AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
Phase: PHASE1
Conditions: Homozygous Familial Hypercholesterolemia (HoFH)
Sponsor: REGENXBIO Inc.

 
 
 
Version Date: 20161027                                        CONFIDENTIAL                                                                Page 1 of 1 
 
STUDY PROTOCOL COVER PAGE 
 
Official Title of the study/Protocol Title: AAV8-mediated Low Density Lipoprotein Receptor 
(LDLR) Gene Replacement in Subjects with Homozygous Familial Hypercholesterolemia 
(HoFH) 
 
Protocol Number: FHGT002 
 
NCT Number: NCT02651675 
 
Document Date:  14 December 2018; version 10 
 

Protocol Number: FHGT002 
Version 10 – 14 December 2018 
 
Page 1 of 85 
CONFIDENTIAL 
Proprietary and Confidential and thus exempt from disclosure pursuant to 5 USC §552(b), esp. 5 USC §552 (b)(4). 
 
  
AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene 
Replacement in Subjects with Homozygous Familial 
Hypercholesterolemia (HoFH) 
Protocol Number: FHGT002 
Protocol Version: Version 10 
Protocol Date: 14 December 2018 
 Investigational Product: 
 
 Indication: 
Homozygous Familial Hypercholesterolemia (HoFH) 
 IND/EudraCT 
Number/Health 
Canada #:  
IND 16710/ 2016-001446-25/ 199002 
  
 
 Regulatory Sponsor: 
 
REGENXBIO Inc. 
9600 Blackwell Road, Suite 210 
Rockville, MD, USA 20850 
  
 
 Sponsor’s Responsible Medical 
Monitor 
 
 
  
 
  
 
This study is to be performed in compliance with the protocol, International Conference on 
Harmonization E6: Good Clinical Practice: Consolidated Guideline (ICH E6) and 
applicable regulatory requirements. 
Confidentiality Statement: This document contains confidential business and commercial information and trade 
secrets of REGENXBIO Inc. (REGENXBIO) and is being submitted solely in support of applicable regulatory 
approvals. No other use or disclosure of this document and of the information contained herein is permitted without 
the prior written consent of REGENXBIO. In accordance with 5 USC §552(b), esp. 5 USC §552(b)(4), 
REGENXBIO must be notified in writing of any requests for access to the information in this Protocol to enable 
REGENXBIO to make submissions about any potential disclosure. 

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TABLE OF CONTENTS 
SPONSOR SIGNATURES ............................................................................................................. 2 
LIST OF ABBREVIATIONS ......................................................................................................... 8 
STUDY SUMMARY .................................................................................................................... 11 
1. 
INTRODUCTION ...................................................................................................... 15 
1.1. 
Background ................................................................................................................ 15 
1.1.1. 
Genetics of Homozygous Familial Hypercholesterolemia ........................................ 15 
1.1.2. 
Liver Directed Gene Therapy for HoFH .................................................................... 17 
1.2. 
Investigational Agent ................................................................................................. 17 
1.3. 
Preclinical Data .......................................................................................................... 18 
1.3.1. 
Effect of pre-existing humoral immunity on AAV-mediated gene transfer to 
liver ............................................................................................................................ 18 
1.3.2. 
The role of T cells to AAV capsids ............................................................................ 19 
1.3.3. 
Safety and Pharmacology findings in animal models of HoFH ................................. 19 
1.4. 
Rationale for Dose Choice and Escalation ................................................................. 23 
1.5. 
Clinical Data to Date .................................................................................................. 24 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 28 
2.1. 
Primary Objectives ..................................................................................................... 28 
2.2. 
Secondary Objectives ................................................................................................. 28 
2.3. 
Exploratory Objectives ............................................................................................... 28 
2.4. 
Safety Endpoints ........................................................................................................ 29 
2.5. 
Efficacy Endpoints ..................................................................................................... 29 
2.6. 
Exploratory Study Endpoints ..................................................................................... 30 
3. 
STUDY DESIGN ....................................................................................................... 31 
3.1. 
General Design ........................................................................................................... 31 
4. 
SUBJECT SELECTION AND WITHDRAWAL ..................................................... 34 
4.1. 
Inclusion Criteria ........................................................................................................ 34 
4.2. 
Exclusion Criteria ....................................................................................................... 34 
4.3. 
Subject Recruitment and Screening ........................................................................... 36 
4.3.1. 
Screening Protocol ..................................................................................................... 36 
4.4. 
Informed Consent ....................................................................................................... 36 
4.5. 
Early Withdrawal of Subjects .................................................................................... 38 

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4.6. 
Withdrawal of Informed Consent for Data and Biological Samples ......................... 38 
4.7. 
Confirmation of Eligibility ......................................................................................... 39 
5. 
STUDY PROCEDURES ........................................................................................... 39 
5.1. 
Clinical Laboratory Testing ....................................................................................... 39 
5.2. 
Safety Assessments .................................................................................................... 39 
5.2.1. 
Adverse event driven safety evaluation ..................................................................... 40 
5.3. 
Pharmacodynamic/ Efficacy Assessments ................................................................. 41 
5.3.1. 
Efficacy Assessment in Subjects Receiving Apheresis ............................................. 41 
5.3.2. 
Efficacy Assessment in Subjects Receiving Prophylaxis Steroid Treatment ............ 42 
5.4. 
Assessment of Pharmacokinetics and Immune Response to AAV8 .......................... 42 
5.5. 
Future Use Samples .................................................................................................... 42 
5.6. 
Xanthoma Assessment ............................................................................................... 43 
5.7. 
Specific Study Procedures by Visit ............................................................................ 43 
5.7.1. 
Screening Protocol ..................................................................................................... 43 
5.7.2. 
Visit 1: Consent, Screening and Washout (Weeks -26 to Day -1) ............................. 43 
5.7.3. 
Visit 1a: Laboratory Retesting ................................................................................... 44 
5.7.4. 
Visit 2 ......................................................................................................................... 45 
5.7.5. 
Visit 3: Vector Administration (Day -1, Day 1 and Day 2) ....................................... 45 
5.7.6. 
Visit 4 ......................................................................................................................... 46 
5.7.7. 
Visit 6 ......................................................................................................................... 46 
5.7.8. 
Visit 7, 9, 13: Safety Visits ........................................................................................ 46 
5.7.9. 
Visit 8, 10, 11, 12, 14, 15, 16, 17: Laboratory assessments ....................................... 46 
5.7.10. 
Visit 17.1: 14 Weeks Post Vector Administration ..................................................... 47 
5.7.11. 
Visits 17.2, 17.4, 17.5: Bi-Weekly Lab Assessments and Telephone Contact .......... 47 
5.7.12. 
Visit 17.3 .................................................................................................................... 47 
5.7.13. 
Visits 18,19, 20 .......................................................................................................... 48 
5.7.14. 
Visit 18.1 .................................................................................................................... 48 
5.7.15. 
Visit 21: 78 weeks (± 2 weeks) Post Vector Administration ..................................... 49 
5.7.16. 
Visit 22: 104 weeks (± 2 weeks) Post Vector Administration / Early 
Termination Visit ....................................................................................................... 49 
6. 
STUDY DRUG .......................................................................................................... 49 
6.1. 
Description ................................................................................................................. 49 

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6.2. 
Treatment Regimen .................................................................................................... 49 
6.2.1. 
Method for Assigning Subjects to Treatment Groups ................................................ 49 
6.3. 
Preparation of Vector for Injection ............................................................................ 50 
6.4. 
Prior and Concomitant Therapy ................................................................................. 50 
6.5. 
Corticosteroid Prophylaxis ......................................................................................... 50 
6.6. 
Packaging ................................................................................................................... 51 
6.7. 
Receipt of Drug Supplies ........................................................................................... 51 
6.8. 
Storage ........................................................................................................................ 51 
6.9. 
Return or Destruction of Study Drug ......................................................................... 52 
6.10. 
Reporting Product Complaints ................................................................................... 52 
7. 
STATISTICAL PLAN ............................................................................................... 52 
7.1. 
General ....................................................................................................................... 52 
7.2. 
Sample Size Determination ........................................................................................ 52 
7.3. 
Statistical Methods ..................................................................................................... 53 
7.3.1. 
Disposition ................................................................................................................. 53 
7.3.2. 
Demographics and Baseline Characteristics .............................................................. 53 
7.3.3. 
Efficacy Analyses ....................................................................................................... 53 
7.3.4. 
Safety Analysis ........................................................................................................... 53 
7.3.4.1. 
Adverse Events ........................................................................................................... 53 
7.3.4.2. 
Clinical Laboratory Tests ........................................................................................... 53 
7.3.4.3. 
Vital Signs .................................................................................................................. 53 
7.4. 
Subject Population(s) for Analysis ............................................................................. 54 
7.5. 
Interim Analysis ......................................................................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9. 
SAFETY AND ADVERSE EVENTS ....................................................................... 57 
9.1. 
Definitions .................................................................................................................. 57 
9.1.1. 
Adverse Event ............................................................................................................ 57 
9.1.2. 
Adverse (Drug) Reaction ........................................................................................... 57 
9.1.3. 
Unexpected Adverse Drug Reaction .......................................................................... 57 
9.1.4. 
Serious Adverse Event ............................................................................................... 57 
9.1.5. 
Adverse Event Reporting Period ................................................................................ 58 
9.1.6. 
Preexisting Condition ................................................................................................. 58 
9.1.7. 
General Physical Examination Findings .................................................................... 58 
9.1.8. 
Post-study Adverse Event .......................................................................................... 58 
9.1.9. 
Pregnancy ................................................................................................................... 58 
9.1.10. 
Abnormal Laboratory Values ..................................................................................... 59 
9.1.11. 
Hospitalization, Prolonged Hospitalization or Surgery ............................................. 60 
9.1.12. 
Severity of Adverse Events ........................................................................................ 60 
9.1.13. 
Relationship to Study Drug ........................................................................................ 60 
9.1.14. 
Recording of Adverse Events ..................................................................................... 61 
9.1.15. 
Adverse Events of Special Interest ............................................................................ 61 
9.2. 
Reporting of Serious Adverse Events – Procedures for Investigators ....................... 62 
9.2.1. 
Investigator Reporting ................................................................................................ 63 
9.2.2. 
Regulatory Sponsor Reporting ................................................................................... 63 
9.3. 
Safety Review and Stopping Rules ............................................................................ 63 
9.3.1. 
Medical Monitoring ................................................................................................... 64 
9.3.2. 
Independent Data and Safety Monitoring Board........................................................ 64 
9.3.3. 
Internal Safety Committee (ISC) ............................................................................... 65 
10. 
RISK / BENEFIT ASSESSMENT ............................................................................. 65 
10.1. 
Risks ........................................................................................................................... 65 
10.1.1. 
Risks Associated with Gene Transfer ........................................................................ 65 
10.1.2. 
Risks Associated with Withdrawal of Lipid-lowering Treatment ............................. 67 
10.1.3. 
Risks of Corticosteroids ............................................................................................. 67 
10.1.4. 
Phlebotomy Risks ....................................................................................................... 68 
10.2. 
Potential Study Benefits ............................................................................................. 68 
10.3. 
Benefit:Risk Assessment ............................................................................................ 68 

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10.4. 
Alternatives to Participation ....................................................................................... 69 
11. 
DATA HANDLING AND RECORD KEEPING ...................................................... 69 
11.1. 
Confidentiality ............................................................................................................ 69 
11.2. 
Source Document and Case Report Forms ................................................................ 69 
11.3. 
Data Quality Assurance .............................................................................................. 69 
11.4. 
Records Retention ...................................................................................................... 70 
12. 
STUDY MONITORING, AUDITING, AND INSPECTING ................................... 70 
12.1. 
Study Monitoring Plan ............................................................................................... 70 
12.2. 
Auditing and Inspecting ............................................................................................. 70 
13. 
ETHICAL CONSIDERATIONS ............................................................................... 71 
14. 
STUDY FINANCES .................................................................................................. 71 
14.1. 
Funding Source .......................................................................................................... 71 
14.2. 
Conflict of Interest ..................................................................................................... 71 
15. 
PUBLICATION PLAN .............................................................................................. 71 
16. 
APPENDICES ............................................................................................................ 73 
 
 
 
 
17. 
REFERENCES ........................................................................................................... 80 
18. 
SIGNATURE PAGE .................................................................................................. 85 
 
LIST OF TABLES 
Table 1: 
Safety Review Trigger Event and Actions ................................................................. 12 
Table 2: 
AAV8-based gene therapies listed on ClinicalTrials.gov .......................................... 24 
Table 3: 
Safety Review Trigger Event and Actions ................................................................. 33 
Table 4: 
Prednisone Dose by Study Week ............................................................................... 51 
Table 5: 
Safety Review Trigger Events and Actions ............................................................... 64 
 
LIST OF FIGURES 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
AAV 
Adenoassociated virus 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
ApoB 
Apolipoprotein B 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common terminology criteria for adverse events 
CTL 
Cytotoxic T lymphocyte 
CVD 
Cardiovascular disease 
DKO 
Double knock-out or LDLR-/- Apobec-/- 
DLT 
Dose-limiting toxicity 
DMEM 
Dulbecco’s minimal essential medium 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of study 
FDA 
Food and Drug Administration 
FCR 
Fractional catabolic rate 
FH 
Familial hypercholesterolemia 
FSR 
Fractional synthetic rate 
FWA 
Federalwide Assurance 
GC 
Genome copy 
GCP 
Good Clinical Practices 
GGT 
Gamma Glutamyl Transferase 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practices 
HDL-C 
High density lipoprotein cholesterol 
hLDLR 
Human low density lipoprotein receptor 
HoFH 
Homozygous familial hypercholesterolemia 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 

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IRB 
Institutional Review Board 
ISC 
Internal Safety Committee 
ITR  
Inverted terminal repeat 
IV 
Intravenous 
Kg 
Kilogram 
L 
Liter 
LAHB 
Double knock-out mouse with human APOB or LDRL-/- Apobec-/- 
hAPOB 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LDL-C 
Low density lipoprotein cholesterol 
LDLR 
Low density lipoprotein receptor 
LFTs 
Liver function tests 
Lp(a) 
Lipoprotein a 
LPL 
Lipoprotein lipase 
MED 
Minimal effective dose  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
mLDLR 
Murine low density lipoprotein receptor 
MPS VII 
Mucopolysaccharidosis type VII 
mRNA 
Messenger ribonucleic acid 
MRS 
Magnetic resonance spectroscopy 
MTD 
Maximum tolerated dose 
Nab 
Neutralizing antibody 
NCI 
National Cancer Institute 
NHLBI 
National Heart, Lung and Blood Institute 
NHP 
Non-human primates 
NOAEL 
No observed adverse event level 
Non-HDL-C 
Non-HDL cholesterol  
PBMC 
Peripheral blood mononuclear cell 
PBS 
Phosphate buffered saline 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
Penn 
University of Pennsylvania 
PHI 
Personal health information 
POC 
Proof-of-concept 
polyA 
Polyadenylation  
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
qPCR 
Quantitative PCR 
rAAV 
Recombinant AAV 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 

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SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDV 
Source data verification 
SDS PAGE 
Sodium dodecyl sulphate polyacrilamide electrophoresis 
SOC 
System Organ Class 
SRT 
Safety review trigger 
TBG 
Thyroxine-binding globulin 
TC 
Total cholesterol 
TG 
Triglycerides 
TSH 
Thyroid stimulating hormone 
UADR 
Unexpected adverse drug reaction 
ULN 
Upper limit of normal 
VLDL 
Very low density lipoprotein 
VLDL-C 
Very low density lipoprotein cholesterol 
Vg 
Vector genomes 
WBC 
White blood cell 
WHHL 
Watanabe heritable hyperlipidemic 
 
 
 

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STUDY SUMMARY  
 
Title 
AAV8-mediated Low Density Lipoprotein Receptor Gene Replacement in 
Subjects with Homozygous Familial Hypercholesterolemia 
Short Title 
AAV8.TBG.hLDLR for FH 
Protocol Number 
FHGT002 
Phase 
Phase I/IIa   
Study Design  
This is a 104-week Phase I/IIa, multicenter, open-label, single arm, dose 
escalation study of AAV8.TBG.hLDLR in adults with a clinical 
presentation consistent with Homozygous Familial Hypercholesterolemia 
(HoFH) and carrying 2 mutations in the gene encoding for the LDL 
receptor (LDLR). Safety will be the primary focus, with a secondary focus 
on clinical response to AAV8.TBG.hLDLR. The primary safety endpoint 
is at Week 24. Approximately 12 subjects will be enrolled into one of 3 
dose cohorts, 2.5×1012 GC/kg (Dose 1),7.5×1012 GC/kg (Dose 2), or 
2.5×1013 GC/kg (Dose 3), and will receive a single dose of 
AAV8.TBG.hLDLR administered by IV infusion into a peripheral vein (or 
into an existing arteriovenous (AV) fistula). Following completion of the 
primary study period at Week 24, subjects will continue to be assessed (for 
safety and efficacy) for up to 104 weeks following treatment with 
AAV8.TBG.hLDLR. At the end of the study, all subjects will be invited to 
participate in a long-term follow-up study.  
In this trial, two groups will assess data accumulated from the trial, an 
external Data Safety Monitoring Board (DSMB) and the Sponsor’s 
Internal Safety Committee (ISC). The primary role of the independent 
DSMB is to assess safety at periodic intervals and to provide 
recommendations on safety and dose escalation. The primary role of the 
ISC is to monitor safety on an ongoing basis. 
The initial Dose 1 cohort of AAV8.TBG.hLDLR will receive 2.5×1012 
GC/kg. Dosing of subjects will be staggered by at least 4 weeks A formal 
review of all safety data will be performed by the DSMB after the 3rd subject 
is dosed and completes the 4 weeks post-dosing visit, primarily to determine 
if dose escalation can occur. However, the DSMB could recommend to 
expand the cohort, lower the dose, or stop the trial. 
If the recommendation is to dose escalate, the Dose 2 cohort will be 
initiated at a dose of 7.5×1012 GC/kg (Dose 2). Dosing of subjects will be 
staggered by at least 4 weeks. A formal review of all safety data will be 
performed by the DSMB after the 3rd subject is dosed and completes the 4 
weeks post-dosing visit, primarily to determine if dose escalation can 

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Any Grade 3 AE  
considered unrelated to treatment (by 
the Investigator) 
An ISC will review all available safety 
data. If safety concerns arise while a 
cohort is being enrolled, the committee 
may ask the DSMB to review and make a 
recommendation on whether to keep 
enrolling subjects in that cohort. 
Any report by the Investigator of 
technical issues with the product 
administration that may warrant 
modifications to the procedure 
All subjects, including those that were deemed eligible based on their 
participation in a companion screening protocol, will be invited to undergo 
a screening visit (Visit 1) to confirm eligibility for this clinical trial. 
Subjects that agree to participate will be withdrawn from selected lipid-
lowering drugs for at least 4 weeks prior to vector administration. An 
additional Visit 1a may be scheduled as a blood draw either at the study 
site or by a home healthcare nurse to perform a lipid panel up to 2 weeks 
prior to the dosing visit (Visit 3). 
All subjects will be admitted at the research inpatient unit the day of or the 
day before vector administration and eligibility and willingness to 
participate in the trial will be appropriately re-confirmed. Following 
AAV8.TBG.hLDLR administration, safety assessments and laboratory 
draws will occur for 24 hours post dosing, after which the subject will be 
discharged from the research unit. Subject will return to the Research Unit 
for a safety visit 48 hours post-dosing.  Blood will be drawn weekly for 
safety testing from Week 2 to Week 12. Based on the experience 
accumulated with subjects dosed under earlier versions of this protocol, 
prophylactic corticosteroids will be administered to any future dosed  
subjects starting 1 day prior to dosing through the end of Week 13. 
After week 14, subjects will undergo study site visits at Weeks 18, 24, 36, 
and 52 for the active study and at Weeks 78 and 104 during the follow up 
period. Additional laboratory assessments will occur at least biweekly 
between Week 14 and Week 24. Both liver function tests (LFTs) and 
LDL-C collected locally either at local lab or by health care nurse will be 
recorded in the Clinical Database.  Long-term follow-up will be conducted 
via a separate protocol. All visits and follow-up will be indexed to the date 
of the vector infusion. 
  
  
Study Duration 
The study duration is 104 weeks, made up of an active study period 
through Week 52 and a follow-up period after Week 52 visit through 
Week 104 after which the subject will be invited to enter a long-term 
follow up study, as a separate study.   

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Study Center(s) 
Approximately 13 sites in the US, Canada and Europe 
Objectives 
The primary objective will be to determine the safety of 
AAV8.TBG.hLDLR administration in this patient population. The key 
secondary objective is to assess the efficacy of LDL-C reduction achieved 
with AAV8.TBG.hLDLR administration. 
 Number of      
Subjects 
Approximately12 subjects. 
Diagnosis and 
Main Inclusion 
Criteria 
The subject population will be male and female subjects with the 
following characteristics: 
1. Age: 18 years or older; 
Carry 2 molecularly defined LDLR mutations and clinical presentation 
consistent with HoFH; 
No cardiovascular event or cardiovascular intervention within 12 weeks of 
enrollment; 
A baseline serum AAV8 neutralizing antibody titer ≤ 1:10. 
Study Product, 
Dose, Route, 
Regimen 
 
 
 
 
 
 
 
 
 
 
 
Reference 
Therapy 
None 
Statistical 
Methodology 
All data will be presented in subject data listings. Categorical variables 
will be summarized using frequencies and percentages, and continuous 
variables will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum). Graphical displays 
will be presented as appropriate.  
Safety and pharmacodynamic (PD) endpoints will be reported by dose 
group and may also be reported for all dose groups combined. 
No formal calculation was performed to determine sample size. 
 
 
 

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1. 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
In November 2018, the University of Pennsylvania notified all Regulatory Authorities that 
sponsorship of this study had been transferred to REGENXBIO Inc. This transfer was completed 
on November 12 2018, with updates of study documentation, including this protocol, reflecting 
REGENXBIO as the study sponsor. 
1.1. 
Background 
1.1.1. 
Genetics of Homozygous Familial Hypercholesterolemia  
Familial hypercholesterolemia (FH) is a life-threatening disorder caused by mutations in genes 
that affect LDL receptor (LDLR) function (Goldstein et al. 2001). It is estimated that >90% of 
patients with molecularly confirmed FH carry mutations in the gene encoding for the LDLR 
(LDLR, MIM 606945). The remainder of the patients carry mutations on three additional genes: 
APOB (MIM 107730) encoding apolipoprotein (apo) B, PCSK9 (MIM 607786) encoding 
proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLRAP1 (MIM 695747) encoding 
LDLR adapter protein 1. The latter is the only gene mutation that is associated with a recessive 
trait. Homozygosis is usually conferred by the presence of mutations in the 2 alleles of the same 
gene; however, cases have been reported of patients with double heterozygosis (two heterozygous 
mutations, one each in two different genes). Based on prevalence rates of between 1 in 500 and 1 
in 200 for heterozygous FH (Nordestgaard et al. 2013, Sjouke et al. 2014), it is estimated that 
between 7,000 and 43,000 people worldwide have homozygous FH (HoFH). 
Characterization of mutant LDLR alleles has revealed a variety of mutations including deletions, 
insertions, missense mutations, and nonsense mutations (Goldstein et al. 2001). More than 1700 
LDLR mutations have been reported. This genotypic heterogeneity leads to variable consequences 
in the biochemical function of the receptor which are classified in four general groups. Class 1 
mutations are associated with no detectable protein and are often caused by gene deletions. Class 
2 mutations lead to abnormalities in intracellular processing of the protein. Class 3 mutations 
specifically affect binding of the ligand LDL, and Class 4 mutations encode receptor proteins that 
do not cluster in coated pits. Based on residual LDLR activity assessed using patients’ cultured 
fibroblasts, mutations are also classified as receptor negative (<2% residual activity of the LDLR) 
or receptor-defective (2 to 25% residual activity). Patients that are receptor-defective have, on 
average, lower LDL-C levels and a less malignant cardiovascular course compared to those that 
are receptor negative. This was evident among a cohort of patients that was followed over several 
years at the University of Pennsylvania (Kolansky et al. 2008), in which receptor-defective 
patients had lower cholesterol levels, a delayed appearance of xanthomas and clinically evident 
cardiovascular disease, and a better response to standard lipid-lowering therapy.  
As a consequence of impaired LDL receptor function, untreated total plasma cholesterol levels in 
patients with HoFH are typically greater than 500 mg/dl, resulting in premature and aggressive 
atherosclerosis often leading to cardiovascular disease (CVD) before age 20 and death before age 

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30 (Cuchel et al. 2014, Goldstein et al. 2001). Early initiation of aggressive treatment for these 
patients is therefore essential (Kolansky et al. 2008). Unfortunately, the available options are 
severely limited. Statins are considered the first line for pharmacological treatment. Even at 
maximal doses, only a 10 to 25% reduction in LDL-C plasma levels is observed in most patients 
(Marais et al. 2008, Raal et al. 2000). The addition of the cholesterol absorption inhibitor, 
ezetimibe, to statin therapy may result in a further 10 to 20% reduction in LDL-C levels (Gagne 
et al. 2002).  Use of other cholesterol lowering medications, including bile acid sequestrants, 
niacin, fibrates, and probucol have been used successfully in the pre-statin era and can be 
considered to achieve further LDL-C reduction in HoFH; however, their use is limited by 
tolerability and drug availability. This approach has been shown to reduce CVD and all-cause 
mortality (Raal et al. 2011). Despite the implementation of an aggressive multi-drug therapy 
approach, the LDL-C levels of HoFH patients remain elevated and their mean life expectancy 
remains approximately 32 years (Raal et al. 2011). Several non-pharmacological options have 
also been tested over the years. Surgical interventions, such as portacaval shunting (Bilheimer 
1989, Forman et al. 1982) and ileal bypass (Deckelbaum et al. 1977), have resulted only in partial 
and transient LDL-C lowering and are now considered nonviable approaches. Orthotopic liver 
transplantation has been demonstrated to substantially reduce LDL-C levels in HoFH patients 
(Ibrahim et al. 2012, Kucukkartallar et al. 2011), but disadvantages and risks limit the use of this 
approach, including the high risk of post-transplantation surgical complications and mortality, the 
scarcity of donors, and the need for life-long treatment with immunosuppressive therapy 
(Malatack 2011, Starzl et al. 1984). The current standard of care in HoFH includes lipoprotein 
apheresis, a physical method of purging the plasma of LDL-C which can transiently reduce LDL-
C by more than 50% (Thompson 2003, Vella et al. 2001). Rapid re-accumulation of LDL-C in 
plasma after treatment sessions (Eder and Rader. 1996) necessitates weekly or biweekly 
apheresis. Although this procedure may delay the onset of atherosclerosis (Thompson et al. 1995, 
Vella et al. 2001), it is laborious, expensive, and not readily available.  Furthermore, although it is 
a procedure that is generally well tolerated, the fact that it requires frequent repetition and 
intravenous access can be challenging for many HoFH patients. 
Recently, three new drugs have been approved by the FDA as add-on therapy specifically for 
HoFH. Two of them, lomitapide and mipomersen, inhibit the assembly and secretion of 
apoB-containing lipoproteins, although they do so via different molecular mechanisms (Cuchel et 
al. 2007, Raal et al. 2010). This approach results in a significant reduction of LDL-C that reaches 
an average of ~50% with lomitapide (Cuchel et al. 2013) and ~25% with mipomersen (Raal et al. 
2010). However, their use is associated with an array of adverse events that may affect tolerance 
and long-term adherence and include liver fat accumulation, the long term consequences of which 
have not yet been fully clarified.  
The third is part of a novel class of lipid-lowering drugs, monoclonal antibodies against PCSK9 
that have been shown to be effective in lowering LDL-C levels with an apparently favorable 
safety profile in patients with heterozygous FH (Raal et al. 2012, Raal et al. 2015, Stein et al. 
2012). Treatment of HoFH with the PCSK9 inhibitor evolocumab 420 mg every 4 weeks for 12 
weeks has been shown to provide about a 30% reduction in LDL-C as compared with placebo 
(Raal et al. 2015). Efficacy of PCSK9 inhibitors is, however, dependent on the residual LDLR 
activity, with no effect in patients with no residual LDLR activity (Raal et al. 2015, Stein et al. 
2013). Although the addition of PCSK9 inhibitors may become standard of care for FH and may 

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provide an additional further reduction to lower cholesterol in a subset of HoFH patients, it will 
not dramatically impact the clinical management of this condition. Therefore, there is a 
tremendous unmet medical need for new medical therapies for this life-threatening orphan 
disease.  
1.1.2. 
Liver Directed Gene Therapy for HoFH 
The correction of the hypercholesterolemia observed in patients with HoFH who underwent liver 
transplant (Ibrahim et al. 2012, Kucukkartallar et al. 2011) underscores the importance of the 
liver in regulating levels of circulating lipid and lipoproteins. Thus, a gene therapy approach that 
focuses on delivering the correct transgene to the liver may represent a viable approach. A 
considerable number of proof-of principle studies using gene transfer of the LDLR have been 
performed in animal models of HoFH. The administration of a first-generation adenovirus 
encoding the human LDLR transiently reduced LDL cholesterol levels in chow-fed LDLR 
deficient mice (Ishibashi et al. 1993). Injection of a recombinant first-generation adenovirus 
encoding the LDLR into Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model 
homozygous for a natural mutation in the LDLR, transiently reduced LDL cholesterol levels 
(Kozarsky et al. 1994). A helper-dependent adenovirus expressing LDLR was shown to provide 
long-term reduction in cholesterol in LDLR KO mice (Nomura et al. 2004). An AAV8-based 
vector encoding LDLR also provided sustained correction of hypercholesterolemia (Lebherz et al. 
2004). A pilot human study was previously conducted at the University of Pennsylvania to 
evaluate the effect of ex vivo gene therapy in patients with HoFH (Grossman et al. 1995). In that 
study, five patients underwent hepatic resection, and isolated hepatocytes were infected ex vivo 
with a recombinant retrovirus encoding the human LDLR gene. The genetically modified 
autologous hepatocytes were re-infused into the patients via a portal catheter placed at the first 
procedure. Three of the five patients had a transient 6 to 25% reduction in their LDL cholesterol 
levels. Liver biopsies performed 4 months after treatment revealed LDLR transgene expression 
by in situ hybridization in all five patients. Based on preclinical studies conducted more recently 
using an AAV8-based vector, an investigational agent has been developed to be tested in a Phase 
I/IIa study in patients with HoFH.  
1.2. 
Investigational Agent 
The investigational agent is an AAV8 vector expressing the transgene human low-density 
lipoprotein receptor, (hLDLR) under control of a liver-specific promoter (thyroxine-binding 
globulin, TBG) and is referred to in this document as AAV8.TBG.hLDLR. 
 
 
 
 
 
 
 
 
 
 
 

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1.3. 
Preclinical Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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. 

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1.4. 
Rationale for Dose Choice and Escalation  
This is a Phase I/IIa dose escalation study of AAV8.TBG.hLDLR in patients with HoFH. The 
study will characterize the safety and tolerability of this vector and identify doses for further 
clinical investigation. The rationale for implementing a Phase I/IIa dose-escalating clinical study 
is based on a robust biological rationale established through proof-of-concept animal studies and 
non-clinical pharmacology/toxicology data. As this is a first-in-human study using 
AAV8.TBG.hLDLR, a staggered dose escalation is utilized to evaluate safety prior to treating a 
subsequent subject.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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benefit:risk of dose escalation while minimizing the number of subjects exposed to 
subtherapeutic doses.  
Data has also been reported from a Phase I/II clinical trial assessing the safety and optimal dosing 
level of an investigational factor IX rAAV8-based gene therapy treatment for hemophilia B 
(NCT01687608) (Shire). Based on public information released by the sponsor, a total of seven 
patients in three sequentially-ascending dosing cohorts [2×1011 vg/kg (n=2), 1×1012 vg/kg (n=3) 
and 3×1012 vg/kg (n=2)] have been treated in the trial with evidence of a dose-related response. 
Two patients in the high dose cohort are reported by the sponsor to have experienced an immune 
response which led to decreased factor IX expression, with one patient resuming regular factor IX 
infusions (due to inadequate production of transgene product).  
Additional subjects have been dosed with AAV8 based gene therapy trials for hemophilia B 
(NCT01620801), chronic HCV infection (NCT01899092), late onset OTC (NCT02991144) and 
age-related macular degeneration (NCT03066258). Accumulating data from ongoing trials 
continue to support a favorable benefit:risk for AAV based gene therapy for these conditions. 
Notably, the doses proposed for this study are within the range of the intravenous doses being 
investigated in other ongoing AAV8-based gene therapy trials shown in Table 2. These include 
X-linked myotubular myopathy (up to 5×1014 GC/kg), Crigler-Najjar Syndrome (up to 1.5×1013 
GC/kg) and late onset OTC deficiency (up to 1×1013 GC/kg). Data on the first 3 subjects enrolled 
into the myotubular myopathy gene therapy trial, all treated at an IV dose of 1×1014 GC/kg, has 
been made publicly available (Audentes. 2018). Although data is limited for this trial, reported 
possibly/probably treatment-related AEs include asymptomatic elevations in liver enzymes (n=1), 
elevated troponin (n=1) and exacerbation of pre-existing elevated bilirubin (n=1); all of these 
responded to treatment, including to corticosteroids. For the first 6 subjects enrolled into the OTC 
deficiency trial (2×1012 GC/kg (n=3) and 6×1012 GC/kg (n=3)), the only treatment-related adverse 
events reported in Cohort 1 were mild, clinically asymptomatic elevations in alanine 
aminotransferase (ALT) in two subjects (Ultragenyx 2018). The only treatment-related adverse 
events in Cohort 2 were the mild, clinically asymptomatic elevations in ALT in the first patient in 
Cohort 2. 
As in this study, these trials also employ a dose escalation design (including half-log increases) in 
which the safety of each cohort is carefully reviewed before escalating to the next higher dose 
cohort. As in other trials, asymptomatic increases in transaminases have been observed in this 
trial in the first 3 subjects in Cohort 2 (7.5×1012 GC/kg) approximately 4-6 weeks post dosing. 
These transaminase elevations have responded to oral prednisone and resulted in normalization of 
transaminase levels. It is anticipated that the prophylactic administration of corticosteroids during 
the first 13 weeks of the trial may attenuate or possibly eliminate transaminase increases post 
dosing. 
To summarize, the AAV8 vector containing an identical capsid as that used in the 
AAV8.TBG.hLDLR program are being or have been investigated as a gene therapy vector in 
clinical trials across a range of conditions and organ systems. Accumulating data has shown that 
recombinant, replication deficient AAV8 as a gene therapy vector is safe for investigational use 
in patients, as well as results in promising preliminary evidence of clinical benefit. A T-cell 
response to the capsid or the transgene product with subsequent hepatocyte injury may explain 
the asymptomatic elevations in transaminases, although the relationship between this and loss of 

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transgene product expression remains unclear. It is possible that immunosuppression with 
corticosteroids may mitigate this effect (Gernoux et al. 2017). 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objectives  
 To determine the safety of AAV8.TBG.hLDLR administration in patients with 
homozygous familial hypercholesterolemia (HoFH) as assessed by the number of 
reported adverse events, changes noted on physical examinations, and clinical 
laboratory parameters assessed up to 24 weeks post vector administration.  
2.2. 
Secondary Objectives  
 To assess the LDL-C reduction achieved with AAV8.TBG.hLDLR administration as 
defined by percent change in LDL-C at 12 weeks (Cohort 1 only) or 18 weeks after 
vector administration (or 4 weeks after steroid termination or prior to changing lipid 
lowering therapies) compared to baseline.  
 To assess changes in other lipid parameters at 12 weeks (Cohort 1 only) or 18 weeks 
after vector administration (or 4 weeks after steroid termination or prior to changing 
lipid lowering therapies) compared to baseline values, specifically percent change in 
total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), HDL-C, 
fasting triglycerides (TG), very low density lipoprotein cholesterol (VLDL-C), 
lipoprotein(a) (Lp(a)), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). 
 To determine the safety of AAV8.TBG.hLDLR administration as assessed by the 
number of reported adverse events, changes noted on physical examinations and clinical 
laboratory parameters assessed at multiple time points up to 104 weeks post vector 
administration.  
 To assess vector shedding in plasma and urine. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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2.4. 
Safety Endpoints 
Safety assessment is the primary objective of this Phase I/IIa study. Safety assessments will be 
performed before and at multiple time points after vector administration up to the 104 week post 
dosing visit, as detailed in Table 16.1 (see Section 16.1). The primary study period will be at 
Week 24. Safety assessment will include reported adverse events, changes noted on physical 
examinations, and laboratory parameters.  
Laboratory Assessments 
Biochemical Profile: sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, 
lactate dehydrogenase (LDH), creatinine, creatine phosphokinase, calcium, total protein, albumin, 
AST, ALT, alkaline phosphatase, total bilirubin. Gamma glutamyl transferase (GGT) will be 
measured at screening and only as clinically indicated through the study.   
Complete Blood Count (CBC): white blood cell (WBC) count, hemoglobin, hematocrit, platelet 
count, red cell distribution width, mean corpuscular volume, mean corpuscular hemoglobin, and 
mean corpuscular hemoglobin concentration. 
HbA1c 
Coagulation: prothrombin time (PT), international normalized ratio (INR), partial thromboplastin 
time (PTT) at screening and baseline, and as needed through the study. 
Urinalysis: urinary color, turbidity, pH, glucose, bilirubin, ketones, RBCs, protein, WBCs 
 Vector concentration: AAV8 concentration in plasma and urine, measured as vector 
genomes by PCR. 
Adverse Events of Special Interest 
Based on the pre-specified laboratory and clinical assessments described above, the number of 
subjects who have the following will be presented: 
 Liver injury 
 Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 or 
higher lab result for bilirubin (>1.5 × ULN) or liver enzymes (AST > 3 × ULN, 
ALT > 3 × ULN, AlkPhos > 2.5 × ULN). 
 Hepatotoxicity (i.e., meet criteria for “Hy’s law”) 
 ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and no other reason can be 
found to explain the changes observed. This event would meet the study Stopping 
Rules (Section 9.3). 
Additionally, ALT or AST elevations that may trigger initiation or adjustment of corticosteroid 
therapy will be flagged and reported. 
2.5. 
Efficacy Endpoints 
The secondary endpoints are based on a detailed assessment of the percent change in lipid 
parameters at 12 weeks (Cohort 1 only) or 18 weeks after vector administration (or 4 weeks after 

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steroid termination or prior to changing lipid lowering therapies), following administration of 
AAV8.TBG.hLDLR compared to baseline. This will include: 
 Percent changes in LDL-C 
 Percent changes in Total Cholesterol, VLDL-C, HDL-C, non-HDL-C, TG, apoA-I, 
apoB, and Lp(a) 
Efficacy will primarily be defined using LDL-C measured by beta quantification 
 
 The baseline LDL-C value 
will be determined using qualified LDL-C drawn prior to administration of AAV8.TBG.hLDLR. 
Qualified LDL-C draws will be those taken after sufficient washout of selected lipid lowering 
medications has occurred and pre-apheresis in subjects receiving apheresis (i.e., the day of 
apheresis). Baseline LDL-C value will be calculated as the average of up to 2 of the most recent 
qualified fasting LDL-C levels obtained during stable lipid lowering treatment before 
administration of AAV8.TBG.hLDLR. The 2 most recent LDL-C values should be no more than 
approximately 4 weeks apart. Baseline LDL-C values based on both beta-quantification and 
direct methods will be based on the same visit dates. Similar methods to define the baseline value 
will be applied to other lipid parameters. Lipid lowering treatment must be stable as per 
inclusion/exclusion criteria by the time of the first laboratory assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1. 
General Design 
This is a 104-week Phase I/IIa, multicenter, open-label, single arm, dose escalation study of 
AAV8.TBG.hLDLR in adults with a clinical presentation consistent with HoFH and carrying 2 
mutations in the LDLR gene. Safety will be the primary focus, with a secondary focus on clinical 
response to AAV8.TBG.hLDLR. The primary safety endpoint is at Week 24. Approximately 12 
subjects will be enrolled into one of 3 possible dose cohorts, 2.5×1012 GC/kg (Dose 1), 7.5×1012 
GC/kg (Dose 2), or 2.5×1013 GC/kg (Dose 3), and will receive a single dose of 
AAV8.TBG.hLDLR administered by IV infusion into a peripheral vein (or into an existing AV 
fistula). Following completion of the primary study period at Week 24, subjects will continue to 
be assessed (for safety and efficacy) for up to 104 weeks following treatment with 
AAV8.TBG.hLDLR. At the end of the study, all subjects will be invited to participate in a long-
term follow-up study.  

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In this trial, two groups will assess data accumulated from the trial, an external DSMB and the 
Sponsor’s ISC. The primary role of the independent DSMB is to assess safety at periodic 
intervals and to provide recommendations on safety and dose escalation. The primary role of the 
ISC is to monitor safety on an ongoing basis. 
The initial Dose 1 cohort of AAV8.TBG.hLDLR will receive 2.5×1012 GC/kg. Dosing of subjects 
will be staggered by at least 4 weeks. A formal review of all safety data will be performed by the 
DSMB after the 3rd subject is dosed and completes the 4 weeks post-dosing visit, primarily to 
determine if dose escalation can occur, however the DSMB may recommend to expand the cohort, 
lower the dose, or stop the trial. 
If the recommendation is to dose escalate, the Dose 2 cohort will be initiated at a dose of 7.5×1012 
GC/kg (Dose 2). Dosing of subjects will be staggered by at least 4 weeks. A formal review of all 
safety data will be performed by the DSMB after the 3rd subject is dosed and completes the 4 
weeks post-dosing visit, primarily to determine if dose escalation can occur. However, the DSMB 
could recommend to expand the cohort, lower the dose, or stop the trial. If expansion of the Dose 
2 cohort is recommended, up to 3 additional subjects will be enrolled and receive prophylactic 
corticosteroids as described in this protocol (Section 6.5). Subject dosing will be staggered by at 
least 6 weeks. After enrollment of the 3rd subject in the expanded Dose 2 cohort (or fewer 
subjects, upon agreement by the DSMB), a review of all safety data will be performed by the 
DSMB to determine if dose escalation can occur. After completion of the Dose 2 cohort, the 
DSMB will need to recommend dose escalation in order for the Dose 3 cohort to be initiated. 
After initiation of the Dose 3 cohort (2.5×1013 GC/kg), dosing of subjects will be staggered by at 
least 6 weeks. Up to 3 subjects will be enrolled into the cohort. 
At any time, if there are safety concerns, the ISC may share safety concerns with the DSMB. The 
DSMB may recommend to stop the trial, dose additional subject(s) at the current dose, or proceed 
at a lower dose. 
If at any time during dosing an event meets the criteria of a Stopping Rule (Section 9.3), dosing 
of any new subjects will be suspended until a complete review of all safety data by the external 
DSMB and the ISC has been performed. 
At any given DSMB meeting, whether called for by a Safety Review Trigger (SRT) or at the 
planned DSMB meeting at the conclusion of a dose cohort, the DSMB may recommend stopping 
the trial, dosing additional subjects at the current dose, proceeding to the next dose cohort, or 
proceeding at a lower dose. After the final subject has been dosed, a review of all safety data by 
the DSMB will be performed. 
A summary of safety review triggers and expected actions is provided in Table 3. 
 

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4. 
SUBJECT SELECTION AND WITHDRAWAL 
4.1. 
Inclusion Criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
1. Male or female ≥ 18 years of age. 
2. Untreated and/or treated LDL-C levels and clinical presentation consistent with the 
diagnosis of homozygous FH 
3. Molecularly defined LDLR mutations at both LDLR alleles. 
4. Concurrent allowed lipid lowering medication must be stable for ≥ 4 weeks before the 
baseline visit and must remain stable until 18 weeks after vector administration (or 4 weeks 
post steroid termination). These include but are not limited to: statins, ezetimibe, bile acid 
sequestrants, PCSK9 inhibitors, and LDL and/or plasma apheresis. Subjects on other 
lipid-lowering medications are eligible for the study but must wash out of these medications 
for the pre-specified time period. 
5. Females of childbearing potential must have a negative pregnancy test at screening and 
baseline visits and be willing to have additional pregnancy tests during the study. 
6. Sexually active subjects (both female and male) must be willing to use a medically accepted 
method of contraception from screening visit until 6 months after vector administration 
7. A baseline serum AAV8 NAb titer ≤ 1:10. 
8. Subjects must be able to comprehend and be willing to provide a signed institutional review 
board/ethics committee (IRB/EC) approved Informed Consent Form (ICF).  
9. Subjects must be willing to comply with all study-related procedures and be available for 
the duration of the study. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified time 
period: 
a. niacin > 250 mg/day: within 6 weeks of baseline 
b. fibrates: within 4 weeks of baseline 
c. lomitapide: within 8 weeks of baseline 
d. mipomersen: within 24 weeks of baseline 
2. Heart failure defined by the NYHA classification as functional Class III with history of 
hospitalization(s) within 12 weeks of the baseline visit or functional Class IV. 
3. History within 12 weeks of the baseline visit of a myocardial infarction (MI), unstable 
angina leading to hospitalization, coronary artery bypass graft surgery (CABG), 
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or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular 
procedure or surgical intervention.   
4. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic blood 
pressure > 95 mmHg. 
5. Uncontrolled diabetes defined as HbA1c > 8.5% or an average fasting glucose ≥ 160 mg/dl. 
6. Known hypersensitivity to prednisone 
7. History of cirrhosis or chronic liver disease based on documented histological evaluation 
or non-invasive imaging or testing. 
8. Documented diagnosis of any of the following liver diseases: 
a. Nonalcoholic steatohepatitis (biopsy-proven) 
b. Alcoholic liver disease 
c. Autoimmune hepatitis 
d. Liver cancer 
e. Primary biliary cirrhosis 
f. Primary sclerosing cholangitis 
g. Wilson’s disease 
h. Hemochromatosis 
i. 1 anti-trypsin deficiency 
9. Abnormal liver function tests (LFTs) at screening (AST or ALT > 2 × upper limit of normal 
(ULN) and/or Total Bilirubin of  1.5 × ULN unless patient has unconjugated 
hyperbilirubinemia due to Gilbert’s syndrome). 
10. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA 
11. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.   
12. History of chronic alcohol abuse within 52 weeks of the screening visit.   
13. Certain prohibited medications known to be potentially hepatotoxic, especially those that 
can induce microvesicular or macrovesicular steatosis. These include but are not limited to: 
Accutane (isotretinoin), amiodarone, HAART medications, heavy acetaminophen use 
(2 g/day more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen, or 
valproate. 
14. Active tuberculosis, systemic fungal disease, or other chronic infection. 
15. History of immunodeficiency diseases, including a positive HIV test result. 
16. Chronic renal insufficiency defined as estimated GFR < 30 mL/min/1.73m2.  
17. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer. 
18. Previous organ transplantation.  
19. Administration of an investigational drug within 12 weeks or 5 half-lives of the drug 
(whichever is longer) prior to the screening visit and until 52 weeks after receiving 

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AAV8.TBG.hLDLR. Subjects are not prohibited from receiving investigational drugs after 
52 weeks. 
20. Any major surgical procedure occurring less than 3 months prior to the screening visit, or 
any planned future surgical procedure within 3 months of baseline. 
21. Serious or unstable medical or psychological conditions that, in the opinion of the 
investigator, would compromise the subject’s safety or successful participation in the study. 
22. Any other medical condition or finding that would make it not in the subject’s best interest 
to participate in the study 
23. Study staff member or any direct family member. 
4.3. 
Subject Recruitment and Screening 
Subjects will be recruited from study sites. Patients may be contacted through a companion 
screening protocol entitled “Screening Protocol for a Gene Therapy Trial in Subjects with 
Homozygous Familial Hypercholesterolemia.” Methods to identify patients used in this and in the 
companion screening protocol include IRB/EC approved recruitment letters, referrals, and non-
profit research foundations. Institutionally approved consent forms will be provided to patients. 
Consent of subjects that are not fluent in English will be obtained using appropriately translated 
informed consent forms (ICFs) and appropriate interpreters. Those who express an interest during 
the screening process will have the opportunity to discuss the study in detail again and confirm 
their consent to participate before vector administration.   
4.3.1. 
Screening Protocol 
Subjects with a diagnosis of HoFH that may have participated in a separate companion Screening 
Protocol will be contacted to participate in this clinical trial. Screening Protocol procedures 
include genetic analysis to confirm the presence of two mutations in the LDLR gene, lipid profile, 
NAb titer, and the collection of a detailed medical history as well as a detailed description of the 
procedures and risks of participating in the gene therapy trial. Subjects who preliminarily 
qualified based on the results from the Screening Protocol and that expressed interest in 
participating in the gene therapy trial will be invited to participate in this gene therapy clinical 
trial. Participation in the companion Screening Protocol is not obligatory. Eligibility for this 
clinical trial will be determined based on data collected during the screening visit (Visit 1) of the 
protocol described herein.  
4.4. 
Informed Consent 
Written informed consent will be obtained from each potential study subject prior to the conduct 
of any study procedures. Both the protocol and consent forms will be discussed with the potential 
study subject during documented informed consent sessions. Copies of the consent forms will be 
provided in advance for the patient's perusal. The subject will have ample time to ask questions 
and to discuss the study with their family and personal care physicians before and after the 
screening visit.  
During the informed consent sessions, particular emphasis will be given to the following: 

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 The experimental nature of the study and the relative lack of experience with AAV8 
vectors in humans. 
 The potential for no benefit. 
 The need to discontinue other selected lipid lowering medications for at least 4 weeks 
to establish baseline plasma cholesterol levels, and for 18 weeks (or 4 weeks post steroid 
termination if steroids have not been discontinued by at least 4 weeks at the Week 18 
visit or prior to changing lipid lowering therapies) after vector infusion to assess 
efficacy. Lipoprotein and/or plasma apheresis will be allowed to continue as per 
standard of care if available and necessary for safety of the patient as determined by the 
caring physician. 
 The observation of asymptomatic and transient increase transaminases in subjects 
enrolled in the previous cohort, risk of liver injury and treatment with corticosteroids. 
 The toxicity and efficacy of AAV8 vectors in preclinical animal studies. 
 The outcome of the previous studies that used AAV-based vector, including 
complications. 
 The theoretical potential for germline transmission and malignancy. 
 The potential for development of anti-human NAbs (e.g., inhibitors to LDLR). 
 The nature and duration of follow-up including the need for long-term follow-up. 
 The alternatives to gene transfer. 
 That the subject is free to refuse to enter the study or to withdraw from it at any time. 
 That the subject will be provided any new information during the course of the study 
that might affect their continued participation in the study. 
Subjects who live within driving distance of the study site will be consented during an in-person 
visit. Subjects who live a long distance from the study site may be consented remotely at the 
discretion of the investigator. In this case, subjects will be provided with two copies of the 
consent form so that they have one copy to keep and one copy to mail back to the study site. They 
will be asked to set up a remote appointment (via phone or video-conference) with the research 
team after receiving and reading the consent form. During the in-person or remote consent 
session, the potential study participant and the research team will have an opportunity to review 
the study in detail. The subject will also have the opportunity to have all questions answered. 
These conversations will be documented in the subject’s file. 
A representative(s) of the potential subject’s choosing will be encouraged to attend the consenting 
session with the subject. At the end of the consent session, subjects will be asked to sign the 
consent form. Subjects consented remotely will be asked to return the signed consent form using 
pre-paid envelopes. Subjects are considered enrolled when they have signed the informed consent 
document. No study procedures will be performed in subjects consented remotely until a signed 
copy of the consent form is received by the study site. Each subject enrolled in the study will 
receive the study agent, the dose of which will be dependent on the cohort to which he/she is 
admitted.  

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4.5. 
Early Withdrawal of Subjects  
Any subject who withdraws from the study after signing the final consent document, but before 
the administration of the vector, will be replaced. This clinical trial involves a single 
administration of vector and therefore “withdrawal” after the single dose of vector applies only to 
loss of follow-up, not to ongoing administration of study agent. Every effort will be made to 
continue to follow-up subjects for study duration (104 weeks) after enrollment and vector 
administration. 
4.6. 
Withdrawal of Informed Consent for Data and Biological Samples 
Biological Samples Obtained for the Main Study 
Study data are protected by the use of an identification number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study sample 
to a subject. A subject’s consent to the use of data does not have a specific expiration date, but the 
subject may withdraw consent at any time by notifying the investigator. If consent is withdrawn, 
any samples collected prior to that time may still be given to and used by the sponsor but no new 
data or samples will be collected unless specifically required to monitor safety of the subject. 
Samples Obtained for Future Research 
Research samples, including serum, plasma, DNA, RNA, and cells will be collected and stored 
for follow-up exploration of study findings, efficacy measures and/or adverse events (e.g., 
measurement of immune response, antibodies against LDLR, measurement of cytokine and 
chemokine levels or other inflammatory biomarkers) in this or subsequent studies of 
AAV8.TBG.hLDLR.  Any unused sample collected throughout the study for routine lab analysis 
may also be stored for future research.   
Samples will be labeled with the same identification number used for other study-related 
information and will not be labeled with personal identifiers such as the subject’s name. If the 
subject withdraws consent, this link will allow the sponsor to locate the subject’s sample and 
destroy it. The coding of samples and results is to ensure that these research results are kept 
confidential by keeping the subject’s identity and these results separate.  
This additional research may not start immediately and may start at any time during the storage 
period. The subject’s sample(s) will be stored with similar samples from other subjects at a secure 
central laboratory for up to 10 years for use in research as noted above.  
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent to 
the central laboratory, the investigator will arrange to have it destroyed. If consent is withdrawn 
after the subject’s research sample(s) have been stored, the sponsor and the investigator will 
ensure that these sample(s) are destroyed unless the sample identification number has been 
removed and the subject can no longer be linked to any sample(s). However, if the subject’s 
samples have already been used for research, the sponsor is not required to destroy results of this 
research. In this case only the remaining sample(s) will be destroyed. 

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4.7. 
Confirmation of Eligibility   
Eligibility is initially determined by the site primary Principal Investigator.  The study Medical 
Monitor will confirm eligibility of all subjects who will be dosed, regardless of the local site at 
which they are enrolled. To confirm eligibility, sites must provide the Medical Monitor with key 
medical records which provide supporting documentation of eligibility criteria. These documents 
should be provided shortly after eligibility is determined by the local site and before the subject 
travels to the University of Pennsylvania or other selected sites for dosing.  
5. 
STUDY PROCEDURES 
Refer to the “Schedule of Events” table in the Appendix (see Section 16.1) for a list and 
frequency of study procedures and laboratory parameters that will be performed as part of this 
clinical trial.  
5.1. 
Clinical Laboratory Testing 
Samples for laboratory testing will be collected at time points according to the “Schedule of 
Events” and analyzed by a central laboratory (Central Lab) during the study. Laboratory samples 
may be drawn at a site local to the subject’s residence or by a home nursing service and shipped 
to the Central Lab. If local labs are drawn, including lipid panel, results should be entered into the 
Clinical Database. Detailed instructions for blood sample collection and processing will be 
described in a separate laboratory manual. The investigator must document his or her review of 
each laboratory report by signing or initialing and dating each report. Laboratory values that fall 
outside a clinically accepted reference range or values that differ significantly from previous 
values must be evaluated. When multiple laboratory values are out of range but not clinically 
significant (NCS), "all labs NCS" or a general comment may be written on the laboratory page. 
However, all clinically significant (CS) laboratory values must be individually marked with "CS."  
5.2. 
Safety Assessments 
Safety will be evaluated by the incidence, severity, and relationship to study drug of adverse 
events (AEs), and changes from baseline in laboratory test results, physical examination and vital 
sign measurements at any time after the subject has received study drug.  
 Laboratory assessments include: 
 Biochemical panel: sodium, potassium, chloride, carbon dioxide, glucose, blood urea 
nitrogen, lactate dehydrogenase, creatinine, creatine phosphokinase, calcium, total 
protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, and GGT (GGT 
will be measured at screening and only as clinically indicated through the study). 
 CBC: WBC, hemoglobin, hematocrit, platelet count, red cell distribution width, mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration 
 HbA1c 

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 Coagulation: PT, INR, PTT (at screening and baseline, and through the study as 
deemed necessary) 
 Urinalysis: urine color, turbidity, pH, glucose, bilirubin, ketones, RBCs, protein, 
WBCs 
 Vector concentration: AAV8 concentration in plasma and urine, measured as vector 
genomes by PCR. 
 
Physical Examinations include: 
The complete physical examination will include evaluation of the following organ or body 
systems: 
 Skin 
 Head, eyes, ears, nose, and throat 
 Thyroid 
 Respiratory system 
 Cardiovascular system 
 Abdomen (liver and spleen) 
 Lymph nodes 
 CNS 
 Musculoskeletal  
 
The targeted physical examination will include evaluation of the following organ or body 
systems: 
 Respiratory system 
 Cardiovascular system 
 Abdomen (liver and spleen) 
 Any other system prompted by complaints/symptoms 
5.2.1. 
Adverse event driven safety evaluation 
Additional ad hoc laboratory testing may be performed if a subject is experiencing an adverse 
event that is preliminarily deemed at least possibly related to the study vector. If an inflammatory 
response is suspected, additional testing may include (but may not be limited to) inflammatory 
markers, such as high-sensitivity C-reactive protein (hsCRP), ferritin, fibrinogen and cytokines 
panel. 

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5.3. 
Pharmacodynamic/ Efficacy Assessments 
Given the difficulty to directly assess the presence of the gene product, the membrane-bound 
LDLR, efficacy will be primarily assessed by changes in plasma lipid and lipoprotein profile. In 
the context of this trial, we assume that LDL-C is the main indirect measure of LDLR expression.  
The following efficacy laboratory tests will be evaluated under fasting conditions as described in 
the “Schedule of Events”:   
 LDL-C 
 Lipid panel: total cholesterol, VLDL-C, non-HDL-C, HDL-C, TG, Lp(a)  
 Apolipoproteins: apoB and apoA-I   
Lipid lowering efficacy will be assessed as percent changes from baseline at 12 (Cohort 1 only), 
18 (or 4 week post steroid termination or prior to changing lipid lowering therapies), 24, 36, 52, 
78 and 104 weeks post vector administration. Baseline LDL-C value will be calculated as the 
average of up to 2 of the most recent qualified fasting LDL-C levels obtained during stable lipid 
lowering treatment before administration of AAV8.TBG.hLDLR. The 2 most recent LDL-C 
values should be no more than approximately 4 weeks apart. The percent change from baseline in 
LDL-C at 12 weeks (Cohort 1 only) or 18 weeks post vector administration (or 4 weeks after 
steroid termination or prior to changing lipid lowering therapies) will be considered the primary 
measure of gene transfer activity.  
 
 
 
  
5.3.1. 
Efficacy Assessment in Subjects Receiving Apheresis 
For subjects receiving apheresis, efficacy will be evaluated on the basis of pre-apheresis lipid 
levels.  
Apheresis treatment causes a sharp drop in LDL-C, followed by a rebound phase and therefore in 
subjects undergoing apheresis, it is important that lipid parameters are evaluated at a time that is 
as close as possible to and before the scheduled apheresis treatment. Once established, this time 
point for lipid assessment blood draws should always be maintained, relative to the previous 
apheresis visit, so that lipid assessments are always performed at the same point on the LDL 
rebound curve. During the run-in phase a stable frequency regimen (i.e., apheresis every X 
number of days) will be established and needs to be maintained on as regular a schedule as 
possible during the efficacy phase. Frequency of apheresis is usually personalized to meet the 
patients' needs and the centers' capacity, and therefore we have included a window for each visit 
to allow for flexibility when patients can be seen. If the visit schedule is inconsistent with a 
subject's apheresis schedule, then the investigator should contact the Contract Research 
Organization (CRO) and Sponsor. If a subject is unable to come for an apheresis treatment per 
his/her usual regimen, apheresis should be rescheduled as soon as possible. If apheresis was 
missed at a time a study visit was scheduled, then blood for lipid parameters should be drawn 
before apheresis treatment and as close as possible to the apheresis regimen established during 

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the run-in period or as revised if during the safety phase. However, fasting lipids must be drawn 
just prior to the apheresis treatment and apheresis must occur ± 1 day from the regimen 
established during the run-in period. 
Subjects will be asked to allow the collection of pre-apheresis LDL levels collected as part of 
standard of care to be captured in the clinical database.  
5.3.2. 
Efficacy Assessment in Subjects Receiving Prophylaxis Steroid Treatment  
Steroid treatment has the potential to affect lipid metabolism and, consequently, to affect efficacy 
assessments, thus limiting the possibility to assess efficacy during such treatment.  In subjects 
who undergo steroid treatment, the primary measure of gene transfer activity will be the percent 
change from baseline in LDL-C assessed 4 weeks after steroid treatment termination. This 
assessment may coincide with week 18 post vector administration in subjects that receive steroid 
prophylaxis as per Section 6.5, but may vary if steroid treatment needs to be personalized. 
Secondary measures of efficacy are changes from baseline of lipid and lipoprotein parameters at 
18 (or 4 week post steroid termination if steroids have not been discontinued by at least 4 weeks 
at the Week 18 visit or prior to changing lipid lowering therapies), 24, 36, 52, 78 and 104 weeks 
post vector administration.   
5.4. 
Assessment of Pharmacokinetics and Immune Response to AAV8 
The following tests will be evaluated as described in the “Schedule of Events”:   
 Immune response monitoring:  
 AAV8 NAb; sample used for testing the AAV8 NAb titer and for assay validation 
 T-cell responses to AAV8 vector and hLDLR. An additional PBMC sample may 
be collected at the discretion of the Sponsor Medical Monitor to assess immune 
response based on safety events.   
 Vector concentration: AAV8 concentrations in plasma and urine 
 Human Leukocyte Antigen Typing (HLA type): HLA-A, HLA-B, HLA-C for Class I 
and HLA-DRB1/DRB345, DQB1 and DPB1 for Class II 
5.5. 
Future Use Samples 
Future use samples, including serum, DNA, and RNA will be collected and stored for follow-up 
exploration of study findings, efficacy measures and/or adverse events (e.g., measurement of 
immune response, antibodies against LDLR, measurement of cytokine and chemokine levels or 
other inflammatory biomarkers) in this or subsequent studies of AAV8.TBG.hLDLR. Future use 
for these samples may include, but will not be limited to, research and development in the 
cardiovascular indication, assay validation, or any other area that supports the furthering of 
science in these areas. Research samples will be coded to maintain patient confidentiality and 
may be stored for up to 10 years for use in research as noted above. 

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5.6. 
Xanthoma Assessment 
Physical exams will include identification, examination, and description of any xanthomas. 
Documentation of xanthoma location and type will be determined by investigator (i.e., cutaneous, 
palpebral (eye), tuberous, and/or tendinous). Where possible, metric rulers or calipers will be 
used to document size of xanthomas (largest and smallest extents) during physical exam. All 
efforts should be made to take photographs using a standard digital camera of xanthomas that are 
the most extensive and readily identifiable, with placement of a tape ruler (metric with 
millimeters) next to the lesion(s). 
5.7. 
Specific Study Procedures by Visit 
Subjects will be asked to fast (except water) for a minimum of 12 hours prior to all visits unless 
otherwise noted. A detailed study time-table and list of all procedures to be performed at each 
visit is included in the “Schedule of Events” table located in the Appendix (see Section 16.1). 
5.7.1. 
Screening Protocol 
Potential subjects may participate in a separate companion Screening Protocol to obtain results 
for genotyping, lipids and NAb titer, as well as medical records. Subjects who are interested in 
participating in the gene therapy trial and who preliminarily qualify based on the results from the 
Screening Protocol will be invited to participate in the gene therapy clinical trial. Participation to 
the Screening protocol is not obligatory. Final eligibility of subjects that participated in the 
screening protocol, including AAV8 NAb titer as well as all other eligibility criteria, except for 
the genetic testing, will be reassessed during the study screening visit (Visit 1) procedures.   
5.7.2. 
Visit 1: Consent, Screening and Washout (Weeks -26 to Day -1) 
Potential subjects will be contacted and asked to schedule a visit at the Study Site.  
The following procedures will be performed during this visit: 
 Subject to review and sign the IRB-approved ICF (see Section 4.4 “Informed Consent” 
for detailed description of the consenting procedures). 
 Review medical history including current medications, tobacco, drug, and alcohol 
consumption. 
 
 
 
 
 
 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events” table (Section 16.1).  
 Collect a blood sample to confirm molecular diagnosis (only for subjects that did not 
participate to the Screening Protocol) 
 Concomitant medications will be recorded.     

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 Have procedures performed as described in the “Schedule of Events” table 
(Section 16.1), including physical examination, vitals, 12-lead ECG, and xanthoma 
assessment (can be assessed at Visit 1 or 3). 
 Assessment of AEs 
These procedures can be performed over several days/weeks. Subjects that are known to carry 
LDLR gene mutations at both alleles and that are potentially eligible based on their participation 
in the companion Screening Protocol and/or their medical history may, in agreement with the 
caring physician, start washout from selected lipid lowering medications before other screening 
procedures are completed (see “Subject Selection and Withdrawal” section for washout 
requirements). Subjects with genetic diagnosis determined by a reputable laboratory (medical 
history) could start washout before receiving the genetic results of Visit 1. 
The baseline LDL-C value will be determined using qualified LDL-C drawn prior to 
administration of AAV8.TBG.hLDLR. Qualified LDL-C draws will be those taken after 
sufficient washout of selected lipid lowering medications has occurred and pre-apheresis in 
subjects receiving apheresis (i.e., the day of apheresis). Baseline LDL-C value will be calculated 
as the average of up to 2 of the most recent qualified fasting LDL-C levels obtained during stable 
lipid lowering treatment before administration of AAV8.TBG.hLDLR. The 2 most recent LDL-C 
values should be no more than approximately 4 weeks apart. 
5.7.3. 
Visit 1a: Laboratory Retesting 
Subjects will undergo Visit 1a up to 2 weeks prior to the dosing visit (Visit 3) if any of the 
following conditions apply: 
 The interval between the Visit 1 blood draw date for NAbs and Visit 3 is or will be 
greater than 26 weeks: Blood for NAbs must be redrawn to determine eligibility. 
Retesting of NAb titer should be scheduled to allow for sufficient time for NAb titer 
analysis prior to dosing. 
 The interval between the Visit 1 blood draw date for LDL-C and Visit 3 is or will 
be greater than approximately 4 weeks: Visit 1a will be scheduled at the end of the 
wash-out period. Blood for a complete lipid panel including LDL-C by beta-
quantification will be performed at Visit 1a. The baseline LDL-C value can be 
calculated by averaging the LDL-C levels obtained under fasting conditions at Visit 1a 
and Visit 3 (prior to AAV8.TBG.hLDLR administration). The blood drawn for lipid 
panel for subjects undergoing apheresis must be done prior to the apheresis treatment 
as described in Section 5.3.1. 
 
Blood sampling for this visit may be conducted either at the study site or by a home healthcare 
nurse.  
If the interval between Visit 1 and Visit 3 is less than 26 weeks, repetition of standard clinical 
laboratory assessment may be conducted at the discretion of the investigator. In this case, the 
assessment will be recorded as “unscheduled visit”. 

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5.7.4. 
Visit 2 
This visit only refers to a visit that is performed for the optional kinetic study.   
5.7.5. 
Visit 3: Vector Administration (Day -1, Day 1 and Day 2) 
This visit will take place at the University of Pennsylvania or at other selected dosing sites. For 
subjects that need to travel to the dosing site, a communication plan to share relevant medical 
information will be implemented between the 2 sites before the subject travels. Subjects will be 
admitted the day of or the day before vector administration and eligibility confirmed before 
dosing.  
Subjects enrolled under this protocol will begin prophylactic corticosteroids and receive the first 
dose of oral prednisone (40mg daily) on Day -1. Prior to discharge, subjects will be provided with 
a sufficient supply of prednisone to last for at least 8 weeks. See Section 6.5. 
The following will be performed prior to AAV8.TBG.hLDLR administration: 
 Subject to review the IRB-approved ICF (see Section 4.4 “Informed Consent” for 
detailed description of the consenting procedures) and re-confirm willingness to 
participate in the clinical trial 
 Review eligibility prior to vector administration  
 Review medical history including current medications and alcohol consumption 
 Conduct complete physical exam as described in Section 5.2 
 Xanthoma assessment  
 12 lead-ECG 
 Measure vital signs as listed in the Schedule of Events 
 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events”. 
 Dipstick urine pregnancy test for women 
 Assessment of AEs 
 Initiate oral corticosteroids 
Subjects will receive AAV8.TBG.hLDLR via a peripheral vein by IV administration. The volume 
and infusion rate varying according to the dose given and the weight of the subject at time of 
admission. Vital signs will be monitored frequently during the subject’s stay in the research unit.  
The following will be performed 24 hours after AAV8.TBG.hLDLR administration: 
 Conduct targeted physical exam as described in Section 5.2 
 12 lead-ECG 
 Measure vital signs as listed in the Schedule of Events 
 Collect blood samples for laboratory testing as described in the “Schedule of Events” 

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The subject can be discharged from the inpatient unit after 24 hours of observation post-vector 
infusion or may remain admitted for a longer duration if deemed necessary by the investigator. 
5.7.6. 
Visit 4 
Subjects will have a visit 48 hours after AAV8.TBG.hLDLR administration. The following will 
be performed: 
 Review medical history including current medications and alcohol consumption 
 Conduct physical exam as described in Section 5.2 
 Measure vital signs as listed in the Schedule of Events 
 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events” table (Section 16.1) 
 Assessment of AEs  
5.7.7. 
Visit 6 
Subjects will have a visit on Day 7 (±2 days) after AAV8.TBG.hLDLR administration to assess 
vital signs, AEs, and medical history & medications including subject’s prophylactic 
corticosteroid compliance. This visit can be conducted at a study site or at the subject’s home by 
a home healthcare nurse visit. 
Note: Visit 5 was removed from Protocol version 10 and later. 
5.7.8. 
Visit 7, 9, 13: Safety Visits  
A full safety visit will occur on days 14, 28, and 56 (±3 days)). These study visits will be 
performed at a study site. The following procedures will be performed during these visits: 
 Review medical history including current medications and alcohol consumption 
 Confirm subject’s prophylactic corticosteroid compliance  
 Conduct physical exam as described in Section 5.2 (complete at Visit 9, targeted at 
Visits 7 and 13) 
 Measure vital signs as listed in the Schedule of Events 
 12 lead-ECG (Visits 9 and 13) 
 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events” table (Section 16.1) 
 Dipstick urine pregnancy test for women (Visit 9 only) 
 Assessment of AEs  
5.7.9. 
Visit 8, 10, 11, 12, 14, 15, 16, 17: Laboratory assessments  
Subjects will have labs drawn for liver function tests, as well as LDL-C, ApoB, and other 
laboratory assessment as listed in the “Schedule of Events” table on days 21, 35, 42, 49, 63, 70, 

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77 and 84 (±3 days). Blood sampling for these visits may be conducted by a home healthcare 
nurse or local laboratory to be sent sample to central laboratory. Other safety laboratories will 
only be drawn if needed and at the discretion of the investigator and will be entered into the 
clinical database.  
Subjects will be contacted by the site on Day 63, 70, 77, and 84 (Visit 14, 15, 16, and 17) to 
review and confirm the subject’s prophylactic corticosteroid regimen and dose.   
5.7.10. 
Visit 17.1: 14 Weeks Post Vector Administration 
Subjects will be asked to return to the study site for an outpatient visit. The following procedures 
will be performed during this visit: 
 Review medical history including current medications and alcohol consumption  
 Confirm subject’s prophylactic corticosteroid compliance 
 Conduct complete physical exam as described in Section 5.2 
 Measure vital signs as listed in the Schedule of Events 
 12 lead-ECG 
 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events” table (Section 16.1) 
 Assessment of AEs 
5.7.11. 
Visits 17.2, 17.4, 17.5: Bi-Weekly Lab Assessments and Telephone Contact  
After Visit 17.1, subjects will have blood drawn for liver function testing and lipid panel, 
including ApoB every two weeks to Week 24 (Visit 18). These visits can be assessed at the local 
study site or by a home nurse visit with samples sent to the Central Laboratory. Investigators may 
draw additional blood for LFTs or LDL-C at their discretion. Subject will be asked to allow 
sharing any laboratory samples collected outside of the protocol specified schedule of events 
during the study to be recorded in the Clinical Database.   
5.7.12. 
Visit 17.3  
At Week 18 (or 4 week post steroid termination if steroids have not been discontinued by at least 
4 weeks at the Week 18 visit or prior to changing lipid lowering therapies), subjects will be asked 
to return to the study site for an outpatient visit.  The following procedures will be performed 
during the visit:  
 Review medical history including current medications and alcohol consumption  
 Conduct complete physical exam as described in Section 5.2 
 Xanthoma assessment  
 Measure vital signs as listed in the Schedule of Events 
 12 lead-ECG 

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 Collect blood and urine samples for laboratory testing as described in the “Schedule of 
Events” table (Section 16.1) 
 Dipstick urine pregnancy test for women 
 Assessment of AEs 
Subjects will be permitted to receive lipid lowering therapies as per standard of care after the 
Week 18 visit (or 4 week post steroid termination). 
 
 
 
 
 
 
 
   
5.7.13. 
Visits 18,19, 20 
Subjects will return to the study site for a 24, 36, and 52 week visit post vector administration. 
The following procedures will be performed during these visits: 
 Review medical history including current medications and alcohol consumption 
 Conduct complete physical exam (Week 24 and 52 only) or targeted exam (Week 36 
only) as described in Section 5.2 
 Measure vital signs as listed in the Schedule of Events 
 12 lead-ECG 
 Collect blood and urine samples for laboratory testing as described in the Schedule of 
Events 
 Dipstick urine pregnancy test for women 
 Assessment of AEs 
 Xanthoma assessment (only at the 52 week visit) 
Week 52 is the last visit of the active study period.  Subjects will not be prohibited from receiving 
other investigational therapies after Week 52, should they wish to do so. 
5.7.14. 
Visit 18.1  
Subjects enrolled under Protocol version 10 and following will have a week 30 visit that will be a 
laboratory visit only. Subjects will have a blood drawn at for liver function testing and lipid 
panel, including ApoB on Week 30 (±2 weeks) (Visit 18.1).  This visit can occur at the local 
study site, by a home nurse visit or other testing laboratory, with samples sent to the Central 
Laboratory.   

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5.7.15. 
Visit 21: 78 weeks (± 2 weeks) Post Vector Administration 
This visit can be assessed at the local study site, by a home nurse visit or with a local laboratory 
(results sent to central laboratory). Subjects may be contacted by telephone by the study site. 
 Review medical history including current medications and alcohol consumption  
 Assessment of AEs 
 Fasting standard lipid panel (may be performed locally) 
5.7.16. 
Visit 22: 104 weeks (± 2 weeks) Post Vector Administration / Early Termination 
Visit 
Subjects will return to the study site for a 104 week visit post vector administration. This is the 
last visit of the follow up study period. The following procedures will be performed: 
 Review medical history including current medications and alcohol consumption  
 Conduct complete physical exam 
 12 lead-ECG 
 Measure vital signs as listed in the Schedule of Events 
 Collect blood and urine samples for laboratory testing as described in the Schedule of 
Events 
 Assessment of AEs  
Subjects will be asked to participate in a separate long-term follow-up protocol after the Week 
104 visit (Visit 22). The primary objective of this study will be safety and will also include 
assessment of LDL-C. 
6. 
STUDY DRUG  
6.1. 
Description 
The investigational agent is an AAV8 vector expressing the transgene for the human low density 
lipoprotein receptor (hLDLR) under control of a liver-specific promoter (thyroxine-binding 
globulin, TBG) and is referred to in this document as AAV8.TBG.hLDLR.  
6.2. 
Treatment Regimen 
Subjects will receive a single dose of AAV8.TBG.hLDLR administered via a peripheral vein by 
infusion.  
6.2.1. 
Method for Assigning Subjects to Treatment Groups 
There is no randomization in this Phase I/IIa, open-label, single ascending dose study. Subjects 
will be assigned to dose cohorts as defined in the overall study design. 

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6.3. 
Preparation of Vector for Injection 
The vector will be prepared for administration at the study site. Full details regarding product 
preparation and administration are found in the study Investigational Product Manual.  Upon 
thaw of the frozen product, the product should be a clear colorless liquid with no evidence of 
solids. The vials should be swabbed extensively with 70% sterilizing agent before withdrawing 
contents in a laminar flow biosafety cabinet. After drug preparation, the syringe containing the 
product should be stored at room temperature. Vector administration within 0-4 hours after 
preparation is recommended. Should there be any delay period before administration, the syringe 
containing the product could be stored at room temperature for up to 8 hours.  
6.4. 
Prior and Concomitant Therapy 
Subjects will be withdrawn from selected lipid lowering medications as specified in the “Subjects 
Selection and Withdrawal” section for at least one month prior to vector administration. Subjects 
will be permitted to resume lipid lowering therapies 18 weeks (or 4 weeks post steroid 
termination) after vector administration. Use of other medications not excluded in the entry 
criteria will be permitted at the discretion of the investigator. Any medication, including over the 
counter (OTC) medications, used during the course of the study will be documented. 
6.5. 
Corticosteroid Prophylaxis 
Subjects dosed under Protocol version 10 and later will receive daily prophylactic corticosteroids 
beginning on Study Day -1 prior to dosing. The starting dose is prednisone 40 mg once daily with 
a taper beginning at Week 9 and continuing through the end of Week 13. The first dose should be 
given on Day -1 at least 8 hours before scheduled dosing with study vector. 
This intervention is based on the premise that elevated transaminases post-AAV based gene 
therapy are the result of an immune response that results in a cytotoxic (e.g., T-cell mediated) 
destruction of hepatocytes that have been transfected with the AAV vector. This may be of added 
importance at higher vector doses given the potential for dose-dependent toxicity. Therefore, 
prophylactic immunosuppression theoretically could halt the loss of hepatocytes expressing the 
transgenic LDL receptor. However published data to date have not conclusively demonstrated the 
effectiveness of this approach (Nathwani 2014, Rangarajan 2017, George 2017). Regardless, 
corticosteroids are relatively safe and justified as an attempt to preserve transgene expression. 
Use of corticosteroids such as prednisone may cause acne, dizziness, facial flushing, general body 
discomfort, headache, increased appetite, weight gain, increased sweating, nausea, nervousness, 
and sleeplessness (Prednisone Prescribing Information 2016). Additional information will be 
outlined in the Investigator’s Brochure.   
The daily prednisone dose of each study week is presented in Table 4. 
 

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6.9. 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug provided, drug used, 
and drug remaining. This reconciliation will be logged on a drug reconciliation form, signed and 
dated. Any discrepancies noted will be investigated, resolved, and documented prior to return of 
unused study drug. Drug destroyed on site will be performed according to institutional policy and 
with prior written permission of the sponsor. On-site drug destruction will be documented and 
filed in the study files. 
6.10. 
Reporting Product Complaints 
Any defects with the investigational product must be reported within 24 hours to the Sponsor’s 
Product Complaint Department by the site with further notification to the site monitor. All defects 
will be communicated to the Product Compliant Department and investigated further.  
The Product Compliant Department contact information for reporting product complaints: 
productcomplaints@regenxbio.com. 
7. 
STATISTICAL PLAN 
This section describes the planned statistical analyses in general terms. A complete description of 
the methodology will be specified in a statistical analysis plan (SAP). Any changes in the 
statistical methods described in this protocol that occur prior to database lock will be documented 
in the SAP and will not require a protocol amendment. 
7.1. 
General 
All data will be presented in subject data listings. Categorical variables will be summarized using 
frequencies and percentages, and continuous variables will be summarized using descriptive 
statistics (number of non-missing observations, mean, standard deviation, median, minimum, and 
maximum). Graphical displays will be presented as appropriate. 
After all subjects have completed the primary study period (i.e., through Week 24), analyses will 
be performed for all safety, PD, and efficacy endpoints for primary period.  
After all subjects have completed the end of study (EOS) period (through Week 104), analyses will be 
performed for all safety, PD, and efficacy endpoints.  
Safety, PD, and efficacy endpoints will be reported by dose cohort and may also be reported for 
all dose cohorts combined. 
7.2. 
Sample Size Determination 
The sample size chosen for this study is not based on statistical considerations, as HoFH is a very 
rare disease. Approximately 12 subjects are planned to be treated.  

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7.3. 
Statistical Methods 
7.3.1. 
Disposition 
The number of subjects enrolled, the number of subjects treated, the number of subjects who 
complete the study, and the number of subjects who withdraw from the study, along with the 
reasons for their withdrawal, will be summarized by dose cohort and by the study overall. In 
addition, the total number of subjects screened and the number of screen failures, along with the 
reason for screen failure, will be summarized. 
7.3.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by dose cohort, as 
well as for the study overall.  
Past and current medical history will be summarized by treatment group using the system organ 
class (SOC) as coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary.  
Deviations from inclusion/exclusion criteria as well as subject's status will only be listed. 
7.3.3. 
Efficacy Analyses 
Observed values and changes from baseline over time (as applicable) will be summarized 
descriptively by dose cohort and by the study overall for the PD measures and efficacy endpoints 
(defined in the SAP). 
7.3.4. 
Safety Analysis 
7.3.4.1. 
Adverse Events 
AEs occurring prior to a treatment dose will be listed and presented separately from those that 
occur during or after receiving a treatment dose. The incidences of treatment-emergent adverse 
events (TEAEs), treatment-related TEAEs, and TEAEs by severity (intensity) will be provided. 
All AEs will be coded using MedDRA and will be summarized by SOC and Preferred Term. 
7.3.4.2. 
Clinical Laboratory Tests 
Observed values and changes from baseline (as applicable) through Week 104 will be 
summarized descriptively by dose cohort and by the study overall for each biochemical profile, 
CBC, coagulation, and urinalysis parameter. In addition, the incidence of subjects who meet pre-
defined criteria for clinically significant abnormal values (or abnormal change) may also be 
summarized by dose cohort and by the study overall. 
7.3.4.3. 
Vital Signs 
Observed values and changes from baseline (as applicable) through Week 104 will be 
summarized descriptively by dose cohort and by the study overall. In addition, the incidence of 
subjects who meet pre-defined criteria for clinically significant abnormal values (or abnormal 
change) may also be summarized by dose cohort and by the study overall. 

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9. 
SAFETY AND ADVERSE EVENTS  
9.1. 
Definitions 
9.1.1. 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness, or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
9.1.2. 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction (ADR). “Responses” to a medicinal product means that a 
causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out.  
9.1.3. 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction (UADR) is defined as an adverse reaction, the nature or 
severity of which is not consistent with the applicable product information. For 
AAV8.TBG.hLDLR the reference safety information is included in the Investigator’s Brochure.  
9.1.4. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event (SAE) is any AE 
that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 

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seizure that did not result in inpatient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
Adverse events that do not meet any of the criteria for serious adverse events should be regarded 
as non-serious adverse events. 
9.1.5. 
Adverse Event Reporting Period 
All AEs will be recorded from the time the subject signs the ICF to the end of the study 
(Week 104). Long-term follow-up will be conducted via a separate protocol (starting after 104 
weeks post vector administration) for up to 5 years’ cumulative duration in this study plus the 
follow-up study.  
9.1.6. 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
9.1.7. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. 
During the study, any new clinically significant findings/abnormalities that meet the definition of 
an adverse event, or any preexisting physical exam findings that worsen, must also be recorded 
and documented as adverse events.  
9.1.8. 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study. The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study. The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly in 
a subsequently conceived offspring of a subject that has participated in this study.  
9.1.9. 
Pregnancy 
Sexually active subjects (both females of childbearing potential and males) must be willing to use 
a highly effective method of contraception from screening visit until 6 months (26 weeks) after 
vector administration.  
Male subjects engaged in sexual relationship with a female of childbearing potential will be 
required to use condoms from screening visit until 6 months after vector administration, and must 
also encourage their partner to use a medically accepted method of contraception from screening 
visit until 6 months (26 weeks) after vector administration. 
 

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For the purpose of this study, highly effective methods of contraception include the following: 
1. Combined hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, transdermal) 
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable) 
3. Intrauterine device (IUD) 
4. Intrauterine hormone-releasing system (IUS) 
5. Bilateral tubal occlusion 
6. Vasectomized partner 
7. Sexual abstinence 
Females of childbearing potential must have a negative pregnancy test at screening and baseline 
visits. Pregnancy tests will be repeated at regular intervals throughout the study. Additionally, 
females of childbearing potential must be willing to have additional pregnancy tests during the 
study when steroid treatment is initiated (prior to initiation) and if a menstrual cycle is delayed by 
more than 1 week. 
If the subject or partner of a subject participating in the study becomes pregnant within 6 months 
from vector administration, 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.  
The subject 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 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the investigator should follow the procedures for reporting an 
SAE. 
9.1.10. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if the following 
conditions are met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality. 
 The abnormality suggests a disease and/or organ toxicity. 
 The abnormality is of a degree that requires active management; e.g., change of dose, 
discontinuation of drug, more frequent follow-up assessments, further diagnostic 
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9.1.11. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event if 
the condition meets the criteria for an adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as judged 
by the clinical investigator. 
9.1.12. 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0). The majority of AEs 
can be graded using the CTCAE criteria; however, if an AE cannot be graded using the CTCAE 
criteria, it should be graded according to the following definitions: 
 Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and are of minor 
irritant type causing no loss of time from normal activities. Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient.   
 Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
 Severe (Grade 3): Events interrupt the participant’s normal daily activities and 
generally require systemic drug therapy or other treatment; they are usually 
incapacitating. 
 Life-threatening (Grade 4): Events that place the subject at immediate risk of death 
or are disabling requiring urgent intervention. 
 Death (Grade 5): Events that result in death. 
9.1.13. 
Relationship to Study Drug 
The investigator will assess the potential relationship of the AE to study drug using the following 
definitions: 

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 Not Related: This category applies to an AE that is clearly not related to the 
investigational product/procedure, beyond a reasonable doubt. That is, another cause of 
the event is most plausible; and/or a clinically plausible temporal sequence is 
inconsistent with the onset of the event and the exposure to study drug and/or causal 
relationship is considered biologically implausible. 
 Possibly Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been produced 
by a number of other factors. 
 Probably Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug and that could not be reasonably explained 
by the subject’s concurrent disease or other drugs or chemicals. 
 Definitely Related: This category applies to an AE where there is clear evidence that 
the event is related to the use of study drug. 
An event that has been rated “possibly related,” “probably related” or “definitely related” will be 
classified as “related” for regulatory reporting requirements. An event that has been rated “not 
related” will be classified as “unrelated” for regulatory reporting requirements.  
9.1.14. 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
9.1.15. 
Adverse Events of Special Interest 
Liver function tests abnormalities identified either by the Central Lab or by local labs as part of 
regular medical care have specific reporting requirements. 
 The following adverse events of special interest will require expedited reporting to the sponsor 
within 1 working day, regardless of whether the adverse event meets the definition of a SAE:  
 Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 or higher 
lab result for bilirubin (> 1.5 × ULN) or liver enzymes (AST > 3 × ULN, ALT > 3 × 
ULN, AlkPhos > 2.5 × ULN). 

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 Hepatotoxicity (i.e., meet criteria for “Hy’s law”) 
 ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and no other reason can be 
found to explain the changes observed. This event would meet the study Stopping 
Rules (Section 9.3) 
 
Use of corticosteroids for presumed T-cell mediated immune transaminitis 
All subjects dosed under Protocol version 10 and later will receive a 13 week course of daily 
prednisone beginning on the day prior to dosing (Day -1) and ending with a taper (see Section 
6.5). An increase in ALT or AST (e.g., a doubling from baseline levels or ≥ 2 × ULN) may 
trigger a discussion between the PI and the Sponsor’s Medical Monitor to decide on whether to 
administer or modify the dose of corticosteroids to prevent a potential loss of transgene 
expression. More frequent monitoring of ALT or AST may be considered initially (e.g., every 48-
72 hours) to determine the subject’s response to corticosteroids. The initiation and duration of the 
corticosteroid taper should be dictated by the clinical status of the subject, time course of the 
transaminase elevations, and per the site’s accepted standards of care. Transaminases should be 
monitored more frequently in these subjects until levels consistently decline and/or approach 
normalization.  
9.2. 
Reporting of Serious Adverse Events – Procedures for Investigators 
All SAEs occurring from the time of consent must be reported to Medpace Clinical Safety within 
24 hours of the knowledge of the occurrence. SAEs should be collected through 104 weeks post 
vector administration.   
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access the EDC system, send an email to Medpace Safety at medpace-
safetynotification@medpace.com or call the Medpace SAE hotline (phone number listed below), 
and fax the completed paper SAE form to Medpace (fax number listed below) within 24 hours of 
awareness. When the EDC system becomes available, the SAE information must be entered 
within 24 hours of the system becoming available. 
 
 
 
 
 
 
 
 

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Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
subject 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 (e.g., 
subject 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.  
9.2.1. 
Investigator Reporting 
Each investigator must report to their local regulatory committees as required by their institution.  
9.2.2. 
Regulatory Sponsor Reporting 
The sponsor of the IND/CTA is required to report certain study events in an expedited fashion to 
the FDA and other regulatory agencies. These written notifications of adverse events are referred 
to as safety reports. The following describes the safety reporting requirements by timeline for 
reporting and associated type of event: 
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 regulatory authorities, and in 
any case no later than seven days after knowledge by the sponsor of such a case, and that relevant 
follow-up information will subsequently be communicated within an additional eight days.  
All other suspected unexpected serious adverse reactions will be reported to the regulatory 
authorities as soon as possible but within a maximum of 15 days of first knowledge by the 
sponsor.  
9.3. 
Safety Review and Stopping Rules  
A summary of safety review triggers and expected actions is provided in Table 5. 

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9.3.3. 
Internal Safety Committee (ISC) 
The Internal Safety Committee will be comprised of REGENXBIO employees and designees and 
be charged with Sponsor oversight for the safe conduct of the study. 
10. 
RISK / BENEFIT ASSESSMENT  
10.1. 
Risks 
The clinical safety and efficacy of AAV serotypes carrying a therapeutic transgene is supported 
by an approved gene therapy, GLYBERA® (alipogene tiparvovec; Goldstein et al. 2001) for 
lipoprotein lipase deficiency, as well as by clinical trials for inherited forms of blindness 
(MacLaren et al, 2014; Maguire et al. 2008), hemophilia B (Nathwani et al 2014) and many other 
diseases (Luo et al. 2015). In addition, LUXTURNA™ (voretigene neparvovec), an AAV2 vector 
gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65-
mediated inherited retinal disease, marks the first approved AAV gene therapy in the US 
(Luxturna Prescribing Information, 2017) and Europe. AAV8 has been studied in various human 
diseases as described previously and has a growing track record of safety supporting ongoing 
clinical trials. However, clinical data addressing long-term risks of AAV-mediated gene 
transfer are limited, and the long-term risks remain unknown. 
The Phase I/IIa study is a first-in-human study to evaluate the safety and collect preliminary data 
on efficacy of an AAV8-based vector for gene transfer in patients with HoFH. Because this is a 
new experimental treatment, its risks are largely unknown. Evaluation of potential risks comes 
from preclinical studies and clinical studies that assessed the safety of a similar vector for gene 
transfer in a different disease.  
10.1.1. 
Risks Associated with Gene Transfer  
Potential risks associated with the administration of AAV8.TBG.hLDLR (the gene and gene 
transfer vector) include:  
Humoral Immune response to the vector (AAV8):  
Existing data suggest that the administration of AAV results in a serotype-specific production of 
NAbs and that once these antibodies are present in circulations, re-administration of the same 
vector is ineffective. Thus, participation in this trial may preclude future administration of an 
AAV8-based gene transfer vector, which could be a problem if a sub-therapeutic dose is 
administered. For this reason the lower dose used in the proposed study has been selected to be 
safe and to have realistic potential to result in a clinically relevant LDL lowering. Subjects that at 
screening have a NAb titer against AAV8 greater than 1:10 will be excluded from the study. 
Humoral Immune response to the transgene (LDLR): 
There is the theoretical possibility of the production of antibodies against the transgene product 
LDLR. This has not been observed in preclinical studies conducted up to now. Samples will be 
collected through the study for the assessment of antibodies against LDLR.  
 

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Vector-induced hepatitis and hepatotoxicity:  
Based on observations in the current study, as well as preclinical and clinical studies with a 
similar vector, hepatotoxicity is the most likely treatment-related toxicity. Immune mediated 
transaminitis in some patients is an anticipated consequence of AAV vector administration. While 
not seen in preclinical studies, elevation in other LFTs, such as alkaline phosphatase and 
bilirubin, are also possible. Preclinical data in mice and NHPs suggest a low likelihood of these 
events; however a transient delayed increase in transaminases was observed in previous gene 
therapy trials using similar vector (Nathwani et al. 2014, Baxalta 2015). The possible 
mechanisms of this event are discussed in the Introduction. Because of this anticipated possible 
toxicity, LFTs will be carefully monitored at regular intervals. The Medical Monitor will review 
all LFTs and will consult as needed with the study site, the Sponsor’s Internal Safety Committee 
or other expert consultants (e.g., hepatologist) to discuss any concerns. As suggested by the 
experience of previous and ongoing trials with AAV vectors, increases of transaminases may be a 
sign of T-cell mediated immune transaminitis that is some cases can be associated with loss of 
transgene activity. To limit the immune response, a course of corticosteroids is initiated in those 
clinical trials.  
All subjects dosed under Protocol version 10 and later will receive a 13 week course of daily 
prednisone beginning one day prior to dosing and ending with a taper through Week 13 (see 
Section 6.5). An increase in ALT or AST (e.g., a doubling from baseline levels or ≥ 2 × ULN) 
may trigger a discussion between the PI and the Sponsor’s Medical Monitor to decide on whether 
to administer or modify the dose of corticosteroids to prevent a potential loss of transgene 
expression. 
Risk of integration into the host chromosome  
Recombinant AAV vector genomes display inefficient integration into the host chromosome and 
predominantly persist in episomal form (McCarty et al. 2004). However, there is uncertainty 
regarding the long-term risk of integration. The most extensive experience is with AAV2 
expressing different genes than used in this study. There is one report of an increased incidence of 
hepatocellular carcinomas in mucopolysaccharidosis type VII (MPS VII) mice (a C57BL/6 strain) 
treated neonatally with IV recombinant AAV containing a β-glucuronidase gene and a chicken β-
actin promoter (Donsante et al. 2001). However, the number of affected animals was very small 
and there was no difference in numbers of GCs of vector per diploid genome in tumor tissue 
versus non-tumor tissue, suggesting that the tumors were not related to insertional mutagenesis. 
In a larger and more controlled study that examined the risk of insertional mutagenesis in several 
strains of mice and including specific experimental measures to increase the likelihood of tumor 
promotion, an increase in tumors over mock-infected controls was only observed in C3H/HeJ 
mice, which are much more tumor-prone than C57BL/6 mice (Rosas et al. 2012). Similarly, an 
imbalance of liver tumors was observed in male mice of the B6C3F1 hybrid background that had 
been treated with the LacZ gene. As before, there was no increase in vector DNA in tumor tissue 
relative to non-tumor tissues (Bell et al. 2005). Several other studies in adult mice, monkeys, and 
humans that received AAV vectors have not reported cancer findings at a higher rate than 
controls (Bell et al. 2005, Gil-Farina et al. 2016, Li et al. 2011, Nathwani et al. 2011). In view of 
the relatively high background incidence of hepatocellular neoplasms in mice, albeit varying by 
strain, and the lack of evidence of neoplasms in other tissues, the weight of evidence suggests that 

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recombinant AAV vectors are not carcinogenic (Bell et al. 2006). However, the theoretical 
concern regarding insertional mutagenesis cannot be completely eliminated, although most AAVs 
are episomal and the frequency of integration by recombinant AAV vectors is significantly lower 
than that observed for retroviral vectors. In summary, the risk of tumorigenesis in humans due to 
insertional mutagenesis is unknown but considered low at this time. 
As the true risk of this serious complication is unknown at this time, long-term safety monitoring 
is warranted. Subjects will be followed for up to 104 weeks after vector administration in the 
study and then invited to participate in a longer-term safety follow-up study for up to 5 years’ 
cumulative duration since the vector administration in the parent (previous) study. 
Risk of transfer to the offspring  
A theoretical risk for AAV8.TBG.hLDLR therapy is the transfer of the AAV vector through 
semen to the offspring of the treated subject. In human studies with IV administered AAV2, the 
vector has been found to be detectable in semen for several weeks, but data were consistent with 
the notion that the vector is present in the seminal fluid without transducing motile sperm (Manno 
et al. 2006). This result was corroborated by studies evaluating the risk of germline transmission 
of AAV2 and AAV8 in an animal model (Favaro 2009).  In this study, sexually active subjects 
(both females of childbearing potential and males) must be willing to use a highly effective 
method of contraception from screening visit until 6 months after vector administration. 
10.1.2. 
Risks Associated with Withdrawal of Lipid-lowering Treatment  
Subjects will be allowed to continue conventional lipid-lowering treatment with statin, ezetimibe, 
bile acid sequestrants, PCSK9 inhibitors, and LDL or plasma apheresis, but will be asked to 
withdraw from other lipid lowering drugs at least one month to 24 weeks depending on the 
medication and for 18 weeks (or 4 weeks post steroid termination) following the administration 
of the vector. This will facilitate the assessment of efficacy (a secondary objective) by monitoring 
of LDL-C levels. Withdrawal from selected concomitant medications is a common requirement in 
clinical trials with investigational lipid-lowering treatments, including those in HoFH (Raal et al. 
2000, Raal et al. 2010, Cuchel et al. 2007, Raal et al. 2015). Historical clinical data suggest that 
withdrawal from lipid-lowering drugs for a length of time similar to the one proposed in the 
clinical protocol, does not pose any acute risk to subjects. Although it is probable that during this 
period LDL-C levels will increase, there is no known acute risk associated with 
hypercholesterolemia and no acute events were reported in the cited studies during the wash out 
period. The protocol does not contain any upper limit for LDL-C to trigger a lipid-lowering 
intervention; however, lipid levels will be monitored frequently until additional medication can 
be re-initiated. 
10.1.3. 
Risks of Corticosteroids 
In order to prevent a potential loss of transgene expression, subjects dosed under Protocol version 
10 and later will receive a 13 week course of daily prednisone beginning on study Day -1 and 
ending with a taper (see Section 6.5). Corticosteroids may be administered to any subject in the 
trial with an increase in ALT or AST. Short-term use of corticosteroids such as prednisone may 
cause acne, dizziness, facial flushing, general body discomfort, headache, stomach ache, nausea, 

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increased appetite, weight gain, increased sweating, nausea, nervousness, increased blood sugar, 
and sleeplessness (Prednisone Prescribing Information 2016).  
Any adverse event that is thought to be at least possibly related to the steroid prophylaxis will be 
treated as per standard of care. 
Patients that for their pre-existing conditions may be at higher risk of onset of steroid associated 
adverse events will receive ad-hoc monitoring.   Eligible patients with a diagnosis of heart failure 
will be asked to monitor their weight daily while on prophylaxis steroid treatment, keep a daily 
chart, and instructed to promptly notify the study team if a weight gain of > 2 pounds is noted 
within 1 -2 days. It is responsibility of the study team to ensure appropriate communication with 
the patients’ cardiologist to provide additional treatment as per standard of care.  Eligible patients 
with a diagnosis of diabetes will have their fasting glucose levels monitored at time of the weekly 
lab draw during the length of steroid treatment. Urgent consult for initiation or intensification of 
insulin therapy will be required for fasting glucose levels ≥200 mg/dl.  It is responsibility of the 
study team to ensure appropriate communication with the physician that follow the subjects’ 
diabetes to provide additional treatment as per standard of care if the steroid treatment is 
associated with worsening of diabetes. 
10.1.4. 
Phlebotomy Risks 
Risks and discomfort associated with venipuncture and presence of an IV catheter are minor and 
include swelling, bruising/bleeding at the site, fainting, and, more rarely, the risk of infection at 
the needle puncture site and the possibility of a clogged catheter that requires replacement. These 
risks are associated with blood draw during laboratory testing, or with infusion of the 
AAV8.TBG.hLDLR or the deuterated leucine. These risks are modest and minimized by use of 
good clinical techniques. 
 
 
10.2. 
Potential Study Benefits 
Patients with HoFH are minimally responsive to available conventional drug therapy and have 
limited treatment options. Thus, if efficacy and safety are confirmed, the primary benefit of the 
proposed study is the potential of AAV8.TBG.hLDLR gene transfer to significantly lower LDL-
C levels and improve response to lipid lowering drugs, such as PCSK9 inhibitors. It may also 
allow a reduction in the frequency of or requirement for apheresis. Furthermore, the lower LDL-
C levels could impact favorably atherosclerosis progression in HoFH patients.  
10.3. 
Benefit:Risk Assessment 
AAV8.TBG.hLDLR is an investigational biologic that is being developed for the treatment of 
HoFH, a life-threatening disease characterized by absence of a functional LDLR, severe 
hypercholesterolemia and development of severe atherosclerotic cardiovascular disease 
(ASCVD) in childhood or adolescence. Current therapy is inadequate to prevent the development 
of serious cardiovascular disease. LDLR expression in the liver plays a crucial role in the control 
of circulating LDL cholesterol levels. Liver-directed stable gene delivery and expression of the 
LDLR would allow an improved response to existing and novel therapies that would result in a 
substantial improvement of the disease management, also in absence of a complete normalization 

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of the hypercholesterolemia. Thus benefit:risk assessment based on all available information 
appear to be acceptable with the potential for a clinically significant LDL lowering accompanied 
by relatively low probability of serious toxicity. Furthermore, HoFH could be a model for the 
development of liver-directed gene therapy for the treatment of other conditions. Refer also to 
Section 1.5 for review of the clinical data available from other AAV based gene therapy 
programs.  
10.4. 
Alternatives to Participation 
The alternative to participation is not to participate. 
11. 
DATA HANDLING AND RECORD KEEPING 
11.1. 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the 
end of their scheduled study period. 
11.2. 
Source Document and Case Report Forms 
It is the Investigator’s responsibility to prepare and maintain adequate and accurate case histories 
that record all observations and other data related to the study for each subject. Case histories 
include the CRFs, and supporting data (i.e. Source Documents) such as signed and dated ICFs, 
medical records, laboratory reports, etc. Case histories for each subject will document that 
informed consent was obtained prior to participation in the study. 
A validated Electronic Data Capture (EDC) system will be used for entry of the data into 
electronic CRFs designed. All data entered in to the CRF must be verifiable; therefore, CRFs will 
be routinely monitored for accuracy, completeness, and clarity and will be cross-checked for 
consistency with source documents. 
11.3. 
Data Quality Assurance 
During routine monitoring visits, the Monitor will perform source data verification (SDV) against 
CRFs to ensure data accuracy, completeness, and clarity including laboratory reports and other 

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subject records with the stipulation that subject confidentiality will be strictly maintained in 
accordance with local and federal regulations, including HIPAA requirements. Instances of 
missing or uninterpretable data will be resolved in coordination with the Investigator. 
In addition to routine monitoring of the data by the Monitor, the electronic data capture (EDC) 
system will include internal quality controls by employing Skip Logics and Edit Checks. Skip 
Logics are programs in the database that restricts entry to particular data fields based on previous 
entered data thus restricting the entry of irrelevant data. Edit Checks are a set of programmed 
instructions in the database to identify and flag discrepancies in the entered data. 
11.4. 
Records Retention 
All study-related documents must be retained for at least 2 years after the last approval of a 
marketing application or until at least 2 years have elapsed since the formal discontinuation of the 
clinical development of the IP. These documents should be retained for a longer period, however, 
if required by the applicable regulatory requirements or by an agreement with the Sponsor. All 
study-related documents must be stored in a secure limited access facility. 
12. 
STUDY MONITORING, AUDITING, AND INSPECTING 
12.1. 
Study Monitoring Plan 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH E6 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 subject in this study, the Sponsor or their designee will review with 
Investigator and site personnel the following documents: protocol, IB, eCRFs 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 eCRFs 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 corrections 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. Description of monitoring and 
reporting activities are provided in Data and Safety Monitoring Plan. 
12.2. 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies and quality assurance groups of all study related 
documents (e.g., source documents, regulatory documents, data collection instruments, study data 

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etc.). The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities’ quality assurance offices. 
13. 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to applicable ICH GCP and FDA regulations and local 
and Institutional research policies and procedures. This protocol and any amendments will be 
submitted to a properly constituted independent IRB/EC, in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IRB/EC concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study. The investigator should 
provide a list of EC/IRB members or Federalwide Assurance (FWA) number and their affiliate to 
the sponsor. 
All subjects for this study will be provided a consent form, describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study. The formal consent of a subject, using the EC/IRB-approved consent form, 
must be obtained before that subject undergoes any study procedure. The consent form must be 
signed and dated by the subject, and the investigator-designated research professional obtaining 
the consent.  
14. 
STUDY FINANCES 
14.1. 
Funding Source 
Funding sources for this trial are the National Heart, Lung, and Blood Institute (NHLBI).  
14.2. 
Conflict of Interest 
All Investigators will be responsible for following the applicable policies related to review and 
management of conflicts of interests at their respective institutions.  
15. 
PUBLICATION PLAN 
Reporting and publication planning shall follow applicable guidelines of the International 
Committee of Medical Journal Editors. Neither the complete nor any part of the results of the 
study carried out under this protocol, nor any of the information provided by the sponsor for the 
purposes of performing the study, will be published or passed on to any third party without the 
consent of the study sponsor or as otherwise permitted in accordance with the clinical trial 
agreement for this study. Any investigator involved with this study is obligated to provide the 
study sponsor with complete test results and all data derived from the study. 

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Study information from this protocol will be posted on www.clinicaltrials.gov within 21 days of 
enrollment of the first participant. 
Where required by applicable regulatory requirements, an investigator signatory will be identified 
for the approval of the clinical trial report. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results at a Sponsor site or other mutually agreeable location. 
The Sponsor will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as appropriate. 
The results summary will be posted to www.clinicaltrials.gov no later than 12 months after the 
last subject’s last visit or sooner, if required by legal agreement, local law, or regulation. A 
manuscript will be processed for publication in the scientific literature if the results provide 
important scientific or medical knowledge and will be submitted to a peer-reviewed journal for 
publication. 
 

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