based on the dosing algorithm (Appendix 3). The site will subsequently communicate to the 
subject the assigned bottle(s) and dosing should be immediately initiated.  

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Subjects who have not responded adequately to rosuvastatin (defined as >100 mg/dL and 
> 15 mg/dL above their Day1 LDL-C level), and who are currently receiving their maximum 
tolerated rosuvastatin dose, will be considered for additional lipid-lowering therapy 
(ezetimibe). The third-party Medical Monitor will contact the site regarding any subject 
meeting this criterion. Ezetimibe will be prescribed and taken as second-line treatment per 
investigator judgement and approval from the Sponsor Medical Monitor or designee. 
Rosuvastatin therapy should be continued as assigned. Ezetimibe should be used in 
accordance with the FDA-approved package insert (Appendix 7).The subjects should also 
continue aldafermin/matched placebo through EOT as assigned.  
Subjects whose LDL-C values are still not adequately managed, (defined as > 100 mg/dL and 
> 15 mg/dL above their Day 1 LDL-C value) and are currently receiving their maximum 
tolerated rosuvastatin dose plus ezetimibe, will be discontinued from the study and an early 
withdrawal study visit completed. The follow up/EOS visit should be scheduled for 6 weeks 
after the early withdrawal study visit. Refer to Appendix 4, Rosuvastatin Dose Reduction 
Algorithm and Appendix 5, Adverse Event of Statin-Related Muscle Pain or Creatine Kinase 
(CK) Algorithm.  
9.4.15 
Diet and Activity Control 
Subjects should maintain their normal level of physical activity, diet, and lifestyle throughout 
the entire study (i.e., will not begin a new exercise program or participate in any unusually 
strenuous physical exertion). For subjects enrolled in the optional PK sub-study, participants 
may be domiciled during dosing and 24-hour sampling and receive a standardized diet at 
scheduled times that do not conflict with other study-related activities. 

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10 
Study Drug 
10.1 
Clinical Supplies 
10.1.1 
Aldafermin 
Aldafermin is formulated in 
 
 
 
 
Aldafermin is provided as a sterile solution for injection in a single-use pre-filled syringe for 
SC administration at doses of 0.3 mg, 1 mg, and 3 mg. The drug product is manufactured for 
NGM under current Good Manufacturing Practice regulations at 
 
 
 
10.1.2 
Aldafermin-matched Placebo 
Aldafermin placebo is formulated in aqueous isosmotic buffer solution 
 
 
 
 
Aldafermin placebo is provided as a sterile solution for injection in a single-use pre-filled 
syringe for SC administration. The drug product is manufactured for NGM under current 
Good Manufacturing Practice regulations 
 
 
10.1.3 
Rosuvastatin 
Commercial rosuvastatin tablets will be over-encapsulated and will be supplied as 5 mg, 
10 mg, 20 mg (2 x 10 mg tablets over-encapsulated into 1 capsule), or 40 mg strengths in 
35-count bottles. Inactive ingredient microcrystalline cellulose will be used to backfill 
overencapsulated rosuvastatin calcium tablets. Placebo capsules for rosuvastatin calcium 
contains only microcrystalline cellulose and will be supplied in 35- count bottles. 
The capsules used for the active and placebo are opaque, Swedish Orange, size A, hard 
gelatin capsules containing gelatin, titanium oxide, and FDA/E172 red iron oxide. Refer to 
the study pharmacy manual for details. 
10.2 
Study-Drug Accountability 
The PI is responsible for ensuring that a current record of inventory/drug accountability 
(aldafermin/matched placebo and rosuvastatin/placebo) is maintained. Inventory records 
must be readily available for inspection by the study monitor and are open to inspection by 
regulatory authorities at any time.  

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Upon receipt of the investigational drug/placebo, the designated site personnel will visually 
inspect the shipment, verify the number and condition of study drug received, and confirm 
receipt of study drug. 
At the completion of the study, all unused study-drug supplies will be returned to the Sponsor 
(or designee) or disposed of by the clinic, per the Sponsor’s (or designee’s) written 
instructions. 
10.3 
Study-Drug Storage 
Aldafermin/matched placebo syringes are to be stored at the clinical site in the provided 
packaging and refrigerated at 2°C–8°C (36°F–46°F) in a secure, controlled-access location 
protected from light. At the subject’s home, aldafermin/matched placebo syringes are to be 
stored in the provided packaging and refrigerated at 2°C–8°C (36°F–46°F) in a location 
protected from light (e.g., their refrigerator). 
Rosuvastatin /placebo bottles should be stored at room temperature, at 68°F–77°F  
(20°C– 25°C) and in a dry place. 
Subjects will be instructed to take care in keeping both study drugs out of the reach of 
children and other family members who may have access to the storage location. 
10.4 
Dose Preparation and Administration 
10.4.1 
Aldafermin 
Subjects will be instructed to dose with aldafermin/matched placebo at home at a similar time 
each day. Study-drug/placebo syringes will be equilibrated to room temperature prior to use. 
Study-drug/placebo will be administered as a SC injection in the abdomen. On Day 1, 
subjects will be trained on self-administering a SC injection. During the on-treatment visits, 
self-administration will occur in the clinic under observation by clinic staff. Re-training will 
be provided as required. Written dose preparation and administration instructions will be 
provided to subjects. Subjects will be required to complete a daily study-drug/placebo 
administration diary. 
10.4.2 
Rosuvastatin 
Subjects will be instructed to take one capsule of rosuvastatin/placebo once a day by mouth 
at approximately the same time each day. All bottles will be blinded. The subject will be 
contacted by the site a few days after study visits and instructed as to which bottle to dose 
from. During the on-treatment visits, subjects will take their study drug to clinic visits and 
dose from the dosing bottle dispensed at the last visit in the clinic under observation by clinic 
staff. The subject will be required to complete a daily study-drug/placebo dosing diary. 

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10.5 
Removal of Study Blind 
Breaking of any blind will be available to the PI through 
 
. The subject’s treatment 
assignment will be available to the PI in the event of a medical emergency or an AE that 
necessitated identification of the study drug for the welfare of that subject. Except in the case 
of a medical emergency, the PI and clinic staff will remain blinded during the conduct of the 
study and until such time that all discrepancies in the clinical database are resolved (i.e., at 
the time of the database lock). The date and time when the PI removed the study blind for an 
individual subject will be documented by 
 
 and an automated notification will be 
sent to the Sponsor. 
 
 

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11 
Adverse Events 
11.1 
Definition and Grading Intensity of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject of clinical investigational 
participation administered a pharmaceutical product, whether or not considered drug related. 
A TEAE is an AE that is reported after a dose of study drug. 
AEs include the following: 
 Unfavorable changes in general condition 
 Subjective or objective signs/symptoms 
 Concomitant diseases or accidents 
 Clinically relevant adverse changes in laboratory parameters observed in a subject 
in the course of a clinical study 
AEs comprise all disturbances of general health status, subjective and objective disease 
symptoms (including laboratory abnormalities), and accidents observed in the context of a 
clinical trial, irrespective of a possible causal relationship with the administration of the trial 
substance. Events occurring in the framework of a clinical trial during drug-free and 
post-treatment periods or under placebo are also to be designated as AEs. 
All AEs, regardless of how identified (e.g., volunteered, elicited, noted on physical 
examination), will be recorded throughout the study (i.e., from Screening until Follow-up). 
Subjects will be followed for resolution of AEs, by querying the subjects for an ongoing AE 
until resolved or until any unresolved AEs are judged by the PI to have stabilized or if lost to 
follow-up. Resolution of all AEs will be promptly documented by the clinic on the subject’s 
CRF. 
Any pregnancy diagnosed during the study must be reported immediately to the PI and 
Sponsor, including pregnancy in female partners of male subjects. The pregnancy will be 
followed to term and/or outcome and this outcome must be reported to the Sponsor. 
Pregnancy, in and of itself, is not regarded as an AE or SAE unless the birth results in a 
congenital anomaly/birth defect or there is suspicion that the study medication may have 
interfered with the effectiveness of a contraceptive medication or method. 
The PI will rate the severity of AEs using the CTCAE v5 to grade the severity. Each CTCAE 
v5 term is a Medical Dictionary for Regulatory Activities (MedDRA) Lowest Level Term 
(LLT). The CTCAE displays Grades 1–5 with unique clinical descriptions of severity for 
each AE. Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with 
fewer than five options for Grade selection. Grade 5 (Death) is not appropriate for some AEs 
and, therefore, is not an option. 

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11.2 
Criteria for Determining Relationship to Study Drug 
The PI will make a blinded determination of the relationship of the AE to 
aldafermin/matched placebo, rosuvastatin/matched placebo or ezetimibe (as applicable). All 
determinations of relationship will be made using a four-category system (not related, 
possible, probable, or definite) according to the following guidelines: 
 NOT RELATED = an AE that does not follow a reasonable temporal sequence from 
administration of the drug and that can be reasonably explained by other factors, 
including underlying disease, complications, concomitant drugs, or concurrent 
treatment; 
 POSSIBLE = an AE that follows a reasonable temporal sequence from the 
administration of the drug (including the course after withdrawal of the drug) and that 
cannot be excluded as being possibly caused by the drug (e.g., existence of similar 
reports attributed to the drug and/or its analogues; reactions attributable to the 
pharmacological effect of the drug), although other factors such as underlying disease, 
complications, concomitant drugs, or concurrent treatment are presumable; 
 PROBABLE = an AE that follows a reasonable temporal sequence from administration 
of the drug (including the course after withdrawal of the drug) and that can be excluded 
as being possibly caused by other factors, such as underlying disease, complications, 
concomitant drugs, or concurrent treatment. 
 DEFINITE = an AE that follows a reasonable temporal sequence from administration 
of the drug (including the course after withdrawal of the drug), follows a known or 
hypothesized cause–effect relationship, and (if appropriate) satisfies the following: 
o Positive results obtained in drug sensitivity tests 
o Toxic level of the drug present in blood or other body fluids 
11.3 
Reporting 
An SAE is any untoward medical occurrence at any dose that results in any of the following 
outcomes: 
 Death 
 A life-threatening event (i.e., places the subject, in the view of the PI, at immediate risk 
of death) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 A congenital anomaly/birth defect 
 Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 

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An unexpected adverse drug event is any adverse drug event the specificity or severity of 
which is not consistent with the current IB or, if an IB is not required or available, the general 
investigational plan or elsewhere in the current application. 
An AE is associated with the use of the drug if a reasonable possibility exists that the event 
may have been caused by the drug. 
SAEs that are unexpected and related to either aldafermin or rosuvastatin are reportable to 
Regulatory Authorities. All SAEs will be reported by the PI to the Sponsor and will be 
reported to the responsible Ethics Committee (EC) in accordance with local requirements. 
The Sponsor’s assigned Safety Representative will be notified in writing (e.g., email or 
facsimile) within 24 hours of when an SAE is first recognized or reported. The Safety 
Representative will subsequently notify the Sponsor and the Sponsor’s assigned Medical 
Monitor or designee of all reported SAEs. 
Suspected statin-related AEs requiring either dose reduction or discontinuation should be 
reported to the third-party Medical Monitor by the Principal Investigator. These subjects will 
be managed as outlined in Section 9.4.14 of the protocol. 
11.4 
Cardiovascular Adjudication 
An external independent Cardiovascular Adjudication Committee (CAC) will adjudicate 
serious adverse events (SAEs). The CAC members will be independent of the Sponsor, and 
the clinical study sites and Investigators. The blinded medical review of known or suspected 
cardiac events will primarily focus on CV death, myocardial infarction, cerebrovascular 
accident (stroke), and hospitalization for heart failure. The event definitions and adjudication 
process are described in a CAC Charter.  
Sites may be asked to provide additional source documentation relevant to any event reported 
to the CAC. 

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As such, the protocol will require a minimum of approximately 35% of subjects with F3 on 
biopsy.  Depending on the overall enrollment rate and the proportion of subjects enrolled 
with F2 or F3, the sponsor may limit the enrollment of F2 subjects to be no greater than 
approximately 65% (99/152 subjects).   
12.3 
Analysis Populations 
Subjects will be analyzed using the following analysis populations: 
 Intent-to-Treat Population 
All randomized subjects will be included in the Intent-to-Treat (ITT) population. The ITT 
population will be based on randomized treatment if this differs from actual treatment 
received. 
 Safety Population 
All subjects who receive at least one dose (full or partial) of study drug will be included in 
the Safety population. All safety endpoints will be summarized using the Safety population 
and will be based on actual treatment received if this differs from the randomized/enrolled 
treatment. 
 Full Analysis Population 
All randomized/enrolled subjects who receive at least one dose (full or partial) of study drug 
and have at least one valid, non-missing post-dose efficacy/PD parameter value will be 
included in the Full Analysis population. The Full Analysis population will be based on 
randomized/enrolled treatment if this differs from actual treatment received.  
 Per Protocol (PP) Population  
The Per Protocol (PP) population will constitute a subset of the Full Analysis population and 
will include subjects that have at least one valid, non-missing baseline and post-dose liver 
biopsy results and do not have protocol deviations that impact the liver biopsy assessments.  
 Pharmacokinetic Population 
All randomized/enrolled subjects who receive at least one dose (full or partial) of drug and 
have quantifiable PK measurements will be included in the PK population. Subjects with 
protocol violations will be assessed by the medical monitor or designee for inclusion in the 
PK population. PK summaries and analyses will be conducted using the PK population. 
The PK population will be based on actual treatment received if it differs from that to which 
the subject was randomized/enrolled. 
12.4 
Demographics and Other Baseline Characteristics 
Demographics (e.g., age, sex, race, body weight, height, etc.) and other baseline 
characteristics will be summarized with descriptive statistics by treatment group for each 
analysis population. 

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12.5 
Efficacy Analyses 
12.5.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is the histologic response at Week 24, defined as 
a subject achieving an improvement in liver fibrosis greater than or equal to one stage 
(NASH CRN fibrosis score) with no worsening of steatohepatitis (defined as no increase in 
NAS for ballooning, inflammation, or steatosis) after 24 weeks of treatment. 
Subjects with two biopsies (baseline and post-baseline) will be considered for this analysis 
only if the second biopsy is taken after at least 12 weeks (i.e., 50% of the intended 24-week 
treatment period) of treatment on study drug. For the primary efficacy analysis, missing 
histologic responses at Week 24 will be imputed using a multiple imputation (MI) method 
under the assumption of missing at random. The details of the MI method will be provided in 
the SAP. 
The primary efficacy endpoint will be analyzed using the MCP-Mod (Multiple Comparison 
Procedure – Modelling) approach to assess the dose-response relationship. Within the 
framework of the MCP-Mod procedure, the null hypothesis of no dose-response will be 
tested at the 5% significance level against the alternative hypothesis that there is a dose-
response. The details of the MCP-Mod approach will be provided in the SAP. 
Sensitivity analyses will include imputations with missing histologic responses as both 
responders and non-responders, and analysis with the assumption of missing not at random 
(e.g., pattern mixture models).  
The primary efficacy analyses will be performed using the ITT population. The Full-Analysis 
and PP populations will be used as sensitivity analyses.  
12.5.2 
Secondary Efficacy Analyses  
Secondary efficacy analyses include the analyses of the primary efficacy endpoint 
(i.e., histologic response at Week 24) based on pair-wise comparisons between treatment 
groups and the analyses of the secondary efficacy endpoints.  
All binary efficacy endpoints (i.e., responders) will be analyzed using a Cochran-Mantel-
Haenszel (CMH) test stratified by baseline fibrosis stage. 
All continuous efficacy endpoints will be analyzed using an analysis of covariance 
(ANCOVA) model with effects for treatment, baseline fibrosis stage and baseline outcome 
value as a covariate.  
All secondary efficacy analyses will be performed using the ITT population. Full-Analysis, 
and PP populations will be used as sensitivity analyses. 

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No multiplicity adjustment will be made between the primary and secondary efficacy 
analyses to control the experiment-wise type I error rate, and thus all secondary efficacy 
analyses are exploratory in nature. 
12.5.3 
Other Efficacy/Pharmacodynamic Analyses 
The details of these analyses will be provided in the SAP. 
12.6 
Safety 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment emergent adverse events (TEAEs) will be summarized by primary 
system organ class and preferred term. Actual values and change from baseline values for 
vital signs, ECGs, clinical laboratory (hematology and chemistry) tests, and other continuous 
safety variables will be summarized with descriptive statistics. Concomitant medications, 
injection site reactions, and other categorical safety variables will be summarized with 
frequency and percentage distribution.  
All safety analyses will be performed using the Safety population.  
  
 
 

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13 
Administrative Aspects 
13.1 
Protocol Adherence 
The PI must adhere to the protocol as detailed in this document and agree that the Sponsor 
must approve any changes to the protocol prior to seeking approval from the EC. 
No alterations in the protocol will occur without agreement between the Sponsor and the PI. 
No alterations in the protocol affecting subject safety will occur without the express written 
approvals of the Sponsor, PI, and EC. 
13.2 
Disclosure 
All information provided regarding the study as well as all information collected/documented 
during the course of the study will be regarded as confidential. The PI agrees not to disclose 
such information in any way without prior written permission from the Sponsor. 
Any publication of the results either in part or in total (articles in journals or newspapers, oral 
presentations, abstracts, etc.) by the PI or their representative(s) shall require prior 
notification and review within a reasonable time frame by the Sponsor and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights. 
13.3 
Monitoring 
The Sponsor’s or designee’s Clinical Research Associate (CRA) will be responsible for 
monitoring this clinical trial. The CRA will monitor the study conduct, proper CRF and 
source documentation completion and retention, and accurate study drug accountability. 
To this end, the CRA will visit the study site at suitable intervals and be in frequent contact 
through verbal and written communication. The PI will grant access to all documents (related 
to the study and the individual subjects) at any time these are requested. In turn, the CRA 
will adhere to all requirements for patient confidentiality as outlined in the ICF. The PI and 
PI’s staff will be expected to cooperate with the CRA, to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information. 
13.4 
Institutional Review Board/Ethics Committee 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB/EC for approval. The IRB/EC approval of the protocol, informed 
consent document, and any advertisement used to recruit study subjects must be obtained 
before the study may be initiated. 
The PI is responsible for keeping the IRB/EC advised of the progress of the study and of any 
changes made to the protocol as deemed appropriate, but in any case, at least once a year. 
The PI is also responsible for notifying the IRB/EC of any reportable AEs that occur during 
the study. 

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13.5 
Informed Consent 
This study will be conducted in compliance with International Conference on Harmonisation 
(ICH) E6 Good Clinical Practice: Consolidated Guidelines pertaining to informed consent. 
At the first visit, prior to initiation of any study related procedures, subjects must give their 
written consent to participate in the study after having been informed about the nature and 
purpose of the study, participation/termination conditions, and risks and benefits. 
The informed consent document must be signed and dated by the subject and PI, or designee, 
prior to study participation. A copy of the informed consent document must be provided to 
the subject. Signed consent forms must remain in the subject’s study file and be available for 
verification by Sponsor or its representative at any time. 
13.6 
Records 
The results from Screening and data collected during the study will be recorded in the 
subject’s CRF. To maintain confidentiality, the subjects will be identified only by numbers 
and initials. 
The completed CRFs will be transferred to the Sponsor or designee. Copies of each CRF will 
be retained by the PI. All source documents, records, and reports will be retained by the 
clinic. 
All primary source data or copies thereof (e.g., laboratory records, CRFs, data sheets, 
correspondence, photographs, and computer records) that are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report will be retained in the clinic archives. 
Sponsor will inform the PI of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest 
(longest) standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or Sponsor standards/procedures; otherwise, the 
retention period will default to the retention period of 15 years following completion of the 
clinical trial. 
Blood and tissue samples will be collected and any remaining or back-up study samples may 
be used for future exploratory and biomarker analysis related to aldafermin treatment or 
metabolic diseases. The samples will be stored for up to 15 years. 
13.7 
Financing and Insurance 
The financing and insurance for this study are outlined in the Clinical Trial Agreement. 
13.8 
Publication Policy 
NGM will retain ownership of all data. All proposed publications based on this study will be 
subject to sponsor’s approval requirements. 

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Investigator Protocol Review and Signature Form 
 
Protocol Number: 
18-0108, Protocol Amendment 4.0 
 
 
Protocol Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, 
Multi-center Study to Evaluate the Efficacy, Safety, and 
Tolerability of Three Doses of Aldafermin Administered for 
24 Weeks for the Treatment of Histologically Confirmed 
Nonalcoholic Steatohepatitis (NASH) 
 
 
I have read the above-mentioned Protocol dated: 
15 January 2020 
 
 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for 
Good Clinical Practices and applicable regulatory requirements, and to inform all who 
assist me in the conduct of this study of their responsibilities and obligations. 
 
 
 
 
 
 
 
 
 
Name of Principal Investigator 
(Please PRINT) 
 
 
 
 
 
 
 
 
 
Principal Investigator 
(Signature) 
 
Date 
 
 
 
 
 
 
Name of Investigational Site 
(Please PRINT) 
 
 
 
 
 

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14 
References 
14.1 
Clinical Study References 
Study No. 
Phase 
Study Title 
Study Population 
12-0101 
1 
A Phase 1 Randomized, Double Blind, Placebo Controlled, 
Single Ascending Dose and Multiple Ascending Dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
NGM282 in Healthy Adult Participants 
Normal 
volunteers 
13-0102 
2a 
A Randomized, Double Blind, Placebo Controlled, Parallel 
Group, Multiple Center Study to Evaluate the Safety, 
Tolerability, and Activity of NGM282 Administered for 28 Days 
to Participants with Type 2 Diabetes Mellitus 
T2D 
15-0105 
2a 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Multiple-Center Study with Additional Open-
Label Single-Blind and Placebo-Controlled 24-Week Histology 
Cohorts to Evaluate the Safety, Tolerability, and Efficacy of 
NGM282 Administered for Up to 24 Weeks in Patients with 
Histologically Confirmed Nonalcoholic Steatohepatitis (NASH) 
NASH 
 
14.2 
Nonclinical Study References 
Study No 
Study Title 
Study 13-PD-NGM282-1007 
A 24-Week Study of Ectopic NGM282 Expression following Intravenous 
Adeno-Associated Viral Delivery in FXR-deficient Mice 
 
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2017;66(1):S430 
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Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for 
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15 
Appendices 
Appendix 1. NASH Clinical Research Network NAFLD Activity Score and 
Fibrosis Score 
 
Steatosis 
S Score 
Lobular 
Inflammation 
L Score 
Hepatocyte 
Ballooning 
B Score 
< 5% 
0 
None 
0 
None 
0 
5%–33% 
1 
< 2 
1 
Few ballooned cells 
1 
34%–66% 
2 
2–4 
2 
Many ballooned cells 
2 
> 66% 
3 
> 4 
3 
— 
— 
NAFLD = nonalcoholic fatty liver disease. 
Note: NAFLD activity grade score = total score: S + L + B (range 0–8). 
 
 
Fibrosis Stage 
Score 
0 
No Fibrosis 
1a 
Zone 3, Mild 
1b 
Zone 3, Moderate 
1c 
Periportal Only 
2 
Zone 3 and Periportal 
3 
Bridging 
4 
Cirrhosis 
 
 

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Appendix 2. Food and Drug Administration Toxicity Grading Scale: Clinical 
Abnormalities in Local Injection Site Symptom Assessments 
Local Reaction to 
Injection Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-Threatening 
(Grade 4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-narcotic 
pain reliever 
more than 
24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
 
 
 
 
 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
 
 
 
 
 
Erythema/ 
Redness a 
2.5–5 cm 
5.1–10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
 
 
 
 
 
Induration/ 
Swelling b 
2.5–5 cm and 
does not 
interfere with 
activity 
5.1–10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
 
 
 
 
 
ER = emergency room. 
Note: The FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers enrolled in 
Preventive Vaccine Clinical Trials can be found at: 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/
Vaccines/ucm074775 htm. 
a  In addition to grading the measured local reaction at the greatest single diameter, the measurements 
should be recorded as a continuous variable. 
b  Induration or Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 

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Appendix 5. Statin-Related Muscle Symptoms or Creatine Kinase (CK) Elevation 
 

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Appendix 6. Rosuvastatin Package Insert 
The package insert for rosuvastatin being used in the study can be found at the following web 
links:  
https://www.accord-healthcare.com/ie/products/accord/rosuvastatin 
https://glenmarkpharma-us.com/rosuvastatin-calcium-tablets 

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Appendix 7. Ezetimibe Package Insert 
The package insert for ezetimibe being used in the study can be found at the following web link:  
 
https://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf 

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Appendix 8. AUDIT-C Alcohol Consumption Questionnaire 
 

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