A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of LY3885125 to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Ascending Dose in Participants With Dyslipidemia and Repeat-Doses in Participants With NAFLD
Phase: PHASE1
Conditions: Dyslipidemias, Non-Alcoholic Fatty Liver Disease
Sponsor: Eli Lilly and Company

Protocol: J4N-MC-YFAA (b) 
A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of LY3885125 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single 
Ascending Dose in Participants With Dyslipidemia and Repeat-Doses in Participants With 
NAFLD. 
NCT06007651 
Approval Date: 21-SEP-2023 

CONFIDENTIAL 
Protocol J4N-MC-YFAA(b) 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical Investigators. It is the property of Eli 
Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical investigation 
of LY3885125, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of LY3885125 to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a 
Single-Ascending Dose in Participants with Dyslipidemia and Repeat-Doses in Participants with 
NAFLD 
Protocol Number: J4N-MC-YFAA 
Amendment Number: (b) 
Compound: LY3885125 
Brief Title: 
A study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
LY3885125 compared with placebo in participants aged 18 to 70 years with dyslipidemia or 
NAFLD 
Study Phase: 1 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Lilly Research Labs, Indianapolis, IN 46285, United States 
Regulatory Agency Identifier Number(s) 
 
IND 165648 
Approval Date: Electronically Signed and Approved by Lilly on date provided below. 
 
Document ID: VV-CLIN-128962 
 
 
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Protocol J4N-MC-YFAA(b) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
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Protocol J4N-MC-YFAA(b) 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment b 
21 September 2023 
Amendment a 
28 July 2023 
Original Protocol 
20 June 2023 
Amendment (b) 
This amendment is substantial because it has a significant impact on study conduct. 
Overall Rationale for the Amendment: 
This amendment to the protocol implements a 
 and other non-
substantial updates, including 
 excluding participants with an eGFR less than or equal to 
 mL/min/
 m2, and 
 clarification of timing and assessments included in Extended Monitoring visits and 
completing participants’ final visits. 
 
 
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Protocol J4N-MC-YFAA(b) 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3.1 Part A Study Schedule (Single Dose 
Cohorts) 
Footnote b clarifies timing of, and 
assessments included in, 
Extended Monitoring visits and 
completing participants’ final 
visits 
Changes were made to clarify 
Extension Monitoring visits 
and completing participants’ 
final visits 
1.3.2 Part B Study Schedule (Repeat Dose 
Cohort) 
5.2 Exclusion Criteria 
Exclusion criteria #23 changed to 
exclude participants with eGFR 
≤ 
mL/min/
m2  
Changes were made in 
response to
 
 
10.8.1 Blood Volumes to be Collected in 
Part A 
Blood volume required for ADA 
assessment updated to 
 
Change was made to better 
inform total and ADA 
assessment blood volumes 
required 
 
 
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Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................16 
1.3. 
Schedule of Activities (SoA) ..........................................................................................17 
1.3.1. 
Part A Study Schedule (Single Dose Cohorts) ...............................................................17 
1.3.2. 
Part B Study Schedule (Repeat Dose Cohort) ................................................................19 
2. 
Introduction ...................................................................................................................22 
2.1. 
Study Rationale ...............................................................................................................22 
2.2. 
Background .....................................................................................................................22 
2.2.1. 
Summary of Nonclinical Data ........................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................26 
3. 
Objectives and Endpoints ............................................................................................28 
4. 
Study Design ..................................................................................................................30 
4.1. 
Overall Design ................................................................................................................30 
4.1.1. 
Part A - Single Ascending Dose (SAD) Cohorts 1-6 (Cohort 6 
optional) ..........................................................................................................................31 
4.1.2. 
Part B – Repeat Dose – Cohort 7 ....................................................................................32 
4.2. 
Scientific Rationale for Study Design ............................................................................34 
4.3. 
Justification for Dose ......................................................................................................35 
4.3.1. 
Starting Dose ...................................................................................................................35 
4.3.2. 
Predicted Efficacious Dose .............................................................................................35 
4.3.3. 
Maximum Dose ...............................................................................................................36 
4.3.4. 
Part B Dose .....................................................................................................................36 
4.4. 
End of Study Definition ..................................................................................................37 
4.5. 
Medical Oversight and Safety Reviews ..........................................................................37 
4.5.1. 
Dose Escalation Stopping Criteria ..................................................................................37 
4.5.2. 
Temporary Stopping Criteria ..........................................................................................38 
4.5.3. 
Early Study Termination Criteria Based on Safety .........................................................39 
5. 
Study Population ...........................................................................................................40 
5.1. 
Inclusion Criteria ............................................................................................................40 
5.2. 
Exclusion Criteria ...........................................................................................................41 
5.3. 
Lifestyle Considerations .................................................................................................44 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................44 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................44 
5.3.3. 
Activity ...........................................................................................................................45 
5.4. 
Screen Failures ................................................................................................................45 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................46 
6.1. 
Study Intervention(s) Administered................................................................................46 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................47 
6.3. 
Assignment of Study Intervention ..................................................................................47 
6.3.1. 
Dose Escalation in Part A ...............................................................................................47 
6.3.2. 
Dosing in Part B ..............................................................................................................49 
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6.4. 
Blinding ..........................................................................................................................49 
6.5. 
Study Intervention Compliance ......................................................................................49 
6.6. 
Dose Modification ..........................................................................................................49 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................49 
6.8. 
Treatment of Overdose ...................................................................................................50 
6.9. 
Prior and Concomitant Therapy ......................................................................................50 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................53 
7.1. 
Discontinuation of Study Intervention ............................................................................53 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................54 
7.1.2. 
QTcF Stopping Criteria...................................................................................................55 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................55 
7.3. 
Lost to Follow-up............................................................................................................56 
8. 
Study Assessments and Procedures.............................................................................57 
8.1. 
Efficacy Assessments .....................................................................................................57 
8.2. 
Safety Assessments .........................................................................................................57 
8.2.1. 
Physical Examinations ....................................................................................................57 
8.2.2. 
Vital Signs .......................................................................................................................57 
8.2.3. 
Electrocardiograms .........................................................................................................58 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................59 
8.2.5. 
Safety Monitoring ...........................................................................................................59 
8.2.6. 
Pregnancy Testing ...........................................................................................................62 
8.2.7. 
Injection Site Reactions (ISR) ........................................................................................62 
8.2.8. 
Hypersensitivity Reactions .............................................................................................63 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................64 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................65 
8.3.2. 
Pregnancy ........................................................................................................................67 
8.3.3. 
Adverse Events of Special Interest .................................................................................68 
8.4. 
Pharmacokinetics ............................................................................................................68 
8.5. 
Pharmacodynamics .........................................................................................................69 
8.6. 
Genetics ..........................................................................................................................69 
8.7. 
Lipid Profile ....................................................................................................................69 
8.8. 
Biomarkers ......................................................................................................................69 
8.9. 
Immunogenicity Assessments.........................................................................................70 
8.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................70 
9. 
Statistical Considerations .............................................................................................71 
9.1. 
Statistical Hypotheses .....................................................................................................71 
9.1.1. 
Multiplicity Adjustment ..................................................................................................71 
9.2. 
Analyses Sets ..................................................................................................................71 
9.3. 
Statistical Analyses .........................................................................................................71 
9.3.1. 
General Considerations ...................................................................................................71 
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Protocol J4N-MC-YFAA(b) 
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9.3.2. 
Primary Endpoint(s) Analysis .........................................................................................72 
9.3.3. 
Secondary Endpoint(s) Analysis .....................................................................................72 
9.3.4. 
Exploratory Endpoint(s) Analysis...................................................................................72 
9.3.5. 
Safety Analyses ...............................................................................................................72 
9.3.6. 
Other Analyses ................................................................................................................73 
9.4. 
Interim Analysis ..............................................................................................................73 
9.5. 
Sample Size Determination ............................................................................................73 
10. 
Supporting Documentation and Operational Considerations ..................................74 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................74 
10.1.1. Regulatory and Ethical Considerations ...........................................................................74 
10.1.2. Financial Disclosure........................................................................................................75 
10.1.3. Informed Consent Process ..............................................................................................75 
10.1.4. Data Protection................................................................................................................75 
10.1.5. Data Quality Assurance ..................................................................................................76 
10.1.6. Source Documents ..........................................................................................................78 
10.1.7. Study and Site Start and Closure ....................................................................................78 
10.1.8. Publication Policy ...........................................................................................................79 
10.1.9. Investigator Information .................................................................................................79 
10.1.10. Long-Term Sample Retention.........................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................80 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................83 
10.3.1. Definition of Adverse Event (AE) ..................................................................................83 
10.3.2. Definition of SAE ...........................................................................................................84 
10.3.3. Definition of Product Complaints ...................................................................................85 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................85 
10.3.5. Reporting of SAEs ..........................................................................................................87 
10.3.6. Regulatory Reporting Requirements ...............................................................................87 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................88 
10.4.1. Definitions.......................................................................................................................88 
10.4.2. Contraception Guidance..................................................................................................88 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................91 
10.5.1. Hepatic Evaluation Testing .............................................................................................95 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................96 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................99 
10.8. 
Blood Sampling Schedule .............................................................................................104 
10.8.1. Blood Volumes to be Collected in Part A .....................................................................104 
10.8.2. Proposed Approximate Blood Volumes to be Collected in Part B ...............................105 
11. 
References ....................................................................................................................106 
 
 
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Protocol J4N-MC-YFAA(b) 
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List of Tables  
Table 2.1 
Margin of Safety for Subcutaneous Injection of LY3885125 Based on 
Administered Dose and Predicted Exposure .................................................... 25 
Table 2.2 
Important Potential Safety Risks with LY3885125 .......................................... 27 
Table 4.1 
Part A Design ................................................................................................... 31 
Table 4.2 
Part B Design .................................................................................................... 33 
Table 4.3 
Projected Human Dose Range Based on SCAP mRNA Knockdown and 
PCSK9 Inhibition-Based on Mouse and Monkey Models ............................... 36 
Table 6.1 
Data Reviewed by Dose Escalation Committee (DEC) ................................... 48 
Table 6.2 
Statin Therapies According to American College of Cardiology (ACC) 
and American Heart Association (AHA) Classificationa ................................. 51 
Table 6.3 
Examples of Prohibited Medications ................................................................ 52 
Table 7.1 
Liver Chemistry Stopping Criteria ................................................................... 54 
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Protocol J4N-MC-YFAA(b) 
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1. Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of LY3885125 to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single-
Ascending Dose in Participants with Dyslipidemia and Repeat-Doses in Participants with 
NAFLD 
Brief Title: 
A study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
LY3885125 compared with placebo in participants aged 18 to 70 years with dyslipidemia or 
NAFLD. 
Regulatory Agency Identifier Number(s):  
IND 165648 
Rationale: 
LY3885125 is a N-acetylgalactosamine (GalNAc)-conjugated small interfering ribonucleic acid 
(siRNA) 
 
. SCAP 
regulates the activation of SREBPs, which are transcription factors that govern de novo 
lipogenesis, cholesterol biosynthesis, and metabolism pathways. 
 
  
This first-in-human (FIH) placebo-controlled study will evaluate the safety, tolerability, and 
pharmacokinetics (PK)/pharmacodynamics (PD) of single ascending subcutaneous (SC) doses of 
LY3885125 in participants with dyslipidemia (Part A of study), and of repeated SC doses of 
LY3885125 in participants with NAFLD and elevated alanine aminotransferase (ALT) (Part B of 
study). In Part A, the response to LY3885125 will be evaluated via changes in circulating levels 
of proprotein convertase substilisin/kexin type 9 (PCSK9),
 
 
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Protocol J4N-MC-YFAA(b) 
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Part A: 
 To determine the safety and 
tolerability of LY3885125 after a 
single SC dose in participants with 
dyslipidemia. 
 
 Adverse events (AEs). 
 Serious adverse events (SAEs). 
Part B: 
 To determine the safety and 
tolerability of LY3885125 after 2 SC 
doses on Days  and 
 in participants 
with NAFLD and elevated ALT. 
 
 AEs. 
 SAEs. 
Secondary 
 
Part A: 
 To assess the PK and PD of 
LY3885125 after a single SC dose. 
 
 LY3885125 area under the 
concentration-time curve (AUC), 
maximum observed concentration (Cmax), 
time of Cmax (Tmax). 
 Changes in PCSK9 and apolipoprotein B 
(ApoB) from baseline relative to placebo. 
Part B: 
 To assess the PK and PD of 
LY3885125 following 2 SC doses on 
Days  and 
. 
 
 LY3885125 AUC, Cmax, Tmax. 
 Relative change of liver fat content from 
baseline to Weeks 
 and 
 by MRI-
PDFF compared with placebo. 
 Changes in PCSK9 and ApoB from 
baseline relative to placebo. 
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Protocol J4N-MC-YFAA(b) 
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Objectives 
Endpoints 
Exploratory 
 
Parts A and B: 
 
 
 
 
 
 
 
 
Part B: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol J4N-MC-YFAA(b) 
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Overall Design 
Study J4N-MC-YFAA is a Phase 1, multicenter, randomized, placebo-controlled, double-blind, 
2-part study in participants with dyslipidemia, and participants with NAFLD and elevated ALT. 
The study design includes: 
 Part A (Cohorts 1 to 6): placebo-controlled, Investigator- and participant-blind, single 
SC dose of LY3885125 in participants with dyslipidemia: 
o 
To evaluate the safety, tolerability, PK, and PD of a single ascending dose (SAD) of 
LY3885125 in up to  cohorts (Cohorts 
). 
o 
 
 
 
o 
Data from Part A will inform the Part B dose. 
 Part B (Cohort 7): placebo-controlled, Investigator- and participant-blind, repeat SC 
doses of LY3885125 in participants with NAFLD and elevated ALT: 
o 
To evaluate the safety, tolerability, PK, PD, and change of liver fat content from 
baseline to Weeks 
 by MRI-PDFF of a repeated dose of LY3885125 at 
Days 
 
o 
The Part B dose will be based on data from Part A and will not exceed what has been 
studied in Part A. The protocol will be amended prior to initiation of Part B to define 
the dose and dosing frequency. 
 
The study will begin with Part A and proceed to Part B following reviews of safety, tolerability, 
and available PK and PD data. 
Dose escalation decisions will be made by the Dose Escalation Committee (DEC).  
Recommendations to temporarily suspend study drug intervention or terminate the study early 
will be evaluated by a Safety Review Committee (SRC). 
In both study parts, the identity of study intervention (LY3885125 or placebo) will be masked to 
participants, Investigators, and site-facing Sponsor personnel. 
 
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Protocol J4N-MC-YFAA(b) 
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Brief Summary 
The primary purpose of this study is to determine a safe and tolerable dose of LY3885125 in 
participants with dyslipidemia (Part A) and in participants with NAFLD and elevated ALT 
(Part B). 
In Part A, the approximate total duration of study participation for each participant may be up to 
 days (
 weeks), across the following study intervals: 
 Screening, approximately 28 days. 
 Participants will be admitted to the site on Day -1 for an inpatient treatment period of 
approximately  days, during which participants will receive a single dose of LY3885125 
or placebo on Day 1. The single doses planned to be administered in Part A are as 
follows: 
. If more than  mL of solution is 
required to deliver a dose, then it will be split into multiple injections, each with a 
maximum volume of  mL. 
 Participants will then attend follow-up visits as outpatients for a minimum of 25 weeks as 
outlined in the schedule of activities.  
 If discontinuation criteria are not met as outlined in the schedule of activities, participants 
will continue visits for up to a total of 
 weeks, as needed, including during the 
Monitoring Extension, unless discontinuation criteria are met. 
 Each participant in Part A will be followed until the plasma concentration of 
 has 
returned to at least 
% of the baseline level after administration of the single dose . 
 
In Part B, the approximate total duration of study participation for each participant may be up 
to 
 days (
 weeks), across the following study intervals: 
 Screening, approximately 28 days. 
 Participants will be admitted to the site on Day -1 for the first inpatient treatment period 
of approximately 2 days, during which they will receive the first dose of LY3885125 or 
placebo (Day 1). 
 Participants will attend the first series of follow-up visits as outpatients every other week 
post first dose as outlined in the schedule of activities. 
 Participants will be readmitted to the site on 
 for a second inpatient treatment 
period of approximately 2 days, during which they will receive the second dose of 
LY3885125 or placebo (
). 
 Participants will then attend a second series of follow-up visits as outpatients for a 
minimum of 
 weeks post-second dose as outlined in the schedule of activities.  
 If discontinuation criteria are not met as outlined in the schedule of activities, participants 
will continue visits for up to a total of 
 weeks post second dose, as needed, including 
during the Monitoring Extension, unless discontinuation criteria are met. 
Study Population: 
Males, and females of nonchildbearing potential, aged 18 to 70 years, with dyslipidemia or 
NAFLD and 
. 
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Protocol J4N-MC-YFAA(b) 
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Number of Participants: 
Enrollment for Part A will enable completion of up to 
 participants in up to 6 cohorts. 
Enrollment for Part B will enable completion of approximately 
 participants in a single cohort 
(Cohort 7) that consists of 3 treatment arms with 2 doses administered per arm. 
Intervention Groups: 
Intervention Groups 
Participants will be sequentially enrolled into the study. After the screening period, eligible 
participants will be randomized to receive either LY3885125 or placebo. 
Part A: 
Part A 
Cohort 
n 
Randomization 
(LY3885125:placebo) 
1-2 
 
6:2 
3-5 
 
9:2 
6 (optional) 
 
10:9 
 
Part B: 
 Cohort 7: This is a repeat dose cohort evaluating a single dose level administered on 
 as shown in the table below. A total of 
 participants will be randomized 
at the start of Cohort 7 to 1 of 3 treatment arms: 
o 
Arm 1: Participants will receive the same dose of LY3885125 
. 
o 
Arm 2: Participants will receive a dose of LY3885125 (same as in Arm 1) on 
 
. 
o 
Arm 3: Participants will receive placebo on 
. 
 
Part B (Cohort 7) 
Treatment Arm 
 
First Dose (
)a 
Second Dose (
)a 
1 
 
LY3885125 
LY3885125 
2 
 
LY3885125 
Placebo 
3 
 
Placebo 
Placebo 
a 
The dose administered on 
 (first dose) and 
 (second dose) will be the same dose level 
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Dose Modification 
Increases or decreases in dose levels or additional dose levels may be warranted as determined 
by the DEC, based on a review of all safety data and available PK and PD data from prior dose 
levels. 
No dosing decision can occur without prior discussion and agreement of the DEC. If the dose 
escalation stopping criteria (Section 4.5.1)  are met, the dose level will not be repeated or 
exceeded. If the temporary stopping criteria are met (Section 4.5.2), dosing in the study will be 
paused. The SRC will be convened in either scenario to review available data and provide 
recommendations regarding the continued conduct of the study.  
Safety Review Committee: A Safety Review Committee (SRC) will be employed to review the 
benefit-risk profile of the LY3885125 throughout the conduct of the study. The SRC will meet 
 and may be convened in response to any emerging safety signal (see Safety Review 
Committee Charter for additional details).
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1.2. 
Schema  
 
Abbreviations: ALT = alanine aminotransferase; SAD = single ascending dose; SC = subcutaneous. 
Arm 2 Dose 1 – Active
Arm 3 Dose 1 - Placebo
Arm 3 Dose 2 – Placebo 
DE3
DE4
C1
DE2
DE1
C2
C3
C4
C5
C6 
(Optional)
Part A: 5 SAD cohorts with optional cohort 6 (participants on statin therapy) 
Part B: Repeat dose cohort.  2 Doses administered, 
 and 
DE1 – DE4
Data reviews to inform dose escalation 
decisions in Part A and to inform 
decision to start repeat dose Part B 
C6
(Optional)
 
 
 
  
C1 – C5
Single ascending SC dose in 
dyslipidemia participants to provide 
PK/PD, safety data, and signals of 
target engagement 
Repeat SC dose in non-alcoholic fatty 
liver disease (NAFLD) participants 
with 
.  Participants will 
be randomized into one of three Arms.  
First dose administered on 
and 
second dose administered on 
.  
Data reviews in Part A will inform 
decision to start repeat dose Part B 
C7
First Dose 
(
)
Second Dose 
(
)
C7
Arm 2 Dose 2 – Placebo 
Arm 1 Dose 1 – Active
Arm 1 Dose 2 – Active 
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Protocol J4N-MC-YFAA(b) 
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1.3. 
Schedule of Activities (SoA)  
1.3.1. 
Part A Study Schedule (Single Dose Cohorts)  
Procedure 
Screening 
Inpatient Visit 
Outpatient Follow-up Visitsa 
ET 
Post-Dose 
Monitoring Extensionb 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/confirm I/E criteria 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Administer study interventionf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination (PE)g 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Symptom directed PE 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weighth 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
COVID-19 PCR testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
FSHk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic serologiesl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen and ethanol 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Safety laboratory tests 
X 
 
P 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Body Temperature 
X 
 
P 
 
 
 
 
 
X 
 
 
 
X 
Vital signs - PR/BP/RR 
X 
 
 
 
 
 
 X 
X 
X 
X 
 
X 
X 
12-lead ECGm 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Plasma PK samplesn 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel, (fasting)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ApoB (fasting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored samples (fasting) 
 
 
P 
 
 
 
X 
X 
X 
X 
D43, 57, 85, 169 
 
 
ISR assessments 
 
 
Following spontaneous report from participant, complete ISR CRF and Pain VAS assessment 
 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
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Protocol J4N-MC-YFAA(b) 
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Abbreviations: AE = adverse event; ApoB = apolipoprotein B; BP = blood pressure; COVID-19 = Coronavirus disease 2019; CRF = case report form; 
CRU = clinical research unit; D = day; ECG = electrocardiogram; ET = early termination; h = hour(s), FSH = follicle-stimulating hormone; HCV = hepatitis C 
virus; HDL-C = high-density lipoprotein cholesterol; I/E = inclusion/exclusion; ISR = injection-site reaction; LDL-C = low-density lipoprotein cholesterol; 
 min = minutes; P = predose; PCSK9 = proprotein convertase subtilisin/kexin type 9; PCR = polymerase chain reaction; 
PD = pharmacodynamics; PE = physical examination; PK = pharmacokinetics; PR = pulse rate; Q2W = once every 2 weeks; PUC = preparative 
ultracentrifugation; Q4W = once every 4 weeks; RR = respiration rate; SC = subcutaneous; TEAE = treatment-emergent AE; TG = triglyceride; VAS = visual 
analog score; VLDL-C = very low-density lipoprotein cholesterol. 
a All follow-up visits should take place in the morning after an overnight fast of at a minimum  hours. Water is permitted ad libitum during the fasting period. 
b After Day 
, once any treatment related AEs are resolved and PCSK9 levels return to at least 
% of baseline, the Monitoring Extension visits may be 
discontinued. The final visit of a participant who completes the study will be the first scheduled Monitoring Extension visit after they report no ongoing AEs, 
and after PCSK9 levels have returned to at least 80% of baseline in a blood sample collected at one of the preceding visits. At the participant’s final visit, they 
will receive the assessments performed at ET, except for the collection of a blood sample for PCSK9 assessment. 
c Outpatient follow-up visits on Days 
 will be conducted through a remote telehealth visit assessing AE/concomitant medications. 
d On Day -1 prior to randomization review AEs, concomitant medications, and compliance to Inclusion/Exclusion criteria. 
e Discharge from CRU after all assessments have been completed. 
f 
All doses of study intervention will be administered SC in the morning after an overnight fast of approximately 8 hours duration. 
g Complete physical examination performed at Screening, ET and last visit., and symptom-directed examinations at all other visits. 
h Body weight is measured at any time before breakfast. 
i 
A COVID-19 PCR test will be performed at Screening and on Day -1 prior to dosing. If test results are positive for the virus the participant will be excluded 
from the study. 
j 
A serum pregnancy will be performed at screening. Urine pregnancy tests may be performed at all other visits. If a urine test result is positive, the result will 
be confirmed with a serum test. 
k A serum FSH test will be performed in women at screening to confirm postmenopausal status. 
l 
If the HCV antibody test is positive, it must be followed by an HCV RNA test. Participants who are positive for HCV antibody and negative for HCV RNA 
may be enrolled. See Exclusion Criterion #8, Section 5.2. 
m Single 12-lead ECG at screening, safety follow-up and ET visit. Three triplicate 12-lead ECGs at pre-dose 2 minutes apart to establish baseline. Triplicate 
12-lead ECGs at all other scheduled times. The actual day and time must be documented in the CRF. 
n PK samples identified with an X may be obtained at any time within the scheduled days; the exact date and time of blood sample collection must be recorded 
in the CRF. 
o Lipid panel: TG, total cholesterol, LDL-C (PUC), VLDL-C (calculated), HDL-C, non-HDL-C (calculated). 
 
 
PCSK9 
X 
 
P 
 
 
X 
X 
X 
X 
X 
 
X 
X 
HbA1c 
X 
 
P 
 
 
 
 
 
X 
 
 
 
X 
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Protocol J4N-MC-YFAA(b) 
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1.3.2. 
Part B Study Schedule (Repeat Dose Cohort)  
Procedure 
Screening 
Inpatient Visit 1 
Outpatient 
Follow-up Visitsa 
Inpatient Visit 2 
Outpatient Follow-up Visitsa 
ET 
Post-Dose 
Monitoring 
Extentionb 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review/confirm I/E criteria 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from CRUe 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Administer study interventionf 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
X 
X 
X X X X X X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weighth 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
COVID-19 PCR testi 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
FSHk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic serologiesl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen and ethanol 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
X X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Safety laboratory tests 
X 
 
P 
X 
X X X X X 
 
P 
X 
X 
X 
X 
X 
X 
 
X 
X 
Body Temperaturem 
X 
 
P 
 
 
 
 
 
 
 
P 
 
 
 
 
 
 
 
 
X 
Vital signs -- PR/BP/RR 
X 
 
 
 X X X X X X 
 
 X 
X 
X 
X 
X 
 
X 
X 
12-lead ECGn, v 
X 
 
 
 X 
 
 
 
 
 
 
 X 
 
 
 
 
 
X 
X 
Transient Elastographyo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI-PDFF and MRI
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Plasma PK samplesp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel (fasting)q 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ApoB (fasting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored samples (fasting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol J4N-MC-YFAA(b) 
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Procedure 
Screening 
Inpatient Visit 1 
Outpatient 
Follow-up Visitsa 
Inpatient Visit 2 
Outpatient Follow-up Visitsa 
ET 
Post-Dose 
Monitoring 
Extentionb 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ISR assessments 
 
 
Following spontaneous report from participant, complete ISR CRF and Pain VAS assessment 
 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/concomitant medications 
X 
X 
X 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
P 
 
 
 
 
 
 
 
P 
 
 
 
 
 
X 
D260 
 
X 
PCSK9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
r 
X 
 
P 
 
 
X 
 
X 
 
 
P 
 
 
X 
 
 
X 
D176, 260 
X 
 
Abbreviations: AE = adverse event; Apo = apolipoprotein; BP = blood pressure; CAP = controlled attenuation parameter; 
; 
COVID-19 = Coronavirus disease 2019; CRF = case report form; CRU = clinical research unit; 
; D = day; 
ECG = electrocardiogram; 
; ET = early termination; 
; h = hour(s), FSH = follicle-stimulating hormone; 
HbA1c = glycated hemoglobin; HCV = hepatitis C virus; HDL-C = high-density lipoprotein cholesterol; I/E = inclusion/exclusion; ISR = injection-site reaction; 
LDL-C = low-density lipoprotein cholesterol; 
; min = minutes; MRI-PDFF = magnetic resonance imaging proton density fat fraction; 
; 
; 
P = predose; PCR = polymerase chain reaction; PCSK9 = proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamics; PK = pharmacokinetics; 
PR = pulse rate; 
; PR = pulse rate; RR = respiration rate; SC = subcutaneous; TEAE = treatment-emergent AE; 
TG = triglyceride; VAS = visual analog score; VLDL-C = very low-density lipoprotein cholesterol. 
a All follow-up visits should take place in the morning after an overnight fast of at minimum 8 hours. Water is permitted ad libitum during the fasting period. 
b After Day 260, once any treatment related AEs are resolved and PCSK9 levels return to at least 
% of baseline, the Monitoring Extension visits may be 
discontinued. The final visit of a participant who completes the study will be the first scheduled Monitoring Extension visit after they report no ongoing AEs, 
and after PCSK9 levels have returned to at least 
% of baseline in a blood sample collected at one of the preceding visits. At the participant’s final visit, they 
will receive the assessments performed at ET, except for the collection of a blood sample for PCSK9 assessment. 
c Outpatient follow-up visits on Days 
 and 
 will be conducted through a remote telehealth visit assessing AE/concomitant medications. 
d On Day -1 prior to randomization review AEs, concomitant medications, and compliance to protocol restrictions. 
e Discharge from CRU after all assessments have been completed. 
f 
All doses of study intervention will be administered SC in the morning after an overnight fast of at minimum 8 hours. Water is permitted ad libitum during 
the fasting period. 
g Complete physical examination at screening; symptom-directed examinations at all other visits. 
h Body weight is measured at any time before breakfast. 
i 
A COVID-19 PCR test will be performed at Screening. and on Days -1 and 84 upon admission to CRU. If test results are positive for the virus the participant 
will be excluded from the study. 
j 
A serum pregnancy will be performed at screening. Urine pregnancy tests will be performed at all other visits. If a urine test result is positive, the result will 
be confirmed with a serum test. 
k A serum FSH test should be performed in women at screening to confirm postmenopausal status. 
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Protocol J4N-MC-YFAA(b) 
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l 
If the HCV antibody test is positive, it must be followed by an HCV RNA test. Participants who are positive for HCV antibody and negative for HCV RNA 
may be enrolled. See Exclusion Criterion #8, Section 5.2. 
m Temperature also measured at any additional time points as clinically indicated. 
n Single 12-lead ECG at screening, safety follow-up and/ ET visit. Three triplicate 12-lead ECGs at pre-dose 2 minutes apart to establish baseline. Triplicate 
12-lead ECGs at all other scheduled times. The actual day and time must be documented in the CRF. 
o Participants must meet the CAP inclusion criteria prior to MRI assessment (Section 5.1). If CAP has been completed within 4 weeks before screening, this 
test does not need to be repeated. 
p Recording times identified with an X may be obtained at any time within the scheduled days; the exact date and time of recording must be recorded in the 
CRF. 
q Lipid panel: TG, total cholesterol, LDL-C, VLDL-C (calculated), HDL-C, non-HDL-C (calculated). 
r 
 
 
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Protocol J4N-MC-YFAA(b) 
22 
2. Introduction  
LY3885125 
 is a novel Dicer-substrate small interfering ribonucleic acid 
(DsiRNA) conjugated to N-acetylgalactosamine 
 designed to specifically knock down 
sterol regulatory element binding protein (SREBP) cleavage activating protein (SCAP) 
messenger ribonucleic acid (mRNA) in the liver. SCAP regulates the activation of SREBPs, 
which are transcription factors that govern de novo lipogenesis, cholesterol biosynthesis, and 
metabolism pathways. LY3885125 is being developed to reduce hepatic SCAP mRNA levels 
and thereby reduce SCAP protein expression.
 
2.1. 
Study Rationale  
 
 
Given these effects, there is potential for LY3885125 as a treatment 
for dyslipidemia and nonalcoholic fatty liver disease (NAFLD). 
Study J4N-MC-YFAA is a first-in-human (FIH) placebo-controlled study, which will evaluate 
the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending 
subcutaneous (SC) doses of LY3885125 in participants with dyslipidemia (Part A), and of 
repeated SC doses of LY3885125 in participants with NAFLD and 
 
 (Part B). In Part A, response to LY3885125 will be assessed based on 
changes in circulating proprotein convertase substilisin/kexin type 9 (PCSK9) concentration. In 
Part B the effect of LY3885125 compared with placebo on liver fat content (LFC) will be 
evaluated through changes in magnetic resonance imaging proton density fat fraction (MRI 
PDFF). 
2.2. 
Background  
NAFLD is characterized by hepatic steatosis when no other causes for hepatic fat accumulation 
can be identified. NAFLD ranges from simple steatosis (nonalcoholic fatty liver), NASH with or 
without fibrosis through to cirrhosis (Rinella et al. 2023). The prevalence of NAFLD is 
increasingly becoming a leading cause of chronic liver disease worldwide (Powell et al. 2021). In 
the USA 25% to 30% of the adult population suffers from NAFLD (Rinella et al. 2023). Obesity, 
Type 2 diabetes mellitus (T2DM), and dyslipidemia are considered important risk factors for 
NAFLD (Younossi et al. 2016; Chalasani et al. 2018). NAFLD is seen in 47.3 to 63.7% of 
people with T2DM and up to 80% of people with obesity (Younossi et al. 2019; Polyzos et al. 
2019). NAFLD has become the most rapidly increasing cause of liver-related mortality 
worldwide and is an important cause of end-stage liver disease, primary liver cancer, and liver 
transplantation (Powell et al. 2021). NASH is the progressive stage of NAFLD and is 
characterized histologically by steatosis, lobular inflammation and hepatocyte injury (ballooning) 
with or without fibrosis (Chalasani et al. 2018). Patients with NASH have increased overall and 
liver -specific mortality (Singh et al. 2015; Younossi et al. 2016), and they have increased risks 
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Protocol J4N-MC-YFAA(b) 
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of cirrhosis, liver failure, and hepatocellular carcinoma (HCC) (Chalasani et al. 2018). The 
burden of NASH is expected to increase in line with the global epidemic of obesity, T2DM, and 
metabolic syndrome (Estes et al. 2018). There are currently no approved pharmacological 
therapies available for treatment of NAFLD and NASH. The beneficial effects of weight loss on 
NAFLD and NASH are well-documented (Vilar-Gomez et al. 2015; Chalasani et al. 2018; 
Semmler et al. 2021); therefore, currently diet and exercise are considered the standard treatment 
for NAFLD and NASH (Rinella et al. 2023). 
SCAP is a sterol-sensing protein that plays a critical role in cholesterol homeostasis in 
mammalian cells. It is a transmembrane protein that normally resides in the endoplasmic 
reticulum (ER). When cells are deprived of cholesterol, SCAP escorts SREBPs from the ER to 
the Golgi. Two Golgi proteases (site-1 protease [S1P], and site-2 protease [S2P]) then 
sequentially cleave SREBPs, releasing their active NH2-terminal transcription factor domains, 
which travel to the nucleus and activate genes involved in lipid metabolism (Brown et al. 2018). 
There are several SREBP isoforms: SREBP2 regulates cholesterol synthesis and uptake, 
SREBP1 isoform c (SREBP1c) regulates fatty acid and TG biosynthesis, while SREBP1 isoform 
a (SREBP1a) regulates both pathways. 
SCAP is expressed in the liver and extrahepatic tissues. Liver-specific knockout of SCAP in 
mouse models led to significant inhibition of de novo synthesis of free fatty acid and cholesterol. 
In the leptin-deficient (ob/ob) mouse model and the diet-induced-obesity (DIO) mouse model, 
SCAP deficiency led to significant suppression of liver TG levels and liver total cholesterol 
levels. In hamsters fed with a high-sucrose diet, reduction in SCAP mRNA expression by siRNA 
reduced liver TG and total cholesterol levels and normalized plasma TG levels (Moon et al. 
2012). In rhesus monkeys, knockdown of SCAP mRNA by siRNA resulted in dose dependent 
reduction in serum TG and LDL-C, with minimal impact on high-density lipoprotein cholesterol 
(HDL-C) (Jensen et al. 2016). Based on these observations from preclinical models, inhibiting 
SCAP via siRNA may be of therapeutic benefit for the treatment of dyslipidemia and fatty liver 
disease, including NASH. 
 
 
2.2.1. 
Summary of Nonclinical Data  
The cynomolgus monkey and Sprague Dawley rat were selected as the species for safety 
assessment. Due to the homology of the SCAP mRNA target sequence with humans, 
cynomolgus monkeys (and not rat) are pharmacologically responsive to LY3885125 and allow 
assessment of adverse effects related to the intended pharmacologic activity. This species 
selection strategy allows for evaluation of off-target and oligonucleotide-related class effects in 
both species and potential exaggerated pharmacology in monkeys. This is an accepted approach 
for the safety evaluation of oligonucleotides (Kornbrust et al. 2013; FDA/CDER Onpattro NDA 
210922). 
A single-dose monkey study 
 was conducted to assess cytokine and complement 
activation after a single administration of LY3885125. Administration of 
 
 or 
 mg/kg LY3885125 
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Protocol J4N-MC-YFAA(b) 
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to male cynomolgus monkeys (Macaca fascicularis) once via SC injection resulted in no 
LY3885125-related effects on mean body weight, clinical observations, coagulation or clinical 
chemistry parameters, or effects on cytokine (
) and complement (
 
) parameters. 
A standalone cardiovascular study was conducted to evaluate the potential cardiovascular effects 
of LY3885125 in instrumented male cynomolgus monkeys (
). 
 male 
cynomolgus monkeys were administered by SC injection single doses of control 
 
 or 
 mg LY3885125/kg via SC injection 
(  males per group). 
No LY3885125-related qualitative electrocardiogram (ECG) abnormalities or quantitative 
changes in PR interval, QRS duration, QT interval, or individual heart rate-adjusted QT (QTc) 
interval were noted up to 
 postdose following administration of 
. 
Monkeys administered 
 LY3885125 were noted to have a transient increase in heart 
rate (of up to
 bpm) from 
 hours postdose, which resolved by 
 
postdose; a transient increase in systolic (
), diastolic (
 
), and mean arterial blood pressure 
 from 
 postdose, 
which resolved by 
; and an increase in body temperature (
) 
from 
 postdose, which resolved by 
 postdose. No heart rate, blood 
pressure, or body temperature changes were noted in monkeys administered 
 
No LY3885125-related changes in arterial pulse pressure or dP/dtmax (maximal rate of rise in 
pressure), or changes in locomotor activity were noted up to 
 following administration 
of 
 
The toxicity of LY3885125 was evaluated in GLP -month repeat-dose studies in cynomolgus 
monkeys 
 and Sprague Dawley rats (
). Administration of 
LY3885125 was not associated with significant toxicological findings in the rat and monkey 
studies. 
 
 
 
 
 
 
In conclusion, the available nonclinical pharmacology, PK, and toxicology data support the use 
of LY3885125 in the proposed clinical trial. 
The margin of safety for SC injection of LY3885125 in humans based on administered dose and 
predicted exposure from nonclinical studies is presented in Table 2.1. 
Additional details of the nonclinical studies are provided in the Investigator’s Brochure (IB). 
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Protocol J4N-MC-YFAA(b) 
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Table 2.1 
Margin of Safety for Subcutaneous Injection of LY3885125 Based on Administered 
Dose and Predicted Exposure 
 
Dose 
(mg/kg) 
Dose 
(mg/m2) 
Dose 
Multipl
ea 
AUC 
(ng·h/mL) 
Exposure 
Multiplee 
Human Starting 
Dose (5 mg)b 
 
 
– 
 
 
Rat NOAELc 
 
 
 
 
 
Monkey 
NOAELd 
 
 
 
 
 
 
Human 
Maximum Dose 
(
 mg)b 
 
  
– 
 
 
Rat NOAELc 
 
 
 
 
 
Monkey 
NOAELd 
 
 
 
 
 
Abbreviations: AUC = area under the plasma concentration time curve; NOAEL = no-observed-adverse-effect 
level; SC = subcutaneous. 
a Dose multiple is the dose in animals/dose in humans based on mg/m2 using a human body weight of 70 kg. 
Exposure multiple is the calculated AUC in animals / predicted AUC in humans (see Section 4.2.3 of the 
Investigator’s Brochure). 
b Assume human body weight = 70 kg to predict human exposure. The maximum dose for the study will be 
limited to 
 mg until additional data from Part A cohorts are available to inform the safety, tolerability, and 
impact on PCSK9 as a biomarker of 
 knockdown. A protocol amendment will be submitted with 
supporting data if doses above 
 mg are to be evaluated. 
c 
-month ( -dose) rat toxicology study, Day 
 AUC0-48 exposure (
). 
d 
-month ( -dose) monkey toxicology study, Day 
 AUC0-48 exposure (
). 
e 
AUC multiple: based on predicted human AUC0-∞ using allometric scaling from rat. Allometric slopes are 
fixed to 0.75 for clearance (CL) and 1 for volume of distribution (V). Bioavailability (F) is approximately 
% 
based on rat data at 
 mg/kg SC. 
 
 
 
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Protocol J4N-MC-YFAA(b) 
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2.3. 
Benefit/Risk Assessment  
The nonclinical safety information for LY3885125 adequately supports the transition from 
preclinical status to a clinical study. 
Based on the nonclinical data, LY3885125 is not considered to be a high-risk compound. The 
nonclinical cardiovascular safety data
 
 SCAP is expressed in the 
liver and extrahepatic tissues. 
 
 
 
 
 
 
 
 
In summary, while the clinical safety profile of LY3885125 is not yet established, the available 
information suggests a low likelihood of significant toxicity. LY3885125 has not been 
administered to humans previously. This FIH study with LY3885125 will mitigate risks by a 
design that is in accordance with principles outlined in the Guideline on Strategies to Identify 
and Mitigate Risks for FIH and Early Clinical Trials with Investigational Medicinal Products. 
The important potential safety risks are summarized in Table 2.2. Any potential risks are 
considered monitorable and manageable in dyslipidemia and NAFLD participants. More detailed 
information about the known and expected benefits and risks and reasonably expected adverse 
events (AEs) of LY3885125 may be found in the IB. 
 
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Table 2.2 
Important Potential Safety Risks with LY3885125  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation/Monitoring Strategy 
Hypersensitivity or allergic 
reactions 
Not specific to LY3885125. 
Oligonucleotide therapies, both 
marketed and those in development, 
have been associated with 
hypersensitivity events. 
Monitor for hypersensitivity 
reactions in participants. Assess 
spontaneously reported adverse 
events for their likelihood to 
represent hypersensitivity reactions. 
Once identified, investigative site 
personnel will collect additional 
information to characterize the type 
of reaction using standardized forms. 
Qualified staff will have received 
training and have access to 
supportive measures to manage the 
reactions. 
Injection-site reactions 
Not specific to LY3885125. As this 
molecule is an injectable therapeutic, 
there is the potential risk of localized 
injection-site reactions.  
Qualified staff will have received 
training and have access to 
supportive measures to manage the 
reactions. 
 
Specific to LY3885125. 
 
 
 
 
 
Further 
information is provided in the IB. 
Vital signs and ECG will be recorded 
across multiple scheduled time points 
following single and multiple doses. 
 
 
 
  
 
 
 
 
  
 
 
 
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Protocol J4N-MC-YFAA(b) 
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3. Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
Part A: 
 To determine the safety and 
tolerability of LY3885125 after a 
single SC dose in participants with 
dyslipidemia. 
 
 AEs. 
 Serious adverse events (SAEs). 
Part B: 
 To determine the safety and 
tolerability of LY3885125 after 2 SC 
doses on Days 
 in participants 
with NAFLD and elevated ALT. 
 
 AEs. 
 SAEs. 
Secondary 
 
Part A: 
 To assess the PK and PD of 
LY3885125 after a single SC dose. 
 
 LY3885125 area under the 
concentration-time curve (AUC), 
maximum observed concentration (Cmax), 
time of Cmax (Tmax). 
 Changes in PCSK9 and apolipoprotein B 
(ApoB) from baseline relative to placebo. 
Part B: 
 To assess the PK and PD of 
LY3885125 following 2 SC doses on 
Days 
. 
 
 LY3885125 AUC, Cmax, Tmax. 
 Relative change of liver fat content from 
baseline to Weeks 
 by magnetic 
resonance imaging proton density fat 
fraction (MRI-PDFF) compared with 
placebo. 
 Changes in PCSK9 and ApoB from 
baseline relative to placebo. 
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Objectives 
Endpoints 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. Study Design  
4.1. 
Overall Design  
Study J4N-MC-YFAA is a Phase 1, multicenter, randomized, placebo-controlled, double-blind, 
2-part study in participants with dyslipidemia, and participants with NAFLD and elevated ALT. 
The study design includes: 
 Part A (Cohorts 1 to 6): placebo-controlled, Investigator- and participant-blind, single 
SC dose of LY3885125 in participants with dyslipidemia: 
o 
To evaluate the safety, tolerability, PK, and PD of a single ascending dose (SAD) of 
LY3885125 in up to 6 Cohorts. 
o 
Data from Part A will inform the dose for Part B. 
 Part B (Cohort 7): placebo-controlled, Investigator- and participant-blind, repeat SC 
doses of LY3885125 in participants with NAFLD and 
: 
o 
To evaluate the safety, tolerability, PK, PD, and change of LFC from baseline to 
Weeks 
 by MRI-PDFF of a repeated dose of LY3885125 at
. 
o 
The dose and dosing frequency in Part B will be based on data from Part A. The 
protocol will be amended prior to initiation of Part B. 
 
The study will begin with Part A, with Dose Escalation Meetings of the DEC between each 
cohort, and will proceed to Part B after reviewing emerging data from Part A and potentially use 
modelling to select an appropriate dose and frequency of dosing.  
During Part A of the study, there will be ongoing reviews of safety, tolerability, and PK data as 
described in Section 6.3.1. Based on these reviews, the following may be adjusted: 
 Planned dose levels; 
 Sample collection schedule; 
 Safety measurement schedules; 
 Length of inpatient stay. 
 
In addition to oversight by the DEC, a SRC will meet 
 throughout the study to evaluate 
the safety and tolerability of LY3885125. The SRC may make recommendations regarding 
conduct of the study as described in Section 4.5 and in the SRC Charter.  
The study schema is presented in Section 1.2. 
Participants should complete the study assessments and procedures as specified in the Schedule 
of Activities (SoA) in Section 1.3. 
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4.1.1. 
Part A - Single Ascending Dose (SAD) Cohorts 1-6 (Cohort 6 
optional)  
Part A will consist of up to 6 single-dose levels, Cohorts 1 to 6, with the following numbers of 
participants randomized to LY3885125 or placebo as follows and also summarized in Table 4.1: 
 Cohorts 1 and 2: a total of 
 participants (  per cohort) randomized 6:2 to 
LY3885125:placebo. 
 Cohorts 3 through 5: total of 
 participants (
 per cohort) randomized 9:2 to 
LY3885125:placebo. 
 Cohort 6 (optional): total of 
 participants randomized 10:9 to LY3885125:placebo. 
This cohort will consist of participants with dyslipidemia on a stable moderate or 
high -intensity dose of statin;
 
 
Table 4.1 
Part A Design  
Part A 
Cohort 
n 
Randomization 
(LY3885125:placebo) 
1-2 
 
6:2 
3-5 
 
9:2 
6 (optional) 
 
10:9 
 
The single doses of LY3885125 planned to be administered in Part A to Cohorts 1 to 5 are as 
follows: mg, 
 mg, 
 mg, 
mg, and 
 mg . The doses specified are the planned doses; 
the actual doses will be selected during the Dose Escalation Meetings based on the available 
safety and PK data, with projected levels of systemic exposure within limits determined by 
margin of safety to the NOAEL as described in Section 4.3 (Justification for Dose). Data from 
the Part A cohorts will provide safety, tolerability, available PK, and PD data to inform the 
Part B dose and dosing frequency. 
For the optional Cohort 6 of Part A (
 
) the planned dose of LY3885125 will not exceed the dose administered in 
Cohort 5. 
Sentinel dosing will be used in Part A to reduce the risk of exposing all participants in a cohort to 
study intervention and the potential for unexpected AEs occurring simultaneously. Two 
participants from each SAD cohort will be included in the sentinel dosing regimen to allow for 
one participant treated with study intervention and one participant treated with placebo to be 
dosed prior to dosing the remaining participants in the cohort. There will be
 
 in each Part A cohort. 
4.1.1.1. 
Screening (Part A)  
Participant eligibility for Part A will be determined at a screening visit within 28 days prior to 
dosing with study intervention (LY3885125 or placebo) on Day 1. 
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4.1.1.2. 
Treatment Period (Part A)  
In each period, participants will be admitted to the clinical research unit (CRU) on the day prior 
to dosing (Day -1) for 4 overnight stays. Participants will be monitored as inpatients in the CRU 
up to Day . 
Participants will be given a SC dose of LY3885125 or placebo on Day 1. 
The single doses planned to be administered in Part A are as follows: mg, 
 mg, 
 mg, 
 mg, and
 mg. 
The safety data to be reviewed at each dose level will include, but are not limited to, AEs, 
clinical laboratory safety tests, vital signs, ECGs, physical examination (symptom-directed). The 
dose level for each cohort may be adjusted based on emerging safety, tolerability, and available 
PK and PD data from preceding cohorts.  
After review of these data, the DEC will decide if the planned dose needs to be modified The 
magnitude of dose escalations may be reduced following data review. 
The conduct of DEC meetings is described in Section 6.3.1, the dose escalation stopping criteria 
are described in Section 4.5.1, and the temporary stopping criteria are described in Section 4.5.2 
Details of assessments and their timing in Part A are provided in the SoA (Section 1.3.1) and in 
Section 8 (study assessments and procedures). 
4.1.1.3. 
Follow-up (Part A)  
Participants will attend follow-up visits as outpatients as outlined in the SoA (Section 1.3.1). 
Each participant enrolled in a Part A cohort will be followed 
 
 
4.1.2. 
Part B – Repeat Dose – Cohort 7  
Part B may be initiated, at the earliest, after review of safety, tolerability, PK, and PD data from 
Part A. The dose administered in Part B will not exceed what has been studied in Part A. The 
protocol will be amended prior to initiation of Part B to define the dose and dosing frequency. 
Changes in biomarkers of drug pharmacology other than
 in Part A may guide the Part B 
dose selection 
 
For Part B (Cohort 7) a total of approximately 44 participants (NAFLD participants with 
) will be randomized into 3 treatment arms to receive 2 SC doses of study 
intervention (LY3885125 or placebo), one on 
 and one on 
. 
 
. The assignment of study intervention (LY3885125 or 
placebo) in each treatment arm and number of participants is shown in Table 4.2. 
The proposed dosing interval of 
 days between the two doses administered on 
 and 
 
 of Part B will be confirmed or modified, if necessary, when the protocol amendment is 
submitted prior to initiation of Part B.
 
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Table 4.2 
Part B Design  
Part B (Cohort 7) Treatment 
Arm 
n 
First Dose (
 
Second Dose (
) 
1 
11 
LY3885125 
LY3885125 
2 
11 
LY3885125 
Placebo 
3 
22 
Placebo 
Placebo 
a The dose administered on 
 (first dose) and 
 (second dose) will be the same dose level 
 
4.1.2.1. 
Screening (Part B)  
Participant eligibility for Part B will be determined at a screening visit within 
 days prior to 
dosing with study intervention (LY3885125 or placebo) on Day 1. The participants will undergo 
assessment of 
 during the 
screening period to assess their eligibility for the study. 
 assessment may be deferred if 
 
assessment has been done within  weeks of the screening visit. Participants must meet the 
 
inclusion criteria prior to MRI assessment. 
4.1.2.2. 
Treatment Period (Part B)  
For Part B treatment period, participants will be admitted to the CRU on the days prior to dosing 
(
 and 
) and will stay in the CRU for  nights. Participants will be monitored as 
inpatients in the CRU up to 2 days after dosing (to 
 and 
, respectively). 
Participants will be given an SC dose of LY3885125 or placebo on 
 and 
. The dose 
will be based on review of data from Part A. 
Details of assessments and their timing in Part B are provided in the SoA (Section 1.3.2). 
4.1.2.3. 
Follow-up (Part B)  
Participant will attend follow-up visits as outpatients as outlined in the SoA (Section 1.3.2). 
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4.2. 
Scientific Rationale for Study Design  
Study J4N-MC-YFAA is a FIH study of LY3885125 with 2 parts, a single ascending dose in 
participants with dyslipidemia, and repeated dose in participants with NAFLD and 
 
. Both study parts are Investigator- and participant-blinded and placebo-controlled to avoid 
bias in the collection and evaluation of data. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment related or reflective of the study conditions. 
A sentinel dosing strategy for all dose levels in Part A will be used, as the study drug has not 
previously been administered to participants. There will be a minimum interval of 
 
between the administration of the Investigational Product to the sentinel pair and the remaining 
participants in each Part A cohort.A DEC will meet between each cohort to review safety and 
available PK and PD data to determine if adjustments to the planned dose are needed. The DEC 
will also review the data against the dose escalation and temporary stopping criteria. If any of 
these criteria are met, the SRC will be convened to review available data and make 
recommendations regarding continued study conduct. 
 
. In Part A, the single-dose escalation 
design is appropriate to assess the LY3885125 safety profile in a way that minimizes participant 
risk. The number of participants is adequate to explore safety, tolerability, PK, and PD across a 
broad range of doses to determine appropriate dosage regimens to evaluate in future studies. The 
potential of LY3885125 to reduce ApoB concentration will be assessed in all cohorts. 
 
 
for repeated SC doses of LY3885125. Part B will use a 3-arm design and assess the safety, 
tolerability, PK and PD effects of LY3885125. Potential effects of LY3885125 use during 
pregnancy and lactation are not known. To minimize potential risk, this first-in-human study is 
excluding women of childbearing potential and including contraception requirements for men 
(Section 10.4.2.2). Additional details can be found in the IB. 
ApoB  
In Part A, the potential for LY3885125 to reduce ApoB concentration will be assessed in all 
cohorts. Apo B is a key structural component of lipoproteins, each lipoprotein particle carrying 
one ApoB molecule. Consequently, the ApoB level can also provide a measure of the number of 
circulating lipoprotein particles and is also a potential biomarker for cardiovascular disease 
(Harper and Jacobson, 2010; Lu et al. 2022). 
PCSK9 
In Part A, the effect of LY3885125 will be assessed based on changes in circulating PCSK9 
concentration. PCSK9 is a circulating protein that is mainly produced by the liver. It plays an 
important role in cholesterol metabolism. PCSK9 inhibition leads to improvement in 
dyslipidemia. PCSK9 mRNA expression is directly regulated by the SCAP-SREBP pathway. 
 
These data support circulating PCSK9 as a biomarker for SCAP 
siRNA in human trials. 
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MRI 
In Part B, the effect of LY3885125 compared with placebo on liver fat content will be evaluated 
through changes in MRI Proton Density Fat Fraction (PDFF). MRI-PDFF is a quantitative 
 which provides accurate, quantitative assessment of liver fat. MRI-PDFF has 
been validated as an accurate imaging biomarker when compared with liver histology 
(Loomba et al. 2020). MRI-PDFF is reproducible and is a sensitive method to assess hepatic 
steatosis. Studies have shown that MRI-PDFF is sensitive to small longitudinal changes (<5%) 
of liver fat (Middleton et al. 2017) and ≥30% relative decrease in MRI-PDFF (Tamaki et al. 
2022) is an independent predictor of improvement in NAFLD activity score and liver fibrosis. 
Previous studies have also shown correlation between improvement in liver fat measured by 
MRI-PDFF and non-invasive biomarkers like enhanced liver fibrosis score, 
, and 
cytokeratin-18 (Stine et al. 2021). MRI-PDFF has the advantage of being non-invasive and can 
provide longitudinal quantitative change of liver fat in clinical trials. 
In addition, 
 will be determined as an exploratory endpoint in 
all Part B participants. 
 has been shown to correlate with fibroinflammatory activity on liver 
biopsy and to have high diagnostic accuracy to identify participants with NAFLD, NASH, and 
NASH with higher stages of fibrosis. Furthermore, studies suggest 
 
 at greatest risk of disease progression (Andersson 
et al. 2021). 
4.3. 
Justification for Dose  
Doses of LY3885125 selected for this study are based on Good Laboratory Practice (GLP) 
toxicology results, nonclinical pharmacology studies in mouse and monkey, and predicted 
human PK. The planned single SC dose levels are  mg, 
 mg, 
 mg, 
 mg, and 
 mg. 
4.3.1. 
Starting Dose  
The NOAELs in the -month toxicity studies were 
 mg/kg in both rat and monkey. Starting 
dose was determined from the NOAELs in the -week toxicity studies in rats and monkeys 
extrapolated to a human equivalent dose and applying a safety factor (FDA 2005). The starting 
dose of  mg is expected to have minimal pharmacological effect, given that humans are 
expected to respond more like monkey than mouse to SCAP knockdown. The  mg starting dose 
has a safety margin of 
-fold to 
-fold dose margin to the NOAEL in rats and monkeys, 
respectively (
 
4.3.2. 
Predicted Efficacious Dose  
Based on SCAP mRNA knockdown and PCSK9 inhibition in hydrodynamic injection (HDI) and 
DIO mouse models, the predicted human efficacious dose range is 
 mg to 
 mg. The monkey 
pharmacology study at  mg/kg demonstrated 
% to 
% reduction in SCAP mRNA, and the 
effect lasted for at least 
 weeks. When this dose is scaled allometrically to human, the 
efficacious dose is expected to be approximately 
 to 
 mg (
 to  mg/kg). Therefore, 
considering both the mouse and monkey models, the predicted efficacious dose range is 
 mg to 
 mg. 
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4.3.3. 
Maximum Dose  
A maximum dose of 
 mg (Table 4.3) allows for the assessment of a dose range to cover the 
predicted human efficacious dose and has approximately -fold to 
-fold dose margin to the 
NOAEL in rats and monkeys, respectively (Table 2.1). At a dose of 
 mg, approximately 
% 
to 
% reduction in SCAP mRNA is predicted, based on the range of estimates from the mouse 
and monkey modelsTable 4.3). 
While a 
-mg dose is specified as the maximum dose for Cohort 5, the actual dose 
administered may be lower, depending on the safety and available pharmacokinetic (PK) data 
from preceding cohorts. Data to be reviewed during dose escalation meetings by the DEC will 
ultimately drive dose selection for any given cohort, as described in Section 6.3.1. 
The maximum dose for the study will be limited to 
 mg until additional data from Part A 
cohorts are available to inform the safety, tolerability, and impact on PCSK9 as a biomarker of 
SCAP mRNA knockdown. A protocol amendment will be submitted with supporting data if 
doses above 
 mg are to be evaluated.  
Table 4.3 
Projected Human Dose Range Based on SCAP mRNA Knockdown and PCSK9 
Inhibition-Based on Mouse and Monkey Models  
Human Dose 
(mg) 
SCAP mRNA 
Knockdown Based on 
Mouse Model 
Serum PCSK9 
Inhibition in Based on 
Mouse Model 
SCAP Knockdown Based on Rhesus 
Monkey Model 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: PCSK9 = proprotein convertase substilisin/kexin type 9; SCAP = sterol regulatory element 
binding protein (SREBP) cleavage activating protein. 
 
4.3.4. 
Part B Dose  
The dose of LY3885125 for Cohort 7 in Part B will not exceed what has already been dosed in 
Part A. The primary criteria for selection of dose for the first dose level in Part B will be safety 
and tolerability data from Part A. Additionally, changes in biomarkers of drug pharmacology in 
Part A may guide the dose selection. The protocol will be amended prior to initiation of Part B to 
define the dose and dosing frequency. 
Although the predicted plasma half-life (t1/2) of LY3885125 is relatively short, the maximum 
effect is expected to be reached after  or more weeks and may take  months or longer to return 
to baseline levels after a single dose. The suitability of the proposed dosing interval of 
 days 
between the two doses to be administered in Part B will be informed by the rate of return of 
PCSK9 plasma concentrations in Part A study participants. 
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4.4. 
End of Study Definition  
End of the study is the date of the last visit or last scheduled procedure shown in the SoA for the 
last participant in Part B or last participant meets the discontinuation criteria outline in the SoA 
(Section 1.3.1). 
4.5. 
Medical Oversight and Safety Reviews  
Ongoing safety review(s) by designated Sponsor personnel will occur and be documented. Such 
reviews will include 
 
monitoring and assessing the safety information collected during the trial both in real 
time and periodically; 
 
reviewing safety data for trends that need action, and 
 
identifying potential adverse drug reactions. 
The Dose Escalation Committee (DEC) will meet between each cohort in Part A to assess the 
safety and tolerability of the individual dose cohorts. The timing, structure, and data that will be 
reviewed in the meetings are described in Section 6.3.1. 
The DEC will include the following individuals, none of whom will have interactions with site-
facing personnel: 
 PK/PD scientist 
 Clinical pharmacologist experienced with siRNA therapeutics 
 Liver safety expert 
 Clinical development lead for the molecule 
 Asset manager for the molecule 
The DEC will determine if the planned dose for the next cohort is appropriate, should be 
adjusted, or if further analysis of the data is warranted before proceeding. The DEC will consider 
the criteria outlined in Sections 4.5.1, 4.5.2, and 4.5.3. 
4.5.1. 
Dose Escalation Stopping Criteria  
A dose level will not be repeated or exceeded, if 
 the results of safety evaluations for that dose level give the Sponsor or Investigator cause 
for concern, or 
 the Investigator or Sponsor considers the dose level to be poorly tolerated.  
  
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4.5.2. 
Temporary Stopping Criteria  
If any of the following scenarios occur, dosing in all ongoing cohorts will be temporarily halted 
until written guidance from the Sponsor pending a full review of safety and available PK and PD 
data by the Safety Review Committee (SRC): 
 
 meet individual participant discontinuation criteria for liver 
function test elevations in a given cohort (see Section 7.1.1) 
 
 meet individual participant discontinuation criteria for QTcF 
prolongation in a given cohort (see Section 7.1.2); or 
 
 hypersensitivity reactions. 
Individual participant or study discontinuation criteria are provided in Section 7.1. 
If the DEC recommends temporary suspension of the trial due to emerging safety issues, the 
SRC will be convened to perform a full review of available safety data.  
The SRC will be comprised of the following personnel, none of whom will have any interactions 
with site-facing personnel: 
 SRC chairperson: Chief Medical Officer for Chorus, a division of Lilly Research 
Laboratories 
 SRC Secretary: Head of Global Regulatory Affairs for Chorus, a division of Lilly 
Research Laboratories 
 Sponsor Representative: expert from Lilly’s Global Patient Safety department 
 Other SRC members will include: 
o Team’s PK/PD scientist (will not have a vote given study team affiliation) 
o Statistician unaffiliated with the study team, and 
o Medical representatives, 1 with relevant clinical pharmacology and siRNA 
experience, and 1 with extensive liver safety experience. 
Neither the principal investigator for the study nor the Sponsor’s medical monitor for the study 
will be members of the SRC. The SRC will review blinded data initially and may be unblinded if 
certain criteria are met. 
The SRC will meet 
 while the study is being conducted to perform review of emerging 
safety data 
  
An ad hoc meeting can be convened in response to emerging safety signals (for example, based 
on recommendations from the DEC or Investigator). An SRC meeting must be convened if there 
is a recommendation to temporarily pause study drug intervention or enrollment in the study. 
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The SRC meetings will be focused on reviewing the overall safety and tolerability of 
LY3885125. The SRC will document outcomes and recommended actions regarding: 
o No safety findings of concern, recommend study proceed without modification 
o Identified safety concerns that should be monitored more closely, recommend 
modifications to the study protocol/procedures, Investigator’s Brochure, and/or Informed 
Consent Forms 
o Identified safety concerns that the SRC would like to explore further, recommend 
unblinding the SRC members for further analysis and communication to senior 
management 
o Identified safety concerns that are concerning, recommend study drug intervention or 
enrollment to be paused while additional analyses are performed and escalation to senior 
management. 
4.5.3. 
Early Study Termination Criteria Based on Safety  
The Sponsor reserves the right to terminate the study at any time for any reason. The study will 
be discontinued if Lilly judges it is necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and Good Clinical Practice. 
The SRC will use the following criteria when considering if the study should be terminated early 
due to safety concerns: 
 
 develop the same treatment emergent adverse event (TEAE) or serious 
adverse event (SAE) regardless of causality that is severe or medically significant, but 
not immediately life-threatening; or where hospitalization or prolongation of 
hospitalization is indicated; or is disabling; or limits self-care activities of daily 
living; 
 
 develop any TEAE or SAE regardless of attribution to study drug that 
has life-threatening consequences or requires urgent intervention; 
 
Death of any subject at any time related to adverse event.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the Institutional Ethics Committees/Institutional Review Boards, the regulatory 
authorities, and any contract research organization used in the study of the reason for termination 
or suspension, as specified by the applicable regulatory requirements. The Investigator shall 
promptly inform the participants and assure appropriate participant therapy and/or follow-up. 
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5. Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
The eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG. The nature 
of any conditions present at the time of the physical examination and any preexisting conditions 
will be documented. 
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
(Days -28 to -1), and prior to randomization when participants arrive at the clinic on Day -1 only. 
Screening will occur up to 
 days prior to enrollment. Participants who are not enrolled within 
 days of screening may undergo additional medical assessment, clinical measurements, or both 
to confirm their eligibility. In such instances, the following screening tests and procedures will 
be repeated: medical assessment, vital signs, clinical laboratory tests, and ECG. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Participants in Part A and B: 
1. Males, or females not of childbearing potential (also see Section 10.4). 
a. 
Males who agree to use highly effective or effective methods of contraception may 
participate in this trial. 
i. 
All men must refrain from sperm donation for duration of the study and for 3 
months following the last dose of study intervention. 
ii. 
Men with partners of childbearing-potential must either remain abstinent (if 
this is their preferred and usual lifestyle), or must use condoms during 
intercourse for the duration of the study, and for
 days following the last 
dose of study intervention. 
b 
Female participants must be of nonchildbearing potential. If female, the participant 
must be either of nonchildbearing potential, defined as either surgically sterilized or 
at least 1 year postmenopausal (confirmed as FSH >40 IU/L at screening). 
2. 18 to 70 years of age inclusive, at the time of signing the informed consent. 
3. On a stable diet for the 3 months prior to randomization and plan to continue 
approximately the same stable diet during the study. 
4. Reliable and willing to be available for the duration of the study and willing to follow 
study procedures, and have given signed informed consent approved by the Sponsor and 
the Independent Ethics Committee (IEC) governing the site, prior to beginning any study-
specific procedures. 
Additional Inclusion Criteria for Part A Participants: 
5. Dyslipidemic with following fasted blood levels at screening: 
a. 
 mg/dL ≤TG 
 mg/dL. 
b. LDL-C 
 mg/dL. 
6. Body mass index (BMI) in range 18.5 to 45.0 kg/m2. 
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Additional Inclusion Criteria for Part A Cohort 6 Participants: 
7. Cohort 6 only: Must be on a 
 
before screening and plan to remain on the same 
medication and dose for the duration of the study. 
 
Additional Inclusion Criteria for Part B Participants: 
8. NAFLD with liver fat content 
% as determined by MRI-PDFF. 
9. Serum ALT 
 U/L and less than
 × upper limit of normal (ULN) (as described in 
Exclusion Criteria, Section 5.2). 
10. Controlled attenuation parameter (CAP) 
 dB/m by transient elastography done at 
screening visit or done within 
 days of screening visit. Participants must meet the CAP 
inclusion criteria prior to MRI assessment. 
11. BMI 
 and 
 kg/m2. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Participants in Part A and B: 
1. Sponsor (Eli Lilly and Company) employees, contract research organization (CRO) 
employees, Investigator or site personnel directly affiliated with this study or their 
immediate families (spouse, parent, child, or sibling, whether biological or legally 
adopted). 
2. Treatment with another investigational drug, biological agent, or device within 30 days of 
Screening Visit or 5 half-lives of investigational agent, whichever is longer. 
3. History or presence of medical illness including, but not limited to, any cardiovascular, 
thromboembolism or bleeding disorder, hepatic, respiratory, hematological, endocrine, 
immune, psychiatric, or neurological disease, convulsions, or any clinically significant 
laboratory abnormality that, in the judgment of the Investigator, indicate a medical 
problem that would preclude study participation. 
4. Supine heart rate greater than 
 bpm. A repeat measure is permitted. 
5. Uncontrolled hypertension with a resting blood pressure ≥ 160 mmHg systolic or ≥ 100 
mmHg diastolic at visit 1; a repeat assessment is permitted. 
6. Have had any of the following within the past 
days prior to screening: myocardial 
infarction, unstable angina, coronary artery bypass graft, percutaneous coronary 
intervention (diagnostic angiograms are permitted), transient ischemic attack, 
cerebrovascular accident, hospitalization due to heart failure. 
7. Have New York Heart Association functional Classification III-IV congestive heart 
failure. 
8. Current infection with Coronavirus disease 2019 (COVID-19). 
9. Current infection with hepatitis B virus (HBV), that is, positive for hepatitis B surface 
antigen (HBsAg) and/or polymerase chain reaction (PCR) positive for HBV 
deoxyribonucleic acid (DNA). 
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10. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA. Participants treated 
for hepatitis C (and diagnosed as cured) must have a RNA test at screening and be RNA 
negative for at least 2 years prior to screening to be eligible for the study. 
11. Human immunodeficiency virus (HIV) infection. 
12. Average weekly alcohol intake that exceeds 21 units per week (males) or 14 units per 
week (females), or are unwilling to stop alcohol consumption from 48 hours prior to 
admission to and while resident at the CRU (1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits).  
13. 
 
14. 
 for the reference range. 
15. 
 ULN for the reference range (except for cases of known 
Gilbert’s Syndrome). 
16. Platelet count 
/mm3. 
17. Clinical, laboratory, histological or imaging evidence of cirrhosis. 
18. Clinical evidence of hepatic decompensation as defined by the presence of any of the 
following abnormalities: 
a. 
Serum albumin 
 
b. International normalized ratio (INR)
. 
c. 
Direct bilirubin 
 
d. History of 
 
19. 
 
20. 
 
21. Taken drugs associated with hepatic steatosis (e.g., amiodarone, valproic acid, 
methotrexate, tamoxifen) for more than 2 weeks in the 3 months prior to screening visit. 
Note: If the use of such drugs is anticipated to be medically necessary within the next 6 
months, the participant should also be excluded 
22. Receiving chronic 
) systemic glucocorticoid therapy (excluding topical, intra 
ocular, intranasal, or inhaled preparations) or have received such therapy within 3 months 
prior to screening visit. 
23. eGFR less than or equal to 
, calculated by Chronic Kidney Disease 
Epidemiology (CKD-EPI) at screening.  
24. Hypersensitivity to LY3885125 or to any of the excipients. 
25. Any recent or recurrent infection within 14 days before dosing. 
26. Type 1 diabetes mellitus or any other type of diabetes mellitus other than T2DM. 
a. 
Poorly controlled T2DM with glycated hemoglobin (HbA1c) of 
 is excluded. 
27. Unwillingness to discontinue over-the counter (OTC) herbal medications that in the 
opinion of the Investigator can interfere with the study (see Section 6.9). 
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28. Initiation of an OTC medication in the 7 days prior to dose administration, or a new 
prescription medication in the 14 days prior to dose administration (including any 
medications for the treatment of obesity), except for hormone replacement therapy, 
vitamin and mineral supplements, low-dose aspirin, and occasional use of acetaminophen 
or ibuprofen. Additionally: 
a. 
A stable dose of statin medication for at least 8 weeks prior to screening is allowed; 
b. For participants with T2DM, stable treatment for at least 3 months prior to 
screening visit consisting of: 
i. 
Either diet/physical activity alone; or 
ii. 
Stable (
 change) dose of basal insulin and/or oral antihyperglycemic 
medications (
 
; see 
Exclusion Criteria 19). 
c. 
For participants with hypertension, a stable dose of up to 2 antihypertensive 
medications for 
 months prior to screening is allowed. 
d. Hormone replacement therapy in postmenopausal women is allowed, but women 
must be on stable therapy for months prior to screening. 
e. 
If any medications (other than those that are specifically allowed) are taken, an 
otherwise suitable participant may be included following the agreement between 
the Investigator and the Sponsor. 
29. Treatment with any oligonucleotide (siRNA and Antisense Oligonucleotide) therapy 
within the past 
 months. 
30. Treatment with GLP-1 RA and GIP/GLP-1 RA and approved or experimental agents that 
target PCSK9 within  months prior to screening visit. 
31. Thyroid-stimulating hormone (TSH) levels outside the normal reference range for the 
central laboratory at screening visit. Participants with hypothyroidism who are clinically 
euthyroid and on stable thyroid replacement therapy for at least 2 months prior to 
screening visit and who are anticipated to remain on this dose throughout the trial period 
are acceptable exceptions to this criterion.  
32. Blood donation of 
 mL within the previous  weeks of study screening or a blood 
transfusion or severe blood loss within the prior  months, or have a hemoglobin value 
 (males) or 
 (females).  
33. Unable to abide by investigative site restrictions on smoking and nicotine containing 
products. 
34. Positive result on urine drug test for drugs of abuse at screening and/or randomization. 
One re-test for a positive result may be allowed. A positive test for a medically 
appropriate drug in the opinion of the Investigator is not exclusionary. 
35. Are unwilling to comply with the dietary restrictions required for this study. 
 
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Additional Exclusion Criteria for Part B Participants: 
1. Evidence of other forms of chronic liver disease. 
2. Transferrin saturation
 except when it has been demonstrated that a diagnosis of 
hemochromatosis has been excluded by genetic testing or when a previous liver biopsy 
has demonstrated no evidence of iron overload. 
3. Initiated treatment with, or changed dose of, medications that may cause significant 
weight gain or weight loss, within  months prior to the screening visit. 
4. Have a self-reported change in body weight 
 months prior to 
screening visit. 
5. Prior surgical/endoscopic/device-based treatment/procedure for obesity. However, the 
following are allowed if performed >1 year before screening visit: liposuction, 
abdominoplasty, cryolipolysis. Prior device-based therapy is acceptable if device removal 
was more than 180 days prior to the screening visit. 
6. Contraindication to MRI, such as persons with cardiac pacemaker or implants made of 
metal (for example, cochlear implant, nerve stimulators, magnetic vascular clips, or 
metallic heart valve) other contraindications for MRI or have claustrophobia (note: other 
condition that precludes completion of an MRI examination. 
5.3. 
Lifestyle Considerations  
 Participants will be instructed to abstain from alcohol and foods containing poppy seeds 
48 hours prior to screening and prior to admission on Day 1 for Part A and Day 1 and 
Day 
 for Part B. 
 Lifestyle considerations which constitute exclusion criteria are provided in Section 5.2. 
Reproductive and contraceptive guidance is provided in Appendix 4 (Section 10.4). 
5.3.1. 
Meals and Dietary Restrictions  
Participants will fast overnight for at minimum 8 hours prior to dosing with study intervention 
and prior to all follow-up visits. Water is permitted ad libitum during the fasting period. All 
doses of study intervention will be administered SC in the morning after the overnight fast. All 
follow-up visits should also take place in the morning after the overnight fast.  
Standard meals will be provided during the stay at the CRU. Otherwise, participants will 
maintain their own dietary habits throughout the duration of the study. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco  
 While inpatients at the CRU, participants will be allowed to maintain their regular 
caffeine consumption throughout the study period. 
 No alcohol will be allowed at least 24 hours before each CRU admission and each 
outpatient visit, and throughout the duration of each CRU visit. Between CRU visits, 
weekly alcohol intake should not exceed 21 units for males and 14 units for females (a 
unit is defined in Exclusion Criterion 23, Section 5.2). 
 During the study, participants should not intentionally change their consumption of 
tobacco-containing products, except while inpatient at the CRU, when participants 
should abide by CRU restrictions on smoking and nicotine-containing product. 
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5.3.3. 
Activity  
Participants must refrain from strenuous exercise during the in-house period of the study and 
within 72 hours prior to scheduled blood sample collections for clinical safety labs. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened once at the discretion of the Investigator with Sponsor’s approval. If a participant is 
re-screened, they would be assigned a new participant number and would need to sign a new 
informed consent form (ICF). 
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6. Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. The study intervention used in this protocol is LY3885125 and 
matching placebo (commercially available sterile 0.9% saline, USP). 
6.1. 
Study Intervention(s) Administered  
LY3885125 or placebo will be administered as SC injections in the morning. Participants in Part 
A of the study will receive a single SC dose on Day 1 of Part A. Participants in the Part B will 
receive 2 SC doses, one on 
 of Part B and one on 
 of Part B. 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3885125 
Placebo 
Dosage Level(s) 
Part A: 
Cohorts 1 to 5: single ascending 
doses from  mg to 
 mg on 
Day 1. 
Cohort 6 (optional): Single dose 
to participants with dyslipidemia 
on stable moderate or 
high- intensity dose of statin. 
Part A: 
Cohorts 1 to 5: single dose on 
Day 1. 
 
Cohort 6 (Optional): Single dose 
to participants with dyslipidemia 
Part B: 
Cohort 7 (NAFLD participants 
with elevated ALT): Single dose 
on 
 and on 
. Data 
review in Part A will inform 
Part B dose. 
Part B: 
Cohort 7 (NAFLD participants 
with 
): Single dose 
on 
 and on 
. 
Route of 
Administration 
Subcutaneous 
Subcutaneous 
 
Packaging and labeling 
Study interventions will be supplied by the Sponsor or its designee in accordance with current 
Good Manufacturing Practice (GMP). Study interventions will be labeled as appropriate for 
country requirements. 
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6.2. 
Preparation, Handling, Storage, and Accountability  
 The Investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. 
 All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized study personnel. 
 The Investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
 Further guidance and information for the final disposition of unused study interventions 
are provided in the laboratory manual.  
6.3. 
Assignment of Study Intervention  
On Day -1 participants will be assigned a unique number (randomization number) in ascending 
numerical order. The randomization number encodes the participant’s assignment to the study 
intervention, according to the randomization schedule generated prior to the study by the 
statistics department at the Sponsor or designee. Each participant will be dispensed blinded study 
intervention, labeled with the participant’s unique randomization number, throughout the study. 
The blinding procedures for this study are provided in Section 6.4. 
Details of assignment of study intervention in Part A and B of the study, as well as stopping 
criteria are provided below. 
6.3.1. 
Dose Escalation in Part A  
Participants in Part A (Cohort 1 through 6) of the study will receive a single SC dose of 
LY3885125 or placebo on Day 1 of Part A, randomized as described in the following table: 
Part A 
Cohort 
n 
Randomization 
(LY3885125:placebo) 
1-2 
 
6:2 
3-5 
 
9:2 
6 (optional) 
 
10:9 
 
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Dose Escalation Committee 
The DEC will meet once data are available from at least  participants in Cohorts 1 and 2, and at 
least  participants in Cohorts 3 to 5. There will be 2 parts to each DEC meeting: an open session 
and a closed session.  
 
In the open session, aggregate safety data from each cohort will be reviewed in blinded manner. 
The Investigator and medical monitor will be in attendance along with the DEC members who 
will have access to the treatment assignment of individual participants if required. No unblinded 
data will be shared during the open session. 
 
In the closed session, DEC members with access to the treatment assignment of individual 
participants across all completed and ongoing cohorts will agree on proceeding to the next cohort 
as planned. The DEC will also consider whether the next intended dose level is appropriate or 
whether this should be adjusted (for example, a lower dose given) in the next cohort. Decisions 
will be based on criteria described in Section 4.5.1 (dose escalation stopping criteria) and 4.5.2 
(temporary stopping criteria).  
The DEC will review all safety data, laboratory parameters, and available PK/PD data as 
described in Table 6.1. 
 
Table 6.1 
Data Reviewed by Dose Escalation Committee (DEC)  
 
Safety and Tolerability 
Pharmacokinetics 
Part A 
(SAD) 
Dose 
Progression 
Cohort 2  
All data from  or more participants from the prior 
SAD cohort, up to at least 
 at the prior dose 
level 
 
Cohorts 3 to 5 
All data from  or more participants from the prior 
SAD cohort, up to at least 
 at the prior dose 
level 
Available data 
Part B 
Initiation of 
First dose 
Part B (Cohort 7) will be initiated after the review 
of all available data, including 
 data, up 
to at least 
 of Cohort 5 in Part A.  
 
 
Available 
cumulative data, 
including data up to 
at least 
  
SAD = single ascending dose 
 
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6.3.2. 
Dosing in Part B  
For Part B (Cohort 7) a total of approximately 44 participants will be randomized into 
3 treatment arms to receive 2 SC doses of study intervention (LY3885125 or placebo), one dose 
on 
 and one dose approximately 
 weeks later on 
 
The assignment of study intervention (LY3885125 or placebo) in each treatment arm and 
number of participants is shown in Section 4.1.2. The dose for Part B will not exceed the dose 
tested and deemed to be safe in Part A as shown above in Table 6.1. The protocol will be 
amended prior to initiation of Part B to define the dose level and frequency of dosing. 
6.4. 
Blinding  
This study will be participant- and Investigator-blind. Site-facing Sponsor personnel will also be 
blinded throughout the study. Non-site-facing Sponsor personnel may be unblinded as necessary, 
and this information will be recorded. 
Blinding will be maintained throughout the conduct of the study. One set of sealed envelopes 
containing the randomization code will be made available to the investigator at the start of the 
trial. A code envelope, which reveals the treatment for a specific study participant, may be 
opened during the study only if the participant’s well-being requires knowledge of the 
participant’s treatment assignment. In case of an emergency, the Investigator has responsibility 
for determining if the unblinding of a participant’s treatment assignment is warranted for medical 
management of the event. The participant’s safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, it is the 
responsibility of the Investigator to promptly document the decision and rationale and notify 
Sponsor study personnel as soon as possible. 
If an Investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from treatment. In cases where there are ethical reasons to have 
the participant remain in the study, the Investigator must obtain specific approval from the 
Sponsor’s Clinical Research Physician (CRP) for the participant to continue in the study. 
6.5. 
Study Intervention Compliance  
Not applicable. 
6.6. 
Dose Modification  
For dose modification see Section 6.3. 
6.7. 
Continued Access to Study Intervention after the End of the Study  
Not applicable. 
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6.8. 
Treatment of Overdose  
For this study, any dose of study intervention greater than assigned through enrollment will be 
considered an overdose. 
In the event of an overdose, the Investigator or the treating physician should: 
 Contact the medical monitor immediately. 
 Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities as until the 
study intervention no longer has a clinical effect or can no longer be detected 
systemically (at least 10 days). 
 Obtain a plasma sample for PK analysis as soon as possible. 
 Document the quantity of excess dose as well as the duration of the overdose in the case 
report form (CRF). 
6.9. 
Prior and Concomitant Therapy  
In general, concomitant medication other than those specified should be avoided; however, OTC 
medications may be administered at the Investigator’s discretion (e.g., acetaminophen for 
treatment of headache at doses ≤2 grams/24 hours). 
If the need for concomitant medication (other than OTC medications) arises, inclusion or 
continuation of the participant may be at the discretion of the Investigator after consultation with 
the Sponsor. 
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrollment or receives during the 
study must be documented along with: 
 Reason for use. 
 Dates of administration including start and end dates. 
 Dosage information including dose, route of administration, and frequency for 
concomitant therapy of special interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
ACC/AHA Statin Therapies 
Below in Table 6.2 are listed the different types of statin therapy by intensity according to the 
American College of Cardiology (ACC) and the American Heart Association (AHA) rating 
system (Stone et al. 2014). 
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Table 6.2 
Statin Therapies According to American College of Cardiology (ACC) and 
American Heart Association (AHA) Classificationa  
High-Intensity Statin Therapy  
Moderate-Intensity Statin Therapy  
Daily dose lowers LDL-C by 
approximately ≥50%  
Daily dose lowers LDL-C by approximately 
30% to <50%  
Atorvastatin 40 mg, 80 mg 
Rosuvastatin 20 mg, 40 mg  
Atorvastatin 10 mg, 20 mg  
Rosuvastatin 5 mg, 10 mg 
Simvastatin 20 mg, 40 mgb 
Pravastatin 40 mg, 80 mg  
Lovastatin 40 mg  
Fluvastatin XL 80 mg  
Fluvastatin 40 mg twice daily  
Pitavastatin 2 mg, 4 mg 
a Stone et al. 2014 
b Simvastatin 80 mg is not allowed in this study. 
 
Prohibited Medications 
The following medications are prohibited throughout the study: 
 GLP-1 RA or other incretin-based therapies and DPP-4 inhibitors. 
 Medications intended to promote weight loss, including prescribed, OTC, or alternative 
remedies. 
 Drugs reported to induce hepatic steatosis. 
 Long-term (>14 days) systemic corticosteroid therapy. 
 
Examples of medications prohibited throughout the study are presented in Table 6.3. 
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Table 6.3 
Examples of Prohibited Medications  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.9.1. 
Standard of Care for Participants with Type 2 Diabetes Mellitus  
Patients with well-controlled T2DM may enroll in this study. Although it is not anticipated that 
LY3885125 will have an adverse effect on blood glucose levels, it is possible that glycemic 
control may worsen during this study due to the natural history of T2DM. Investigators and other 
study team members are expected to treat study participants according to the nationally 
established standards of care for diabetes management in respective participating countries, 
except where that treatment would be in conflict with the protocol-provided treatment 
requirements (see Section 6.9 prohibited medications). The investigators should follow current 
published standards of care from the American Diabetes Association (ADA) (ElSayed et al. 
2023), and consensus guidelines of ADA and European Association for the Study of Diabetes 
(EASD) (Davies et al. 2022). 
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7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
Participants discontinuing from study intervention prematurely for any reason should complete 
AE and other follow-up procedures per the SoA (Section 1.3)of this protocol. 
7.1. 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention (applies only 
to Part B). If study intervention is permanently discontinued, the participant will remain in the 
study to complete procedures for an early termination visit and post-treatment follow-up, if 
applicable, as shown in the SoA (Section 1.3). 
In Part B, prior to the repeat dose, all available safety data will be reviewed. Any clinically 
significant findings that may determine if further dosing should be discontinued will be 
determined by the Investigator in consultation with the Sponsor. A second dose will not be 
administered if the study participant experienced a hypersensitivity reaction after receiving the 
first dose in Part B of the study. 
A participant should be permanently discontinued from study intervention if: 
 The participant becomes pregnant during the study 
 The participant decides to discontinue study intervention 
 The Investigator decides that the participant should be discontinued due to AEs (the 
participant will be followed until the AE resolves) 
 The participant has a SAE considered related to study treatment. 
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7.1.1. 
Liver Chemistry Stopping Criteria  
Study intervention should be interrupted or discontinued if one or more of the conditions listed in 
Table 7.1 occur. 
Table 7.1 
Liver Chemistry Stopping Criteria  
Participants with Normal or Near Normal 
Baseline ALT, AST, ALP (<1.5 × ULN) 
Participants with Elevated Baseline ALT, 
AST, ALP (≥1.5 × ULN) 
ALT or AST >5 × ULN 
ALT or AST >3 × baseline 
ALT or AST >3 × ULN and either TBL >2 × 
ULN or INR >1.5  
(Except for participants with Gilbert’s 
syndrome)a 
ALT or AST >2 × baseline and either TBL >2 
× ULN or INR >1.5 
(Except for participants with Gilbert’s 
syndrome)a 
ALT or AST >3 × ULN with the appearance 
of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
ALT or AST >2 × baseline with the 
appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
ALP >3 × ULN, when the source of increased 
ALP is the liver 
ALP >2.5x baseline when the source of 
increased ALP is the liver 
ALP >2.5x ULN and TBL > 2x ULN 
ALP >2x baseline and TBL > 2x ULN 
ALP >2.5x ULN with the appearance of 
fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
ALP >2x baseline with the appearance of 
fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
a For participants with Gilbert’s syndrome, doubling of direct bilirubin should be used for drug interruption 
decisions rather than TBL >2 × ULN. 
 
Resumption of the study intervention can be considered only in consultation with the Sponsors 
designated medical monitor and only if the liver test results return to baseline and if a self-
limited non drug-etiology is identified (see Section 8.2.5.1 for further details). Otherwise, the 
study intervention should be discontinued. Participants who discontinue from study intervention 
due to the abnormal liver tests will undergo monitoring as described in Appendix 5 
(Section 10.5). 
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7.1.2. 
QTcF Stopping Criteria  
If a clinically significant finding is identified on ECG, including, but not limited to changes from 
Day 1 predose baseline in QT interval corrected using Fridericia’s formula [QTcF] after 
enrollment, the Investigator or qualified designee will determine if the participant can continue in 
the study and if any change in participant management is needed. QTcF > 500 confirmed from 
the average of triplicate ECGs is a criterion to stop dosing in a participant. This review of the 
ECG printed at the time of collection must be documented. Any new clinically relevant finding 
should be reported as an AE. The predose baseline used for the calculation of the change in QTc 
value is the average of the triplicate ECG taken closest to the time point of dosing on Day 1. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study: 
 At any time at the participant’s own request for any reason or without providing any 
reason. 
 At the request of the participant’s designee (for example, parents or legal guardian). 
 At the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons. 
 If enrolled in any other clinical study involving an investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
 If the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to the 
introduction of the new agent. 
 
At the time of discontinuation from the study, if possible, the participant will complete 
procedures for an early discontinuation visit and post-treatment follow-up, if applicable, as 
shown in the SoA (Section 1.3). If the participant has not already discontinued study 
intervention, the participant will be permanently discontinued from the study intervention at the 
time of the decision to discontinue the participant from the study. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the Investigator must document this in the site study records. 
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7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not receive study intervention. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 
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8. Study Assessments and Procedures  
 Study procedures and their timing are summarized in the SoA (Section 1.3). 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1. 
Efficacy Assessments  
Efficacy is not evaluated in this study. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations  
Complete physical examinations and symptom-directed physical assessment will be conducted at 
the visits specified in the SoA (Section 1.3). Symptom-directed physical assessment may also be 
conducted at other visits, as determined by the Investigator, if a participant presents with 
complaints: 
 A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded as noted in the SoA. 
 A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
 Investigators should pay special attention to the clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs  
For each participant, vital signs measurements will be conducted at the visits specified in the 
SoA (Section 1.3) and as clinically indicated. Participants must be supine for approximately 
5 minutes before blood pressure and pulse rate collection and remain supine but awake during 
measurement. Systolic and diastolic blood pressure and pulse rate should be measured after the 
ECG is recorded (if the ECG is recorded at the same time point) and before other procedures. 
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8.2.3. 
Electrocardiograms  
Triplicate 12-lead ECGs will be obtained on the days and times specified in the SoA 
(Section 1.3). ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc 
withdrawal criteria and any additional QTc readings that may be necessary: 
 At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but at least 1 minute apart. 
 The ECGs must be recorded before collecting any blood samples. Participants must be 
supine for at least 5 minutes before ECG collection and remain supine but awake during 
ECG collection. ECGs may be obtained at additional times, when deemed clinically 
necessary. Collection of additional ECGs at a particular time point is allowed to ensure 
high-quality records. 
 
ECGs will be interpreted by a qualified physician, the Investigator, or qualified designee at the 
site as soon after the time of ECG collection as possible. Ideally, the Investigator should be 
present: 
 To determine whether the participant meets entry criteria at screening; and 
 For immediate participant management, should any clinically relevant findings be 
identified. 
 
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the Investigator will determine if the participant can 
continue in the study (Section 7.1.2). The Investigator, or qualified designee, is responsible for 
determining if any change in participant management is needed and must document his/her 
review of the ECG printed at the time of evaluation. Any new clinically relevant finding should 
be reported as an AE. 
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless the Investigator considers there is a need for over-read of the ECGs prior to 
completion of the final study report (in which case the overread data would be used). 
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8.2.4. 
Clinical Safety Laboratory Tests  
 See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency of tests. 
 The Investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant's condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or medical monitor. 
o 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
o 
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual. 
 If laboratory values from non-protocol specified laboratory assessments performed at an 
Investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the Investigator (for example, SAE or AE or dose 
modification), then report the information as an AE. 
8.2.5. 
Safety Monitoring  
The Sponsor’s CRP will monitor safety data throughout the course of the study. 
The Sponsor will review SAEs within time frames mandated by company procedures. When 
appropriate, the Sponsor CRP will consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical research scientist. 
 The medical monitor will periodically review the following data: 
 trends in safety data 
 laboratory analytes, and 
 SAEs and non-SAEs, including monitoring of GI events, hypoglycemia, injection-site 
reactions, hypersensitivity reactions, and reported and adjudicated pancreatitis. 
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8.2.5.1. 
Hepatic Safety  
Close Hepatic Monitoring 
Laboratory tests (Section 10.2), including ALP, ALT, AST, TBL, direct bilirubin, GGT, and 
creatine kinase (CK) should be repeated within 
 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if 1 or more of these conditions occur: 
If a participant with baseline results of.... 
develops the following elevations: 
ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN 
ALP <1.5 × ULN 
ALP ≥2 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with 
Gilbert’s syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline (except for participants 
with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the Investigator in consultation with 
the Sponsor’s designated medical monitor. At a minimum, this evaluation should include 
physical examination and a thorough medical history, including symptoms, recent illnesses, (for 
example, heart failure, systemic infection, hypotension, or seizures), recent travel, history of 
concomitant medications (including OTC), herbal and dietary supplements, history of alcohol 
drinking, and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to 
, if the 
participant’s clinical condition and clinical laboratory results stabilize. Monitoring of ALT, AST, 
ALP, and TBL should continue until levels normalize or return to approximate baseline levels. 
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Comprehensive Hepatic Evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline results of.... 
develops the following elevations: 
ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN 
ALP <1.5 × ULN 
ALP ≥2 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with 
Gilbert’s syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline (except for participants 
with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time international normalized ratio 
(PT-INR), viral hepatitis A, B, C, and E, tests for autoimmune hepatitis, and an abdominal 
imaging study (for example, ultrasound or computed tomography [CT] scan). 
Based on the participant’s history and initial results, further testing should be considered, in 
consultation with the Sponsor’s designated medical monitor, including tests for: 
 Hepatitis D virus (HDV) 
 Cytomegalovirus (CMV) 
 Epstein-Barr virus (EBV) 
 Acetaminophen levels 
 Acetaminophen protein adducts 
 Urine toxicology screen 
 Wilson’s disease 
 Blood alcohol levels 
 Urinary ethyl glucuronide; and 
 Blood phosphatidylethanol 
 
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Based on the circumstances and the Investigator’s assessment of the participant’s clinical 
condition, the Investigator should consider referring the participant for: 
 Hepatologist or gastroenterologist consultation 
 Magnetic resonance cholangiopancreatography (MRCP) 
 Endoscopic retrograde cholangiopancreatography (ERCP) 
 Cardiac echocardiogram; or 
 Liver biopsy 
 
Additional Hepatic Data Collection (Hepatic Safety CRF) in Study Participants who have 
Abnormal Liver Tests during the Study 
Additional hepatic safety data collection (hepatic safety CRF) should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5 × ULN). 
 
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT ≥3 × baseline 
on 2 or more consecutive tests. 
2. Elevated TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome). 
 
In participants with baseline TBL ≥1.5 × ULN, the threshold should be TBL ≥2 × 
baseline. 
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN). 
4. Hepatic event is considered to be a SAE. 
5. Discontinuation of study intervention due to a hepatic event. 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will occur as indicated in the SoA (Section 1.3). 
8.2.7. 
Injection Site Reactions (ISR)  
Symptoms of a local ISR may include: 
 Erythema 
 Induration 
 Pain 
 Pruritus, and 
 Edema 
If an ISR is reported by a participant or investigator, the ISR Case Report Form (CRF) will be 
used to capture additional information about this reaction (for example, degree and area of 
erythema, induration, pruritus, and edema). 
All positive responses of pain will require an additional assessment using the Pain Visual Analog 
Scale (Pain VAS). Pain measurements will be quantified using the 100-mm VAS pain score. 
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Management of ISRs will consist of ice packs and may include topical administration of 
antihistamines to alleviate itching. 
8.2.8. 
Hypersensitivity Reactions  
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided 
to the Sponsor in the electronic CRF. If the Investigator, after consultation with the Sponsor-
designated medical monitor, determines that a systemic hypersensitivity reaction has occurred 
related to study drug administration, the participant should be permanently discontinued from 
further study intervention. 
The investigative sites should have appropriately trained medical staff and appropriate medical 
equipment available when study participants are receiving study intervention. It is recommended 
that participants who experience a systemic hypersensitivity reaction be treated with systemic 
antihistamines, intravenous steroids, and in case of a severe allergic reaction (for example, 
anaphylactic reaction), epinephrine (in accordance with severity of the reaction and local 
standard of care). 
Additional information will be collected on the CRF, including signs and symptoms related to 
the main event, as well as relevant medical history and the participant’s potential risk factors. If 
the study participant experiences changes in blood pressure or pyrexia/fever, additional vital sign 
information, including blood pressure, temperature, and pulse, should be collected. The timing of 
the AE and any treatments administered should also be collected.   
In case of generalized urticaria or anaphylaxis, additional blood samples should be collected as 
described below. 
Laboratory assessments (hypersensitivity laboratory testing kit) will be performed if the 
participant experiences generalized urticaria or if anaphylaxis is suspected. The sample will be 
collected after the participant has been stabilized, and 
. Samples 
may, however, be obtained 
 after the event occurred as analytes can remain altered 
for an extended period of time. The time the sample was collected will be recorded. A follow-up 
sample will be 
, whichever is later. 
The samples will be analyzed to determine levels of the following: 
 LY3885125 concentrations 
 Tryptase 
 N-methylhistamine 
 Basophil activation test 
 Complement (C3, C3a, and C5A) 
 Cytokine panel (IL-6, IL-1β, and IL-10) 
Samples will be taken and stored for future immunogenicity testing and analysis for drug-
specific immunoglobulin E (IgE). 
In the event of a hypersensitivity reaction, participants will continue to be followed according to 
the schedule of activities. 
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8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
 AEs 
 SAEs 
 Product complaints. 
 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the Investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
For product complaints, the Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
 
 
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8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events: 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation has 
ended and the 
Investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
The predicted 
time until 
estimated 
plasma levels 
of partner 
would be 
below the 
level of 
toxicologic 
concern, plus 
93 days 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
Product Complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the Investigator 
N/A 
PC (if 
Investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product Complaint 
form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event 
*Serious adverse events should not be reported unless the Investigator deems them to be possibly related to study 
treatment or study participation. 
 
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8.3.2. 
Pregnancy  
Collection of Pregnancy Information 
Male participants with partners who become pregnant: 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant within 93 days of last visit while the male 
participant is in this study. This applies only to male participants who receive study 
intervention. 
 After learning of a pregnancy in the female partner of a study participant, the Investigator 
will: 
o Obtain a consent to release information from the pregnant female partner 
directly; and 
o Within 24 hours after obtaining this consent will record pregnancy 
information on the appropriate form and submit it to the Sponsor. 
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female participants who become pregnant: 
Female participants must be considered of nonchildbearing potential to participate in the study 
(see Sections 5 and 10.4). However, in the event a participant becomes pregnant, the following 
action must be taken: 
 The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant's pregnancy. 
 The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of gestational age, fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
 A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at ≥20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 
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 Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in protocol 
Section 8.3.1. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. If the participant discontinues the study, follow the 
standard discontinuation process and continue directly to the follow-up phase. The 
follow-up on the pregnancy outcome should continue independent of intervention or 
study discontinuation. 
8.3.3. 
Adverse Events of Special Interest  
Not applicable 
8.4. 
Pharmacokinetics  
In Parts A and B blood samples will be collected to determine plasma concentrations of 
LY3885125. The blood samples will be collected on the days and times specified in the SoA 
(Section 1.3). The plasma samples will be prepared for analysis as detailed in the laboratory 
manual provided separately to sites. 
The PK of LY3885125 will be assessed in Part A after a single SC dose of LY3885125 on 
 
 on 
 and 
. The PK endpoints to be 
determined include AUC, Cmax, Tmax. 
A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between the Investigator and the Sponsor. The timing of sampling 
may be altered during the study based on newly available data (for example, to obtain data closer 
to the time of peak plasma concentrations) to ensure appropriate monitoring. 
Instructions for the collection and handling of biological samples will be provided by the site. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
Samples collected for analyses of LY3885125 plasma concentration may also be used to evaluate 
LY3885125 pharmacology or safety aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
Urine samples will be collected for the characterization of renal clearance. Total urine output for 
the appropriate period after study intervention administration will be collected, pooled, and 
refrigerated. At the end of the collection period, the total urine volume will be recorded. Urine 
samples will be used to determine creatinine, quantification of LY3885125 and if applicable 
major metabolite and exploratory metabolite identification. Assessment of renal clearance will be 
an exploratory assessment; therefore, failure to collect samples or analyze all collected samples 
will not be a deviation. 
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8.5. 
Pharmacodynamics  
PCSK9 and Apo Panel 
In Parts A and B blood samples will be collected to determine plasma levels of PCSK9 and 
ApoB/Apo panel as markers of the PD of LY3885125: 
 For Part A, the changes in PCSK9 and ApoB from baseline relative to placebo after the 
single dose of LY3885125 on Day 1 will be determined; and 
 For Part B, the changes in PCSK9 and ApoB from baseline to Weeks 
 and 
 relative 
to placebo will be determined.  
 
Fasting blood samples will be collected at visits and times specified in the SoA (Section 1.3), and 
the samples prepared for analysis as detailed in the laboratory manual provided separately to 
sites.  
Liver Fat Content 
In Part B liver fat content will be estimated on MRI-PDFF, which will be performed at visits and 
times specified in the SoA (Section 1.3), and as detailed in the laboratory manual. 
The relative change in liver fat content (relative percent) from Baseline to Weeks 
 and
 by 
MRI-PDFF compared to placebo following the 2 SC doses on Days  and Day 
 will be 
assessed. 
8.6. 
Genetics  
Genetics are not evaluated in this study. 
8.7. 
Lipid Profile  
 
 
8.8. 
Biomarkers  
Serum Biomarkers 
 
 
 
Blood samples will be collected at the visits and times in the SoA (Section 1.3), and the serum 
samples prepared for analysis as detailed in the laboratory manual provided separately to sites. 
The Sponsor may store the samples for up to 15 years after the end of the study to achieve study 
objectives. Additionally, with participants’ consent, samples may be used for further research by 
the Sponsor. 
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8.9. 
Immunogenicity Assessments  
Antibodies targeting or binding to LY3885125 will be evaluated in serum collected from all 
participants at the visits and times in the SoA (Section 1.3). 
Serum samples will be screened for antibodies binding to study intervention, and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify the 
stability of antibodies to study intervention and/or further characterize the immunogenicity of 
study intervention. 
The detection and characterization of antibodies to study intervention will be performed using a 
validated assay method by or under the supervision of the Sponsor. All samples collected for 
detection of antibodies to study intervention will also be evaluated for study intervention serum 
concentration to enable interpretation of the antibody data. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study intervention. 
Samples may be stored for a maximum of 15 years (or according to local regulations) following 
the last participant’s last study visit at a facility selected by the Sponsor to enable further analysis 
of immune responses to study intervention. 
8.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Not applicable 
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9. Statistical Considerations  
9.1. 
Statistical Hypotheses  
No inferential analyses are planned for either Part A or Part B, so no formal statistical 
hypotheses are defined. Only descriptive summary statistics will be provided for endpoints of 
interest. 
9.1.1. 
Multiplicity Adjustment  
No inferential analyses are planned for either Part A or Part B, so no adjustment for multiplicity 
is necessary. 
9.2. 
Analyses Sets  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set / 
Population 
Description 
Full analysis set (FAS) 
All randomized participants. 
Safety analysis set 
All participants who are exposed to study intervention. 
Pharmacodynamics (PD) 
analysis set 
All participants in the Safety analysis set who have at least one 
PD assessment 
Pharmacokinetics (PK) 
analysis set 
All participants who have received at least one dose of 
LY3885125 and have sufficient concentration-time data to 
estimate PK parameters. 
The full analysis set is used to analyze disposition and baseline characteristics, the safety 
analysis set is used to analyze the endpoints and assessments related to safety, the PD analysis 
set is used to analyze PD endpoints, and the PK analysis set is used for the PK analyses. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. Details 
of statistical analysis methods will be described in the Statistical Analysis Plan (SAP). 
Bayesian analyses will be performed using the primary PD marker – change from baseline in 
PCSK9 in Part A and relative change of liver fat content (percent) by MRI-PDFF in Part B at 
Weeks 
. All other analyses will only provide descriptive statistics tabulated by cohort. 
Some descriptive summaries, e.g., participant accounting, study disposition, and participant 
demographics, will also provide descriptive statistics for all cohorts pooled together. 
Incidence based summaries and analyses with binomial outcomes will use all observed data for 
participants in the respective analysis set with presentation of number and percent of participants. 
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Summaries for continuous variables will include the number of participants in the analysis, 
mean, standard deviation, median, minimum, and maximum.  
Any change to the data analysis methods described in the protocol will require a protocol 
amendment ONLY if it changes a principal feature of the protocol. Any other changes to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the SAP or clinical study report (CSR). 
Handling of missing, unused, and spurious data will be addressed in the SAP, where appropriate. 
Adjustments to the planned analyses will be described in the final CSR. 
SAS software version 9.4 or higher will be used to perform statistical analyses, unless otherwise 
specified. 
9.3.2. 
Primary Endpoint(s) Analysis  
The primary endpoints in Part A and in Part B are AEs and SAEs. The analyses for AEs and 
SAEs will focus on events that emerge or worsen after the first dose of LY3885125. Events that 
occur after the last follow-up visit or early termination visit will only be included in an analysis 
if the investigation believes the event is at least possibly related to LY3885125. 
9.3.3. 
Secondary Endpoint(s) Analysis  
The secondary endpoints in Part A are: 
 PK - LY3885125 AUC, Cmax, Tmax. 
 PD - Changes in PCSK9 and ApoB from baseline relative to placebo. 
The secondary endpoints in Part B are: 
 PK - LY3885125 AUC, Cmax, Tmax. 
 PD - Relative change of liver fat content (percent) from baseline to 
 by 
MRI-PDFF compared to placebo. 
 PD - Changes in PCSK9 and ApoB from baseline relative to placebo. 
9.3.4. 
Exploratory Endpoint(s) Analysis  
 
 
 
 
 
 
 
 
 
 
 
9.3.5. 
Safety Analyses  
Safety analyses will be conducted on all participants who received at least one dose of study 
treatment. No statistical comparisons of treatment groups will be completed for safety endpoints. 
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Adverse events will be summarized and listed. Quantitative measurements, such as clinical 
laboratory safety tests, vital signs and ECGs, will be descriptively summarized by treatment 
group using number of participants, mean, median, standard deviation, minimum and maximum. 
Categorical endpoints will be summarized using number of participants, frequency, and 
percentages. Additional analysis will be performed if warranted upon review of the data. 
9.3.6. 
Other Analyses  
A concentration-response analysis will be performed according to International Council for 
Harmonisation (ICH)-E14 (the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs) guidelines. 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. 
9.5. 
Sample Size Determination  
Enrollment for Part A will enable completion of approximately 68 participants in up to 6 cohorts. 
Enrollment of 19 participants, randomized 10:9 to LY3885125:placebo in Cohort 6 was 
 
 
 
  
Enrollment for Part B will enable completion of approximately 44 participants in a single cohort 
that consists of 3 treatment arms with 2 doses administered per arm. The sample size for Part B 
was
 
 
Participants may be replaced at the discretion of the sponsor for adequate evaluation of study 
endpoints. 
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10. Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines. 
○ Applicable International Council for Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines. 
○ Applicable laws and regulations. 
● The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure (IB), and other relevant documents (for example, advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethic 
Committees (IEC) by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The Investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. 
○ Notifying the IRB/IEC of serious adverse events (SAEs) or other significant 
safety findings as required by IRB/IEC procedures. 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), 
ICH guidelines, the IRB/IEC, and all other applicable local regulations. 
○ Reporting to the Sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity. 
● Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement (CTA). 
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10.1.2. 
Financial Disclosure  
Not applicable for Phase 1 study. 
10.1.3. 
Informed Consent Process  
● The Investigator or the Investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
● Potential participants must be informed that their participation is voluntary. 
Participants will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and 
data protection requirements, where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the Sponsor. Any participant 
records, datasets or tissue samples that are transferred to the Sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the Sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent. 
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The contract research organisation (CRO)has processes in place to ensure data 
protection, information security, and data integrity. These processes include 
appropriate contingency plan(s) for appropriate and timely response in the event 
of a data security breach. 
 
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by the Sponsor to all Investigators (for example, by phone and/or 
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email) as soon as possible. It will be a requirement that Investigators respond upon receipt to 
confirm that they understand the communication and have taken the appropriate action prior to 
further dosing any participants with study intervention. Any Investigator not responding will be 
followed up by Sponsor personnel prior to any further planned dosing. If a dose is planned 
imminently, Sponsor personnel will immediately, and continually, use all efforts to reach 
Investigators until contact is made and instructions verified. 
Reports 
The Sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The Sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case by case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.5. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the Sponsor or designee electronically (for example, 
laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
● The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. Source data may include laboratory 
tests, medical records, and clinical notes. 
● The Investigator must review and confirm that data entries are accurate and 
complete throughout the duration of the study, by physically or electronically 
signing the CRF, as instructed by the Sponsor. All completed CRFs must be 
signed prior to archival. 
● The Investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source documents. 
● Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan. 
● The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
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● The Sponsor assumes accountability for actions delegated to other individuals (for 
example, CROs). 
● The Sponsor or designee will perform monitoring to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for the time period outlined in the CTA 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or 
party without written notification to the Sponsor. 
● In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by Sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor. 
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The Investigator maintains a separate source for the data entered by the Investigator or 
designee into the EDC system. The Investigator is responsible for the identification of any data 
to be considered a source and for the confirmation that data reported are accurate and complete 
by signing the CRF. 
Data collected via the CRO data capture system will be stored by the CRO. The Investigator will 
have continuous access to the data during the study and until decommissioning of the data 
capture system. Prior to decommissioning, the Investigator will receive or access an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
Investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the Sponsor data warehouse. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 
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10.1.6. 
Source Documents  
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
● Data reported on or entered in the CRF and may be transcribed from source 
documents and must be consistent with the source documents or the discrepancies 
must be explained. The Investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in Section 10.1.5. 
10.1.7. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or Site Termination 
The Sponsor or Sponsor’s designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of the Sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
● Discontinuation of further study intervention development 
For site termination: 
● Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
● Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) (CRO[s]) used in the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should ensure appropriate participant therapy and/or follow-up. 
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10.1.8. 
Publication Policy  
In accordance with the Sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.9. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the Sponsor, 
will participate as Investigators in this clinical trial. 
10.1.10. 
Long-Term Sample Retention  
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3885125 or after LY3885125 become(s) commercially available. 
The following table lists the maximum retention period for sample types. The retention period 
begins after the last participant visit for the study. 
The maximum retention times may be shorter, if specified in local regulations and/or if ethical 
review boards/IRBs impose shorter time limits. 
Any samples remaining after the specified retention period will be destroyed. 
The sample retention facility will be selected by the Sponsor or its designee. 
Sample Type 
Custodian 
Retention Period After Last 
Participant Visit* 
Pharmacokinetics 
Sponsor or Designee 
2 years 
Biomarkers 
Sponsor or Designee 
15 years 
 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
● The clinical laboratory safety tests detailed in the table below will be performed 
by the designated central and local laboratories. 
● In circumstances where the Sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
● Investigators must document their review of the laboratory safety results. 
Clinical laboratory test results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 
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Safety Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin 
Erythrocyte/red blood cell (RBC) count  
Mean cell volume 
Mean cell hemoglobin 
Mean cell hemoglobin concentration 
Leukocytes/white blood cell (WBC) count 
Platelets 
 
Differential WBC [Absolute counts and %] of: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Coagulation: 
International normalized ratio (INR) 
Prothrombin Time (PT) 
Activated partial thromboplastin Time (aPTT) 
 
Glycated hemoglobin (HbA1c) 
Clinical Chemistry: 
Sodium 
Potassium 
Bicarbonate 
Chloride 
Calcium total 
Phosphorus 
Magnesiuma 
Glucose (random) 
Creatinine 
Blood urea nitrogen (BUN) 
Total protein 
Albumin 
Direct bilirubin 
Total bilirubin (TBL) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Creatine kinase (CK) 
Gamma-glutamyl transferase (GGT) 
Lactate dehydrogenase (LDH) 
Iron 
Transferrin 
Transferrin saturationa 
Estimated glomerular filtration rate (eGFR) 
calculated by Chronic Kidney Disease Epidemiology 
(CKD-EPI)a 
Urinalysis: 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Blood 
Nitrite 
 
 
 
 
 
 
 
Lipids: 
Total cholesterol 
Triglycerides (TG) 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
Very low-density lipoprotein (VLDL) 
 
 
PCSK9 (Proprotein convertase subtilisan/kexin type 9) 
and ApoB 
 
Ethanol testinga,b 
Urine drug screena,b 
Hepatic serologies:a 
Hepatitis B surface antigen (HBsAg) 
HBV DNA  
Hepatitis C antibody 
HCV RNA 
 
Stored sample  
Human immunodeficiency virus (HIV)a 
COVID-19 PCR testc 
Pregnancy testd 
Follicle-stimulating hormone (FSH)e 
Thyroid-stimulating hormone (TSH) a 
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FIB-4 formula = Age (years) × AST (IU/L) / {platelet count (109/L) × ALT (IU/L)1/2} 
a 
Performed at screening only. 
b Urine drug screen and ethanol level must be repeated prior to admission to the clinical research unit (CRU) 
and at other times indicated in the Schedule of Activities (SoA) in Section 1.3. 
c 
A COVID-19 PCR test will be performed at Screening. and on Day 1 prior to dosing. If test results are 
positive for the virus the participant will be excluded from the study. 
d Serum pregnancy test at screening; urine pregnancy test may be performed at all other timepoints and at other 
times indicated in Schedule of Activities (SoA ) 
e 
A serum FSH test should be performed in women at screening to confirm postmenopausal status if applicable. 
f 
  
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
10.3.1. 
Definition of Adverse Event (AE)  
AE Definition 
 An adverse event (AE) is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with the 
study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after administration of study intervention even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of study intervention, including signs, symptoms, or 
clinical sequelae. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
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10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
 Results in death. 
 Is life-threatening: 
o The term life-threatening in the definition of serious refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization: 
o In general, hospitalization signifies that the participant has been admitted to 
hospital or emergency ward (usually involving at least an overnight stay) for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
o Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability/incapacity: 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (for example, sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
 Is a congenital anomaly/birth defect: 
o Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Other situations: 
o Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
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10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention When the ability to use the study intervention safely 
is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product 
Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the Investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The Investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the Investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and product 
complaint information is reported on the Product Complaint Form. 
 Note: An event may meet the definition of both a product complaint and an AE/SAE. In 
such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested by 
the Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
 
 
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Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The Investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure (IB) in their assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
important that the Investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to Sponsor or designee. 
 The Investigator may change their opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
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Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor or designee with a copy of any postmortem 
findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the Sponsor, or designee. 
 Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the SAE Report. 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met: 
 The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
Investigators. 
 An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (for example, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Term 
Definition 
Women of 
childbearing 
potential (WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they: 
 Have a congenital anomaly such as Müllerian agenesis; 
 Are infertile due to surgical sterilization; or 
 Are postmenopausal (the last menstrual period was at least 
12 months ago, and follicle-stimulating hormone (FSH) at 
screening confirms post-menopausal status). 
Examples of surgical sterilization include total hysterectomy, bilateral 
tubal ligation, bilateral salpingo-oophorectomy, bilateral 
salpingectomy, or bilateral oophorectomy. 
Post-menopausal 
state 
The postmenopausal state is defined as: no menses for 12 months 
without an alternative medical cause. A high FSH level in the 
postmenopausal range may be used to confirm a post-menopausal state 
in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
10.4.2. 
Contraception Guidance  
10.4.2.1. Female Participants  
Only women not of childbearing potential (WNOCBP) can participate in this trial. See 
Section 10.4.1 for definitions. 
10.4.2.2. Male Participants  
The table below describes contraceptive guidance for men. 
Males who agree to use highly effective or effective methods of contraception may participate in 
this trial. 
All men must refrain from sperm donation for duration of the study and for 93 days following 
the last dose of study intervention. 
Men with partners of childbearing potential must either remain abstinent (if this is their preferred 
and usual lifestyle), or must use condoms during intercourse for the duration of the study, and for 
93 days following the last dose of study intervention. 
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Topic 
Guidance 
For all men 
All men should refrain from sperm donation for the duration 
of the study and for and for 93 days following the last dose 
of study intervention. 
Contraception for men with 
partners of childbearing 
potential 
 Either remain abstinent (if this is their preferred and 
usual lifestyle); or 
 Must use condoms during intercourse for the 
duration of the study; and 
 For 93 days following the last dose of study 
intervention. 
Contraception for men in 
exclusively same sex 
relationships, as their preferred 
and usual lifestyle 
Are not required to use contraception 
 
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Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below. 
Topic 
Guidance 
Highly effective contraception 
 Combination of oral contraceptive pill and mini-pill 
 Implanted contraceptives 
 Injectable contraceptives 
 Contraceptive patch (only women <198 pounds or 
90 kg) 
 Total abstinence 
 Vasectomy (if only sexual partner) 
 Fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 Combined contraceptive vaginal ring, or 
 Intrauterine devices 
Effective contraception 
 Male or female condoms with spermicide 
 Diaphragms with spermicide or cervical sponges 
 Barrier method with use of a spermicide 
 Condom with spermicide 
 Diaphragm with spermicide, or 
 Female condom with spermicide 
Note: The barrier method must include use of a spermicide 
(that is, condom with spermicide, diaphragm with 
spermicide, female condom with spermicide) to be 
considered effective. 
Ineffective forms of 
contraception 
 Spermicide alone 
 Immunocontraceptives 
 Periodic abstinence 
 Fertility awareness (calendar method, temperature 
method, combination of above 2, cervical mucus, 
symptothermal) 
 Withdrawal 
 Post-coital douche 
 Lactational amenorrhea 
 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Close Hepatic Monitoring 
In case of a hepatic abnormality, laboratory tests should be repeated within 48 to 72 hours to 
confirm the abnormality. These laboratory tests should include, at a minimum: 
 
alanine aminotransferase (ALT) 
 
aspartate aminotransferase (AST) 
 
alkaline phosphatase (ALP) 
 
total bilirubin (TBL) 
 
direct bilirubin (DBL) 
 
gamma-glutamyl transferase (GGT), and 
 
creatine kinase (CK). 
These results should be used to determine if it is increasing or decreasing if 1 or more of these 
conditions occur. 
If a participant with baseline 
results of.... 
develops the following elevations: 
ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN 
ALP <1.5 × ULN 
ALP ≥2 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline (except for participants with 
Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
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If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests, should be initiated by the investigator in consultation 
with the study physician. At a minimum, this evaluation should include physical examination 
and a thorough medical history, including: 
 
Symptoms 
 
Recent illnesses (for example, heart failure, systemic infection, hypotension, or seizures) 
 
Recent travel 
 
History of concomitant medications (including over-the-counter [OTC]) 
 
Herbal and dietary supplements 
 
History of alcohol drinking, and 
 
Other substance abuse. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
 
Comprehensive Hepatic Evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur. 
If a participant with baseline 
results of.... 
develops the following elevations: 
ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN with hepatic signs/symptomsa or  
ALT or AST ≥5 × ULN 
ALP <1.5× ULN 
ALP ≥3 × ULN 
TBL <1.5× ULN 
TBL ≥2 × ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline with hepatic signs/symptomsa or 
ALT or AST ≥3 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥3 × baseline (except for participants with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5% 
 
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At a minimum, this evaluation should include a physical examination and a thorough medical 
history, as outlined above, as well as: 
 
Tests for prothrombin time-international normalized ratio 
 
Tests for viral hepatitis A, B, C, or E 
 
Tests for haemolysis 
 
Tests for autoimmune hepatitis; and 
 
An abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the study physician, including tests for 
 
Hepatitis D virus 
 
Cytomegalovirus 
 
Epstein-Barr virus 
 
Acetaminophen levels 
 
Acetaminophen protein adducts 
 
Urine toxicology screen 
 
Wilson’s disease 
 
Blood alcohol levels 
 
Urinary ethyl glucuronide, and 
 
Blood phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant to their primary physician for 
further management. 
 
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Additional hepatic data collection (hepatic safety electronic CRF [eCRF]) in study 
participants who have abnormal liver tests during the study 
Additional hepatic safety data collection in hepatic safety eCRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5 × upper limit of normal (ULN) on 2 or more consecutive 
blood tests (if baseline ALT <1.5 × ULN): 
a. 
In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3 × baseline on 
2 or more consecutive tests. 
2. Elevated TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome): 
a 
In participants with baseline TBL ≥1.5 × ULN, the threshold is TBL ≥2 × baseline. 
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN): 
a In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests. 
4. Hepatic event considered to be an SAE. 
5. Discontinuation of study intervention due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
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10.5.1. 
Hepatic Evaluation Testing  
See Section 7.1.1 for Hepatic stopping criteria. 
Results will be reported if a validated test or calculation is available. 
Hepatic Haematology Panel: 
Hepatic Clinical Chemistry Panel: 
Haemoglobin 
Total bilirubin 
Haematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry: 
Basophils 
Alkaline phosphatase isoenzymesd 
Eosinophils 
Haptoglobin 
Platelets 
Immunoglobulin IgA (quantitative) 
Cell morphology (RBC and WBC) 
Immunoglobulin IgG (quantitative) 
Hepatic Coagulation Panel: 
Immunoglobulin IgM (quantitative) 
Prothrombin time, INR (PT-INR) 
Urine Chemistry: 
Hepatitis A virus (HAV) testing: 
Drug screen 
HAV total antibody 
Ethyl glucuronide (EtG)d 
HAV IgM antibody 
Epstein-Barr virus (EBV) testing: 
Hepatis B virus (HBV) testing: 
EBV antibody d 
Hepatitis B surface antigen (HBsAg) 
EBV DNAb,d 
Hepatitis B surface antibody (anti-HBs) 
Cytomegalovirus (CMV) testing: 
Hepatitis B core total antibody (anti-HBc) 
CMV antibodyd 
Hepatitis B core IgM antibody 
CMV DNAb,d 
HBV DNAb, d 
Herpes simplex virus (HSV) testing: 
Hepatis C virus (HCV) testing: 
HSV (Type 1 and 2) antibodyd 
HCV antibody 
HCV RNAb,d 
HSV (Type 1 and 2) DNAb,d 
Liver kidney microsomal type 1 (LKM-1) 
antibodyd 
Hepatitis D virus (HDV) testing: 
HDV antibody 
Hepatitis E virus (HEV) testing: 
HEV IgG antibodyd 
HEV IgM antibodyd 
HEV RNAb,d 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody is tested. 
d Assayed only by an investigator-designated qualified laboratory. 
 
 
 
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10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this Appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
Investigator. 
Exceptional Circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
Investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing Changes under Exceptional Circumstances 
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the Sponsor grants written approval for changes in study conduct, the Sponsor will also 
provide additional written guidance, if needed. 
Considerations for Making a Change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed Consent 
Additional consent from the participant will be obtained, if required, for: 
 Participation in remote visits, as defined in Section “Remote Visits”, and 
 Provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in Study Conduct During Exceptional Circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote Visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but 
are not limited to, symptom-directed physical assessments and evaluations of AEs.  
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Data Capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety Reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged.  
Return to On-Site Visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local Laboratory Testing Option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for: PCSK9 and ApoB. The local laboratory must be qualified 
in accordance with applicable local regulations. 
Screening Period Guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening visit are valid for a maximum of 28 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for less than 28 days from screening to randomization visit: 
The participant will proceed to the next study visit per the usual Schedule of 
Activities (SoA, Section 1.3), provided that the randomization visit must be 
conducted within 28 days from first screening.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 28 days from screening to randomization visit: 
The participant must be discontinued because of screening interruption due to an 
exceptional circumstance. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the 
usual SoA should be followed, starting with the screening visit to ensure participant 
eligibility by randomization visit. 
 
Adjustments to Visit Windows 
Whenever possible and safe to do so, as determined by the Investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the Sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
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For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Documentation of Changes to Study Conduct 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source Documents at Alternate Locations 
Source documents generated at a location other than the study site should be part of the 
Investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
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10.7. 
Appendix 7: Abbreviations and Definitions  
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ACC 
American College of Cardiology 
ADA 
American Diabetes Association 
ADR 
adverse drug reaction 
AE 
adverse event 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
Apo 
apolipoprotein 
ApoB 
Apolipoprotein B 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
blinding/masking 
A single-blind study is one in which the Investigator and/or the Investigator’s staff are 
aware of the treatment but the participant is not, or vice versa, or when the Sponsor is 
aware of the treatment but the Investigator and/the Investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the Investigator 
or Sponsor staff who are involved in the treatment or clinical evaluation of participants 
are aware of the treatment received. 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAP 
controlled attenuation parameter 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
 
 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
Cmax 
maximum observed plasma concentration 
CMV 
cytomegalovirus 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
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Term 
Definition 
CRF 
Case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the Sponsor for each trial 
participant. 
CRO 
contract research organization 
CRP 
Clinical Research Physician: Individual responsible for the medical conduct of the 
study. Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRU 
clinical research unit 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
Clinical Trial Agreement 
DEC 
Dose Escalation Committee 
DIO 
diet-induced-obesity 
DNA 
deoxyribonucleic acid 
DPP-4i 
dipeptidyl peptidase 4 inhibitor (gliptin) 
DsiRNA 
dicer-substrate small interfering RNA 
DSUR 
development safety update report 
EASD 
European Association for the Study of Diabetes 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
 
 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ER 
endoplasmic reticulum 
ERCP 
endoscopic retrograde cholangiopancreatography 
FDA 
Food and Drug Administration 
 
 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GalNAc 
N-acetylgalactosamine 
GalXC-SCAP-3339 
LY3885125 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GIP RA 
glucose-dependent insulinotropic polypeptide receptor agonist 
GLP 
Good Laboratory Practice 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
GMP 
Good Manufacturing Practice 
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Term 
Definition 
HbA1c 
glycated hemoglobin 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDL 
High-density lipoprotein 
HDL-C 
high-density lipoprotein cholesterol 
HDI 
hydrodynamic injection 
HDV 
hepatitis D virus  
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented 
by means of a written, signed and dated informed consent form. 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection-site reactions 
LDH 
lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
 
 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or 
more of the five “rights” of medication use: the right participant, the right drug, the 
right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that is either inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MRCP 
magnetic resonance cholangiopancreatography 
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Term 
Definition 
 
 
MRI-PDFF 
magnetic resonance imaging proton density fat fraction 
mRNA 
messenger ribonucleic acid 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis  
 
 
 
NOAEL 
no-observed-adverse-effect level 
ob/ob 
leptin-deficient 
OTC 
over-the-counter 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PCR 
polymerase chain reaction 
PCSK9 
proprotein convertase substilisin/kexin type 9 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
 
 
PT 
prothrombin time 
PUC 
preparative ultracentrifugation 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RNA 
ribonucleic acid 
S1P 
site-1 protease 
S2P 
site-2 protease 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SRC 
Safety Review Committee 
SC 
subcutaneous(ly) 
SCAP 
SREBP cleavage activating protein 
screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study.  
siRNA 
small interfering RNA 
SoA 
Schedule of Activities 
SREBP 
sterol regulatory element-binding protein 
SREBP1a 
sterol regulatory element-binding protein 1 isoform a 
SREBP1c 
sterol regulatory element-binding protein 1 isoform c 
SREBP2 
sterol regulatory element-binding protein 2 
t1/2 
half-life 
T2DM 
Type 2 diabetes mellitus (T2DM) 
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Term 
Definition 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment. 
TG 
triglyceride 
Tmax 
time of maximum observed concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
USP 
United States Pharmacopeia 
VLDL 
very low-density lipoprotein 
WBC 
white blood cell 
 
 
 
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10.8. 
Blood Sampling Schedule  
10.8.1. 
Blood Volumes to be Collected in Part A  
Purpose 
Blood Volume (mL) 
Each sample 
Number of 
Samples (n) 
Total Volume 
(ml) 
Comments 
 
 
 
 
  
 
 
 
 
 
 
 
Includes HCV antibody test  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To be stored by Lilly 
specialist laboratory 
 
 
Abbreviations: 
 
 
 
 
 
 
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10.8.2. 
Proposed Approximate Blood Volumes to be Collected in Part B  
Purpose 
Blood Volume (mL) 
each sample 
Number of 
Samples (n) 
Total Volume 
(ml) 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: 
 
 
 
 
 
 
 
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11.  References  
Andersson A, Kelly M, Imajo K, et al. Clinical utility of magnetic resonance imaging biomarkers 
for identifying nonalcoholic steatohepatitis patients at high risk of progression: a multi-center 
pooled data and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:2451-61. 
https://doi.org/10.1016/j.cgh.2021.09.041. 
Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on Cholesterol Homeostasis: The 
Central Role of Scap. Annu Rev Biochem. 2018;87:783-807. https://doi.org/10.1146/annurev-
biochem-062917-011852 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty 
liver disease: practice guidance from the American Association for the Study of Liver Diseases. 
Hepatology. 2018;67:328-357. https://doi.org/10.1002/hep.29367 
Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 
2022. A consensus report by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD). Diab Care. 2022;45:2753-86. 
https://doi.org/10.2337/dci22-0034 
ElSayed NA, Aleppo G, Aroda VR, et al on behalf of the American Diabetes Association. 
Glycemic targets: standards of care in diabetes. Diab Care. 2023;46:S97-S110. 
https://doi.org/10.2337/dc23-S006 
Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, 
Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. 
J Hepatol. 2018;69:896-904. https://doi.org/10.1016/j.jhep.2018.05.036 
Harper CR, Jacobson TA. Using apolipoprotein B to manage dyslipidemic patients: time for a 
change? Mayo Clin Proc. 2010;85(5):440–45. https://doi.org/10.4065%2Fmcp.2009.0517 
Janas MM, Schlegel MK, Harbison CE, et al. Selection of GalNAc-conjugated siRNAs with 
limited off-target-driven rat hepatotoxicity. Nat Commun. 2018;9(1):723. 
https://doi.org/10.1038/s41467-018-02989-4 
Jensen KK, Tadin-Strapps M, S-P Wang et al. Dose-dependent effects of siRNA-mediated 
inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey[S]. 
J Lipid Res. 2016; 57:2150-162. https://doi.org/10.1194/jlr.M071498 
Eli Lilly and Company. Study 8485208: Cardiovascular Safety Pharmacology Evaluation of 
LY3885125 Administered by Subcutaneous Injection to Male Telemetry-Instrumented 
Conscious Monkeys. 17 November 2022. 
Eli Lilly and Company. Study 8485230: LY3885125: Bacterial Reverse Mutation Assay. 
18 November 2022. 
Eli Lilly and Company. Study 8485231: LY3885125: Rat Bone Marrow Micronucleus Assay. 
11 October 2022. 
Eli Lilly and Company. Study 8485232: LY3885125: In Vitro TK6 Micronucleus Assay. 
11 October 2022. 
Approved on 21 Sep 2023 GMT

CONFIDENTIAL 
Protocol J4N-MC-YFAA(b) 
107 
Eli Lilly and Company. Study 8485850: Evaluation of Cytokine and Complement Parameters in 
Cynomolgus Monkeys Following a Single Subcutaneous Injection of LY3885125. 30 January 
2023. 
Eli Lilly and Company. Study 8485851: A Repeat-Dose Toxicity and Toxicokinetic Study in 
Rats Administered LY3885125 Once Monthly by Subcutaneous Injection for 3 Months with a 3 
Month Recovery Phase. 05 June 2023. 
Eli Lilly and Company. Study 8485852: A Repeat-Dose Toxicity and Toxicokinetic Study in 
Cynomolgus Monkeys Administered LY3885125 Once Monthly by Subcutaneous Injection for 3 
Months with a 3 Month Recovery Phase. 05 June 2023. 
Kornbrust D, Cavagnaro J, Levin A, et al. Oligo safety working group exaggerated 
pharmacology subcommittee consensus document. Nucleic Acid Ther. 2013;23(1):21-8. 
https://doi.org/10.1089/nat.2012.0399 
Loomba R, Neuschwander-Tetri BA, Sanyal A, et al. Multicenter validation of association 
between decline in MRI-PDFF and histologic response in NASH. Hepatology 2020;72:1219-29. 
https://doi.org/10.1002/hep.31121 
Lu Y, Cui X, Zhang L, et al. The functional role of lipoproteins in atherosclerosis: novel 
directions for diagnosis and targeting therapy. Aging Dis. 2022;13(2):491–520. 
https://doi.org/10.14336%2FAD.2021.0929 
Middleton MS, Heba ER, Hooker CA, et al. Agreement between magnetic resonance imaging 
proton density fat fraction measurements and pathologist-assigned steatosis grade of liver 
biopsies from adults with nonalcoholic steatohepatitis. Gastroenterology, 2017;153:753-61. 
https://doi.org/10.1053/j.gastro.2017.06.005 
Moon Y-A, Liang G, Xie X, et al. The Scap/SREBP pathway is essential for developing diabetic 
fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab. 
2012;15:240-46. https://doi.org/10.1016/j.cmet.2011.12.017 
Onpattro® (patisiran) injection – Full Prescribing Information. US Food and Drug 
Administration, May 2021. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210922s009lbl.pdf (Accessed 
19 June 2023) 
Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: From 
pathophysiology to therapeutics. Metabolism. 2019;92:82-97. 
https://doi.org/10.1016/j.metabol.2018.11.014 
Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet 2021: 397:2212-24. 
https://doi.org/10.1016/S0140-6736(20)32511-3 
Rinella ME, Neuschwander-Tetri BA, Shadab Siddiqui M, et al. AASLD Practice Guidance on 
the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease. Hepatology. 
2023;77:1797-1835. https://doi.org/10.1097/HEP.0000000000000323 
Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: beyond the 
obvious. Liver Int 2021;41:2249–68. https://doi.org/10.1111/liv.15024 
Approved on 21 Sep 2023 GMT

CONFIDENTIAL 
Protocol J4N-MC-YFAA(b) 
108 
Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs 
nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. 
Clin Gastroenterol Hepatol. 2015;13:643-54.e1-9. https://doi.org/10.1016/j.cgh.2014.04.014 
Stine JG, Munaganuru N, Barnard A, et al. Changes in MRI-PDFF and histologic response in 
patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis. Clin 
Gastroenterol Hepatol 2021;19:2274-83. https://doi.org/10.1016/j.cgh.2020.08.061 
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of 
blood cholesterol to reduce atherosclerotic cardiovascular risk in adults; a report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am 
Coll Cardiol. 2014;63:2889-934. https://doi.org/10.1016/j.jacc.2013.11.002 
Sutherland JE, Hettinger JL, Chan A, et al. Nonclinical Safety Profile of Revusiran, a 1st-
Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated 
Amyloidosis. Nucleic Acid Ther. 2020;30(1):33-49. https://doi.org/10.1089/nat.2019.0796 
Tamaki N, Munaganuru N, Jung J, et al. Clinical utility of 30% relative decline in MRI-PDFF in 
predicting fibrosis regression in non-alcoholic fatty liver disease. Gut. 2022;71:983-90. 
https://doi.org/10.1136/gutjnl-2021-324264 
US Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry: Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. 
https://www.fda.gov/media/72309/download (Accessed 19 June 2023) 
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle 
Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 
2015;149(2):367-78. https://doi.org/10.1053/j.gastro.2015.04.005 
Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in 
patients with type 2 diabetes: A systematic review and meta-analysis. 2019;71(4):793-801. 
https://doi.org/10.1016/j.jhep.2019.06.021 
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver 
disease – meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 
2016;64:73-84. https://doi.org/10.1002/hep.28431 
 
 
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