An Open Label, Multicenter, Dose Escalation Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of SBC-102 (Sebelipase Alfa) in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
Phase: PHASE2
Conditions: Lysosomal Acid Lipase Deficiency, Wolman Disease
Sponsor: Alexion Pharmaceuticals, Inc.

An Open Label, Multicenter, Dose Escalation Study to 
Evaluate the Safety, Tolerability, Efficacy, 
Pharmacokinetics, and Pharmacodynamics of SBC-102 in 
Children with Growth Failure Due to Lysosomal Acid 
Lipase Deficiency 
 
Unique Protocol ID: 
LAL-CL03 
NCT Number: 
NCT01371825 
EudraCT Number:  
2011-000032-28 
Date of Protocol:  
05 January 2016 
 

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AN OPEN LABEL, MULTICENTER, DOSE ESCALATION 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
EFFICACY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF SBC-102 IN CHILDREN WITH 
GROWTH FAILURE DUE TO LYSOSOMAL ACID LIPASE 
DEFICIENCY 
 
 
Protocol Number:  
LAL-CL03 
Date of Protocol: 
05 January 2016  
Amendment: 
12.0 
 
Product: 
Sebelipase alfa (SBC-102) 
IND No.: 
108460 
EUDRACT No.: 
2011-000032-28 
Sponsor: 
Alexion Pharmaceuticals, Inc.  
 
352 Knotter Drive 
Cheshire, CT 06410 
USA 
 
Amendment History 
Protocol 
Date of Approval 
Original 
10 January 2011 
Amendment 1 
09 February 2011 
Amendment 2 (country-specific: France) 
19 April 2011 
Amendment 3  
20 May 2011 
Amendment 4 (country-specific: France) 
02 June 2011 
Amendment 5 (country-specific: Germany) 
20 September 2011 
Amendment 6 
05 April 2012 
Amendment 7 
23 October 2012 
Amendment 8 
05 February 2013 
Amendment 9 
19 March 2013 
Amendment 10 
24 January 2014 
Amendment 10 (country-specific: France) 
11 August 2014 
Amendment 11 
21 November 2014 
Amendment 12.0 
05 January 2016 

PPD

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PROTOCOL SIGNATURE PAGE 
Protocol title:  
An Open Label, Multicenter, Dose Escalation Study to 
Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, 
and Pharmacodynamics of SBC-102 in Children with Growth 
Failure Due to Lysosomal Acid Lipase Deficiency 
Protocol Number:  
LAL-CL03 
 
 
Date of Protocol: 
05 January 2016 
 
Amendment: 
12.0 
 
Product: 
Sebelipase alfa (SBC-102) 
 
IND No.: 
108460 
 
EUDRACT No.: 
2011-000032-28 
 
Sponsor: 
Alexion Pharmaceuticals, Inc.  
 
352 Knotter Drive 
Cheshire, CT 06410 
USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
 
Date 
 
 
PPD

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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 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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Protocol Synopsis 
 
Summary of planned clinical study 
Protocol Number 
(study identifier) 
LAL-CL03 
Title 
An Open Label, Multicenter, Dose Escalation Study to Evaluate the Safety, 
Tolerability, 
Efficacy, 
Pharmacokinetics, 
and 
Pharmacodynamics 
of 
SBC-102 in Children with Growth Failure Due to Lysosomal Acid Lipase 
Deficiency 
Study design features 
This is an open-label, repeat-dose, dose escalation study of SBC-102 
(USAN: sebelipase alfa) in children with growth failure due to LAL 
Deficiency. Eligible subjects will receive once-weekly (qw) infusions of 
sebelipase alfa for up to 5 years. Subjects who are on treatment for at least 
96 weeks and are on a stable dose for at least 24 weeks may be considered 
to transition to an every other week dosing schedule. All subjects will initiate 
treatment at a dose of 0.35 mg/kg- qw. Dose escalation to 1 mg/kg qw will 
occur in all subjects, contingent upon acceptable safety and tolerability, and 
a further dose escalation to 3 mg/kg qw may be permitted in subjects who 
meet defined criteria. All subjects will be evaluated for safety, tolerability, and 
efficacy. Where feasible, given blood volume thresholds based on subject 
weight, blood samples will also be collected for analyses of the 
pharmacokinetics (PK) and pharmacodynamics (PD) of sebelipase alfa and 
for an exploratory analysis of potential disease-related biomarkers in this 
patient population. 
Background (rationale) 
Lysosomal Acid Lipase (LAL) Deficiency is a rare autosomal recessive lipid 
storage disorder that is caused by a marked decrease or almost complete 
absence of LAL, leading to the accumulation of lipids, predominately 
cholesteryl esters and triglycerides, in various tissues and cell types. In the 
liver, accumulation of lipids leads to hepatomegaly, liver dysfunction, and 
hepatic failure. In the small intestine, lipid-laden macrophage accumulation 
in the lamina propria leads to profound malabsorption.  
LAL Deficiency presenting in infancy is an extremely rare form of LAL 
Deficiency that is usually fatal within the first 6 months of life (Assmann, 
2001, The Metabolic and Molecular Basis of Inherited Disease). It is 
characterized by profound malabsorption, growth failure, and hepatic failure. 
There is currently no safe or effective therapy for the treatment of LAL 
Deficiency.  
Main objective(s) 
The primary objective of the study is to evaluate the effect of sebelipase alfa 
therapy on survival at 12 months of age in children with growth failure due to 
LAL Deficiency. 
The secondary objectives are (1) to evaluate the safety and tolerability of 
sebelipase alfa in children with growth failure due to LAL Deficiency; (2) to 
evaluate the effect of sebelipase alfa therapy on survival beyond 12 months 
of age in children with growth failure due to LAL Deficiency; (3) to evaluate 
the effects of sebelipase alfa on growth parameters in children with growth 
failure due to LAL Deficiency; (4) to evaluate the effects of sebelipase alfa 
on hepatomegaly, splenomegaly, and liver function in children with growth 
failure due to LAL Deficiency; (5) to determine the effects of sebelipase alfa 
on hematological parameters in children with growth failure due to LAL 
Deficiency; and (6) to characterize the PK of sebelipase alfa delivered by 

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intravenous (IV) infusion. 
The exploratory objectives are (1) to determine the effects of sebelipase alfa 
on lipid parameters in children with growth failure due to LAL Deficiency; (2) 
to assess the effects of sebelipase alfa on achievement of developmental 
milestones in children with growth failure due to LAL Deficiency; (3) to 
assess the effects of sebelipase alfa on the ability of children with LAL 
Deficiency to tolerate an unrestricted diet; and (4) to evaluate potential 
disease-related biomarkers. 
Study population and 
subset definition 
The study population is children with growth failure due to LAL Deficiency. 
Number of study 
participants (e.g. age, 
sex, severity) 
Approximately 10 subjects will be enrolled in this study, including a minimum 
of 8 subjects who are 8 months of age or younger on the date of the first 
infusion of sebelipase alfa and thus eligible for the primary analysis of 
survival. 
Main inclusion criteria 
A subject must meet all of the following criteria to be eligible to participate in 
this study: 
1. Subject’s parent or legal guardian understands the full nature and 
purpose of the study, including possible risks and side effects, and 
provides written informed consent/permission prior to any study 
procedures being performed. 
2. Male or female child with a documented decreased LAL activity relative 
to the normal range of the lab performing the assay or documented 
result of molecular genetic testing (2 mutations) confirming a diagnosis 
of LAL Deficiency. 
3. Growth failure* with onset before 6 months of age, as defined by: 
weight decreasing across at least 2 of the 11 major centiles on a 
standard World Health Organization (WHO) weight-for-age (WFA) 
chart (1st, 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97th, 99th); 
OR 
body weight in kg below the 10th centile on a standard WHO WFA 
chart AND no weight gain for the 2 weeks prior to screening;  
OR 
loss of >5% of birth weight in a child who is older than 2 weeks of 
age. 
 
*NOTE regarding Inclusion Criterion # 3: In the unusual circumstance 
where a child has a rapidly progressive course of LAL Deficiency but 
does not meet growth failure criteria as defined above, the child may be 
included in the study if the Investigator has substantial clinical concerns 
based on evidence of the rapid disease progression requiring urgent 
medical intervention.  Inclusion under these exceptional circumstances 
requires submission of a written summary of the infant’s medical status 
for review by the Sponsor and must be approved by a written 
confirmation from the Sponsor after consultation with the Safety 
Committee (SC).  The subject must meet all other entry criteria as 
stated. 
Main exclusion criteria 
A subject who meets any of the following criteria will be ineligible to 
participate in this study: 
1. Clinically important concurrent disease or co-morbidities which, in the 

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opinion of the Investigator and Sponsor, would interfere with study 
participation, including, but not restricted to, congestive heart failure, 
ongoing circulatory collapse requiring inotropic support, acute or chronic 
renal failure, additional severe congenital abnormality, or other 
extenuating circumstances such as life-threatening under nutrition or 
rapidly progressive liver disease. 
2. Subject is >24 months of age. (Note: Subjects >8 months of age on the 
date of first infusion will not be eligible for the primary efficacy analysis.)  
3. Has received an investigational medicinal product other than 
sebelipase alfa within 14 days prior to the first dose of sebelipase alfa 
in this study. 
4. Myeloablative preparation, or other systemic pre-transplant conditioning, 
for hematopoietic stem cell or liver transplantation. 
5. Previous hematopoietic stem cell or liver transplant. 
6. Known hypersensitivity to eggs. 
Randomization 
strategy 
This study is open label and is not randomized. 
Location (e.g. regions) 
Multi-center (approximately 10 primary study centers globally).   
Subjects who are medically stable, as determined by the Investigator, may 
transfer to a local medical center for long-term treatment, contingent upon 
the local medical center being appropriately qualified and securing the 
required regulatory and Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC) approvals.  Scheduled study assessments may also be 
performed at a local medical center with access to the appropriate facilities 
and expertise. 
Study duration for 
participants 
The duration of each subject’s treatment in the study is expected to be at 
least 18 months, and subjects may continue to receive treatment in the study 
for up to 5 years.   
Dosage, treatment 
regimen, route of 
administration and 
dose escalation 
strategy  
Sebelipase alfa, a recombinant human lysosomal acid lipase (rhLAL) 
produced in transgenic Gallus, will be administered by IV infusion.   
All subjects will initiate treatment with sebelipase alfa at a dose 0.35 mg/kg 
qw. After receiving 2 infusions at this starting dose, a subject will receive a 
dose increase to 1 mg/kg qw, contingent upon acceptable safety and 
tolerability of preceding infusions. A further dose escalation to 3 mg/kg qw 
may be considered for a subject who has received at least 4 infusions at a 
dose of 1 mg/kg qw and meets dose escalation criteria, as defined below, 
contingent upon acceptable safety and tolerability of preceding infusions. 
An independent Safety Committee will oversee safety in this study. The SC 
will review available safety data for each subject (1) following the first 
2 infusions at a dose of 0.35 mg/kg qw to determine the acceptability of 
escalating the dose to 1 mg/kg qw and (2) following the first 2 infusions at a 
dose of 1 mg/kg qw to determine the acceptability of continuing treatment at 
this dose level. In addition, for subjects who exhibit either an early or late 
suboptimal clinical response at a dose of 1 mg/kg qw and are escalated to a 
dose of 3 mg/kg qw, the SC will review their safety data following the first 
2 infusions at a dose of 3 mg/kg qw to determine the acceptability of 
continuing treatment at this dose level. The remainder of the safety data for 
all subjects will be reviewed during at least semi-annual periodic meetings of 
the SC and on an ad-hoc basis as needed in the event of unanticipated 
safety findings. 
If the SC does not approve a subject’s dose escalation from 0.35 mg/kg qw 

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to 1 mg/kg qw, but deems it safe for the subject to continue treatment at the 
starting dose of 0.35 mg/kg qw, the subject may continue to receive this 
starting dose.  Re-evaluation of dose escalation will be considered after 
subsequent SC review and discussion with Sponsor. 
Subjects who do not tolerate a dose of 3 mg/kg qw or 1 mg/kg qw may 
receive a dose reduction to 1 mg/kg qw or 0.35 mg/kg qw, respectively, 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 qw, 
despite measures taken to manage any infusion-associated reactions 
(IARs), the subject will be discontinued from the study. 
Subjects who are on treatment for at least 96 weeks and have been on a 
stable dose for at least 24 weeks, may transition to an every other week 
dosing schedule at the same dose they received on the weekly dosing 
schedule. If the subject meets dose escalation criteria while on the every 
other week dosing schedule they will either revert back to weekly dosing or if 
on 1 mg/kg qow can increase to 3 mg/kg qow dosing. 
Dose Escalation Criteria 
During the first 3 months of treatment, a subject may be considered to meet 
dose escalation criteria if he/she meets 2 or more of the following criteria 
after at least 4 infusions at a dose of 1 mg/kg qw:  
 
Failure to gain an average of 5 g/kg body weight per day AND the 
presence of either of the following: 
o 
weight-for-length (WFL) or weight-for-height (WFH) z-score 
<-2 based on WHO child growth standards; and/or 
o 
length-for-age (LFA) or height-for-age (HFA) z-score <-2 based 
on WHO child growth standards. 
 
Albumin <3.5 g/dL; 
 
Alanine aminotransferase (ALT) >2x upper limit of normal (ULN); 
 
Ongoing requirement for blood and/or platelet transfusion. 
 
A subject may also be considered for dose escalation after at least 3 months 
of treatment if they meet the below criteria: 
 
Any other clinically important manifestation of LAL Deficiency on either 
clinical examination, laboratory assessment, or imaging which has either  
o 
not improved from baseline  
o 
improved and plateaued but has not normalized  
(Note:  The definition of a plateauing of effect requires 
consideration of a minimal of 3 assessments.) 
o 
failed to normalize within 12 months of initiation of treatment 
o 
 
Manifestations include but are not restricted to the following: A decrease in 
weight for age defined as crossing >2 major centile lines on standard weight 
for age curves, serum transaminases, albumin <3.5 g/dL, hepatomegaly, 
splenomegaly or lymphadenopathy. 
If the subject continues to meet the above defined dose escalation criteria 
after at least 4 infusions at a dose of 3 mg/kg qw, the Investigator may 
request of the Sponsor (in consultation with the SC) to increase the dose up 
to a maximum of 5 mg/kg qw. Requests will be reviewed on a case-by-case 
basis.  

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Controls 
There is no placebo or comparator in this study. 
Rescue treatment  
No approved therapy has been shown to be effective for the treatment of 
LAL Deficiency.  Hematopoietic stem cell transplantation has been used 
experimentally but has a high morbidity and mortality in this patient 
population.  
Criteria for evaluation 
Efficacy 
The primary efficacy endpoint will be the proportion of subjects surviving to 
12 months of age.  Secondary survival endpoints will include proportion of 
subjects surviving to 18 and 24 months of age, and other timepoints, as data 
permit, and estimated median age at death.  Survival rates and median age 
at death derived from this study will be compared to rates/times reported in 
the literature and information derived from a natural history study in a similar 
patient population (study LAL-1-NH01). 
Other secondary efficacy endpoints will include (1) changes from baseline in 
percentiles and/or z-scores for WFA, WFL/WFH, and LFA/HFA and the 
corresponding growth status indicators of underweight, wasting, and 
stunting, as well as changes from baseline in z-scores for head 
circumference-for-age (HCFA) and mid-upper arm circumference-for-age 
(MUACFA); (2) changes from baseline in aspartate aminotransferase (AST) 
and ALT; (3) normalization of hemoglobin levels without requirement for 
blood transfusion; and (4) change from baseline in serum ferritin. 
Exploratory efficacy endpoints will include changes and/or percent changes 
from baseline (or first available measurement if baseline data are 
unavailable) in (1) alkaline phosphatase, gamma glutamyltransferase (GGT), 
albumin, and direct (conjugated), indirect (unconjugated), and total bilirubin 
levels; (2) liver and spleen size/volume, as measured by ultrasound or 
magnetic resonance imaging (MRI); (3) hepatomegaly and/or splenomegaly 
(abdominal girth, liver size, and spleen size) by physical examination; 
(4) platelet levels; and (5) serum lipid levels (total cholesterol, triglycerides, 
high density lipoprotein [HDL], low density lipoprotein [LDL]). Dietary 
changes, including discontinuation of a low-fat/low-cholesterol diet and/or 
introduction of an unrestricted age-appropriate diet, will be evaluated on an 
exploratory basis. Development will also be assessed using Denver II 
developmental screening test.   
The impact of anti-drug antibodies (ADAs) on efficacy endpoints will also be 
explored. 
Safety 
Safety endpoints will include the incidence of adverse events (AEs), serious 
adverse events (SAEs), and IARs; changes from baseline clinical laboratory 
tests; changes in vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) during and post-infusion relative to pre-infusion values; 
physical examination findings; use of concomitant medications/therapies; 
and Characterization of ADAs, including ADA positivity rate, time to ADA 
positivity, median and peak ADA titer and time to peak ADA titer. The impact 
of ADAs on safety endpoints will also be explored. Further characterization 
of ADAs, including inhibitory and/or neutralizing ADAs and measurement of 
specific ADA subtypes (e.g., IgE), may be performed, if appropriate. 
Pharmacokinetics 
PK endpoints will include maximum observed serum concentration (Cmax) 

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and apparent serum clearance (CL), as data permit.  The impact of ADAs on 
sebelipase alfa PK will also be explored. 
Pharmacodynamics 
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. 
Sample size 
Approximately 8 subjects who meet the requirements for inclusion in the 
Primary Efficacy Analysis Set (see definition below) will be enrolled in this 
study.  If 8 subjects are included in the Primary Efficacy Analysis set and 6 of 
these subjects survive to 12 months of age, the exact 95% confidence 
interval (CI) for 12-month survival would be (34.91%, 96.81%), with the lower 
limit exceeding the upper limit of the CI for a similar population of untreated 
patients in the natural history study LAL-1-NH01.  In study LAL-1-NH01, of 
the 18 patients who had growth failure and had a known date of death, only 
one patient survived past 12 months of age (95% CI for 12-month 
survival = (0.14%, 27.29%)). 
Statistical plan 
(including study 
conduct and analysis) 
Analysis Sets 
The Full Analysis Set (FAS) will include all subjects who received any 
amount of investigational medicinal product (IMP). 
The Primary Efficacy Analysis Set will include subjects in the FAS who were 
no older than 8 months of age on the date of the first infusion of sebelipase 
alfa. 
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 this study.  
The Per Protocol Set (PPS) will include subjects in the Primary Efficacy 
Analysis Set who, in addition, receive at least 4 complete infusions of 
sebelipase alfa.  This set will be used for sensitivity analyses of efficacy 
endpoints. 
General Considerations 
All data will be presented in listings, and summary tables and/or graphs will 
be provided, as appropriate.  Unless otherwise noted, tabulations for efficacy 
endpoints will be presented for subjects in the Primary Efficacy Analysis Set 
and tabulations for other endpoints will be presented for subjects in the FAS. 
Descriptive summary statistics (n, mean, median, standard deviation, 
minimum and maximum) will be calculated for the continuous variables. Shift 
tables and/or frequencies and percentages will be produced for the 
categorical variables. As noted, 95% two-sided CIs will be calculated around 
the estimates based on the exact binomial distribution for binomial endpoints 
and the t-distribution for continuous endpoints.   
Baseline will be defined as the last measurement prior to the first infusion of 
sebelipase alfa.  (Note: For exploratory analyses, the first available 
measurement after initiation of treatment may be used as baseline if a 
pretreatment measurement is unavailable.)  Survival rates will be based on 
the age of the subject.  Other endpoints, unless otherwise noted, will be 
based on exposure (i.e., duration of time since the first infusion of sebelipase 
alfa).  
A clinical study report (CSR) will be produced following analysis of the 

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primary endpoint (12-month survival) and will include all subject data 
available through 12 months of age or the date of death or early withdrawal.  
A final CSR will be generated after study completion.  
 
Efficacy 
Efficacy will be analyzed for the Primary Efficacy Analysis Set.  If the PPS is 
not identical to the Primary Efficacy Analysis Set (i.e., if at least one patient 
in the Primary Efficacy Analysis Set is excluded from the PPS), efficacy 
analyses will be repeated for the PPS. 
The primary efficacy endpoint is the proportion of subjects surviving to 
12 months of age.  It is not anticipated that any subjects will be lost to 
follow-up prior to 12 months of age, but a subject who is not confirmed to 
have survived to 12 months of age will not be considered to have met the 
primary endpoint. As a complementary analysis, Kaplan-Meier survival 
curves of survival since birth and survival since first dose of IMP will be 
presented.  Survival at 18 and 24 months of age will be analyzed as 
described for the primary endpoint.  Median age at death will also be 
calculated.  A Kaplan-Meier estimate of median survival past first dose of 
IMP will be computed.  Estimated survival rates and median age at death 
derived from this study will be compared to rates/times reported in the 
literature, and will be discussed in conjunction with information derived from 
a natural history study in a similar patient population (study LAL-1-NH01). 
Anthropometric indicators of growth, standardized by age and gender in 
accordance with the methodology described by the WHO and using WHO 
growth charts, will be listed by study time point as observed values and as 
changes from baseline.  Change from baseline in anthropometric data will be 
tabulated as continuous data.  In addition, the percentages of subjects who 
meet criteria for underweight, stunting, and wasting will be tabulated for each 
timepoint.  For anthropometric indicators of growth, age will be adjusted for 
prematurity if gestational age is <37 weeks and the subject is under 
12 months of age.  The adjustment will be made such that corrected 
age equals the chronological age minus the number of months premature. 
Change and/or percent changes from baseline in AST, ALT, and serum 
ferritin will be tabulated for each evaluation timepoint.  The proportion of 
subjects with abnormal hemoglobin at baseline who achieve transfusion-free 
hemoglobin normalization (TFHN) will be summarized, as will the proportion 
of subjects who maintain transfusion-free normal hemoglobin. 
The Denver II total score and functional area scores will be derived from the 
questionnaire in accordance with the Technical Manual and compared to 
appropriate demographic norms.  The total score and functional area scores 
will be summarized as continuous data and according to the classification as 
to whether the subject displays abnormal/normal development. 
Shift tables will be used to tabulate dietary changes, including 
discontinuation of low-fat/low-cholesterol diet and/or introduction of an 
unrestricted age-appropriate diet.  Observed values and changes and/or 
percent changes from baseline in other exploratory efficacy endpoints will be 
tabulated for each evaluation timepoint.   
Safety 
Safety will be analyzed for the FAS.  
All reported AEs will be listed from the date of written informed consent until  

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the end of participation in this study.  Separate listings of SAEs and IARs will 
also be provided. The numbers and percentages of subjects experiencing 
any AE, any SAE, any IAR, any related AE, any related SAE, and 
discontinuations due to an AE will be tabulated.  The frequency of treatment-
emergent AEs, SAEs, and IARs by SOC and preferred term (coded using 
Medical Dictionary for Regulatory Activities [MedDRA®] version 14 or higher) 
will be tabulated.  Frequencies will also be presented by the classifications of 
severity and causality.  In addition, frequency of AEs, SAEs, and IARs will be 
presented for time periods spanning the entire course of treatment with 
sebelipase alfa: from the start of dosing with sebelipase alfa in this study to 
3 months after the first dose, >3 to 6 months, >6 to 12 months, >12 to 18 
months, >18 to 24 months and >24 months.  As appropriate, additional 
listings, summary tables and graphics 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. 
Observed measurements and changes from baseline to each study 
timepoint in clinical laboratory data will be summarized.  Clinically significant 
abnormal values will be listed.  Frequencies of abnormal values relative to 
the laboratory normal range and clinically significant abnormal values will be 
tabulated for each study timepoint.  Shift tables may also be provided. 
The percentage of subjects who become ADA positive, time to ADA 
positivity, median and peak immunoglobulin G (IgG) antibody titer, time to 
peak IgG antibody titer, and percentage of subjects who tolerize will be 
summarized; IgG antibody titer values will be tabulated at each study visit 
using summary statistics appropriate to the data.  
Changes in vital signs from pre-infusion values to each time point during or 
post-infusion will be summarized.  Abnormal findings/values for physical 
examinations, vital signs, and ECGs will also be listed. Concomitant 
medication/treatment data will be coded using the WHO-DRUG dictionary.  
All data will be listed, and the percentages of subjects receiving each 
concomitant medication/treatment will be tabulated. 
Pharmacokinetics 
Pharmacokinetics will be analyzed for the PK Analysis Set.  Cmax will be 
recorded 
from 
direct 
observation, 
and 
CL 
will 
be 
derived 
by 
non-compartmental analysis.  PK parameters will be summarized by dose of 
sebelipase alfa, if applicable. 
Pharmacodynamics 
Pharmacodynamics will be analyzed for the FAS.  Potential disease-related 
biomarkers will be listed, and observed values and changes and/or percent 
changes from baseline will be summarized by timepoint. 
Subgroup Analyses 
The impact of ADAs on safety, efficacy, PK, and PD endpoints will be 
explored descriptively.  As subject numbers permit, other subgroup analyses 
of interest may be performed including, but are not limited to, age, gender, 
and race.  
Measures to minimize 
pain and distress (only 
if specific for this 
study) 
Local analgesic cream (e.g., eutectic mixture of local anesthetics [EMLA]) 
will be allowed at least 20-30 minutes (or according to applicable institutional 
guidelines) prior to IV placement or blood sampling. 

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External safety review  
Safety Committee 
 
 

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Table of Contents 
PROTOCOL SYNOPSIS .............................................................................................................................. 4 
LIST OF ABBREVIATIONS........................................................................................................................ 16 
1 
INTRODUCTION ................................................................................................................................ 18 
1.1 
BACKGROUND .............................................................................................................................. 18 
1.1.1 
Lysosomal Acid Lipase Deficiency ........................................................................................ 18 
1.1.2 
LAL Deficiency Presenting in Infancy .................................................................................... 18 
1.1.3 
Medical Plausibility of Enzyme Replacement Therapy for LAL Deficiency ........................... 19 
1.2 
INVESTIGATIONAL AGENT .............................................................................................................. 20 
1.3 
PRECLINICAL DATA ...................................................................................................................... 20 
1.4 
CLINICAL DATA ............................................................................................................................ 22 
1.5 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 22 
1.5.1 
Dose Rationale ...................................................................................................................... 22 
1.5.2 
Risk/Benefit Assessment ....................................................................................................... 24 
2 
STUDY OBJECTIVES ....................................................................................................................... 25 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 25 
2.2 
SECONDARY OBJECTIVES ............................................................................................................. 25 
2.3 
EXPLORATORY OBJECTIVES ......................................................................................................... 25 
3 
STUDY DESIGN ................................................................................................................................. 26 
3.1 
OVERVIEW OF STUDY DESIGN AND FLOW CHART ........................................................................... 26 
3.1.1 
Dose Escalation..................................................................................................................... 27 
3.2 
RATIONALE FOR STUDY DESIGN .................................................................................................... 30 
3.2.1 
Dose Selection ...................................................................................................................... 30 
3.2.2 
Outcome Variable Selection .................................................................................................. 30 
3.2.3 
Study Duration ....................................................................................................................... 32 
4 
STUDY POPULATION ....................................................................................................................... 33 
4.1 
TARGET POPULATION ................................................................................................................... 33 
4.2 
NUMBER OF SUBJECTS ................................................................................................................. 33 
4.3 
INCLUSION CRITERIA .................................................................................................................... 33 
4.4 
EXCLUSION CRITERIA ................................................................................................................... 34 
4.5 
CONCOMITANT MEDICATION AND TREATMENT ............................................................................... 34 
4.6 
DISCONTINUATION OF SUBJECTS FROM TREATMENT OR ASSESSMENT ............................................ 34 
4.6.1 
Premature Withdrawal from Study Participation ................................................................... 34 
4.6.2 
Procedures for Discontinuation ............................................................................................. 35 
4.7 
SUBJECT REPLACEMENT POLICY .................................................................................................. 35 
4.8 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 36 
5 
SCHEDULE OF ASSESSMENTS AND STUDY PROCEDURES ..................................................... 37 
5.1 
STUDY ASSESSMENTS .................................................................................................................. 37 
5.1.1 
Informed Consent .................................................................................................................. 37 
5.1.2 
Subject Eligibility.................................................................................................................... 37 
5.1.3 
Medical History ...................................................................................................................... 38 
5.1.4 
Demographic Information ...................................................................................................... 38 
5.1.5 
Anthropometrics .................................................................................................................... 38 
5.1.6 
Physical Examination ............................................................................................................ 38 
5.1.7 
Abdominal Ultrasound ........................................................................................................... 39 
5.1.8 
Abdominal MRI ...................................................................................................................... 39 
5.1.9 
Vital Signs .............................................................................................................................. 39 

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5.1.10 
Electrocardiogram ............................................................................................................. 40 
5.1.11 
Laboratory Assessments .................................................................................................. 40 
5.1.12 
Denver II Developmental Screening Test ......................................................................... 41 
5.1.13 
Exploratory Biomarkers ..................................................................................................... 42 
5.1.14 
Pharmacokinetic Assessments ......................................................................................... 42 
5.1.15 
DNA Sample ..................................................................................................................... 42 
5.1.16 
LAL Enzyme Activity ......................................................................................................... 43 
5.1.17 
Liver Biopsy ....................................................................................................................... 43 
6 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................................... 45 
6.1 
DESCRIPTION OF IMP ................................................................................................................... 45 
6.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 45 
6.3 
STORAGE AND DISPOSITION OF IMP ............................................................................................. 45 
6.3.1 
Receipt of IMP ....................................................................................................................... 45 
6.3.2 
Storage .................................................................................................................................. 45 
6.3.3 
Disposition ............................................................................................................................. 46 
6.4 
PREPARATION AND ADMINISTRATION OF IMP ................................................................................. 46 
6.4.1 
Preparation of IMP ................................................................................................................ 46 
6.4.2 
Administration of IMP ............................................................................................................ 46 
6.5 
INFUSION ASSOCIATED REACTIONS ............................................................................................... 47 
6.6 
BLINDING OF IMP ......................................................................................................................... 48 
6.7 
DESTRUCTION OF IMP.................................................................................................................. 48 
7 
ASSESSMENT OF SAFETY ............................................................................................................. 49 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES ................................................................... 49 
7.1.1 
Clinical Adverse Events ......................................................................................................... 49 
7.1.2 
Laboratory Test Abnormality ................................................................................................. 51 
7.2 
HANDLING OF SAFETY PARAMETERS ............................................................................................. 51 
7.2.1 
Serious Adverse Events and Infusion-Associated Reactions(Immediately Reportable to the 
Sponsor) ............................................................................................................................................. 51 
7.2.2 
Adverse Event Reporting Period ........................................................................................... 51 
7.2.3 
Treatment and Follow-up of Adverse Events ........................................................................ 51 
7.2.4 
Follow-up of Abnormal Laboratory Test Values .................................................................... 51 
7.2.5 
Pregnancy ............................................................................................................................. 52 
7.3 
RECORDING OF ADVERSE EVENTS ................................................................................................ 52 
7.4 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 52 
7.4.1 
Investigator Reporting: Notifying the Study Sponsor ............................................................ 53 
7.4.2 
Investigator Reporting: Notifying the IRB/IEC ....................................................................... 53 
7.4.3 
Sponsor Reporting: Notifying Regulatory Authorities ............................................................ 53 
7.4.4 
Sponsor Reporting: Notifying Participating Investigators ...................................................... 54 
7.5 
DOSE MODIFICATION AND STOPPING RULES .................................................................................. 54 
SPECIFIC RULES FOR SUSPENDING DOSING IN AN INDIVIDUAL SUBJECT ARE PROVIDED IN APPENDIX C. .......... 54 
7.6 
MEDICAL MONITORING ................................................................................................................. 54 
7.6.1 
Independent Safety Committee ............................................................................................. 54 
8 
STATISTICAL PLAN ......................................................................................................................... 56 
8.1 
GENERAL CONSIDERATIONS ......................................................................................................... 56 
8.2 
DETERMINATION OF SAMPLE SIZE ................................................................................................. 56 
8.3 
ANALYSIS SETS............................................................................................................................ 57 
8.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................................ 57 
8.5 
SUBJECT ACCOUNTABILITY ........................................................................................................... 57 
8.6 
STUDY TREATMENT USAGE AND COMPLIANCE ............................................................................... 58 
8.7 
EFFICACY ANALYSIS ..................................................................................................................... 58 
8.8 
SAFETY ANALYSIS ........................................................................................................................ 59 

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8.8.1 
Adverse Events ..................................................................................................................... 59 
8.8.2 
Clinical Laboratory Tests ....................................................................................................... 60 
8.8.3 
Other Safety Data .................................................................................................................. 60 
8.9 
PHARMACOKINETICS .................................................................................................................... 60 
8.10 
PHARMACODYNAMIC ANALYSIS ..................................................................................................... 60 
8.11 
OTHER STATISTICAL ISSUES ......................................................................................................... 60 
8.11.1 
Significance Levels ........................................................................................................... 60 
8.12 
SUBGROUP ANALYSES ................................................................................................................. 60 
8.13 
MISSING OR INVALID DATA ............................................................................................................ 60 
8.14 
INTERIM ANALYSIS ....................................................................................................................... 61 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 61 
9.1 
CONFIDENTIALITY ......................................................................................................................... 61 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 61 
9.3 
CASE REPORT FORMS.................................................................................................................. 61 
9.4 
RECORDS RETENTION .................................................................................................................. 61 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 62 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 62 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 62 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 63 
12 
CLINICAL STUDY REPORT AND PUBLICATION PLAN ................................................................ 64 
13 
REFERENCES ................................................................................................................................... 65 
14 
APPENDICES .................................................................................................................................... 68 
APPENDIX A: SCHEDULE OF ASSESSMENTS TABLE 1 -- SCREENING THROUGH WEEK 24 .............................. 69 
APPENDIX B: DIAGNOSIS AND RECOMMENDATIONS FOR MANAGEMENT OF INFUSION ASSOCIATED REACTIONS
 ................................................................................................................................................................ 74 
APPENDIX C: DOSE MODIFICATION AND STOPPING RULES FOR LAL-CL03 STUDY ....................................... 76 
 
LIST OF TABLES 
TABLE 1 
MEAN BLOOD VOLUME, BY AGE .................................................................................................... 37 
TABLE 2 
CLINICAL LABORATORY TESTS, BY TIER ........................................................................................ 40 
TABLE 3 
ASSESSMENT OF CAUSALITY ........................................................................................................ 50 
 
 
 

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List of Abbreviations 
 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ALT/SGPT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST/SGOT 
Aspartate Aminotransferase 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Observed Plasma Concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBS 
Dried Blood Spot 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic Case Report Form  
EMA 
European Medicines Agency 
EMLA 
Eutectic Mixture of Local Anesthetics 
ERT 
Enzyme Replacement Therapy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GlcNAc 
N-acetylglucosamine 
GGT 
Gamma Glutamyltransferase 
HDL 
High Density Lipoprotein 
HFA 
Height-for-Age 
HCFA  
Head circumference-for-age 
IAR 
Infusion Associated Reaction 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAL 
Lysosomal Acid Lipase 
LDL 
Low Density Lipoprotein 
LFA 
Length-for-Age 
LLN 
Lower Limit of Normal 
LSD 
Lysosomal Storage Disorder 
M6P 
Mannose-6-Phosphate 
MCV 
Mean Corpuscular Volume 

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MCH(C) 
Mean Corpuscular Hemoglobin (Concentration) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MMR 
Macrophage Mannose Receptor 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MUACFA 
Mid-upper Arm Circumference-for-Age 
PBMC 
Peripheral Blood Mononuclear Cells 
PT (INR) 
Prothrombin Time (International Normalized Ratio) 
PD  
Pharmacodynamics  
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
rhLAL 
Recombinant Human Lysosomal Acid Lipase 
SAE 
Serious Adverse Event 
SC 
Safety Committee 
SOC 
System Organ Class 
TFHN 
Transfusion-Free Hemoglobin Normalization 
WFA 
Weight-for-Age 
WFH 
Weight-for-Height 
WFL 
Weight-for-Length 
 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to United States and international standards of Good Clinical Practice (GCP) (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 or almost complete absence of the lysosomal enzyme, 
LAL.  
The marked reduction or almost complete absence of LAL in patients with LAL Deficiency leads 
to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various 
tissues and cell types, particularly the liver leading to hepatomegaly, liver dysfunction, and 
hepatic failure, and in the small intestinal macrophages leading to profound malabsorption. LAL 
Deficiency presenting in infancy is characterized by profound malabsorption, growth failure, and 
hepatic failure and is usually fatal within the 6 months of life. In children and adults with LAL 
Deficiency, liver involvement and type II hyperlipidemia dominate the clinical picture. All 
presentations of LAL Deficiency are due to mutations in the LIPA gene located on chromosome 
10q23.2-q23.3. In LAL Deficiency presenting in children and adults, many cases are associated 
with a common mutated allele resulting in some residual enzyme activity, whereas in LAL 
Deficiency presenting in infants there are a variety of private mutations with complete loss of 
enzyme function (Assmann, 2001, The Metabolic and Molecular Basis of Inherited Disease). It 
has been hypothesized that there may be a correlation between enzyme activity and the 
severity of the disease.  
1.1.2 LAL Deficiency Presenting in Infancy 
LAL Deficiency presenting in infants, historically called Wolman disease or LAL 
Deficiency/Wolman phenotype is a very rare form of LAL Deficiency that is usually fatal within 
the first 6 months of life (Assmann, 2001, The Metabolic and Molecular Basis of Inherited 
Disease). This form of the disease, named after the physician who first described it (Abramov, 
1956, AMA J Dis Child), is the most rapidly progressive presentation of LAL Deficiency with 
growth failure and severe hepatic disease, as evidenced by liver enlargement, elevation of 
transaminases, hyperbilirubinemia, coagulopathy and hypoalbuminemia, as the predominant 
clinical features and key contributors to the early mortality (Anderson, 1999, Mol Genet Metab; 
Mayatepek, 1999, J Inherit Metab Dis).  Fibrosis and cirrhosis develop rapidly and have been 
described in affected infants within the first 6 months of life (Marshall, 1969, Arch Dis Child; 
Konno, 1966, Tohoku J Exp Med; Crocker, 1965, Pediatrics). 
Diagnosis of LAL Deficiency is established through both physical findings and laboratory 
analyses.  Infants are typically hospitalized within the first 2 months of life due to diarrhea, 
persistent vomiting, feeding difficulty and growth failure (Wolman, 1995, Clin Pediatr).  Physical 

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findings include abdominal distention with hepatomegaly and splenomegaly.  Radiographic 
examination often reveals calcification of the adrenal glands.  Laboratory evaluations typically 
reveal elevated levels of serum transaminases and absent or markedly reduced LAL enzyme 
activity (Assmann, 2001, The Metabolic and Molecular Basis of Inherited Disease; Mayatepek, 
1999, J Inherited Metab Dis; Surve, 2005, Indian J Pediatr).  
At present, there are no safe or effective therapies for the treatment of patients with LAL 
Deficiency.  A variety of supportive therapies are used in an attempt to mitigate some of the 
effects of this rapidly fatal disease.  Antibiotics may be prescribed to address pyrexia or 
documented infections.  In an attempt to mitigate the complications due to lipid accumulation 
within the target cells and vital organs, dietary restriction of either breast milk or formulas 
containing triglycerides and cholesteryl esters and the use of a fatty ester free diet is 
recommended (Wolman, 1995, Clin Pediatr).  Although some stabilization of the clinical 
condition has been described with nutritional support, these interventions do not substantially 
modify the outcome in affected patients (LAL-1-NH01; Hoeg, 1984, Am J Hum Genet; Meyers, 
1985, Nutr Res).   
Outcomes with hematopoietic stem cell transplantation in affected infants have recently been 
reviewed in the literature, and while there are reports that 3 transplanted patients have survived 
beyond 3 years, the majority of transplant attempts resulted in early death due to liver failure 
from progressive disease, or sinusoidal obstruction syndrome (veno-occlusive disease) or other 
transplant-related complications (Gramatges, 2009, Bone Marrow Transplant; Krivit 1992, Bone 
Marrow Transplant; Krivit, 2000, Bone Marrow Transplant; Tolar, 2009, Bone Marrow 
Transplant; Yanir, 2013, Mol Gen Metab).  The toxicity of conditioning regimens and time 
required for engraftment create substantial risks in the setting of such a rapidly progressive 
disease as LAL Deficiency presenting in infants. 
1.1.3 Medical Plausibility of 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 LSDs. 
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 or 

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MMR, 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. 
Biological activity of sebelipase alfa in patients with LAL Deficiency has been demonstrated in 
clinical study LAL-CL01 and LAL-CL04, including decreases in transaminases and evidence of 
early lipid mobilization and correction of dyslipidemia with longer term dosing, This information 
and the encouraging initial response to sebelipase alfa in LAL-CL03, including improvements in 
weight gain, decrease in hepatic and splenic size, resolution of vomiting and diarrhea, and 
improvement in biochemical markers, provides the first human evidence in support of the 
potential for ERT for this disease). 
1.2 Investigational Agent 
Sebelipase alfa  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 Preclinical Data 
In in vitro studies, sebelipase alfa demonstrated uptake and localization to lysosomes, and 
produced a dose-dependent correction of LAL activity in human fibroblasts deficient in this 
enzyme.   
In homozygous LAL-deficient rats, a nonclinical disease model of LAL Deficiency, intravenous 
(IV) administration of sebelipase alfa restored enzyme activity in the liver and other key target 
tissues, and was associated with a marked reduction in substrate accumulation (cholesteryl 
esters and triglycerides) in the liver, spleen, gut, and lymph nodes relative to placebo-treated 
animals.  Homozygous LAL-deficient rats demonstrate liver and spleen abnormalities, which 
resemble the abnormalities seen in patients with LAL Deficiency including accumulation of 
cholesteryl esters and triglycerides, hepatosplenomegaly, transaminase elevation, Kupffer cell 

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expansion with disruption of normal liver architecture and liver fibrosis (Leavitt, 2011, J Hepatol).  
In addition, the LAL-deficient rats show other abnormalities that are prominent in rapidly 
progressing LAL Deficiency, including gastrointestinal  involvement with abnormal lipid 
accumulation in macrophages in the lamina propria of the small intestine, markedly impaired 
weight gain, and early mortality (Leavitt, 2011, J Ped Gastroenterol Nutr;  Sponsor data on file).  
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.  Of note, the 
improvements in weight gain were statistically significant within 2 weeks of initiation of the first 
dose.  Liver abnormalities were all markedly improved within 4 weeks of treatment initiation.  In 
a subsequent study, sebelipase alfa was administered to LAL-deficient rats qw at a dose of 
3 mg/kg (given by bolus tail vein injection) for 19 weeks, beginning at 8 weeks of age, to 
investigate the effectiveness of sebelipase alfa in the presence of more advanced disease and 
to determine whether restoration of growth and correction of other disease-related abnormalities 
with sebelipase alfa treatment was associated with extended survival.  In this study, sebelipase 
alfa treatment resulted in substantial improvements in the phenotypic abnormalities seen in this 
disease model.  Sebelipase alfa-treated LAL-deficient rats gained more weight than vehicle-
treated animals, and survived without exception to the scheduled sacrifice time (27 weeks of 
age); in a separate study, untreated animals did not survive beyond 14 weeks of age.  The 
growth rate of the sebelipase alfa-treated LAL-deficient rats was sustained through study 
termination in a manner comparable to wildtype rats.  Favorable responses were observed with 
regard to organomegaly, with reductions in the size of all affected organs examined, and a 
concomitant reduction in hepatic levels of LAL substrates, consistent with the expected 
mechanism of action of sebelipase alfa.  The reduction in hepatomegaly was also accompanied 
by a normalization of serum transaminases.  Histologically, the appearance of the liver in the 
sebelipase alfa -treated LAL-deficient rats resembled that of the wildtype rat.  These positive 
disease-modifying effects of sebelipase alfa were comparable to the effects observed following 
short-term (4 weeks) administration.  Additional discussions of the dose response of the effects 
seen in the nonclinical model are included in Section 1.5.1.  
There were no meaningful toxicological findings in 4-week repeat dose toxicology studies in the 
Sprague-Dawley rat and Cynomolgus monkey administered IV infusions of sebelipase alfa at 
doses up to 50 mg/kg qw.  In a 6-month repeated dose toxicity study in juvenile 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 diphenhydramine 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.   

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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.   
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 (PD) 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. 
1.5 Dose Rationale and Risk/Benefits 
1.5.1 Dose Rationale 
In this study, sebelipase alfa will be administered at a starting dose of 0.35 mg/kg qw and all 
subjects will receive a dose increase to 1 mg/kg (contingent on safety), with an option for a 
further dose increase to 3 mg/kg qw.  These doses of sebelipase alfa were selected based on 
the following: 
 
As discussed in Section 1.4, clinical data are available from a completed study in 
patients with LAL Deficiency (LAL-CL01) administered qw infusions of sebelipase alfa at 
doses of 0.35 mg/kg, 1 mg/kg, or 3 mg/kg as well as 1 mg/kg, or 3 mg/kg qow 
(LAL-CL04).  These data show: 
o All 3 dose levels of sebelipase alfa were well tolerated. 
o Sebelipase alfa therapy produced rapid and comparable reductions in serum 
transaminases at all 3 dose levels.   
o Increases in serum lipids were seen at all 3 dose levels within 4 weeks of 
treatment initiation, consistent with the known mechanism of action of sebelipase 
alfa.  These effects were more marked with the 3 mg/kg qw dose and may 
therefore be dose related.  Compared to a dose of 3 mg/kg qw, doses of 0.35 
and 1 mg/kg qw may have less marked short-term effects on serum lipids, but a 
potentially comparable clinical benefit.   

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o Maintenance of clinical response (reduction in ALT and AST and improvement of 
lipid levels) was observed in adult subjects treated with qow dosing in LAL-CL04.  
 
  There is an adequate safety margin for sebelipase alfa based on nonclinical toxicology 
studies. Refer to the IB for further information. 
o 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 an approximately 23.0- to 46.1-fold safety 
margin relative to the planned starting dose of 0.35 mg/kg in the current study. 
o Sebelipase alfa was well tolerated in a 6-month repeated dose toxicity study in 
Cynomolgus monkeys given qw IV infusions at doses up to 30 mg/kg.  Based on 
the human equivalent dose (9.7 mg/kg), this provides an approximately 27.7-fold 
safety margin relative to the planned starting dose of 0.35 mg/kg in the current 
study.  The absence of any sebelipase alfa related changes in study parameters 
supports the long-term dosing with sebelipase alfa. 
 
As expected, based on the number and composition of glycan structures, 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.  Consistent with these findings, 
sebelipase alfa has a short plasma half-life in adult patients with late onset LAL 
Deficiency.  Clinical PK data for sebelipase alfa are not yet available for children and 
adolescents, but plasma half-life is expected to be short in these patients. 
 
A dose of 0.35 mg/kg dose qw was established as the minimally effective dose in a rat 
model of LAL Deficiency.  
 
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 and O’Callaghan, 2008). 
 
The Investigational Medicinal Product (IMP) has an amino acid sequence identical to the 
Genbank reference sequence for human LAL with no engineering of enhancements in 
biological activity. 
For ERTs, plasma PK data have limited utility for dose selection and escalation, as the proteins 
have a short plasma half-life and the main biological activity is in the target tissue.  
Given the extreme rarity and immediate life-threatening nature of growth failure due to 
LAL Deficiency, this study will allow within-subject dose escalation from the initial starting dose, 
as the pre-clinical model demonstrated dose dependent pharmacological effects. The proposed 
dose increment permitted in this study will be 3-fold, which will allow assessment of safety, 
tolerability and efficacy in children across a range of doses on a mg/kg basis. In the preclinical 
rat model, it was established that the pharmacodynamic (PD) effects of 3 mg/kg qw and 5 mg/kg 
qw are comparable. Based on this information, it is not anticipated that exploration of doses 

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greater than 3 mg/kg qw in subjects with LAL Deficiency will be required unless there is 
evidence of a loss of efficacy due to the potential development of neutralizing antibodies. 
1.5.2 Risk/Benefit Assessment  
LAL Deficiency is a very rare disease with no safe or effective therapies.  LAL Deficiency 
presenting in infants results in significant morbidity and death typically within 6 months of age 
(Assmann, 2001, The Metabolic and Molecular Basis of Inherited Disease). 
No significant toxicities were identified in pre-clinical pharmacology and toxicology studies at 
doses equivalent to and substantially greater than the planned doses for the current study (see 
Section 1.3 for details). 
Clinical experience with sebelipase alfa in adult patients with LAL Deficiency treated in study 
LAL-CL01 and LAL-CL04 indicates that sebelipase alfa is well tolerated at doses ranging from 
0.35 mg/kg qw to 3 mg/kg qw and produces rapid improvements in serum transaminases and 
other evidence of biological activity.  Sebelipase alfa has also demonstrated an acceptable 
safety profile and positive treatment effects in infants receiving doses up to 3 mg/kg qw on an 
expanded access basis and in the current study.  See Section 1.4 and the IB for further details 
on the clinical experience with sebelipase alfa.  Thus, there is a reasonable basis to conclude 
that sebelipase alfa therapy in this study will be well tolerated and associated with beneficial 
effects on disease activity.   
In addition to clinical experience with sebelipase alfa, extensive human experience exists for 
ERTs in the treatment of other LSDs including Gaucher, Pompe, and Fabry disease. The main 
unfavorable effects associated with administration of approved ERTs (including but not limited 
to Cerezyme®, VPRIV®, Myozyme®/Lumizyme®,  Fabrazyme®) are IARs, which typically occur 
during or within several hours following completion of the infusion and 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. Given the propensity 
for infusion reactions with ERT administration, measures have been incorporated in this protocol 
to minimize risk and monitor subject safety. 
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.   
Given the relatively low level of subject risk relative to the terminal nature of untreated LAL 
Deficiency presenting in infancy, 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 effect of sebelipase alfa therapy on survival 
at 12 months of age in children with growth failure due to LAL Deficiency. 
2.2 Secondary Objectives 
The secondary objectives are: 
 
To evaluate the safety and tolerability of sebelipase alfa in children with growth failure 
due to LAL Deficiency;  
 
To evaluate the effect of sebelipase alfa therapy on survival beyond 12 months of age in 
children with growth failure due to LAL Deficiency; 
 
To evaluate the effects of sebelipase alfa on growth parameters in children with growth 
failure due to LAL Deficiency; 
 
To evaluate the effects of sebelipase alfa on hepatomegaly, splenomegaly, and liver 
function in children with growth failure due to LAL Deficiency; 
 
To determine the effects of sebelipase alfa on hematological parameters in children with 
growth failure due to LAL Deficiency; 
 
To characterize the PK of sebelipase alfa delivered by IV infusion. 
2.3 Exploratory Objectives 
The exploratory objectives are: 
 
To determine the effects of sebelipase alfa on lipid parameters in children with growth 
failure due to LAL Deficiency; 
 
To assess the effects of sebelipase alfa on achievement of developmental milestones in 
children with growth failure due to LAL Deficiency;  
 
To assess the effects of sebelipase alfa on the ability of children with LAL Deficiency to 
tolerate an unrestricted diet; 
 
To evaluate potential disease-related biomarkers. 

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3 Study Design 
3.1 Overview of Study Design and Flow Chart 
This is an open-label, repeat-dose, dose escalation study of sebelipase alfa  in children with 
growth failure due to LAL Deficiency.  Eligible subjects will receive IV infusions of sebelipase 
alfa for up to 5 years, as described below.  All subjects will be evaluated for safety, tolerability, 
and efficacy. Where feasible, given blood volume thresholds based on subject weight, blood 
samples will also be collected for analyses of the PK and PD of sebelipase alfa and for an 
exploratory analysis of potential disease-related biomarkers in this patient population. 
All subjects will initiate treatment with sebelipase alfa at a dose of 0.35 mg/kg qw.  After 
receiving 2 infusions at this starting dose, a subject will receive a dose increase to 1 mg/kg qw, 
contingent upon acceptable safety and tolerability of preceding infusions.  A further dose 
escalation to 3 mg/kg qw may be considered for a subject who has received at least 4 infusions 
at a dose of 1 mg/kg qw, and meets the criteria for dose escalation defined in Section 3.1.1, 
contingent upon acceptable safety and tolerability of preceding infusions. 
An independent safety committee will oversee safety in this study.  The SC will review available 
safety data for each subject (1) following the first 2 infusions at a dose of 0.35 mg/kg qw to 
determine the acceptability of escalating the dose to 1 mg/kg qw and (2) following the first 
2 infusions at a dose of 1 mg/kg qw to determine the acceptability of continuing treatment at this 
dose level.  In addition, for subjects who are escalated to a dose of 3 mg/kg qw, the SC will 
review their safety data following the first 2 infusions at a dose of 3 mg/kg qw to determine the 
acceptability of continuing treatment at this dose level.  The remainder of the safety data for all 
subjects will be reviewed during at least biannual periodic meetings of the SC and on an ad-hoc 
basis as needed in the event of unanticipated safety findings. 
If the SC does not approve a subject’s dose escalation from 0.35 mg/kg qw to 1 mg/kg qw, but 
deems it safe for the subject to continue treatment at the starting dose of 0.35 mg/kg qw, the 
subject may continue to receive this starting dose.  Re-evaluation of dose escalation will be 
considered after subsequent SC review and discussion with Sponsor. 
Subjects who do not tolerate a dose of 3 mg/kg qw or 1 mg/kg qw may receive a dose reduction 
to 1 mg/kg qw or 0.35 mg/kg qw, respectively, 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 qw, despite measures taken to manage any IARs, the subject will be discontinued 
from the study. 
Subjects who are on treatment for at least 96 weeks and have been on a stable dose for at least 
24 weeks, may transition to an every other week dosing schedule at the same dose they 
received on the weekly dosing schedule. If the subject meets the criteria for dose escalation 
while on the every other week dosing schedule they will either revert back to weekly dosing or if 
on 1 mg/kg qow can increase to 3 mg/kg qow dosing.  
Given the severity and life threatening nature of rapidly progressive LAL Deficiency, it is likely 
that these subjects will be hospitalized during the first several weeks on study. For the subjects 

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who are stable enough to be treated on an outpatient basis, safety follow-up assessments for 
AEs will be conducted by telephone 24 hours following the first 2 infusions of 0.35 mg/kg qw, 
1 mg/kg qw, as well as 3 mg/kg qw, if needed. Additional details about the SC review process 
can be found in Section 7.6.  Refer to Appendix A for the full Schedule of Assessments.  
Subjects who appear to have an acute illness (e.g., upper respiratory infection or febrile illness) 
should have their scheduled infusions postponed by up to 2 days (5 days if subject is on a qow 
infusion schedule) to allow for resolution.  If the illness persists for longer than 2 days (5 days if 
subject is on a qow infusion schedule), the infusion schedule should reset to the next scheduled 
infusion after the subject’s recovery. The Investigator may conduct an unscheduled visit at any 
time during the study at his/her discretion.  Assessments performed at this visit should be 
symptom directed. Safety laboratory testing may be performed if the Investigator considers it 
necessary. Repeat laboratory testing may be needed based on results from the unscheduled 
laboratory testing. If the subject is discontinued from study treatment at a scheduled visit or at 
an unscheduled visit, the subject should return no earlier than 7 days after the last dose of IMP 
for an End of Study assessment.  
3.1.1 Dose Escalation  
The Investigator, in consultation with the Sponsor and Safety Committee (SC), may consider 
increasing a subject's dose to 3 mg/kg qw by monitoring subjects for evidence of the below 
specified criteria that may reflect a need for a dose increase. These considerations should 
include evaluation of other potential causes of any clinical manifestations that are thought 
negatively impact these criteria. 
.  Other causes could include: 
 
missed study infusions, 
 
onset of acute cholecystitis or initiation of a potentially hepatotoxic concomitant 
medication in a subject with elevated ALT,  
 
concomitant illness in a subject with reduced weight gain such as an upper respiratory 
tract infections or other childhood viral infection.  
3.1.1.1 Dose escalation criteria during first 3 months of treatment 
During this period, a subject may be considered for dose escalation if he/she meets 2 or more of 
the following criteria after at least 4 infusions at a dose of 1 mg/kg qw:  
 
Failure to gain an average of 5 g/kg body weight per day AND the presence of either of the 
following: 
o weight-for-length (WFL) or weight-for-height (WFH) z-score <-2 based on World 
Health Organization (WHO) child growth standards; and/or 
o length-for-age (LFA) or height-for-age (HFA) z-score <-2 based on WHO child 
growth standards. 
 
 
Albumin <3.5 g/dL; 
 
Alanine aminotransferase (ALT) >2x upper limit of normal (ULN); 

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 
Ongoing requirement for blood and/or platelet transfusion. 
3.1.1.2 Dose escalation after at least 3 months of treatment  
 
Any other clinically important manifestation of LAL Deficiency on either clinical examination, 
laboratory assessment, or imaging which has either  
 
not improved from baseline  
 
improved and plateaued but has not normalized  
(Note:  The definition of a plateauing of effect requires consideration of a minimal of 
3 assessments.) 
 
failed to normalize within 12 months of initiation of treatment,   
Manifestations include but are not restricted to the following: A decrease in weight for 
age defined as crossing >2 major centile lines on standard weight for age curves, serum 
transaminases, albumin <3.5 g/dL, hepatomegaly, splenomegaly or lymphadenopathy. 
    
If the subject continues to have criteria for dose escalation after at least 4 infusions at a dose of 
3 mg/kg qw, the Investigator, may request of the Sponsor (in consultation with the SC) to 
increase the dose up to a maximum of 5 mg/kg qw on a case by case basis.  
Prior to any dose change, serum lipid, serum liver, hematology, chemistry, ferritin and hs-CRP 
shall be obtained. Serum lipid and serum liver assessments should be taken 4, 8, and 12 weeks 
following any study drug or lipid drug dose change. 

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Figure 1 
Initial Dose Escalation- Safety Committee Review Flow 
 
Note: All dose increases are contingent upon acceptable safety and tolerability during preceding infusions. 
Note: Dose reductions are permitted in the event of poor tolerability. See Section 3.1 for details. *Subjects will receive 
a dose of 1 mg/kg qw through 96 weeks, except where a subject's dose after at least 4 infusions of 1 mg/kg qw meets 
dose escalation criteria as defined in Section 3.1.1) and a dose increase to 3 mg/kg qw is approved. Subjects may 
transition to an every other week dosing schedule after 96 weeks if on a stable dose for at least 24 weeks. 
Meets 
escalation  
criteria 

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3.2 Rationale for Study Design 
3.2.1 Dose Selection 
Refer to Section 1.5.1 for the dose selection rationale.  
3.2.2 Outcome Variable Selection 
3.2.2.1 Efficacy 
The study is designed primarily to evaluate the efficacy of treatment with sebelipase alfa.  The 
primary efficacy endpoint will be the proportion of subjects surviving to 12 months of age.  
Secondary survival endpoints will include proportion of subjects surviving to 18 and 24 months 
of age, and other timepoints, as data permit, and estimated median age at death. Survival rates 
and median age at death derived from this study will be compared to rates/times reported in the 
literature and information derived from a natural history study in a similar patient populations 
(study LAL-1-NH01). 
Subjects with untreated early onset LAL Deficiency typically stop growing and this growth 
failure, in addition to being the predominant clinical feature, is also one of the main contributors 
to mortality. Improvement in growth is anticipated to be a prerequisite for any beneficial effects 
of sebelipase alfa on survival. Therefore, secondary efficacy endpoints will include changes 
from baseline in the following growth parameters: 
 
Percentiles and/or z-scores, based on WHO child growth standards 
(WHO Multicentre Growth Reference Study Group, 2006 and 2007), for the following 
parameters: 
 
Weight-for-age (WFA); 
 
WFL or WFH; 
 
LFA or HFA; 
 
Head circumference-for-age (HCFA); 
 
Mid-upper arm circumference-for-age (MUACFA).  
 
Dichotomous growth status indicators for underweight, wasting, and stunting based 
on WFA, WFL/WFH, and LFA/HFA, respectively (UNICEF, 2009). 
Note: Given the switch at age 2 years from measurement of length to measurement of height, 
growth parameters include weight related to both length and height and age related to both 
length and height. 
A successful therapy for LAL Deficiency presenting in infancy should mitigate the liver and 
hematological changes associated with the disease.  Therefore, the following laboratory 
parameters will also be included as secondary efficacy endpoints:   
 
Changes from baseline in aspartate aminotransferase [AST] and ALT levels;  

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 
Normalization of hemoglobin levels without requirement for blood transfusion; 
 
Changes from baseline in serum ferritin levels. 
Additional exploratory efficacy parameters will be investigated to provide supportive evidence of 
an improvement of LAL Deficiency with sebelipase alfa treatment, and will include changes or 
percent changes from baseline (or first available assessment if baseline data are unavailable) 
in:  
 
Alkaline phosphatase, gamma glutamyltransferase (GGT), albumin, and direct 
(conjugated), indirect (unconjugated), and total bilirubin levels;  
 
Liver and spleen size/volume, as measured by ultrasound or magnetic resonance 
imaging (MRI); 
 
Hepatomegaly and/or splenomegaly (abdominal girth, liver size, and spleen size) by 
physical examination; 
 
Platelet levels; 
 
Serum lipid levels (total cholesterol, triglycerides, high density lipoprotein [HDL], and 
LDL). 
Because LAL Deficiency presenting in infancy is rapidly progressive and patients often die 
within 6 months of age (Assmann, 2001, The Metabolic and Molecular Basis of Inherited 
Disease), information on development is limited in this patient population. The potential 
extended life expectancy in subjects receiving long-term treatment with sebelipase alfa provides 
an opportunity to improve the medical community’s understanding of the developmental process 
in infants with LAL Deficiency treated with sebelipase alfa. To this end, the study will include an 
exploratory analysis of developmental outcomes, as assessed by the Denver II developmental 
screening test.  
Dietary changes, including discontinuation of a low-fat/low-cholesterol diet and/or introduction of 
an unrestricted age-appropriate diet, will also be evaluated on an exploratory basis.   
Given the potential for ADAs to alter the PD effect of sebelipase alfa, the impact of ADAs on 
efficacy endpoints will be explored. 
3.2.2.2 Safety 
The safety and tolerability of treatment with sebelipase alfa, administered by IV infusion, will 
also be evaluated in this study.  Endpoints for safety of sebelipase alfa in infants with LAL 
Deficiency will include: 
 
Incidence of AEs, SAEs, and IARs; 
 
Changes from baseline clinical laboratory tests; 
 
Changes in vital signs during and post-infusion, relative to pre-infusion values; 
 
Physical examination findings; 

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 
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.   
Given the potential for ADAs to alter the safety profile of sebelipase alfa, the impact of ADAs on 
safety endpoints will be explored.  Further characterization of ADAs, including inhibitory and/or 
neutralizing ADAs and measurement of specific ADA subtypes (e.g., IgE), may be performed, if 
appropriate. 
3.2.2.3 Pharmacokinetics 
The PK of sebelipase alfa in infants with LAL Deficiency will be characterized in this study, 
blood volume permitting.  PK endpoints will include the following sebelipase alfa PK parameters 
in serum, as data permit:  
 
maximum observed serum concentration (Cmax) 
 
apparent serum clearance (CL) 
The impact of ADAs on sebelipase alfa PK will also be explored, if data permit.   
3.2.2.4 Pharmacodynamics 
Blood samples will also be collected to support exploratory analyses of changes or percent 
changes from baseline in potential disease-related biomarkers, which may be identified based 
on emerging information from the sebelipase alfa development program and scientific literature.  
3.2.3 Study Duration 
The duration of each subject’s treatment in the study is expected to be at least 18 months, and 
subjects may continue to receive treatment in the study for up to up to 5 years.  Therefore, the 
overall duration of a subject's participation in the study, inclusive of a 3-week screening period 
and a 4-week follow-up period, may be up to 5 years and 7 weeks. 

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4 Study Population 
4.1 Target Population 
The target population for this study is male and female children with growth failure due to 
LAL Deficiency. 
4.2 Number of Subjects 
In light of the extremely low prevalence of the target disease, approximately 10 subjects will be 
enrolled in the study, including a minimum of 8 subjects who are 8 months of age or younger on 
the date of the first infusion of sebelipase alfa and thus eligible for the primary analysis of 
survival. 
4.3 Inclusion Criteria 
A subject must meet all of the following criteria to be eligible to participate in this study:  
1. Subject’s parent or legal guardian understands the full nature and purpose of the study, 
including possible risks and side effects, and provides written informed 
consent/permission prior to any study procedures being performed. 
2. Male or female child with a documented decreased LAL activity relative to the normal 
range of the lab performing the assay or documented result of molecular genetic testing 
(2 mutations) confirming a diagnosis of LAL Deficiency. 
3. Growth failure*  with onset before 6 months of age, as defined by: 
weight decreasing across at least 2 of the 11 major centiles on a standard WHO 
WFA chart (1st, 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97th, 99th); 
OR 
body weight in kg below the 10th centile on a standard WHO WFA chart AND no 
weight gain for the 2 weeks prior to screening; 
OR 
loss of >5% of birth weight in a child who is older than 2 weeks of age. 
 
*NOTE regarding Inclusion Criterion # 3: In the unusual circumstance where a child has 
a rapidly progressive course of LAL Deficiency but does not meet growth failure criteria 
as defined above, the child may be included in the study if the Investigator has 
substantial clinical concerns based on evidence of the rapid disease progression 
requiring urgent medical intervention.  Inclusion under these exceptional circumstances 
requires submission of a written summary of the infant’s medical status for review by the 
Sponsor and must be approved by a written confirmation from the Sponsor after 
consultation with the  SC.  The subject must meet all other entry criteria as stated. 

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4.4 Exclusion Criteria 
A subject who meets any of the following criteria will be ineligible to participate in the study: 
1. Clinically important concurrent disease or co-morbidities which, in the opinion of the 
Investigator and Sponsor, would interfere with study participation, including, but not 
restricted to, congestive heart failure, ongoing circulatory collapse requiring inotropic 
support, acute or chronic renal failure, additional severe congenital abnormality, or other 
extenuating circumstances such as life-threatening under nutrition or rapidly progressive 
liver disease.  
2. Subject is >24 months of age. (Note: Subjects >8 months of age on the date of first 
infusion will not be eligible for the primary efficacy analysis.)  
3. Has received an investigational medicinal product other than sebelipase alfa within 14 
days prior to the first dose of sebelipase alfa in this study. 
4. Myeloablative preparation, or other systemic pre-transplant conditioning, for 
hematopoietic stem cell or liver transplantation. 
5. Previous hematopoietic stem cell or liver transplant. 
6. Known hypersensitivity to eggs. 
4.5 Concomitant Medication and Treatment 
A concomitant medication is any drug or substance taken during the study after the informed 
consent is signed.  Any concomitant medications (including over the counter medications, 
herbal medications, preventive vaccines, vitamins and food supplements), treatments and 
procedures (including parenteral feeds, surgery, or physical therapy) received by the subject 
through completion of the follow-up visit, approximately 30 days after the last dose of IMP, must 
be recorded in the electronic case report form (eCRF).  A description of the type of drug or 
procedure, the amount, duration, reason for administration of drug and the outcome of any 
procedure must be documented.  Adverse events (AEs) related to the administration of a 
concomitant medication or the performance of a procedure must also be documented on the AE 
page of the eCRF. 
Information about a subject's diet prior to initiation of treatment with sebelipase alfa in this study 
or under an expanded access program, and any changes in a subject's diet during treatment in 
this study (e.g., discontinuation of a low-fat/low-cholesterol diet and/or introduction of an 
unrestricted age-appropriate diet) will be recorded in the 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, subject’s parent or legal guardian have the right 
to withdraw from the study at any time for any reason.  

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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; 
 
Medically significant AEs; 
 
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 
A subject’s parent or legal guardian is free to withdraw consent and/or discontinue the subject’s 
participation in the study at any time, without prejudice to further treatment. A subject’s 
participation in the study may also be discontinued at any time at the discretion of the 
Investigator or Sponsor.  Should a subject’s parent or legal guardian decide to withdraw 
consent, all efforts will be made to complete and report the observations as thoroughly as 
possible. The parent or legal guardian of subjects who are discontinued 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. Subjects who discontinue prior 
to IMP administration will be replaced. 
Subjects who are prematurely withdrawn from the study will be asked to complete all 
discontinuation assessments prior to withdrawal (see Appendix A), if possible.  Information on 
the survival of discontinued subjects will be collected until completion of the study.  Serious AEs 
will be followed according to Section 7.2.3 and reported according to Section 7.4.  A subject will 
be considered early terminated if the subject does not complete the study after enrollment.  A 
subject will be considered discontinued due to an AE if the subject received any infusion or 
partial infusion of the investigational medicinal product, but did not complete the study because 
of an AE, whether or not considered drug related.  At the end of the subject’s participation in the 
study, the Investigator will document the reason(s) for study discontinuation in the eCRF. 
In the event that a subject dies, permission will be sought (through a separate informed consent 
form) from the subject’s parent or legal guardian for an autopsy.  Samples collected from these 
procedures will be used to further understand LAL Deficiency and the effect of sebelipase alfa. 
When a subject fails to return for scheduled assessments, the following efforts should be made 
to contact his/her parent or legal guardian to determine a reason for the failure to return: 
3 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. 
4.7 Subject Replacement Policy 
Subjects are not replaced per se in this study.  If a subject who qualifies for the Primary Efficacy 
Analysis Set discontinues the trial prematurely before receiving at least 4 infusions of 

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sebelipase alfa, an additional subject may be enrolled, at the discretion of the Sponsor, to 
achieve a minimum of 8 subjects who have at least 4 infusions. 
4.8 Subject Recruitment and Screening 
Subjects may be recruited into the study directly from the Investigators’ or sub-investigators’ 
clinical practices, or referred to the investigative sites from other clinics.  Information about the 
study will be posted on the http://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ 
websites.  
Subject screening should occur between 1 and 21 days prior to the infusion at Week 0 (Day 0). 

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5 Schedule of Assessments and Study Procedures 
The schedule of assessments is presented in Appendix A.  
Subjects who are clinically stable enough to tolerate general anesthesia may be considered for 
central line placement for long-term vascular access, in accordance with institutional guidelines.  
Magnetic resonance imaging (MRI) should be considered for subjects receiving general 
anesthesia and/or sedation for central line placement or for other procedures (see 
Section 5.1.8). 
European Medicines Agency (EMA) recommended blood volume limits should be used as a 
guidance 
for 
blood 
sampling 
in 
this study: 
http://www.emea.europa.eu/docs/en_GB/ 
document_library/Scientific_guideline/2009/09/WC500003754.pdf.  Per individual, the study-
related blood loss should not exceed 3% of the total blood volume during a 4-week period or 1% 
of total blood volume at any single time.  The actual situation of the child (sleep/activity, severity 
of anemia, and hemodynamic state) must permit such blood sampling.  Table 11 summarizes 
mean blood volume per body weight based on an individual's age.  Assuming a total blood 
volume of 80 mL/kg body weight for an average patient in this study, 3% of total blood volume 
corresponds to 2.4 mL/kg body weight and 1% of total blood volume corresponds to about 0.8 
mL/kg body weight. 
Table 1 
Mean Blood Volume, by Age 
Age 
Mean blood volume per weight (mL/kg) 
Newborn, 24 hours 
83.3 
Children, 3 months 
87 
Children, 6 months 
86 
Children, 1 year 
80 
Children, 6 years 
80 
Children, 10 years 
75 
Children, 15 years 
71 
Source: Geigy Scientific Tables, 7th Ed. 
5.1 Study Assessments 
5.1.1 Informed Consent 
The parent or legal guardian of a potential subject will be given a verbal explanation of the study 
and the procedures involved and will have all questions addressed.  The subject’s parent or 
legal guardian must sign and date a consent form that has been approved by the appropriate 
institutional review board/independent ethics committee (IRB/IEC) before the screening 
procedures are initiated.  The subject’s parent or legal guardian 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 Section 4.3 and Section 4.4 and background clinical information collected. 

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5.1.3 Medical History 
Complete medical history, including prenatal, birth history, family history and disease history will 
be recorded at Screening. 
5.1.4 Demographic Information 
The following demographic information will be collected at Screening: date of birth, birth weight, 
gender, race and ethnicity. 
5.1.5 Anthropometrics 
Anthropometrics, including weight, recumbent length (subjects ≤2 years of age at the time of 
examination) or height (subjects >2 years of age at the time of examination), head 
circumference, mid-upper arm circumference, and abdominal circumference, will be measured 
at the timepoints specified in Appendix A. 
Refer to the SOM for a detailed description of the procedure for each anthropometric 
measurement. 
 
Percentiles or z-scores for WFA, WFL/WFH, LFA/HFA, HCFA, and MUACFA will be determined 
based on WHO child growth standards (WHO Multicentre Growth Reference Study Group, 2006 
and 2007).  Growth status will also be classified according to 3 dichotomous indicators: 
underweight (<-2 standard deviations [SD] from the median for WFA), wasting (<-2 SD from the 
median for WFL/WFH), and stunting (<-2 SD from the median for LFA/HFA). 
5.1.6 Physical Examination 
A physical examination will be performed by the Investigator or qualified designee 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, 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 captured in the eCRF. 
Every physical examination 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. 

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 
Digital Photograph:A digital photographic image of the subject in a supine position (full 
length and abdominal close up) will obtained during selected physical examinations, as 
specified in Appendix A. 
Refer to the Site Operations Manual (SOM) for a detailed description of the physical 
examination procedure and instructions for photographs. 
5.1.7 Abdominal Ultrasound 
Abdominal ultrasonography will be performed at the timepoints specified in Appendix A to 
measure the liver and spleen size. 
Abdominal ultrasonography will be performed by a qualified person, and results will be 
interpreted by a radiologist trained in ultrasonography. 
5.1.8 Abdominal MRI 
Abdominal MRIs should be considered at the timepoints specified in Appendix A to provide a 
more accurate quantification of liver and spleen volume. If an Abdominal MRI cannot be 
performed, an Abdominal Ultrasound will be performed instead at that timepoint. 
Investigators are encouraged to obtain abdominal MRIs in subjects receiving general 
anesthesia or sedation for other procedures at a scheduled imaging timepoint.  To allow 
flexibility in scheduling MRIs, a broad time window is given for each MRI assessment in 
Appendix A.  For example, the baseline MRI may be obtained at any time from Screening 
through the Week 0 study visit. 
Because MRI can provide important information on liver and spleen volume that can be related 
to expected normal values abdominal MRIs should be obtained during the treatment phase, 
even if a subject did not provide a baseline MRI. 
All imaging scans will be acquired and the results interpreted by a magnetic resonance 
technician or other qualified individual using standardized imaging protocols.   
Refer to the Imaging Manual for instructions on image acquisition and analysis. 
5.1.9 Vital Signs 
Vital signs will include pulse rate, respiratory rate, systolic and diastolic blood pressure and core 
body temperature (rectal or oral).  Assessment of pulse rate and blood pressure will be taken 
after the subject has been in a supine position. 
Vital signs will be measured at the timepoints specified in Appendix A.  On dosing days, vital 
signs will initially be recorded pre-infusion, every 15 (±5) minutes during infusion and every 
30 (±10) minutes from 0 to 4 hours after completion of the infusion.  Once a subject has 
received a stable dose for at least 2 months, with no moderate-to-severe IARs, 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.  After a subject has successfully completed at least 1 year of 
treatment with no occurrence of moderate-to-severe IARs, the post-infusion period for vital sign 
monitoring may be shortened from 4 hours to 2 hours.  

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Additional readings may be taken at the discretion of the Investigator and in the event of an IAR. 
5.1.10 Electrocardiogram 
An age-appropriate 12-lead electrocardiogram (ECG) will be obtained at Screening and 
reviewed by a qualified clinician.  Additional age-appropriate 12-lead ECGs may be obtained at 
subsequent study visits, if clinically indicated.  Any abnormalities identified by the clinician will 
be specified as clinically significant or not clinically significant.   
5.1.11 Laboratory Assessments 
Blood and urine samples for laboratory tests will be collected at the timepoints specified in 
Appendix A.  
Prior to any dose change, serum lipid, serum liver, hematology, chemistry, ferritin and hs-CRP 
shall be obtained. Serum lipid and serum liver assessments should be taken 4, 8, and 12 weeks 
following any study drug or lipid drug dose change. 
Due to the limitations on the volume of blood collection that is considered to be acceptable in 
young children with very small total circulating blood volumes (see Section 5), the laboratory 
samples will be ranked in the order corresponding to the study objectives, as shown in Table 2.  
Only Tier 1 assessments are considered mandatory and all efforts should be made to collect 
these in all subjects.  Samples for the Tier 2 and Tier 3 assessments will only be collected if the 
blood volume threshold for subject’s weight, as well as the subject’s clinical status, permit (see 
Section 5 for further details).  
 
Table 2 
Clinical Laboratory Tests, By Tier 
Tier 1 (Mandatory) 
CBC/Hematology: 
White blood cell count, red blood cell count, 
hemoglobin, hematocrit, MCV, MCH, MCHC, platelet 
count, neutrophil, lymphocytes, monocytes, 
eosinophils, basophils, peripheral smear for 
examination of cell morphology 
Chemistry Panel: 
Glucose, urea nitrogen, creatinine, sodium, 
potassium, chloride, calcium, magnesium, inorganic 
phosphorus, total protein, lactate dehydrogenase 
Liver Function Tests: 
 
AST/SGOT, ALT/SGPT, alkaline phosphatase, GGT, 
albumin, bilirubin (direct, indirect, total) 
Anti-drug Antibody: 
Anti- sebelipase alfa antibody 
Urinalysis: 
pH, glucose, ketones, blood, protein, nitrite, and 
leukocytes (microscopic examination will only be done 
if blood, nitrite and/or leukocytes are abnormal) 

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Coagulation Studies: 
 
PT (INR), aPTT 
DNA Sample  
See Section 5.1.15 
LAL Enzyme Activity  
See Section 5.1.16 
Tier 2 (Optional) 
Lipid Panel:  
Total cholesterol, triglyceride, HDL, LDL 
Other Chemistry: 
Serum ferritin 
Tier 3 (Optional) 
Pharmacokinetic Assessments 
See Section 5.1.14 
Exploratory Biomarkers 
See Section 5.1.13 
 
Coagulation studies are required at Screening only. Thereafter, they should be completed only if 
the preceding assessment was abnormal or if it is clinically indicated based on emerging 
evidence of liver dysfunction. 
Laboratory reports will be reviewed by the Investigator, or designee, and any abnormalities will 
be specified as clinically significant  or not clinically significant.  In the event of unexplained 
clinically significant abnormal laboratory test values, 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 laboratory manual for further details regarding the collection, processing, and 
storage of these samples. 
5.1.12 Denver II Developmental Screening Test 
The Denver II will be administered at the timepoints specified in Appendix A. 
The Denver II is a standardized measure to assess development in children from 1 month to 6 
years of age (Frankenberg, 1992, Pediatr). The Denver II includes performance-based and 
parent-reported items in 4 functional areas: fine motor-adaptive, gross motor, personal-social, 
and language skills. The test was normed on a diverse sample of children who were full term 
and had no obvious developmental disabilities; the norms indicate when 25%, 50%, 75%, and 
90% of children passed each item. The Denver II has good inter-rater and test-retest reliability 
(correlations ≥ 0.90 for most tests). 
The Denver II must be administered by a trained clinician and takes an average of 10 to 
20 minutes to complete.  Administration and scoring of the Denver II is based upon the child's 
age.  (Note that for premature infants, the number of months premature is subtracted from the 
infant's chronological age.)  For each test item administered, the clinician determines if the 
child's response falls within or outside of the normal expected range of success on that item for 
the child's age. The interpretation of the individual test items is then used to classify the child's 
development in each functional area and for the overall test. 

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5.1.13 Exploratory Biomarkers 
Whenever feasible, based on the blood volume threshold for the subject’s weight, a blood 
sample for serum isolation (2 aliquots) will be obtained at the timepoints specified in 
Appendix A. The serum sample will be used to identify baseline disease and dynamic markers 
that will help better understand the pathogenesis of LAL Deficiency, 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.  
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples. 
5.1.14 Pharmacokinetic Assessments 
To reduce risk of iatrogenic anemia, PK sampling may be limited.  In order of importance 
samples will be collected to derive Cmax and  CL.  
PK samples should not be taken from the same extremity where the infusion catheter is in 
place.  Sampling for measurement of sebelipase alfa serum levels will be performed during the 
study visits indicated in Appendix A.  These samples will be collected within designated time 
windows, rather than at discrete timepoints, to allow more flexibility in the management of PK 
sampling in these subjects and to provide opportunities for measurement of drug concentrations 
across a broader timeperiod with limited sampling.   
In all subjects: 
 
0 to 1 hours after the start of the infusion; 
 
Between 1 hour after the start of the infusion and the end of the infusion 
(i.e. when the infusion bag has been emptied, but prior to the sodium chloride 
flush). 
In those subjects for whom the thresholds for allowed blood collection volumes have not been 
exceeded:  
 
0 to 0.5 hours after completion of the infusion; 
 
0.5 to 1 hour after completion of the infusion; 
 
1 to 2 hours after completion of the infusion. 
All PK samples, at time points that coincide with a vital sign assessment, will be taken before 
cuff inflation for blood pressure assessment on the non-infusion arm.  PK samples at other time 
points will be taken at least 5 minutes after cuff deflation. 
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples. 
5.1.15 DNA Sample 
The Sponsor intends to apply pharmacogenetics to the sebelipase alfa program in order to 
explore how genetic variations may affect clinical parameters associated with sebelipase alfa 
use and acid lipase biology.  DNA sequences, including both the protein coding sequence and 

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sequences that regulate gene transcription, messenger ribonucleic acid (mRNA) stability and 
the efficiency of protein translation that may be investigated include: 
1. LAL (LIPA); 
2. Genes coding for other proteins involved in lipid biology that may contribute to and/or 
modify the disease phenotype of LAL Deficiency, e.g. ABCA1; 
3. Genes that may modify susceptibility to any sebelipase alfa related AEs. 
Where possible and in compliance with local regulations, a blood sample for DNA extraction will 
be collected from the subject at Screening or as soon as practically possible thereafter based on 
blood volume collection threshold, unless a stored DNA sample is already available for the 
subject.  The DNA will be stored and used as part of a later pooled analysis.  This will include 
determining the spectrum of LAL mutations in subjects with growth failure due to LAL Deficiency 
and the relationship between gene mutation, safety, efficacy and susceptibility to anti- 
sebelipase alfa antibody development.  
If feasible, a blood sample for DNA extraction and testing of the LAL gene mutations will be 
collected from the subjects’ biological parents after a separate consent has been obtained. 
The Sponsor will only analyze DNA sequences within genes relevant to the mode of action and 
response to sebelipase alfa, including variants important in understanding AEs, and candidate 
genes with a potential role in the etiology, pathogenesis, and progression of LAL Deficiency. 
Samples will be stored by the Sponsor, or designee, in a secure, monitored, and controlled 
environment.  No additional testing will be performed on the samples collected in the study. 
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples. 
5.1.16 LAL Enzyme Activity 
Study inclusion will be contingent on documented decreased LAL activity relative to the normal 
range of the lab performing the assay or a documented result of molecular genetic testing 
confirming a diagnosis of LAL Deficiency.  
Blood samples will also be collected at Screening to measure LAL activity in peripheral blood 
mononuclear cells (PBMCs) and in a dried blood spot (DBS) collected on filter paper to ensure 
consistency of LAL activity measurement in all subjects. In the unlikely event of a discrepancy 
between the diagnosis of LAL Deficiency based on baseline LAL activity in PBMCs and/or DBS 
and the previously documented diagnosis, a subject may be discontinued from the study and 
may be replaced.  
5.1.17 Liver Biopsy 
An optional liver biopsy will be obtained for evaluation of hepatic histology after at least 1 year of 
treatment, at the timpoints suggested in Appendix A.  Biopsies will be performed only with 
consent from the subject’s parent/guardian and where local regulations permit, and are subject 
to discretionary approval from each center's IRB/IEC. 

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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. 

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6 Investigational Medicinal Product 
6.1  Description of IMP 
Details of the non-clinical 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. The solution (total 10.5 mL 
including 5% overfill) has an approximate concentration of 2 mg/mL. Exact concentration will be 
on the individual vials.  
Sebelipase alfa contains no preservatives and vials are single use only. 
Sodium chloride (0.9%) for injection, for use in preparation of diluted solutions for infusion, will 
be sourced locally by the study center. 
6.2 Method for Assigning Subjects to Treatment Groups 
No randomization schemes will be employed; all subjects will receive the same starting dose of 
sebelipase alfa in this study.   
Each subject will be assigned an enrollment number after informed consent has been obtained 
from the subject's parent or legal guardian.  This enrollment number will be used to identify the 
subject throughout his/her participation in the study. 
A subject who does not meet all study eligibility criteria due to a potentially transient condition 
observed at screening (e.g., discontinuation of another investigational medicinal product within 
14 days, or failure to meet protocol-defined growth failure criteria in a subject <6 months of 
age), will be allowed to return for re-screening.   
6.3 Storage and Disposition of IMP 
6.3.1 Receipt of IMP 
Upon receipt of the IMP, an inventory must be performed and verified by the person accepting 
the shipment.  It is important that upon IMP delivery 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 Investigator 
must notify study Sponsor of any damaged or unusable IMP that was supplied to the 
Investigator’s site. 
6.3.2 Storage 
All sebelipase alfa vials must be stored under controlled refrigerated conditions at 2ºC to 8ºC 
(36ºF to 46ºF).  (Note: temperature excursions up to 25ºC for up to 12 hours have not been 
shown to be associated with loss of enzyme activity.)  Vials should not be frozen and should be 
protected from light during storage.   

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The infusion bag or syringe containing sebelipase alfa diluted in 0.9% sodium chloride should 
be prepared just prior to the start of infusion administration.  For study sites where there is a 
requirement for dilution at a separate location this needs to be done in a place with controlled 
and aseptic conditions.  Although the infusion bag or syringe is stable at room temperature 
(23ºC to 26ºC) for 12 hours, it should be used as soon as possible after preparation. 
6.3.3 Disposition 
The Investigator or designated person (e.g. a licensed pharmacist) will be responsible for 
maintaining accurate records for all IMP used.  Opened sebelipase alfa vials still containing any 
residual volume may be stored at room temperature for IMP accountability.  Following IMP 
accountability, the Sponsor or designee will give written authorization to the Investigator to 
return or destroy any remaining IMP as instructed. 
6.4 Preparation and Administration of IMP 
Under no circumstances will the IMP be used other than as directed in the protocol. 
6.4.1 Preparation of IMP 
 The infusion bag (or syringe) containing sebelipase alfa will be prepared just prior to the start of 
infusion administration. Prior to preparation of the infusion, the vials of study drug will be visually 
inspected.  The solution should not be used if it contains foreign particulate matter or is 
discolored.  The solution may be used if a small number of visible translucent to opalescent or 
white amorphous or threadlike particles are present in the vial. The contents should NOT be 
warmed using a microwave or other heat source. Sebelipase alfa is a protein and will be 
handled and mixed gently to prevent foaming. 
If subject’s weight cannot reliably be obtained on the morning of the infusion then the subject’s 
most recent weight measurement within 7 days, rounded to the nearest 0.1 kg, will be used for 
calculating the volume of study drug to be withdrawn from the vial(s) to prepare the infusion.  
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. 
6.4.2 
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 
under close supervision of the Investigator, or designee. Sebelipase alfa should not be 
administered at an infusion rate exceeding 4 ml/kg/hr.  For detailed administration instructions 
please refer to the IMP manual. 
Subjects who are medically stable, as determined by the Investigator, may transfer to a local 
medical center for long-term treatment, contingent upon the local medical center being 
appropriately qualified and securing the required regulatory and IRB/IEC approvals.  Scheduled 

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study assessments may also be performed at a local medical center with access to the 
appropriate facilities and expertise. 
6.5 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 IMP infusion is completed 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 hypersensitivity reaction related to administration of study drug, the 
symptoms should be recorded as an AE(s) and designated as an IAR(s). Individual adverse 
event terms should be recorded rather than the terms, IAR or Infusion Associated Reaction. 
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 limited 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 in Section 7.1.1. 
 
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. 
If any of the above signs and symptoms are observed during the infusion and the subject 
remains hemodynamically stable: 
 
The infusion rate must be slowed by 50% (reduced to half the rate being given at the 
onset of the event, e.g. from 10 mL/hr to 5 mL/hr) and the infusion time extended in 
accordance with the institutional standard of care. The infusion rate may be decreased 
further by 25% if symptoms persist. If the event resolves, 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.  If the subject tolerates infusion at 75% of the 
original rate for at least 30 minutes the original rate may be restored for the remainder 
of the infusion. 
 
In accordance with institutional standard of care for subject’s age, treatment with oral 
anti-pyretic and/or antihistamine should be considered. 
In subjects who experience severe IAR with clinically significant cardiovascular effects (e.g., 
hypertension or hypotension defined as a decline approaching 20-30% of their preinfusion value 
without alternative etiology, agitation, pain, fluid overload, dehydration), respiratory symptoms 
(significant shortness of breath, stridor, wheezing, laryngeal edema or swelling of tongue), 

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cardiac arrhythmias,  or anaphylactic/anaphylicatoid shock with hypotension and circulatory 
collapse: 
 
The infusion should be stopped. 
 
The subject should be treated  with oxygen if available, IV antihistamines, 
corticosteroids, and IM epinephrine, if necessary, in accordance with institutional 
standard of care for the subject's age.  
 
Dosing of the subject will be suspended until the Safety Review Committee has 
completed review of the IAR, and any other relevant safety data.  
 
Subjects who experience a moderate or severe IAR should have a serum sample 
collected for tryptase 1-3 hours after the IAR onset and another serum sample for 
tryptase and ADA during the next study visit (>4 days after the IAR) prior to the 
infusion. Skin testing may be considered. 
Additional details on the management of subjects with infusion reactions are outlined in the 
table in Appendix B. 
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; 
 
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.  
7.1 Adverse Events and Laboratory Abnormalities 
7.1.1 Clinical Adverse Events 
Adverse Event 
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 as 
described in Section 7.3. 
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 Medical Dictionary for 
Regulatory Activities (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. 
Causality: AEs will be assessed by the Investigator as not related, unlikely related, possibly 
related, or related to IMP.  Table 3 provides general guidance on the assessment of causality.  
Assessment of causality should be based on the Investigator’s medical judgment and the 
observed symptoms associated with the event.  For data reporting purposes, related AEs will be 

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those assessed by the Investigator as possibly related or related to IMP, and unrelated AEs will 
be those assessed by the Investigator as not related or unlikely related to IMP.  
Table 3 
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.  
Serious Adverse Event 
A serious adverse event is any AE that results in any of the following outcomes:  
 
Death 
 
Immediately life threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in congenital anomaly/birth defect 
 
Results in a persistent or significant disability or incapacity 
 
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. 
All AEs that do not meet any of the criteria for serious, should be regarded as non-serious 
adverse events.  Given the severity and life threatening nature of LAL Deficiency in infants, it is 
likely that these subjects will be hospitalized during the first several weeks on study.  

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Continuation of this initial hospitalization for participation in the trial is not considered an SAE.  
Also, a hospitalization to accommodate a study procedure is not considered an SAE.  However, 
during the hospitalization, AEs will be collected and assessed for seriousness & reported 
appropriately (e.g., important medical event or prolonged hospitalization). 
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 on the laboratory page of the eCRF.  Out of range 
laboratory test values will be reported as AEs (on the AE page of the eCRF) if they are 
considered to be clinically significant abnormalities by the Investigator and represent a change 
from the subject’s baseline values.  
7.2 Handling of Safety Parameters 
7.2.1 Serious 
Adverse 
Events 
and 
Infusion-Associated 
Reactions(Immediately 
Reportable to the Sponsor) 
All SAEs and IARs, irrespective of the treatment received by the subject, must be reported to 
the Sponsor or designee immediately and no later than 24 hours of the Investigator’s first 
knowledge of the event (expedited reporting). 
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 informed consent to the end of the study treatment follow-up.  AEs occurring after signing the 
informed consent but prior to the first dose of study medication will only be recorded if assessed 
as related to protocol procedures or requirements.  For this study, the study treatment follow-up 
is defined as a minimum of 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. 
7.2.3 Treatment and Follow-up of Adverse Events 
During the study, all AEs and SAEs will be followed up until they have returned to baseline 
status or stabilized or until the Investigator and Sponsor or designee agree that follow up is no 
longer necessary.  If a clear explanation is established, it should be documented. 
Treatment of AEs is at the discretion of the Investigator, and should follow the standards of 
medical care at the Investigator's institution. 
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 
documented. 

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7.2.5 Pregnancy 
Subjects in this study will be of non-reproductive potential.  
7.3 Recording of Adverse Events 
At each contact with the subject (and the subject’s parent or legal guardian), the Investigator 
must seek information on AEs by specific questioning and, as appropriate, by examination.  
Information on all AEs should be recorded immediately in the source documentation, and in the 
eCRF.  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
be recorded under one diagnosis.  
 
AEs will be recorded from the time of signing of the informed consent until completion of the last 
scheduled visit, i.e., the follow-up visit.  AEs occurring after signing the informed consent but 
prior to the first dose of study medication will only be recorded if assessed as related to protocol 
procedures or requirements.  Any AEs remaining unresolved at the completion of the last 
scheduled visit should be recorded as ongoing.  Ongoing AEs/SAEs should continue to be 
followed up for the period specified in Section 7.2.2 but without further recording in the eCRF.  
However, follow-up information on SAEs must be reported to the Sponsor or designee as 
described in Section 7.4.1.  Any SAE that occurs after the study period and is considered to be 
related to the study treatment or study participation should be recorded and reported 
immediately. 
Any AE that occurs within 24 hours of the infusion will be recorded by time and date, AEs 
occurring 24 hours after the infusion will be recorded by date only.  The date and time, or the 
date when the AE started and stopped, as well as the intensity, seriousness, action taken with 
regard to the study treatment, causality assessment and outcome of the event will be recorded 
for each AE. 
7.4 Reporting of Serious Adverse Events 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. (§13 GCP-V; Detailed 
guidance on the collection, verification and presentation of adverse event/reaction reports 
arising from clinical trials on medicinal products for human use [‘CT-3’]; US CFR Title 21, 
§312.32, Investigational New Drug [IND] safety reporting).  The Sponsor or designee will report 
all reportable events to all regulatory authorities  and Investigators as required by local 
regulations. 
All SAEs, IARs, and other reportable events (see Section 7.4.3) must be reported to the 
Sponsor or designee in an expedited manner according to timelines described in Section 7.4.1. 
Periodic Safety reporting to competent authorities will be done by the Sponsor according to 
national and local regulations. 

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7.4.1 Investigator Reporting: Notifying the Study Sponsor 
Any SAE, IAR or unanticipated problem posing risk of harm to subjects, must be reported to the 
Sponsor, or designee immediately, and no later than 24 hours of the Investigator’s first 
knowledge of the event.  To report such events, a SAE/IAR form must be completed by the 
Investigator and sent to the study Sponsor or designee within 24 hours.  The Investigator will 
keep a copy of this SAE or IAR form on file at the study site.   
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 diagnostic 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. 
Report SAEs and IARs by phone, fax or email to: 
For cases in North America 
For cases in Europe 
Phone: 
 
Fax:
Email
Fax: 
 
Email:
 
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 according to local regulations.  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 study Sponsor is required to report certain study events in an expedited fashion to the Food 
and Drug Administration (FDA), the EMA 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: 
Immediately and within 7 calendar days 
 
Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and fatal or life threatening.   
 
Follow-up information must be reported in the following 8 days. 
Immediately and within 15 calendar days 
 
Any suspected adverse reaction that is associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening 
 
Any finding from tests in laboratory animals that suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
Any event in connection with the conduct of the study or the development of the IMP 
which may affect the safety of the trial subjects. 
PPD
PPD
PPD
PPD
PPD

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 
Follow-up information must be reported within 15 calendar days 
The Sponsor will comply with all additional local safety requirements, as applicable.  Periodic safety 
reporting to competent authorities will be done by the Sponsor or designee according to national and local 
regulations. 
7.4.4 Sponsor Reporting: Notifying Participating Investigators 
It is the responsibility of the study Sponsor to immediately notify all participating Investigators, in 
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 Dose Modification and Stopping Rules  
Upon a recommendation from the independent SC (see Section 7.6.1), the Sponsor may 
suspend dosing for an individual subject or all subjects enrolled in the study, at any time, due to 
poor tolerance or potential safety risks. 
Specific rules for suspending dosing in an individual subject are provided in Appendix C.   
7.6 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 a thorough 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 10).  Medical monitoring will include a regular assessment of the number and type 
of SAEs. 
7.6.1 Independent Safety Committee 
The oversight of the subject safety in the study will be provided by an independent Safety 
Committee.  The activities and composition of the SC will be outlined in the SC Charter which 
will be ratified during the initial meeting, prior to commencement of dosing of the study subjects.  
The SC will be tasked with ongoing review of safety and efficacy data in order to advise the 
study Investigators regarding dose continuation and dose escalation decisions for the study 
(see Section 3.1 for details).  The SC will be comprised of a group of individuals with pertinent 
medical expertise that reviews, on a regular basis, the conduct of this study and the emergent 
safety data.  This SC will provide oversight and monitoring of the clinical study in compliance 
with GCP and associated guidance materials.  These safety monitoring functions and the 
oversight of such activities are distinct from the requirement for study review and approval by an 
IRB or IEC.  
The SC is an independent body of experts that serves in an advisory capacity to the Sponsor to 
ensure that clinical trial participants are not exposed to unreasonable or unnecessary risks.  
Collectively, the SC 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 last for its 
duration.  

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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. 

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8 Statistical Plan 
The Sponsor or its designee 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 reports. 
The primary analysis and all planned secondary and exploratory analyses will be performed 
after all subjects have reached 12 months of age or have died or withdrawn from the study.  All 
formal statistical conclusions will be drawn based on these analyses.   
Final analyses will also be performed after all subjects have completed treatment in the study 
(up to 5 years) or have died or withdrawn from the study.  These analyses will be considered 
supportive rather than confirmatory. 
Prior to locking the database for each of the above-mentioned analyses, 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.  
8.1 General Considerations 
All data will be presented in listings, and summary tables and/or graphs will be provided, as 
appropriate.  Unless otherwise noted, all tabulations for efficacy endpoints will be presented for 
subjects in the Primary Efficacy Analysis Set and tabulations for other endpoints will be 
presented for subjects in the Full Analysis Set (FAS).  Descriptive summary statistics (n, mean, 
median, standard deviation, minimum and maximum) will be calculated for the continuous 
variables.  Shift tables and/or frequencies and percentages will be produced for the categorical 
variables.  When percentages are reported, the number of treated subjects will be used as the 
denominator.  As noted, 95% two-sided confidence intervals (CIs) will be calculated around the 
estimates based on the exact binomial distribution for binomial endpoints and the t-distribution 
for continuous endpoints.   
Baseline will be defined as the last measurement prior to the first infusion of sebelipase alfa.  
(Note: For exploratory analyses, the first available measurement after initiation of treatment may 
be used as baseline if a pretreatment measurement is unavailable.)  Survival rates will be based 
on the age of the subject.  Other endpoints, unless otherwise noted, will be based on exposure 
(i.e., duration of time since the first infusion of sebelipase alfa).  
Details of the planned analyses and statistical methodologies will be provided in a separate 
Statistical Analysis Plan (SAP). 
8.2 Determination of Sample Size 
Approximately 8 subjects who meet the requirements for inclusion in the Primary Efficacy 
Analysis Set (i.e., subjects whose first dose is on or before the age of 8 months) will be enrolled 
in this study.  Additional subjects who meet the same entry criteria, but are between 8 and 
24 months on the date of first dose, may be enrolled and followed for safety information.  

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This sample size was selected to facilitate comparison with natural history study (LAL-1-NH01) 
in patients with early onset LAL Deficiency.  An analysis of preliminary data from study 
LAL-1-NH01 shows that, of the 18 patients who met growth failure criteria and had known date 
of death, only one patient survived past 12 months of age.  (Note: Of these 18 patients, 5 had 
received a hematopoietic stem cell transplant and one had received a liver transplant.)  An 
exact 95% CI for survival past 12 months of age in these patients is (0.14%, 27.29%).  An 
analysis of survival, beginning on the date that growth failure criteria were met, indicated no 
relationship between age at onset of growth failure and survival past onset of growth failure.  
Thus, if the lower limit of an exact 95% CI for the 12-month survival rate in the current study is 
greater than 27.29%, there would be statistical evidence that the rate of 12-month survival in the 
current study is superior to that in study LAL-1-NH01 for a similar patient population.  For the 
current study, if 8 subjects are included in the Primary Efficacy Analysis Set and 6 of these 
subjects survive to 12 months of age, the exact 95% CI for 12-month survival would be 
(34.91%, 96.81%), with the lower limit exceeding the upper limit of the CI for study LAL-1-NH01.  
8.3 Analysis Sets 
The following analysis sets will be defined:  
Full Analysis Set 
The FAS will include all subjects who received any amount of IMP. 
Primary Efficacy Analysis Set 
The Efficacy Analysis Set will include subjects in the FAS who were no older than 8 months of 
age on the date of the first infusion of sebelipase alfa. 
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 this study.   
Per Protocol Analysis Set 
The Per Protocol Set (PPS) will include subjects in the Primary Efficacy Analysis Set who, in 
addition, receive at least 4 complete infusions of sebelipase alfa.  This set will be used for 
sensitivity analyses of efficacy endpoints. 
8.4 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be listed for each subject and tabulated.  
Chronological age will be reported in months to one decimal (xx.x months).   
8.5 Subject Accountability 
Data from all subjects who are enrolled (i.e., treated) 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. 

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8.6 Study Treatment Usage and Compliance 
Number of weeks in the study and number of study infusions received by subjects will be 
summarized. The number (percent) of subjects who receive all study infusions 'per protocol' 
(i.e., subjects without missed infusions or infusion interruptions or rate changes) will be 
provided.  A listing will be provided that summarizes sebelipase alfa exposure by subject, and 
date of first dose and total number of doses (by dose level) of sebelipase alfa under study 
LAL-CL03.   
8.7 Efficacy Analysis 
Efficacy will be analyzed for the Primary Efficacy Analysis Set.  If the PPS is not identical to the 
Primary Efficacy Analysis Set (i.e., if at least one patient in the Primary Efficacy Analysis Set is 
excluded from the PPS), efficacy analyses will be repeated for the PPS. 
The primary efficacy endpoint is the proportion of subjects surviving to 12 months of age.  It is 
not anticipated that any subjects will be lost to follow-up prior to 12 months of age, but a subject 
who is not confirmed to have survived to 12 months of age will not be considered to have met 
the primary endpoint.  As a complementary analysis, Kaplan-Meier survival curves of survival 
since birth and survival since first dose of IMP will be presented.   
Survival at 18 and 24 months of age will be analyzed as described for the primary endpoint.  
Median age at death will also be calculated.  A Kaplan-Meier estimate of median survival past 
first dose of IMP will be computed. 
Estimated survival rates and median age at death derived from this study will be compared to 
rates/times reported in the literature, and will be discussed in conjunction with information 
derived from a natural history study in a similar patient population (study LAL-1-NH01). 
Anthropometric indicators of growth, standardized by age and gender in accordance with the 
methodology described by the WHO and using WHO growth charts will be listed by study time 
point as observed values and as changes from baseline.  Change from baseline in 
anthropometric data will be tabulated as continuous data.  In addition, the percentages of 
subjects who meet criteria for underweight, stunting, and wasting will be tabulated for each 
timepoint.  For anthropometric indicators of growth, age will be adjusted for prematurity if 
gestational age is <37 weeks and the subject is under 12 months of age.  The adjustment will 
be made such that corrected age = chronological age minus the number of months premature. 
Change and/or percent changes from baseline in AST, ALT, and serum ferritin will be tabulated 
for each evaluation timepoint. 
A subject will be considered to have achieved transfusion-free hemoglobin normalization 
(TFHN) if the subject meets all of the following criteria: 
1. Has two post-baseline measurements of hemoglobin at least 4 weeks apart that are both 
above the age-adjusted lower limit of normal (LLN); 
2. Has no known additional measurements of hemoglobin that are below the age-adjusted 
LLN during the (minimum) 4-week period; and 

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3. Had no transfusions during the (minimum) 4-week period, and also no transfusions for 
2 weeks prior to the first hemoglobin measurement in the (minimum) 4-week period. 
If all 3 criteria are met, the subject will be considered to have achieved TFHN on the date of the 
first hemoglobin assessment in the 4-week period. The proportion of subjects who achieve 
TFHN will be summarized and, if sufficient data are available, a summary of time to TFHN will 
be created. 
A subject who is transfusion-free beginning at Week 6 will be considered to have maintained 
transfusion-free normal hemoglobin if, regardless of baseline hemoglobin value, the subject has 
no abnormally low hemoglobin values beginning at Week 8 of the study and continuing for at 
least 13 weeks (3 months).  The proportion of subjects who have maintained transfusion-free 
normal hemoglobin will be summarized. 
The Denver II total score and functional area scores will be derived from the questionnaire in 
accordance with the Technical Manual and compared to appropriate demographic norms.  The 
total score and functional area scores will be summarized as continuous data and according to 
the classification as to whether the subject displays abnormal/normal development (Polat, 2010, 
Pediatr Int). 
Shift tables will be used to tabulate dietary changes, including discontinuation of a low-fat/low-
cholesterol diet and/or introduction of an unrestricted age-appropriate diet.  Observed values 
and changes and/or percent changes from baseline in other exploratory efficacy endpoints will 
be tabulated for each evaluation timepoint.   
8.8 Safety Analysis 
Safety will be analyzed for the FAS.   
8.8.1 Adverse Events 
All reported AEs will be listed from the start of dosing with sebelipase alfa to the end of 
participation in this study.  Separate listings of SAEs and IARs will also be provided.  The 
numbers and percentages of subjects experiencing any AE, any SAE, any IAR, any related AE, 
any related SAE, and discontinuations due to an AE will be tabulated. 
The frequency of treatment-emergent AEs, SAEs, and IARs by system organ class SOC and 
preferred term (coded using Medical Dictionary for Regulatory Activities [MedDRA®] version 14 
or higher) will be tabulated.  Frequencies will also be presented by the classifications of severity 
and causality.  In addition, frequency of AEs, SAEs, and IARs will be presented for time periods 
spanning the entire course of treatment with sebelipase alfa: from the start of dosing with 
sebelipase alfa in this study to 3 months after the first dose, >3 to 6 months, >6 to 12 months, 
>12 to 18 months, >18 to 24 months and >24 months.  As appropriate, additional listings, 
summary tables and graphics 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. 

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8.8.2 Clinical Laboratory Tests 
Observed measurements and changes from baseline to each study timepoint in clinical 
laboratory data will be summarized.  Clinically significant abnormal values will be listed.  
Frequencies of abnormal values relative to the laboratory normal range and clinically significant 
abnormal values will be tabulated for each study timepoint.  Shift tables may also be provided. 
The percentage of subjects who become ADA positive, time to ADA positivity, median and peak 
IgG antibody titer, time to peak IgG antibody titer, and percentage of subjects who tolerize will 
be summarized; IgG antibody titer values will be tabulated at each study visit using summary 
statistics appropriate to the data.  
8.8.3 Other Safety Data 
Changes in vital signs from pre-infusion values to each time point during or post-infusion will be 
summarized.  Abnormal findings/values for physical examinations, vital signs, and ECGs will 
also be listed.  
Concomitant medication/treatment data will be coded using the WHO-DRUG dictionary.  All 
data will be listed, and the percentages of subjects receiving each concomitant 
medication/treatment will be tabulated. 
8.9 Pharmacokinetics  
Pharmacokinetics will be analyzed for the PK Analysis Set.  Cmax will be recorded from direct 
observation, and CL will be derived by non-compartmental analysis.  PK parameters will be 
summarized by dose of sebelipase alfa, if applicable. 
8.10 Pharmacodynamic Analysis 
Potential disease-related biomarkers will be listed, and observed values and changes and/or 
percent changes from baseline will be summarized at available timepoints. 
8.11 Other Statistical Issues 
8.11.1 Significance Levels 
No formal hypothesis tests are planned. P-values, 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. 
8.12 Subgroup Analyses 
The impact of ADAs on safety, efficacy, PK, and PD endpoints will be explored descriptively.  As 
subject numbers permit, other subgroup analyses of interest may be performed.  These may 
include, but are not limited to age, gender, and race.  
8.13 Missing or Invalid Data 
All data will be analyzed as they were collected in the database.  

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8.14 Interim Analysis 
No interim analyses are planned.  
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 trial necessary for the reconstruction and evaluation of the trial.  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 unless 
otherwise specified in this document.  Except for data points for which the protocol indicates 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 investigational product.  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 authorities, 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. 
Each subject's parent or legal guardian for this study will be provided a consent form describing 
this study and providing sufficient information for the subject's parent or legal guardian to make 
an informed decision about their child’s 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’s 
parent or legal guardian, 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 
A clinical study report will be produced after all subjects have reached 12 months of age or have 
died or withdrawn from the study, and will include all available subject data through 12 months 
of age or the date of death or early withdrawal.  A final clinical study report will be produced 
after study completion, and will include cumulative subject data for the entire period of treatment 
in the study.  A coordinating Investigator will be designated to review and sign the completed 
clinical study reports.  
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 
Andrews L and O’Callaghan M. Enzyme Replacement Therapies. From Preclinical Safety 
Evaluation of Biopharmaceuticals: a Science-Based Approach to Facilitating Clinical Trials. 
Edited by Joy A. Cavagnaro. John Wiley and Sons. 2008. 
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 Bases of Inherited Disease (online). 8th ed. New York: McGraw Hill Inc.; 
2001:1-49. 
Abramov A, Schorr S, Wolman M. Generalized xanthomatosis with calcified adrenals. Am J Dis 
Childr. 1956;91:282-286. 
Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine 
phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999;68:333-
345. 
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. 
Cerezyme (imiglucerase for injection) prescribing information. Cambridge, MA: Genzyme 
Corporation; 2005. 
Crocker AC, Vawter GF, Neuhauser EBD, Rosowsky A. Wolman's disease: Three new patients 
with a recently described lipidosis. Pediatrics. 1965;35:627-540. 
Fabrazyme (agalsidase beta) prescribing information. Cambridge, MA: Genzyme Corporation; 
2003. 
Frankenberg, WK, Dodds, J, Archer, P, et al: The Denver II: A major revision and 
restandardization of the Denver Developmental Screening Test. Pediatrics. 1992;89:91-97. 
Gramatges MM, Dvorak CC, Regula DP, Enns GM, Weinberg K, Agarwal R. Pathological 
evidence of Wolman's disease following hematopoietic stem cell transplantation despite 
correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009;44(7):449-50. 
Hoeg JM, Demosky SJ, Pescovitz OH, Brewer J,HB. Cholesteryl ester storage disease and 
Wolman disease: Phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency. 
Am J Hum Genet. 1984;36:1190-1203. 
Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid -glucosidase: Major clinical 
benefits in infantile-onset Pompe disease. Neurology. 2007;68:99-109. 

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Krivit W, Peters C, Dusenbery K, Ben-Yoseph Y, Ramsay NKC, Wagner JE, Anderson R.  
Wolman disease successfully treated by bone marrow transplantation.  Bone Marrow 
Transplant. 2000;26:567-570. 
Krivit W, Freese D, Chan KW, Kulkarni R. Wolman's disease: a review of treatment with bone 
marrow transplantation and considerations for the future. Bone Marrow Transplant. 
1992;10(Suppl 1):97-101. 
Konno T and Fujii M. Wolman's disease: The first case in Japan. Tohoku J Exp Med. 
1966;90(4):375-389. 
Leavitt M, Burt AD, Hu W, Canty D, Gray M, Bray A, Harvey A, Day CP, Quinn AG. 
Recombinant lysosomal acid lipase normalizes liver weight, transaminases and 
histopathological abnormalities in an in vivo model of cholesteryl ester storage disease. 
J Hepatol. 2011(a);54:S358. 
Leavitt M, Hu, W, Canty D, Gray M, Bray A, Rutkowski J, Harvey A, Quinn AG.  Efficacy of 
SBC-102, a recombinant enzyme replacement therapy, across a broad range of doses in an in 
vivo model of lysosomal acid lipase deficiency. J Ped Gastroenterol Nutr. 2011b;59: E20. 
Lumizyme (alglucosidase alfa) prescribing information. Cambridge, MA: Genzyme Corporation; 
2010. 
Marshall WC, Ockenden BG, Fosbrooke AS, Cumings JN. Wolman's disease. A rare lipidosis 
with adrenal calcification. Arch Dis Child. 1969;44(235):331-341. 
Mayatepek E, Seedorf U, Wiebusch H, Lenhartz H, Assmann G. Fatal genetic defect causing 
Wolman disease (short report). J Inherited Metab Dis. 1999;22:93-94. 
Meyers WF, Hoeg JM, Demosky SJ, Herbst JJ, Brewer HB. The use of parenteral 
hyperalimentation and elemental formula feeding in the treatment of Wolman disease. Nutr Res. 
1985;5:423-429. 
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). MolGenet 
Metab. 2007;90:329-337. 
Myozyme (alglucosidase alfa) prescribing information. Cambridge, MA: Genzyme Corporation; 
2010. 
Polat S, Okuvaz C, Hallioglu O, Mert E, Makharoblidze K. Evaluation of growth and 
neurodevelopment in children with congenital heart disease. Pediatr Int. August 12, 2010 
(online). doi: 10.1111/j.1442-200X.2010.03230.x. 
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. 
Surve TY, Muranjan MN, Barucha BA. Wolman disease: diagnosis by leucocyte acid lipase 
estimation. Indian J Pediatr. 2005;72:353-354. 

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Tolar J, Petryk A, Khan K, Bjoraker KJ, Jessurun J, Dolan M, et al. Long-term metabolic, 
endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman 
disease. Bone Marrow Transplant. 2009;43:21-7. 
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. 
WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass 
index-for-age: Methods and development. Geneva: World Health Organization, 2006 (312 
pages). 
WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Head 
circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and subscapular 
skinfold-for-age: Methods and development. Geneva: World Health Organization, 2007 (217 
pages). 
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. 
Wolman M. Wolman disease and its treatment. Clin Pediatr. 1995;34:207-212. 
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. 
 
Yanir A, Allatif MA, Weintraub M, Stepensky P. Unfavorable outcome of hematopoietic stem cell 
transplantation in two siblings with Wolman disease due to graft failure and hepatic 
complications. Mol Gen Metab. 2013;109:224-6. 

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14 Appendices 
 
 
 
 
 
 
 
 
 

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Appendix A: Schedule of Assessments Table 1 -- Screening through Week 24 
* All visits will be calculated from Week 0; consecutive infusions must be administered at least 5 days apart. 
P Pre-dose 
1  Abdominal MRI should be considered in subjects receiving general anesthesia and/or sedation for other procedures.  The MRI should be scheduled at least 3 months after the 
preceding MRI assessment. If an MRI cannot be performed, an Ultrasound will be performed. 
  
Screening 
Screening to Week 24,* 
Assessments 
Day -21 to 
Day -1 
Week 
0 
Week 
 1, 6, 
10, 14 
Week 
2 
Week 
3 
Week 4 
Week  
5, 7, 11, 13 
Week  
8, 16  
Week  
9, 15 
Week 
12 
Week  
17, 18, 
19,  
21, 23 
Week 
20 
Week 
22 
Week 
24 
  
± 2 
days 
± 2 
days 
± 2 
days 
± 2 days 
± 2 days 
± 2 
days 
± 2 days 
± 2 
days 
± 2 days 
± 2 
days 
± 2 
days 
± 2 
days 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion  
X 
XP 
  
  
  
  
  
  
  
  
  
  
  
  
Medical/Family History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
  
  
  
XP 
  
  
  
XP 
  
  
XP  
  
XP 
Photographs 
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
X 
Anthropometrics 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
XP 
XP 
XP  
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
 Recumbent length or height, and 
abdominal circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Head and mid-upper arm 
circumference 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
If clinically indicated 
If clinically indicated 
Denver II 
X 
  
  
  
  
  
  
  
  
  
  
  
  
XP 
Abdominal Ultrasound 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
Abdominal MRI 
X 
  
  
  
  
  
  
  
 X1 
  
  
  
X1 
Liver Biopsy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical LabTests 
X 
XP 
XP 
XP 
XP 
XP 
  
XP 
  
XP 
  
XP 
  
XP 
Exploratory Biomarkers  
X 
  
  
XP 
  
  
  
XP 
  
XP 
  
  
  
XP 
DNA Sample (subject)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
DNA Sample (parents) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
PK Sample 
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
PBMC LAL Activity  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
DBS LAL Activity  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Sebelipase alfa Dosing 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug Antibody  
XP 
  
XP 
  
  
  
XP 
  
XP 
  
XP 
  
XP 
Adverse Events2 
CONTINUOUS 
Concomitant Therapies 
CONTINUOUS 

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2  For the subjects who are stable enough to be treated on an outpatient basis, safety follow-up assessments for AEs will be conducted by telephone 24 hours following the first 
2 infusions of 0.35 mg·kg-1 qw, 1 mg·kg-1 qw, and, if applicable, 3 mg·kg-1 qw and 5 mg·kg-1 qw.  

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Appendix A: Schedule of Assessments Table 2 -- Week 25 through 156 (Year 3)* 
 
  
 Week 25-Week 156 
Assessments 
Every 
week 
Week 
32 
Week 
36 
Week 
40 
Week 
48 
Week 
60 
Week 
72 
Week 
84 
Week 
96 
Week 
108 
Week 
120 
Week 
132 
Week 
144 
Week 
156 
 
  
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
Physical Exam 
 
 
XP 
 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Photographs 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Anthropometrics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Recumbent length or height, and         
abdominal circumference 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Head and mid-upper arm circumference 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
If clinically indicated 
Denver II 1 
 
 
 
 
 
 
XP 
 
 
 
XP 
 
 
 
Abdominal Ultrasound 1 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Abdominal MRI 1,2 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Liver Biopsy 
  
  
  
  
Optional after at least 1 year of treatment 
Clinical LabTests 3 
 
XP 
 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Exploratory Biomarkers 3 
 
 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
PK Sample 3 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Sebelipase alfa Dosing 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-drug Antibody 3 
 
 
XP 
 
XP  
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Adverse Events 5 
CONTINUOUS 
Concomitant Therapies 
CONTINUOUS 
* All visits will be calculated from Week 0; consecutive infusions must be administered at least 5 days apart. 
P Pre-dose 
1 Assessments can be performed (±15) days of scheduled visit. 
2  Abdominal MRI should be considered in subjects receiving general anesthesia and/or sedation for other procedures.  The MRI should be scheduled at least 3 months after the preceding 
MRI assessment. If an MRI cannot be performed, an ultrasound will be performed. 
3  If blood volume is limited, refer to Section 5.1.11 for tiered assessments. 
4 Subjects may transition to an every other week dosing schedule after 96 weeks if on a stable dose for at least 24 weeks. 

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5  For the subjects who are stable enough to be treated on an outpatient basis, safety follow-up assessments for AEs will be conducted by telephone 24 hours following the first 2 infusions of 
0.35 mg·kg-1 qw, 1 mg·kg-1 qw, and, if applicable, 3 mg·kg-1 qw and 5 mg·kg-1 qw.  
Appendix A: Schedule of Assessments Table 3 -- Week 157 through 260 (Year 5)* 
  
Week 157- Week 260 
Assessments 
Every week 
Week 
168 
Week 
180 
Week 
192 
Week 
204 
Week 
216 
Week 
228 
Week 
240 
Week 
252 
Follow-up/ Early Withdrawal 1 
  
± 2 
days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 7 days  
Physical Exam 
 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
X 
Photographs 
 
X 
 
 
 
X 
 
 
 
 
  
Anthropometrics 
 
 
 
 
 
 
 
 
 
 
Weight 
XP 
 
 
 
 
 
 
 
 
X 
 Recumbent length or height, and abdominal 
circumference 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
 
 
 
 
 
  
12-lead ECG 
  
If clinically indicated 
  
Denver II 2 
  
X 
  
  
  
X 
  
  
  
  
X 
Abdominal Ultrasound 2 
  
X 
  
  
  
X 
  
  
  
  
  
Abdominal MRI 2,3 
  
X 
  
  
  
X 
  
  
  
  
  
Liver Biopsy 
  
Optional after at least 1 year of treatment 
  
Clinical LabTests 4 
 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
X 
Exploratory Biomarkers 4 
 
XP 
 
XP 
 
XP 
 
XP 
 
X 
Sebelipase alfa Dosing 5 
X 
 
 
 
 
 
 
 
 
  
Anti-drug Antibody 4 
 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
X 
Adverse Events 6 
CONTINUOUS 
  
Concomitant Therapies 
CONTINUOUS 
  
* All visits will be calculated from Week 0; consecutive infusions must be administered at least 5 days apart. 
P Pre-dose 
1  The follow-up / early withdrawal visit will be conducted 30 (+7) days after the last dose of IMP. 
2 Assessments can be performed (±15) days of scheduled visit. 
3  Abdominal MRI should be considered in subjects receiving general anesthesia and/or sedation for other procedures.  The MRI should be scheduled at least 3 months after the 
preceding MRI assessment. If an MRI cannot be performed, an Ultrasound will be performed. 
4  If blood volume is limited, refer to Section 5.1.11 for tiered assessments. 
5 Subjects may transition to an every other week dosing schedule after 96 weeks if on a stable dose for at least 24 weeks. 

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6  For the subjects who are stable enough to be treated on an outpatient basis, safety follow-up assessments for AEs will be conducted by telephone 24 hours following the first 
2 infusions of 0.35 mg·kg-1 qw, 1 mg·kg-1 qw, and, if applicable, 3 mg·kg-1 qw and 5 mg·kg-1 qw.  

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Appendix B: Diagnosis and Recommendations for Management of Infusion Associated 
Reactions 
Symptoms may include but are not 
limited to: 
Actions in accordance with institutional 
standard of care   
Mild  
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 anti-
histamine 
 Decrease infusion rate by a further 25% if 
symptoms persist 
 Increase infusion time  
 If the event resolves, the infusion should 
continue at reduced rate for a minimum of 
30 minutes before infusion is increased to 
75% of original rate.  If subject tolerates 
infusion at 75% of the original rate for at 
least 30 minutes the original rate may be 
restored for the remainder of the infusion. 
 If symptoms continue despite rate reduction 
stop infusion 
 Pre-treat with oral antihistamine and 
antipyretic prior (approximately 1.5h) to 
next infusion 
o e.g., diphenhydramine (1 mg/kg po) and 
acetaminophen (15 mg/kg po) 
Moderate Reaction 
 Hyperemia (flushing) 
 Chest discomfort 
 Itching and/or raised urticarial rash 
 Severe headache 
 Gastro intestinal symptoms, vomiting, 
diarrhoea, abdominal cramping. 
 
 
Stop infusion 
 
Give antihistamine IV and consider IV 
steroids  
 
Give any prescribed inhaler treatment 
if appropriate 
 
If the event has resolves, the infusion 
may continue at reduced rate of 50% 
of the original for a minimum of 30 
minutes before infusion is increased to 
75% of original rate.  If patient 
tolerates infusion at 75% of the original 
rate for at least 30 minutes the original 
rate may be restored for the remainder 
of the infusion.  
 
Pre-treat with oral antihistamine and 
antipyretic prior to next infusion 
 
Collect serum sample for tryptase 1-3 
hours after the IAR onset and another 
serum sample for tryptase and ADA 
during the next study visit (> 4 days 
after the IAR) prior to the infusion.  
 
Skin testing may be considered. 

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Severe  Reaction 
 
 
Clinically significant cardiovascular 
effects: e.g., hypertension or hypotension 
defined as a decline approaching 20-30% 
of their preinfusion value without 
alternative etiology, agitation, pain, fluid 
overload, dehydration 
 
Respiratory symptoms: Significant 
shortness of breath, stridor, wheezing, 
laryngeal oedema, swelling of tongue. 
 
Cardiac Arrhythmias 
 
Anaphylactic/Anaphylactoid shock with 
hypotension and circulatory collapse. 
 
Stop Infusion 
 
Give oxygen, if available 
 
Give epinephrine (adrenaline) IM or 
inhaled 
 
Give antihistamines IV and steroids IV  
 
Collect serum sample for tryptase 1-3 
hours after the IAR onset and another 
serum sample for tryptase and ADA during 
the next study visit (> 4 days after the IAR) 
prior to the infusion.  
 
Skin testing may be considered 
 
Dosing of the subject will be suspended 
until the Safety Committee has completed 
the review of the IAR and any other 
relevant safety data (Section 6.5) 
 
 
 

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Appendix C: Dose Modification and Stopping Rules for LAL-CL03 Study 
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 stopping rules apply to the decision to pause dosing in individual subjects: 
 
For IARs (refer to the definition in Section 6.5), the following stopping rules will apply:  
 
Subjects who develop a Grade 3 (severe) or higher IAR must stop treatment until their information 
is reviewed by the SC. Dosing with alterations to the 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.