An Open Label Multicenter Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of SBC-102 in Adult Subjects With Liver Dysfunction Due to Lysosomal Acid Lipase Deficiency Who Previously Received Treatment in Study LAL-CL01
Phase: PHASE2
Conditions: Cholesterol Ester Storage Disease (CESD), Lysosomal Acid Lipase Deficiency, LAL-Deficiency
Sponsor: Alexion Pharmaceuticals, Inc.

AN OPEN LABEL MULTICENTER EXTENSION STUDY 
TO EVALUATE THE LONG-TERM SAFETY, 
TOLERABILITY, AND EFFICACY OF SBC-102 IN 
ADULT SUBJECTS WITH LIVER DYSFUNCTION DUE 
TO LYSOSOMAL ACID LIPASE DEFICIENCY WHO 
PREVIOUSLY RECEIVED TREATMENT IN 
STUDY LAL-CL01 
 
 
 
Unique Protocol ID: 
LAL-CL04 
NCT Number 
NCT01488097 
EudraCT Number 
2011-001513-13 
Date of Protocol 
05 January 2016 
 
 
 

LAL-CL04 Protocol Amendment 6.0 
 
05 January 2016 
AN OPEN LABEL MULTICENTER EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY, TOLERABILITY, AND 
EFFICACY OF SBC-102 IN ADULT SUBJECTS WITH LIVER 
DYSFUNCTION DUE TO LYSOSOMAL ACID LIPASE 
DEFICIENCY WHO PREVIOUSLY RECEIVED TREATMENT IN 
STUDY LAL-CL01 
 
 
Protocol Number:  
LAL-CL04 
Date of Protocol: 
05 January 2016 
Amendment: 
6.0 
Product: 
Sebelipase alfa (SBC-102) 
IND No.: 
108460 
EudraCT No.: 
2011-001513-13 
Sponsor: 
Alexion Pharmaceuticals, Inc.  
352 Knotter Drive 
Cheshire, CT 06410 
USA 
 
 
 
Amendment History 
Protocol 
Date of Approval 
Original 
25 March 2011 
Amendment 1.0 
17 June 2011 
Amendment 2.0 (country-specific: United Kingdom) 
03 October 2011 
Amendment 3.0  
24 January 2012 
Amendment 4.0 
13 February 2013 
Amendment 5.0 
25 September 2014 
Amendment 6.0 
05 January 2016 
 
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PROTOCOL SIGNATURE PAGE 
Protocol title: 
Protocol Number: 
Date of Protocol: 
Amendment: 
Product: 
IND No.: 
EudraCT No.: 
Sponsor: 
An Open Label Multicenter Extension Study to Evaluate the 
Long-Term Safety, Tolerability, and Efficacy of SBC-102 in 
Adult Subjects with Liver Dysfunction Due to Lysosomal Acid 
Lipase Deficiency Who Previously Received Treatment in 
Study LAL-CL01 
LAL-CL04 
05 January 2016 
6.0 
Sebelipase alfa (SBC-1 02) 
108460 
2011-001513-13 
Alexion Pharmaceuticals, Inc. 
352 Knotter Drive 
Cheshire, CT 06410 
USA 
fr; T !bv 
Date 
Alexion Pharmaceuticals, Inc. 
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PPD

LAL-CL04 Protocol Amendment 6.0 
 
05 January 2016 
INVESTIGATOR AGREEMENT 
 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol and will only make changes in the protocol after notifying the Sponsor. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes 
necessary to protect the best interests of the study subjects.  This study may be terminated at 
any time by the Sponsor, with or without cause. 
 
I agree to personally conduct or supervise this investigation and to ensure that all associates, 
colleagues, and employees assisting in the conduct of this study are informed about their 
obligations in meeting these commitments. 
 
I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, 
and the moral, ethical and scientific principles that justify medical research.  The study will be 
conducted in accordance with all relevant laws and regulations relating to clinical studies and 
the protection of subjects.  
 
I will ensure that the requirements relating to Institutional Review Boards/Independent Ethics 
Committees (IRB/IEC) review and approval are met.  I will provide the Sponsor with any 
material which is provided to the IRB/IEC for ethical approval. 
 
I agree to maintain adequate and accurate records and to make those records available for 
audit and inspection in accordance with relevant regulatory requirements. 
 
I agree to promptly report to the IRB/IEC any changes in the research activity and all 
unanticipated problems involving risks to human subjects or others.  Additionally, I will not make 
any changes in the research without IRB/IEC approval, except where necessary to ensure the 
safety of study participants. 
 
 
 
____________________________________   _____________________________________ 
Print Name                                                          Institution 
 
 
_______________________________________ 
_____________________ 
Signature 
 
 
 
 
 
Date 
 
 
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LAL-CL04 Protocol Amendment 6.0 
 
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Protocol Synopsis 
Title 
An Open Label Multicenter Extension Study to Evaluate the Long-Term Safety, 
Tolerability, and Efficacy of SBC-102 in Adult Subjects with Liver Dysfunction 
Due to Lysosomal Acid Lipase Deficiency Who Previously Received Treatment 
in Study LAL-CL01 
Protocol Number 
LAL-CL04 
Phase 
Phase 2 
Methodology 
This Phase 2, open-label, extension study will evaluate the long-term safety, 
tolerability, and efficacy of sebelipase alfa (SBC-102) in adult subjects with liver 
dysfunction due to Lysosomal Acid Lipase (LAL) Deficiency who previously 
received 4 doses of sebelipase alfa in the Phase 1/2 repeat-dose, dose 
escalation study (Study LAL-CL01).  
After completing all follow-up assessments for study LAL-CL01 (and no sooner 
than 4 weeks after the last dose in that study), eligible subjects will initiate 
treatment in the current extension study at a once-weekly (qw) dose of 
sebelipase alfa equivalent to the dose administered during their fourth infusion in 
study LAL-CL01.  After the 4th infusion under this protocol, all subjects will move 
to an every other week (qow) dosing regimen of 1 or 3 mg/kg.  Subsequent dose 
modifications may be considered for individual subjects based on observed 
safety and tolerability and/or clinical response to treatment after Week 12.  All 
such decisions will be made jointly by the Investigator and Sponsor. 
Safety, tolerability, and efficacy assessments will be conducted at regular 
intervals throughout the extension study.  In addition, blood samples will be 
obtained at selected timepoints for analysis of sebelipase alfa pharmacokinetics 
(PK) and biomarkers of sebelipase alfa pharmacodynamic (PD) activity.  Blood 
and urine samples will also be collected for an exploratory analysis of potential 
disease-related biomarkers in this patient population, and Health-Related Quality 
of Life (HRQOL) will be assessed through subject questionnaires. 
A follow-up visit will be conducted for all subjects at 30 (+7) days after the last 
dose of investigational medicinal product (IMP). 
Study Duration 
Treatment under this protocol is expected to continue for approximately five (5) 
years. 
Study Center(s) 
Approximately 9 primary study centers will participate in this study. 
At any time during the extension study, a subject may choose to transfer to a 
local medical center to receive their IMP infusions.  Scheduled study 
assessments may also be performed at the local medical center provided that 
the center has access to the appropriate facilities and expertise. 
Home infusions may be permitted for subjects who have been on a stable dosing 
regimen of sebelipase alfa for at least 12 months and have had no infusion-
associated reactions (IARs) requiring medical intervention/management and no 
serious adverse events (SAEs) related to IMP within the prior 6 months. 
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Objectives 
The primary objective of the study is to evaluate the long-term safety and 
tolerability of sebelipase alfa in subjects with liver dysfunction due to 
LAL Deficiency. 
The secondary objectives are (1) to evaluate the long-term efficacy of 
sebelipase alfa in subjects with liver dysfunction due to LAL Deficiency; (2) to 
characterize repeat-dose pharmacokinetics of sebelipase alfa delivered by 
intravenous (IV) infusion; and (3) to determine the effect of sebelipase alfa on 
pharmacodynamic biomarkers. 
The exploratory objectives are (1) to determine the effect of sebelipase alfa on 
patient 
HRQOL 
measures; 
(2) 
to 
evaluate 
the 
acceptability 
of 
an 
everyother week dosing regimen of sebelipase alfa, and (3) to evaluate liver 
histology. 
Number of 
Subjects 
Up to 9 subjects will be enrolled in this study after successfully completing 
treatment in study LAL-CL01. 
Main Inclusion 
and Criteria for 
Evaluation 
A subject must meet all of the following inclusion criteria to be eligible for this 
study: 
1. Subject understands the full nature and purpose of the study, including 
possible risks and side effects, and is willing and able to comply with all 
study procedures and provide informed consent. 
2. Subject received all 4 scheduled doses of sebelipase alfa in study LAL-CL01 
with no life-threatening or unmanageable study drug toxicity.  
3. Female subjects have a negative serum pregnancy test at screening, and 
are not breast-feeding. 
4. Female subjects of childbearing potential are willing and able to use a highly 
effective and approved contraceptive method(s) from the date of informed 
consent until 30 days after last dose of IMP. 
A subject who meets any of the following exclusion criteria will be ineligible for 
this study: 
1. Clinically significant concurrent disease, serious inter-current illness, 
concomitant medications, or other extenuating circumstances that, in the 
opinion of the Investigator, would interfere with study participation or the 
interpretation of the effects of sebelipase alfa. 
2. Clinically significant abnormal values on screening laboratory tests, other 
than liver function or lipid panel tests.  Subjects with an abnormal laboratory 
value that is of borderline significance may be allowed to undergo repeat 
testing once within a 30-day period. 
Investigational 
Medicinal 
Product, Dose, 
Route, Regimen 
Sebelipase alfa (SBC-102), a recombinant human lysosomal acid lipase 
(rhLAL) produced in the transgenic Gallus, will be administered by IV infusion.  
The following dosing regimens of sebelipase alfa may be administered in 
this study: 0.35 mg/kg qw, 1 mg/kg qw, 3 mg/kg qw, 1 mg/kg qow, and 
3 mg/kg qow. 
Subjects will initiate treatment in the extension study at least 30 days after their 
last dose of sebelipase alfa in study LAL-CL01.  Each subject will initiate 
treatment in the extension study at the same once-weekly dose of sebelipase 
alfa that he/she received during the fourth infusion in study LAL-CL01, 
i.e., 0.35 mg/kg qw, 1 mg/kg qw, or 3 mg/kg qw.  Subsequent modifications to 
the dose and dosing frequency will be undertaken for individual subjects as 
outlined below based on observed safety and tolerability and clinical response to 
treatment.  All such decisions will be made jointly by the Investigator and 
Sponsor: 
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• 
At Week 6 (and after at least 4 infusions in the extension study), subjects 
receiving a starting dose of 0.35 mg/kg qw or 1 mg/kg qw will have their 
dose changed to 1 mg/kg qow.  Similarly, subjects who were receiving a 
starting dose of 3 mg/kg qw for the first 4 infusions will transition to the 
3 mg/kg qow regimen. 
• 
After Week 12, subjects receiving a dose of 1 mg/kg qow may have their 
dose increased to 3 mg/kg qow based on observed safety and 
tolerability and/or clinical response to treatment. 
• 
After Week 12, subjects receiving a dose of 3 mg/kg qow may be 
considered for a dose adjustment to 3 mg/kg qw based on observed 
safety and tolerability and/or clinical response to treatment. 
• 
In the event of poor tolerability at any time during the extension study, 
the dose may be reduced at the discretion of the Investigator.  If a 
subject cannot tolerate the lowest starting dose (0.35 mg/kg qw) despite 
measures taken to manage any IARs, he/she will be discontinued from 
treatment. 
Duration of IMP 
administration 
The duration of each subject’s treatment in the study will vary but is expected to 
be at least 26 weeks and approximately 5 years. 
Reference 
therapy 
No reference therapy will be administered in this study. 
Criteria for 
Evaluation 
Safety 
The primary safety endpoints will include the incidence of adverse events (AEs) 
SAEs, and IARs; changes in vital signs (blood pressure, heart rate, respiratory 
rate, and temperature), physical examination findings, 12-lead electrocardiogram 
(ECG) parameters, and clinical laboratory tests (CBC/hematology, serum 
chemistry and urinalysis); use of concomitant medications/therapies; and 
characterization of anti-sebelipase alfa anti-drug antibodies (ADAs), including 
ADA positive rate, time to ADA positivity, peak ADA titer, and time to peak ADA 
titer.  The effect of ADAs on the safety of sebelipase alfa will also be explored.  A 
further characterization of ADAs, including inhibitory ADAs, may be performed as 
a separate pooled analysis across studies, and will be reported separately from 
this protocol. 
Efficacy 
Efficacy assessments will include change and/or percent change in liver and 
spleen volumes by magnetic resonance imaging (MRI), liver and spleen fat 
content by MRI and 1H-magnetic resonance spectroscopy (MRS) (if available), 
and liver cholesteryl ester signature by 13C- MRS (in a subset of subjects 
receiving treatment at sites with access to this imaging technology).  Histologic 
assessment of liver disease will be evaluated in subjects who agree to an 
optional liver biopsy.  The effect of ADAs on the efficacy of sebelipase alfa will 
also be explored. 
Pharmacodynamics 
Pharmacodynamic endpoints will include change in serum transaminases, serum 
lipids, and acute phase reactants (e.g., serum ferritin).  The effect of ADAs on 
the PD of sebelipase alfa will also be explored. 
Exploratory disease-related biomarkers, which may be identified based on 
emerging information from the sebelipase alfa development program and 
scientific literature, will be analyzed by changes or percent changes from 
baseline. 
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Health-Related Quality of Life (HRQOL) Outcomes 
Health-Related Quality of Life measures will include changes in scores for the 
36-item Short Form Health Survey (SF-36®), Functional Assessment of Chronic 
Illness Therapy (FACIT)-Fatigue scale, and Chronic Liver Disease Questionnaire 
(CLDQ). 
Pharmacokinetics 
PK parameters will include maximum observed serum concentration (Cmax), 
minimum observed serum concentration (Cmin), area under the serum 
concentration-time curve from time zero extrapolated to infinity (AUCinf), terminal 
elimination half-life (T1/2), apparent serum clearance (CL), and steady state 
volume of distribution (Vss).  The effect of ADAs on sebelipase alfa PK will also 
be explored. 
Statistical 
Methodology 
Sample size is based on the estimated total enrollment in study LAL-CL01, and 
assumes that all subjects treated in that study will be eligible and willing to 
participate in this extension study. 
Data collected in this study will be reported using summary tables, graphs and 
subject data listings.  All subject data listings will be sorted by subject number.  
Descriptive summary statistics (n, mean, median, standard deviation, minimum 
and maximum) will be calculated for the continuous variables and shift tables 
and/or frequencies and percentages will be produced for the categorical 
variables.  As noted, 95% two-sided confidence interval (CI) will be 
calculated around the estimates based on the exact binomial distribution for 
categorical endpoints and the t-distribution for continuous endpoints.  Effect 
of anti-drug antibodies will be examined for efficacy, safety, PD, and PK 
endpoints.  Numbers permitting, analyses may be conducted in other subgroups 
of interest. 
Baseline will be defined as the last measurement prior to the first infusion of 
sebelipase alfa in study LAL-CL04.  As appropriate, a CL01 Study Baseline, 
defined as the last measurement prior to the first infusion in study LAL-CL01, 
may also be used for selected study endpoints.  For endpoints that are 
computed as changes from baseline, a comparison between change from 
Baseline and change from the CL01 Study Baseline will be performed, as 
appropriate.  Unless otherwise noted, all tabulations will present data overall and 
by dose and dosing frequency (qw, qow), i.e., dosing regimen. 
Details of the planned analyses and statistical methodologies will be provided in 
a separate Statistical Analysis Plan (SAP). 
Safety 
Safety will be analyzed using the Safety Analysis Set.  As appropriate, the effect 
of dosing regimen and/or treatment duration on safety endpoints will also be 
explored.  
Observed measurements and changes from baseline to each study timepoint in 
vital signs, clinical laboratory data, and 12-lead ECG parameters will be 
summarized.  For laboratory data, clinically significant abnormal values will be 
listed, and frequencies of abnormal values relative to the laboratory normal 
range and clinically significant abnormal values will be summarized.  Abnormal 
findings/values for physical examinations, vital signs, and ECGs will also be 
listed.  The number and percentages of subjects receiving each concomitant 
medication/treatment will be tabulated.  The percentage of subjects who become 
ADA positive, time to ADA positivity and time to peak titer, and median and peak 
immunoglobulin G (IgG) antibody titer will be summarized; IgG antibody titer 
values will be tabulated using summary statistics at each study visit. 
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All AEs, SAEs, and IARs will be listed, and the number and percent of subjects 
experiencing any AE, any SAE, any IAR, any related AE, any related SAE, and 
discontinuations due to an AE will be tabulated, Treatment-emergent AEs, SAEs, 
and IARs will be tabulated by system organ class and preferred term, for all 
events and for events by severity and causality.  As appropriate, additional 
listings and summary statistics will be generated to evaluate IAR frequency and 
severity over time.  A listing of subjects who withdraw from the study due to AEs 
will be presented, and the incidence of AEs leading to study discontinuation will 
be summarized. 
Efficacy, Pharmacodynamics, and Patient Health-Related Quality of Life 
(HRQOL) Outcomes 
Efficacy, PD, and HRQOL outcomes will be analyzed using the Full Analysis Set.  
Observed measurements and changes or percent changes from baseline to 
study timepoints in liver and spleen volumes, liver and spleen fat content, liver 
cholesteryl ester signature, serum transaminases, plasma lipids, and acute 
phase reactants (e.g., serum ferritin) will be summarized overall and by dosing 
regimen.  The percentage of subjects with abnormal transaminases at each 
timepoint will also be summarized overall and by dosing regimen.  Scores and 
changes from baseline to study timepoints in the SF-36®, FACIT-Fatigue, and 
CLDQ will be summarized.  Histologic assessments of liver disease will be 
described. 
Pharmacokinetics 
Pharmacokinetics will be characterized using the PK Analysis Set.  Cmax and Cmin 
will be recorded from direct observation, and other PK parameters will be derived 
by non-compartmental analysis.  All PK parameters will be summarized by 
dosing regimen. 
Analysis Sets 
The following populations are proposed for analysis of study endpoints: 
Full Analysis Set 
The Full Analysis Set (FAS) will include all subjects who received at least one 
complete infusion of IMP in the extension study and have at least one 
post-treatment measurement in the extension study. 
Safety Analysis Set 
The Safety Analysis Set will include all subjects who received any amount of IMP 
in the extension study.   
PK Analysis Set 
The PK Analysis Set will include all available sebelipase alfa serum 
concentration data for subjects who received at least one complete infusion of 
IMP in the extension study. 
Per Protocol Analysis Set 
The Per Protocol Analysis Set will consist of all subjects in the FAS who have no 
protocol violations that could potentially confound the interpretation of serum 
transaminase or lipid results.  The list of subjects to be included in the per-
protocol analysis set will be determined before database lock.  If all patients in 
the FAS are also in the per-protocol analysis set, then separate analyses for the 
per-protocol analysis set will not be performed. 
Interim Analysis 
A clinical study report (CSR) of interim data will be produced to support 
regulatory filings.  A final CSR to summarize long-term efficacy, safety, and PK 
parameters will be produced at study completion, which will include data on all 
patients in the study for approximately 5 years.  No inferential statistical analyses 
are planned. 
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Table of Contents 
 
PROTOCOL SYNOPSIS .............................................................................................................................. 4 
LIST OF ABBREVIATIONS AND TERMS ................................................................................................. 12 
1 
INTRODUCTION ....................................................................................................................... 14 
1.1 
BACKGROUND .............................................................................................................................. 14 
1.1.1 
Lysosomal Acid Lipase Deficiency ........................................................................................ 14 
1.1.2 
Late Onset LAL Deficiency .................................................................................................... 14 
1.1.3 
Medical Plausibility for Enzyme Replacement Therapy for LAL Deficiency .......................... 15 
1.2 
INVESTIGATIONAL AGENT .............................................................................................................. 16 
1.3 
NONCLINICAL DATA ...................................................................................................................... 16 
1.4 
CLINICAL DATA ............................................................................................................................ 17 
1.5 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 18 
1.5.1 
Dose Rationale ...................................................................................................................... 18 
1.5.2 
Risk/Benefit Assessment ....................................................................................................... 19 
2 
STUDY OBJECTIVES ............................................................................................................... 21 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 21 
2.2 
SECONDARY OBJECTIVE ............................................................................................................... 21 
2.3 
EXPLORATORY OBJECTIVE ........................................................................................................... 21 
3 
STUDY DESIGN ........................................................................................................................ 22 
3.1 
OVERVIEW OF STUDY DESIGN ...................................................................................................... 22 
3.2 
RATIONALE FOR STUDY DESIGN.................................................................................................... 23 
3.2.1 
Dose Selection ...................................................................................................................... 23 
3.2.2 
Outcome Variable Selection .................................................................................................. 23 
3.2.3 
Study Duration ....................................................................................................................... 25 
4 
STUDY POPULATION .............................................................................................................. 25 
4.1 
TARGET POPULATION ................................................................................................................... 25 
4.2 
NUMBER OF SUBJECTS ................................................................................................................. 25 
4.3 
INCLUSION CRITERIA .................................................................................................................... 25 
4.4 
EXCLUSION CRITERIA ................................................................................................................... 26 
4.5 
CONCOMITANT MEDICATIONS AND TREATMENTS............................................................................ 26 
4.6 
DISCONTINUATION OF SUBJECTS FROM TREATMENT OR ASSESSMENT ............................................ 27 
4.6.1 
Premature Withdrawal from Study Participation ................................................................... 27 
4.6.2 
Procedures for Discontinuation ............................................................................................. 27 
4.7 
SUBJECT REPLACEMENT POLICY .................................................................................................. 28 
4.8 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 28 
5 
SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES ............................................ 28 
5.1 
STUDY ASSESSMENTS .................................................................................................................. 28 
5.1.1 
Informed Consent .................................................................................................................. 28 
5.1.2 
Subject Eligibility.................................................................................................................... 28 
5.1.3 
Medical History ...................................................................................................................... 28 
5.1.4 
Demographic Information ...................................................................................................... 29 
5.1.5 
Physical Examination ............................................................................................................ 29 
5.1.6 
Health-Related Quality of Life (HRQOL) Outcomes .............................................................. 29 
5.1.7 
Abdominal MRI/MRS ............................................................................................................. 30 
5.1.8 
Vital Signs .............................................................................................................................. 30 
5.1.9 
Electrocardiogram ................................................................................................................. 30 
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5.1.10 
Laboratory Assessments .................................................................................................. 31 
5.1.11 
Exploratory Biomarkers ..................................................................................................... 32 
5.1.12 
Pharmacokinetic Assessments ......................................................................................... 32 
5.1.13 
Liver Biopsy ....................................................................................................................... 33 
6 
TREATMENTS .......................................................................................................................... 33 
6.1 
TREATMENTS ADMINISTERED ........................................................................................................ 33 
6.1.1 
Dose Escalation..................................................................................................................... 34 
6.1.2 
Dose Reduction ..................................................................................................................... 34 
6.1.3 
Home Infusions...................................................................................................................... 35 
6.2 
DESCRIPTION OF IMP ................................................................................................................... 35 
6.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT ..................................................................... 35 
6.4 
RECEIPT, STORAGE, AND DISPOSITION OF IMP ............................................................................. 35 
6.4.1 
Receipt of IMP ....................................................................................................................... 35 
6.4.2 
Storage .................................................................................................................................. 36 
6.4.3 
Disposition ............................................................................................................................. 36 
6.5 
PREPARATION AND ADMINISTRATION OF IMP ................................................................................. 36 
6.5.1 
Preparation of IMP ................................................................................................................ 36 
6.5.2 
Administration of IMP ............................................................................................................ 36 
6.6 
BLINDING OF IMP ......................................................................................................................... 37 
6.7 
DESTRUCTION OF IMP ................................................................................................................. 37 
7 
ASSESSMENT OF SAFETY ..................................................................................................... 38 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES ................................................................... 38 
7.1.1 
Clinical Adverse Events ......................................................................................................... 38 
7.1.2 
Laboratory Test Abnormality ................................................................................................. 40 
7.1.3 
Infusion Associated Reactions .............................................................................................. 40 
7.2 
HANDLING OF SAFETY PARAMETERS ............................................................................................. 41 
7.2.1 
Serious Adverse Events (Immediately Reportable to the Sponsor) ...................................... 41 
7.2.2 
Adverse Event Reporting Period ........................................................................................... 41 
7.2.3 
Treatment and Follow-up of Adverse Events ........................................................................ 42 
7.2.4 
Follow-up of Abnormal Laboratory Test Values .................................................................... 42 
7.2.5 
Pregnancy ............................................................................................................................. 42 
7.3 
RECORDING OF ADVERSE EVENTS ................................................................................................ 42 
7.4 
REPORTING OF SERIOUS ADVERSE EVENTS, INFUSION ASSOCIATED REACTIONS AND 
UNANTICIPATED PROBLEMS .......................................................................................................... 43 
7.4.1 
Investigator Reporting: Notifying the Sponsor ....................................................................... 43 
7.4.2 
Investigator Reporting: Notifying the IRB/IEC ....................................................................... 44 
7.4.3 
Sponsor Reporting: Notifying Regulatory Authorities ............................................................ 44 
7.4.4 
Notifying Participating Investigators ...................................................................................... 44 
7.5 
MEDICAL MONITORING ................................................................................................................. 44 
7.5.1 
Independent Safety Committee ............................................................................................. 44 
7.6 
DOSE MODIFICATION AND STOPPING RULES.................................................................................. 45 
8 
STATISTICAL PLAN................................................................................................................. 46 
8.1 
GENERAL CONSIDERATIONS ......................................................................................................... 46 
8.2 
DETERMINATION OF SAMPLE SIZE ................................................................................................. 46 
8.3 
ANALYSIS SETS ........................................................................................................................... 47 
8.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................................... 47 
8.5 
SUBJECT ACCOUNTABILITY ........................................................................................................... 47 
8.6 
STUDY TREATMENT USAGE AND COMPLIANCE ............................................................................... 47 
8.7 
SAFETY ANALYSIS ........................................................................................................................ 48 
8.7.1 
Adverse Events ..................................................................................................................... 48 
8.7.2 
Clinical Laboratory Tests ....................................................................................................... 48 
8.7.3 
Other Safety Data .................................................................................................................. 48 
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8.8 
EFFICACY, PHARMACODYNAMIC, AND PATIENT HEALTH-RELATED QUALITY OF LIFE (HRQOL) 
OUTCOMES ANALYSES ................................................................................................................. 49 
8.9 
PHARMACOKINETICS .................................................................................................................... 49 
8.10 
OTHER STATISTICAL ISSUES ......................................................................................................... 49 
8.10.1 
Significance Levels ........................................................................................................... 49 
8.11 
MISSING OR INVALID DATA ............................................................................................................ 49 
8.12 
INTERIM ANALYSIS ....................................................................................................................... 49 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................... 50 
9.1 
CONFIDENTIALITY ......................................................................................................................... 50 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 50 
9.3 
CASE REPORT FORMS ................................................................................................................. 50 
9.4 
RECORDS RETENTION .................................................................................................................. 50 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .......................................................... 51 
10.1 
STUDY MONITORING PLAN............................................................................................................ 51 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 51 
11 
ETHICAL CONSIDERATIONS ................................................................................................. 52 
12 
CLINICAL STUDY REPORT AND PUBLICATION PLAN ....................................................... 53 
13 
REFERENCES .......................................................................................................................... 54 
14 
APPENDICES ........................................................................................................................... 56 
APPENDIX A: SCHEDULES OF ASSESSMENTS .............................................................................................. 57 
APPENDIX B: SF-36® V2 HEALTH SURVEY ................................................................................................. 61 
APPENDIX C: FACIT FATIGUE SCALE......................................................................................................... 67 
APPENDIX D: THE CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ) ........................................................ 68 
APPENDIX E: DOSE MODIFICATION AND STOPPING RULES FOR STUDY LAL-CL04 ....................................... 74 
APPENDIX F: DIAGNOSIS AND MANAGEMENT OF INFUSION ASSOCIATED REACTIONS .................................... 75 
 
List of Tables 
Table 1 
Assessment of Causality ............................................................................................................. 39 
 
List of Figures 
Figure 1 
Study Flow Diagram ..................................................................................................................... 23 
 
 
 
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List of Abbreviations and Terms 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ALT/SGPT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST/SGOT 
Aspartate Aminotransferase 
AUCinf 
Area Under the Serum Concentration-time Curve from Time 
Zero Extrapolated to Infinity 
CBC 
Complete Blood Count 
CESD 
Cholesteryl  Ester Storage Disease 
CI 
Confidence Interval 
CL 
Apparent Serum Clearance 
CLDQ 
Chronic Liver Disease Questionnaire 
Cmax 
Maximum Observed Serum Concentration 
Cmin 
Minimum Observed Serum Concentration 
CRP 
C- Reactive Protein 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
ERT 
Enzyme Replacement Therapy 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue  
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GlcNAc 
N-acetylglucosamine 
GGTP 
Gamma Glutamyl Transpeptidase 
GI 
Gastrointestinal 
HDL 
High Density Lipoprotein 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HRQOL 
Health-Related Quality of Life 
IAR 
Infusion Associated Reaction 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
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IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intra Uterine Device 
IV 
Intravenous 
LAL 
Lysosomal Acid Lipase 
LDL 
Low Density Lipoprotein 
LSD 
Lysosomal Storage Disorder 
M6P 
Mannose-6-Phosphate 
MCV 
Mean Corpuscular Volume 
MCH(C) 
Mean Corpuscular Hemoglobin (Concentration) 
MCS 
Mental Component Summary 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
Macrophage Mannose Receptor 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MRS 
Magnetic Resonance Spectroscopy 
NCS 
Not Clinically Significant 
PCS 
Physical Component Summary 
PT 
Preferred Term 
PT (INR) 
Prothrombin Time (International Normalized Ratio) 
PHI 
Protected Health Information 
PD  
Pharmacodynamics  
PK 
Pharmacokinetics 
PO 
By Mouth 
qw 
Once-weekly 
qow 
Every Other Week 
rhLAL 
Recombinant Human Lysosomal Acid Lipase 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SC 
Safety Committee 
SF-36® 
36-item Short Form Health Survey 
SOC 
System Organ Class 
SOM 
Study Operations Manual 
T1/2 
Terminal Elimination Half-life 
Vss 
Steady State Volume of Distribution 
 
 
 
 
 
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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 (GCP) (Food and Drug 
Administration (FDA) Title 21 part 312 and International Conference on Harmonisation (ICH) 
guidelines), applicable government regulations and institutional research policies and 
procedures. 
1.1 Background 
1.1.1 Lysosomal Acid Lipase Deficiency 
Lysosomal Acid Lipase (LAL) Deficiency is a rare autosomal recessive lipid storage disorder 
that is caused by a marked decrease of the lysosomal enzyme, LAL.  Although a single disease, 
LAL Deficiency presents as a clinical continuum with two major phenotypes: the late onset 
phenotype is frequently known as Cholesteryl Ester Storage Disease (CESD) and the early 
onset phenotype is typically referred to as Wolman Disease.  For purposes of clarity in this 
document, CESD will hereinafter be referred to as late onset LAL Deficiency and Wolman 
Disease as early onset LAL Deficiency. 
The marked reduction of LAL in patients with LAL Deficiency (early and late onset phenotypes) 
leads to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various 
tissues and cell types.  Lipid accumulation is most evident in the liver, leading to hepatomegaly, 
liver dysfunction, and hepatic failure, and in the small intestinal macrophages, leading to 
malabsorption.  Early onset LAL Deficiency is characterized by profound malabsorption, growth 
failure, and hepatic failure and is usually fatal within the first year of life.  In late onset 
LAL Deficiency, liver involvement and type II hyperlipidemia dominate the clinical picture.  Both 
the early onset and late onset phenotypes are due to mutations in the LAL gene located on 
chromosome 10q23.2-q23.3.  In the late onset LAL Deficiency, many cases are associated with 
a common allele resulting in some residual enzyme activity, whereas in the early onset 
phenotype there are a variety of private mutations with complete loss of enzyme function 
(Assmann, 2001, The Metabolic and Molecular Basis of Inherited Disease (online)).  In general, 
there appears to be an inverse correlation between enzyme activity and the severity of the 
disease. 
1.1.2 Late Onset LAL Deficiency 
In late onset LAL Deficiency, large amounts of lipids accumulate in cells and tissues throughout 
the body with predominant hepatic and cardiovascular involvement.  Adrenal calcification, which 
is prominent in the early onset LAL Deficiency, is not typically associated with this phenotype 
(Assmann, 2001, The Metabolic and Molecular Basis of Inherited Disease (online).  The liver is 
most severely affected with marked hepatomegaly, elevation of transaminases, and liver 
fibrosis, and the cardiovascular involvement is characterized by dyslipidemia (high cholesterol, 
high triglyceride and low high-density lipoprotein [HDL]) and accelerated atherosclerosis 
(Anderson, 1999, Mol Genet Metab; Beaudet, 1977, J Pediatr; Elleder, 2000, J Hepatol).  
In addition, chronic liver disease (cirrhosis) can develop.  An accumulation of fatty deposits on 
the artery walls (atherosclerosis) is described early in life.  The presentation of late onset 
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LAL Deficiency is highly variable with some patients going undiagnosed until complications 
manifest in adulthood, while others can present with liver dysfunction in early childhood.  Early 
onset LAL Deficiency is associated with shortened lifespan and significant ill health; the life 
expectancy of those with late onset LAL Deficiency depends on the severity of the associated 
complications. 
Although no approved therapies are available for treatment of LAL Deficiency, supportive 
therapies are used in an attempt to mitigate some of the effects of the disease. 
Current treatment options for late onset LAL Deficiency are focused on control of blood 
lipid levels through a diet that excludes foods rich in cholesterol and triglycerides 
and suppression 
of 
cholesterol 
synthesis and 
apolipoprotein 
B 
production 
through 
administration of statins and other lipid lowering therapies.  Although some clinical improvement 
may be seen, the underlying disease manifestations persist and disease progression still occurs 
(Assmann, 2001, The Metabolic 
and 
Molecular 
Basis 
of 
Inherited 
Disease 
(online); 
Di Bisceglie, 1990, Hepatol; Gasche, 1997, J Hepatol; Ginsberg, 1987, J Clin Invest; 
Glueck, 1992, Pediatr Res; Tadiboyina, 2005; Lipids Health Dis; Tarantino, 1991, J Pediatr; 
Yokoyama, 1992, J Inherit Met Dis).  As liver function deteriorates, liver transplantation may be 
required.  At present there is limited information on the long-term outcomes of liver 
transplantation in late onset LAL Deficiency patients (Ferry, 1991, J Pediatr Gastroenterol Nutr; 
Hansen, 2008, Liver Transplant). 
1.1.3 Medical Plausibility for Enzyme Replacement Therapy for LAL Deficiency 
LAL Deficiency resembles other lysosomal storage disorders (LSDs) with the accumulation of 
substrate in a number of tissues and cell types.  The successful treatment of Gaucher disease 
with placental glucocerebrosidase in the 1990s and, with the follow-on enzyme produced by 
recombinant deoxyribonucleic acid (DNA) technology, established the medical value and long-
term safety of enzyme replacement therapy (ERT) for LSDs (Barton, 1990, Proc Natl Acad Sci; 
Barton, 1991, N Engl J Med).  The scientific concepts established by these initial 
studies have now been extended to a broader range of disorders including Pompe Disease 
(Kishnani, 2007, Neurology; van der Ploeg, 2010, N Engl J Med), Fabry disease 
(Wilcox, 2004, Am J Hum Genet), Mucopolysaccharidosis I (Wraith, 2004, J Pediatr), and 
Mucopolysaccharidosis II (Muenzer, 2007, Mol Genet Metab), and there is now extensive 
clinical experience of long-term ERT in patients with lysosomal storage disorders. 
In LAL Deficiency, substrate accumulation is most marked in cells of the reticuloendothelial 
system, including Kupffer cells in the liver, histiocytes in the spleen and macrophages in the 
lamina propria of the small intestine.  Reticuloendothelial cells express the macrophage 
mannose/N-acetylglucosamine receptor (also known as macrophage mannose receptor [MMR] 
or CD206), which mediates binding, cell uptake and lysosomal internalization of proteins with 
N-acetylglucosamine 
(GlcNAc) 
or 
mannose 
terminated 
N-glycans, 
and 
provides 
a 
pathway for the potential correction of the enzyme deficiency in these key cell types 
(Stahl, 1978, Proc Natl Acad Sci).  This knowledge and the precedent established for other 
LSDs provides plausibility that ERT with sebelipase alfa, which has the appropriate glycan 
characteristics for targeting macrophages and other key cells, will benefit patients with 
LAL Deficiency. 
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1.2 Investigational Agent 
Sebelipase alfa (SBC-102) is a recombinant human lysosomal acid lipase (rhLAL) with the 
same amino acid sequence as the native enzyme.  Sebelipase alfa is a highly purified 
recombinant form of the naturally occurring human lysosomal acid lipase enzyme responsible 
for the metabolism and degradation of cholesteryl esters and triglycerides that are delivered to 
lysosomes by a variety of routes including low-density lipoprotein (LDL) receptor mediated 
endocytosis.  Sebelipase alfa is a glycoprotein with a molecular weight of approximately 55 kD 
with 5 N-linked glycosylation sites.  
Sebelipase alfa is produced by recombinant DNA technology in egg white using a transgenic 
Gallus expression system and contains predominantly GlcNAc and mannose terminated 
N-linked glycan structures, some of which contain mannose-6-phosphate (M6P).  GlcNAc and 
mannose terminated glycans are specifically recognized and internalized via the MMR present 
on the surface of macrophages.  These cells are one of the most important cell types that 
accumulate cholesteryl esters and triglycerides in patients with LAL Deficiency.  In addition, the 
presence of M6P allows delivery to cells that display the widely expressed M6P receptor. 
1.3 Nonclinical Data 
Sebelipase alfa demonstrated uptake and localization to lysosomes in in vitro studies in 
macrophages.  In human fibroblasts deficient in LAL enzyme activity, sebelipase alfa corrected 
the enzyme deficiency at a cellular level in a dose-dependent manner.  In a nonclinical disease 
model of LAL Deficiency, intravenous (IV) administration of sebelipase alfa restored enzyme 
activity in key target tissues including the liver.  Correction of enzyme deficiency was associated 
with a marked reduction in the accumulation of cholesteryl esters and triglycerides relative to a 
placebo treated group in the liver and spleen. In other tissues, including gut and lymph nodes, 
substrate reduction by sebelipase alfa was demonstrated by a decrease in oil red staining 
(Quinn, 2010, American Society of Human Genetics Annual Meeting). 
Homozygous LAL deficient rats demonstrate liver abnormalities, which resemble the 
abnormalities seen in patients with LAL Deficiency including hepatomegaly, transaminase 
elevation, and hepatic accumulation of cholesteryl esters and triglycerides.  In addition, the 
LAL-deficient rats show a marked increase in organ (liver, spleen, small intestine) size and 
substantial histopathological abnormalities due to substrate accumulation compared with wild 
type controls, as well as markedly impaired weight gain resembling that in patients with 
LAL Deficiency presenting in infancy.  Once weekly (qw) and every other week (qow) 
administration of sebelipase alfa by IV injection administered over a 4 week period led to a 
statistically significant improvement (p < 0.05) in weight gain and organ size compared to 
placebo-treated LAL deficient rats.  Improvements in weight gain were statistically significant 
within 2 weeks of initiation of the first dose.  Liver abnormalities were all markedly improved with 
sebelipase alfa treatment.  Additional discussions of the dose response of the effects seen in 
the nonclinical model are included in Section 1.5. 
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There were no meaningful toxicological findings in 4-week repeat dose toxicology studies in the 
Sprague-Dawley rat and Cynomolgus monkey administered intravenous infusions of sebelipase 
alfa at doses up to 50 mg/kg once weekly.  In a 6-month repeated dose toxicity study in 
Cynomolgus monkeys administered qw IV infusions of sebelipase alfa at doses of 3 mg/kg, 
10 mg/kg or 30 mg/kg (5 males and 5 females per dose group), or placebo infusions 
(5 males, 5 females), sebelipase alfa was well tolerated up to the highest dose level of 
30 mg/kg.  There were no sebelipase alfa related changes in any of the study parameters, 
although there was an apparent infusion reaction observed in one animal on Day 1 of dosing 
following administration of sebelipase alfa at a dose of 10 mg/kg.  With Benadryl pretreatment, 
no additional reactions were observed during the subsequent 25 infusions in this animal.  No 
infusion reactions were observed in a total of 754 infusions administered to the other 29 animals 
in this study.  These results support the long-term dosing with sebelipase alfa.   
As expected, based on the number and composition of glycan structures, pharmacokinetic (PK) 
studies in Sprague-Dawley rats administered IV bolus injections of sebelipase alfa at doses of 
1 mg/kg and 5 mg/kg demonstrate that sebelipase alfa is rapidly cleared from the circulation and 
uptake appears to be saturable.  Based on these data, sebelipase alfa is anticipated to have a 
short plasma half-life in humans. 
1.4 Clinical Data 
The clinical development program is investigating the safety and tolerability of sebelipase alfa 
and its clinically meaningful effects on the medical complications of LAL Deficiency.  LAL-CL01, 
a Phase 1/2 dose-finding study in adults with LAL Deficiency, has completed.  An extension 
study, LAL-CL04, is ongoing in subjects who completed LAL-CL01.  LAL-CL03 is an ongoing 
Phase 2/3 study to evaluate the safety, tolerability, efficacy, PK and pharmacodynamics of 
sebelipase alfa in pediatric subjects with LAL Deficiency who developed growth failure or other 
clinical evidence of rapidly progressive LAL Deficiency before 6 months of age.  LAL-CL02 is an 
ongoing Phase 3 study to evaluate efficacy, safety, and PK of sebelipase alfa or placebo in 
pediatric and adult subjects with LAL Deficiency.  LAL-CL06 is a Phase 2 study in a broad 
population of subjects ≥ 8 months with LAL Deficiency who may not have been eligible for other 
studies.  LAL-CL08 is a Phase 2 study in infant subjects with rapidly progressive 
LAL Deficiency.  Please refer to the IB for further information on the clinical experience with 
sebelipase alfa. 
Extensive human experience exists for ERTs in the treatment of other lysosomal storage 
disorders including Gaucher, Pompe, and Fabry disease.  While these diseases have distinct 
clinical manifestations and demonstrate differences in the targeting and biological effects of the 
ERT, there are relevant data from these studies which inform the use of investigational products 
of this class.  Most of the AEs associated with clinical use of ERTs relate to infusion associated 
events which occur typically either during or within several hours following completion of the 
infusion.  Given the propensity for infusion reactions with ERT administration, measures have 
been incorporated in this protocol to minimize risk and monitor subject safety. 
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1.5 Dose Rationale and Risk/Benefits 
1.5.1 Dose Rationale 
In this extension study, each individual subject will receive a starting dose of sebelipase alfa 
equivalent to the dose that he/she received during the fourth infusion of sebelipase alfa in study 
LAL-CL01.  This starting dose is contingent upon that dose being deemed safe and 
well tolerated following evaluation of safety data for all subjects receiving that dose in study 
LAL-CL01. 
Subjects with LAL Deficiency are expected to require long-term treatment with ERT.  Reducing 
the frequency of infusions during maintenance therapy would lessen the burden of therapy on 
these patients, thereby improving quality of life and possibly patient compliance.  In this study, 
subjects will transition to a qow dosing regimen after Week 4 (after the first 4 infusions in the 
extension study).  Each subject will be expected to transition to a dose of 1 mg/kg qow or 
3 mg/kg qow, which based on the currently available preclinical data is expected to provide a 
therapeutic benefit: 
• 
In a 4-week study, the minimum effective dose of sebelipase alfa in the nonclinical 
model of LAL Deficiency was 0.35 mg/kg qw, and was generally comparable to the 
PD effects of sebelipase alfa at a dose of 1 mg/kg qow.  These data suggest that a qow 
dose < 1 mg/kg has a decreased probability of demonstrating efficacy. 
• 
In a nonclinical model of LAL Deficiency, the PD effects of sebelipase alfa were broadly 
comparable at the two highest qw dosing regimens (3 mg/kg qw and 5 mg/kg qw) and 
the two highest qow dosing regimens (3 mg/kg qow and 5 mg/kg qow) studied.  These 
data indicate that 3 mg/kg is a maximally effective dose with both qw and qow 
administration. 
• 
In patients with late onset LAL Deficiency, substrate accumulation and pathology are 
most prominent in the liver and spleen.  Dose response analysis in the preclinical model 
demonstrates that substrate is markedly reduced in these organs with a 3 mg/kg qow 
regimen, and that a 1 mg/kg qow regimen is also effective, but can be differentiated from 
the 3 mg/kg qow regimen based on effects on growth and liver cholesteryl ester 
substrate content. 
All planned doses of sebelipase alfa in the extension study are anticipated to be safe and well 
tolerated based upon the following: 
• 
The Investigational Medicinal Product (IMP) has an amino acid sequence identical to the 
natural enzyme with no engineering of enhancements in biological activity. 
• 
Knowledge of the biochemistry of LAL Deficiency and the mode of action of sebelipase 
alfa do not raise concerns for unexpected toxicity in humans. 
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• 
There were no meaningful toxicological findings in 4-week repeated dose toxicology 
studies in the Sprague-Dawley rat and Cynomolgus monkey at doses up to 50 mg/kg.  
Based on the human equivalent doses in rats (8.1 mg/kg) and monkeys (16.1 mg/kg), 
this represents a 2.7-to 5.4-fold safety margin relative to the proposed top dose in the 
current study (3 mg/kg). 
• 
Sebelipase alfa was well-tolerated in a 6-month repeated dose toxicity study in 
Cynomolgus monkeys treated qw at doses up to 30 mg/kg, the highest dose level 
evaluated.  Based on the human equivalent dose of 9.7 mg/kg, this represents a 3.2-fold 
safety margin relative to the proposed top dose in the current study.  The absence of any 
sebelipase alfa related changes in study parameters supports the long-term dosing with 
sebelipase alfa. 
• 
Safety and tolerability data from study LAL-CL01 are available to inform decisions 
regarding within-subject dose escalation. 
• 
In general for LSDs, the enzymatic activities and mechanisms for lysosomal targeting 
are conserved across species.  Toxicological studies of this class of therapy consistently 
demonstrate low systemic toxicity (Andrews, 2008, Enzyme Replacement Therapies. 
In: Cavagnaro 
JA, 
ed. 
Preclinical 
Safety 
Evaluation 
of 
Biopharmaceuticals: 
A Science-Based Approach to Facilitating Clinical Trials.). 
As ERTs have a short plasma half-life and biological activity is primarily driven by enzyme 
concentrations in the target tissue and the rate of substrate accumulation, sebelipase alfa 
plasma concentrations are being measured only for analysis of sebelipase alfa 
pharmacokinetics, and will not routinely be used for decisions regarding changes in dose or 
dosing frequency. 
1.5.2 Risk/Benefit Assessment  
As discussed in Section 1.1.2, LAL Deficiency is a very rare disease with no approved therapies 
that leads to significant morbidity and mortality.  
Nonclinical studies conducted in a relevant rodent disease model at pharmacological doses and 
in other nonclinical species at doses substantially in excess of those proposed in this study, 
revealed no significant risks.  
Extensive clinical experience, with approved enzyme replacement therapies from other 
LSD indications, is relevant for risk evaluation of sebelipase alfa.  The most common 
AEs associated with administration of approved ERTs (including but not restricted to 
Cerezyme®, VPRIV®, Myozyme®/Lumizyme®, Fabrazyme®) are infusion reactions.  These are 
usually mild and can be managed by changes in infusion rate and/or the administration of 
antipyretics and antihistamines.  Severe infusion reactions, including anaphylaxis, and SAEs 
related to ERT administration occur rarely and can require intensive medical intervention.  
Anti-drug antibodies (ADAs) have been reported with approved ERTs and these may be 
associated with altered response to treatment and/or increased risk of infusion reactions.  
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Based on the results from the completed study LAL-CL01, which showed good tolerability of 
sebelipase alfa infusions at all dosing regimens studied and no SAEs or IARs, as well as rapid 
improvements in serum transaminases combined with other evidence of biological activity 
(refer to the IB for further information), there is a reasonable basis to conclude that sebelipase 
alfa will continue to demonstrate beneficial effects on disease activity as these subjects resume 
treatment in the current long-term extension study.  Irrespective of the immediate clinical value 
to the individual patient, the information provided from the current long-term extension study will 
provide benefit to patients with LAL Deficiency by guiding future clinical development. 
Based on current understanding of sebelipase alfa, it was anticipated that the increases in 
serum lipid levels observed in study LAL-CL01 will not be sustained with continuous treatment.  
This has now been confirmed. 
Given the relatively low level of subject risk relative to the progressive and potentially 
life-threatening nature of untreated LAL Deficiency, it is concluded that the risks to subjects in 
this study are reasonable in relation to the anticipated benefits and/or knowledge that can be 
expected from the results. 
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2 Study Objectives 
2.1 Primary Objective  
The primary objective of the study is to evaluate the long-term safety and tolerability of 
sebelipase alfa in patients with liver dysfunction due to LAL Deficiency. 
2.2 Secondary Objective 
The secondary objectives are: 
• 
To evaluate the long-term efficacy of sebelipase alfa in patients with liver dysfunction 
due to LAL Deficiency;  
• 
To characterize repeat-dose pharmacokinetics of sebelipase alfa delivered by 
IV infusion; 
• 
To determine the effect of sebelipase alfa on pharmacodynamic biomarkers. 
2.3 Exploratory Objective 
The exploratory objectives are: 
• 
To determine the effect of sebelipase alfa on Health-Related Quality of Life (HRQOL) 
outcome measures; 
• 
To evaluate the acceptability of an every other week dosing regimen of sebelipase alfa; 
• 
To evaluate liver histology. 
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3 Study Design 
3.1 Overview of Study Design 
This Phase 2, open-label, extension study will evaluate the long-term safety, tolerability, and 
efficacy of sebelipase alfa in adult patients with liver dysfunction due to LAL Deficiency who 
previously received 4 doses of sebelipase alfa in the Phase 1/2 repeat-dose, dose escalation 
study (Study LAL-CL01).  The study will consist of a screening period, treatment period, and 
follow-up period. 
Subjects who successfully receive all 4 doses of sebelipase alfa in study LAL-CL01 and wish to 
continue treatment with sebelipase alfa in the extension study will undergo screening 
assessments to determine study eligibility (Note: Assessments performed in study LAL-CL01 
within a defined time period may not need to be repeated at the screening visit; 
see Appendix A: Schedules of Assessments for further details).  
Eligible subjects will initiate treatment in the current extension study at least 4 weeks after their 
last dose of sebelipase alfa in study LAL-CL01.  Each subject will initiate treatment in the 
extension study at the same once-weekly dose of sebelipase alfa that he/she received during 
the fourth infusion in study LAL-CL01, i.e., 0.35 mg/kg qw, 1 mg/kg qw, or 3 mg/kg qw.  
Subsequent modifications to the dose and dosing frequency will be undertaken for individual 
subjects as outlined below based on observed safety and tolerability and clinical response to 
treatment.  All such decisions will be made jointly by the Investigator and Sponsor. 
• 
At Week 6 (and after at least 4 infusions in the extension study), subjects receiving a 
starting dose of 0.35 mg/kg qw or 1 mg/kg qw will have their dose changed to 
1 mg/kg qow.  Similarly, subjects who were receiving a starting dose of 3 mg/kg qw for 
the first 4 infusions will transition to the 3 mg/kg qow regimen. 
• 
After Week 12, subjects receiving a dose of 1 mg/kg qow may be considered for a dose 
increase to 3 mg/kg qow based on observed safety and tolerability and/or clinical 
response to treatment.  Refer to Section 6.1 for additional details. 
• 
After Week 12, subjects receiving a dose of 3 mg/kg qow may be considered for a dose 
adjustment to 3 mg/kg qw based on observed safety and tolerability and/or clinical 
response to treatment.  Refer to Section 6.1 for additional details. 
• 
In the event of poor tolerability at any time during the extension study, the dose may be 
reduced at the discretion of the Investigator.  If a subject cannot tolerate the lowest 
starting dose (0.35 mg/kg qow) despite measures taken to manage any IARs, he/she will 
be discontinued from treatment. 
Safety, tolerability, and efficacy assessments will be conducted at regular intervals throughout 
the extension study.  In addition, blood samples will be obtained at selected timepoints for 
analysis of sebelipase alfa PK and biomarkers of sebelipase alfa PD activity.  Blood samples 
will also be collected for an exploratory analysis of potential disease-related biomarkers in this 
patient population, and HRQOL measures will be assessed through subject questionnaires. 
A follow-up visit will be conducted for all subjects at 30 (+7) days after the last dose of IMP.   
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Figure 1 
Study Flow Diagram 
 
 
Week 1 – 4 
Week 6 – onward 
  Week 14 – onward* 
(Inadequate clinical 
response) 
 
 
 
 
 
 
 
 
 
 
 
*After Week 12, a dose adjustment from 1 mg/kg qow to 3 mg/kg qow, or from 3 mg/kg qow to 
3 mg/kg qw, may be considered based on safety and tolerability and/or clinical response to treatment.  A 
dose reduction is permitted at any time in the event of poor tolerability. 
3.2 Rationale for Study Design 
3.2.1 Dose Selection 
The rationale for dose selection is described in Section 1.5. 
3.2.2 Outcome Variable Selection 
3.2.2.1 Safety 
The study is designed to primarily evaluate the safety and tolerability of long-term treatment with 
sebelipase alfa, administered by weekly and biweekly IV infusions.  As such, the main outcome 
variables in this study will assess safety and tolerability of sebelipase alfa in adult patients with 
liver dysfunction due to LAL Deficiency, and will include: 
• 
Changes from baseline in vital signs, physical examination findings, clinical 
laboratory tests, and 12-lead electrocardiogram (ECG) parameters. 
• 
The incidence of AEs, SAEs, and IARs. 
• 
Use of concomitant medications/therapies. 
• 
Characterization of ADAs, including ADA positivity rate, time to ADA positivity, 
median and peak ADA titer, and time to peak ADA titer. 
Screening 
0.35 mg/kg 
qw 
1 mg/kg  
qw 
3 mg/kg  
qw 
1 mg/kg  
qow 
1 mg/kg  
qow 
3 mg/kg  
qow 
3 mg/kg 
qow 
3 mg/kg  
qow 
3 mg/kg  
qw 
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• 
Given the potential for ADAs to alter the safety profile of sebelipase alfa, a subgroup 
analysis will be conducted comparing safety endpoints in ADA-positive and 
ADA-negative subjects.  
• 
A further characterization of ADAs, including inhibitory ADAs, may be performed as a 
separate pooled analysis across studies, and will be reported separately from this 
protocol. 
3.2.2.2 Efficacy 
The biological effects of ERT for LAL Deficiency have not been fully established.  However, any 
successful therapy for late onset LAL Deficiency must be able to mitigate the progressive liver 
deterioration that is a predominant clinical feature of this disorder.  The following efficacy 
measures will be utilized to investigate the effect of sebelipase alfa on hepatic dysfunction in 
LAL Deficiency:  
• 
Liver and spleen volume by magnetic resonance imaging (MRI). 
• 
Liver and spleen fat content by multi-echo gradient-echo MRI and 1H magnetic 
resonance spectroscopy (MRS) (if available). 
• 
Liver cholesteryl ester signature (as measured by 13C MRS) in a subset of subjects 
receiving treatment at sites with access to this imaging technology.  
• 
An assessment of hepatic histopathology will also be conducted in those subjects 
who agree to an optional liver biopsy. 
3.2.2.3 Pharmacodynamics 
Based on a review of the literature, input from experts in the field, and insights from the 
nonclinical disease model (Section 1.3), the following biomarkers will also be investigated for 
their potential utility in describing pharmacodynamic responses to sebelipase alfa:  
• 
Serum transaminases 
• 
Serum lipids 
• 
Acute phase reactants (e.g., serum ferritin) 
Blood and urine samples will also be collected to support exploratory analyses of changes or 
percent changes from baseline in additional disease-related biomarkers, which may be 
identified based on emerging information from the sebelipase alfa development program and 
scientific literature. 
Given the potential for ADAs to alter the PD effect of sebelipase alfa, a subgroup analysis will 
be conducted for the efficacy and PD endpoints comparing ADA-positive and ADA-negative 
subjects.  
3.2.2.4 Health-Related Quality of Life (HRQOL) Outcomes 
Based on the effects of ERT in other diseases, significant health benefits are anticipated with 
sebelipase alfa treatment.  As there are currently no validated tool(s) to assess HRQOL in 
LAL Deficiency, HRQOL will be assessed using tools developed for other diseases.  Changes in 
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scores for the 36-item Short Form (SF 36®) Health Survey, Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACIT-Fatigue) scale, and Chronic Liver Disease Questionnaire 
(CLDQ) will be determined.  Positive treatment effects on HRQOL will provide supporting 
evidence of sebelipase alfa treatment benefit. 
3.2.2.5 Pharmacokinetics 
The preliminary clinical pharmacokinetics of seblipase alfa will be characterized in study 
LAL-CL01.  Clinical pharmacokinetic data will continue to be collected in this extension study to 
permit a more robust assessment of sebelipase alfa pharmacokinetics.  This will include the 
steady state pharmacokinetic profile of the qow dosing regimen and an assessment of the 
impact of ADAs (if any) on sebelipase alfa pharmacokinetics.  PK parameters will include 
maximum observed serum concentration (Cmax), minimum observed serum concentration (Cmin), 
area under the serum concentration-time curve from time zero extrapolated to infinity (AUCinf), 
terminal elimination half-life (T1/2), apparent serum clearance (CL), and steady state volume of 
distribution (Vss). 
3.2.3 Study Duration 
Given the progressive and potentially life-threatening nature of untreated LAL Deficiency, and 
the low likelihood that beneficial effects of sebelipase alfa therapy will be maintained after 
discontinuation of treatment, subjects enrolled in this extension study will be given the option to 
continue to receive treatment under this protocol.  Each patient may receive up to 5 years of 
treatment under this protocol.  
4 Study Population 
4.1 Target Population 
The target population for this study is male and female subjects (≥ 18 years of age) with liver 
dysfunction due to LAL Deficiency who received treatment with sebelipase alfa in study 
LAL-CL01. 
4.2 Number of Subjects 
Up to 9 subjects will be enrolled in this study after successfully completing treatment in study 
LAL-CL01.  
4.3 Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for this study: 
1. Subject understands the full nature and purpose of the study, including possible risks and 
side effects, and is willing and able to comply with all study procedures and provide 
informed consent. 
2. Subject received all 4 scheduled doses of sebelipase alfa in study LAL-CL01 with no 
life-threatening or unmanageable study drug toxicity.  
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3. Female subjects have a negative serum pregnancy test at screening, and are not 
breast-feeding. 
4. Female subjects of childbearing potential are willing and able to use a highly effective and 
approved contraceptive method(s) from the date of informed consent until 30 days after last 
dose of IMP.  A highly effective method of contraception is defined as fulfilling at least one of 
the following:  
a. Strict abstinence;  
b. Bilateral tubal ligation;  
c. Combined oral contraceptives (estrogens and progesterone), inserted, applied, 
implanted or injectable contraceptives on a stable dose for at least 1 month prior 
to the screening visit; 
d. Hormonal intra-uterine device (IUD) inserted at least 1 month prior to the 
screening visit; 
e. Vasectomized partner for at least 3 months prior to the screening visit; 
f. Condom with spermicide. 
 
Women may be considered of non-childbearing potential if they are surgically sterile 
(i.e., total hysterectomy or bilateral salpingo-oophorectomy) or post-menopausal (defined as 
a complete cessation of menstruation for at least one year after the age of 45 years). 
4.4 Exclusion Criteria 
A subject who meets any of the following exclusion criteria will be ineligible for this study: 
1. Clinically significant concurrent disease, serious inter-current illness, concomitant 
medications, or other extenuating circumstances that, in the opinion of the Investigator, 
would either interfere with study participation or the interpretation of the effects of sebelipase 
alfa. 
2. Clinically significant abnormal values on laboratory screening tests, other than liver function 
or lipid panel tests.  Subjects with an abnormal laboratory value that is of borderline 
significance may be allowed to undergo repeat testing once within a 30-day period. 
4.5 Concomitant Medications and Treatments 
Reasonable efforts will be made to ascertain all concomitant medications and treatments 
(pharmacological and non-pharmacological) received by the subject from the last assessment in 
study LAL-CL01 until completion of the follow-up visit approximately 30 days after the last dose 
of IMP.  Concomitant medications include prescription and over-the-counter medications, herbal 
medications, prophylactic and therapeutic vaccines, vitamins, and dietary supplements.  
Concomitant 
treatments 
include 
diagnostic, 
palliative, 
or 
interventional 
procedures 
(e.g., surgery, physical therapy). 
All concomitant medications and treatments will be recorded in the electronic case report form 
(eCRF).  The following information will be recorded: name of the medication (brand or generic) 
or therapy, reason for use, start date, stop date, dose and route of administration (if applicable), 
and frequency of administration. 
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Dose adjustments or discontinuation of lipid-lowering medications may be considered in 
consultation with the Sponsor for medical reasons including reconsideration of the need for lipid 
lowering therapy based on longer-term effects of sebelipase alfa on lipid levels. 
Information about any major changes in diet (e.g., initiation or termination of a low-cholesterol 
diet) should be documented in the electronic case report form (eCRF).  
4.6 Discontinuation of Subjects from Treatment or Assessment 
4.6.1 Premature Withdrawal from Study Participation  
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason, without prejudice to further treatment.  
The Investigator and Sponsor also have the right to withdraw subjects from the study at any 
time.  Specific reasons for discontinuation may include but are not restricted to the following: 
• 
Intercurrent illness 
• 
AEs 
• 
Pregnancy 
• 
Protocol deviation or non-compliance 
• 
Termination of the study by the Sponsor 
Unnecessary withdrawals should be avoided as an excessive rate of withdrawal can render the 
study uninterpretable.  
4.6.2 Procedures for Discontinuation 
All subjects who discontinue from the study should be asked about the reason(s) for their 
discontinuation and about the presence of AEs.  The date and the reason for discontinuation will 
be recorded in the eCRF.   
A subject will be considered early terminated if he/she discontinues treatment in the study prior 
to the Sponsor notifying the Investigators that the study will end.  A subject will be considered 
discontinued due to an AE if the subject received any infusion or partial infusion of the IMP, but 
did not complete the study because of an AE, whether or not considered drug related.  
Subjects who prematurely discontinue treatment in the study will also be asked to complete all 
discontinuation assessments prior to withdrawal, if possible.  Post-study SAEs will be reported 
according to Section 7.4 for all subjects prematurely discontinuing treatment in the study.  
When a subject fails to return for scheduled assessments, the following efforts should be made 
to contact him/her to determine a reason for the failure to return: three phone attempts, 
including the date and time, to be documented in the subject’s chart.  If there is no response to 
the phone calls, a certified letter should be sent.  After these efforts have been exhausted, a 
subject should be identified as lost to follow-up in the eCRF. 
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In the event that a subject dies, permission for an autopsy may be sought (through a separate 
informed consent form) from the subject’s next of kin.  Samples collected from these procedures 
will be used to further understand LAL Deficiency and the effect of ERT. 
4.7 Subject Replacement Policy 
Subjects who discontinue the study for any reason will not be replaced. 
4.8 Subject Recruitment and Screening 
Each Investigator (or designee) responsible for the clinical management of a subject in study 
LAL-CL01 will notify that subject of the potential to continue to receive treatment with sebelipase 
alfa in the current extension study. 
Information 
about 
this 
study 
will 
be 
posted 
on 
the 
http://clinicaltrials.gov/ 
and 
https://www.clinicaltrialsregister.eu/ websites. 
5 Schedule of Assessments and Study Procedures 
The following Schedules of Assessments are presented in Appendix A: 
• 
Screening through Week 24; 
• 
Week 26 through Week 52; 
• 
52-week schedule of repeating assessments. 
The Investigator may also perform an unscheduled visit at any time during the study at his/her 
discretion.  Assessments performed at an unscheduled visit should be symptom directed, and 
will be recorded in the eCRF if the Investigator determines the subject may remain on IMP. 
5.1 Study Assessments 
5.1.1 Informed Consent 
Subjects will be given a verbal explanation of the study and the procedures involved and will 
have all questions addressed.  The subject must sign and date a consent form that has been 
approved by the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) before the screening procedures are initiated.  All subjects will be given a copy of the 
signed and dated informed consent form. 
5.1.2 Subject Eligibility 
All subjects will be assessed for eligibility against the inclusion and exclusion criteria described 
in Sections 4.3 and 4.4 and background clinical information collected. 
5.1.3 Medical History 
Medical history will be collected for the time period between a subject’s completion of the final 
follow-up visit in study LAL-CL01 and the subject’s first screening assessment in the extension 
study. 
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5.1.4 Demographic Information 
Demographic information will not be recorded during screening for the extension study, as this 
information was previously recorded during screening for study LAL-CL01. 
5.1.5 Physical Examination 
A general physical examination will be performed by the Investigator or qualified designee.  A 
complete physical examination will be conducted at the timepoints specified in Appendix A.  The 
examination will include an assessment of the subject’s general appearance, skin, head, eyes, 
ears, nose, and throat (HEENT), heart, lungs, abdomen, extremities/joints, and neurological 
status.  Whenever possible, the same person should perform the physical examination at each 
study visit.  Abnormal findings will be recorded in the eCRF.  Height will be measured at the 
screening examination, and weight will be measured at all physical examinations.   
The physical examinations will also include the following: 
• 
Liver size: A clinical assessment of liver size (palpable/non palpable and centimeters 
below costal margin), regularity (smooth/nodular) and sensitivity (tender/non tender) will 
be made.  
• 
Spleen size: A clinical assessment of spleen size (palpable/non palpable and 
centimeters below costal margin), regularity (smooth/nodular) and sensitivity (tender/ 
non-tender) will be made.  
• 
Lymphadenopathy: An assessment of the size, location, and character of any palpable 
lymph 
nodes 
will 
be 
made. 
 
Areas 
to 
be 
examined 
include 
cephalic 
(occipital, preauricular, postauricular, submental, submandibular), cervical, clavicular, 
axillary, and inguinal.  Any enlarged nodes will be characterized as tender or non-tender. 
• 
Arterial disease: Right and left Posterior Tibialis and Dorsalis Pedis pulses will be 
assessed clinically. 
5.1.6 Health-Related Quality of Life (HRQOL) Outcomes 
Subjects will be instructed to complete the following HRQOL questionnaires at the timepoints 
specified in Appendix A: 
• 
SF-36® (refer to Appendix B for details) 
• 
FACIT-Fatigue (refer to Appendix C for details) 
• 
CLDQ (refer to Appendix D for details) 
Questionnaires should be administered in the same sequence at each study visit, and prior to 
any other study procedures being conducted at that visit.  Detailed instructions on administration 
of HRQOL questionnaires are provided in the Study Operations Manual (SOM).  The SF-36 was 
developed during the Medical Outcomes Study to measure generic physical and mental health 
concepts relevant across age, disease, and treatment groups.  A total of 21 items within the 
4 subscales of physical functioning, role-physical (i.e., role limitations due to physical problems), 
bodily pain, and general health compose the Physical Health summary measure and a total of 
14 items within the 4 subscales of vitality, social functioning, role-emotional (i.e., role limitations 
due to emotional problems), and mental health compose the Mental Health summary measure 
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(one item, self-reported health transition, is not included in a summary measure).  In addition to 
the scores for each subscale, higher-order summary scores, the Physical Component Summary 
(PCS) and Mental Component Summary (MCS), are derived using standard scoring algorithms 
based on the correlation of each of the 8 subscales with physical and mental health, 
respectively.  The SF-36 can be administered in approximately 5-10 minutes. In this study, the 
SF-36 version 2 will be self-administered.  A sample questionnaire is provided in Appendix B. 
The 13-item FACIT-Fatigue scale was developed to measure levels of fatigue in people living 
with a chronic disease.  In this study, the FACIT-Fatigue scale version 4 will be 
self-administered.  A sample questionnaire is provided in Appendix C. 
The CLDQ is a disease-specific instrument designed to assess health-related quality of life in 
subjects with chronic liver disease.  In this study, the CLDQ will be self-administered.  A sample 
questionnaire is provided in Appendix D. 
5.1.7 Abdominal MRI/MRS 
Abdominal MRI and 1H-MRS will be performed at the timepoints specified in Appendix A to 
quantify the organ volume and fat content of both the liver and spleen.  Whenever feasible, 
additional abdominal imaging scans will be obtained at the same timepoints using 13C-MRS to 
permit an exploratory analysis of the liver cholesteryl ester signature.  All MR imaging and 
spectroscopy will be performed by an MR technician or other qualified individual.   
Detailed instructions on image acquisition and analysis will be provided in the Imaging Manual.  
5.1.8 Vital Signs 
Vital signs, including pulse rate, respiratory rate, systolic and diastolic blood pressure, and body 
temperature, will be measured at the timepoints specified in Appendix A.  On dosing days, vital 
signs will be recorded pre-infusion and every 30 (±10) minutes during infusion and from 0 to 4 
hours after completion of the infusion.  Additional readings may be taken at the discretion of the 
Investigator in the event of an IAR.  For each subject, the duration of post-infusion vital sign 
monitoring may be shortened to 2 hours after 6 months of treatment with no occurrence of IARs, 
and to 1 hour after 12 months of treatment with no occurrence of IARs, contingent upon 
approval by the Sponsor. 
5.1.9 Electrocardiogram 
12-lead ECGs will be obtained at the timepoints specified in Appendix A.  In addition, 
unscheduled ECG(s) should be obtained in any subject exhibiting cardiovascular symptoms 
(e.g., palpitations, chest pain or tightness, tachypnea) or clinically significant changes in resting 
heart rate.  ECGs will be reviewed by the Investigator, or designee, and any abnormalities will 
be specified as clinically significant (CS) or not clinically significant (NCS).  If deemed to be 
clinically significant, these abnormalities must be recorded as Adverse Events in the electronic 
case report form (eCRF).  In the event of any unexpected findings, subjects should be 
appropriately evaluated in accordance with local procedures. 
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5.1.10 Laboratory Assessments 
Blood and urine samples for clinical laboratory tests will be collected at the timepoints indicated 
in Appendix A.  
The following clinical laboratory tests will be performed in this study: 
CBC/Hematology: 
 
White blood cell count, red blood cell count, hemoglobin, 
hematocrit, MCV, MCH, MCHC, platelet count, neutrophil, 
lymphocytes, monocytes, eosinophils, basophils 
Serum Chemistry: 
 
Glucose, urea nitrogen, creatinine, sodium, potassium, 
chloride, calcium, magnesium, inorganic phosphorus, total 
protein, lactate dehydrogenase, uric acid  
Liver Panel: 
 
AST/SGOT, ALT/SGPT, alkaline phosphatase, GGT, 
albumin, bilirubin (direct, total) 
Lipid Panel: 
  
 
Total cholesterol, triglyceride, HDL, LDL 
 
 
Coagulation: 
  
 
PT (INR), aPTT 
(if screening results are abnormal, repeat at subsequent visits until results return to normal) 
Urinalysis: 
 
Glucose, ketones, blood, pH, protein, nitrite, and 
leukocytes (microscopic examination will be done if 
urinalysis is positive for blood, protein (only if > 1+), nitrite, 
and/or leukocytes) 
Anti-drug Antibody: 
  
 
Anti-sebelipase alfa antibody 
Acute Phase Reactants:  
 
High sensitivity CRP and serum ferritin 
Pregnancy: 
 
Pregnancy testing will be performed for all female subjects.  
A serum pregnancy test will be performed at screening, 
and urine pregnancy tests will be performed at all other 
scheduled visits.  If a positive result is recorded at any time 
the procedure detailed in Section 7.2.5 should be followed. 
Exploratory Biomarkers:  
See Section 5.1.11 
Subjects will fast for at least 9 hours (no more than 12 hours is required) and refrain from 
ingestion of alcohol for 24 hours prior to collection of blood samples for the lipid and liver 
panels.  Subjects will only be permitted to drink water during this time.  Whenever possible, lab 
samples for these visits should be drawn in the morning.  
All laboratory tests will be performed by a central laboratory with the exception of PT (INR), 
aPTT, urinalysis, and urine pregnancy tests. 
NOTE: Any subject who undergoes a dose modification, as described in Section 6.1, or 
changes in lipid-lowering therapies, as described in Section 4.5, will have the following 
additional laboratory monitoring schedule of selected analytes (all collected pre-dose): 
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• 
Prior to 1st infusion of new dose/schedule or change in lipid-lowering medication: serum 
lipid panel, liver panel, hematology, serum chemistry, ferritin, hs-CRP; 
• 
4 weeks after starting new dose/schedule or change in lipid-lowering medication: serum 
lipid panel, liver panel; 
• 
8 weeks after starting new dose/schedule or change in lipid-lowering medication: serum 
lipid panel, liver panel; 
• 
12 weeks after starting new dose/schedule or change in lipid-lowering medication: serum 
lipid panel, liver panel, hematology, serum chemistry. 
In the event that any of the above additional laboratory monitoring time points coincides with the 
standard laboratory assessment, the standard laboratory assessment will supersede the 
additional laboratory monitoring. 
Laboratory reports will be reviewed by the Investigator, or designee, and any abnormalities will 
be specified as ‘CS’ or ‘NCS’.  In the event of unexplained clinically significant abnormal 
laboratory test results, the tests should be repeated as soon as possible (preferably within 
24 hours) and followed up until they have returned to within the normal range and/or an 
adequate explanation has been identified. 
Refer to the SOM and/or laboratory manual for further details regarding the collection, 
processing, and storage of these samples. 
5.1.11 Exploratory Biomarkers 
Blood samples for serum isolation (2 aliquots) will be obtained at the timepoints specified in the 
Schedule of Assessments (Appendix A) for exploratory biomarker analysis, as blood volume 
threshold permits.  A urine sample will also be obtained at these same timepoints for exploratory 
biomarker analysis.  These serum and urine samples will be used to identify baseline disease 
and dynamic markers that will help the Sponsor to better understand the pathogenesis of 
LAL Deficiency and related comorbidities and response to treatment.  Given the rarity of 
LAL Deficiency and the paucity of information on disease characteristics, the definitive list of 
analytes remains to be determined.  Samples will be stored by the Sponsor, or designee, in a 
secure and controlled environment until analysis.   
Refer to the SOM and/or laboratory manual for further details regarding the collection, 
processing, and storage of these samples.  
Collection of samples, for storage as described above, will be subject to discretionary approval 
from each center’s IRB/IEC and the subject’s specific written consent.  This section of the 
protocol only applies if approval for collection of these additional samples has been granted.  If 
the IRB/IEC does not approve the collection of additional samples, this must be stated in the 
approval letter. 
5.1.12 Pharmacokinetic Assessments 
Blood samples for determination of sebelipase alfa serum concentrations will be collected 
during the study visits indicated in Appendix A.  On each PK visit, samples will be collected at 
the following timepoints relative to infusion of IMP:  
• 
Immediately pre-dose (within 30 minutes of dosing) 
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• 
At 10(±1), 15(±1), 20(±1), 40(±5), 60(±5) and 90(±5) minutes during the infusion and at 
the end of the infusion 
• 
At 5(±1), 10(±1), 20(±1), 30(±5), 40(±5), 60(±5) and 120(±5) minutes after completion of 
the infusion 
All PK samples will be taken from the arm opposite the infusion cannula.  PK samples 
scheduled for the same nominal timepoint as a vital sign assessment will be taken prior to cuff 
inflation for the blood pressure measurement.  All other PK samples will be taken at least 
5 minutes after cuff deflation. 
Refer to the SOM and/or laboratory manual for further details regarding the collection, 
processing, and storage of these samples.  
5.1.13 Liver Biopsy 
As is the case with many rare metabolic chronic liver diseases, there is paucity of available 
information regarding the histopathological features of LAL Deficiency.  Long term dosing in the 
pre-clinical disease model is associated with marked improvement in liver pathology.  At present 
there is no information on the long term effects of sebelipase alfa on liver pathology in humans.  
Although baseline assessment of liver histology was not performed, information on liver 
histology after longer term dosing may provide useful information about the effects of sebelipase 
alfa in patients with late onset LAL Deficiency. 
Optional liver biopsies will be obtained for evaluation of hepatic histology between Week 52 and 
Week 104.  If a subject had a liver biopsy within 3 years prior to screening as part of clinical 
standard of care and the results of that biopsy are available, these results should be recorded in 
the eCRF.  In addition, slides or scanned images from these biopsies should be submitted for 
evaluation by a central pathologist, if possible.  Biopsies will be performed only with consent 
from the subject and where local regulations permit, and are subject to discretionary approval 
from each center's IRB/IEC. 
Liver biopsy procedures should be performed according to the local institutional practices by a 
qualified professional. 
All biopsies collected in this study will be centrally evaluated by a pathologist with the 
appropriate expertise.  This evaluation will include an assessment of the overall disease activity 
as well as a description of specific histopathological features of the disease. 
Refer to the Histopathology Manual for further details on the collection and processing of liver 
biopsies. 
6 Treatments 
6.1 Treatments Administered 
Subjects will receive repeat IV infusions of sebelipase alfa, beginning at least 4 weeks after their 
last dose in study LAL-CL01 and continuing for approximately 5 years. 
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Each subject will initiate treatment at the same once-weekly dose of sebelipase alfa that he/she 
received during the fourth infusion in study LAL-CL01 (i.e., 0.35 mg/kg qw, 1 mg/kg qw, or 
3 mg/kg qw), and will transition to a qow dosing regimen at Week 6 as described in Section 3.1. 
At any time during the extension study, a subject may choose to transfer to a local medical 
center to receive their IMP infusions.  Scheduled study assessments may also be performed at 
the local medical center provided that the center has access to the appropriate facilities and 
expertise. 
6.1.1 Dose Escalation 
After a minimum of 12 weeks of treatment in study LAL-CL04, a subject may be considered for 
a dose escalation, either from 1 mg/kg qow to 3 mg/kg qow or from 3 mg/kg qow to 3 mg/kg qw, 
if the subject exhibits an inadequate clinical response (see below).  Prior to considering a dose 
increase, the subject should be evaluated for other potential causes of any clinical 
manifestations that are thought to reflect a suboptimal response.  Other causes could include: 
• 
missed study infusions, 
• 
development of a new intercurrent illness, with the potential to confound the 
interpretation of biochemical efficacy measures, e.g., 
o development of viral or autoimmune hepatitis or other alternative etiology of liver 
disease,   
o initiation of a potentially hepatotoxic concomitant medication in a subject with 
elevated ALT 
o initiation or modification of concomitant medication known to impact serum lipid 
levels. 
Inadequate clinical response is defined as: 
• 
Clinically important manifestations of LAL Deficiency on either clinical examination, 
laboratory assessment, liver biopsy or imaging which have either  
a. not improved from baseline,  
b. improved and plateaued but have not normalized,  
(Note: The definition of a plateauing of effect requires consideration of a 
minimum of 3 assessments.) 
c. failed to normalize within 12 months of initiation of treatment.   
Manifestations include but are not restricted to the following: elevated hepatic 
transaminases, abnormal liver function or coagulation tests, dyslipidemia, hepatomegaly, 
splenomegaly, significant histological abnormalities of the liver, or lymphadenopathy. 
6.1.2 Dose Reduction 
Subjects who do not tolerate their current dose level may receive a dose reduction to the next 
lowest dose level, i.e., 1 mg/kg qow or 0.35 mg/kg qow, at the discretion of the Investigator in 
consultation with the Sponsor and, where appropriate, the SC.  
If a subject cannot tolerate a dose of 0.35 mg/kg qow, despite measures taken to manage any 
IARs, the subject will be discontinued from the study. 
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NOTE: Any subject who undergoes a dose modification, as described above, will have 
additional laboratory monitoring schedule of selected analytes, as detailed in Section 5.1.10. 
6.1.3 Home Infusions 
Subjects who are in the maintenance phase of the study may be eligible to receive infusions at 
home, if appropriate, where infrastructure, resources, and procedures are established and 
available, allowed by local regulations, and approved by the Investigator and Sponsor. 
To be considered for home infusions, a subject must have been on a stable dose of sebelipase 
alfa for at least 12 months and must meet all of the following criteria during the prior 6 months: 
• 
No occurrences of IARs that required medical intervention or management; 
• 
No SAEs determined to be related to IMP. 
Subjects who are approved for home infusions will continue to return to the clinical site (or local 
medical center) for scheduled study assessments. 
6.2 Description of IMP 
Sebelipase alfa is a recombinant human lysosomal acid lipase produced in transgenic Gallus.  
Details of the nonclinical experience to date with sebelipase alfa, as well as IMP stability 
information, can be found in the current version of the Investigator Brochure (IB).  Sebelipase 
alfa must be administered under close supervision of the Investigator, or designee. 
Sebelipase alfa is provided in single dose 10 mL glass vials as a clear liquid.  The solution 
(total 10.5 mL including 5% overfill) has an approximate concentration of 2 mg/mL.  
Sebelipase alfa contains no preservatives and vials are single use only. 
6.3 Method for Assigning Subjects to Treatment  
No randomization schemes will be employed.  All subjects will receive a starting dose equivalent 
to the dose of sebelipase alfa administered during their fourth infusion in study LAL-CL01.  
Subsequent modifications in dose and/or dosing frequency will be made in accordance with the 
protocol.  See Section 3.1. 
Subjects will retain the same subject number that they were assigned upon enrollment in study 
LAL-CL01.  All IMP supply for the extension study will be linked to a unique active subject 
enrollment number. 
6.4 Receipt, Storage, and Disposition of IMP 
6.4.1 Receipt of IMP 
Upon receipt of the IMP supplies, an inventory must be performed and a drug receipt log filled 
out and signed by the person accepting the shipment.  It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory.  
Any damaged or unusable IMP in a given shipment will be documented in the study files.  The 
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Investigator must notify the Sponsor of any damaged or unusable IMP that was supplied to the 
Investigator’s site. 
6.4.2 Storage 
Vials of IMP must be stored under controlled refrigerated conditions at 2 °C to 8 °C 
(36 °F to 46 °F).  Vials should not be frozen and should be protected from light during storage. 
The infusion bag containing sebelipase alfa should be prepared just prior to the start of infusion 
administration.  Although the product in the infusion bag is stable at room temperature 
(23°C to 26°C) for up to 12 hours, the infusion should be initiated as soon as possible after 
preparation. 
6.4.3 Disposition 
The Investigator or designated person (e.g., a licensed pharmacist) will be responsible for 
maintaining accurate records for all supplies used.  Opened sebelipase alfa vials still containing 
any residual volume may be stored at room temperature for IMP accountability.  Following IMP 
accountability, the Sponsor will give written authorization to the Investigator to return or destroy 
any remaining IMP as instructed. 
Under no circumstances will the IMP be used other than as directed in the protocol. 
6.5 Preparation and Administration of IMP 
6.5.1 Preparation of IMP 
The subject’s most recent protocol-scheduled weight measurement, rounded to the nearest 
1.0 kg, will be used for calculating sebelipase alfa volume for each infusion.  If a subject has a 
change in body weight of more than 10% during an interval between protocol-scheduled weight 
assessments, the unscheduled weight measurement should be used. 
Dose preparation and administration should be performed using sterile, non-pyrogenic 
disposable materials including, but not restricted to syringes, needles, transfer tubing, and 
stopcocks. 
Sebelipase alfa is a protein and should be handled and mixed gently to prevent foaming, as this 
has been associated with post-translational modification to other therapeutic proteins.  
Prior to administration, the admixture should be inspected visually for particulate matter and 
discoloration.  The contents should NOT be heated using a microwave or other heat source. 
Sebelipase alfa should be diluted to a concentration of 0.1 to 1.5 mg/ml for infusion. Refer to the 
IMP manual for detailed instructions regarding preparation.  
6.5.2 Administration of IMP 
Sebelipase alfa should not be infused with other products in the same infusion tubing as the 
compatibility in solution with other products has not been evaluated.  IMP infusions will be 
administered at an infusion rate depending on the subject’s weight, and must be administered 
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under close supervision of the Investigator, or designee.  Sebelipase alfa should not be 
administered at an infusion rate exceeding 4 ml/kg/hr.  Refer to the IMP manual for detailed 
instructions regarding administration. 
6.6 Blinding of IMP 
This is an open label study with no requirement for blinding. 
6.7 Destruction of IMP 
Following IMP accountability and written permission from the Sponsor to destroy IMP, 
documentation of destruction must contain, at a minimum, the following: 
• 
Identity, lot number, or subject number  
• 
Quantity of IMP destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of person or company responsible for destruction 
 
 
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7 Assessment of Safety  
The methods for collecting safety data are described below.  All personnel involved with the 
study must ensure they are familiar with the content of this section.  
7.1 Adverse Events and Laboratory Abnormalities 
7.1.1 Clinical Adverse Events 
An Adverse Event is any untoward medical occurrence in a subject, which does not necessarily 
have to have a causal relationship with the administration of an IMP.  An AE can therefore be 
any unfavorable and unintended sign, symptom or disease temporally associated with the use 
of the IMP, whether or not considered related to the medicinal product.  Pre-existing conditions 
that worsen in severity during the course of the study are to be reported as AEs. 
All AEs occurring during the clinical study will be reported on the AE page of the eCRF. 
The Investigator will assess the severity, causality (relationship to IMP), and seriousness of 
each AE. 
Severity: The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 or higher.  The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on the 
general guideline below.  Detailed instructions on grading of events by MedDRA system organ 
class and lower level term are available online.  
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily life (e.g., preparing meals, shopping for 
groceries or clothes, using the telephone, managing money). 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily life (e.g., bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden). 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5: Death related to AE. 
Note: Severity is distinct from seriousness.  Thus, a Grade 4 AE is not by default an SAE.  An 
AE will be reported as serious only if the Investigator judges the event to meet the definition of 
an SAE as provided below. 
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Causality: AEs will be assessed as not related, unlikely related, possibly related, or related to 
IMP.  Table 1 provides general guidance on the assessment of causality.  For data reporting 
purposes, AEs assessed as not related or unlikely related will be reported as unrelated to IMP, 
and AEs assessed as possibly related or related will be reported as related to IMP.  Assessment 
of causality should be based on the Investigator’s medical judgment and the observed 
symptoms associated with the event.   
Table 1 
Assessment of Causality 
Relationship to IMP  
Criteria for Judgment 
Related  
Reasonable temporal relationship of the clinical event to IMP 
administration AND cannot be reasonably explained by other 
factors (such as the subject’s clinical state, concomitant 
therapy, and / or other interventions).  
Possibly Related  
The temporal relationship of the clinical event to IMP 
administration makes causal relationship possible but not 
unlikely AND other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation 
for the observed event.  
Unlikely Related 
The temporal relationship of the clinical event to IMP 
administration makes causal relationship unlikely but not 
impossible AND other drugs, therapeutic interventions or 
underlying conditions provide a plausible explanation for the 
observed event.  
Not Related  
Data are available to clearly identify an alternative cause for 
the reaction.  
Seriousness: AEs will be classified as serious or non-serious according to the definitions 
provided below.  
A serious adverse event is any AE that is or leads to any of the following:  
• 
Death 
• 
Immediately life threatening (An AE is considered “life threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death.  It does not include an AE that, had it occurred in a more severe form, might have 
caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Congenital anomaly/birth defect 
• 
Persistent or significant disability or incapacity 
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• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Planned hospitalizations to accommodate a study procedure are not considered an SAE.  
However, during the hospitalization, adverse events will be collected and assessed for 
seriousness & reported appropriately (i.e., Important medical event or prolonged 
hospitalization). 
All AEs that do not meet any of the criteria for an SAE should be regarded as non-serious 
adverse events.  
All SAEs and IARs must be reported to the Sponsor as described in Section 7.4. 
7.1.2 Laboratory Test Abnormality 
Laboratory test results will be recorded, or provided on the laboratory reports submitted directly 
from the central laboratory.  Out of range laboratory test values should not be reported as AEs 
UNLESS they are considered to be a clinically significant abnormality by the Investigator. 
7.1.3 Infusion Associated Reactions 
Infusion-associated reactions will be considered AEs of special interest.  Any AE that occurs 
during the infusion or within 4 hours after the infusion and is assessed by the Investigator as at 
least possibly related to IMP will be designated as an IAR.  In addition, if, at any time during the 
study, the Investigator observes symptoms that he/she considers to be consistent with an 
IAR or a hypersensitivity reaction related to the administration of IMP, the symptoms will be 
recorded as an AE(s) and designated as an IAR(s). 
As with any ERT, medications and equipment for the treatment of hypersensitivity reactions 
must be available for immediate use in case of unexpected severe hypersensitivity reactions.  
These supplies include, but are not restricted to, oxygen, acetaminophen, antihistamines 
(e.g. diphenhydramine, 
parenteral 
and 
oral 
[PO]), 
corticosteroids, 
epinephrine, 
and 
cardiopulmonary resuscitation devices. 
General guidelines for classifying the severity of a reaction are provided below, and examples of 
mild, moderate, and severe IARs are provided in Appendix F. 
For similar biological products, most acute IARs occur within 2 hours of the infusion.  Signs of a 
possible acute IAR may include: 
• 
Hyperemia, flushing, fever and/or chills, nausea, pruritus, urticaria, gastro-intestinal 
symptoms (vomiting, diarrhea, abdominal cramping), cardiopulmonary reactions, 
including chest pain, dyspnea, wheezing, stridor, hypotension or hypertension. 
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If any of the above signs and symptoms are observed during the infusion and the subject does 
not show any respiratory symptoms and remains hemodynamically stable: 
a) The infusion rate must be slowed (reduced to half the rate being given at the onset of the 
event, e.g. from 125 mL/hr to 62.5 mL/hr) and the infusion time extended.  Once the 
event has resolved, the infusion should continue for a minimum of 30 minutes at the 
reduced rate before the rate is increased to 75% of the original rate on the infusion 
schedule.   
b) In accordance with institutional standard of care for the subject’s age, treatment with an 
antihistamine should be considered.  
In subjects who experience severe infusion reactions with clinically significant cardiovascular 
effects (hypotension defined as a decline approaching 20-30% of their pre-infusion value), 
respiratory effects (significant shortness of breath, stridor, laryngeal edema or swelling of 
tongue), or other effects: 
a) The infusion should be discontinued. 
b) The subject should be treated for an anaphylactic reaction with intravenous 
antihistamines, corticosteroids, and epinephrine, if necessary in accordance with 
institutional standard of care for the subject’s age.  
c) Dosing of the patient will be suspended until the Safety Committee has completed 
review of the IAR, and any other relevant safety data. 
d) Subjects who experience a moderate or severe IAR should have a serum sample collected 
for tryptase 1 to 3 hours after the IAR onset and another serum sample for tryptase and 
ADA at least 4 days after the IAR.  Skin testing may be considered. 
Additional details on the management of subjects with IARs are provided in Appendix F. 
7.2 Handling of Safety Parameters 
7.2.1 Serious Adverse Events (Immediately Reportable to the Sponsor) 
All SAEs and IARs (serious and nonserious), must be reported to the Sponsor or designee 
immediately and no later than 24 hours after the Investigator’s first knowledge of the event 
(expedited reporting). 
The definition and reporting requirements are in accordance with ICH Guidance for Clinical 
Safety Data Management, Definitions and Standards for Expedited Reporting (Topic E2, 1995). 
7.2.2 Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from the signature 
of written consent to the end of the study treatment follow-up.  For this study, AEs will be 
reported from the date of written informed consent until completion of the follow-up visit at 
approximately 30 days after the last dose of IMP.  If a subject experiences an SAE that is 
considered to be related to study treatment at any time after the study, it must be reported to the 
Sponsor. 
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7.2.3 Treatment and Follow-up of Adverse Events 
Treatment of AEs is at the discretion of the Investigator and should follow the standards of 
medical care at the Investigator’s institution. 
All AEs and SAEs will be followed until resolution, the condition stabilizes, or the Investigator 
and Sponsor agree that follow up is no longer necessary.  SAEs that are ongoing after 
completion of the last scheduled visit should continue to be followed up to determine the final 
outcome.  Non-serious AEs that are ongoing after completion of the last scheduled visit should 
be followed up until the event resolves or stabilizes, or for a minimum of 30 days after the last 
dose of IMP (whichever occurs first).  Rules for AE/SAE follow-up apply to all subjects, including 
those withdrawn prematurely, to the extent allowed by the subject’s consent. 
The Investigator will ensure that AE/SAE follow-up includes further investigations consistent 
with appropriate medical management and subject consent to elucidate the nature and/or 
causality of the AE/SAE. 
7.2.4 Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained clinically significant abnormal laboratory values, the tests should be 
repeated and followed up until they have returned to baseline values and/or an adequate 
explanation of the abnormality is found.  If a clear explanation is established, it should be 
recorded in the eCRF. 
7.2.5 Pregnancy 
It is not known what effects sebelipase alfa has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner.  Nonsterilized female 
patients of reproductive age group and male patients must agree to use a highly effective and 
approved contraceptive method(s) for the duration of the study and to continue to use for 
30 days after the last dose of IMP.  Highly effective methods of contraception are defined in 
Section 4.3.  Regular pregnancy tests will be performed as defined in Section 5.1.10. 
A female subject or a male subject with a female partner must immediately inform the 
Investigator if she becomes pregnant during the study.  The female subject must not receive 
further sebelipase alfa infusions.  Pregnancies occurring up to 90 days after the completion of 
the last infusion must be reported to the Investigator.  The Investigator must report all 
pregnancies to the Sponsor within 24 hours of notification.  The Investigator should counsel the 
subject discussing the risks of continuing with the pregnancy and the possible effects on the 
fetus. Monitoring of the subject should continue until conclusion of the pregnancy. 
7.3 Recording of Adverse Events 
At each scheduled contact with the subject, the Investigator must seek information on AEs by 
specific questioning and, as appropriate, by examination.  Information on all AE should be 
recorded in the source document, and also in the appropriate AE module of the eCRF.  All 
clearly related signs, symptoms, and abnormal diagnostic procedure results should be recorded 
in the source document, grouped under one diagnosis. 
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The date/time when the AE started and stopped, severity, seriousness, action taken with regard 
to the study drug, causality assessment, and outcome of the event will be recorded in the eCRF 
for each AE. 
Any AEs/SAEs remaining unresolved after completion of the last scheduled visit (i.e., follow-up 
visit) should be recorded as ongoing in the eCRF.  Ongoing AEs/SAEs should continue to be 
followed up for the period specified in Section 7.2.3, but without further recording in the eCRF.  
However, follow-up information on SAEs must be reported to the Sponsor as described in 
Section 7.4.  
7.4 Reporting of Serious Adverse Events, Infusion Associated Reactions and 
Unanticipated Problems  
Investigators and the Sponsor must conform to the AE reporting timelines, formats and 
requirements of the various entities to which they are responsible.  At a minimum the events 
that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others (see definitions, Section 7.1).  
If the SAE/IAR report is supplied as a narrative, the minimum necessary information to be 
provided at the time of the initial report includes: 
• 
Protocol number 
• 
Investigator name and site 
number 
• 
Subject number 
• 
A description of the event 
• 
Date of  onset 
• 
Time and amount of last IMP 
administration 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as 
serious (if an SAE) 
• 
Investigator assessment of the relationship 
between the event and study treatment 
• 
Severity 
7.4.1 Investigator Reporting: Notifying the Sponsor 
Any SAE, IAR or unanticipated problem posing risk of harm to subjects, must be reported to the 
Sponsor, or designee, within 24 hours of the event.  To report such events, a SAE or IAR form 
must be completed by the Investigator and sent to the Sponsor within 24 hours.  The 
Investigator will keep a copy of this SAE or IAR form on file at the study site.  Report SAEs and 
IARs by phone, fax or email to: 
For cases in North America 
For cases in Europe 
Phone: 
 
Fax: 
 
Email:
 
Fax: 
 
Email: 
 
 
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PPD
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The Investigator must promptly provide further information on the SAE, IAR, or the 
unanticipated problem.  This should include a copy of the completed SAE or IAR form, and any 
other information that will assist the understanding of the event.  Significant new information on 
ongoing SAEs or IARs must be reported to the Sponsor or designee immediately and no later 
than 24 hours of the Investigator’s knowledge. 
7.4.2 Investigator Reporting: Notifying the IRB/IEC 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
IRB/IEC per their institutional policy.  Copies of each report and documentation of IRB/IEC 
notification and acknowledgement of receipt will be kept in the Investigator’s study file. 
7.4.3 Sponsor Reporting: Notifying Regulatory Authorities 
The Sponsor is required to report certain study events in an expedited manner to the FDA, the 
European Medicines Agency, and to all country Regulatory Authorities where the study is being 
conducted.  The following describes the safety reporting requirements by timeline for reporting 
and associated type of event: 
Within 7 calendar days 
Any study event that is: 
associated with the use of the study drug, unexpected, fatal or life-threatening. 
Within 15 calendar days 
Any study event that is: 
associated with the use of the study drug, unexpected, and serious, but not fatal or life-
threatening. 
7.4.4 Notifying Participating Investigators 
It is the responsibility of the Sponsor or designee to immediately notify all participating 
Investigators of any suspected AE associated with the use of the drug that is both serious and 
unexpected, as well as any finding from tests in laboratory animals that suggest a significant risk 
for human subjects. 
7.5 Medical Monitoring 
It is the responsibility of the Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of AEs as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan 
(see Section 9).  Medical monitoring will include a regular assessment of the number and type 
of SAEs. 
7.5.1 Independent Safety Committee 
Additional oversight of subject safety will be provided by an independent Safety Committee (SC) 
comprised of individuals with pertinent medical expertise who will serve in advisory capacity to 
the Sponsor to ensure that clinical trial participants are not exposed to unreasonable or 
unnecessary risks.  
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Collectively, the SC members will have methodological and clinical expertise relevant to the 
study design and population.  SC membership will begin before the start of the clinical trial and 
is expected to last for its duration.  Core members of the SC will not participate in the trial as 
Investigators or sub-investigators, as members of any team otherwise participating in the trial, or 
in any other capacity that may compromise their privileged activities on the SC.  Neither 
members of the SC nor their immediate families will have a direct financial interest in the 
Sponsor or an interest that is dependent on the outcome of the trial.  To be considered for SC 
membership, all candidates must disclose all actual or potential conflicts of interest, including 
any financial interests in, or research activity on a competing product. SC members will be 
compensated at an appropriate market rate for time spent reviewing, discussing, and attending 
the meetings.  The Sponsor will also reimburse SC members for any out-of-pocket travel 
expenses required for attendance at the meetings.  Aside from the above, SC members will 
receive no additional compensation for their membership on the committee. 
The SC will perform periodic reviews of aggregate safety data from study LAL-CL04 on at least 
a biannual basis (i.e., every 6 months) from the date of enrollment of the first subject until 
completion of dosing for all subjects in the study.  Ad-hoc reviews of safety data will also be 
performed by the SC on an as needed basis in the event of emerging safety signals of clinical 
concern in one or more subjects, including potential safety risks that meet the pre-defined 
stopping rules for study treatment (see Section 7.6).  Following each periodic and ad-hoc review 
of safety data, the SC will indicate whether dosing of sebelipase alfa may continue 
(or be resumed) for all subjects or a subset of subjects in the study. 
The composition and activities of the SC will be outlined in the SC Charter, which will be ratified 
during the initial meeting of the SC and prior to commencement of dosing in the extension 
study. 
7.6 Dose Modification and Stopping Rules 
The Sponsor or independent SC (see Section 7.5.1) may suspend dosing at any time for an 
individual subject, a cohort of subjects receiving a given dose, or all subjects enrolled in the 
study due to poor tolerance or potential safety risks. 
Possible reasons for suspending dosing in an individual subject include SAE(s), Grade 3 
(severe) or higher IAR(s).  Specific dose modification and stopping rules for study LAL-CL04 are 
provided in Appendix E. 
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8 Statistical Plan 
The Sponsor will be responsible for data collection and editing, reviewing and validating all the 
information in the eCRFs, statistical analysis, and generation of the clinical study report. 
Prior to locking the database, all data editing will be complete and decisions regarding the 
evaluability of all subject data for inclusion in the statistical analysis will be made.  The rationale 
for excluding any data from the statistical analyses will be prospectively defined, and 
classification of all or part of a subject’s data as non-evaluable will be completed and 
documented before the entire database is locked.  
A separate Statistical Analysis Plan (SAP) will be finalized prior to locking the database.  The 
SAP will document any changes from the analyses as specified in the protocol and its 
amendments.  The final clinical study report will document any changes from the SAP.  The 
analysis will be performed using the SAS® statistical software system.  If appropriate, other 
commercially available software may be utilized for graphical presentations. 
8.1 General Considerations 
All data collected in this study will be provided in subject data listings sorted by subject number. 
Data collected in this study will be reported using summary tables and graphs as appropriate to 
the data.  Descriptive summary statistics (n, mean, median, standard deviation, minimum and 
maximum) will be calculated for the continuous variables and shift tables and/or frequencies 
and percentages will be produced for the categorical variables.  As noted, 95% two-sided 
confidence interval (CI) will be calculated around the estimates based on the exact binomial 
distribution for categorical endpoints and the t-distribution for continuous endpoints.  Effect of 
anti-drug antibodies will be examined for efficacy, safety, and PK endpoints.  Numbers 
permitting, analyses may be conducted in other subgroups of interest. 
Baseline will be defined as the last measurement prior to the first infusion of sebelipase alfa in 
study LAL-CL04.  As appropriate, a CL01 Study Baseline defined as the last measurement prior 
to the first infusion in study LAL-CL01, may also be used for selected study endpoints.  For 
endpoints that are computed as changes from baseline, a comparison between change from 
Baseline and change from the CL01 Study Baseline will be performed, as appropriate. 
Unless otherwise noted, all tabulations will present data overall and by dose and dosing 
frequency (qw, qow) – i.e., dosing regimen. 
8.2 Determination of Sample Size 
Sample size is based on the estimated total enrollment in study LAL-CL01, and assumes that all 
subjects treated in that study will be eligible and willing to participate in this extension study. 
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8.3 Analysis Sets 
Full Analysis Set (FAS): This analysis set consists of all subjects who received at least 
one complete infusion of IMP in the extension study, and have at least one post-treatment 
measurement in the extension study.  This analysis set will be used for analysis of 
efficacy, pharmacodynamic, and patient health outcomes data.  
Safety Analysis Set: This analysis set consists of all subjects who received any amount 
of IMP in the extension study, and will be used for all safety analyses. 
Per-Protocol Analysis Set: This analysis set will consist of all subjects in the FAS who 
have no protocol violations that could potentially confound the interpretation of serum 
transaminase or lipid results.  The list of subjects to be included in the per-protocol 
analysis set will be determined before database lock.  If all patients in the FAS are also in 
the per-protocol analysis set, then separate analyses for the per-protocol analysis set will 
not be performed.   
PK Analysis Set: This analysis set will include all available sebelipase alfa serum 
concentration data for subjects who receive at least one complete infusion of IMP in the 
extension study, and will be used for all PK analyses. 
8.4 Demographics and Baseline Characteristics 
Demographic and baseline data (e.g., medical history, disease history) collected during study 
LAL-CL01 will be listed and tabulated overall for those subjects who enroll in the extension 
study.  Dose of sebelipase alfa administered at the start of LAL-CL04 will be listed and 
summarized. 
8.5 Subject Accountability 
A subject data listing, sorted by subject number, will be prepared and will include dose of 
sebelipase alfa first administered on the LAL-CL04 study, age, gender, date of consent, date of 
first dose of sebelipase alfa under LAL-CL01, date of first dose of study drug under LAL-CL04, 
date of completion or premature discontinuation from the study and reason for discontinuation if 
the subject discontinues prematurely.  Data from all subjects who are enrolled in the study will 
be included in the summary of subject accountability.  The frequency and percentage of 
subjects who are enrolled in the study, discontinued from the study, and completed the study, 
along with reasons for discontinuation, will be summarized. 
8.6 Study Treatment Usage and Compliance 
Number of weeks in the study and number of study infusions received by subjects will be 
summarized overall, by dosing regimen, by dose across all frequencies and by frequency 
(qw or qow).  Descriptive summaries of rate of infusion, volume, and number (percent) of 
subjects who receive all study infusions 'per protocol' (i.e., subjects without missed infusions or 
infusion interruptions or rate changes) will also be provided. 
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8.7 Safety Analysis 
Safety will be analyzed in Safety Analysis Set.  As appropriate, the effect of dosing regimen 
and/or treatment duration on safety endpoints will also be explored. 
8.7.1 Adverse Events 
All AEs, SAEs, and IARs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and presented in by-subject listings that will include dosing regimen prior to the 
event, time of onset, severity, causality, actions taken regarding treatment, and outcome.  The 
number and percent of subjects experiencing any AE, any SAE, any IAR, any related AE, any 
related SAE, and discontinuations due to an AE will be tabulated. 
Treatment-emergent AEs, SAEs, and IARs will be tabulated (frequencies and percentages) by 
Preferred Term (PT) within System Organ Class (SOC), for all events and for events by severity 
and causality.  If a subject experiences more than one occurrence of the same AE, and these 
differ in severity and/or causality, the AE will be tabulated according to the greatest severity and 
nearest relationship to IMP.  As appropriate, additional listings and summary statistics will be 
generated to evaluate IAR frequency and severity over time.  A listing of subjects who withdraw 
from the study due to AEs will be presented, and the incidence of AEs leading to study 
discontinuation will be summarized.   
8.7.2 Clinical Laboratory Tests 
Observed measurements and changes from baseline to study timepoints in clinical chemistry, 
hematology, and urinalysis will be summarized.  All laboratory values will be classified as 
normal, above normal, or below normal based on normal ranges provided by the laboratory. All 
laboratory values, and all clinical significant abnormal laboratory values, will be presented in by-
subject listings.  Frequencies of abnormal values relative to the laboratory normal range and 
clinically significant abnormal values will also be summarized.  
Percentage of subjects who become ADA positive, time to ADA positivity and time to peak titer, 
and median and peak immunoglobulin G (IgG) antibody titer will be summarized.  IgG antibody 
titer values will be tabulated using summary statistics at each study visit.  All data will be 
presented in by-subject listings. Descriptive summaries may also be provided as appropriate. 
8.7.3 Other Safety Data 
Observed measurements and changes from baseline to study timepoints in vital signs 
(blood pressure, heart rate, respiratory rate, and temperature), and 12-lead ECG parameters 
will be summarized.  Listings of abnormal findings/values for physical examinations, vital signs, 
and ECGs will be presented, as appropriate. 
Concomitant medication/treatment data will be coded using the WHO-DRUG dictionary.  All 
data will be listed, and the number and percentages of subjects receiving each concomitant 
medication/treatment will be tabulated. 
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8.8 
Efficacy, Pharmacodynamic, and Patient Health-Related Quality of Life 
(HRQOL) Outcomes Analyses 
Data will be presented for subjects in the Full Analysis Set.  All data will be presented by study 
visit in subject data listings.  Observed measurements and changes or percent changes from 
baseline to study timepoints in liver and spleen volumes and liver and spleen fat content, liver 
cholesteryl ester signature, serum transaminases, plasma lipids, and acute phase reactants 
(e.g., serum ferritin) will be summarized overall and by dosing regimen.  The percentage of 
subjects with abnormal transaminases at each timepoint will also be summarized overall and by 
dosing regimen.  Scores and changes from baseline to study timepoints for the SF-36®, 
FACIT-Fatigue, and CLDQ will be summarized. 
8.9 Pharmacokinetics  
Cmax and Cmin will be recorded from direct observation, and other PK parameters will be derived 
by non-compartmental analysis.  Pharmacokinetics will be characterized using the PK Analysis 
Set.  All PK parameters will be summarized by dosing by dosing regimen. 
8.10 Other Statistical Issues 
8.10.1 Significance Levels 
No formal hypothesis tests are planned.  P-values and confidence intervals, where presented, 
will be based on a 2-sided alpha of 0.05 and are intended to guide clinical judgment and 
interpretation of the data. 
8.11 Missing or Invalid Data 
All data will be analyzed as they were collected in the database.  Missing data will not be 
imputed using statistical methods. 
8.12 Interim Analysis 
Summaries of interim data will be created to support a regulatory filing(s).  Safety, efficacy, PK, 
and/or PD data available by a designated cutoff date prior to the regulatory filing(s) will be 
presented in subject data listings and reported using summary tables and graphs, as 
appropriate to the data.  No inferential statistical analyses are planned. 
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9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of applicable local regulations. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
9.3 Case Report Forms 
Required data for this study will be captured on eCRFs via electronic data capture (EDC) unless 
otherwise specified in this document.  Except for data points for which the protocol or SOM 
indicate that the eCRF may serve as source documentation, data are to be obtained from the 
subject’s source documents and then entered into the eCRF by authorized site personnel.  
Clinical data that are not recorded on the eCRF will be captured and transferred to the Sponsor 
or its designee.  
9.4 Records Retention 
It is the Investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP.  These documents should be retained 
for a longer period if required by an agreement with the Sponsor.  In such an instance, it is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these documents 
no longer need to be retained.  
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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the study monitoring plan.  The Investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure that the 
monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the IRB/IEC, 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 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 and applicable compliance and quality assurance offices. 
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11 Ethical Considerations 
This study is to be conducted according to US and international standards of GCP 
(FDA Title 21 part 312 and ICH guidelines), applicable government regulations and Institutional 
research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted IRB/IEC, in 
agreement with local legal prescriptions, for formal approval of the study conduct.  The decision 
of the IRB/IEC 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 IRB/IEC members 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 
IRB/IEC for the study.  The formal consent of a subject, using the IRB/IEC-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The consent form 
must be signed by the subject or legally acceptable surrogate, and the Investigator-designated 
research professional obtaining the consent.  
Any changes in the study protocol, such as changes in the study design, objectives or 
endpoints, inclusion and exclusion criteria, and/or procedures (except to eliminate an immediate 
hazard) will be implemented only after the mutual agreement of the Investigator and the 
Sponsor or designee.  All protocol changes must be documented in protocol amendment(s).  
Protocol amendment(s) must be signed by the Investigator and approved by the IRB/IEC prior 
to implementation.  Any changes in study conduct that result from a pending amendment will be 
considered protocol deviations until IRB/IEC approval is granted.  Documentation of IRB/IEC 
approval must be returned to the Sponsor or designee. 
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12 Clinical Study Report and Publication Plan 
An interim clinical study report (CSR) will be produced to support regulatory filings.  A final CSR 
to summarize the long-term efficacy, safety, and PK parameters will be produced after study 
completion.  
A coordinating Investigator will be designated to review and sign the completed clinical study 
reports.  The process for identifying the coordinating Investigator will include evaluation of 
relevant criteria such as: 
1. Member of the external Scientific Advisory Board 
2. Contribution to study development and/or implementation 
3. Demonstrated understanding of, and adherence to, this protocol  
All information concerning study medication and the Sponsor operations, such as patent 
applications, formula, manufacturing processes, basic scientific data, or formulation information, 
supplied by the Sponsor and not previously published, is considered confidential.  The 
Investigator agrees to use this information only in accomplishing this study and will not use it for 
their purposes without the prior written consent of the Sponsor. 
All information developed in this clinical study is the sole and exclusive property of the Sponsor.  
This information will be used by the Sponsor and its affiliates in connection with the 
development of the study medication and, therefore, may be disclosed by the Sponsor, as 
required, to other clinical Investigators, other pharmaceutical companies, and other regulatory 
authorities, and to other governmental agencies.  In order to allow for the use of the information 
derived from clinical studies, the Investigator agrees to provide the Sponsor with complete test 
results and all data developed in this study.  All test results, data, and information provided to 
the Sponsor must be complete and accurate. 
It is intended that the results from this research will be submitted to a peer-reviewed medical 
publication, once the study is completed, regardless of the outcome. 
 
 
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13 References 
Anderson, RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine 
phenotype in Wolman and cholesterol ester storage disease.  Mol Genet Metab. 1990;68:333-
345. 
Andrews L, O’Callaghan M. Enzyme Replacement Therapies. In: Cavagnaro JA, ed. Preclinical 
Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical 
Trials. Hoboken, NJ: John Wiley & Sons, Inc., 2008:517-35. 
Assmann G, Seedorf U. Acid lipase deficiency: Wolman disease and cholesteryl ester storage 
disease. In: Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, eds. The Metabolic 
and Molecular Basis of Inherited Disease (online). 8th ed. New York: McGraw Hill Inc.; 
2001:1-49. 
Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme 
deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 
1991;324(21):1464-1470. 
Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO. Therapeutic response to intravenous 
infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci. 
1990;87:1913-1916. 
Beaudet AL, Ferry GD, Nichols BL, Rosenberg HA. Cholesterol ester storage disease: Clinical, 
biochemical, and pathological studies. J. Pediatr. 1977; 90:910-914. 
Cerezyme (imiglucerase for injection) prescribing information. Cambridge, MA: Genzyme 
Corporation; 2005. 
Fabrazyme (agalsidase beta) prescribing information. Cambridge, MA: Genzyme Corporation; 
2003. 
Di Bisceglie AM, Ishak KG, Rabin L, Hoeg JM. Cholesteryl ester storage disease: 
hepatopathology and effects of therapy with lovastatin. Hepatol. 1990;11:764-772. 
Elleder M, Chlumska A, Hyanek J, Poupetova H, Ledvinova J, Maas S. et al.  Subclinical course 
of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated 
atherosclerosis, and liver cancer. J Hepatol. 2000;32:528-534. 
Ferry GD, Whisennand HH, Finegold MJ, Alpert E, Glombicki A. Liver transplantation for 
cholesteryl ester storage disease. J Pediatr Gastroenterol. Nutr. 1991;12:376-378. 
Gasche C. Aslanidis C, Kain R, Exner M, Helbich T, Dejaco C, et al. A novel variant of 
lysosomal acid lipase in cholesteryl ester storage disease associate with mild phenotype and 
improvement on lovastatin. J Hepatol. 1997;27:744-750. 
Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ.  Suppression of apolipoprotein B 
production during treatment of cholesteryl ester storage disease with lovastatin. J Clin Invest. 
1987;80:1692-1697. 
Glueck CJ, Lichtenstein P, Tracy T, Speirs J.  Safety and efficacy of treatment of pediatric 
cholesteryl ester storage disease with lovastatin. Pediatr Res. 1992;32:547-552. 
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05 January 2016 
Hansen K, Horslen S.  Metabolic liver disease in children. Liver Transplant. 2008;14:713-733. 
Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid α-glucosidase: Major clinical 
benefits in infantile-onset Pompe disease. Neurology. 2007;68:99-109. 
Lumizyme (alglucosidase alfa) prescribing information. Cambridge, MA: Genzyme Corporation; 
2010. 
Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical 
trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet 
Metab. 2007;90:329-337. 
Myozyme (alglucosidase alfa) prescribing information. Cambridge, MA: Genzyme Corporation; 
2010. 
Quinn, A.G. et al., 2010. SBC-102, a recombinant enzyme replacement therapy, corrects key 
abnormalities due to lysosomal acid lipase deficiency. American Society of Human Genetics 
Annual Meeting, Program Number 3069. 
Stahl PD, Rodman JS, Miller MJ, Schlesinger PH. Evidence for receptor-mediated binding of 
glycoproteins, glycoconjugates, and lysosomal glycosides by alveolar macrophages. Proc Natl 
Acad Sci. 1978;75:1399-1403. 
Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA.  Treatment of dyslipidemia with 
lovastatin and ezetimibe in an adolescent with cholesteryl ester storage disease. Lipids in 
Health and Disease. 2005;4:26-31. 
Tarantino MD, McNamara DJ, Granstrom P, Ellefson RD, Unger EC, Udall JN.  Lovastatin 
therapy for cholesteryl ester storage disease in two sisters. J Pediatr. 1991;118:131-135. 
US Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute.  Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.  
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf.  Published 28 Mary 2009. Updated (v4.02) 15 September 2009.  
Accessed 08 March 2011. 
van der Ploeg AT, Clemens PR, Corzo D. A randomized study of alglucosidase alfa in late-
onset Pompe’s disease. N Engl J Med. 2010;362:1396-1406. 
VPRIV (velaglucerase alfa for injection) prescribing information. Cambridge, MA: Shire Human 
Genetic Therapies, Inc; 2010. 
Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme 
replacement therapy for Fabry disease. Am J Hum Genet. 2004;75:65-74. 
Wraith JE, Clarke LA, Beck M, et al. Enzyme replacement therapy for mucopolysaccharidosis I: 
a randomized, double-blinded, placebo-controlled, multinational study of recombinant human a-
l-iduronidase (Laronidase). J Pediatr. 2004;144:581-588. 
Yokoyama S, McCoy E.  Long-term treatment of a homozygous cholesteryl ester storage 
disease with combined cholestyramine and lovastatin. J Inherit Met Dis. 1992;15:291-292. 
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14 Appendices
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Appendix A: Schedules of Assessments 
Schedule of Assessments: Screening through Week 24* 
Assessments 
Screening 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Day -14 to 
Day -1 
±2 
days 
±2 
days 
±2 
days 
±2 
days 
±4 
days 
±4 
days 
±4  
days 
±4  
days 
±4  
days 
±4 
days 
±4 
days 
±4 
days 
±4 
days 
±4 
days 
Informed Consent 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Medical History 
X 
 
Health-Related Quality of Life1 
X 
X 
X 
12-lead ECG 
X 
XP 
 
Physical Examination2 
X 
XP 
XP 
 
Pregnancy Test3 
X8 
XP 
XP 
XP 
XP 
XP 
XP 
Clinical Laboratory Tests4  
X8 
XP 
XP 
XP 
Liver and Lipid Panels 
X8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Coagulation Tests4 
X8 
XP 
XP 
XP 
XP 
Anti sebelipase alfa Antibody 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Exploratory 
Biomarker Collection 
X 
 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
PK Profile5 
X 
Abdominal MRI/MRS6 
X 
X 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sebelipase alfa Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X9 
X 
X 
X 
X 
X 
Adverse Events 
Continuous 
Concomitant Meds/Therapies 
Continuous 
*  All visits will be calculated from Week 1; consecutive infusions must be administered at least 7 days apart.  
P  Pre-dose 
1  Includes SF-36, FACIT-Fatigue, and CLDQ. 
2  Physical examination will include measurement of weight (height only at screening), assessment of liver and spleen size, lymphadenopathy and arterial disease.   
3  Serum pregnancy test will be performed at screening.  Urine pregnancy tests will be performed at all visits thereafter. 
4  Clinical laboratory tests include CBC/hematology, serum chemistry, acute phase reactants and urinalysis.  Coagulation tests will be performed at screening and, 
if results are abnormal, tests will be repeated until normal. 
5  Pre-dose, 10, 15, 20, 40, 60, and 90 minutes during the infusion, at the end of the infusion, and at 5, 10, 20, 30, 40, 60 and 120 minutes after the end of infusion. 
6  An MRI and 1H-MRS (if available) will be performed for all subjects.  13C-MRS will also be performed for subjects enrolled at sites with access to this imaging 
modality. 
7  Vital signs will be measured pre-dose, every 30 (±10) minutes during the infusion, and from 0 to 4 hours post-infusion.  
8  Results must be reviewed prior to the start of dosing in the extension study. 
9  After Week 12, a dose adjustment from 1 mg kg-1 qow to 3 mg kg-1 qow, or from 3 mg kg-1 qow to 3 mg kg-1 qw, may be considered based on safety and 
tolerability and/or clinical response to treatment.  All such decisions will be made jointly by the Investigator and Sponsor. 
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Schedule of Assessments: Week 25 through Week 52* 
Assessments 
Week 
258 
Week 
268 
Week 
288 
Week 
30 
Week
32 
Week
34 
Week
36 
Week
38 
Week
40 
Week 
42 
Week 
44 
Week 
46 
Week 
48 
Week 
50 
Week 
52 
±1  
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
Health-Related Quality of Life 1 
 
 
 
X 
 
X 
12-lead ECG 
 
 
 
XP 
 
XP 
Physical Examination2 
 
 
 
XP 
 
XP 
Urine Pregnancy Test 
 
XP 
 
XP 
XP 
XP 
XP 
XP 
 
XP 
Clinical Laboratory Tests3 
 
 
 
XP 
 
XP 
Liver and Lipid Panels4 
X 
 
XP 
 
XP 
 
XP 
Coagulation Tests3 
 
 
 
XP 
 
XP 
Anti sebelipase alfa Antibody 
 
 
XP 
 
XP 
 
XP 
Serum and Urine Exploratory 
Biomarker Collection 
 
 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
PK Profile5 
 
 
 
 
X 
Abdominal MRI/MRS6 
 
 
 
 
X 
Vital Signs7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sebelipase Dosing  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Continuous 
Concomitant Meds/Therapies 
Continuous 
*  All visits will be calculated from Week 1; consecutive infusions must be administered at least 7 days apart.  
P  Pre-dose  
1  Includes SF-36, FACIT-Fatigue and CLDQ 
2  Physical examination will include measurement of weight, assessment of liver and spleen size, lymphadenopathy and arterial disease. 
3  Clinical laboratory tests include CBC/hematology, serum chemistry, acute phase reactants and urinalysis.  Coagulation tests will be performed, only if abnormal 
at previous visit. 
4  In subjects with prior abnormal lipid results, more frequent monitoring of lipid levels may be performed; the need for such monitoring will be jointly assessed by 
the Investigator and Sponsor 
5  Pre-dose, 10, 15, 20, 40, 60, and 90 minutes during the infusion, at the end of the infusion, and at 5, 10, 20, 30, 40, 60 and 120 minutes after the end of infusion. 
6  An MRI and 1H-MRS (if available) will be performed for all subjects.  13C-MRS will also be performed for subjects enrolled at sites with access to this imaging 
modality. 
7  Vital signs will be measured pre-dose, every 30 (±10) minutes during the infusion, and from 0 to 4 hours post-infusion.  Post-infusion observation period may be 
shortened to 2 hours after 6 months of treatment with no occurrence of IARs, and to 1 hour after 12 months of treatment with no occurrence of IARs, contingent 
upon approval by the Sponsor. 
8  This visit should occur 7 days after the Week 24 infusion.  If scheduling does not permit, the visit may instead be scheduled 7 days after either the Week 26 or 
Week 28 infusion. 
 
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Repeating 52-Week Schedule of Assessments: Week 54 through Study Completion*¥ 
Year 2 
Year 3 
Year 4 
Year 5 
 
 
Wk 
54 
106 
158 
210 
 
 
Wk 
56 
108 
160 
212 
 
 
Wk 
58 
110 
162 
214 
 
 
Wk 
60 
112 
164 
216 
 
 
Wk 
62 
114 
166 
218 
 
 
Wk 
64 
116 
168 
220 
 
 
Wk 
66 
118 
170 
222 
 
 
Wk 
68 
120 
172 
224 
 
 
Wk 
70 
122 
174 
226 
 
 
Wk 
72 
124 
176 
228 
 
 
Wk 
74 
126 
178 
230 
 
 
Wk 
76 
128 
180 
232 
 
 
Wk 
78 
130 
182 
234 
 
 
Wk 
80 
132 
184 
236 
 
 
Wk 
82 
134 
186 
238 
 
 
Wk 
84 
136 
188 
240 
 
 
Wk 
86 
138 
190 
242 
 
 
Wk 
88 
140 
192 
244 
 
 
Wk 
90 
142 
194 
246 
 
 
Wk 
92 
144 
196 
248 
 
 
Wk 
94 
146 
198 
250 
 
 
Wk 
96 
148 
200 
252 
 
 
Wk 
98 
150 
202 
254 
 
 
Wk 
100 
152 
204 
256 
 
 
Wk 
102 
154 
206 
258 
 
 
Wk 
104 
156  
208/ 
260 
End of 
Study8,9 
Assessments 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
±7 
days 
Health-Related Quality 
of Life1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
Physical Examination2 
 
 
XP 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Urine Pregnancy Test 
XP 
 
XP 
XP 
XP 
XP 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Clinical Laboratory 
Tests3 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Liver and Lipid Panels 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Coagulation Tests3 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Anti sebelipase alfa 
Antibody 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
Serum and Urine 
Exploratory Biomarker 
Collection 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
PK Profile4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
Abdominal MRI/MRS5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Liver Biopsy6 
X6 
Vital Signs7  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
Sebelipase alfa Dosing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X8 
Adverse Events 
Continuous 
Concomitant 
Meds/Therapies 
Continuous 
*  All visits will be calculated from Week 1; consecutive infusions must be administered at least 7 days apart 
P  Pre-dose  
¥  Weeks will be numbered chronologically in the repeating 52-week modules (i.e., beginning in year 3, Week 106, 108, 110, etc). 
1  Includes SF-36, FACIT-Fatigue, and CLDQ. 
2  Physical examination will include measurement of weight, assessment of liver and spleen size, lymphadenopathy, and arterial disease. 
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3  Clinical laboratory tests include CBC/hematology, serum chemistry, acute phase reactants and urinalysis.  Coagulation tests will be performed, only if abnormal at 
previous visit. 
4  Performed only at Week 104 of the first 52-week period (i.e., non-repeating).  Pre-dose, 10, 15, 20, 40, 60, and 90 minutes during the infusion, at the end of the 
infusion and at 5, 10, 20, 30, 40, 60 and 120 minutes after the end of infusion. 
5  An MRI and 1H-MRS (if available) will be performed for all subjects.  13C-MRS will also be performed for subjects enrolled at sites with access to this imaging 
modality. 
6  Liver biopsy can be scheduled at any time between Week 52 and 104. 
7  Vital signs will be measured pre-dose, every 30 (±10) minutes during the infusion, and from 0 to 4 hours post-infusion.  Post-infusion observation period may be 
shortened to 2 hours after 6 months of treatment with no occurrence of IARs, and to 1 hour after 12 months of treatment with no occurrence of IARs, contingent upon 
approval by the Sponsor. 
8  All subjects will have an End of Study visit 30 (+7) days after last dose of IMP.  All Week 104 procedures, excepting dosing, serial vital signs and PK assessments, 
will be performed. 
 9 Subjects prematurely discontinuing treatment in the study will have an End of Study visit.   
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Appendix B: SF-36® v2 Health Survey 
 
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Appendix C: FACIT Fatigue Scale 
 
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Appendix D: The Chronic Liver Disease Questionnaire (CLDQ) 
 
 
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Appendix E: Dose Modification and Stopping Rules for Study LAL-CL04 
In the absence of an approved grading scale that can be applied to specific patient populations, 
this protocol will apply the National Cancer Institute Common Toxicity Classification of Adverse 
Events 
(NCI 
CTCAE), 
version 
4.0 
or 
higher.  
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).   
 
The following dose modification and stopping rules apply to the decision to pause dosing 
in individual subjects: 
For IARs (refer to the definition in Section 7.1.3), the following stopping rules will apply:  
• 
Subjects who develop a Grade 3 (severe) or higher IAR, defined as significant 
hypo/hypertension, increased temperature and rigors, significant tachypnea with 
wheezing and/or stridor, OR are IgE or skin test positive must stop treatment until their 
information is reviewed by the SC.  Dosing with alterations to the dose or infusion 
regimen (e.g., pretreatment and/or slowing the rate of infusion) may resume once the 
SC and the Sponsor approve.  Confirmation may also be sought from regulatory 
authorities prior to resuming dosing.  Subjects with Grade 1 (mild) and/or Grade 2 
(moderate) IARs can continue in the study.  The SC and/or Sponsor may recommend 
alterations to the infusion regimen (e.g., pretreatment and/or slowing the rate of infusion). 
 
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Appendix F: Diagnosis and Management of Infusion Associated Reactions 
General guidelines for the diagnosis and management of IARs are provided below.  These guidelines are not intended to be 
comprehensive.  The Investigator should use his/her clinical judgment in the management of IARs in individual subjects participating 
in this study.  In the case of a severe life-threatening reaction, current medical standards for emergency treatment are to be followed. 
 
Symptoms 
Management 
Post-IAR Activities 
Mild IAR (Grade 1) 
Common 
• Hyperemia (Flushing) 
• Lightheadedness  
• Nausea 
• Mild chest discomfort (tightness) 
 
Less Common 
• Fever and/or shivering 
• Palpitations 
• Headache  
• Irritability (especially in young 
children) 
• Slow infusion rate by 50% 
• Administer oral anti-pyretic 
and/or antihistamine 
• Decrease infusion rate by a 
further 25% if symptoms 
persist 
• If symptoms continue 
despite rate reduction stop 
infusion 
• Pre-treat with oral antihistamine and antipyretic prior to 
(approximately 1.5 hrs) the next infusion 
Moderate IAR (Grade 2)* 
• 
Hyperemia (flushing) 
• Chest discomfort 
• Itching and/or raised urticarial rash 
• Severe headache 
• Gastro intestinal symptoms, 
vomiting, diarrhea, abdominal 
cramping. 
• 
Stop infusion  
• 
Give antihistamine IV and 
consider PO or IV 
corticosteroids  
• 
Consider giving a beta-
adrenergic inhaler 
treatment, if appropriate 
• 
*Collect sample for serum tryptase within 1-2 hours of event 
• 
*Obtain serum sample for determination of IgE status at least 3 
days after last dose, unless a pre-infusion ADA serum sample 
was collected  
• 
Pre-treat with oral antihistamine and antipyretic prior to 
(approximately 1.5 hrs) the next infusion 
• 
Slowly up-titrate the infusion rate during the subsequent infusion 
o 
e.g., if previous rate was 50 ml/hr, begin at 0.25 x previous 
rate (12.5 ml/hr) x 15min, then increase to 0.5 x rate 
(25 ml/hr) x 15min, then increase to 0.75 x rate (37.5 ml/hr) x 
15 min, then increase to full rate (50 ml/hr) for the remainder 
of the infusion 
*If suspected to be immune mediated IAR 
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Symptoms 
Management 
Post-IAR Activities 
Severe, Life-threatening, or Anaphylactic IAR (Grade 3 or higher) 
• 
Hypo/hypertension (> 40 mmHg 
SBP) 
• 
Respiratory symptoms.  Shortness 
of breath, wheezing, laryngeal 
edema. 
• 
Cardiac arrhythmias 
• 
Anaphylactic/Anaphylactoid shock 
with hypotension and circulatory 
collapse. 
• Stop Infusion 
• Give oxygen, if available 
Give epinephrine IM 
• Give antihistamine IV and 
consider PO or IV 
corticosteroids  
• Consider giving a beta-
adrenergic inhaler 
treatment, if appropriate 
• Collect sample for serum tryptase within 1-2 hours of event 
• Obtain serum sample for determination of IgE status at least 
3 days after last dose, unless a pre-infusion ADA serum sample 
was collected  
• Pre-treat with oral antihistamine, antipyretic and corticosteroids 
prior to (approximately 1.5 hrs) the next infusion 
• Slowly up-titrate the infusion rate during the subsequent infusion 
o 
e.g., if previous rate was 50 ml/hr, begin at 0.25 x previous 
rate (12.5 ml/hr) x 15min, then increase to 0.5 x rate 
(25 ml/hr) x 15min, then increase to 0.75 x rate (37.5 ml/hr) x 
15min, then increase to full rate (50 ml/hr) for the remainder 
of the infusion 
If a subject’s serum is IgE+ (positive), the subject may continue in the study after the review of his/her data by the Safety Committee 
and agreement with the Investigator.  If a subject’s serum is IgE- (negative) and the event was suspected to be immune mediated 
and was moderate to severe in nature, the subject will be skin tested (according to the Skin Testing guidelines provided in the Study 
Operations Manual) prior to receiving the next infusion.  If results of skin test are negative, the subject may continue in the study.  If 
results of skin test are positive, the subject may only continue in the study after the review of his/her data by the Safety Committee 
and agreement with the Investigator. 
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