A First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics After Single Ascending Dose of HM15211(Efocipegtrutide) in Healthy Obese Subjects
Phase: PHASE1
Conditions: Obesity
Sponsor: Hanmi Pharmaceutical Company Limited

_________________________________________________________ 
Clinical Development HM15211 
Clinical Study Protocol HM-TRIA-101 
A First-in-Human, Double-blind, Randomized, Placebo-
controlled, Single Ascending Dose Study to Assess Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
HM15211 in Healthy Obese Subjects 
 
Sponsor: 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu 
Seoul, 05545 
Korea 
Sponsor Contact: 
Jahoon Kang  
Executive Director of Clinical Research and Development 
Telephone: +82-2-410-9041 
Clinical Research 
Organization: 
ProSciento, Inc. 
855 3rd Avenue, 
Chula Vista, CA, 91911 
USA 
Authors: 
Marcus Hompesch, MD (ProSciento, Inc.), Youngmin Kim, 
MS (Hanmi Pharm. Co., Ltd), Jae Duk Choi, PhD (Hanmi 
Pharm. Co., Ltd) 
Document type: 
Clinical Study Protocol 
IND number: 
137766 
Version number: 
V 4.0 
Development phase: 
1 
Release date: 
06 Apr 2018 
 
 
Statement of Confidentiality 
This document contains ProSciento, Inc. and Hanmi Pharmaceutical Co., Ltd privileged or 
confidential information and is provided to you as an investigator, potential investigator, sponsor, 
or consultant, solely for review by you, your staff, and applicable institutional review board(s). 
The information is not to be disclosed to others without written authorization from ProSciento, 
Inc. and Hanmi Pharmaceutical Co., Ltd. 

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Protocol No. HM-TRIA-101 
 
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1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided. 
1.2 
Approval 
Representatives of Sponsor and Principal Investigator will sign the agreement on the 
protocol. 
1.3 
Document History 
Version 
Revision Date 
Revision Description 
1.0 
08-Dec-2017 
Original Document 
2.0 
04-Feb-2018 
FDA Review Based Revisions: 
1. Addition of Maximum Dose and Dose Escalation 
Steps 
The maximum human dose is determined by the 
exposure seen at the NOAEL in the 4-week 
toxicology study in the rat which corresponds to 
approximately 0.16 mg/kg in a human according to 
pharmacokinetic (PK) prediction. Doses between 
cohorts will not exceed a 2-fold increase relative to 
the specified doses stated below. The maximum dose 
for each cohort will be defined as: Cohort 1 - Starting 
dose 0.01 mg/kg; 
Cohort 2 – Dose will not exceed 0.02 mg/kg; 
Cohort 3 – Dose will not exceed 0.04 mg/kg; 
Cohort 4 – Dose will not exceed 0.08 mg/kg; 
Cohort 5 – Dose will not exceed 0.16 mg/kg. 
Dose escalation will be based on clinical safety and 
available PK data. 
Section 2.0 Study Summary, section 4.4 Rationale for 
Starting and Maximum Dose, section 4.5 Dose 
Escalation Algorithm 
Additional Revisions: 
2. Correction of Placebo Description 
Placebo is a sterile, matching solution (all 
components except the drug substance) and free of 
visible particles. 
Section 8.1.2 Placebo 

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3. Safety Review and Dose Escalation Meetings 
Safety Review and Dose Escalation Meeting to be 
held after all subjects of one cohort have completed 
at least the D10 Visit. Therefore, cohorts may 
overlap. After PK modeling from preclinical 3 animal 
species, human Cmax is expected to be reached 
approximately 3 days after dosing. As dose limiting 
adverse events occur at or around Cmax, safety data 
beyond Day 10 are not critical for a dose escalation 
decision.  
Section 2.0 Study Summary, section 4.5 Dose 
Escalation Algorithm, section 6.1 Study Design, 
Figure 6-2 Dose Escalation Schematic, section 6.3 
Rationale for Study Design and Endpoints 
4. Change of Principal Investigator (PI) 
PI change from Dr. Rodriguez to Dr. Morrow due to 
Sponsor preference. 
Investigator Approval Page (page 5) 
5. Addition of Biomarkers to Exploratory Endpoints 
Incretin secretion: Glucagon-like peptide-1 (GLP-1) 
and Gastric inhibitory polypeptide (GIP) are added to 
exploratory endpoints. GLP-1 and GIP will be 
collected at timepoints of glucagon (GCG) collection 
and analysis. 
These additional biomarkers will be analyzed to 
expand the PD assessment of the drug. 
Section 2.0 Study Summary, section 5.2 Exploratory 
Objectives and Endpoints, section 9.1.17 
Pharmacodynamic Assessments and Schedule, Table 
9-3 PD Sampling Schedule, Table 12-1 Study 
Endpoints, section 12.2.4 Analysis of the 
Pharmacodynamic Endpoints and Table 16-1 
Schedule of Events. 
6. Addition of timepoints for the existing PD 
endpoint fasting plasma glucose (FPG) analyses 
Blood samples for the analysis of FPG will be 
collected and analyzed on a daily basis during In-
house Period, Outpatient Visits and Follow-up Visit 
to expand the assessment of this PD parameter. 
Section 9.1.17 Pharmacodynamic Assessments and 
Schedule, Table 9-3 PD Sampling Schedule and 
Table 16-1 Schedule of Events 

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7. Adjustment of Blood Volume. 
Due to revisions # 4 and 5, but combination of 
analyses, additional blood volume of approximately 
20 mL is necessary per subject. 
Section 9.1.20 Blood Volume 
8. Clarifications: 
a) Markers in Schedule of Events (SOE) 
‘Lipid panel, incl. FFA’, and ‘FPG’ rows in the SOE: 
Timepoints for analyses of the parameters are to be 
performed per protocol at Screening, but fields in 
table were not marked with an ‘X’. Adjustment of 
footnotes. 
Table 16-1 Schedule of Events 
b) Urine Pregnancy Test 
Urine pregnancy testing via commercial kit at CRU 
will be performed at timepoints stated in the 
Schedule of Events. Urine pregnancy testing may be 
performed per Investigator’s discretion at additional 
timepoints during the study, if there is reason to 
believe the subject might be pregnant. 
Table 9-1 Clinical Laboratory Assessments 
c) Correction of Typographical Error 
Screening period stated with 30 days instead of 28 
days. 
Figure 6-1 Study Design Schematic 
3.0 
09-Feb-2018 
FDA Review Based Revisions: 
1. Change of Storage Condition for Investigational 
Product 
Recommended storage condition at room temperature 
is up to 4 hours instead of up to 12 hours, considering 
the potential risk of biological products and 
formulations. 
Section 8.3 Storage and Drug Accountability of 
Investigational Product. 
4.0 
06-Apr-2018 
Revisions for this Amendment: 
1. Change of Dose Escalation  
The dose escalation decision for subsequent cohorts 
can be made after a minimum of 6 subjects (at least 4 
subjects on active drug) have completed at least Day 
10, and safety and available PK data have been 

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reviewed. Four subjects are sufficient for the initial 
assessment of safety risks and for the selection of the 
drug dose for the next cohort. 
Section 4.5 Dose Escalation Algorithm and section 
6.1 Study Design 
Additional Revisions: 
2. Clarifications: 
a) Sentinel Dosing 
Dosing will follow a sentinel approach, comprising 
one active- and one placebo-treated subject at the 
start of each cohort followed by the remainder of the 
cohort, after a dosing interval of at least 24 hours. 
Adjustment of language in section 6.1. 
Section 6.1 Study Design 
b) PK/PD Sampling Time Windows 
The actual time of PK sampling should not deviate 
from the nominal time by more than ± 5 minutes 
during inpatient period. The study window on 
outpatient visits (±1 day) and follow-up visit (± 2 
days) will apply for the PK sampling at these visits. 
The PK sampling windows apply to all PD sampling 
timepoints as well. 
Section9.1.16 Pharmacokinetic Assessments and 
Schedule and 9.1.17 Pharmacodynamic Assessments 
and Schedule  
c) Contraception 
During the course of the study, regular serum human 
chorionic gonadotropin (hCG) pregnancy tests will 
be performed for sterilized women, when medical 
records are not available. Adjustment of language for 
consistency throughout the protocol. 
Section 9.1.9 Contraception 
d) Clarification of Randomization Codes 
Language added to describe the assignment of 
randomization codes for subjects that need to be 
replaced during the study.  
Section 8.6 Randomization and Blinding 
e) Clarification of ECG Procedures 
ECG’s will be performed as triplicate 12-lead ECG’s 
throughout the study, except for the Screening Visit. 
Language and footnote added. 

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Section 9.1.11 ECG Procedure, Table 16-1 Schedule 
of Events 
f) Clarification of Measurements for Vital Signs 
Pulse rate and respiration rate: Pulse rate will be 
assessed in combination with both, supine and 
standing blood pressure measurements. Respiration 
rate will be assessed at time points of supine blood 
pressure measurements. 
The blood pressure measurement will start with the 
supine measurements after 5 minutes resting, but the 
standing blood pressure measurement will be taken 
within 3 minutes in upright position.    
Section 9.1.6 Vital Signs, Footnote 1 to Table 16-1 
Schedule of Events 
3. Addition of Amino Acids Analysis 
During the course of the study, additional blood 
samples will be taken for the analysis of amino acid 
profiles. Samples will be taken at the same 
timepoints stated for GIP/ GLP-1 sampling. Amino 
acids will be analyzed to expand the PD assessment 
of the drug. 
Table 9-3 PD Sampling Schedule, Table 16-1 
Schedule of Events and section 9.1.17 
Pharmacodynamic Assessments and Schedule  
4. FSH level for Postmenopausal Women 
Lower limit of FSH value for postmenopausal 
women will be updated from > 40 to ≥ 25.8 mIU/mL 
according to laboratory reference.  
Additionally, female subjects who are 
postmenopausal, but have a FSH value < 25.8 
mIU/mL, may still be enrolled in the study, if they 
have a negative serum hCG pregnancy test and agree 
to be on a highly contraceptive method.  
Section 9.1.9 Contraception 

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Protocol No. HM-TRIA-101 
 
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Investigator Approval Page 
 
Protocol Title: 
A First-in-Human, Double-blind, Randomized, Placebo-
controlled, Single Ascending Dose Study to Assess Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
HM15211 in Healthy Obese Subjects 
Protocol Number: 
HM-TRIA-101 
Protocol Version: 
4.0 
Date: 
 
06-Apr-2018 
The Principal Investigator agrees to conduct this study as outlined in this protocol in 
reference to national/local regulations and in accordance with current Good Clinical 
Practice (GCP) guidelines described in the International Committee for Harmonization 
(ICH) Guidance document E6, the FDA regulations for clinical trials, 21 CFR 312, the 
Health Insurance Portability and Accountability Act (HIPAA), and the most current 
version of the Declaration of Helsinki. Any modification to the protocol must be agreed 
upon by both the Investigator and Sponsor and documented in writing. By written 
agreement to this protocol, the Investigator agrees to allow direct access to all 
documentation, including source data, to authorized individuals representing the Sponsor 
(including monitoring staff and auditors), to Institutional Review Boards/Independent 
Ethics Committees (IRB/IEC) and/or to regulatory authorities. 
 
Principal Investigator: 
Name:  
Linda Morrow, MD 
Function: 
Chief Operating Officer (COO) 
Address: 
ProSciento, Inc.  
                       855 3rd Avenue, Chula Vista, CA, 91911, USA 
E-mail: 
linda.morrow@prosciento.com 
Name (printed) 
Signature 
Date 
 

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Protocol No. HM-TRIA-101 
 
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Sponsor Protocol Approval Page 
 
Protocol Title: 
A First-in-Human, Double-blind, Randomized, Placebo-
controlled, Single Ascending Dose Study to Assess Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
HM15211 in Healthy Obese Subjects  
Protocol Number: 
HM-TRIA-101 
Protocol Version: 
4.0 
Date:  
 
06-Apr-2018 
The Sponsor agrees to conduct the trial as outlined in this protocol in reference to 
national/local regulations and in accordance with current Good Clinical Practice (GCP) 
guidelines described in the International Committee for Harmonization (ICH) Guidance 
document E6, the FDA regulations for clinical trials, 21 CFR 312, the Health Insurance 
Portability and Accountability Act (HIPAA), and the most current version of the 
Declaration of Helsinki. Any modification to the Protocol must be agreed upon by both the 
Investigator and Sponsor and documented in writing. By written agreement to this protocol, 
the Sponsor agrees to allow direct access to all documentation, including source data, to 
authorized individuals representing the Sponsor (including monitoring staff and auditors), 
to Institutional Review Boards/Independent Ethics Committees (IRB/IEC) and/or to 
regulatory authorities. 
 
Approved for the Sponsor by:  
Name:  
Jahoon Kang  
Function: 
Executive Director of Clinical Research and Development 
Address: 
Hanmi Pharmaceutical Co., Ltd. 
14, Wiryeseong-daero, Songpa-gu 
Seoul, 05545, Korea 
Telephone: 
+82-2-410-9041 
 
E-mail: 
jhkang@hanmi.co.kr 
 
 
Name (printed) 
Signature 
Date 

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TABLE OF CONTENTS 
_________________________________________________________................1 
1.0 
ADMINISTRATIVE INFORMATION ............................................................2 
1.1 
Contacts........................................................................................................2 
1.2 
Approval ......................................................................................................2 
1.3 
Document History ........................................................................................2 
2.0 
STUDY SUMMARY.......................................................................................13 
3.0 
LIST OF ABBREVIATIONS ..........................................................................22 
4.0 
INTRODUCTION ...........................................................................................25 
4.1 
Background ................................................................................................25 
4.2 
Rationale for the Proposed Study ..............................................................26 
4.3 
Summary of Pre-Clinical Studies...............................................................26 
4.4 
Rationale for Starting and Maximum Dose ...............................................27 
4.5 
Dose Escalation Algorithm ........................................................................28 
5.0 
STUDY OBJECTIVES ....................................................................................30 
5.1 
Primary Objectives and Endpoints.............................................................30 
5.2 
Exploratory Objectives and Endpoints ......................................................31 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................32 
6.1 
Study Design ..............................................................................................32 
6.2 
Study Description.......................................................................................33 
6.3 
Rationale for Study Design and Endpoints ................................................35 
6.4 
Study Discontinuation and Stopping Criteria ............................................35 
6.4.1 
Dose Escalation Stopping Criteria ................................................35 
6.4.2 
Criteria for Early Termination of the Study .................................36 
6.4.3 
Criteria for Early Termination of Individual Subjects ..................36 
7.0 
STUDY POPULATION ..................................................................................38 
7.1 
Inclusion Criteria .......................................................................................38 
7.2 
Exclusion Criteria ......................................................................................38 
7.3 
Prohibited Medications ..............................................................................41 
7.4 
Check in Criteria ........................................................................................41 
8.0 
STUDY MATERIALS ....................................................................................43 
8.1 
Investigational Products (IPs) ....................................................................43 
8.1.1 
HM15211 ......................................................................................43 
8.1.2 
Placebo ..........................................................................................43 
8.2 
Packaging, and Labeling of Investigational Products ................................43 

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8.3 
Storage and Drug Accountability of Investigational Products ..................43 
8.4 
Dose Regimen ............................................................................................44 
8.5 
Overdose ....................................................................................................44 
8.6 
Randomization and Blinding .....................................................................44 
8.7 
Auxiliary Supply ........................................................................................45 
9.0 
STUDY PLAN .................................................................................................46 
9.1 
Study Procedures .......................................................................................46 
9.1.1 
Informed Consent and HIPPAA Release ......................................46 
9.1.2 
Screening ......................................................................................46 
9.1.3 
Demographics and Medical History .............................................47 
9.1.4 
Physical Examination ...................................................................47 
9.1.5 
Height, Weight, and BMI .............................................................47 
9.1.6 
Vital Signs ....................................................................................47 
9.1.7 
Concomitant Illness and Therapy .................................................48 
9.1.8 
Procedures for Clinical Laboratory Samples ................................48 
9.1.9 
Contraception ................................................................................50 
9.1.10 
Pregnancy .....................................................................................51 
9.1.11 
ECG Procedure .............................................................................52 
9.1.12 
Check-in Procedure ......................................................................52 
9.1.13 
Standardized Meals .......................................................................53 
9.1.14 
ABPM ...........................................................................................53 
9.1.15 
Holter Monitoring .........................................................................53 
9.1.16 
Pharmacokinetic Assessments and Schedule ................................54 
9.1.17 
Pharmacodynamic Assessments and Schedule .............................55 
9.1.18 
Immunogenicity Assessments ......................................................56 
9.1.19 
Tolerability Assessments ..............................................................56 
9.1.20 
Blood Volume ...............................................................................57 
10.0 
ADVERSE EVENTS .......................................................................................58 
10.1 
Definitions..................................................................................................58 
10.1.1 
Adverse Event (AE) ......................................................................58 
10.1.2 
Treatment Emergent Adverse Event (TEAE) ...............................58 
10.1.3 
Clinical Laboratory Event .............................................................58 
10.1.4 
Adverse Reaction ..........................................................................58 
10.1.5 
Suspected Adverse Reaction .........................................................58 
10.1.6 
Unexpected Adverse Event/ Unexpected Suspected Adverse 
Reaction ........................................................................................59 

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10.1.7 
Serious Adverse Event (SAE)/ Serious Suspected Adverse 
Reaction ........................................................................................59 
10.1.8 
Life-Threatening Adverse Event/Life-Threatening Suspected 
Adverse Reaction ..........................................................................60 
10.2 
Severity of AEs ..........................................................................................60 
10.3 
Relationship to Study Treatment ...............................................................60 
10.4 
Procedures ..................................................................................................61 
10.4.1 
Collection and Recording of AEs .................................................61 
10.4.2 
Collection and Reporting of SAEs ...............................................61 
10.5 
Anticipated Adverse Events .......................................................................62 
Risks related to repeated blood draws .............................................................62 
10.6 
Follow-up of AEs and SAEs ......................................................................62 
10.6.1 
Safety Reporting to IRBs or IECs, and Regulatory Authorities ...62 
11.0 
DATA HANDLING AND MANAGEMENT .................................................64 
11.1 
Data Management ......................................................................................64 
11.2 
CRFs (Electronic) ......................................................................................64 
11.2.1 
Clinical Data Management Workflow ..........................................64 
11.2.2 
Data Entry of eCRFs .....................................................................65 
11.2.3 
Corrections to eCRFs ....................................................................65 
11.2.4 
PI Approval of eCRF Data ...........................................................65 
11.3 
Retention of Documents ............................................................................65 
12.0 
STATISTICAL METHODS ............................................................................66 
12.1 
Statistical and Analytical Plans ..................................................................66 
12.2 
Study Endpoints .........................................................................................66 
12.2.1 
Analysis Sets .................................................................................67 
12.2.2 
Analysis of Demographics and Other Baseline Characteristics ...67 
12.2.3 
Analysis of the Pharmacokinetic Endpoints .................................68 
12.2.4 
Analysis of the Pharmacodynamic Endpoints ..............................68 
12.2.5 
Safety Analysis and Endpoints .....................................................68 
12.3 
Interim Analysis .........................................................................................69 
12.4 
Determination of Sample Size ...................................................................69 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................70 
13.1 
Monitoring .................................................................................................70 
13.2 
Protocol Deviations ....................................................................................70 
14.0 
ETHICAL ASPECTS OF THE STUDY .........................................................71 
14.1 
Institutional Review Board and/or Independent Ethics Committee ..........71 

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14.2 
Regulatory Authorities ...............................................................................71 
14.3 
Responsibilities of the Investigator ............................................................71 
14.4 
Informed Consent.......................................................................................72 
14.5 
Subject Confidentiality ..............................................................................72 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy ...............73 
14.7 
Insurance and Compensation for Injury .....................................................73 
15.0 
REFERENCES ................................................................................................74 
16.0 
APPENDIX ......................................................................................................75 
 
LIST OF IN-TEXT TABLES 
Table 4-1 Starting Dose Calculations ..........................................................................27 
Table 4-3 Sample Allocation and Dose Escalation......................................................28 
Table 7-1 Prohibited Medications ................................................................................41 
Table 9-1 Clinical Laboratory Assessments ................................................................48 
Table 9-2 PK Sampling Schedule ................................................................................54 
Table 9-3 PD Sampling Schedule ................................................................................55 
Table 12-1 Study Endpoints.........................................................................................66 
Table 16-1 Schedule of Events ....................................................................................75 
 
LIST OF IN-TEXT FIGURES 
Figure 6-1 Study Design Schematic ............................................................................32 
Figure 6-2 Dose Escalation Schematic ........................................................................33 
 

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2.0 
STUDY SUMMARY 
Name of Study 
Drug 
HM15211 
Protocol Number 
HM-TRIA-101 
Protocol Title  
 
A First-in-Human, Double-blind, Randomized, Placebo-
controlled, Single Ascending Dose Study to Assess Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
HM15211 in Healthy Obese Subjects 
Primary 
Objectives and 
Endpoints 
To assess safety and tolerability of HM15211 after single 
subcutaneous (SC) doses, in regard to: 
• Incidence of adverse events 
• Incidence of clinical laboratory abnormalities (including 
serum amylase, serum lipase, coagulation, thyroid 
stimulating hormone (TSH), serum calcitonin) 
• Immunogenicity (Anti-drug antibodies [ADAbs], 
neutralizing antibodies [nAbs], anti-polyethylene glycol 
antibodies [anti-PEG]) 
• Change from baseline in vital signs (blood pressure, 
respiratory rate, temperature, and heart rate) 
measurements 
• Incidence and severity of clinical findings on physical 
examination 
• Injection site reaction 
• Change from baseline in 12-lead ECG parameters; the 
primary ECG endpoint will be QTcF 
• Blood pressure (BP) assessed by 24-hour ambulatory 
blood pressure monitoring (ABPM); (Mean day- and 
night time systolic/diastolic BP)  
• Heart rate activity assessed by 24-hour ambulatory 
electrocardiography monitoring (Holter ECG); (Heart rate 
[HR] and heart rate variability [HRV], e.g. mean heart 
rate, difference between day and night HR, mean normal 
to normal [NN] intervals, standard deviation of all NN 
intervals [SDNN]) 
To assess the pharmacokinetic (PK) profile of HM15211 after 
single SC doses in regards, but not limited to:  

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• Maximum concentration (Cmax) 
• Time to reach Cmax (Tmax) 
• Total area under the concentration time curve (AUC), 
including AUC(0-inf) 
• Apparent terminal half-life (t1/2) 
• Apparent clearance (CL/F) 
• Apparent volume of distribution at terminal phase (Vz/F) 
• Terminal elimination rate constant (kel) 
Exploratory 
Objectives and 
Endpoints 
To assess pharmacodynamics (PD) properties of HM15211 after 
single SC doses in comparison to placebo on: 
• Lipid metabolism: 
o Total cholesterol 
o Low-density lipoprotein (LDL) 
o High-density lipoprotein (HDL) 
o Very low-density lipoprotein (VLDL) 
o Triglycerides 
o Free fatty acid (FFA) 
• Body weight 
• Glucose metabolism: 
o Fasting plasma glucose (FPG) 
o Insulin 
o C-peptide 
• Incretin secretion: 
o Glucagon (GCG) 
o Leptin 
o Glucagon-like peptide-1 (GLP-1) 
o Gastric inhibitory peptide (GIP) 
• Inflammatory marker: 
o C-reactive protein (CRP) 
Phase of 
Development 
1 
Number of Study 
Sites 
1 
Subjects 
Healthy Obese Subjects 

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Number of 
Subjects 
Approximately 40 subjects, divided in 5 cohorts with 8 subjects 
per cohort. 
Summary of 
Study Design 
This is a double-blind, randomized, placebo controlled, SAD 
study to investigate the safety, tolerability, and PK of the 
subcutaneous (SC) administration of HM15211 in healthy obese 
subjects. 
The study will be conducted in 5 sequential dosing cohorts, 
enrolling 8 subjects per cohort. Cohorts may partially overlap, if 
dose escalation decision after the Day 10 Visit has been made. 
Subjects will be randomized to HM15211 or placebo in a ratio of 
6:2 (6 on active, 2 on placebo). 
Dosing will follow a sentinel approach with dosing at least 24 
hours apart. Based on available safety, tolerability, and PK data, 
and following a safety review and dose escalation meeting 
between the investigator and the sponsor, dose escalation to the 
next cohort may proceed. If dose escalation is stopped, dose de-
escalation may occur in additional cohorts, to further refine 
clinically relevant dose levels. 
Adjustments to the procedures may occur after the review of 
available safety and PK data: 
• Adjustments to the number of study cohorts may occur: 
Additional cohorts may be enrolled and proceed at a 
higher or a lower dose. If deemed appropriate by the 
investigator and sponsor, there may be more than one 
cohort investigated at the same dose level. 
• Adjustments to the 24-hr BP and HR monitoring: After 
the evaluation of the first cohort, tests may be 
rescheduled, or measurement periods may be focused on 
specific days to capture the 24-h measurement around the 
PKpeak.  
• Adjustments to the visit schedule: If PK data suggest, 
additional sampling times and/or outpatient visits may be 
added to the study schedule. 
Each subject will undergo a screening visit, up to 28 days prior to 
the first dosing.  
Each subject will undergo one in-house period of 9-day duration, 
two outpatient visits, and a follow-up visit.  
Screening: 

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A Screening Visit will be performed up to 28 days prior to the 
first dosing to identify eligible subjects for the study. 
In-house Period: 
Subjects will check in to the clinic in the morning on Day -2 for a 
9-day In-house Period. They will receive standardized meals 
throughout their inpatient stay. Subjects will be connected to an 
ABPM system, and overnight measurements will be taken to 
familiarize the subjects with the device. ABPM measurements 
will continue throughout Day 4. Only 24-hour monitoring data 
from Day -1 will be used for the baseline monitoring evaluation. 
In the morning of Day -1, subjects will get connected to a Holter 
ECG for 24-hour measurements and will continue these until the 
morning of Day 4. Only 24-hour monitoring data from Day -1 
will be used for the baseline monitoring evaluation. 
Subjects will be randomized to a single SC injection of HM15211 
or placebo. 
On Day 1, the active study drug or placebo, will be administered 
in the morning at approximately 08:00 hours (t=0), SC into the 
abdominal wall by qualified study staff. Measurements of vital 
signs, PK and laboratory parameter will be performed for safety 
evaluation. 
ABPM and Holter ECG monitoring will be continued until the 
morning of Day 4 for the post-dose evaluation. 24-hour 
monitoring evaluations will be performed together with available 
PK data, in order to determine the best time period for 24-h 
monitoring period around PKpeak. 
Subjects will continue to stay in-house for safety evaluations and 
PK. They will be released from the clinical research unit (CRU) 
in the morning of Day 7 and will return for two outpatient visits 
on Day 10 and 17. 
Outpatient Visits: 
Subjects will return to the CRU on Days 10 (± 1) and 17 (± 1) for 
two outpatient visits. Blood samples for PK analysis will be 
collected, additional safety assessments as stated in Table 16-1 
will occur. 
Follow-up Visit: 
A follow-up visit will take place on Day 30 (± 2). 

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Time points for study procedures and sample collections for PK 
measurements will be specified in detail in Table 16-1 of the 
protocol. 
Safety assessments will occur throughout the duration of the 
study. 
Treatment 
Sample Treatment Schedule: 
Cohorts 
Number of 
Subjects 
Treatment Period 
Cohort 1 
N=6 
HM15211 - 0.01 mg/kg 
N=2 
Placebo 
Cohort 2 
N=6 
HM15211 ≤ 0.02 mg/kg 
N=2 
Placebo 
Cohort 3 
N=6 
HM15211 ≤ 0.04 mg/kg 
N=2 
Placebo 
Cohort 4 
N=6 
HM15211 ≤ 0.08 mg/kg 
N=2 
Placebo 
Cohort 5 
N=6 
HM15211 ≤ 0.16 mg/kg 
N=2 
Placebo 
• 
Starting dose is determined with 0.01 mg/kg for Cohort 1. The maximum 
human dose is determined by the exposure seen at the NOAEL in the  
4-week toxicology study in the rat which corresponds to approximately 
0.16 mg/kg in a human according to PK prediction. Doses between 
cohorts will not exceed a 2-fold increase relative to the specified doses 
stated above. Dose escalation will be determined in safety review and 
dose escalation meeting by Sponsor and Investigator and will be based on 
clinical safety and available PK data. 
Route of 
Administration 
All study drugs will be administered by SC injection into the 
abdominal wall. 
Duration of 
Participation 
The duration of participation in this study, including Screening, 
Treatment and Follow-up will be approximately 9 weeks for each 
subject. 
Inclusion Criteria 
 
Subjects who meet all criteria at Screening will be included in the 
study:  
1. Male and female subjects. 

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2. Age ≥ 18 to ≤ 65 years. 
3. Body mass index (BMI) ≥ 30 to ≤ 40 kg/m2, with stable 
body weight by history for 3 months (defined as change < 
5%). 
4. HbA1c < 6.5 %. 
5. Female subjects must be non-pregnant and non-lactating. 
Females of child bearing potential must use highly 
effective contraceptive methods, stable at least 2 months 
prior to the screening. Male subjects must be surgically 
sterile, abstinent or if engaged in sexual relations of child-
bearing potential, the subject and his partner must use an 
acceptable method of contraception.  
6. Ability to provide written informed consent. 
Exclusion 
Criteria 
Subjects who meet any of the following criteria will be excluded 
from the study:  
1. Previous surgical treatment for obesity (bariatric surgery, 
gastric banding, etc.) or any other gastrointestinal surgery 
that may induce malabsorption, history of bowel resection 
> 20 cm, any malabsorption disorder, severe 
gastroparesis, any GI procedure for weight loss (including 
LAP-BAND®), as well as clinically significant 
gastrointestinal disorders (e.g. peptic ulcers, severe 
GERD) at Screening.  
2. Use of antacids, anticoagulants, drugs that directly modify 
gastrointestinal (GI) motility, including, but not limited 
to, anticholinergics, antispasmodics, 5HT3 antagonists, 
dopamine antagonists, or opiates within 2 weeks of 
screening. 
3. Uncontrolled hypertension, defined as systolic blood 
pressure >150 mmHg and/or diastolic blood pressure ≥ 
100 mmHg at screening (reading may be repeated on a 
different day). (Subjects with uncontrolled hypertension 
may be rescreened after 3 months, following initiation or 
adjustment of antihypertensive therapy). 
4. Use of any drugs that are known to interfere with glucose 
or insulin metabolism, including but not limited to oral or 
parenteral corticosteroids or topiramate, monoamine 
oxidase (MAO) inhibitors, growth hormone, within 3 
months prior to screening.  

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5. Treatment with antihypertensive medication and statins, 
unless on stable dose for at least 3 months prior to 
screening. 
6. Any weight control treatment, including over-the-counter 
and herbal medication and supplements, or any 
medication with a labelled indication for weight loss or 
weight gain within 3 months prior to screening. 
7. Any prior treatment with GLP‐1 receptor agonists (e.g., 
exenatide, liraglutide, dulaglutide), dipeptidylpeptidase‐4 
(DPP‐4) inhibitors, oral antidiabetic drugs and insulin. 
8. Participation in an investigational study within 30 days 
prior to dosing or 5 half-lives within the last dose of 
investigational product whichever is longer. 
9. Calcitonin levels > 20 pg/mL at screening. 
10. Personal history or current diagnosis of acute or chronic 
pancreatitis or factors for pancreatitis, such as a history of 
cholelithiasis (without cholecystectomy) or alcohol abuse.  
11. History of major depression, anxiety, or other psychiatric 
disorder (within 2 years of screening), requiring medical 
treatment, including selective serotonin reuptake 
inhibitors (SSRIs), serotonin norepinephrine reuptake 
inhibitors (SNRIs), antipsychotics, lithium. (Use of SSRIs 
and SNRIs [including bupropion] for reasons other than 
active psychiatric indications [eg, migraine, weight loss, 
smoking cessation] must meet a 3-month wash-out) 
12. History of significant suicidal ideation or suicidal 
behavior/attempts. 
13. History of any major surgery within 6 months prior to 
screening. 
14. History of any serious adverse reaction or hypersensitivity 
to study drugs components. 
15. History or current diagnosis of heart disease, defined as 
symptomatic heart failure (New York Heart Association 
class III or IV), myocardial infarction, unstable angina 
requiring medication, transient ischemic attack, cerebral 
infarct, or cerebral hemorrhage or invasive cardiovascular 
procedure, such as coronary artery bypass graft surgery 
(CABG), or angioplasty/percutaneous coronary 
intervention (PCI) within 6 months of screening. (A 

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diagnostic cardiac catheterization without any 
intervention does not exclude the subject) 
16. Cardiac arrhythmia requiring medical or surgical 
treatment within 6 months prior to screening. 
17. Personal or family history of medullary thyroid carcinoma 
(MTC) or a genetic condition that predispose to MTC (ie, 
multiple endocrine neoplasia type 2). 
18. Abnormal laboratory results for TSH (> 1.5 x ULN or < 
0.5 mIU/L) 
19. Abnormal laboratory results for fasting triglycerides 
>1151 mg/dL (≥ 13.0 mmol/L). Elevated values may be 
repeated once on a separate day. (Subjects with fasting 
triglycerides ≥ 13.0 mmol/L may be included in the study 
if LDL < 131 mg/dL (< 3.4 mmol/L) and if they have no 
history of pancreatitis, CVA, transient ischemic stroke, or 
myocardial infarction as approved per Investigator’s 
discretion.) 
20. Abnormal laboratory results for LDL 189 mg/dL (>4.9 
mmol/L) for untreated dyslipidemia or > 158 mg/dL (> 
4.1 mmol/L) for treated dyslipidemia. Elevated values 
may be repeated once on a separate day. 
21. Clinically significant abnormal hepatic function tests 
suggestive of hepatic impairment (eg, ALT and AST >2 x 
ULN). 
22. Clinically significant abnormal pancreatic function tests 
suggestive of pancreatic impairment (eg, amylase and 
lipase >3 x ULN). 
23. History of renal disease or abnormal kidney function tests 
at Screening (glomerular filtration rate [GFR] < 60 
mL/min/1.73m2 as estimated using the MDRD equation).  
24. History of any active infection, other than mild viral 
illness within 30 days prior to dosing as judged by the 
investigator. 
25. Use of a very-low calorie (1,000 kcal/day) liquid weight 
loss diet within 6 months prior to screening 
26. History of alcohol or illicit drug abuse as judged by the 
Investigator within approximately 1 year. 

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27. Daily use of more than 10 cigarettes/day, or 2 cigars/day, 
or equivalent use of any tobacco product within 6 weeks 
prior to Screening.  
28. Frequent use of marijuana within 6 weeks, or clinically 
under the effect at screening, as per Investigator 
evaluation. 
29. Known history of or positive test for hepatitis B surface 
antigen (HBsAg), hepatitis C antibody (HCV Ab), or 
human immunodeficiency virus type 1 (HIV-1) or type 2 
(HIV-2) antibody. 
30. Any anticipated procedures (eg, surgery), that might 
interfere with the compliance or completion of the study. 
31. Presence of clinically significant physical, laboratory, or 
ECG findings (eg, QTcF > 450 msec for males, QTcF > 
470 msec for females, LBBB) at screening that, in the 
opinion of the Investigator, may interfere with any aspect 
of study conduct or interpretation of results. 
32. Donation or loss of >500 mL of blood or blood product 
within 56 days of dosing. 
33. Mental incapacity, unwillingness or language barriers 
precluding adequate understanding or cooperation. 
34. Is employed by Hanmi or ProSciento (permanent, 
temporary contract worker, or designee responsible for 
the conduct of the study) or is immediate family of Hanmi 
or ProSciento, defined as a spouse, parent, sibling, or 
child, whether biological or legally adopted. 
Statistical 
Methods 
Data analyses will follow a statistical analysis plan (SAP). 
PK and PD assessments for all dose groups will be analyzed 
using descriptive and comparative statistical methods. 
No formal sample size calculation will be performed. Safety and 
tolerability of the study drug will be assessed based on adverse 
events, laboratory parameters, physical examination, vital signs, 
and ECG parameters throughout the duration of the study. Safety 
analysis will involve examination of the descriptive statistics and 
individual subject listings for any effects of study treatment on 
clinical tolerability and safety. 
 

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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABPM 
Ambulatory blood pressure measurement 
ADAbs 
Anti-drug antibodies  
ADCC 
Antibody dependent cellular toxicity  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
Anti-PEG 
Anti-polyethylene glycol antibody 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BG 
Blood glucose 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BP 
Blood pressure 
BW 
Body weight 
CDC 
Complement dependent cytotoxicity 
CDM 
Clinical data management 
C.I. 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum concentration  
CRF 
Case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CV 
Coefficient of variation 
DFT 
Deviation from target 
DIO  
Diet-induced obesity 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
ECG  
Electrocardiogram 
eCRF 
Electronic CRF 
EE 
Energy expenditure  
FDA 
Food and Drug Administration 
FFA 
Free fatty acid 
FPG 
Fasting plasma glucose 
FSFV 
First subject first visit 
GCG 
Glucagon 
GCGR 
Glucagon receptor 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 

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GIP 
Glucose dependent insulinotropic polypeptide/ gastric 
inhibitory peptide 
GIPR 
Glucose dependent insulinotropic polypeptide/ gastric 
inhibitory peptide receptor 
GLP-1 
Glucagon-like peptide 
GLP-1R 
Glucagon-like peptide receptor 
HbA1C 
Glycosylated hemoglobin 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HRV 
Heart rate variability 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
ipGTT 
Intra-peritoneal glucose tolerance test  
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
lb 
Pound 
LBBB 
Left brunch bundle block 
LS mean 
Least square mean 
MAL-PEG-ALD 
Maleimide-Polyethylene glycol- Aldehyde  
Mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
nAbs 
Neutralizing antibodies  
NAFLD 
Nonalcoholic fatty liver disease  
NCA 
Non-compartmental analysis 
NDA 
New Drug Application 
Nmol 
Nanomol 
NN 
Normal to normal  
NOAEL 
No-observed-adverse-effect level 
NPH 
Neutral Protamine Hagedorn insulin 
NSAID 
Non-steroid anti-inflammatory drugs 
OTC 
Over the counter 
PD 
Pharmacodynamics 
PE 
Physical examination 
PEG 
Polyethylene glycol 

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PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
rDNA 
Recombinant deoxyribonucleic acid 
RHI 
Regular human insulin 
RR 
Respiration rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SDNN 
Standard deviation of all normal intervals 
SDRM 
Safety data review and dose escalation meeting 
SOE 
Schedule of event 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides 
Tmax 
Time to maximum serum concentration (in concentration 
time curve) 
TSH 
Thyroid-stimulating hormone 
U 
Unit 
ULN 
Upper limit of normal 
US 
United States  
USP 
Unites States Pharmacopeia 
Vz/F 
Apparent volume of distribution at terminal phase 
WHO 
World Health Organization 
 

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4.0 
INTRODUCTION 
4.1 
Background 
Overweight has become an epidemic disease and impairs the health of more than 1.9 
billion adults, of whom 650 million are obese, defined by a. BMI of ≥ 30kg/m2. This 
represents about 13% of the worlds adult population.1 
Obesity impacts many organ systems. One affected system is the cardiovascular system, 
including an increased prevalence of heart failure, hypertension and coronary heart 
disease. Obstructive sleep apnea and asthma are also common in the obese. Non-
alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), 
is on the rise and may become the leading cause of cirrhosis and hepatocellular 
carcinoma. Psychosocial and psychiatric consequences of obesity are also increasing.2 
Dual agonists have been developed that co-target the glucagon and glucagon like peptide  
(GLP-1) receptors for obesity treatment.3 Additionally, triple agonists, which have added 
a gastric inhibitory polypeptide receptor (GIPR) agonist to the combination, are under 
development in early phase clinical studies. 
HM15211 is a novel long-acting triple incretin agonist. It is a chemical conjugate of a 
chimeric peptide (GLP-1/Glucagon/GIP triple agonist; named as TA15211) and human 
immunoglobulin G4 Fc fragment (named as HMC001) linked via a bifunctional 
Maleimide-Polyethylene glycol- Aldehyde (MAL-PEG-ALD) linker molecule.  
TA15211 is produced by chemical synthesis and the quality of TA15211 is controlled by 
complying with in-house specification. The HMC001 moiety was derived from the 
constant region of human immunoglobulin G4 fragment and produced in the transformed 
E. coli as an inclusion body. The inclusion body was purified after successive refolding 
and purification steps, and the quality of HMC001 was controlled by in-house 
specification. Human immunoglobulin G4 Fc fragment (HMC001) was chosen as the 
stabilizing agent because it is the most prevalent blood protein and has an in vivo half-life 
of several weeks without effector functions including antibody dependent cellular toxicity 
(ADCC) and complement dependent cytotoxicity (CDC). The linker is a 10 kDa 
polyethylene glycol (PEG) with bifunctional reactive groups (maleimide aldehyde 
reactive groups at individual ends, MAL-PEG-ALD). The conjugation of TA15211 and 
HMC001 is carried out through the formation of a thioether and amine bond between 
hetero-bifunctional MAL-PEG-ALD, Cys40 in TA15211, and the N-terminal amino acid 
in HMC001. 
HM15211 is a long-acting GLP-1/Glucagon/GIP triple agonist with extended half-life 
through reduced renal clearance and possibly by vascular endothelial recycling via FcRn 
binding. HM15211 showed triple-agonistic properties with potent glucagon activity in 
addition to balanced GLP-1 and GIP activity.  
According to series of in vivo pharmacologic studies, HM15211 can be an attractive 
treatment option for obese patients based on its potent body weight loss efficacy from 

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energy intake inhibition and energy expenditure enhancement. Glucagon activity 
provides potent body weight loss primarily from fat mass reduction as shown in efficacy 
studies in diet-induced obesity (DIO) mice. Furthermore, GLP-1/GIP activities negate a 
possible hyperglycemic risk as demonstrated in intra-peritoneal glucose tolerance test 
(ipGTT) studies in normal and DIO mice.  
Above all, liver preferential distribution, and following hepatic lipid metabolism 
improvement, renders HM15211 a suitable therapeutic option for NASH and hepatic 
fibrosis. Therefore, HM15211 is expected to have favorable therapeutic profiles in both, 
obesity and NASH as well as convenience in its clinical dosing regimen. 
For further information please refer to the Investigator’s brochure (IB). 
4.2 
Rationale for the Proposed Study 
The aim of this first-in-human, single ascending dose study is to investigate safety and 
tolerability of the drug as well as the PK profile in healthy obese subjects. Five cohorts of 
8 subjects will investigate the drug, and will include a placebo comparison in each cohort. 
Based on the pre-clinical data and existing research on the drug components/ drug class 
that exists in the public domain, as well as the proposed monitoring conditions of the 
proposed inpatient study, it is reasonable and appropriate to investigate the study drug in 
the intended potential target population. Healthy obese subjects will ensure that a robust 
and relevant set of safety and PK data can be generated to inform the design of 
subsequent clinical studies. 
4.3 
Summary of Pre-Clinical Studies 
To date, no human studies have been conducted with HM15211. 
In vitro activity of HM15211 was evaluated using respective receptors, human GLP-1 
receptor (hGLP-1R), human glucagon receptor (hGlucagonR), and human GIP receptor 
(hGIPR). HM15211 showed dose-dependent activation of all three receptors with potent 
glucagon activity in addition to balanced GLP-1 and GIP activity. Simultaneous 
activation of three incretin receptors could provide synergistic metabolic benefits on body 
weight loss and lipid profile improvement whilst avoiding hyperglycemic risk.  
Further in vitro studies confirmed, that since HM15211 includes an aglycosylated Fc 
moiety derived from human IgG4, it shows minimal immune-mediated effector functions. 
In addition, due to Fc moiety, HM15211 retained pH-dependent FcRn binding property, 
which is essential for vascular endothelial recycling. 
In vivo pharmacology studies using obese mice showed that HM15211 enables potent 
body weight loss from both, food intake inhibition and enhanced energy expenditure. The 
body weight loss was mainly from fat mass reduction, along with lowered serum lipid 
profile. Glucagon action increased energy expenditure and thus enhanced body weight 
loss and hyperglycemic risk by glucagon was effectively buffered by actions of GLP-
1/GIP. In NASH induced models, HM15211 effectively reduced hepatic triglycerides 

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(TG), oxidative stress and inflammatory markers. Furthermore, HM15211 treated animals 
showed significant reduction in NAFLD activity score and hepatic fibrogenic markers, 
suggesting HM15211 as an effective pharmacotherapy for NASH with hepatic fibrosis. 
Safety pharmacology studies were conducted to evaluate the effects on the 
cardiovascular, respiratory, central nervous systems and in vitro hERG channel assay. No 
significant effect was observed in the safety pharmacology studies and in vitro human 
ether-a go-go related gene (hERG) channel assay.  
In pharmacokinetic studies, HM15211 exhibited a prolonged half-life (t½) after 
subcutaneous (SC) or intravenous (IV) dosing, which ranged from approximately 42.7 to 
85.6 hours in mice, 74.7 to 86.0 hours in rats, and 35.7 to 79.7 hours in dogs, indicating 
that HM15211 is a long acting triple-agonist. HM15211 is preferentially distributed in the 
liver, making HM15211 a favorable treatment option for dysfunction in lipid metabolism 
specifically in the liver. 
The toxicity studies of HM15211, repeat dose toxicity up to 4 weeks in rats and monkeys, 
and in vitro genotoxicity studies, were conducted. Local tolerance of HM15211 was 
investigated in 4-week repeated rat and monkey studies. Additional studies were 
conducted with HMC001 (inactive ingredient) in rat and monkey up to 4 weeks repeat 
dose toxicity studies.  
No target organ was identified during the 4 weeks repeat dose toxicity studies of 
HM15211. All changes were completely or partially reversible during the recovery 
period.  
The majority of findings were related to fasting effect or pharmacological effect of 
glucagon. No adverse test article-related findings at the injection sites were noted. No 
adverse events were observed in HMC001 studies.  
4.4 
Rationale for Starting and Maximum Dose 
The proposed starting dose of HM15211 is 0.01mg/kg, selected based on the results of 
the 28 days toxicology assessments of HM15211 in monkeys and rats, and the application 
of an additional safety factor, as described in Table 4-1 below.  
Table 4-1 Starting Dose Calculations  
Species 
28-day 
Toxicity Study  
NOAEL 
(mg/kg) 
HED 
(mg/kg) 
Planned 
Starting Dose 
Safety Margin 
vs. NOAEL 
HED 
Rat 
0.4 
0.07 
0.01 
7 
Monkey 
2 
0.7 
70 
 

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The NOAEL was 0.4 mg/kg in rats and 2 mg/kg in monkeys. For conversion to a human 
equivalent dose (HED), these values were divided by 6.2 for rats and 3.1 for monkeys, 
resulting in a HED of 0.07 mg/kg for rats and 0.7 mg/kg for monkeys. The starting dose 
of 0.01 mg/kg in this clinical study is approximately 1/7th of the NOAEL for rats and 
1/70th of the NOAEL in monkeys during the 28-day toxicity evaluation of HM15211. 
Additionally, the starting dose of 0.01 mg/kg is between the ED10 pharmacologically 
active dose for mice (0.013 mg/kg) and rats (0.007 mg/kg).5,6 
 
The maximum human dose is determined by the exposure seen at the NOAEL in the  
4-week toxicology study in the rat which corresponds to approximately 0.16 mg/kg in a 
human according to PK prediction. Dose escalation will be determined in safety review 
and dose escalation meeting by Sponsor and Investigator and will be based on clinical 
safety and available PK data. 
4.5 
Dose Escalation Algorithm 
The proposed dose escalation algorithm for HM15211 may include the following steps: 
Table 4-2 Sample Allocation and Dose Escalation  
Cohorts 
Number of Subjects 
Treatment Period 
Cohort 1 
N=6 
HM15211-  0.01 mg/kg 
N=2 
Placebo 
Cohort 2 
N=6 
HM15211 ≤ 0.02 mg/kg 
N=2 
Placebo 
Cohort 3 
N=6 
HM15211 ≤ 0.04 mg/kg 
N=2 
Placebo 
Cohort 4 
N=6 
HM15211 ≤ 0.08 mg/kg 
N=2 
Placebo 
Cohort 5 
N=6 
HM15211 ≤ 0.16 mg/kg 
N=2 
Placebo 
 
Each subject will be randomized to HM15211 or placebo according to the table above. 
The dose will be 0.01 mg/kg, based on the body weight measured prior to dosing. For 
dose calculation and rounding, please refer to the Operational Manual/Pharmacy Manual. 

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After at least 6 subjects (n ≥ 4 subjects on active drug HM15211) in each cohort have 
completed at least Day 10, safety and available PK data will be reviewed and a dose 
decision/ dose escalation decision for the subsequent cohort will be made by the Sponsor 
and the Investigator. Doses between cohorts will not exceed a 2-fold increase relative to 
the specified doses stated in the Table 4-3 above. Following the dose escalation decision, 
the procedures for the subsequent cohorts will be identical to those described above. 
Adjustments to the procedures/cohorts may occur after the review of available safety and 
PK data: 
• Adjustments to the number of study cohorts may occur: Additional cohorts may 
be enrolled and proceed at a higher or a lower dose. If deemed appropriate by the 
investigator and sponsor, there may be more than one cohort investigated at the 
same dose level. 
• Adjustments to the 24-hr BP and HR monitoring: After the evaluation of the first 
cohort, tests may be rescheduled, or measurement periods may be focused on 
specific days to capture the 24-h measurement around the PKpeak.  
• Adjustments to the visit schedule: If PK data suggest, additional sampling times 
and/or outpatient visits may be added to the study schedule. 

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5.0 
STUDY OBJECTIVES 
5.1 
Primary Objectives and Endpoints 
To assess safety and tolerability of HM15211 after single SC doses, in regard to: 
• Incidence of adverse events 
• Incidence of clinical laboratory abnormalities (including serum amylase, serum 
lipase, coagulation, thyroid stimulating hormone (TSH), serum calcitonin) 
• Immunogenicity (Anti-drug antibodies [ADAbs], neutralizing anti-drug 
antibodies [nAbs], anti-polyethylene glycol antibodies [anti-PEG]) 
• Change from baseline in vital signs (blood pressure, respiratory rate, temperature, 
and heart rate) measurements 
• Incidence and severity of clinical findings on physical examination 
• Injection site reaction 
• Change from baseline in 12-lead ECG parameters; the primary ECG endpoint will 
be QTcF 
• Blood pressure (BP) assessed by 24-hour ambulatory blood pressure monitoring 
(ABPM); (Mean day- and night time systolic/diastolic BP)  
• Heart rate activity assessed by 24-hour ambulatory electrocardiography 
monitoring (Holter ECG); (Heart rate [HR] and heart rate variability [HRV], e.g. 
mean heart rate, difference between day and night HR, mean normal to normal 
[NN] intervals, standard deviation of all NN intervals [SDNN]) 
To assess the pharmacokinetic (PK) profile of HM15211 after single SC doses in regards, 
but not limited to:  
• Maximum concentration (Cmax) 
• Time to reach Cmax (Tmax) 
• Total area under the concentration time curve (AUC), including AUC(0-inf) 
• Apparent terminal half-life (t1/2) 
• Apparent clearance (CL/F) 
• Apparent volume of distribution at terminal phase (Vz/F) 
• Terminal elimination rate constant (kel) 

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5.2 
Exploratory Objectives and Endpoints 
To assess pharmacodynamics (PD) properties of HM15211 after single SC doses in 
comparison to placebo on: 
• Lipid metabolism: 
o Total cholesterol 
o Low-density lipoprotein (LDL) 
o High-density lipoprotein (HDL) 
o Very low-density lipoprotein (VLDL) 
o Triglycerides 
o Free fatty acid (FFA) 
• Body weight 
• Glucose metabolism: 
o Fasting plasma glucose (FPG) 
o Insulin 
o C-peptide 
• Incretin secretion: 
o Glucagon (GCG) 
o Leptin 
o Glucagon-like peptide-1 (GLP-1) 
o Gastric inhibitory peptide (GIP) 
• Inflammatory marker: 
o C-reactive protein (CRP) 

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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a first-in-human, randomized, double-blind, SAD study to evaluate the safety, 
tolerability, and PK of HM15211 as primary objectives in healthy obese subjects.  
The study will be conducted in five sequential cohorts (cohort 1 to 5) comprising a total 
of up to approximately 40 subjects. Each cohort will enroll subjects to ensure that at least 
8 subjects per cohort will complete the study. Drop-outs may be replaced in order to have 
8 completed subjects in each cohort. Subjects will be allocated into sequential dosing 
cohorts based on their order of entry into the study and be randomized to investigational 
product (IP) or placebo in a 3:1 ratio, with 6 subjects on IP and 2 subjects on placebo. 
Cohorts may partially overlap after at least 6 subjects have completed at least D10 and a 
dose escalation decision has been made. 
Dosing will follow a sentinel approach with the dosing between the first 2 subjects (1 on 
active, 1 on placebo) and the remainder of the cohort at least 24 hours apart. A minimum 
of 10-days between the start date of consecutive dose levels will be maintained. Based on 
available safety, tolerability, and PK data of each cohort, and following a safety review 
and dose escalation meeting between the investigator and the sponsor, dose escalation to 
the next cohort may proceed. If dose escalation is stopped (please see dose escalation 
stopping criteria in section 6.4.1), dose de-escalation may occur in additional cohorts, to 
further refine clinically relevant dose levels. 
Each subject will undergo a screening visit, followed by one in-house/ treatment period 
per subject. Two additional outpatient visits will occur, prior to a final follow-up visit that 
will conclude subject study participation. 
The duration of subject participation in this study, including screening, treatment and 
follow-up will approximately be 9 weeks for subjects. 
Figure 6-1 Study Design Schematic 
 
 

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Figure 6-2 Dose Escalation Schematic 
 
6.2 
Study Description 
Each subject will undergo the following procedures during the study: 
Screening Visit: 
Before the screening takes place, potential subjects for the trial will be provided with 
written and oral information about the trial and the procedures involved. Subjects must 
sign the informed consent form (ICF) prior to entering the study. Please see section 9.1.1 
for further details.  
The screening visit will be performed up to 28 days prior to the first dosing day, to 
identify eligible subjects for the study. All assessments performed at the screening visit 
are stated in Table 16-1 and will be recorded in the electronic case report form (eCRF). 
Please see section 9.1.2 and 11.2 for further details.  
In-house Period: 
Subjects will check in to the clinical research unit (CRU) in the morning of Day -2 for a 
9-day in-house period. They will receive standardized meals throughout their in-house 
stay. A 12-lead standard ECG will be performed. Subjects will be connected to an ABPM 
system for measurement of blood pressure (BP), and measurements will be started 
overnight on Day -2 to familiarize the subjects with the device. Measurements will 
continue until the morning of Day 4.  

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In the morning of Day -1, subjects will get connected to a Holter ECG for continued 
measurement of the heart rate activity until the morning of Day 4.  
Only 24-hour monitoring data from Day -1 to Day 1 will be used for the monitoring 
evaluation as baseline assessments for ABPM and Holter ECG monitoring. For 
measuring timepoints, please see sections 9.1.14 and 9.1.15. 
Subjects will be randomized to a single SC injection of HM15211 or placebo. 
Randomization will take place as close to the drug administration as possible. 
On Day 1, after an ≥ 10 h overnight fast, subjects will be dosed with HM15211or placebo 
at approximately 08:00 hours (t=0), through SC injection into the abdominal wall by 
qualified study staff. Measurements of vital signs, ECG, blood sampling for PK and PD 
analyses, local injection site evaluation, and laboratory parameter will be performed for 
safety evaluation, at timepoints stated in Table 16-1. 
ABPM and Holter ECG monitoring will be continued until the morning of Day 4 for the 
post-dose evaluation. 24-hour monitoring evaluations will be performed together with 
available PK data, in order to determine the best time period for 24-h monitoring period 
around PKpeak. 
Subjects will continue to stay in-house for safety evaluations, PK and PD assessments. 
They will be released from the CRU in the morning of Day 7 and will return for two 
outpatient visits on Day 10 and 17. 
Outpatient Visits: 
Subjects will return to the CRU on Days 10 (± 1) and 17 (± 1) for two outpatient visits. 
Blood samples for PK and PD analyses will be collected, and additional safety 
assessments will be performed as stated in the Table 16-1. 
Follow-up Visit: 
A Follow-up Visit will be performed on Day 30 (± 2) for final safety procedures. Please 
see Table 16-1Schedule of Events for details. 
Sampling and Assessment: 
Time points for study procedures and sample collection are specified in the Table 16-1. 
Safety assessments will occur throughout the duration of the study, including monitoring 
of adverse events (AEs), clinical laboratory tests (eg, chemistry, hematology, 
coagulation, amylase, lipase and urinalysis), vital signs measurements (blood pressure, 
heart rate, respiration rate, and aural temperature), 12-lead electrocardiograms (ECGs), 
ABPM, Holter ECG monitoring, and physical examinations. 
Local tolerability assessments will be performed by injection site inspection at specific 
time-points. 
Immunogenicity samples for assessment of ADAbs, nAbs and anti-PEG will be taken 
prior to dosing, on Day 17, and at follow-up, as stated in the Table 16-1.  

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The PK samples will be taken in accordance with the PK sampling schedule in section 
9.1.16. Sampling may be adjusted based on the results of the SDRM. 
The PD samples will be taken in accordance with the PD sampling schedule in section 
9.1.17. Sampling time points may be adjusted based on the results of the SDRM. 
6.3 
Rationale for Study Design and Endpoints  
This SAD study will assess the safety and tolerability as well as PK of HM15211 as 
primary objectives.  
Cohorts will be assessed in ascending order, but may overlap, to determine a clinically 
appropriate dose for the subjects and will include the comparison with placebo. 
Randomization is used to avoid bias introduced through an association between study 
drug allocation order and subject characteristics. 
A double-blind design has been chosen to avoid bias and to maintain the blind between 
the administration of the study drug and placebo. 
Healthy obese subjects will participate in the study, as these subjects are an important 
target population for the novel triple agonist. Enrollment criteria will favor the target 
population, as body mass index will be limited to ≥ 30 to ≤ 40 kg/m2. 
After PK modeling, Cmax is expected to be reached approximately 3 days after dosing. As 
this is a first-in-human study, measurements for the assessment of cardiovascular events 
will start right after dosing and will continue until Day 4. After evaluation of the PK 
values in the initial cohort(s), the monitoring period will be adjusted, to ensure that the 
24-h period around the PKpeak is captured. 
The proposed PK endpoints are well-established, commonly used parameters to 
characterize pharmacological profiles of drugs. For the PK endpoints, blood samples for 
determination of HM15211 will be analyzed using a validated assay. 
This is an exploratory study. No formal sample size calculation and no statistical 
hypothesis testing will be performed. 
The study will be conducted at a specialized early phase research centre, where the 
subjects will be under supervision of physicians, research nurses and additional medical 
staff experienced in conducting early phase clinical studies investigating new metabolic 
compounds. 
6.4 
Study Discontinuation and Stopping Criteria 
6.4.1 Dose Escalation Stopping Criteria 
Dose escalation will be stopped if one of the following conditions apply: 
• Death of a subject (AE grade 5 toxicity) in one cohort, at any time, that is considered 
related to the IP, judged by the Investigator 

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• One subject in a cohort develops an AE ≥ Grade 3 toxicity, that is considered related 
to the IP, judged by the Investigator 
• One subject in a cohort develops an AE Grade 2 toxicity that persists for more than 7 
days and is considered related to the IP, judged by the Investigator 
• 2 or more of the subjects in a cohort have experienced severe adverse events, judged 
to be possibly or probably related to the IP, judged by the Investigator; 
• 2 or more subjects receiving HM15211 develop similar clinically significant 
laboratory, significant ECG or vital signs abnormalities, or severe AEs in the same 
organ class, indicating dose-limiting intolerance. Dose escalation may proceed if after 
review of the data by the Investigator and discussion with Sponsor, it is concluded 
that the events are not drug related; 
• It is determined that the limit of safety and/or tolerability has been reached. Decision 
will be made between Sponsor and Investigator. 
6.4.2 Criteria for Early Termination of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied  
• violation of Good Clinical Practice (GCP) that compromises the ability to achieve the 
primary study objectives or compromises subject safety. 
• Failure to meet expected enrollment goals 
• Administrative Reasons 
In case that the Sponsor, an institutional review board (IRB)/ independent ethics 
committee (IEC), or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension. 
6.4.3 Criteria for Early Termination of Individual Subjects 
Subjects may withdraw their consent to participate in the study at any time. 
If a subject withdraws consent, the date and reason for consent withdrawal should be 
documented. Subjects will be encouraged to remain in the clinic for safety assessments 
until the Investigator deems that it is safe for the subject to be discharged. Subject data 
will be included in the analysis up to the date of the consent withdrawal. 
• AE or SAE that requires discontinuation at the discretion of the Investigator 
• Protocol violation: If protocol violation or concurrent illness occurs, which, in the 
clinical judgment of the Investigator or after discussion with the Sponsor, may 

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invalidate the study by interfering pharmacokinetically or pharmacodynamically with 
the investigational products, subject will be withdrawn by the Investigator. 
• Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
• Voluntary withdrawal of consent (mandatory removal from study) 
• Discretion of Investigator (document reason on CRF) 
• Subject becomes pregnant or begins breastfeeding (mandatory) 
• Study discontinuation by Sponsor 
Wherever possible, the tests and evaluations, including those listed for the Follow-up 
Visit should be performed for all subjects who discontinue prior to the completion of the 
study. 
In the event the Investigator determines to terminate a subject participation in the Clinical 
Study, the Investigator must notify the Sponsor of such decision and rationale 
immediately in writing. In all cases, the appropriate IRB/IEC and other applicable 
regulatory authorities shall be informed. 

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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Subjects who meet all criteria at Screening will be included in the study:  
1. Male and female subjects. 
2. Age ≥ 18 to ≤ 65 years. 
3. Body mass index (BMI) ≥ 30 to ≤ 40 kg/m2, with stable body weight by history 
for 3 months (defined as change < 5%). 
4. HbA1c < 6.5 %. 
5. Female subjects must be non-pregnant and non-lactating. Females of child 
bearing potential must use highly effective contraceptive methods, stable at least 2 
months prior to the screening. Male subjects must be surgically sterile, abstinent 
or if engaged in sexual relations of child-bearing potential, the subject and his 
partner must use an acceptable method of contraception.  
6. Ability to provide written informed consent. 
7.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study:  
1. Previous surgical treatment for obesity (bariatric surgery, gastric banding etc.) or 
any other gastrointestinal surgery that may induce malabsorption, history of 
bowel resection >20 cm, any malabsorption disorder, severe gastroparesis, any GI 
procedure for weight loss (including LAP-BAND®), as well as clinically 
significant gastrointestinal disorders (e.g. peptic ulcers, severe GERD) at 
Screening.  
2. Use of antacids, anticoagulants, drugs that directly modify gastrointestinal (GI) 
motility, including, but not limited to, anticholinergics, antispasmodics, 5HT3 
antagonists, dopamine antagonists, or opiates within 2 weeks of screening. 
3. Uncontrolled hypertension, defined as systolic blood pressure >150 mmHg and/or 
diastolic blood pressure ≥ 100 mmHg at screening (reading may be repeated on a 
different day). (Subjects with uncontrolled hypertension may be rescreened after 3 
months, following initiation or adjustment of antihypertensive therapy). 
4. Use of any drugs that are known to interfere with glucose or insulin metabolism, 
including but not limited to oral or parenteral corticosteroids or topiramate, 
monoamine oxidase (MAO) inhibitors, growth hormone, oral antidiabetic drugs 
and insulin within 3 months prior to screening.  
5. Treatment with antihypertensive medication and statins, unless on stable dose for 
at least 3 months prior to screening. 

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6. Any weight control treatment, including over-the-counter and herbal medication 
and supplements, or any medication with a labelled indication for weight loss or 
weight gain within 3 months prior to screening. 
7. Any prior treatment with GLP‐1 receptor agonists (e.g., exenatide, liraglutide, 
dulaglutide), dipeptidylpeptidase‐4 (DPP‐4) inhibitors, oral antidiabetic drugs and 
insulin. 
8. Participation in an investigational study within 30 days prior to dosing or 5 half-
lives within the last dose of investigational product whichever is longer. 
9. Calcitonin levels > 20 pg/mL at screening. 
10. Personal history or current diagnosis of acute or chronic pancreatitis or factors for 
pancreatitis, such as a history of cholelithiasis (without cholecystectomy) or 
alcohol abuse.  
11. History of major depression, anxiety, or other psychiatric disorder (within 2 years 
of screening), requiring medical treatment, including selective serotonin reuptake 
inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), 
antipsychotics, lithium. (Use of SSRIs and SNRIs [including bupropion] for 
reason other than active psychiatric indications [eg, migraine, weight loss, 
smoking cessation] must meet a 3-month wash-out) 
12. History of significant suicidal ideation or suicidal behavior/attempts. 
13. History of any major surgery within 6 months prior to screening. 
14. History of any serious adverse reaction or hypersensitivity to study drugs 
components. 
15. History or current diagnosis of heart disease, defined as symptomatic heart failure 
(New York Heart Association class III or IV), myocardial infarction, unstable 
angina requiring medication, transient ischemic attack, cerebral infarct, or 
cerebral hemorrhage or invasive cardiovascular procedure, such as coronary 
artery bypass graft surgery (CABG), or angioplasty/percutaneous coronary 
intervention (PCI) within 6 months of screening. (A diagnostic cardiac 
catheterization without any intervention does not exclude the subject) 
16. Cardiac arrhythmia requiring medical or surgical treatment within 6 months prior 
to screening. 
17. Personal or family history of medullary thyroid carcinoma (MTC) or a genetic 
condition that predispose to MTC (ie, multiple endocrine neoplasia type 2). 
18. Abnormal laboratory results for TSH (> 1.5 x ULN or < 0.5 mIU/L) 
19. Abnormal laboratory results for fasting triglycerides ≥ 1151 mg/dL (≥ 13.0 
mmol/L). Elevated values may be repeated once on a separate day. (Subjects with 
fasting triglycerides ≥ 13.0 mmol/L may be included in the study if LDL< 131 
mg/dL (< 3.4 mmol/L) and if they have no history of pancreatitis, CVA, transient 

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ischemic stroke, or myocardial infarction as approved per Investigator’s 
discretion.) 
20. Abnormal laboratory results for LDL >189 mg/dL (>4.9 mmol/L) for untreated 
dyslipidemia or >158 mg/dL (> 4.1 mmol/L) for treated dyslipidemia. Elevated 
values may be repeated once on a separate day. 
21. Clinically significant abnormal hepatic function tests suggestive of hepatic 
impairment (eg, ALT and AST >2 x ULN). 
22. Clinically significant abnormal pancreatic function tests suggestive of pancreatic 
impairment (eg, amylase and lipase >3 x ULN). 
23. History of renal disease or abnormal kidney function tests at Screening 
(glomerular filtration rate [GFR] < 60 mL/min/1.73m2 as estimated using the 
MDRD equation).  
24. History of any active infection, other than mild viral illness within 30 days prior 
to dosing as judged by the investigator. 
25. Use of a very-low calorie (1,000 kcal/day) liquid weight loss diet within 6 months 
prior to screening 
26. History of alcohol or illicit drug abuse as judged by the Investigator within 
approximately 1 year. 
27. Daily use of more than 10 cigarettes/day, or 2 cigars/day, or equivalent use of any 
tobacco product within 6 weeks prior to Screening.  
28. Frequent use of marijuana within 6 weeks, or clinically under the effect at 
screening, as per Investigator evaluation. 
29. Known history of or positive test for hepatitis B surface antigen (HBsAg), 
hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-
1) or type 2 (HIV-2) antibody. 
30. Any anticipated procedures (eg, surgery), that might interfere with the compliance 
or completion of the study. 
31. Presence of clinically significant physical, laboratory, or ECG findings (eg, QTcF 
> 450 msec for males, QTcF > 470 msec for females, LBBB) at screening that, in 
the opinion of the Investigator, may interfere with any aspect of study conduct or 
interpretation of results. 
32. Donation or loss of >500 mL of blood or blood product within 56 days of dosing. 
33. Mental incapacity, unwillingness or language barriers precluding adequate 
understanding or cooperation. 
34. Is employed by Hanmi or ProSciento (permanent, temporary contract worker, or 
designee responsible for the conduct of the study) or is immediate family of 

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Hanmi or ProSciento, defined as a spouse, parent, sibling, or child, whether 
biological or legally adopted. 
7.3 
Prohibited Medications 
Use of the agents listed in Table 7-1 (prescription or nonprescription) is prohibited from 
the time points specified until completion of all study activities. 
Table 7-1 Prohibited Medications 
Medication or Class 
Indication/Reason 
From time point specified 
antacids, anticoagulants, 
anticholinergics, 
antispasmodics, 5HT3 
antagonists, dopamine 
antagonists, or opiates  
Reduction/modification of GI 
motility 
within 2 weeks of screening 
oral or parenteral 
corticosteroids or topiramate, 
MAO inhibitors, growth 
hormone 
Interference with glucose or 
insulin metabolism 
within 3 months prior to 
screening. 
Orlistat, lorcaserin, sibutramine 
Weight control treatment, 
including over-the-counter and 
herbal medication and 
supplements, or any 
medication with a labelled 
indication for weight loss or 
gain 
within 3 months prior to 
screening. 
GLP‐1 receptor agonists (e.g., 
exenatide, liraglutide, 
dulaglutide), 
dipeptidylpeptidase‐4 (DPP‐4), 
oral antidiabetic agents (e.g. 
SGLT2 inhibitors), insulin 
Interference with glucose or 
insulin metabolism 
any prior treatment 
selective serotonin reuptake 
inhibitors (SSRIs), serotonin 
norepinephrine reuptake 
inhibitors (SNRIs), 
antipsychotics, lithium. 
Depression, anxiety, or other 
psychiatric disorder 
within 2 years of screening 
Use of SSRIs and SNRIs 
(including bupropion) are 
allowed 
If taken for reason other than 
active psychiatric indications 
[eg, migraine, weight loss, 
smoking cessation] 
must meet a 3-month wash-out 
7.4 
Check in Criteria 
Subjects will be educated about influencing factors, such as to refrain from strenuous 
exercise throughout the entire course of the study, to avoid alcohol and herbal 
supplements, (especially 24 hours prior to dosing), caffeinated drinks (caffeine containing 

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food and beverages 24 hours prior to dosing), smoking or medication and 
illness/infection. 
At check-in for any in patient period(s), a subject will not be allowed to check in if they 
meet any of the following criteria and the treatment period may be rescheduled one time. 
The Sponsor will be notified about the rescheduling in a timely manner. 
1. Positive alcohol breath test. 
2. Positive urine drug screen test. 
3. Positive urine pregnancy test in female subjects.  
4. Any medical condition that could interfere with the study, as judged by the 
Investigator. 
5. Any use of medicine other than any allowed concomitant medications within the 
last 24 hours. 

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8.0 
STUDY MATERIALS 
8.1 
Investigational Products (IPs) 
8.1.1 HM15211 
A sterile solution of HM15211 contained in 0.52 mL pre-filled syringes will be provided. 
The concentration of HM15211 is 10 mg/mL as protein. HM15211 is manufactured by 
Hanmi Pharmaceuticals, Seoul, South Korea.  
8.1.2 Placebo 
Placebo is a sterile, matching solution (all components except drug substance) and free of 
visible particles. Placebo solution will be supplied in 0.52 mL pre-filled syringes by 
Hanmi Pharmaceuticals, Seoul, South Korea. Storage: 2 ℃ to 8 ℃. 
8.2 
Packaging, and Labeling of Investigational Products 
The Sponsor will provide the Investigator with the labeled IPs in accordance with 
specific country regulatory requirements. 
The IP will be packaged and shipped to the clinical research unit (CRU) in an open label 
manner. Hanmi will prepare each syringe and place them in an independent paper 
box/carton. 
8.3 
Storage and Drug Accountability of Investigational Products 
All clinical material will be kept in an appropriate, limited-access, secure location. 
The investigational product, and its storage and preparation instructions, will be provided 
by the Sponsor. The IP must be stored securely at 2 ℃ to 8 ℃ (36 °F to 46 °F), and 
should not be exposed to excessive heat and never be frozen. It should be protected from 
direct sunlight and therefore should be kept in its carton until ready to be used.  
HM15211 is stable at room temperature up to 4 hours. 
The study staff is required to document the receipt, dispensing, and return/destruction of 
Study Drugs and supplies provided by or on behalf of the Sponsor. The CRU will destroy 
all used syringes of HM15211 and placebo at the CRU by the end of the study. Unused 
syringes of HM15211 and placebo will be processed as requested by the Sponsor by the 
end of the study.  
The Investigator or Investigator’s authorized staff must ensure the availability of proper 
storage conditions. The temperature of all study drugs will be monitored over 24 hours a 
day, 7 days a week (24/7). In case of incorrect storage, the Sponsor and monitor must be 
contacted without delay. 
No study drugs may be dispensed to any person not enrolled in the study.  

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8.4 
Dose Regimen 
The IPs, HM15211 or placebo will be administered after an ≥ 10 h overnight fast, by 
qualified staff while subjects are in the CRU. The products will be administered by SC 
injection into a lifted skin fold of the abdominal wall. The injection needle should be 
placed at a 45 to 90°degree angle and kept in the skin fold for 5-10 seconds. Aim is to 
dose at approximately the same clock time (eg, at approximately 08:00 h) for all subjects. 
The actual clock time of dosing is defined as t=0. The actual time of each dosing will be 
recorded in the source documents and on the eCRFs.  
8.5 
Overdose 
If a study medication error occurs, it should be documented as Protocol Deviation. A 
brief description should be provided in the deviation, including whether the subject was 
symptomatic (list symptoms) or asymptomatic and whether the event accidental or 
intentional. 
Dosing details should be captured on the Dosing Case Report Form. If the subject takes a 
dose of IP that exceeds protocol specifications and the subject is symptomatic, then the 
symptom(s) should be documented as an AE and be reported.  
Should an overdose occur, the Investigator or designee should contact the Sponsor or 
designee within 24 hours.  
8.6 
Randomization and Blinding 
To maintain the double-blind of the study, except for the unblinded persons involved in 
the preparation of the IPs (these persons are not involved in any other study activities), 
everyone involved in the trial will be blinded until after completion of the study and the 
final data review. Subjects will be randomized to IP or placebo in a ratio of 3:1 (6 
subjects to IP, 2 subjects to placebo) prior to dosing.  
Subjects will be randomized to treatment based on a randomization list that will be 
developed by a statistician. Individual treatment codes, indicating the treatment 
randomization for each randomized subject, will be available to the Investigator(s) or 
pharmacy staff at the CRU.  
Subjects will be assigned to the lowest randomization number available. Subjects who 
withdraw prior to dosing on Day 1 may be replaced. If the replacement subject drops 
from the study, a second replacement subject may be enrolled. Subjects will be replaced 
at the end of the study following discussion between the Investigator and Sponsor. 
The code for a subject may be broken in a medical emergency, if knowing the identity of 
the treatment allocation would influence the treatment decision of the subject or if 
demanded by the subject. Whenever a code is broken, the person breaking the code must 
record the time, date, and reason as well as his/her initials in the source documents. 
During un-blinding procedure in case of medical emergency, it should be ensured that no 
study personnel is unblinded to other subjects. 

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If the CRU need to break the code, the sponsor should, if possible, be contacted prior to 
breaking the blinding. In all cases, the Trial Monitor must be notified within 24 hours 
after an emergency un-blinding without revealing the treatment. 
All codes (whether broken or not) must be kept throughout the trial period. 
Accountability of all broken or unbroken codes (hard copy or electronic) will be 
performed at or after trial closure and will be collected by the Monitor. A copy may be 
maintained in the Trial Master File (TMF). 
The randomization code will include 4-digit subject numbers, 1001-1008 for the first 
cohort, 2001-2008 for the second cohort and follow the same numbering rationale for 
cohorts 3 through 5. 
In case a subject need to be replaced, the replacement subject will receive the same 
treatment as the dropout subject. The replacement randomization numbers will have the 
second digit replaced (X1XX), for example subject 2101 will replace subject 2001 with 
the same treatment. If the replacement subject drops from the study, a second 
replacement subject may be enrolled with replacement number (X2XX). No replacement 
randomization list will be generated.  
8.7 
Auxiliary Supply 
ProSciento will supply laboratory material necessary for PK and PD sampling, all the 
safety hematology, biochemistry, and urinalyses (incl. pregnancy test), and for the 
immunogenicity sampling in collaboration with the laboratories. 

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9.0 
STUDY PLAN 
9.1 
Study Procedures 
9.1.1 Informed Consent and HIPPAA Release 
Written informed consent will be obtained from each subject prior to performing any 
study-specific evaluations. The HIPAA release is embedded in the informed consent 
document. The informed consent document is subject to review and approval by the 
Sponsor and will be approved by a qualified IRB. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent set forth in applicable 
law. Only the most recently IRB-approved informed consent document must be used to 
consent prospective study subjects. The Investigator (according to applicable regulatory 
requirements), or a person designated by the Investigator and under the Investigator’s 
responsibility, will fully inform the potential study subject of all pertinent aspects of the 
Clinical Study, including written information given approval/favorable opinion by the 
IRB/IEC.  
 
Subjects will be fully informed of their responsibilities and of all the procedures involved 
in the study, the possible risks, and disadvantages of being dosed with the investigational 
products, and their rights while participating in the study. They will have the opportunity 
to ask questions. 
 
Prior to the potential subject’s participation in the Clinical Study, the written informed 
consent form must be signed, name filled in and personally dated by the subject and by 
the person who conducted the informed consent discussion, and by the Investigator. One 
copy of the signed and dated informed consent document will be given to the subject and 
the original retained by the Investigator/CRU. 
9.1.2 Screening 
Investigators must account for all subjects who sign informed consent forms. The 
Investigator will keep a Subject Screening and Enrollment Log at the investigational site. 
Subjects who have screen failed may be allowed to re-screen once at the discretion of the 
Investigator. A new screening number will be assigned. 
Subjects who meet all inclusion criteria and none of the exclusion criteria are eligible for 
this study and will be invited for the in-house period. Subjects will be instructed on 
influencing factors, such as refraining from strenuous exercise throughout the entire 
course of the study, avoidance of alcohol and herbal supplements, caffeinated drinks, 
smoking or medication and illness/infection as stated in section 7.4. 
If subjects are fasting (only water for ≥10 hours), all screening assessments may be done 
on the same day. If subjects are not fasting, they will be invited to return for a second 
screening visit to complete any missing screening procedures (e.g. laboratory 
assessments). 

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9.1.3 Demographics and Medical History 
Demographic information and medical history, including smoking status, and medication 
history will be obtained at Screening.  
9.1.4 Physical Examination 
The baseline physical examination will consist of the following body systems: (1) eyes; 
(2) ears, nose, throat, neck, thyroid; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system, mouth; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) central and peripheral nervous system and (10) lymph nodes. 
An abbreviated physical exam (based on symptoms and including examination of 
cardiovascular, respiratory, and gastrointestinal system) will be performed by the 
Investigator (or a qualified physician at the CRU) at time points indicated in the Table 
16-1. A complete physical examination may be performed in case the subjects have 
symptoms or at the discretion of the Investigator. 
9.1.5 Height, Weight, and BMI 
Height (without shoes) will be measured once, during the Screening visit. 
Weight (without shoes) will be measured fasting in the morning, with light clothing and 
post void at time points indicated in the Table 16-1. The measurement on Day 1 will be 
taken prior to dosing. 
BMI (kg/m2) will be calculated from height and weight. 
9.1.6 Vital Signs 
Vital signs will include body temperature (aural), supine and standing blood pressure 
(supine BP after 5 minutes resting, standing BP within 3 minutes in upright position), 
respiration rate and pulse rate (after 5 minutes resting). Vital sign measurements will be 
performed at days indicated in the Table 16-1. 
Body temperature: Assessments will be performed once daily, as stated in the Table 16-1. 
Measurements may be taken more frequently, if deemed necessary by the Investigator. 
Measurement on Day -1 will be performed as baseline assessment. Measurements will 
continue throughout the study. Timepoints must not interfere with ABPM measurements. 
Blood pressure: 
Supine and standing assessments will be performed. Measurements will be taken once at 
Screening and once on Day -2 and twice (morning and evening) on Day -1. The rest of 
the measurements will follow the following sampling schedule: On Day 1, measurements 
will be performed pre-dose and at 4, 8 and 12 hours post-dose. On Day 2 at 24 and 36 
hours, on Day 3 at 48 hours, on Day 4 at 72 hours, on Day 5 at 96 hours, on Day 6 at 120 
hours, on Day 7 at 144 hours post-dose with a sampling window of ± 15 min for each 
timepoint. Additional measurements will be taken on Day 10 at 216 hours (± 1 day), on 
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Measurements will be performed on the arm that is not connected to the ABPM system. 
Timepoints must not interfere with the ABPM measurements. 
Pulse rate and respiration rate: Assessments will be performed as stated in the Table 16-1 
at timepoints for blood pressure measurements. Pulse rate will be assessed in 
combination with both, supine and standing blood pressure measurements. Respiratory 
rate will be assessed at timepoints of supine blood pressure measurements. 
9.1.7 Concomitant Illness and Therapy 
Concomitant therapy is any medication given in addition to the investigational product 
(including over-the-counter medications, herbal medications, and vitamin supplements) 
administered between screening and follow-up.  
Concomitant illness is any significant medical condition or disease that is present at study 
start (signing of informed consent). This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at Screening 
examination. 
Details of all concomitant illnesses and therapies must be recorded at study entry and 
must be recorded on the subject’s CRF. Any changes in concomitant medication must be 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
study, the Sponsor must be informed. The information collected for each concomitant 
medication includes, at a minimum, start date, stop date or continuing, and indication.  
AEs related to administration of these therapies or procedures must also be documented 
on the appropriate CRF. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. 
Laboratory samples (Table 9-1) will be taken as described in the Schedule of Events. 
Table 9-1 Clinical Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis 
CBC with differential: 
Hematocrit 
Hemoglobin 
mean corpuscular volume 
(MCV) 
mean corpuscular hemoglobin 
(MCH) 
mean corpuscular hemoglobin 
concentration (MCHC) 
red cell distribution width 
(RDW) 
percentage and absolute 
differential counts 
platelet count 
Hepatic function panel: 
Alanine aminotransferase 
(ALT/SGPT) 
alkaline phosphatase, serum 
aspartate aminotransferase 
(AST/SGOT) 
bilirubin, direct 
bilirubin, total 
protein, total, serum 
Renal function panel: 
Albumin, serum 
BUN 
BUN: creatinine ratio 
Routine urinalysis with 
microscopic examination on 
positives(a): 
Color 
appearance, 
specific gravity 
pH 
protein 
glucose 
ketones 
occult blood 
leukocyte esterase 
nitrite 
bilirubin 

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red cell count (RBC) 
white blood cell count (WBC) 
 
calcium, serum 
carbon dioxide, total 
chloride, serum 
creatinine, serum 
glucose, serum 
phosphorus, serum 
potassium, serum 
sodium, serum 
Lipid panel: 
Cholesterol, total 
high-density lipoprotein (HDL) 
cholesterol 
low-density lipoprotein (LDL) 
cholesterol (calculated) 
triglycerides 
very low-density lipoprotein 
(VLDL) cholesterol (calculated) 
Additional parameters: 
Amylase 
Lipase 
Calcitonin 
Lactic acid dehydrogenase 
(LDH) 
Gamma-Glutamyl Transferase 
Magnesium 
Uric Acid 
Free fatty acid (FFA) 
C-reactive protein (CRP) 
 
urobilinogen 
 
Diagnostic Screening 
Serum/Plasma/Whole Blood 
Urine 
Breath 
HBsAg 
Anti-HCV 
HIV 1/2 
TSH(b) 
PTT 
PT 
INR 
HbA1c 
 
Drug Screen Profile 
Amphetamines 
Barbiturates 
Benzodiazepines 
cocaine (as benzoylecgonine) 
methylenedioxymetamphetamines 
opiates 
Oxycodon 
phencyclidine (PCP) 
propoxyphene (Darvon®) 
tricyclic anti-depressants 
 
Urine drug screen as stated in the 
SOE via commercial kit at the 
CRU. 
 
Female Subjects Only 
Alcohol breath test at 
timepoints stated in the SOE 
at the CRU 

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human chorionic gonadotropin 
(hCG)performed at Screening. 
Follicle-stimulating hormone 
(FSH) test for postmenopausal 
women (defined as amenorrheic 
female subjects <60 years of age 
and not surgically sterile) at 
Screening. 
Urine pregnancy testing via 
commercial kit at CRU will be 
performed at timepoints stated in 
the Schedule of Events. Urine 
pregnancy testing may be 
performed per Investigator’s 
discretion at additional timepoints 
during the study, if there is reason 
to believe the subject might be 
pregnant. 
 
(a) Microscopic analysis should be performed only if urine evaluations are abnormal. 
(b) In the event of abnormal TSH, Free T3/T4 may be collected at Investigator discretion. 
 
The local laboratory will perform all necessary laboratory tests listed above. The results 
of laboratory tests will be sent to the Investigator or designee, who is responsible for 
reviewing these results. All laboratory safety data will be faxed or transferred 
electronically. 
Laboratory reports must be signed and dated by the Investigator or designee indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. 
All clinically significant laboratory abnormalities must be recorded as an AE. A clinically 
significant laboratory abnormality may be verified by retesting and may be followed 
upon discretion of the Investigator. 
9.1.9 Contraception 
Females must be non-pregnant and non-lactating, and either surgically sterile (eg, tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-
menopausal for >12 months. The site will make an effort to retrieve medical records to 
document the sterility, however, the absence of records will not exclude the subject. In 
case that medical records cannot be obtained, serum pregnancy testing will be conducted 
at Screening, and urine pregnancy testing will be conducted throughout the study. 
Postmenopausal status will be confirmed through testing of FSH levels ≥ 25.8 mIU/mL at 
screening for amenorrheic female subjects <60 years of age. Female subjects who state 
they are postmenopausal at the screening visit but have a FSH value < 25.8 mIU/mL, 
may have a serum hCG pregnancy test performed on a separate day. If test is negative 

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and the subject agrees to be on a highly effective contraceptive method, subject may be 
enrolled in the study at the discretion of the Investigator. 
Female subjects of child-bearing potential must use highly effective contraceptive 
methods., Highly effective contraceptive methods are considered those with failure rate 
less than 1% undesired pregnancies per year, including hormonal intrauterine devices 
(coil), oral hormonal contraceptives, sexual abstinence, or a surgically sterilized partner. 
Oral hormonal contraceptives have to be taken at least 2 months prior to Screening until 
30 days after the last Follow-up Visit.  
During the course of the study, regular serum human chorionic gonadotropin (hCG) 
pregnancy tests will be performed for sterilized women, when medical records are not 
available. In addition to a negative serum hCG pregnancy test at Screening, subjects also 
must have a negative urine hCG pregnancy test at check-in to in-house periods. 
Males must be surgically sterile (at least 1-year post vasectomy), abstinent or if engaged 
in sexual relations of child-bearing potential, the subject and his partner must be using an 
acceptable contraceptive method from screening and for a period of 30 days after the last 
Follow-up visit. Acceptable methods of contraception are the use of condoms together 
with spermicidal foam/gel/film/cream/suppository. In addition, they must be advised not 
to donate sperm during this period. Male subjects must also encourage their female 
partner to use effective contraception. Effective contraceptive for the female partner 
includes surgical sterilization (e.g., bilateral tubal ligation, bilateral salpingectomy, 
bilateral oophorectomy), hormonal contraception, intrauterine contraception/device, or 
barrier methods (female condom, diaphragm, sponge, cervical cap) together with 
spermicidal foam/gel/film/cream/ suppository. The adequacy of other methods of 
contraception will be assessed on a case-by-case basis by the Principal Investigator. 
9.1.10 Pregnancy 
In the event a subject becomes pregnant during the study, she should be withdrawn. 
However, the subject will be encouraged to complete the post-treatment follow-up 
portion of the study to the extent that study procedures do not interfere with the 
pregnancy. 
In addition, any pregnancies in the partner of a male subject during the study or for 60 
days after the last dose should also be recorded.  
If the pregnancy occurs at any time during the study and the 60 days of last dose of active 
study medication, the pregnancy should be reported immediately to the Sponsor, using a 
pregnancy notification form. 
Study subjects will give consent on enrollment that the Investigator will report any 
pregnancy during the study to the Sponsor and that they will be asked to provide 
information about her pregnancy, delivery, and the health of her infant until age one 
month. Payment for all aspects of obstetrical care, child, or related care will be the 
subject’s responsibility.  

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All reported pregnancies will be followed up to final outcome, using the pregnancy and 
pregnancy follow-up forms. The outcome, including any premature termination, will be 
reported to the Sponsor. An evaluation after the birth of the child may also be conducted. 
Pregnancy complications must be recorded as adverse event(s). If the infant has a 
congenital anomaly/birth defect this must be reported and followed up as a serious 
adverse event. 
9.1.11 ECG Procedure  
All ECG’s throughout this study will be performed as standard triplicate 12-lead ECG’s, 
except the ECG at Screening. ECG’s will be recorded after 5 minutes in a supine 
position. Only the Triplicate ECG’s will be recorded at least 1 minute apart from each 
other, not exceeding a time period of 5 minutes for the completion of all three ECG’s. 
The Investigator (or designee) will interpret the ECG’s by use of an electronic 
measurement using the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal with clinical significance. ECG’s are performed 
according to the Table 16-1. The following parameters will be recorded from the 
subject’s ECG trace: heart rate, QT interval, PR interval, QRS interval, R-R interval, and 
QTcF (corrected). 
The Investigator will be responsible for assessing the accuracy of the electronic QTc 
interval recording using Fridericia correction formula 
• Fridericia correction: QTcF = QT ÷ cube root of the R-R interval (where R-R is 
the duration of the entire cardiac cycle)  
When ECGs are to be collected at the same time point as a blood collection, ECGs should 
be collected first to avoid any artificially increased heart rates due to the blood collection. 
ECG measurements are to be collected during screening and on Day -2 before subjects 
are connected to the ABPM device. Additionally, ECG measurements are taken on Day 
4, after ambulatory devices (Holter and ABPM) are removed, and Days 5, 7, 10, 17 and 
30. 
In some cases, it may be appropriate to repeat abnormal ECGs. If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if the Investigator’s 
interpretation determines that the QTc value is in the acceptable range. 
9.1.12 Check-in Procedure 
All subjects will check in to the clinic in the morning for the In-house Period. The 
following will be assessed: 
1. Alcohol breath test. 
2. Urine drug screen. 
3. Urine pregnancy test.  

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4. Any use of prescription or non-prescription medicine other than the allowed 
concomitant medications within the last 12 hours. 
5. Any medical condition that could interfere with glucose metabolism, as judged by the 
Investigator. 
Subjects who fulfill one or more of the stated criteria at check–in, will not be able to 
continue onto the treatment period. The treatment period will be rescheduled. Each 
treatment period may be rescheduled no more than twice. After that, the subject will be 
excluded from the study. Replacement of subjects for the dosing period may be permitted 
to enroll sufficient subjects into the study after discussion with Sponsor and Investigator. 
9.1.13 Standardized Meals 
During in-house period, subjects will receive standardized meals. The standardized 
weight maintaining meals will be provided using estimated BMR× activity factor of 1.5 
to determine daily caloric intake.  
9.1.14 ABPM 
The 24-hour blood pressure will be measured by an ABPM device. A validated, reliable, 
automated, and accurate monitor will be used with a storage function. Blood pressure 
measurements will be started overnight on Day -2 to familiarize the subjects with the 
device. During this period, measurements will be taken every 2 hours until the morning 
of Day -1.  
The baseline assessment period will start in the morning of Day -1 until Day 1. 
Measurements will be taken hourly up to 14 hours and then 2-hourly until 24 hours. 
The post-dose assessment period will start in the morning of Day 1.  Measurements will 
be taken hourly up to 14 hours and then 2-hourly until 24 hours every day (for every 24-
hour period), until the morning of Day 4.  
Time points stated in the Table 16-1. Adequate cuff size will be documented for each 
subject, after determination of the patient’s non-dominant arm circumference. Subject’s 
bedtime and awakening will be recorded to divide the downloaded data into diurnal and 
nocturnal values. Depending on available PK and safety data, timepoints for 
measurements may be adjusted for the following cohorts. 
Specifications about the ABPM model will be described in the Operational Manual and 
ABPM Procedure Manual, as well as detailed instructions of blood pressure frequency, 
data management and medical review.  
9.1.15 Holter Monitoring 
24-hour heart rate activity will be continuously recorded with an ambulatory Holter 
monitoring system (eg, Mortara surveyor central system with or without a central reader). 
Holter electrodes (12 lead, 3-channel placement) will be placed to the subject’s chest and 
will be attached to a small recording monitor. The Holter monitor will be carried in a 

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pocket or small pouch. Subject’s activities or exercises will be recorded while wearing 
the monitor. 
Specifications about the Holter model will be described in the Operational Manual and 
Holter Procedure Manual, as well as detailed instructions of data management and 
medical review.  
9.1.16 Pharmacokinetic Assessments and Schedule 
Blood for PK analysis of the study drugs will be collected at the time points indicated in 
the Table 16-1 Schedule of Events and follow the PK sampling schedule Table 9-2. One 
2-mL sample per scheduled time point will be collected to provide a minimum of 500 µL 
of serum for PK measurements and 500 µL of serum as a secondary back-up sample. 
Instructions for sample processing and shipment will be provided in the PK Sample and 
Shipping Instructions. Pre-dose sampling will be taken within 10 minutes before dosing. 
The actual time of PK sampling should not deviate from the nominal time by more than  
± 5 minutes during the Inpatient Period, and by more than ± 1 day for the Outpatient 
Visits and by more than Follow-up Visit ± 2 days for the Follow-up Visit. The actual 
time of dosing, actual sampling dates and times should be recorded. 
Table 9-2 PK Sampling Schedule 
 
 
PK sampling times may be adjusted between the cohorts in case available PK data show 
that any other times would be more beneficial. 

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9.1.17 Pharmacodynamic Assessments and Schedule 
Blood for PD analyses will be collected at the time points indicated in the Table 16-1 and 
follow the PD sampling schedule in Table 9-3. Sampling for insulin, C-peptide, GCG, 
GLP-1, GIP and amino acids will follow the PK sampling schedule, including PK 
sampling windows. PK sampling windows will apply for all other PD samples as well. 
Instructions for sample processing and shipment will be provided in the laboratory 
manual. Pre-dose sampling on Day 1 will be taken within 10 minutes before dosing.  
Table 9-3 PD Sampling Schedule 
 
 

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9.1.18 Immunogenicity Assessments 
Blood samples will be acquired to determine ADAbs, nAbs and anti -PEG prior to the 
treatment, on Day 17, and at the Follow-up Visit. One 12-mL sample per scheduled time 
point will be collected to provide a minimum of 6 mL serum for the 3 anti-assays.  
The serum will be split to provide for the following: 
A minimum of 1.5 mL of serum for the ADAbs measurements and 0.5 mL of serum as a 
secondary back-up sample.  
A minimum of 1.5 mL of serum for the nAbs measurements and 0.5 mL of serum as a 
secondary back-up sample. 
A minimum of 1.0 mL of serum for the ant-PEG measurements and 0.5 mL of serum as a 
secondary back-up sample 
Instructions for sample processing and shipment will be provided in the 
PK/Immunogenicity Sample and Shipping Instructions.  
9.1.19 Tolerability Assessments 
After injection of the study drug, the injection site will be marked with a pen. Assessment 
of study drug injection site will be performed pre-dose, at 4 and 12-hour post-dose on 
Day 1 and then daily from Day 2 to Day 7 (a window of ±15 minutes is allowed). 
The local reaction from the injection site, the insertion site, and the adhesive will be 
evaluated quantitatively using a Draize scale or similar scale. If an injection site reaction 
like pain on palpation, itching, erythema, edema, induration is observed, it must be 
recorded as an AE and then will be evaluated using the following scale: 
 Erythema will be evaluated as follows:    
• 
 0 – No erythema  
• 
 1 – Very slight erythema (barely perceptible)  
• 
 2 – Well-defined erythema  
• 
 3 – Moderate to severe erythema  
• 
 4 – Severe erythema (beet redness) to slight eschar formations (injuries in 
depth)  
Edema will be evaluated as follows:  
• 
 0 – No edema  
• 
 1 – Very slight edema (barely perceptible)  
• 
 2 – Slight edema (edges of area well defined by definite raising)  
• 
 3 – Moderate edema (raised approximately 1 mm)  

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• 
 4 – Severe edema (raised more than 1 mm and extending beyond the area 
of exposure)  
For the irritation assessment, all irritation events will be documented as AEs. The 
diameter of the affected area will be measured with a paper measuring tape in centimeter 
(cm) and the condition of the injection site will be recorded. Digital photography will be 
used to document all positive injection site reactions. In case of clinically significant 
injection site reactions, subjects may undergo a dermatological consultation and/or 
cutaneous biopsies for further histological examination of the injection site reaction. 
Biopsies will be performed using a 4-mm punch biopsy centered on the injection site. 
The biopsy area will be anesthetized with lidocaine prior to the biopsy. Wound closure 
will be performed with Steristrips. If stitches are necessary to close the punch area, they 
will be removed approximately 2 weeks later. The time between injection and biopsy will 
be recorded. Microscopic and histological examination of the punch biopsies will be 
performed at a qualified lab. 
9.1.20 Blood Volume 
Total blood sampling volume for subjects will approximately be 370 mL.  
Even in case of further unexpected blood sampling, extension of blood sampling period 
or necessary retesting, sampling volume will increase to approximately 400 mL. 
 
 

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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Event (AE) 
An AE is any undesirable and unintended medical event occurring to a subject in a 
clinical study, whether or not related to the study products. This includes events from the 
first study related activity after the subject has signed the informed consent and until post 
treatment follow-up period as defined in the protocol. The following should not be 
recorded as AEs, if recorded as medical history/concomitant illness on the CRF at 
screening: 
• 
Pre-planned procedure, unless the condition for which the procedure was planned 
has worsened from the first study related activity after the subject has signed the 
informed consent 
• 
Pre-existing conditions found as a result of screening procedures 
• 
Pre-existing events that has not worsened in intensity or frequency from baseline 
10.1.2 Treatment Emergent Adverse Event (TEAE) 
A treatment-emergent AE (TEAE) is defined as any clinically significant event not 
present before exposure to study drug or any event already present that worsens in either 
intensity or frequency after exposure to study drug. 
10.1.3 Clinical Laboratory Event 
A clinical laboratory AE is any clinically significant laboratory abnormality that suggests 
a disease and/or organ toxicity and is of a severity, which requires active management, 
(i.e. change of dose, discontinuation of study product, more frequent follow-up, or 
diagnostic investigation). 
A laboratory re-test and/or continued monitoring of an abnormal value is not considered 
an intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
10.1.4 Adverse Reaction 
An adverse reaction is defined as any adverse event caused by a drug. Adverse reactions 
are a subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event. 
10.1.5 Suspected Adverse Reaction 
Suspected adverse reaction is defined as a subset of any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of IND 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 

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relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lower degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
Reasonable possibility is given if: 
• 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure 
• 
One or more occurrences of an event, that is not commonly associated with drug 
exposure, but otherwise uncommon in the population exposed to the drug 
• 
An aggregate analysis of specific events observed in a clinical study that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
10.1.6 Unexpected Adverse Event/ Unexpected Suspected Adverse Reaction 
An unexpected AE/unexpected suspected adverse reaction is an AE or suspected adverse 
reaction that is not listed in the Investigator Brochure or Protocol, as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation, or is 
not listed at the specificity or severity that has been observed; or, if an Investigator 
Brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. 
10.1.7 Serious Adverse Event (SAE)/ Serious Suspected Adverse Reaction 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is life threatening. 
• The term “life threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization.  
4. Results in persistent or significant disability/incapacity. 
5. Leads to a congenital anomaly/birth defect. 
6. Is an important medical event that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 

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10.1.8 Life-Threatening Adverse Event/Life-Threatening Suspected Adverse 
Reaction 
A life-threatening AE/life-threatening suspected adverse reaction, in the view of either 
the Investigator or Sponsor, places the patient or suspect at immediate risk of death. It 
does not include an adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
The determination of whether an AE is life threatening can be based on the opinion of the 
Investigator or Sponsor. If either, the Sponsor or investigator believes that the event is 
serious or life threatening, the event must be considered serious and evaluated by the 
Sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c)(1)). 
10.2 
Severity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient, easily tolerated by the subject and does not 
affect the subject’s daily activities. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s 
usual daily activities. 
Severe: 
The event is incapacitating and causes considerable interference with 
the subject’s usual activities. 
10.3 
Relationship to Study Treatment 
The relationship of each AE to the study drug(s) will be assessed by the Investigator or 
Sub-Investigator on the basis of his/her clinical judgment and the following definitions: 
1= Related: 
The AE follows a reasonable temporal sequence from the study product administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, or concomitant medications). 
 
The AE follows a reasonable temporal sequence from the investigational product 
administration, and represents a known reaction to the drug under study or other drugs in 
its class, or is predicted by the known pharmacological properties of the drug. 
 
The AE resolves with discontinuation of the investigational product and/or recurs with 
rechallenge, if applicable. 
 
2 = Not Related: 
The AE does not follow a reasonable temporal sequence from investigational product 
administration, or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications). 
 

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3= Not Assessable/ Not Classifiable: 
 The AE cannot be judged because of insufficient or contradictory information. The AE 
cannot be supplemented or verified. 
10.4 
Procedures 
10.4.1 Collection and Recording of AEs 
Collection of all AEs (serious AEs and non-serious AEs) will commence from the time 
the subject signs the informed consent to participate in the study until the post-treatment 
follow-up visit. Throughout the in-house treatment period, the Investigator will assess 
whether any subjective AEs have occurred. In order to avoid bias in eliciting AEs, a non-
specific question, such as “How have you been feeling since your last visit?” may be 
asked. Subjects may report AEs occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored and given appropriate medical treatment at the 
discretion and judgement of the Investigator until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is 
a satisfactory explanation for the changes observed. All AEs will be documented in the 
AE page of the CRF, whether or not the Investigator concludes that the event is related to 
the drug treatment. The event term, start and stop dates, severity, action taken with study 
drug and outcome, will be documented, along with the Investigator’s opinion of the 
causal relationship between the event and the study drug.  
10.4.2 Collection and Reporting of SAEs 
When an SAE occurs, it should be reported according to the following procedure: 
An SAE form must be completed immediately or within 24 hours of first onset or 
notification of the event. The information should be completed as fully as possible but 
contain, at a minimum a short description of the event and the reason why the event is 
categorized as serious, subject identification number, Investigator’s name, name of the 
study medication and a causality assessment. 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to study drug) should be reported to the Sponsor or a 
designated qualified vendor within 24 hours of the Study Center’s first knowledge of the 
event.  
The collection of SAEs will begin after the subject signs the informed consent form and 
stop at the end of the subject’s follow-up period. An Initial Serious Adverse Event Form 
should be completed, and a copy should be faxed to the Sponsor or designated qualified 
vendor. 
All serious and unexpected adverse event reporting will adhere to 21 CFR 312.32 for 
IND drugs and 21 CFR 314.80 for marketed drugs (15-day alerts). The Institutional 

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Review Board(IRB) and all Investigators will be notified of the alert reports per FDA 
regulations. 
10.5 
Anticipated Adverse Events 
Normal precautions taken for a human study, including the provision of emergency 
equipment, will be taken during this study. Qualified and well-trained physicians and 
medical staff will instruct the subjects.  
Possible anticipated, adverse effects from the study procedure are: 
Risks related to repeated blood draws 
Subjects will participate in several blood draws throughout the course of the study which 
have the potential to cause a venous line-vasovagal response, bruising, tenderness, and 
rarely infection. 
10.6 
Follow-up of AEs and SAEs 
All AEs should be followed up and subjects will be rendered appropriate medical care 
and treatment at the discretion of the Investigator until resolution or until the Investigator 
and Sponsor concludes that “further follow-up is not necessary”. If the AE has not 
resolved by the post-treatment follow-up visit, the stop date will be recorded as 
“ongoing.” 
All SAEs should be followed up until resolution or permanent outcome of the event or 
until the Investigator and Sponsor judge that further follow-up is not necessary. 
If information is not available at the time of the first report and becomes available later, 
the Investigator should complete a follow-up SAE form at the earliest possible or provide 
other written documentation and fax it immediately within 24 hours of receipt of 
information to the Sponsor or designee. Copies of any relevant data from the hospital 
notes (e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent accordingly. 
All other non-serious AEs must be followed until the outcome of the event is 
“recovering” (for chronic conditions), or “recovered”, or until the end of the post-
treatment follow-up stated in the protocol, whichever comes first, and until all queries 
related to these AE’s have been resolved. 
10.6.1 Safety Reporting to IRBs or IECs, and Regulatory Authorities 
The Sponsor or designated qualified vendor will be responsible for reporting all 
suspected unexpected serious adverse reactions (SUSARs) and any other applicable 
SAEs to regulatory authorities, Investigators, and IRBs or IECs, as applicable, in 
accordance with national regulations in the countries where the study is conducted.  
Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-

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threatening events and 15 days for other SUSARs, unless otherwise required by national 
regulations.  
The Sponsor or designated qualified vendor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment 
of an investigational product or that would be sufficient to consider changes in the 
investigational product administration or in the overall conduct of the study. The 
investigational site will forward a copy of all expedited reports to his or her IRB or IEC 
in accordance with national regulations. 
Reporting responsibilities of Investigator under 21 CFR 312.64(b) and Sponsor under 21 
CFR 312.32(c)(1)(i) for serious and unexpected suspected adverse reactions will be 
followed. 

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11.0 
DATA HANDLING AND MANAGEMENT 
Clinical Data Management (CDM), including CRF data, is the responsibility of 
ProSciento. With permission of the Sponsor, CDM may be delegated under an agreement 
of transfer of responsibilities to a qualified vendor of ProSciento.  
11.1 
Data Management 
The full details of procedures for data handling will be documented in the Data 
Management Plan (DMP). 
AEs and medical history will be coded using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded 
using the World Health Organization (WHO) WHODrug Global.  
Unique numbers will identify the subject and the biological material obtained from the 
subject. Appropriate measures such as encryption or deletion will be enforced to protect 
the identity of human subjects in all presentations and publications as required by 
local/regional/national requirements. 
Data from screening failures will not be entered into the database. 
Laboratory data from the central laboratory will be electronically transferred to 
ProSciento for database reconciliation purposes. The electronic laboratory data will be 
considered source data. In cases where sensitive non-PK laboratory data is transferred via 
non-secure electronic networks, data will be encrypted during transfer. 
The laboratory will provide one copy of the laboratory reports to the CRU staff. The staff 
will receive all laboratory data electronically or based on FAX reports directly from the 
laboratory. An Investigator must review, evaluate, sign and date the laboratory print-outs 
upon receipt. The signed print-out of the laboratory reports are source data. 
All other results, including PK, PD data, and laboratory tests will be transferred 
electronically to the responsible Data Management Unit.  
11.2 
CRFs (Electronic) 
11.2.1 Clinical Data Management Workflow 
Electronic CRFs will be developed by the CDM department, in collaboration with the 
clinical study team at ProSciento and statistician. CDM will document the process 
workflow in the DMP. After data entry, monitor(s) will source data verify (SDV) the 
eCRFs against the source documents. Queries may be issued to clarify the data entered. 
The PI will electronically sign the eCRFs after all data have been entered, all queries 
have been resolved and all external data has been reconciled with the eCRF data. If 
corrections and/or resolution of queries are required after PI approvals, those eCRFs 
affected by changes will be re-signed by the PI. The database may be locked after the PI 
approvals are completed. 

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After database lock, CDM study design documentation and locked eCRFs (PDF) will be 
created and will be provided to the Sponsor, if requested. 
11.2.2 Data Entry of eCRFs 
Data required for analyses and subject safety assessments will be entered from source 
documentation into eCRFs. Instructions for data entry will be provided in the eCRF 
Completion Guidelines, developed by the CDM department. All staff involved with 
entering data into the eCRFs will be trained prior to gaining access to the study database. 
11.2.3 Corrections to eCRFs 
Queries may be generated by the eCRF system during data entry, and queries may be 
generated by CDM staff, monitors, and other data reviewers during the course of the 
study. Only specific CRU personnel will be authorized to make corrections to the eCRFs; 
CDM will train personnel prior to granting access in the eCRF system. Corrections will 
be made directly in the eCRF – by modifying existing data, adding new data, or deleting 
data, as appropriate. All data corrections will be logged in the electronic audit trail. 
11.2.4 PI Approval of eCRF Data 
The Investigator or Investigator’s authorized staff must ensure that all information 
derived from source documentation is consistent with the source information and 
accurately reflected in the eCRFs. By electronically signing the eCRFs, the Investigator 
confirms that the information is complete and correct. 
11.3 
Retention of Documents 
At the completion of the study, all records created by and under the supervision of the 
Investigator should be maintained in accordance with the requirements of the regulatory 
authority guideline and the GCP Guideline. These will be available for inspection at any 
time by the Sponsor or the FDA. 
Clinical study documents are archived upon completion of the study and maintained for 
at least 15 years from the study closure or longer in accordance with local regulation and 
applicable regulatory authority guidelines, and the study sponsor will be notified prior to 
destruction of study records. 
Current FDA guidelines require records to be retained for a period of 2 years following 
the date a marketing application is approved for the drug, for the indication for which it is 
being investigated. If no application is filed or if the application for the investigated 
indication is not approved, documents will be kept until 2 years after the investigation is 
discontinued and the FDA is notified. It is the sponsor’s responsibility to inform 
ProSciento as to when essential documents are no longer needed to be retained. 
 
 

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12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
The Sponsor will be responsible for the statistical analysis and the statistical analysis plan 
(SAP). Statistical services may be delegated under an agreement of transfer of 
responsibilities to qualified vendors of the Sponsor. 
An SAP will be prepared that will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. It will also 
provide any changes or additions to the analyses that are not apparent in the protocol. 
Procedures for accounting for missing, unused, or spurious data will be discussed in 
detail in the SAP 
12.2 
Study Endpoints 
The study endpoints or derived parameters used to assess whether the study objectives 
have been met. The endpoints for this study are shown in Table 12-1. Additional 
endpoints may be added to the SAP as needed to address the needs of the study. 
Table 12-1 Study Endpoints 
Primary Endpoints 
(Safety Endpoints) 
Primary Endpoints 
(Safety Endpoints) 
Primary Endpoints 
Exploratory 
Endpoints 
To assess the safety of 
HM15211  
To assess the local 
tolerability of 
HM15211 
To assess the PK 
profiles of HM15211 
To assess the PD 
properties of 
HM15211 compared 
to placebo 
∙Clinical findings on 
physical examination 
∙Injection site reaction 
∙Total AUC, including 
AUC(0-inf)  
∙Body weight 
 Clinical laboratory 
abnormalities 
(including serum 
amylase, lipase, 
coagulation, TSH, 
calcitonin) 
 
∙Incremental AUC 
∙Lipid metabolism 
(Total cholesterol, 
LDL, HDL, VLDL, 
Triglycerides, FFA) 
∙Vital signs (BP, 
respiratory rate, 
temperature, and HR) 
measurements 
 
∙Cmax 
∙Glucose metabolism 
(FPG, Insulin, C-
peptide) 
∙12-lead ECG 
parameters (the primary 
ECG endpoint will be 
QTcF) 
 
∙Tmax 
∙Incretin secretion 
(GCG, Leptin, GLP-1, 
GIP) 
∙24-hour ABPM (Mean 
day- and night time 
systolic/diastolic BP) 
 
∙t1/2 
∙Inflammatory marker 
(CRP) 

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Primary Endpoints 
(Safety Endpoints) 
Primary Endpoints 
(Safety Endpoints) 
Primary Endpoints 
Exploratory 
Endpoints 
∙24-hour Holter ECG 
(HR, HRV (e.g. mean 
heart rate, difference 
between day and night 
HR, mean NN intervals, 
SDNN) 
 
∙CL/F 
 
∙Immunogenicity 
(ADAbs, nAbs, anti-
PEG) 
 
∙Vz/F 
 
∙Adverse events 
 
∙kel 
 
 
12.2.1 Analysis Sets 
12.2.1.1 Safety Set 
The Safety analysis set will include all subjects who received study medication (HM 
15211 or Placebo). The Safety analysis set will be used for demographic, baseline 
characteristics and safety summaries.  
12.2.1.2 Pharmacokinetic (PK) Analysis Set 
The PK analysis set will include all subjects who received HM 15211 with all evaluable 
PK data appropriate for the evaluation of interest (without major protocol deviations or 
violations that would have an impact on the absorption, distribution, metabolism, or 
excretion of HM 15211). PK analysis set will be used for analysis of PK endpoints. 
12.2.1.3 Pharmacodynamics (PD) Analysis Set 
The PD analysis set will include all subjects who received HM 15211 or placebo with all 
evaluable PD data appropriate for the evaluation of interest (without major protocol 
deviations or violations that would have an impact on the PD of HM 15211). PD analysis 
set will be used for analysis of PD endpoints. 
12.2.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects overall and 
by cohort and treatment. Summary statistics (e.g., number of subjects, mean, median, 
standard deviation, and range) will be generated for continuous variables (e.g., age and 
weight) and the number and percentage of subjects within each category will be 
presented for categorical variables (eg, gender, ethnicity, and race). 

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12.2.3 Analysis of the Pharmacokinetic Endpoints 
The planned analyses will be described in more detail in the statistical analysis plan 
(SAP). 
The pharmacokinetic endpoints will be derived from the individual serum HM15211 
profiles. Serum concentrations of HM15211 will be determined. Non-compartmental 
analysis (NCA) will be performed for PK parameters such as Cmax, Tmax, AUC, t1/2, kel, 
CL/F and Vz/F, will be estimated for each subject. These will be summarized with 
descriptive statistics by dose and presented graphically if possible. The following 
descriptive statistics will be presented: n, geometric mean, geometric SD, geometric 
coefficient of variation (CV), arithmetic mean, arithmetic SD, median, minimum, and 
maximum. Dose proportionality may be assessed as appropriate. Log-transformation may 
be applied to these PK endpoints if needed to ensure data normality. 
Population PK analysis will be conducted to develop a model for subsequent PK/PD 
analyses. 
12.2.4 Analysis of the Pharmacodynamic Endpoints 
Exploratory PD parameters including FPG, insulin, C-peptide, GCG, leptin, GLP-1, GIP 
as well as CRP, lipid profile, FFA and body weight will be summarized and analyzed.  
All PD parameters will be summarized using appropriate descriptive statistics (eg, n, 
mean or geometric mean, CV, min, median, max) by treatment and collection day as 
specified in the SAP. The placebo group will be pooled across cohorts in the summary 
tables. 
12.2.5 Safety Analysis and Endpoints 
Safety and tolerability of the study drugs will be assessed by collection and review of 
adverse events, tolerability, laboratory parameters, physical examination, vital signs, and 
ECG parameters throughout the duration of the study. Immunogenicity of HM15211 will 
be assessed by the development of ADAbs, nAbs and anti-PEG. 
Safety analysis will involve examination of the descriptive statistics and individual 
subject listings for any effects of study treatment on clinical tolerability and safety. 
The 24-hour blood pressure (day and night time systolic/diastolic BP) collected from 
ABPM, and 24-hour Holter ECG (HR, HRV [eg, difference between day and night HR, 
NN intervals, SDNN]) will be summarized descriptively.  
AEs will be summarized using the safety analysis set. Placebo patients will be pooled 
across cohorts in the safety analysis. 
All AEs will be coded using MedDRA. Data will be summarized using preferred term 
and primary system organ class. 
Adverse event summaries will include the overall incidence (by system organ class and 
preferred term), events by maximum intensity, event by relationship to study treatment, 

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events leading to discontinuation of study drug, and serious adverse events. Physical 
exam, vital signs, blood pressure assessed by ABPM, heart rate assessed by Holter ECG, 
12-lead ECG data, and laboratory parameters (hematology, chemistry, and urinalysis) 
will be summarized descriptively by treatment. 
12.3 
Interim Analysis 
No formal interim analysis is planned. 
12.4 
Determination of Sample Size 
Due to exploratory nature of this study, a sample size of 8 subjects per cohort is 
empirically determined and consistent with typical sample sizes used for similar studies 
to assess PK and safety data. 
 

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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Monitoring 
The study will be monitored by ProSciento’s monitor. 
Monitoring visits to the CRU will be made periodically during the study to ensure that all 
aspects of the protocol and GCP are followed, CRFs are completed correctly, and drug 
accountability is monitored. The Monitor will visit the CRU at least once before First 
Subject First Visit (FSFV) (Initiation Visit), at least once during the clinical part of the 
study, and at least once after Last Subject Last Visit (LSLV). Furthermore, the Monitor 
must be available for discussions by telephone.  
ProSciento may assign additional Clinical Research Associates (CRAs)/Monitors on an 
ad hoc basis for training purposes and to meet required timelines. In addition, if study 
timelines are modified for any reason, e.g., delays in recruitment or accelerated 
enrollment, ProSciento may use additional CRAs at its discretion to ensure study 
expectations are met. 
The Monitor must be given direct access to source documents, such as original 
documents, data, and records. Direct access includes permission to examine, analyze, 
verify any record(s) and report(s) that are important to evaluation of the clinical study. 
The study will be monitored to verify integrity and validity of the data. Monitoring will 
follow a Monitoring Plan. 
Additional QC monitoring of the clinical study for protocol and GCP compliance will be 
conducted periodically by qualified staff of ProSciento. 
13.2 
Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study subjects. Should other circumstances arise that 
will require deviation from protocol-specified procedures, unless there is an emergency 
or immediate need, the Investigator should contact the medical monitor and Sponsor to 
review and discuss the implications of the deviation and determine the appropriate course 
of action. Any deviation must be documented, stating the reason and date, the action 
taken, and the impact for the subject and/or the study. The documentation must be kept in 
the Investigator’s Study File and the Sponsor’s Study Master File. 

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14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted in accordance with the Protocol, the International 
Conference on Harmonization (ICH), Guideline for Good Clinical Practice: Consolidated 
Guidance (E6) and applicable regulatory requirements including clinical research 
guidelines established by the Basic Principles defined in the U.S. 21 CFR Parts 50, 56, 
and 312 and the principles enunciated in the Declaration of Helsinki (revised version 
Fortaleza 2013).7,8 
14.1 
Institutional Review Board and/or Independent Ethics Committee 
Prior to commencement of the study, the protocol, any amendments, subject 
information/informed consent form, any other written information to be provided to the 
subject, subject recruitment procedures, information about payments and compensation 
available to subjects if not mentioned in the subject information, the Investigator’s 
current CV and/or other documentation evidencing qualifications, and other documents 
as required by the local Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) should be submitted. The submission letter should clearly identify (by study 
identification number, including version, title and/or date of the document) which 
documents have been submitted to the IEC/IRB. Written approval/favorable opinion must 
be obtained from IEC/IRB prior to commencement of the clinical study start. 
During the study, the Investigator must promptly report the following to the IEC/IRB: 
Updates to IB, unexpected SAEs where a causal relationship cannot be ruled out, 
substantial amendments to the protocol, non-substantial amendments, deviations to the 
protocol implemented to eliminate immediate hazards to the subjects, new information 
that may affect adversely the safety of the subjects or the conduct of the study (including 
new risk/benefit analysis in case it will have an impact on the planned follow-up of the 
subjects), annually written summaries of the study status and other documents as required 
by the local IEC/IRB. 
Substantial amendments must not be implemented before approval/favorable opinion, 
unless necessary to eliminate hazards to the subjects. 
The Investigator must maintain an accurate and complete record of all submissions made 
to the IEC/IRB. The records should be filed in the Investigator’s Study File and copies 
must be provided to the Sponsor.  
14.2 
Regulatory Authorities 
Regulatory Authorities will receive the Clinical Study Application, Protocol, 
Amendments to the Protocol, reports on SAEs and the Integrated Clinical Study Report 
according to national regulations. 
14.3 
Responsibilities of the Investigator 
The Investigator will conduct this clinical study in compliance with all applicable 
national, state, local or regional laws and regulatory requirements of the countries in 

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which the clinical study is performed. The Investigator will align his or her conduct in 
accordance with the “Responsibilities of the Investigator”. 
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on Investigators by 
the FDA are summarized in the “Statement of Investigators” (Form FDA 1572), which 
must be completed and signed before the Investigator may participate in this study.  
14.4 
Informed Consent 
Once signed, the original informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the 
Investigator’s site file. The Investigator must document the date the subject signs the 
informed consent in the subject’s medical record. Copies of the signed informed consent 
form, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or 
the relevant subject’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed 
consent form. 
14.5 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Subject records will be kept private except when 
ordered by law. The following individuals will have access to study subject records: 
Principal Investigator and designees, study Sponsor, monitors and auditors, the FDA, 
other government offices and the IRB. 
Throughout this study, a subject’s source data will only be linked to the Sponsor’s 
clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, 
age, or date of birth, and subject initials may be used to verify the subject and accuracy of 
the subject’s unique identification number. 
The Investigator must agree to permit the Sponsor’s monitor or designee’s monitor, 
representatives from any regulatory authority, the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s source data or documents, including, 
but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. The confidentiality 
of the verified data and the protection of the subjects must be respected during these 
inspections. 

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Copies of any subject source documents that are provided to the Sponsor must have 
certain personally identifiable information removed. 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy 
The Investigator will provide the Sponsor with truthful, accurate and complete test results 
and all data derived from the study. During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as 
required by law or regulation. Except as otherwise allowable in the clinical study site 
agreement, any public disclosure (including publicly accessible websites) related to the 
protocol or study results, other than study recruitment materials and/or advertisements, is 
the sole responsibility of the Sponsor. 
ProSciento or its designee will be responsible for preparing the Clinical Study Report. 
When all data has been fully analyzed, ProSciento or Sponsor will communicate the 
results of the Clinical Study to the Investigator(s).  
The Investigator or qualified designee agrees to use this information only and strictly in 
connection with this Clinical Study and must not use it for other purposes without the 
prior written permission from the Sponsor. Prior to any publication, the Sponsor must be 
given the opportunity to review and comment upon any manuscript, poster, or paper that 
contains data derived or generated from this study in order to be aware of all written and 
oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 
To ensure that information on clinical studies reaches the public in a timely manner and 
to comply with applicable law, regulation and guidance, this study may be registered on 
Clinicals.gov or other publicly accessible websites before study initiation.  
14.7 
Insurance and Compensation for Injury 
The Sponsor shall carry applicable insurance in the types and amounts necessary to cover 
its obligations herein in accordance with local laws and requirements and/or guidelines 
for conducting clinical studies in any country, unless others have shown negligence. The 
Sponsor renounces liability in the event of negligence or any other liability by the clinics 
or doctors conducting experiments or by persons for whom the said clinic or doctors are 
responsible. The Sponsor accepts liability in accordance with all applicable regulations 
per the Code of Federal Regulations (CFR) and all other applicable federal or state 
regulations. 
Each subject in the study must be insured in accordance with the regulations applicable to 
the CRU where the subject is participating.  
If a subject becomes ill or injured due to an adverse event directly resulting from use of 
the study drug or a study procedure in the course of their participation in this Clinical 
Study, medical treatment will be provided. Sponsor will pay the costs of such treatment. 

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15.0 
REFERENCES 
1. Obesity and overweight fact sheet (2016). 
http://www.who.int/mediacentre/factsheets/fs311/en/ 
2. Finer N. Medical consequences of obesity (2003). Medicine, Vol 43: 2, pp 88-93 
3. Sanchez-Garrido MA, Brandt SJ, Clemmensen C et al (2017). GLP-1/glucagon 
receptor co-agonism for treatment of obesity. Diabetologia Vol 60, pp 1851-1861 
4. Choi IY, Lee JS, Kim JK, et al. (2017). Potent body weight loss and therapeutic 
efficacy in a NASH animal model by a novel long-acting GLP-1/GIP/Glucagon 
tri-agonist (HM15211). Diabetologia, Vol 60: Supplement 1, pp 1-564 
5. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers, Food and Drug 
Administration. Center for Drug Evaluation and Research, July 2005. 
6. European Medicines Agency guidance: Guidelines on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal 
Products, Committee for Medicinal Products for Human Use (CHMP), July 2007 
7. World Medical Association. Declaration of Helsinki. Ethical Principles for 
Medical Research Involving Human Subjects. 52nd WMA General Assembly, 
Edinburgh, Scotland, October 2000. Last amended with Note of Clarification on 
Paragraph 29 by the WMA General Assembly, Washington 2002.and Note of 
clarification on paragraph 30 by the WMA General assembly, Tokyo 2004 
8. International Conference on Harmonization. ICH Harmonized Tripartite 
Guideline. Good Clinical Practice. 01-May-1996 

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16.0 
APPENDIX 
Table 16-1 Schedule of Events 
ASSESSMENT 
SCREEN 
IN-HOUSE PERIOD 
OUTPATIENT 
VISITS 
F/U 
Visit/ 
Timepoint 
(Day) 
- 28 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
10 
(± 1) 
17 
(± 1) 
30 
(± 2) 
IP 
Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sequestered in 
clinic/unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical 
examination 
(PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Hematology, 
serum 
chemistry, 
urinalysis  
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
Amylase, 
Lipase 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Calcitonin 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Coagulation 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hep B, Hep C, 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ADAbs, nAbs 
& anti-PEG 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test 
(urine)  
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Pregancy test 
(serum)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH if 
postmenopausal 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug 
screen & 
alcohol breath 
test 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, BMI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X 
X 
X 
Standardized 
meals 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 76 of 77 
Protocol No. HM-TRIA-101 
 
Version 4.0_06Apr2018 
ASSESSMENT 
SCREEN 
IN-HOUSE PERIOD 
OUTPATIENT 
VISITS 
F/U 
Visit/ 
Timepoint 
(Day) 
- 28 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
10 
(± 1) 
17 
(± 1) 
30 
(± 2) 
IP 
Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Record 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AE’S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site 
assessment 
 
 
 
X3 
X 
X 
X 
X 
X 
X 
 
 
 
12-lead ECG  
X 
X2,7 
 
 
 
 
X2,7 
X7 
 
X7 
X7 
X7 
X7 
Holter 
monitoring4 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
ABP 
monitoring4 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PK assessment5 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Insulin, C-
peptide, 
glucagon6 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
GLP-1, GIP, 
amino acid 
panel6 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
FPG 
X 
 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
Lipid panel, 
incl. FFA 
X 
 
 
X6 
 
X6 
 
 
 
X6 
 
X6 
 
Leptin6 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
CRP6 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
1Measurements of blood pressure will be performed twice (morning and evening) on Day -1. On Day 1, 
measurements will be performed pre-dose and at 4, 8 and 12 hours post-dose, on Day 2 at 24 and 36 hours 
post-dose, on Day 3 at 48 hours, on Day 4 at 72 hours, on Day 5 at 96 hours, on Day 6 at 120 hours, on 
Day 7 at 144 hours post-dose with a sampling window of ± 15 min for each timepoint.  
Measurements of pulse rate and respiration rate will be performed at time points together with blood 
pressure measurements. Pulse rate will be assessed in combination with both, supine and standing blood 
pressure measurements. Respiration rate will be assessed at time points of supine blood pressure 
measurements.  
2ECG measurements are to be collected on Day -2 before subjects are connected to the ABPM and on Day 
4 after subjects have been disconnected from the ambulatory devices. 
3Measurements of local injection site reaction on Day 1 at pre-dose, at 4 and 12-hour post-dose. 
4Timepoints may be adjusted after evaluation of PK data. 
5Sampling timepoints according to Table 9-2 PK Sampling Schedule. 
6Sampling timepoints according to Table 9-3 PD Sampling Schedule. 

Hanmi Pharmaceutical Co., Ltd 
Clinical Study Protocol 
Confidential 
Page 77 of 77 
Protocol No. HM-TRIA-101 
 
Version 4.0_06Apr2018 
7Triplicate ECG’s to be performed.