Clinical trial NCT03847974
Conditions: Hypercholesterolemia
Sponsor: LIB Therapeutics LLC
Start date: 2019-02-14; Completion date: 2020-08-31
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the longer term safety, tolerability, and LDL C lowering efficacy after 52 weeks of additional treatment with LIB003 with subcutaneous (SC) dosing every 4 weeks (Q4W)

Detailed description:
To assess the longer term safety, tolerability, immunogenicity, PK, PD and LDL C lowering efficacy after 52 weeks of additional treatment with LIB003 with subcutaneous (SC) dosing every 4 weeks (Q4W) in patients on stable maximally tolerated statins with or without ezetimibe who completed the phase 2 dose ranging trial LIB003-002

Arms: arm 1: LIB003
Interventions: intervention 1: LIB003
Intervention descriptions: intervention 1: 300 mg SC Q4W

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
Open-Label Extension, Phase 2b Study to Evaluate the Longer 
Term Efficacy and Safety of LIB003 in Patients on Stable 
Lipid-Lowering Therapy Requiring Additional LDL-C Reduction 
 
Investigational Product: LIB003 
Protocol Number: LIB003-010 
IND Number: 134579 
 
 
Sponsor: 
LIB Therapeutics, LLC 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 978-770-8443 
 
 
 
Version Number: 3.0 
Date: 18 March 2020 
Version Number: 2.0 
Date: 10 September 2019  
Version Number: 1.0 
Date: 21 December 2018 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of LIB Therapeutics, LLC, hereinafter LIB Therapeutics, except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for LIB Therapeutics. You are allowed to disclose the contents of this document 
only to your Institutional Review Board and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to LIB Therapeutics and that it may not be further 
disclosed to third parties. 


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SIGNATURE PAGE 
STUDY TITLE: Open-Label Extension, Phase 2b Study to Evaluate the Longer Term 
Efficacy and Safety of LIB003 in Patients on Stable Lipid-Lowering Therapy Requiring 
Additional LDL-C Reduction 
I, the undersigned, have read this protocol and agree that it contains all necessary 
information required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Evan A. Stein, MD PhD 
Chief Medical Officer 
LIB Therapeutics, LLC  
 
 
 
 
 
March 18, 2020


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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by LIB Therapeutics to study personnel under my supervision. I will discuss this material with 
them to ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential and proprietary to LIB Therapeutics and that it 
may not be further disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by LIB Therapeutics, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations, and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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SYNOPSIS 
TITLE:  Open-Label Extension, Phase 2b Study to Evaluate the Longer Term Efficacy and Safety 
of LIB003 in Patients on Stable Lipid-Lowering Therapy Requiring Additional LDL-C Reduction
PROTOCOL NUMBER:  LIB003-010 
INVESTIGATIONAL PRODUCT:  LIB003 
PHASE:  2b 
INDICATION(S): Low-density lipoprotein cholesterol (LDL-C) reduction in patients with 
atherosclerotic cardiovascular disease (ASCVD), high risk of ASCVD, or heterozygous familial 
hypercholesterolemia (HeFH) without cardiovascular disease who need additional LDL-C 
reduction 
OBJECTIVES: 
The primary objectives of this study are to assess the longer term safety, tolerability, and 
LDL-C-lowering efficacy after 52 weeks  of additional treatment with LIB003 at a subcutaneous 
(SC) dose of 300 mg every 4 weeks (Q4W). Study patients will be those with 
hypercholesterolemia on stable diet and oral LDL-C-lowering drug therapy who have completed 
the Phase 2 dose finding study.  
The secondary objectives of this study are the following: 
 To assess the longer term tolerability and safety of LIB003 300 mg Q4W in patients treated 
for an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study;   
 To assess the stability of LDL-C-lowering with LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 
 To assess the pharmacodynamic (PD) effect on serum unbound (free) proprotein convertase 
subtilisin/kexin type 9 (PCSK9) concentrations of LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 
 To assess the effects on serum lipids, including total cholesterol (TC), high-density lipoprotein 
cholesterol (HDL-C), non–HDL-C, very low-density lipoprotein cholesterol (VLDL-C), and 
triglycerides (TG) of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who 
were previously treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the 
Phase 2 double-blind study; 
 To assess the effects on apolipoprotein (apo) B and lipoprotein (a) (Lp[a]) serum 
concentrations of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who 
were previously treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the 
Phase 2 double-blind study;   


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 To assess the pharmacokinetics of LIB003 and PCSK9 following multiple doses of LIB003
300 mg SC Q4W;   
 To assess the frequency of anti-drug (anti-LIB003) antibodies (ADAs) (immunogenicity) of 
LIB003 300 mg Q4W in patients treated for an additional 52 weeks who were previously 
treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo, including those with 
detectable ADAs during the Phase 2 double-blind study; and   
 Patients who develop neutralizing antibodies at Week 52 may be administered up to 3 
additional doses of LIB003 300 mg QW4 for a total of up to 64 weeks exposure to allow for 
the assessment and characterization of this finding. Following the first dose, if NAbs continue 
positive with possible attenuation of free PCSK9 and LDL-C, then up to 2 additional doses 
could be administered. 
POPULATION: 
The population for this study includes men and women who are 18 years of age who completed 
the double-blind, placebo-controlled 16-week Phase 2 study (LIB003-002) and will continue on 
stable lipid-lowering oral drug therapy (eg, tolerable statin with or without ezetimibe). 
STUDY DESIGN AND DURATION: 
This is an open-label, Phase 2b extension study of 52 weeks duration. Approximately 35 men and 
women aged 18 years who have completed the Phase 2 (LIB003-002) study and fulfill the 
inclusion and exclusion criteria will be enrolled at up to 4 sites in the United States. All patients 
will receive LIB003 at a dose of 300 mg administered SC Q4W.   
LIB003-010 Phase 2b Study Design  
 M = month; Q4W = every 4 weeks; SC = subcutaneously; W = week. 
Study Procedures 
Patients who have completed the LIB003-002 study and do not meet any exclusion criteria and 
have completed the informed consent for this extension study will receive LIB003 at a dose of
300 mg Q4W by SC injection at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. In 
addition to a basic lipid profile, LDL-C will be measured by preparative ultracentrifugation at
specified visits during the study. All lipid measurements on Week 0/Month 0 onward will be 
available to the Investigator, patients, and all site and Sponsor personnel involved in the study.
Final safety assessments will include adverse events and the results from physical examinations, 
electrocardiograms (ECGs), clinical laboratory tests (hematology, serum chemistry, and 
urinalysis), and immunogenicity testing. Injection site reactions will be assessed at each visit.  
Patients testing positive for ADAs will be tested for neutralizing antibodies (NAbs) and titer, and 
may be further characterized for isotype, binding site, affinity, and presence of immune 
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Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
follow-up testing.  
In the case of positive NAbs at the final visit (Week 52/Early Termination), patients will be asked 
to return for follow-up testing every 3 months until either NAbs are no longer detectable or the 
patient has been followed for a period of at least 12 months. During the initial 3 months of follow-
up patients may continue to receive LIB003 300mg at visits Q4W for a potential total exposure of 
64 weeks to further characterize the NAb finding. Following the first dose, if NAbs continue 
positive with possible attenuation of free PCSK9 and LDL-C, then up to 2 additional doses could 
be administered. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
All patients will receive SC doses of LIB003 300 mg administered as a SC injection by clinic 
personnel. 
PHARMACOKINETIC VARIABLES: 
Total serum PCSK9 concentrations at Weeks 24 and 36 and 52/Early Termination will be 
assessed.  
PHARMACODYNAMIC VARIABLES:  
The PD parameters include changes from both baseline in the Phase 2 (LIB003-002) study and 
Week 0 in this study in LDL-C (calculated and measured), unbound (free) PCSK9 concentrations, 
serum lipid parameters (TC, HDL-C, non–HDL-C, VLDL-C, TG, apo B, and Lp[a]). 
SAFETY VARIABLES:  
Safety assessments will include adverse events and the results of vital sign measurements, ECGs, 
physical examinations, clinical laboratory tests, and immunogenicity evaluations. Injection site 
reactions will be monitored by physical examination. The incidence of observed adverse events 
will be tabulated and reviewed for potential significance and clinical importance. 
STATISTICAL ANALYSES: 
Efficacy Analyses 
The primary objectives of this study are to assess the percent change from baseline, from the 
original LIB003-002 study, in LDL-C level at Week 52 (both calculated by Friedewald formula) 
with monthly (Q4W) dosing of various doses of LIB003 administered SC in patients with 
hypercholesterolemia on stable diet and oral LDL-C-lowering drug therapy. Interim analyses will 
be carried out at Weeks 24 and 36 weeks. Results will be summarized descriptively. 
Safety Analyses 
The safety endpoint data will be summarized for the Safety Population, which is defined as all 
patients who received at least 1 dose of study drug. Adverse events will be coded using the latest 
version of the Medical Dictionary for Regulatory Activities. A general summary of the adverse 
events and serious adverse events (SAEs) will be summarized by overall number of adverse 
events, severity, and relationship to study drug. The number of adverse events leading to 


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withdrawal and SAEs leading to death will also be summarized. The incidence of adverse events 
will be summarized by system organ class and preferred term. 
The safety laboratory data will be summarized by visit, along with changes from baseline visit of 
the extension study. The values that are below the lower limit or above the upper limit of the 
reference range will be flagged for safety but not efficacy parameters. Those values or changes in 
values that are identified as being clinically significant will be flagged. Laboratory abnormalities 
of special interest, such as liver function tests, will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit, along with the changes from 
baseline. Abnormal physical examination findings will be listed. 
Immunogenicity data will be listed.  
SAMPLE SIZE DETERMINATION: 
The number of patients is not based on statistical consideration and there is no placebo or 
comparator group.  
SITES:  Four sites in the United States  
SPONSOR: 
LIB Therapeutics, LLC 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 978-770-8443 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents ............................................................................................................................ 8 
List of Tables ................................................................................................................................ 12 
List of Abbreviations and Definition of Terms............................................................................. 13 
1 Introduction and Background Information ............................................................................. 15 
1.1 
Rationale ........................................................................................................................ 20 
1.2 
Risk/Benefit ................................................................................................................... 21 
2 Study Objectives ..................................................................................................................... 22 
2.1 
Primary Objective ......................................................................................................... 22 
2.2 
Secondary Objectives .................................................................................................... 22 
3 Study Description.................................................................................................................... 23 
3.1 
Summary of Study Design ............................................................................................ 23 
3.2 
Stopping Rules .............................................................................................................. 23 
4 Selection and Withdrawal of Patients ..................................................................................... 25 
4.1 
Inclusion Criteria ........................................................................................................... 25 
4.2 
Exclusion Criteria .......................................................................................................... 26 
4.3 
Withdrawal Criteria ....................................................................................................... 26 
5 Study Treatments .................................................................................................................... 28 
5.1 
Treatment Group ........................................................................................................... 28 
5.2 
Rationale for Dosing ..................................................................................................... 28 
5.3 
Randomization and Blinding ......................................................................................... 28 
5.4 
Breaking the Blind ........................................................................................................ 28 
5.5 
Drug Supplies ................................................................................................................ 28 
5.5.1 Formulation and Packaging ............................................................................... 28 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 28 
5.5.3 Study Drug Administration ............................................................................... 29 
5.5.4 Treatment Compliance ...................................................................................... 29 
5.5.5 Storage and Accountability ............................................................................... 29 


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5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 29 
5.6.1 Excluded Medications and/or Procedures ......................................................... 29 
5.6.2 Restricted Medications and/or Procedures ........................................................ 30 
5.6.3 Restrictions and Dietary Guidelines .................................................................. 30 
5.6.4 Documentation of Prior and Concomitant Medication Use .............................. 30 
6 Study Procedures .................................................................................................................... 31 
6.1 
Informed Consent .......................................................................................................... 31 
6.2 
Study Schedule .............................................................................................................. 31 
6.2.1 Study Week 0 .................................................................................................... 31 
6.2.2 Study Week 4 .................................................................................................... 32 
6.2.3 Study Week 8 .................................................................................................... 32 
6.2.4 Study Week 12 .................................................................................................. 33 
6.2.5 Study Weeks 16 and 20 ..................................................................................... 33 
6.2.6 Study Week 24 .................................................................................................. 34 
6.2.7 Study Weeks 28 and 32 ..................................................................................... 34 
6.2.8 Study Week 36 .................................................................................................. 35 
6.2.9 Study Weeks 40, 44 and 48 ............................................................................... 35 
6.2.10 Study Week 52/Early Termination .................................................................... 36 
6.2.11 Follow-up Visit for Positive Anti-Drug Antibodies/Neutralizing Antibodies .. 36 
7 Pharmacokinetic and Pharmacodynamic Assessments ........................................................... 38 
7.1 
Pharmacodynamic Endpoints ........................................................................................ 38 
8 Safety Assessments ................................................................................................................. 39 
8.1 
Adverse Events .............................................................................................................. 39 
8.1.1 Adverse (Drug) Reaction .................................................................................. 39 
8.1.2 Assessment of Adverse Events by the Investigator .......................................... 40 
8.1.3 Unexpected Adverse Drug Reaction ................................................................. 41 
8.2 
Serious Adverse Events ................................................................................................. 41 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 42 
8.4 
Pregnancy Reporting ..................................................................................................... 42 
8.5 
Expedited Reporting ...................................................................................................... 43 
8.6 
Clinical Laboratory Evaluations .................................................................................... 43 
8.6.1 Potential Drug-Induced Liver Injury ................................................................. 43 


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8.7 
Immunogenicity ............................................................................................................ 43 
8.8 
Vital Signs ..................................................................................................................... 44 
8.9 
Electrocardiograms ........................................................................................................ 44 
8.10 Physical Examinations .................................................................................................. 44 
9 Statistics .................................................................................................................................. 45 
9.1 
Statistical Methods ........................................................................................................ 45 
9.1.1 Analysis Populations ......................................................................................... 45 
9.1.2 Analysis of Efficacy .......................................................................................... 45 
9.1.3 Pharmacodynamic Analysis .............................................................................. 45 
9.1.4 Immunogenicity Analyses ................................................................................. 45 
9.1.5 Pharmacokinetic Analysis ................................................................................. 45 
9.1.6 Analysis of Safety ............................................................................................. 45 
9.1.7 Demographics and Baseline Characteristics ..................................................... 46 
9.1.8 Interim Analysis ................................................................................................ 46 
9.2 
Sample Size Determination ........................................................................................... 46 
10 Data Management and Record Keeping ................................................................................. 47 
10.1 Data Management ......................................................................................................... 47 
10.1.1 Data Handling ................................................................................................... 47 
10.1.2 Computer Systems ............................................................................................. 47 
10.1.3 Data Entry ......................................................................................................... 47 
10.1.4 Medical Information Coding ............................................................................. 47 
10.1.5 Data Validation ................................................................................................. 47 
10.2 Record Keeping ............................................................................................................. 47 
11 Investigator Requirements and Quality Control ..................................................................... 48 
11.1 Ethical Conduct of the Study ........................................................................................ 48 
11.2 Institutional Review Board ............................................................................................ 48 
11.3 Informed Consent .......................................................................................................... 48 
11.4 Study Monitoring Requirements ................................................................................... 48 
11.5 Disclosure of Data ......................................................................................................... 49 
11.6 Retention of Records ..................................................................................................... 49 
11.7 Publication Policy ......................................................................................................... 49 
11.8 Financial Disclosure ...................................................................................................... 50 


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12 Study Administrative Information .......................................................................................... 51 
12.1 Protocol Amendments ................................................................................................... 51 
12.2 Address List ................................................................................................................... 51 
12.2.1 Sponsor .............................................................................................................. 51 
12.2.2 Contract Research Organization ........................................................................ 51 
12.2.3 Drug Safety ....................................................................................................... 51 
12.2.4 Biological Specimens ........................................................................................ 51 
13 References ............................................................................................................................... 52 
Appendix A: Schedule of Procedures ........................................................................................... 54 
Appendix B: Clinical Laboratory Analytes .................................................................................. 56 


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LIST OF TABLES 
Table 1. 
Summary of Adverse Events for the LIB003-001 SAD Study ................................... 17 
Table 2. 
Overview of Adverse Events for the LIB003-002 Study ............................................ 19 
Table 3. 
Analysis of Variance of Low-Density Lipoprotein Cholesterol (Calculated by 
Friedewald Formula) for the LIB003-002 Study ........................................................ 20 
Table 4. 
Schedule of Procedures ............................................................................................... 54 
 
LIST OF FIGURES 
Figure 1. LIB003 Phase 2b Open-Label Extension Study ......................................................... 23 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ALT 
Alanine transaminase 
apo  
Apolipoprotein 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate transaminase 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CRA 
Clinical Research Associate 
DILI  
Drug-induced liver injury 
ECG 
Electrocardiogram  
eCRF  
Electronic Case Report Form 
EDC  
Electronic data capture  
Enrollment 
The day patient signs informed consent and first procedure performed 
FDA 
Food and Drug Administration 
FH 
Familial hypercholesterolemia 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia   
HSA 
Human serum albumin 
ICF  
Informed consent form 
ICH 
International Council for Harmonisation 
IRB  
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
Laboratory manual 
Manual provided by the central laboratory containing detailed 
information on blood volume, sample collection, processing, storage 
and delivery to the central laboratory 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LOCF 
Last post-baseline observation carried forward 
Lp(a) 
Lipoprotein (a) 
mAb 
Monoclonal antibody 
NAb 
Neutralizing antibody 
OTC  
Over-the-counter 


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Abbreviation 
Definition 
Pharmacy manual  
Manual provided by the Sponsor or CRO containing detailed 
information on study drug (LIB003), receipt and storage, preparation 
(SC), and drug accountability 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
Q4W 
Every 4 weeks 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event  
TG 
Triglycerides 
ULN 
Upper limit of normal  
VLDL-C 
Very low-density lipoprotein cholesterol 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Atherosclerotic cardiovascular disease (ASCVD) is the main cause of morbidity and mortality in 
industrialized countries and, despite progress in treatment, is projected to cause >22 million deaths 
over the next 15 years.1 Low-density lipoprotein cholesterol (LDL-C) has been identified as one 
of the major, and easily modifiable, risk factors for atherosclerosis.2 Significant ASCVD benefit 
has been achieved since the introduction of statin therapy to reduce LDL-C.2 However, significant 
unmet medical need remains for additional LDL-C reduction in patients with existing ASCVD and 
those at increased cardiovascular risk, including patients unable to tolerate statins or effective 
doses of statins and those with more severe elevations of LDL-C, such as those with familial 
hypercholesterolemia (FH).3 Data from the Cholesterol Treatment Trialists’ Collaboration has 
provided evidence that for every 1 mmol/L (~39 mg/dL) reduction in LDL-C, the risk of major 
cardiovascular events is reduced by 24%, although these data were collected mostly with statins.2 
The recent cardiovascular outcome study with proprotein convertase subtilisin/kexin type 9 
(PCSK9) monoclonal antibodies (mAb) and evolocumab (Repatha®) and alirocumab (Praluent®) 
studies, the FOURIER and ODYSSEY Outcome studies, respectively, have confirmed this 
relationship for non–statin-lowering of LDL-C.4,5 Furthermore, recent data from a number of 
studies, including post hoc analysis of the IMPROVE-IT and Phase 3 alirocumab (Praluent®) 
studies, plus the FOURIER and SPIRE (Cardiovascular Efficacy and Safety of Bococizumab in 
High-Risk Patients) studies, have shown that the relationship between absolute LDL-C reduction 
and ASCVD event reduction remains linear and extends to very low LDL-C levels of <15 mg/dL 
without signals of adverse events either from PCSK9 inhibition or very low LDL-C.6,7,8,9,10,11 
Proprotein convertase subtilisin/kexin type 9 is a circulating protein secreted mainly by the liver 
that plays a significant role in the recycling of hepatic low-density lipoprotein receptors (LDLRs) 
and has been identified as a validated drug target for reduction of LDL-C. The LDLR is the primary 
pathway for LDL-C elimination from circulation; plasma PCSK9 binds to the hepatic LDLR along 
with LDL-C, targeting the receptor for degradation after endocytosis and thus reducing the 
expression of LDLRs available to remove LDL-C from circulation. Gain-of-function mutations of 
PCSK9 are associated with elevated LDL-C and constitute a third cause of FH and accelerated 
ASCVD, while loss-of-function mutations of PCSK9 are associated with reduced levels of LDL-C 
and reductions in ASCVD.4,5,11,12 Adverse effects or other metabolic disturbances have not been 
observed in subjects carrying loss-of-function PCSK9 mutations, even in a compound 
heterozygote with no detectable PCSK9 levels and strikingly low LDL-C (14 mg/dL), although 
recent Mendelian randomization studies have suggested the potential for increased diabetes in 
patients with impaired glucose tolerance or metabolic syndrome similar to that seen with 
statins.5,13,14 Nonclinical studies in PCSK9 knockout or overexpressing mice revealed phenotypes 
consistent with the human clinical data.15 Together, the clinical and nonclinical data for the PCSK9 
mechanism of action provide a strong genetic proof of concept for targeting PCSK9 to reduce 
plasma LDL-C levels and lower the risk of coronary heart disease. Based on these observations, 
PCSK9 inhibition is a promising target for developing new non-mAb therapies for reduction of 
plasma cholesterol levels. 
LIB Therapeutics has developed LIB003, a Chinese hamster ovary-cell line-derived recombinant 
fusion protein therapeutic agent consisting of a PCSK9-binding domain and human serum albumin 
(HSA). The HSA contains an alanine substituted for the naturally occurring cysteine at residue 34. 
The PCSK9-binding domain (Adnectin) in LIB003 is derived from the 10th type III domain of 
human fibronectin modified by messenger ribonucleic acid display technology to bind selected 


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targets with high affinity. LIB003 has been designed to target PCSK9 and binds to human PCSK9 
with picomolar affinity in a concentration-dependent manner. The binding of LIB003 to PCSK9 
blocks the interaction between PCSK9 and LDLR, which thereby prevents LDLR degradation, 
increases LDLR recycling, enhances LDL-C clearance, and lowers plasma LDL-C levels. Based 
on this mechanism of action, LIB003 is being developed as an adjunct subcutaneous (SC) therapy 
for the reduction of LDL-C in patients with homozygous and heterozygous FH (HeFH), ASCVD, 
or high risk of ASCVD who require additional LDL-C reduction. 
Based on in vitro and in vivo data demonstrating that LIB003 was unable to bind rodent PCSK9 
with sufficient affinity to modulate pharmacology in wild type rodents, no rodent toxicity studies 
were performed in accordance with International Council for Harmonisation (ICH) 
Guideline S6.16,17,18 To assess the overall toxicity risk of exposing human subjects to LIB003, 
Good Laboratory Practice (GLP) 4-week repeat-dose and 12-week repeat-dose toxicity studies 
were conducted in cynomolgus monkeys. These studies demonstrated that LIB003 was clinically 
well tolerated with no adverse findings at all doses tested (30 mg/kg and 100 mg/kg SC doses; 
100 mg/kg intravenous [IV] dose [4-week study only]). The highest dose of 100 mg/kg was 
considered the no-observed-adverse-effect level in both studies.    
In this current study, as with now numerous studies with mAbs that inhibit PCSK9, inhibition with 
LIB003 is not expected to adversely impact the cardiovascular system since both PCSK9-null mice 
and compound heterozygous humans with PCSK9 loss-of-function mutations exhibit no 
discernable cardiovascular phenotype.19,20,21 Moreover, extensive clinical studies inhibiting 
PCSK9 with monoclonal antibodies have shown only cardiovascular benefit.4,5,7,8,9,10,18,19,20 
Evaluation of the effect of LIB003 on the cardiovascular, central nervous, and respiratory systems 
were included as part of the 4-week GLP toxicity studies in cynomolgus monkeys in accordance 
with ICH S6 and S7 Guidances.16 Results from the study revealed that repeated administration of 
LIB003 had no effect on cardiovascular, central nervous system, or respiratory function. No 
genotoxicity studies were conducted with LIB003 as LIB003 is a fusion protein that does not 
contain an organic linker or any chemical moiety and, therefore, lacks potential for mutagenesis.  
Phase 1 study: 
LIB003 has been studied in a Phase 1 single ascending dose (SAD) study of 63 subjects, 45 on 
LIB003 and 18 placebo, monitored post-dose for at least 43 days. Subcutaneous doses of LIB003 
25 mg, 75 mg, 150 mg, 300 mg, and 600 mg were administered to healthy subjects on no 
lipid-lowering therapy who had baseline LDL-C 100 and 190 mg/dL, and the 150 mg and 
300 mg doses were administered to patients on stable statin therapy with baseline 
LDL-C 100 mg/dL.  
Safety: All subjects had TG 250 mg/dL. LIB003 was safe and well tolerated following single SC 
and IV dosing in healthy subjects at all doses both for SC and IV administration as well as in 
patients with hypercholesterolemia on statin therapy at 150 mg and 300 mg given SC. A summary 
of adverse events is provided in Table 1 and summarized below. 
 


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Table 1. 
Summary of Adverse Events for the LIB003-001 SAD Study 
 
AE = adverse event; CNS = central nervous system; ISR = injection site reaction; IV = intravenous; PBO = placebo; 
Resp Infec = respiratory infection; SAD = single ascending dose; SC = subcutaenous(ly); TEAE = treatment-emergent 
adverse event.  Source: LIB003-001 Clinical Study Report 
There were no deaths or discontinuations due to adverse events. 
One placebo-treated subject experienced a moderate treatment-emergent adverse event (TEAE) 
that was considered not related to study drug; the subject, a 61-year-old male on statin who 
received placebo in cohort 9 (LIB003 300 mg SC or placebo group), experienced an episode of 
syncope with rapid heart rate and was found to be in atrial fibrillation 48 hours following 
administration of study drug. The patient was transported to the emergency room and admitted to 
the hospital, but within a few hours spontaneously reverted to sinus rhythm before being seen by 
a cardiologist and discharged from the hospital. Subsequent follow-up with the cardiologist 
included stress ECHO test and Holter monitoring, which were normal and resulted in no further 
treatment or intervention.   
A total of 6 of 18 (33%) placebo subjects and 13 of 45 (29%) LIB003 subjects reported at least 
1 TEAE; none of the TEAEs were considered serious or drug related (Table 1). 
The most common adverse events reported (by more than 1 subject) were respiratory infections, 
gastrointestinal, eye (blurred vision), central nervous system (headache), and musculoskeletal; all 
other adverse events were reported by 1 subject only. None appeared dose related or more 
frequently in LIB003-treated subjects compared to placebo. 
One of the adverse events that was considered clinically significant was a 39-year-old male subject 
who received 300 mg LIB003 IV and experienced swelling of his lips 48 hours after study drug 
administration. This was confirmed on examination as mild, not affecting speech, food, or fluid 
intake. There was no evidence of tongue or soft palate edema and the subject denied any difficulty 
swallowing or breathing. The subject denied any other symptoms, such as rash or pruritus. There 
was no evidence of any reaction at the infusion site. He had no history of similar symptoms or 
known drug or food allergies. His vitals, electrocardiograms (ECGs), and 48-hour safety labs were 
unremarkable. The subject received oral Benadryl 50 mg and ranitidine 75 mg (which he 
continued twice daily). The Benadryl was replaced with cetirizine 10 mg orally daily and the 
subject was monitored as an outpatient after completing Day 4 in the inpatient unit. The swelling 
subsided after 2 to 3 more days without further intervention. 
cohort
PBO
25 mg
75 mg
150 mg Diet
300 mg Diet
600 mg SC
300 mg IV 600 mg IV 150 mg Statin 300 mg Statin
ALL LIB
N
18
5
5
5
5
5
5
5
5
5
45
Any TEAE n(%)
6 (33%)
2 (40%)
0 (0%)
1 (20%)
2 (40%)
0 (0%)
2 (40%)
2 (40%)
1 (20%)
2 (40%)
13 (29%)
    mild
5
2
0
0
2
0
2
2
1
2
12
    moderate
1
0
0
1
0
0
0
0
0
0
1
    severe
0
0
0
0
0
0
0
0
0
0
0
Serious AE
0
0
0
0
0
0
0
0
0
0
0
Drug related AE
0
0
0
0
0
0
0
0
0
0
0
ISR
0
0
0
0
0
0
0
0
0
0
0
Common TEAEs
  Cardiac
1
0
0
0
0
0
0
0
0
0
0
  Resp Infec
2
2
0
1
0
0
0
0
1
0
4
  Gastrointest
1
0
0
0
0
0
1
1
0
0
2
  Eye-vision
0
0
0
1
1
0
1
0
0
0
3
  MusclSkeletal
2
0
0
0
1
0
0
0
0
0
1
  CNS-headache
3
0
0
1
0
0
1
1
0
1
4


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There were no other clinically remarkable vital sign measurements, physical examination findings, 
physical measurement findings, or clinically remarkable trends from baseline to discharge. 
There were no clinically remarkable trends observed in laboratory findings. A number of subjects 
in both LIB003 and placebo experienced spikes in creatine kinase (CK) that were clearly related 
to exercise or excessive or unusual physical activity, and CK decreased at subsequent testing. 
There were no adverse events based on ECG findings or any findings that were assessed as 
clinically significant by the Investigator. 
Anti-drug (anti-LIB003) antibodies (ADAs) were confirmed in 2 subjects: One subject treated with 
25 mg SC of LIB003 developed low titer non-neutralizing ADAs at Day 43; the titers remained 
low on monthly follow-up, with a stable titer of 160 after 3 months. The second subject, treated 
with 600 mg IV of LIB003, developed an ADA response at Day 22, which increased to a titer of 
2560 by Day 43. The patient was followed at weekly intervals until Day 57 when LDL-C returned 
to within 20% of baseline and was followed at monthly intervals for 2.5 months after Day 43, 
reaching a maximal titer of 5120 at Day 113, which declined 50% on Day 142. There were no 
associated clinical or laboratory adverse effects noted and there did not appear to be any 
neutralizing impact on efficacy as LDL-C and free PCSK9 reduction did not appear attenuated 
compared to other subjects treated with LIB003 in the same cohort. Evaluation in the LIB003 
neutralizing antibody (NAb) assay indicated that these ADAs were neutralizing beginning on 
Day 29 through Day 113 and were no longer neutralizing on Day 142. At a routine clinic visit on 
01 August 2018 (1 month after ending the study) to the Principal Investigator (PI), who was also 
the patient’s lipid doctor, the patient reported a recent upper right lung lobe mass found by their 
primary care physician on 24 July 2018 and on biopsy taken 30 July 2018 diagnosed as 
Epstein-Barr positive diffuse large B cell lymphoma of intra thoracic lymph nodes. The finding 
was determined by the PI as unrelated to study drug. 
Efficacy: Mean reductions in free PCSK9 were rapid with all doses and reached more than 
99% within 12 hours and were sustained in virtually all subjects for at least 3 weeks (Day 22) in 
the cohorts not on lipid-lowering therapy receiving 150 mg of LIB003. While the 300 mg dose 
maintained 99% suppression of free PCSK9 for 29 days in the 150 mg patients on 
non-lipid-lowering subjects, it had decreased to 12% and in those on statins to 54% of baseline 
levels. The reduced effects in free PCSK9 were reflected in less reductions of LDL-C and 
apolipoprotein (apo) B in statin-treated subjects although greater reductions were maintained in 
subjects not on lipid-lowering therapy. However, the 150 mg dose did not reduce free PCSK9 or 
LDL-C sufficiently in all statin-treated patients for 4 weeks. The single 300 mg dose, in both 
non-statin and statin-treated subjects, provided more stable and maximal reductions in free 
PCSK9, LDL-C, and apo B. In addition, based on prior data from studies with mAbs, it is 
anticipated that multiple dosing will result in longer duration of both free PCSK9 suppression and 
LDL-C reduction. Furthermore, extensive prior data show that patients on high-intensity statins 
and those with FH, who have higher baseline PCSK9 levels and likely increased synthesis of 
PCSK9, will require 300 mg or higher doses in order to suppress both free PCSK9 and LDL-C 
fully for 4 weeks. Three doses were selected for the Phase 2 study to be administered SC every 
4 weeks (Q4W); 150 mg, 300 mg, and 350 mg. 


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Phase 2 study: 
Based on the free PCSK9 and LDL-C data from the SAD study and an objective of obtaining 
maximal and stable LDL-C reductions with dosing at least Q4W in a volume that is consistent 
with a single SC injection via an autoinjector (1.5 mL), a 16-week Phase 2 study was done. This 
was a double-blind, placebo-controlled, dose-finding study in approximately 81 patients with 
ASCVD, or at high risk for ASCVD, or HeFH without cardiovascular disease, on stable maximal 
tolerable statin and/or ezetimibe which was completed on 09 November 2018. The doses assessed 
included 150 mg, 300 mg, and 350 mg all administered SC Q4W on Days 1, 29, and 57 with the 
final efficacy endpoint at Day 85 (Week 12). Patients were monitored for 4 additional weeks at 
Days 99 and 113. Patients were randomized within each treatment group to LIB003 or placebo in 
a ratio of 3:1 resulting in 20 patients on placebo and 61 patients in the LIB003 treatment groups 
(21 on 150 mg, 19 on 300 mg, and 21 on 350 mg). Of the 81 patients randomized, 79 completed 
the study; of the 2 patients not completing the study, 1 was terminated after 4 weeks after starting 
on a prescription PCSK9 monoclonal antibody while the second patient withdrew after receiving 
the first dose due to conflict with her work schedule.  
Safety: There were no deaths and all 3 doses were safe and well tolerated (see Table 2). Serious 
adverse events occurred in 5.0% (1/20) subjects in the placebo group, 4.8% (1/21) in the LIB003 
150 mg group, 10.5% (2/19) in the LIB003 300 mg, and 9.5% (2/21) in the LIB003 350 mg group. 
Of the entire 81 patients, 24 were found to have positive ADAs on screening, of which 19 were 
confirmed as positive. This included 2 patients (2.5%) who tested positive prior to receiving study 
drug and whom showed the highest titers (160 and 1280) and in both patients, titers decreased 
progressively after dosing with study drug. Excluding these 2 patients, ADAs were found to be 
present post-dose in 27.8% (17/61) patients treated with LIB003 and 0% (0/20) on placebo. All 
positive ADAs post-dosing of study drug had low, or below level of quantitation, levels and based 
on individual free PCSK9 and LDL-C levels, there did not appear to be a pharmacokinetic 
(PK)/pharmacodynamic (PD) effect. Subsequent testing was negative for treatment-induced 
NAbs. 
 Table 2. Overview of Adverse Events for the LIB003-002 Study 
 
N = number of subjects; Q4W = every 4 weeks; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
Source: LIB003-002 Clinical Study Report 
Efficacy: The co-primary endpoints of percent reduction in LDL-C (calculated by Friedewald 
formula) from baseline compared to placebo at Week 12 and the mean of Weeks 10 and 12 was 
achieved (p<0.0001) for all 3 doses (see Table 3); however, maximal and stable reductions were 


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best seen with the 300 mg dose [least-squares mean (standard error; 95% confidence interval) of  
-77.3% (6.63; -90.5, -64.1)] at Week 12 (last post-baseline observation carried forward [LOCF]) 
and -76.1% (4.99; -86.0, -66.2) at mean of Weeks 10 and 12 (LOCF). These results were consistent 
with LDL-C measured by Hopkins formula and by preparative ultracentrifugation. The lower dose 
of 150 mg, while achieving similar LDL-C reductions at 2 weeks post dose, was insufficient to 
provide consistent free PCSK9, and more importantly LDL-C, reductions for 4 weeks. The larger 
dose of 350 mg Q4W provided no additional LDL-C reduction at any time point. 
Table 3. 
Analysis of Variance of Low-Density Lipoprotein Cholesterol (Calculated by 
Friedewald Formula) for the LIB003-002 Study 
 
CI = confidence interval; LOCF = last post-baseline observation carried forward; LS = least squares; SE = standard error; 
N = number of subjects; vs = versus. 
Source: LIB003-002 Clinical Study Report 
Based on the results the dose of 300 mg (1.2 mL) SC Q4W was selected for the open-label 
extension (LIB003-010) study. 
In summary to date, no specific risks have been identified in the nonclinical or clinical 
development of LIB003.  
1.1 
Rationale 
The rationale for this extension study is to enable longer term assessment of the safety, tolerability, 
and LDL-C-lowering efficacy for a 52-week additional treatment with LIB003 at a SC dose of 
300 mg Q4W. Study patients will be those with hypercholesterolemia on stable diet and oral 
LDL-C-lowering drug therapy who have completed the Phase 2 dose finding study.  
Additional objectives of this study are the following: 
 To assess the frequency of anti-drug (anti-LIB003) antibodies (ADAs) (immunogenicity) of 
LIB003 300 mg Q4W in patients treated for an additional 52 weeks who were previously 
treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo, including those with 
detectable ADAs during the Phase 2 double-blind study; 
 To assess the longer term tolerability and safety of LIB003 300 mg Q4W in patients treated 
for an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study;   
 To assess the stability of LDL-C-lowering with LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 


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 To assess the PD effect on serum unbound (free) PCSK9 concentrations of LIB003 300 mg 
Q4W in patients treated for an additional 52 weeks who were previously treated with LIB003 
at 150 mg, 300 mg, and 350 mg or placebo during the Phase 2 double-blind study; 
 To assess the effects on serum lipids, including total cholesterol (TC), high-density lipoprotein 
cholesterol (HDL-C), non–HDL-C, very low-density lipoprotein cholesterol (VLDL-C), and 
triglycerides (TG) of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who 
were previously treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the 
Phase 2 double-blind study; 
 To assess the PK of LIB003 and PCSK9 following multiple doses of LIB003 300 mg SC Q4W; 
and 
 To assess the effects on apo B and lipoprotein (a) (Lp[a]) serum concentrations of LIB003 
300 mg Q4W in patients treated for an additional 52 weeks who were previously treated with 
LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the Phase 2 double-blind study. 
In patients who are NAb positive at Week 52, the rationale for up to 3 additional doses of LIB003 
300mg QW4 (12 additional weeks of exposure) is to allow for the assessment of the time course 
of NAbs and effects on relevant clinical and laboratory measures including but not limited to free 
PCSK9 and LDL-C. 
The risk of continuing treatment for up to 12 additional weeks (64 weeks total exposure) is 
considered low.  Currently, 3 of 112 (approximately 2.7%) patients who have received LIB003 to 
date have developed NAbs. No patient has had a concurrent change in their clinical or laboratory 
safety or efficacy findings. The PCSK9 free and LDL-C lowering effects remained consistent to 
previous visits when there were no NAbs detected, negating any indication of a neutralizing 
clinical effect. In 2 prior patients, NAbs were detected and then resolved while the patient remained 
on LIB003 treatment or followed after completing treatment in the phase 1 single ascending dose 
trial.   
Safety, immunogenicity, and PD data derived from the study will further support the Phase 3 
studies. 
1.2 
Risk/Benefit 
Patients will receive no known clinical benefit from participating in the study beyond that of an 
assessment of their overall health status and reduction in LDL-C.   
LIB003 at doses of 300 mg given were shown to reduce LDL-C levels >60% and was safe and 
well tolerated in the Phase 2 study these patients previously participated in. Therefore, the risk to 
patients in this study is considered low. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objectives of this study are to assess the longer term safety, tolerability, and 
LDL-C-lowering efficacy after 52 weeks of additional treatment with LIB003 at a SC dose of 
300 mg Q4W. Study patients will be those with hypercholesterolemia on stable diet and oral 
LDL-C-lowering drug therapy who have completed the Phase 2 dose finding study. 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
 To assess the longer term tolerability and safety of LIB003 300 mg Q4W in patients treated 
for an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study;   
 To assess the stability of LDL-C-lowering with LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 
 To assess the PD effect on serum unbound (free) PCSK9 concentrations of LIB003 300 mg 
Q4W in patients treated for an additional 52 weeks who were previously treated with LIB003 
at 150 mg, 300 mg, and 350 mg or placebo during the Phase 2 double-blind study; 
 To assess the effects on serum lipids, including TC, HDL-C, non–HDL-C, VLDL-C, and TG 
of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who were previously 
treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the Phase 2 
double-blind study; 
 To assess the effects on apo B and Lp(a) serum concentrations of LIB003 300 mg Q4W in 
patients treated for an additional 52 weeks who were previously treated with LIB003 at 
150 mg, 300 mg, and 350 mg or placebo during the Phase 2 double-blind study;   
 To assess the PK of LIB003 and PCSK9 following multiple doses of LIB003 300 mg SC Q4W; 
and   
 To assess the frequency of anti-drug (anti-LIB003) antibodies (ADAs) (immunogenicity) of 
LIB003 300 mg Q4W in patients treated for an additional 52 weeks who were previously 
treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo, including those with 
detectable ADAs during the Phase 2 double-blind study. 
 Patients who develop NAbs at Week 52 may be administered up to 3 additional doses of 
LIB003 300 mg QW4 for a total of up to 64 weeks exposure to allow for the assessment and 
characterization of this finding. Following the first dose, if NAbs continue positive with 
possible attenuation of free PCSK9 and LDL-C, then up to 2 additional doses could be 
administered. 
 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is an open-label, Phase 2b extension study of 52 weeks duration. Approximately 35 men and 
women aged 18 years who have completed the Phase 2 (LIB003-002) study and fulfill the 
inclusion and exclusion criteria will be enrolled at up to 4 sites in the United States. All patients 
will receive LIB003 at a dose of 300 mg administered SC Q4W as shown in Figure 1. 
Figure 1. LIB003 Phase 2b Open-Label Extension Study 
 
 
M = month; Q4W = every 4 weeks; SC = subcutaneously; W = week. 
Patients who have completed the LIB003-002 study and do not meet any exclusion criteria and 
have completed the informed consent for this extension study will receive LIB003 at a dose of 
300 mg Q4W by SC injection at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. In addition 
to a basic lipid profile, LDL-C will be measured by preparative ultracentrifugation at specified 
visits during the study. All lipid measurements on Week 0/Month 0 onward will be available to 
the Investigator, patients, and all site and Sponsor personnel involved in the study. Final safety 
assessments will include adverse events and the results from physical examinations, ECGs, clinical 
laboratory tests (hematology, serum chemistry, and urinalysis), and immunogenicity testing. 
Injection site reactions will be assessed at each visit.  
Patients testing positive for ADAs will be tested for NAbs and titer, and may be further 
characterized for isotype, binding site, affinity, and presence of immune complexes.  
Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
follow-up testing.  
In the case of positive NAbs at the final visit (Week 52/Early Termination), patients will be asked 
to return for follow-up testing every 3 months until either NAbs are no longer detectable or the 
patient has been followed for a period of at least 12 months.  During the initial 3 months of follow-
up patients may continue to receive LIB003 300mg at visits Q4W for a potential total exposure of 
64 weeks to further characterize the NAb finding. Following the first dose, if NAbs continue 
positive with possible attenuation of free PCSK9 and LDL-C, then up to 2 additional doses could 
be administered.  
3.2 
Stopping Rules  
Dose-Limiting Toxicity  
Dosing of a patient will be discontinued for any of the following events:  
 Alanine transaminase (ALT) and/or aspartate transaminase (AST) >5  upper limit of normal 
(ULN) (confirmed by immediate repeat); 


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 ALT and/or AST >3  ULN AND total bilirubin >2.0  ULN for patients without Gilbert’s 
syndrome and 2  baseline for those with Gilbert’s syndrome (confirmed by immediate repeat); 
 ALT or AST >3  ULN (confirmed by repeat) with the appearance or worsening of symptoms 
felt by the Investigator to be potentially related to hepatic injury, such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia; or 
 2 patients have AST and/or ALT >5  ULN (confirmed by repeat). 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients must meet all the following criteria to be eligible to participate in the study: 
1. Successful completion of the double-blind, placebo-controlled Phase 2 (LIB003-002) study 
without serious adverse events related to LIB003; 
2. Provision of written and signed informed consent (by patient) prior to any study-specific 
procedure; 
3. Women of childbearing potential must be using an effective form of birth control# and have a 
negative pregnancy test at Week 0. Effective contraception must be maintained during the 
entire time of taking the study drug and for 90 days after the last dose of study drug. ; 
4. Willing to maintain appropriate diet and stable dose of current statin (if tolerable) and/or 
ezetimibe for the duration of the 52-week study;  
5. Male patients will either be surgically sterile or agree to use, from the time study drug is started 
until 90 days following the last dose of study drug, one of the following forms of contraception: 
male or female condom with spermicide; a female partner who is surgically sterile, 
post-menopausal or who agrees to use effective contraception the following contraceptives, 
diaphragm or cervical cap with spermicide; or intrauterine device (IUD), oral, implantable, or 
injectable contraceptives;  
6. Male patients must refrain from sperm donation until 90 days following the last dose of study 
drug; and  
7. Patient is considered by the Investigator to be otherwise healthy, based on medical history 
review, a defined complete physical examination, as well as vital sign measurements, ECGs, 
and laboratory test results. 
# Effective methods of birth control include abstinence, birth control pills or patches, intrauterine devices (IUDs), 
sexual activity with a male partner who has had a vasectomy, condom or diaphragm or cervical cap with spermicide 
or IUD, oral, implantable, or injectable contraceptives.  


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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Failure to complete the Phase 2 (LIB003-002) study or and serious adverse event (SAE) related 
to study drug;  
2. Development since the final visit in LIB003-002 of any concomitant clinical condition or acute 
and/or unstable systemic disease compromising patient inclusion, at the discretion of the 
Investigator, including but not limited to, the following: a history or presence of clinically 
significant pulmonary, hepatic, gallbladder or biliary tract, hematologic, gastrointestinal, 
endocrine (excluding diabetes), immunologic, dermatologic, neurologic, or psychiatric 
disease, which in the Investigator’s opinion would not be suitable for the study from a patient 
safety consideration or could interfere with the results of the study; 
3. Females of childbearing potential not using or willing to use an effective form of 
contraception#, or pregnant or breastfeeding, or who have a positive urine pregnancy test at 
Week 0;  
4. Planned cardiac surgery or revascularization; 
5. New York Heart Association II-IV heart failure; 
6. Patient is currently, or within the prior 2 weeks has taken PCSK9 mAbs or within the last 
6 months PCSK9 small interfering ribonucleic acid or locked nucleic acid-reducing agents; 
7. Currently enrolled in another investigational device or drug study, or less than 30 days or 
5 half-lives since ending another investigational device or drug study(s), or receiving other 
investigational agent(s); 
8. Patient will not be available for protocol-required study visits or procedures, to the best of the 
patient’s and Investigator’s knowledge; 
9. Has any other finding which, in the opinion of the Investigator, would compromise the 
patient’s safety or participation in the study; or 
10. Is an employee or family member of the Investigator or study site personnel. 
# Effective methods of birth control include abstinence, birth control pills or patches, intrauterine devices (IUDs), 
sexual activity with a male partner who has had a vasectomy, condom or diaphragm or cervical cap with spermicide 
or IUD, oral, implantable, or injectable contraceptives.  
4.3 
Withdrawal Criteria 
Participation of a patient in this clinical study is entirely voluntary and may be discontinued for 
any of the following reasons: 
 The patient withdraws consent or requests discontinuation from the study, or study drug, for 
any reason; 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient; 


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 Pregnancy; 
 Requirement of prohibited concomitant medication as outlined above; 
 Patient failure to comply with protocol requirements or study-related procedures which results, 
or could result, in significant increased risk to the patient; or  
 Termination of the study by the Sponsor or the regulatory authority. 
If a patient discontinues prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the study discharge evaluations at Week 52. The 
reason for patient withdrawal must be documented in the electronic Case Report Form (eCRF). 
Withdrawn patients may not be replaced.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Group  
All patients will receive SC LIB003 at a dose of 300 mg Q4W.  
5.2 
Rationale for Dosing 
In the previous Phase 2 study (LIB003-002), the 300 mg SC dose QW4 was safe and well tolerated 
and provided maximal and stable reduction in mean LDL-C for 4 weeks. 
5.3 
Randomization and Blinding 
This is an open-label extension study, therefore, no randomization or blinding is necessary. 
5.4 
Breaking the Blind 
This is an open-label extension study, therefore, no blinding is necessary. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The drug product is a 250 mg/mL solution packaged in 0.85 mL volumes in 2 mL clear glass vials 
with stoppers and aluminum crimp seals.  
The LIB003 formulation contains 20 mM histidine, 150 mM sodium chloride, 
0.02% Polysorbate 80 at pH 6.8, which are common excipients at concentrations used in approved 
protein therapeutics administered as SC doses.  
5.5.2 
Study Drug Preparation and Dispensing 
LIB003 should be withdrawn directly from the vial into a suitable size syringe for injection. 
Solutions of LIB003 may foam; therefore, shaking and excessive agitation of vials should be 
avoided, or if performed, sufficient time allowed for the contents to settle prior to withdrawing the 
contents. Additionally, care must be taken to ensure the sterility of the prepared solution, as the 
drug product does not contain antimicrobial preservatives or bacteriostatic agents. To assure 
sterility of the prepared solutions, the vials are for single use only. 
Trained medical personnel will administer LIB003 to patients within the clinical facility. Site 
personnel should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as determined by LIB Therapeutics as outlined in the 
pharmacy manual. If concerns regarding the quality or appearance of the study drug arise, do not 
dispense the study drug and contact LIB Therapeutics immediately. 
Instructions for LIB003 preparation are documented in a separate pharmacy manual. 


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5.5.3 
Study Drug Administration 
Study drug (LIB003 300 mg) will be administered by SC injection on Week 0 and Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, and 48. Study drug will be administered under the supervision of the 
site personnel. 
Dosing instructions as well as materials required for storage, preparation, and administration are 
documented in the separate pharmacy manual. 
5.5.4 
Treatment Compliance 
Treatment compliance will be dependent on the preparation and administration of study drug by 
the site personnel. 
5.5.5 
Storage and Accountability  
Study drug will be stored in a secure, temperature-controlled location. Study drug will only be 
prepared and dispensed by an authorized pharmacist or trained nurse at the clinical site. Any 
deviation from storage conditions must be reported immediately to the Investigator and LIB 
Therapeutics Medical Monitor. 
Site personnel will maintain accurate records of receipt and condition of study drug upon receipt. 
In addition, accurate records of each dose dispensed to each patient will be kept on a study drug 
accountability log. 
Study drug accountability records will be maintained by the pharmacist or designated qualified 
and trained site staff in a secure location. Drug accountability records will be available for 
verification by LIB Therapeutics personnel. 
Storage and accountability information will be outlined in the separate pharmacy manual. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Concomitant therapy includes all medications and non-medication interventions used by a patient 
during the study.  
Medications include prescription drugs, over-the-counter (OTC) drugs, approved dietary and 
herbal supplements, and nutritional supplements. Examples of non-medication interventions 
include individual psychotherapy, cognitive behavioral therapy, smoking cessation therapy, and 
rehabilitative therapy. All concomitant medications and non-medication interventions should be 
reported to the Investigator and recorded in the concomitant medications eCRF. 
As a general rule, concomitant medications will be permitted unless specifically excluded and 
provided they are anticipated to remain stable throughout the study or do not impact LDL-C. The 
rationale for use of any exceptions is to be discussed between the Investigator and the Sponsor and 
clearly documented. The following medications are exceptions: 
 Medications used to treat adverse events may be prescribed preferably after consultation with 
the Medical Monitor, unless there is an immediate medical need to ensure the well-being of 
the patient that should not be delayed. All therapy and/or medication administered to manage 
adverse events should be recorded in the appropriate eCRF. 


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Any other investigational drug taken within 30 days or 5 half-lives (whichever is longer) prior to 
Week 0 is excluded.  
5.6.2 
Restricted Medications and/or Procedures 
Restricted medications include, but are not limited to, the following: 
 Use of, or treatment with, any prescription PCSK9 drugs. 
5.6.3 
Restrictions and Dietary Guidelines 
Patients should be encouraged to continue on appropriate and same diet and not participate in 
strenuous physical activity or exercise from 48 hours prior to all study visits to prevent 
concomitant increases in creatine kinase and throughout the duration of the study.  
Patients are requested to refrain from using alcohol for the 24-hour period prior to clinic visits due 
to potential impact on serum lipids. 
Fasting is defined as no food or caloric beverages for at least 10 hours. Patients will be permitted 
and encouraged to drink water ad libitum.  
5.6.4 
Documentation of Prior and Concomitant Medication Use 
The Investigator should record the use of all concomitant medications taken during the study, 
including statin, statin dose, and/or ezetimibe plus adherence, both prescribed and OTC, in the 
eCRF and the source document. This includes drugs used on a chronic and as-needed basis. 
Patients should be discouraged from starting any new medication, both prescribed and OTC, 
without consulting the Investigator, unless the new medication is required for an emergency or 
common ailments such as headache, upper respiratory infection, and constipation.  
 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any 
protocol-specific procedures are performed. The Investigator must ensure that patients, or, in those 
situations where consent cannot be given by patients, their legally acceptable representatives, are 
clearly and fully informed about the purpose, potential risks, and other critical issues regarding the 
clinical study in which they volunteer to participate. 
6.2 
Study Schedule  
A 5-day window is allowed for all clinic visits; unanticipated or unavoidable cancellations due 
to weather or public holidays may be scheduled within a 7-day window and will not be considered 
protocol deviations if appropriately documented.  
All blood and urinalysis samples should be collected while the patient is in a fasted state 
(10 hours; ad libitum water is allowed and encouraged) and prior to administration of LIB003.  
6.2.1 
Study Week 0 
The following procedures will be performed at Week 0: 
 Obtain informed consent; 
 Evaluate inclusion/exclusion criteria; 
 Update medical history; 
 Perform urine pregnancy test at clinical site (only women of childbearing potential); 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence since last visit of LIB003-002 study; 
 Perform physical examination; 
 Measure weight and calculate body mass index; 
 Perform 12-lead ECG; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample pre-dose for urinalysis; 
 Collect fasting blood samples pre-dose for the following: 
o Full safety chemistry and hematology panels and thyroid-stimulating hormone; 
o Expanded lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 


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 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 
6.2.2 
Study Week 4 
The following procedures will be performed at Week 4: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting blood samples pre-dose for the following: 
o Brief safety chemistry panel;  
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 
 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 
6.2.3 
Study Week 8 
The following procedures will be performed at Week 8: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting blood samples pre-dose for the following: 
o Brief safety chemistry panel;  
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 
 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 


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6.2.4 
Study Week 12 
The following procedures will be performed at Week 12: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight;  
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample pre-dose for urinalysis;  
 Collect fasting blood samples pre-dose for the following: 
o Full safety chemistry and hematology panels; 
o Expanded lipid panel; 
o PK;  
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 
 Assess injection site pre-dose and 15 minutes post-dose; and 
 Assess adverse events. 
6.2.5 
Study Weeks 16 and 20 
The following procedures will be performed at Weeks 16 and 20:  
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting blood samples pre-dose for the following: 
o Brief safety chemistry panel;  
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 


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 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 
6.2.6 
Study Week 24 
The following procedures will be performed at Week 24: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight;  
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample pre-dose for urinalysis;  
 Collect fasting blood samples pre-dose for the following: 
o Full safety chemistry and hematology panels; 
o Expanded lipid panel; 
o PK;  
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 
 Assess injection site pre-dose and 15 minutes post-dose; and 
 Assess adverse events. 
6.2.7 
Study Weeks 28 and 32 
The following procedures will be performed at Weeks 28 and 32: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting blood samples pre-dose for the following: 
o Brief safety chemistry panel;  
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 


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 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 
6.2.8 
Study Week 36  
The following procedures will be performed at Week 36: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample pre-dose for urinalysis; 
 Collect fasting blood samples pre-dose for the following: 
o Full safety chemistry and hematology panels; 
o Expanded lipid panel; 
o PK;  
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug;  
 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 
6.2.9 
Study Weeks 40, 44, and 48 
The following procedures will be performed at Weeks 40, 44, and 48: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting blood samples pre-dose for the following: 
o Brief safety chemistry panel;  
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Administer SC dose of study drug; 
 Assess injection site pre-dose and 15 minutes post-dose; and  
 Assess adverse events. 


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6.2.10 
Study Week 52/Early Termination  
The following procedures will be performed at Week 52/Early Termination: 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month; 
 Perform urine pregnancy test at clinical site (only women of childbearing potential); 
 Perform physical examination; 
 Obtain body weight; 
 Perform 12-lead ECG; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample for urinalysis; 
 Collect fasting blood samples for the following: 
o Full safety chemistry and hematology panels and thyroid-stimulating hormone; 
o Expanded lipid panel; 
o PK;  
o PCSK9; and 
o Immunogenicity; 
 Assess injection site; and  
 Assess adverse events. 
6.2.11 
Follow-up Visit for Positive Anti-Drug Antibodies/Neutralizing Antibodies 
Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
follow-up testing.  
Patients with positive NAbs at the final visit (Week 52/Early Termination) will be asked to return 
for follow-up testing every 3 months until either NAbs are no longer detectable or the patient has 
been followed for a period of at least 12 months. During the initial 3 months of follow-up patients 
may continue to receive LIB003 300mg at visits Q4W for a potential total exposure of 64 weeks 
to further characterize the NAb finding. 
The following procedures will be performed at the Follow-up Visit(s): 
 Record prior and concomitant medications, including statin, statin dose, and/or ezetimibe plus 
adherence for prior month;  
 Obtain body weight; 
 Record vital signs (blood pressure, heart rate, respiratory rate, and temperature); 
 Collect fasting urine sample for urinalysis; 
 Collect fasting blood samples for the following: 


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o Full safety chemistry and hematology panels; 
o Brief lipid panel; 
o PCSK9; and 
o Immunogenicity; 
 Assess injection site; and  
 Assess adverse events.  
In addition to the procedures outlined above, the following procedures are to be conducted only in 
those patients with positive NAbs at Week 52 who continue up to 12 additional weeks (3 additional 
doses Q4W). Following the first dose, if NAbs continue positive with possible attenuation of free 
PCSK9 and LDL-C, then up to 2 additional doses could be administered. 
 Urine pregnancy, physical examination and ECG will be assessed only at the last visit.   
 LIB003 will be administered at every Q4W visit.   


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7 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
All blood samples should be collected while the patient is in a fasted state (10 hours ad libitum 
water is allowed and encouraged) and prior to administration of LIB003. Instructions for specimen 
collection and storage are detailed in the laboratory manual.  
Detailed instructions for collection, processing, packaging, and shipping of all blood samples will 
be provided to the site in the laboratory manual.  
7.1 
Pharmacodynamic Endpoints  
The percent change from baseline in LIB003-002 study in LDL-C level at Weeks 36 and 52 (by 
Friedewald and Hopkins formula and ultracentrifugation/BQuant).  
The PD parameters include changes from both baseline in the Phase 2 (LIB003-002) study and 
Week 0 in this study in LDL-C (calculated and measured), unbound (free) PCSK9 concentrations, 
serum lipid parameters (TC, HDL-C, non-HDL-C, VLDL-C, TG, apo B, and Lp[a]). 
Baseline is defined as Day 1 of the Phase 2 dose-finding trial. 
 


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time following the first dose of study drug until study participation is 
complete. Patients should be instructed to report any adverse event that they experience to the 
Investigator. From the time following the first dose of study drug, the Investigator should make an 
assessment for adverse events at each visit and record the event on the appropriate adverse event 
eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF.  
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at the time of the first dose of study drug should not be 
reported as an adverse event unless the medical condition or signs or symptoms present at baseline 
changes in nature or seriousness at any time during the study. In this case, it should be reported as 
an adverse event. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at the time of the first dose of study drug and significantly 
worsen during the study should be reported as adverse events. The Investigator will exercise his 
or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Any abnormal test that is determined to be an error does not 
require reporting as an adverse event. Laboratory abnormalities or other abnormal clinical findings 
(eg, ECG abnormalities) should be reported as an adverse event if any of the following are 
applicable: 
 If an intervention is required as a result of the abnormality, 
 If action taken with the study drug is required as a result of the abnormality, or 
 Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 


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relationship between a medicinal product and an adverse event is at least a reasonable possibility 
(ie, the relationship cannot be ruled out). 
8.1.2 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of Severity: 
 Mild – An event that is easily tolerated and generally not interfering with normal daily 
activities. 
 Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
 Severe – An event that is incapacitating with inability to work or perform normal daily 
activities. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 No (unrelated, not related, no relation) – The time course between the administration of study 
drug and the occurrence or worsening of the adverse event rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
 Yes (related) – The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration – The event should occur after the study 
drug is given. The length of time from study drug exposure to event should be evaluated in the 
clinical context of the event. 
 Underlying, concomitant, intercurrent diseases – Each report should be evaluated in the context 
of the natural history and course of the disease being treated and any other disease the patient 
may have. 
 Concomitant drug – The other drugs the patient is taking or the treatment the patient receives 
should be examined to determine whether any of them might be recognized to cause the event 
in question. 
 Known response pattern for this class of study drug – Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect. 


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 Exposure to physical and/or mental stresses – The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event. 
 The pharmacology and PK of the study drug – The known pharmacologic properties 
(absorption, distribution, metabolism, and excretion) of the study drug should be considered. 
8.1.3 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent or elective treatment of a pre-existing 
condition that did not worsen from baseline. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (ie, no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; or 
 An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
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8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent until the end of study visit (Week 36/Early 
Termination) or the Follow-up Visit or 30 days after the last administration of study drug if the 
patient does not complete the study must be reported to Medpace Clinical Safety within 24 hours 
of the knowledge of the occurrence (this refers to any adverse event that meets any of the 
aforementioned serious criteria). All SAEs that the Investigator considers related to study drug 
occurring after the 30-day follow-up period must be reported to the Sponsor. 
Any SAE, regardless of expectedness or causality, should be reported by completing the adverse 
event eCRF form (when Serious = Yes) electronically in the Electronic Data Capture (EDC) 
system. When the form is completed, Medpace Clinical Safety will be notified electronically. If 
the event meets serious criteria and it is not possible to access the EDC system, e-mail or fax a 
completed paper back up-SAE form to the Medpace Clinical Safety contacts listed below within 
24 hours of awareness. When the EDC system becomes available, the SAE information must be 
entered into EDC within 24 hours of the system becoming available. Any supporting 
documentation (eg, patient discharge summary, hospital records, autopsy reports, etc) should be 
submitted to Medpace Clinical Safety via e-mail or fax. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or 513-579-9911, dial 3 
Fax: +1-866-336-5320 or 513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator must continue to follow the patient(s) until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.   
8.4 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during the study 
or within 30 days of discontinuing study drug, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion.  
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and Early Termination study procedures will be performed. 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety.  At the completion of the pregnancy, the Investigator will document the 


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outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the Food and Drug Administration 
(FDA) and in any case no later than 7 days after knowledge by the Sponsor of such a case, and 
that relevant follow-up information will subsequently be communicated within an additional 
8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required.  
8.6 
Clinical Laboratory Evaluations 
Clinical laboratory panels for lipids, hematology, serum chemistry, and urinalysis will be evaluated 
from samples collected after 10 hours of fasting (ad libitum water is allowed and encouraged) 
and prior to administration of LIB003 at the time points specified in Table 4 (Appendix A). 
A urine pregnancy test will be performed by the clinical site at Week 0 and the end of study visit 
(Week 52/Early Termination) only on women of childbearing potential. 
A complete list of laboratory analyses to be performed is presented in Appendix B. 
8.6.1 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs that meet the following criteria, must be reported as SAEs: 
1. ALT or AST levels >3  ULN; 
2. Total bilirubin levels >2  ULN, without initial findings of Gilbert’s syndrome or cholestasis 
(elevated serum alkaline phosphatase); and 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
8.7 
Immunogenicity  
Patients will be assessed for ADAs at designated study visits specified in Table 4 (Appendix A). 
Patients testing positive for LIB003 antibodies will be tested for NAbs and titer, and may be further 
characterized for isotype, binding site, affinity, and presence of immune complexes.  
Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
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In the case of positive NAbs at the final visit (Week 52/Early Termination) patients will be asked 
to return for follow-up testing every 3 months until either NAbs are no longer detectable or the 
patient has been followed for a period of at least 12 months. During the initial 3 months of follow-
up patients may continue to receive LIB003 300mg Q4W for a potential total exposure of 64 weeks 
to further characterize the NAb response. 
8.8 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed at 
designated study visits specified in Table 4 (Appendix A). Blood pressure and heart rate will be 
measured after the patient has been seated or supine for 5 minutes. 
8.9 
Electrocardiograms 
Twelve-lead (single) ECGs will be assessed at designated study visits specified in Table 4 
(Appendix A). Patients should be resting in the supine position for 10 minutes prior to each 
12-lead ECG.  
8.10 
Physical Examinations 
A full physical examination will be performed at the time points specified in Table 4 
(Appendix A). Injection site reactions will be monitored by examination of injection site at the 
time points specified in Table 4 (Appendix A). 


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9 
STATISTICS 
9.1 
Statistical Methods 
9.1.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population is defined as all patients who entered the open-label extension 
study. 
The Safety Population is defined as all patients who received at least 1 dose of study drug. 
9.1.2 
Analysis of Efficacy 
The primary objectives of this study are to assess the percent change from baseline, from the 
original LIB003-002 study, in LDL-C level at Week 52 (both calculated by Friedewald formula) 
with monthly (Q4W) dosing of various doses of LIB003 administered SC in patients with 
hypercholesterolemia on stable diet and oral LDL-C-lowering drug therapy. Results will be 
summarized descriptively.  
Baseline is defined as Day 1 of the Phase 2 dose-finding trial. 
9.1.3 
Pharmacodynamic Analysis  
Pharmacodynamic analysis will be performed based on the ITT Population. Total and unbound 
(free) serum PCSK9 concentrations at Weeks 24 and 36 and 52/Early Termination will be assessed. 
Pharmacodynamic endpoints will be summarized descriptively at each visit.  
9.1.4 
Immunogenicity Analyses 
Immunogenicity data will be listed. Anti-drug antibodieswill be measured at Weeks 0, 12, 24, 36 
and 52. Patients who develop positive ADAs will have additional measurements at visits after the 
last negative measurement  
9.1.5 
Pharmacokinetic Analysis 
Pharmacokinetic analysis will be performed based on the ITT Population. All PK parameters and 
PK concentrations will be summarized descriptively. 
9.1.6 
Analysis of Safety 
The safety endpoint data will be summarized for the Safety Population. Adverse events will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities. A general 
summary of the adverse events and SAEs will be summarized by overall number of adverse events, 
severity, and relationship to study drug. The number of adverse events leading to withdrawal and 
SAEs leading to death will also be summarized. The incidence of adverse events will be 
summarized by system organ class and preferred term and reviewed for potential significance and 
clinical importance. 
The safety laboratory data will be summarized by visit, along with changes from baseline visit of 
the extension study. The values that are below the lower limit or above the upper limit of the 
reference range will be flagged for safety but not efficacy parameters. Those values or changes in 


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values that are identified as being clinically significant will be flagged. Laboratory abnormalities 
of special interest, such as liver function tests, will be summarized. 
Vital signs and 12-lead ECGs will also be summarized by visit, along with the changes from 
baseline. Abnormal physical examination findings will be listed. 
Immunogenicity data will be listed. 
9.1.7 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively. 
9.1.8 
Interim Analysis 
No interim analysis is planned for this study.  
9.2 
Sample Size Determination 
The number of patients is not based on statistical consideration and there is no placebo or 
comparator group. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (CFR) 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
The latest version of the Medical Dictionary for Regulatory Activities for medical history and 
adverse events. The latest versions of the World Health Organization Drug Dictionary will be used 
for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of patients. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, informed consent 
form (ICF), advertisements (if applicable), written information given to the patients, safety 
updates, annual progress reports, and any revisions to these documents will be provided to the IRB 
by the Investigator. 
Federal regulations and ICH require that approval be obtained from an IRB prior to participation 
of patients in research studies. Prior to study onset, the protocol, any protocol amendments, ICFs, 
advertisements to be used for patient recruitment, and any other written information regarding this 
study to be provided to a patient or patient’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 


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and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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11.8 
Financial Disclosure 
The Investigator is required to provide financial disclosure information to the Sponsor to permit 
the Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, the Investigator must 
commit to promptly updating this information if any relevant changes occur during the study and 
for a period of 1 year after the completion of the study. 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigator by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 
12.2 
Address List 
12.2.1 
Sponsor 
LIB Therapeutics, LLC 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 978-770-8443 
12.2.2 
Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 513-579-9911 
Fax: 513-579-0444 
12.2.3 
Drug Safety 
Medpace Clinical Safety  
5375 Medpace Way 
Cincinnati, OH 45227 
Telephone: 800-730-5779, dial 3 or 513-579-9911, dial 3 
Fax: 866-336-5320 or 513-579-0444 
Email: medpace-safetynotification@medpace.com 
12.2.4 
Biological Specimens 
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, OH 45227 
Telephone: 800-749-1737 or 513-336-3270 
Fax: 513-336-3261  
 


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13 
REFERENCES 
 
1. 
Mathers C, Loncar Dejan. Projections of global mortality and burden of disease from 
2002 to 2030. PLoS Med. 2006;3:e442. 
2. 
Cholesterol Treatment Trialists’ Collaboration, Baigent C, Blackwell L, et al. Efficacy 
and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 
170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. 
3. 
Turner T, Raal F, Stein E. Evolving targets of therapy: proprotein convertase 
subtilisin/kexin 9 inhibition. In: Ballantyne C, eds. Clinical lipidology: a companion to 
Braunwald’s heart disease. 2nd ed. 2014;346-357. Elsevier. 
4. 
Sabatine M, Guigliano R, Keech A, et al. Evolocumab and clinical outcomes in patients 
with cardiovascular disease. N Engl J Med. 2017:1-10. 
5. 
Steg PG, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome 
During Treatment With Alirocumab - ODYSSEY OUTCOMES. Presented at American 
College of Cardiology Annual Scientific Session, Orlando, FL, March 10, 2018. 
http://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/09/08/02/odyssey-
outcomes 
6  
Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term safety and efficacy of 
achieving very low levels of low-density lipoprotein cholesterol: a prespecified analysis 
of the IMPROVE-IT Trial. JAMA Cardiol. 2017. [Epub ahead of print]. 
7. 
Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major 
cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab to 
control. Circulation. 2016;134:1931-1943. 
8  
Ridker P, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of 
bococizumab in high-risk patients. N Engl J Med. 2017:1-13. 
9. 
Cannon CP, Blazing MA, Giugliano, RP, et al. Ezetimibe added to statin therapy after 
acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. 
10.  
The Lipid Research Clinics Coronary Primary Prevention Trial Results I. Reduction in 
incidence of coronary heart disease. JAMA. 1984;251:351-364. 
11. 
Giugliano RP, Pedersen TR, Park JG et al Clinical efficacy and safety of achieving very 
low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a 
prespecified secondary analysis of the FOURIER trial. Lancet 2018;390:1962-1971. 
12  
Seidah N, Prat A. The biology and therapeutic targeting of the proprotein convertases. 
Nat Rev Drug Discov. 2012;11:367-383. 
13. 
Abifadel M, Varret M, Rabes J, et al. Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia. Nat Genet. 2003;34:154-156. 
14. 
Cohen J, Boerwinkle E, Mosley T Jr., et al. Sequence variations in PCSK9, low LDL, and 
protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272. 
15. 
Ference B, Robinson J, Brook R, et al. Variation in PCSK9 and HMGCR and risk of 
cardiovascular disease and diabetes. N Engl J Med. 2016;375:2144-2153. 
16. 
Schmidt A, Swerdlow D, Holmes M, et al. PCSK9 genetic variants and risk of type 2 
diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5:97-105. 
17.  
Rashid S, Curtis D, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to 
statins in mice lacking PCSK9. Proc Natl Acad Sci USA. 2005;102:5374-5379. 
 
 


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18. 
Pharmacodynamics of PCSK9 adnectins BMT-260570 and BMT-260571. Bristol-Myers 
Squibb Company; 2016. Document Control No. 930103488. 
19. 
Pharmacokinetics of a test article following administration to CD1 male mice with 
pharmacokinetic time points through 72 hours. LIB Therapeutics; 2017. Testing Facility 
Study Number: 20104650. 
20. 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Guideline S7A: Safety pharmacology studies for 
human pharmaceuticals. 2000. 
21. 
Scamuffa N, Calvo F, Chrétien M, Seidah NG, Khatib AM. Proprotein convertases: 
lessons from knockouts. Faseb J. 2006;1954-1963. 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
Table 4. 
Schedule of Procedures 
Study Week 
0  
4 
8 
12 
16 and 
20 
24 
28 and 
32 
36 
40, 44 
and 48 
52/ET 
Follow-up Visit 
[12] 
Study Procedure 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy/test [1] 
X 
 
 
 
 
 
 
 
 
X 
X[16] 
Prior/concomitant medications [2] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination [3] 
X 
 
 
 
 
 
 
 
 
X 
X[16] 
Body weight 
X 
[4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs [5] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full safety chemistry and hematology panel 
[6] 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Thyroid-stimulating hormone [7] 
X 
 
 
 
 
 
 
 
 
X 
 
Brief safety chemistry panel [8] 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
PK blood sample 
 
 
 
X 
 
X 
 
X 
 
X 
 
PCSK9 measurement [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded lipid/apo panel [10] 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Brief lipid panel only [11] 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Immunogenicity assessment [12] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [12] 
X 
12-lead ECG [13] 
X 
 
 
 
 
 
 
 
 
X 
X[16] 
Study drug administration [14] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X[16] 
Injection site assessment [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes on next page. 
 


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All blood and urinalysis samples should be collected while the patient is in a fasted state (10 hours, ad libitum water is allowed and encouraged) and prior to administration 
of study drug (LIB003). 
A 5-day window is allowed for all clinic visits; unanticipated or unavoidable cancellations due to weather or public holidays may be scheduled within a 7-day window and 
will not be considered protocol deviations if appropriately documented. 
1. 
A urine pregnancy test will be performed by the clinical site at Week 0 and Week 52/ET only on women of childbearing potential. 
2. 
To include current statin, statin dose, and/or ezetimibe plus adherence at each visit. 
3. 
Injection site reactions will be monitored by physical examination. 
4. 
Body mass index will be calculated from body weight and height. 
5. 
Vital signs will include blood pressure, heart rate, respiratory rate, and temperature. Blood pressure and heart rate will be measured after the patient has been seated or 
supine for 5 minutes.  
6. 
A full chemistry and hematology panel as listed in Appendix B. 
7. 
Thyroid-stimulating hormone will be tested at Weeks 0 and 52/ET only. 
8. 
A brief chemistry panel as listed in Appendix B. 
9. 
Samples will be collected at Weeks 0, 4, 8, 12, 16, 20, 28, 32, 40, 44, 48 and 52 for potential measurements of total and unbound (free) PCSK9. Total and unbound (free) 
PCSK9 will initially be measured at Weeks 12, 24, 36, and 52/ET and at additional visits where NAbs are detected. 
10. An expanded lipid panel as listed in Appendix B. 
11. A brief lipid panel as listed in Appendix B. 
12. Samples will be collected at all visits with ADAs measured initially at Weeks 0, 12, 24, 36 and 52. Patients who develop positive ADAs will have additional 
measurements at visits after the last negative measurement. Patients who test positive for binding non-NAbs and have clinical sequelae that are considered safety-related at 
the final visit (Week 52/ET) may be asked to return for additional monthly follow-up testing. If positive NAbs are detected at the final visit (Week 52/ET), patients will be 
asked to return for follow-up testing every 3 months until either NAbs are no longer detectable or the patient has been followed for a period of at least 12 months.  
13. Patients should be resting in the supine position for 10 minutes prior to each 12-lead ECG. 
14. Study drug (LIB003) will be administered at a SC dose of 300 mg. 
15. Injection site assessments will be performed pre-dose and 15 minutes post-dose. 
16. To be conducted only in those patients with positive NAbs at Week 52 who continue up to 12 additional weeks (3 additional doses Q4W). Following the first dose, if 
NAbs continue positive with possible attenuation of free PCSK9 and LDL-C, then up to 2 additional doses could be administered.  Urine pregnancy, physical examination 
and ECG will be assessed only at the last visit.  LIB003 will be administered at every Q4W visit.  
apo = apolipoprotein; ECG = electrocardiogram; ET = Early Termination; NAb = neutralizing antibody; PCSK9 = proprotein convertase subtilisin/kexin type 9; 
PK = pharmacokinetics; SC = subcutaneous. 
 
 


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Full Safety Chemistry Panel (19 tests, 1 calculation) 
Alanine transaminase 
Albumin 
Alkaline phosphatase 
Aspartate transaminase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Glucose 
Inorganic phosphorus 
Potassium 
Sodium 
Total bilirubin [1] 
Total protein 
Uric acid 
Total cholesterol 
Triglyceride 
1. 
If total bilirubin levels increase by >1.1 mg/dL, direct and indirect bilirubin will also be measured. Patients with mild 
unconjugated hyperbilirubinemia due to Gilbert’s syndrome are not excluded. 
 
Brief Safety Chemistry Panel (10 tests, 1 calculation) 
Alanine transaminase 
Alkaline phosphatase 
Aspartate transaminase 
Albumin 
Creatinine 
Creatine kinase 
Estimated glomerular filtration rate 
Glucose 
Total bilirubin [1] 
Total cholesterol 
Triglyceride 
 
1. 
If total bilirubin levels increase by >1.1 mg/dL, direct and indirect bilirubin will also be measured. 
 
Brief Fasting Lipid Panel 
High-density lipoprotein cholesterol (HDL-C) 
Low-density lipoprotein cholesterol (LDL-C) [1] 
Non–HDL-C (Total cholesterol minus HDL-C) 
1. 
LDL-C will be calculated by Friedewald and Hopkins formulae. 
 
Expanded Fasting Lipid Panel 
Brief lipid panel (above) 
LDL-C/very low-density lipoprotein cholesterol by ultracentrifugation (BQuant) 
Apolipoprotein B and lipoprotein (a)  
 
Endocrinology 
Urine pregnancy test for women of childbearing potential – performed at clinical site 
Thyroid-stimulating hormone (TSH) [1] 
1. 
If TSH < lower limit of normal or >1.5  upper limit of normal, free triiodothyronine will be performed. 
 
 
 


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Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Microscopy is performed only as needed based on positive dipstick test results. 
 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
Open-Label Extension, Phase 2b Study to Evaluate the 
Longer Term Efficacy and Safety of LIB003 in Patients on 
Stable Lipid-Lowering Therapy Requiring Additional LDL-
C Reduction 
 
Protocol Number: 
LIB003-010 
Protocol Version/Date: 
2.0, 10 September 2019 
Investigational Product: 
LIB003 
 
 
Sponsor: 
LIB Therapeutics, LLC 
5375 Medpace Way 
Cincinnati, OH 45227 
 
 
SAP Version/Date: 
1.0, 20 January, 2020 
 
 
 
 
 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of LIB Therapeutics, LLC, hereinafter LIB Therapeutics, except to the extent that 
disclosure would be required by law and for the purpose of evaluating and/or conducting a 
clinical study for LIB Therapeutics. You are allowed to disclose the contents of this document 
only to your Institutional Review Board and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to LIB Therapeutics and that it may not be further 
disclosed to third parties. 
 


LIB Therapeutics, LLC 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol LIB003-010 
 
Version 1.0, 20 January 2020 
Page 2 of 17 
 
SIGNATURE PAGE 
Protocol Title: 
Open-Label Extension, Phase 2b Study to Evaluate the 
Longer Term Efficacy and Safety of LIB003 in Patients on 
Stable Lipid-Lowering Therapy Requiring Additional LDL-C 
Reduction 
 
Protocol Number: 
LIB003-010 
SAP Version/Date: 
1.0, 20 January 2020 
 
Prepared By: 
 
  
 
  
Ran Fu, PhD 
Biostatistician, Biostatistics 
Medpace, Inc. 
  
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
  
Signature 
 Date 
 
  
 
 
  
 
  
Juan Liang, PhD 
Associate Director, Biostatistics 
Medpace, Inc. 
  
 
  
 
 
 
 
  
Evan A. Stein, MD PhD 
Chief Medical Officer 
LIB Therapeutics, LLC 
  
 
  
January 21, 2020


LIB Therapeutics, LLC 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol LIB003-010 
 
Version 1.0, 20 January 2020 
Page 3 of 17 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
20 January 2020 
Original signed version 
 
 


LIB Therapeutics, LLC 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol LIB003-010 
 
Version 1.0, 20 January 2020 
Page 4 of 17 
 
TABLE OF CONTENTS 
 
1 
Introduction ........................................................................................................................................... 7 
2 
Study Overview .................................................................................................................................... 7 
2.1 
Study Objectives ........................................................................................................................... 7 
2.1.1 
Primary Objectives ................................................................................................................ 7 
2.1.2 
Secondary Objectives ............................................................................................................ 7 
2.2 
Study Design ................................................................................................................................. 8 
2.2.1 
Overview ............................................................................................................................... 8 
2.2.2 
Randomization and Blinding .............................................................................................. 11 
2.2.3 
Sample Size Determination ................................................................................................. 11 
2.3 
Study Endpoints .......................................................................................................................... 11 
2.3.1 
Efficacy Endpoints .............................................................................................................. 11 
2.3.2 
Pharmacodynamic Endpoints .............................................................................................. 11 
2.3.3 
Pharmacokinetic Endpoints ................................................................................................. 11 
2.3.4 
Safety Endpoints ................................................................................................................. 11 
3 
Statistical Methodology ...................................................................................................................... 12 
3.1 
General Considerations ............................................................................................................... 12 
3.1.1 
Definition of Baseline ......................................................................................................... 12 
3.1.2 
Summary Statistics .............................................................................................................. 12 
3.1.3 
Handling of Dropouts and Missing Data ............................................................................ 13 
3.2 
Analysis Populations ................................................................................................................... 13 
3.2.1 
Intent-to-Treat (ITT) Population ......................................................................................... 13 
3.2.2 
Safety Population ................................................................................................................ 13 
3.3 
Subject Data and Study Conduct ................................................................................................ 13 
3.3.1 
Subject Disposition ............................................................................................................. 13 
3.3.2 
Protocol Deviations ............................................................................................................. 13 
3.3.3 
Demographic and Baseline Characteristics ......................................................................... 13 
3.3.4 
Medical History................................................................................................................... 14 
3.3.5 
Concomitant Medications ................................................................................................... 14 
3.3.6 
Study Compliance ............................................................................................................... 14 
3.4 
Efficacy Assessment ................................................................................................................... 14 
3.5 
Pharmacodynamic Assessment ................................................................................................... 14 
3.6 
Pharmacokinetic (PK) Assessment ............................................................................................. 15 
3.7 
Safety Assessment ...................................................................................................................... 15 
3.7.1 
Adverse Events (AEs) ......................................................................................................... 15 
3.7.2 
Clinical Laboratory Tests .................................................................................................... 15 
3.7.3 
Immunogenicity .................................................................................................................. 16 


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3.7.4 
Vital Signs ........................................................................................................................... 16 
3.7.5 
ECG Parameters .................................................................................................................. 16 
3.7.6 
Physical Examinations ........................................................................................................ 16 
3.7.7 
Injection Site Reaction Analysis ......................................................................................... 17 
3.8 
Additional Analysis .................................................................................................................... 17 
3.9 
Interim Analysis .......................................................................................................................... 17 
4 
Changes from Protocol-Specified Statistical Analyses ....................................................................... 17 
5 
Programming Specifications ............................................................................................................... 17 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine transaminase 
apo  
Apolipoprotein 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
CK 
Creatine kinase 
CSR 
Clinical study report 
ECG 
Electrocardiogram  
HDL-C 
High-density lipoprotein cholesterol 
ITT 
Intent-to-Treat 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein (a) 
LLN 
Lower limit of normal 
NAb 
Neutralizing antibody 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
Q4W 
Every 4 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event  
TG 
Triglycerides 
ULN 
Upper limit of normal  
VLDL-C 
Very low-density lipoprotein cholesterol 
 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number LIB003-
010. The SAP will be finalized prior to database lock.  Any deviations from the SAP after database 
lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objectives 
The primary objectives of this study are to assess the longer term safety, tolerability, and low-
density lipoprotein cholesterol (LDL-C) lowering efficacy after 52 weeks of additional treatment 
with LIB003 at a subcutaneous (SC) dose of 300 mg every 4 weeks (Q4W). Study patients will be 
those with hypercholesterolemia on stable diet and oral LDL-C-lowering drug therapy who have 
completed the Phase 2 dose finding study.  
2.1.2 Secondary Objectives 
The secondary objectives of this study are the following: 
• To assess the longer term tolerability and safety of LIB003 300 mg Q4W in patients treated 
for an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study;   
• To assess the stability of LDL-C-lowering with LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 
• To assess the pharmacodynamic (PD) effect on serum unbound (free) proprotein convertase 
subtilisin/kexin type 9 (PCSK9) concentrations of LIB003 300 mg Q4W in patients treated for 
an additional 52 weeks who were previously treated with LIB003 at 150 mg, 300 mg, and 
350 mg or placebo during the Phase 2 double-blind study; 
• To assess the effects on serum lipids, including total cholesterol (TC), high-density lipoprotein 
cholesterol (HDL-C), non–HDL-C, very low-density lipoprotein cholesterol (VLDL-C), and 
triglycerides (TG) of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who 
were previously treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the 
Phase 2 double-blind study; 
• To assess the effects on apolipoprotein (apo) B and lipoprotein (a) (Lp[a]) serum 
concentrations of LIB003 300 mg Q4W in patients treated for an additional 52 weeks who 
were previously treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo during the 
Phase 2 double-blind study;   
• To assess the pharmacokinetics of LIB003 and PCSK9 following multiple doses of LIB003 
300 mg SC Q4W; and   
• To assess the frequency of anti-drug (anti-LIB003) antibodies (ADAs) (immunogenicity) of 
LIB003 300 mg Q4W in patients treated for an additional 52 weeks who were previously 


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Version 1.0, 20 January 2020 
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treated with LIB003 at 150 mg, 300 mg, and 350 mg or placebo, including those with 
detectable ADAs during the Phase 2 double-blind study. 
2.2 Study Design 
2.2.1 Overview 
This is an open-label, Phase 2b extension study of 52 weeks duration. Approximately 35 men and 
women aged ≥18 years who have completed the Phase 2 (LIB003-002) study and fulfill the 
inclusion and exclusion criteria will be enrolled at up to 4 sites in the United States. All patients 
will receive LIB003 at a dose of 300 mg administered SC Q4W as shown in Figure 1. 
Figure 1. LIB003 Phase 2b Open-Label Extension Study 
 
 
M = month; Q4W = every 4 weeks; SC = subcutaneously; W = week. 
Patients who have completed the LIB003-002 study and do not meet any exclusion criteria and 
have completed the informed consent for this extension study will receive LIB003 at a dose of 300 
mg Q4W by SC injection at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. In addition 
to a basic lipid profile, LDL-C will be measured by preparative ultracentrifugation at specified 
visits during the study. All lipid measurements on Week 0/Month 0 onward will be available to 
the Investigator, patients, and all site and Sponsor personnel involved in the study. Final safety 
assessments will include adverse events and the results from physical examinations, 
electrocardiograms (ECGs), clinical laboratory tests (hematology, serum chemistry, and 
urinalysis), and immunogenicity testing. Injection site reactions will be assessed at each visit.  
Patients testing positive for ADAs will be tested for neutralizing antibodies (NAbs) and titer, and 
may be further characterized for isotype, binding site, affinity, and presence of immune complexes.  
Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
follow-up testing.  
In the case of positive NAbs at the final visit (Week 52/Early Termination), patients will be asked 
to return for follow-up testing every 3 months until either NAbs are no longer detectable or the 
patient has been followed for a period of at least 12 months.  
Table 1 presents the schedule of procedures of the study.


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   Statistical Analysis Plan 
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          Version 1.0, 20 January 2020 
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Table 1. Schedule of Procedures 
Study Week 
0  
4 
8 
12 
16 and 
20 
24 
28 and 
32 
36 
40, 44 
and 48 
52/ET 
Follow-up Visit 
[12] 
Study Procedure 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy/test [1] 
X 
 
 
 
 
 
 
 
 
X 
 
Prior/concomitant medications [2] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination [3] 
X 
 
 
 
 
 
 
 
 
X 
 
Body weight 
X 
[4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs [5] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full safety chemistry and hematology panel 
[6] 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Thyroid-stimulating hormone [7] 
X 
 
 
 
 
 
 
 
 
X 
 
Brief safety chemistry panel [8] 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
PK blood sample 
 
 
 
X 
 
X 
 
X 
 
X 
 
PCSK9 measurement [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded lipid/apo panel [10] 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Brief lipid panel only [11] 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Immunogenicity assessment [12] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [12] 
X 
12-lead ECG [13] 
X 
 
 
 
 
 
 
 
 
X 
 
Study drug administration [14] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection site assessment [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes on next page. 
 


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All blood and urinalysis samples should be collected while the patient is in a fasted state (≥10 hours, ad libitum water is allowed and encouraged) and prior to administration 
of study drug (LIB003). 
A ±5-day window is allowed for all clinic visits; unanticipated or unavoidable cancellations due to weather or public holidays may be scheduled within a 7-day window and 
will not be considered protocol deviations if appropriately documented. 
1. 
A urine pregnancy test will be performed by the clinical site at Week 0 and Week 52/ET only on women of childbearing potential. 
2. 
To include current statin, statin dose, and/or ezetimibe plus adherence at each visit. 
3. 
Injection site reactions will be monitored by physical examination. 
4. 
Body mass index will be calculated from body weight and height. 
5. 
Vital signs will include blood pressure, heart rate, respiratory rate, and temperature. Blood pressure and heart rate will be measured after the patient has been seated or 
supine for ≥5 minutes.  
6. 
A full chemistry and hematology panel as listed in Protocol Appendix B. 
7. 
Thyroid-stimulating hormone will be tested at Weeks 0 and 52/ET only. 
8. 
A brief chemistry panel as listed in Protocol Appendix B. 
9. 
Samples will be collected at Weeks 0, 4, 8, 12, 16, 20, 28, 32, 40, 44, 48 and 52 for potential measurements of total and unbound (free) PCSK9. Total and unbound (free) 
PCSK9 will initially be measured at Weeks 12, 24, 36, and 52/ET and at additional visits where NAbs are detected. 
10. An expanded lipid panel as listed in Protocol Appendix B. 
11. A brief lipid panel as listed in Protocol Appendix B. 
12. Samples will be collected at all visits with ADAs measured initially at Weeks 0, 12, 24, 36 and 52. Patients who develop positive ADAs will have additional 
measurements at visits after the last negative measurement. Patients who test positive for binding non-NAbs and have clinical sequelae that are considered safety-related at 
the final visit (Week 52/ET) may be asked to return for additional monthly follow-up testing. If positive NAbs are detected at the final visit (Week 52/ET), patients will be 
asked to return for follow-up testing every 3 months until either NAbs are no longer detectable or the patient has been followed for a period of at least 12 months.  
13. Patients should be resting in the supine position for ≥10 minutes prior to each 12-lead ECG. 
14. Study drug (LIB003) will be administered at a SC dose of 300 mg. 
15. Injection site assessments will be performed pre-dose and 15 minutes post-dose. 
apo = apolipoprotein; ECG = electrocardiogram; ET = Early Termination; NAb = neutralizing antibody; PCSK9 = proprotein convertase subtilisin/kexin type 9; 
PK = pharmacokinetics; SC = subcutaneous. 
 
 


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2.2.2 Randomization and Blinding 
This is an open-label extension study, therefore, no randomization or blinding is necessary. 
2.2.3 Sample Size Determination 
The number of patients is not based on statistical consideration and there is no placebo or 
comparator group. 
2.3 Study Endpoints 
2.3.1 Efficacy Endpoints 
Two baselines are considered for this study: main study baseline and extension study baseline. 
Main study baseline is defined as Day 1 of the original Phase 2 dose-finding trial, LIB003-002 
study. Extension study baseline is defined as Week 0 of this open-label extension study. 
The primary efficacy endpoint is the percent change from main study baseline,  in LDL-C level at 
Week 52 (both calculated by Friedewald formula) of this extension study. 
The percent change from main study baseline in LIB003-002 study in LDL-C level at Weeks 24, 
36 and 52 (by Friedewald and Hopkins formula and ultracentrifugation/BQuant). 
The changes from both baselines in the Phase 2 (LIB003-002) study and Week 0 in this study in 
LDL-C (calculated and measured), serum lipid parameters (TC, HDL-C, non-HDL-C, VLDL-C, 
TG, apo B, and Lp[a]). 
2.3.2 Pharmacodynamic Endpoints 
Total and unbound (free) serum PCSK9 concentrations at Week 24 and 36 and 52/Early 
Termination will be assessed. 
2.3.3 Pharmacokinetic Endpoints 
All blood samples should be collected while the patient is in a fasted state (≥10 hours ad libitum 
water is allowed and encouraged) and prior to administration of LIB003. 
2.3.4 Safety Endpoints 
Safety assessments will include adverse events and the results of vital sign measurements, ECGs, 
physical examinations, clinical laboratory tests, and immunogenicity evaluations. Injection site 
reactions will be monitored by physical examination. The incidence of observed adverse events 
will be tabulated and reviewed for potential significance and clinical importance.  
2.3.4.1 Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. AEs will be monitored throughout the study and will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA, v21.0). The severity of all AEs should be graded 
using the following categories: mild, moderate and severe. 


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2.3.4.2 Safety Laboratory Evaluations 
Clinical laboratory panels for hematology, serum chemistry, and urinalysis will be evaluated from 
samples collected after ≥10 hours of fasting (ad libitum water is allowed and encouraged) and prior 
to administration of LIB003 at the time points specified in Table 1. 
A urine pregnancy test will be performed by the clinical site at Week 0 and the end of study visit 
(Week 52/Early Termination) only on women of childbearing potential. 
2.3.4.3 Immunogenicity 
Patients will be assessed for ADAs at designated study visits specified in Table 1. Patients testing 
positive for LIB003 antibodies will be tested for NAbs and titer, and may be further characterized 
for isotype, binding site, affinity, and presence of immune complexes.  
Patients who test positive for binding, non-NAbs and have clinical sequelae at Week 52/Early 
Termination that are considered safety related may be asked to return for additional monthly 
follow-up testing.  
In the case of positive NAbs at the final visit (Week 52/Early Termination) patients will be asked 
to return for follow-up testing every 3 months until either NAbs are no longer detectable or the 
patient has been followed for a period of at least 12 months. 
2.3.4.4 Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed at 
designated study visits specified in Table 1. Blood pressure and heart rate will be measured after 
the patient has been seated or supine for ≥5 minutes. 
2.3.4.5 Electrocardiograms 
Twelve-lead (single) ECGs will be assessed at designated study visits specified in Table 1. Patients 
should be resting in the supine position for ≥10 minutes prior to each 12-lead ECG.  
2.3.4.6 Physical Examinations 
A full physical examination will be performed at the time points specified in Table 1. Injection 
site reactions will be monitored by examination of injection site at the time points specified in 
Table 1. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Definition of Baseline  
Two baselines are considered: main study baseline and extension study baseline. Main study 
baseline is defined as Day 1 of the original Phase 2 dose-finding trial, LIB003-002 study. 
Extension study baseline is defined as Week 0 of this open-label extension study. 
3.1.2 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects.  The 
denominator used for the percentage calculation will be clearly defined.  Continuous data will 


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generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, and maximum. 
3.1.3 Handling of Dropouts and Missing Data 
No imputation will be performed for the missing data. Only observed values will be used in data 
analyses and presentations. 
3.2 Analysis Populations 
3.2.1 Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population is defined as all patients who entered the open-label extension 
study and take at least one dose of study medication. 
3.2.2 Safety Population 
The Safety Population is defined as all patients who received at least 1 dose of study drug during 
the open-label extension study. This population will be used to summarize all safety data. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
Subject disposition will be summarized for all enrolled subjects in total. The following subject 
disposition categories will be included in the summary: 
• Subjects who received study drug, 
• Subjects who completed the study, and 
• Subjects who did not complete the study. 
For subjects who did not complete the study, a summary will be provided by reason for 
discontinuation. In addition, the total number of subjects for each defined analysis population will 
be tabulated in total. 
Subject disposition data will be presented in a data listing. 
3.3.2 Protocol Deviations 
Protocol deviations as defined in the Medpace Protocol Deviation Plan will be summarized for the 
ITT Population. The number and percentage of subjects meeting any criteria will be summarized 
for each criterion and overall in total. Subjects deviating from a criterion more than once will be 
counted once for the corresponding criterion. Any subjects who have more than one protocol 
deviation will be counted once in the overall summary.  
A data listing will be provided by subject. 
3.3.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the Safety 
Population in total. Categorical demographic variables (e.g., gender, race, and ethnicity) will be 
summarized using frequency counts and percentages.  Continuous variables (e.g., age at informed 
consent, baseline weight, height, body mass index [BMI], LDL-C level calculated by Friedewald, 


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Hopkins formula and preparative ultracentrifugation/BQuant), TC, HDL-C, non-HDL-C, VLDL-
C, TG, apo B and Lp(a) of this open-label extension study will be summarized using descriptive 
statistics (n, mean, standard deviation, minimum, median, and maximum). 
3.3.4 Medical History 
Medical history will be collected at the screening visit. The reported medical history terms will be 
coded using MedDRA (Version 21.0). Medical history will be summarized for the Safety 
Population in total by MedDRA system organ class and preferred term. 
Listings of all reported medical history will be provided. 
3.3.5 Concomitant Medications 
Concomitant medications are defined as medications taken any time after the first dose of study 
drug of the open-label extension study. Concomitant medications will be coded using the World 
Health Organization Drug Dictionary B3, Sept 2018 version. Concomitant medications will be 
summarized with the number and percentages by Anatomical Therapeutic Chemical (ATC) class 
and preferred term in total for the Safety Population.  
Listings will be presented including the ATC, preferred term and verbatim text. The listings will 
be sorted by subject, chronological start date, therapeutic class, preferred term and verbatim text. 
3.3.6 Study Compliance 
The number of SC injections for each subject will be summarized with counts and percentages in 
total.  
Listings of all study drug administration will be provided.  
3.4 Efficacy Assessment 
The efficacy endpoints analysis will be performed based on the ITT Population. 
Main study baseline is defined as Day 1 of the Phase 2 dose-finding trial. Baseline values of the 
Phase 2 (LIB003-002) study (main study), as well as the actual change and percent change from 
baseline in LDL-C level (by Friedewald and Hopkins formula and ultracentrifugation/BQuant), 
TC, HDL-C, non-HDL-C, TG, apo B, and Lp(a) will be summarized with descriptive statistics at 
each visit in total.  
Extension study baseline is defined as Week 0 of this open-label extension study. Baseline values 
of Week 0 in this study (extension study), as well as the actual change and percent change from 
baseline in LDL-C level (by Friedewald and Hopkins formula and ultracentrifugation/BQuant), 
TC, HDL-C, non-HDL-C, TG, apo B, and Lp(a) will be summarized with descriptive statistics at 
each visit in total. 
Waterfall plots of percent change from baseline to Weeks 24, 36, and 52 in LDL-C, TC, HDL-C, 
non-HDL-C, TG, apo B, and Lp(a) will be provided. 
3.5 Pharmacodynamic Assessment 
The pharmacodynamic endpoints analysis will be performed based on the ITT Population. 


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Total and unbound (free) serum PCSK9 concentrations at Weeks 24 and 36 and 52 will be 
summarized descriptively. Change and percent change from both baselines in the Phase 2 
(LIB003-002) study and Week 0 in this open-label extension study will be summarized with 
descriptive statistics at each visit in total. 
3.6 Pharmacokinetic (PK) Assessment 
The PK concentrations of LIB003 will be summarized descriptively for the ITT Population. 
3.7 Safety Assessment 
Safety data will be summarized in total based on the Safety Population. 
3.7.1 Adverse Events (AEs) 
Treatment-emergent adverse events (TEAEs) are defined as AEs that start after the first dose of 
study drug for this open-label extension study.  
An overview of AEs will be provided including counts and percentages of subjects with the 
following: 
• Any TEAEs (overall and by maximum severity) 
• Any study drug related TEAEs (overall and by maximum severity) 
• Any treatment-emergent serious AEs (TE-SAEs) 
• Any study drug related TE-SAEs 
• Any TEAEs leading to discontinuation of study 
• Any drug related TEAEs leading to discontinuation of study 
• Any TEAEs leading to death 
The number and percentage of subjects who experienced at least one TEAE will be presented by 
system organ class and preferred term. Drug-related TEAEs and study discontinuations due to 
TEAEs will be summarized in the same manner.  
Summaries will be provided by maximum severity for the number and percentage of subjects with 
TEAEs and for subjects with drug-related TEAEs by system organ class and preferred term. 
Listings will be presented specifically for SAEs, TEAEs leading to discontinuation of study, and 
TEAEs leading to death. All adverse events will be listed. 
3.7.2 Clinical Laboratory Tests 
Summary statistics will be provided for safety laboratory tests at baseline of this open-label 
extension study and each scheduled post-baseline visit for hematology, serum chemistry, and 
urinalysis assessments in total for the Safety Population. 
Counts and percentages of subjects with any post-baseline observation that is below the lower limit 
of normal (<LLN) or above the upper limit of normal (>ULN) will be summarized for each 
hematology and serum chemistry parameter in total. 


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Shifts from baseline to worst post-baseline value will be presented for specified lab tests (Alanine 
aminotransferase [ALT], Aspartate aminotransferase [AST], creatine kinase [CK], total bilirubin) 
in total. Results will be categorized based on the criteria in the table below. 
Parameter  
Categories 
ALT  
Normal  
>1xULN 
to 
≤2xULN 
>2xULN 
to 
≤3xULN  
>3xULN 
AST 
Normal  
>1xULN 
to 
≤2xULN 
>2xULN 
to 
≤3xULN  
>3xULN 
CK 
 
Normal  
>1xULN 
to 
≤5xULN 
 
>5xULN 
to 
≤10xULN  
>10xULN 
Total Bilirubin  
Normal  
>1xULN 
to 
≤1.5xULN  
>1.5xULN 
to 
≤2xULN 
>2xULN 
The number and percentage of subjects who meet ALT or AST >3xULN and total bilirubin 
>2xULN at any time after the first dose of the study drug will be identified as potential Hy’s Law 
cases and summarized, and these subjects’ ALT, AST and total bilirubin data will be listed. 
3.7.3 Immunogenicity 
The number and percentage of subjects with positive ADA results will be counted for each time 
point and overall in total, and the immunogenicity data will be listed in total for the Safety 
Population. 
3.7.4 Vital Signs 
Vital signs parameters (weight, body mass index, blood pressure, heart rate, respiratory rate, and 
temperature) will be summarized using descriptive statistics for the Safety Population by visit in 
total. The changes from baseline of this open-label extension study will also be presented. 
A listing of all vital signs will be provided by subject. 
3.7.5 ECG Parameters 
ECG parameters (heart rate, PR, QRS, QT, QTcF, and RR) will be summarized using descriptive 
statistics at baseline and Week 52/ET for the Safety Population in total. The changes from baseline 
of this open-label extension study will also be presented. The overall interpretation will be 
summarized by counts and percentages in total.  
All ECG measurements and the overall interpretation will be listed by subject. 
3.7.6 Physical Examinations 
Each pre-specified assessment and overall assessment of physical examinations will be 
summarized by counts and percentages in total. 
Physical examination findings will be listed. 


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3.7.7 Injection Site Reaction Analysis 
The number and percentage of subjects with injection site reactions will be summarized by reaction 
type (pain, tenderness, erythema, swelling, induration, bruising, and itching) by visit and timepoint 
(pre-dose and 15 minute post-dose) in total. Erythema diameter, swelling diameter, and induration 
diameter will be summarized with descriptive statistics by visit and timepoint in total. 
Injection site assessment data will also be listed. 
3.8 Additional Analysis 
A sensitivity analysis at Weeks 24, 36 and 52 will be performed on only those subjects who are 
within the <+3 day visit window (< Day 31) of their last dose. 
Additional summary may be considered as needed by combining main study efficacy and/or safety 
of LIB003 treatment groups with this extension study. 
3.9 Interim Analysis 
No interim analysis is planned for this study.  
Two stage analysis of the efficacy endpoints will be carried out at Weeks 24 and 36 when all the 
subjects complete Week 24 and 36 visits. 
4 CHANGES 
FROM 
PROTOCOL-SPECIFIED 
STATISTICAL 
ANALYSES 
No changes have been issued or planned. 
5 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be presented 
in subject data listings which will be sorted by subject and visit date as applicable.  Detailed 
Programming Specifications will be provided in a separate document.