Conditions: Mucopolysaccharidosis IIIB
Keywords: MPS IIIB Mucopolysaccharidosis Mucopolysaccharidosis type IIIB Sanfilippo Syndrome Metabolism, Inborn Errors Metabolic Diseases Genetic Diseases, Inborn Carbohydrate Metabolism, Inborn Errors Connective Tissue Diseases Lysosomal Storage Diseases Mucinoses Mucopolysaccharidoses Pathologic Processes
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
Study to evaluate the safety and tolerability of intravenous (IV) administration of SBC-103 in participants with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) with evaluable signs or symptoms of developmental delay.

Detailed description:
This study was designed as a 3-part study to evaluate the safety and tolerability of IV administration of SBC-103. Participants enrolled in Part A (0.3, 1.0, or 3.0 milligrams \[mg\] per kilogram \[kg\] of SBC-103 administered every other week \[QOW\] for 24 consecutive weeks). Participants who completed Part A were eligible for Part B (an increase to 1.0 or 3.0 mg/kg QOW). Participants who completed Part B were eligible for Part C (5.0 and/or 10.0 mg/kg to continue through Week156; no participants received both 5.0 and 10.0 mg/kg). Due to the early termination of the SBC-103 development program, including this study, all participants withdrew from Part C at the sponsor's decision. As a result of the early termination of this program, this report provides only safety data.

Arms:
arm 1: Part A (Initial therapy): Participants received SBC-103, 0.3, 1.0, or 3.0 mg/kg QOW for 24 weeks, followed by a ≥ 4-week treatment break. Participants enrolled in the lowest dosage first.

Part B: Participants were escalated to the next highest dose that was considered safe (1.0 or 3.0 mg/kg QOW) for ≥ 8 weeks. Participants who received doses of 0.3 mg/kg in Part A were considered for a second dose escalation to 3.0 mg/kg at any time during Part B provided that they tolerated at least 2 doses of 1.0 mg/kg in Part B. Participants who received and tolerated at least 4 doses of SBC-103 QOW at 3.0 mg/kg were considered for participation in Part C.

Part C: Participants received SBC-103 5.0 or 10.0 mg/kg administered IV QOW. Dosing in Part C began at the 5.0 mg/kg dose level. The decision to begin dosing the first participant at 10.0 mg/kg was based on the review of safety data at 5.0 mg/kg.

Interventions: intervention 1: SBC-103
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
A Phase I/II Open Label Study in MPS IIIB Subjects to 
Investigate the Safety, Pharmacokinetics, and 
Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously 
 
 
Unique Protocol ID:  
 
NGLU-CL02 
NCT Number:  
 
 
NCT02324049 
EudraCT Number:  
 
2013-003400-39 
Date of Protocol:   
 
21 January 2016 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
A PHASE I/II OPEN LABEL STUDY IN MPS IIIB SUBJECTS TO 
INVESTIGATE THE SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS/EFFICACY OF SBC-103 ADMINISTERED 
INTRAVENOUSLY 
 
Protocol Number: 
NGLU-CL02 
 
Amendment Number: 
 
7 
 
Date of Protocol: 
21 January 2016 
 
EudraCT Number: 
2013-003400-39 
 
IND Number: 
IND 118402 
Product: 
SBC-103 
 
Sponsor: 
Alexion Pharmaceuticals, Inc. 
352 Knotter Drive 
Cheshire, CT 06410 
UNITED STATES 
 
 
 
 
 
 
This study will be conducted according to the protocol and in compliance with  
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki,  
and other applicable regulatory requirements. 
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NGLU-CL02 Protocol Amendment 7 
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Protocol Title: 
Protocol Number: 
Amendment Number: 
Date of Protocol: 
APPROVAL SIGNATURE PAGE 
A PHASE I/II OPEN LABEL STUDY IN MPS IIIB SUBJECTS 
TO INVESTIGATE THE SAFETY, PHARMACOKINETICS, 
AND PHARMACODYNAMICS/EFFICACY OF SBC-103 
ADMINISTERED INTRAVENOUSLY 
NGLU-CL02 
7 
21 January2016 
REVIEWED/APPROVED BY: 
2 :2 :Jc\V\ 2_0 I G 
Alexion Pharmaceuticals, Inc. 
Signature 
Date 
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PPD
PPD


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
INVESTIGATOR STATEMENT 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol. 
I understand that I may terminate or suspend enrollment in the study at any time if it becomes 
necessary to protect the best interests of the study subjects. This study may be terminated at any 
time by the Sponsor, with or without cause. 
I agree to personally conduct and supervise this investigation at my institution 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 Board/Independent Ethics 
Committee (IRB/IEC) review and approval are met. I will provide the Sponsor with any material 
that 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 and Sponsor approval, except where 
necessary to ensure the safety of study subjects. 
 
 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
Investigational site or name of institution  
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CLINICAL STUDY SYNOPSIS 
Protocol Title 
A Phase I/II Open Label Study in MPS IIIB Subjects to Investigate the Safety, 
Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously 
Protocol Number 
NGLU-CL02 
EudraCT Number 
2013-003400-39 
IND Number 
IND 118402 
Objectives 
Primary Objective 
• 
To evaluate the safety and tolerability of intravenous (IV) administration 
of SBC-103 in subjects with mucopolysaccharidosis III, type B 
(MPS IIIB, Sanfilippo B) with evaluable signs or symptoms of 
developmental delay. 
Secondary Objectives 
• 
To characterize the pharmacokinetic (PK) profile of SBC-103 
administered IV. 
• 
To determine the effects of SBC-103 administered IV on the levels, 
onset and magnitude of changes total heparan sulfate (HS) in 
cerebrospinal fluid (CSF), serum, and urine. 
• 
To evaluate the pharmacodynamics (PD)/efficacy of SBC-103 
administered IV as measured by neurocognitive and developmental 
function and change in brain structures. 
• 
To evaluate the impact of temporary interruption of SBC-103 therapy 
(between Parts A and B) on safety, tolerability, and select PD/efficacy 
markers, including the reversibility of changes in levels of total HS in 
CSF, serum, and urine.  
Exploratory Objectives 
• 
To examine the onset, magnitude, and reversibility of changes in 
exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB 
disease characteristics, symptoms, and quality of life (QOL) after IV 
administration of SBC-103.  
Methodology 
This study is designed to evaluate the safety and tolerability of IV 
administration of recombinant human alpha-N-acetylglucosaminidase 
(rhNAGLU), referred to here as SBC-103, for the treatment of MPS IIIB. This 
study will be conducted in 3 parts: Part A (Initial Therapy), Part B (Therapy at 
1 and/or 3 mg/kg), and Part C (Therapy at 5 and/or 10 mg/kg). All subjects who 
participate in Part A may continue SBC-103 dosing in Part B if they qualify for 
continued dosing, and all subjects who participate in Part B are eligible for dose 
escalation in Part C providing that they qualify for dose escalation. 
Part A (Initial Therapy) 
In Part A, following completion of screening assessments to confirm study 
eligibility, approximately 9 subjects will be treated in 1 of 3 different dosing 
cohorts (0.3, 1, or 3 mg/kg). In the event that more than 3 subjects in a cohort 
have entered Screening and are determined to be eligible to participate in the 
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study, an additional subject may be dosed with SBC-103 within the intended 
dose cohort. This will be acceptable provided the following conditions are met: 
1) the Safety Review Committee (SRC) has met and approved the continued 
dosing of the 1st subject in the cohort and the first dose of the 2nd subject and 
2) the Sponsor has reviewed safety information of the 2nd subject in the cohort 
and has approved the 3rd subject to be dosed.  
Each subject in each cohort will be dosed sequentially with SBC-103 
administered by IV infusion once every other week (QOW) for 24 consecutive 
weeks. 
Safety, PK, and PD/efficacy assessments will be performed in all subjects.  All 
subjects will be monitored in an in-patient setting for safety and tolerability for 
at least 24 hours following the first dose of SBC-103 in Part A. 
To evaluate safety, follow-up phone calls will be made to each subject (or the 
subject’s parent or caregiver) within 24 hours after the subject’s second, third, 
and fourth doses in Part A.  
After receiving SBC-103 QOW for 24 consecutive weeks, subjects will have a 
4-week temporary interruption of therapy prior to being considered for 
participation in Part B.   
If a subject will not participate in Part B of the study, an additional follow-up 
phone call will be made 4 weeks after the subject’s last administered dose in 
Part A unless the subject has a scheduled follow-up visit. 
Criteria for Dosing and Dose Escalation in Part A: 
The decision to continue dosing in the 1st subject in the 1st, 2nd, and 3rd cohorts 
will be made by the Sponsor based on SRC recommendations after review of 
24-hour safety data from that subject and available safety data from all other 
subjects. 
The decision to initiate dosing in the 2nd subject of each cohort will be made 
by the Sponsor based on SRC recommendations after review of 24-hour safety 
data from Subject 1 in the same cohort and available safety data from all other 
subjects. 
The decision to initiate dosing in the 3rd subject of each cohort will be made 
by the Sponsor based on 24-hour safety data from Subject 2 in the same cohort 
and available safety data from all other subjects. 
The decision to escalate into the next dose cohort will be made by the 
Sponsor based on SRC recommendations after review of safety data from the 
1st subject who completes the first 4 doses in the dose cohort, 24-hour safety 
data after the first dose from the 3rd subject of the same cohort, and available 
safety data from all other subjects. 
Part B (Therapy at 1 and/or 3 mg/kg): 
Subjects who meet qualifying criteria may commence Part B (Therapy at 
1 and/or 3 mg/kg) after completing Part A, after the SRC and Sponsor have 
evaluated an individual subject’s available safety data, and deemed it acceptable 
for that subject to initiate continued therapy in Part B. Only subjects who meet 
eligibility criteria for Part B will re-initiate SBC-103 dosing in Part B. Eligible 
subjects may re-initiate SBC-103 dosing in Part B no sooner than 4 weeks after 
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the subject’s last dose in Part A. 
In Part B, dose or dosing frequency (eg, QOW or weekly) modifications may be 
considered by the Sponsor after consultation with the SRC, based a review of 
safety, tolerability, and treatment response data.   
With the intent of treating patients with the lowest dose that is safe and 
tolerable and which has potential for efficacy, dose modification (either an 
increase to 1 or 3 mg/kg or a decrease to 0.3 or 1 mg/kg) may be proposed for 
individual subject(s) after the evaluation of safety and tolerability data as well 
as biomarker and treatment response data after 24 weeks of treatment 
(13 doses).  Dose modifications will not be considered until Part B of the study, 
except for instances where a dose reduction is required for reasons of safety and 
tolerability.  Subjects who receive doses of 0.3 mg/kg in Part A may be 
considered for a second dose escalation to 3 mg/kg at any time during Part B 
provided that they have tolerated at least 2 doses of 1 mg/kg in Part B.  
Safety, PK, and PD/efficacy assessments will be conducted at regular intervals 
throughout Part B. 
Subjects who have received and tolerated at least 4 doses of SBC-103 QOW at 
3 mg/kg may be considered for participation in Part C.   
Part C (Therapy at 5 and/or 10 mg/kg): 
Subjects who meet the eligibility criteria for Part C may begin dosing in Part C 
at their next scheduled visit once the necessary regulatory and ethics committee 
review and approval (where required) are obtained and provided that the criteria 
for dosing (see below) are met. 
Part C is a randomized, open-label assessment of SBC-103 at doses of 5 or 
10 mg/kg administered IV.  Subjects will be randomized such that at least 
1 subject from each cohort assigned in Part A will receive SBC-103 at 5 mg/kg 
and at least 1 subject from each cohort assigned in Part A will receive SBC-103 
at 10 mg/kg.  Thus each of the assigned dose levels from Part A will be 
represented in each of the 2 dose levels being studied in Part C. Treatment in 
Part C will continue through Week 156 of the study. 
Criteria for Dosing and Dose Escalation in Part C: 
Dosing in Part C will begin at the 5 mg/kg dose level.  The decision to continue 
dosing in the 1st subject at 5 mg/kg and to initiate dosing in the remaining 
4 subjects at 5 mg/kg will be made by the Sponsor based on SRC 
recommendations after review of 24-hour safety data from that subject. 
The decision to escalate to the 10 mg/kg dose will be made by the Sponsor 
based on SRC recommendations after review of safety data from 1 subject who 
completes the first 2 doses at 5 mg/kg, and review of available safety data from 
any other subjects who have received 5 mg/kg. 
The decision to continue dosing in the 1st subject at 10 mg/kg and to initiate 
dosing in the remaining 5 subjects at 10 mg/kg will be made by the Sponsor 
based on SRC recommendations after review of 24-hour safety data from that 
subject. 
At least 4 weeks after a subject’s last dose of SBC-103 is administered in this 
protocol, the subject (or the subject’s parent or caregiver) will receive a 
follow-up phone call to assess adverse events (AEs) and concomitant 
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medications unless the subject has a scheduled follow-up study visit.  
At any time during this study, the SRC or Sponsor may request a pause in 
dosing in individual, multiple or all subjects based on review of reported events 
and available data.  Dosing will resume only after the review of data and 
agreement to do so by the SRC and Sponsor. 
Study Duration 
The total duration of the study is approximately 164 weeks.  This will include a 
Screening period that will last up to 4 weeks, an initial study treatment period 
that includes 24 weeks on therapy and a 4 week period of time off therapy 
(Part A), an extended treatment period that will last up to 128 weeks (Parts B 
and C), and a 4-week follow-up period after the last dose is administered. 
Study Centers 
Approximately 4 centers are expected to participate in this study. 
Number of Subjects 
Planned 
Approximately 9 subjects are expected to participate in this study.   
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
A subject who meets all of the following inclusion criteria will be eligible to 
participate in this study: 
1. Has a definitive diagnosis of MPS IIIB, as determined by either of the 
following: 
a. Documented deficiency in alpha-N-acetylglucosaminidase 
(NAGLU) enzyme activity ≤10% of the mean value in normal 
individuals (Heron, 2011, Am J Met Genet A) based on test results 
from a central laboratory at Screening. 
OR 
b. Documented functionally-relevant mutations in both alleles of the 
NAGLU gene based on historical test results from a local laboratory 
(if available) or results from the central laboratory at Screening.   
2. Greater than or equal to 2 years old but less than 12 years old at the time 
of written informed consent, and has an age equivalent of ≥1 year on the 
Vineland Adaptive Behavior Scales, Second Edition (Vineland-II). 
3. Has documented developmental delay with onset before 6 years of age, 
as defined by: 
a. Cognitive delay evaluated by Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) or Kaufman Assessment 
Battery for Children, Second Edition (KABC-II). 
OR 
b. Language delay, plateauing or regression of language skills as 
determined by the Investigator and confirmed by the Vineland-II 
(communication domain) administered at Screening (eg, subject uses 
isolated words, associated words such as two-word combination, 
sentences, poor or reduced language and/or language difficult to 
understand). 
4. Subject or subject’s parent or legal guardian (if applicable) consents to 
participate in the study and provides informed consent prior to any study 
procedures being performed.  If the subject is of minor age; he/she is 
willing to provide assent where required per local regulations, and if 
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deemed able to do so. 
5. Female subjects who are of childbearing potential at the time of consent 
or who become of childbearing potential during participation on study 
(a) must have a negative urine pregnancy test at Screening, (b) cannot be 
breast feeding, and (c) must consent to use a highly reliable method of 
birth control (expected failure rate less than 5% per year) for the duration 
of the study and for 30 days after the last dose of SBC-103. Women may 
be considered of non-childbearing potential if they have not started their 
menses or are surgically sterile (ie, total hysterectomy or bilateral 
salpingo-oophorectomy). 
6. Male subjects must consent to use a highly reliable method of birth 
control (expected failure rate less than 5% per year) during any sexual 
contact with females of childbearing potential while participating in the 
study and for 30 days following discontinuation from this study, even if 
he has undergone a successful vasectomy.   
7. Willingness and ability to comply with protocol requirements to the 
extent that may be expected of a subject with cognitive impairment. 
Exclusion Criteria: 
A subject who meets any of the following exclusion criteria will be ineligible to 
participate in this study: 
1. Received treatment with gene therapy at any time, or any investigational 
drug (including high dose genistein > 150 mg/kg/day) or device intended 
as a treatment for MPS IIIB within 30 days prior to Screening, or is 
currently being treated in another study that involves  an investigational 
drug or device.   
2. Has any internal or non-removable external metal items that may present 
a safety risk for study assessments that utilize magnetic fields, or any 
other medical condition or circumstance in which magnetic resonance 
imaging (MRI) is contraindicated according to local institutional policy.   
3. Previous hematopoietic stem cell or bone marrow transplant. 
4. Known or suspected hypersensitivity to anesthesia or the use of a 
sedative is contraindicated for any other reason. 
5. History of poorly controlled seizure disorder. 
6. A bleeding disorder, or any other medical condition or circumstance in 
which a lumbar puncture (for collection of CSF) is contraindicated 
according to local institutional policy. 
7. Known hypersensitivity to eggs.  Subjects at high risk for food allergy 
that may include eggs should be tested according to local guidelines.   
8. Other medical conditions or co-morbidities (eg, alanine aminotransferase 
[ALT] or aspartate aminotransferase [AST] > 3x the upper limit of 
normal [ULN], confirmed by repeat testing, analyzed centrally or locally 
and based on the standardized reference range provided in the central 
laboratory manual), or other markers of clinically significant liver 
dysfunction (eg, elevated bilirubin, [with the exception of patients with 
confirmed Gilberts Disease] confirmed by repeat testing, or elevated 
prothrombin time [PT]/International normalized ratio [INR] confirmed 
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by repeat testing analyzed centrally or locally and based on the 
standardized reference range provided in the central laboratory manual) 
which in the opinion of the Investigator, in consultation with the 
Sponsor, would interfere with study compliance, or confound data 
interpretation. 
Qualifications for Part B (Therapy at 1 and/or 3 mg/kg):   
Subjects are eligible for continued SBC-103 dosing at 1 and/or 3 mg/kg QOW 
in Part B if they do not meet any Exclusion criteria listed above and if they 
meet the following: 
1. Completion of Part A with no unmanageable study drug toxicity;  
2. Continue to meet Inclusion Criteria items 4-7 above; and 
3. SRC and Sponsor have reviewed the subject’s safety data from Part A 
and have deemed it acceptable for the subject to re-initiate dosing in 
Part B. 
Qualifications for Part C (Therapy at 5 and/or 10 mg/kg): 
Subjects are eligible for continued SBC-103 dosing at a higher dose (5 or 
10 mg/kg QOW) in Part C if they do not meet any Exclusion criteria listed 
above and if they: 
1. Have completed at least 4 doses of 3 mg/kg in either Part A or Part B 
with no unmanageable study drug toxicity; and 
2. Continue to meet Inclusion Criteria items 4-7 above 
Investigational 
Product, Dose, Route, 
Regimen 
SBC-103 is rhNAGLU manufactured using transgenic Gallus, which produce 
rhNAGLU in egg white.  
All dose administration is open label. 
Part A (Initial Therapy) Dosing Schedule 
In Part A, 3 dose levels of SBC-103 (0.3, 1, and 3 mg/kg) administered by IV 
infusion QOW for 24 consecutive weeks (13 doses) as follows.  Infusions must 
be administered at least 10 days apart. 
Dose 
Cohort # 
Dose of 
SBC-103* 
Dosing Regimen 
Sample size**  
1 
0.3 mg/kg 
QOW for 24 weeks 
n=3 
2 
1 mg/kg 
QOW for 24 weeks 
n=3 
3 
3 mg/kg 
QOW for 24 weeks 
n=3 
*Intra-patient dose escalation is not planned during Part A.  
**Enrollment of an additional subject in a cohort may occur as described in the Methodology 
section. 
 
Part B (Therapy at 1 and/or 3 mg/kg) Dosing Schedule 
Only subjects who meet eligibility criteria for Part B will re-initiate SBC-103 
dosing in Part B.  Eligible subjects may re-initiate SBC-103 dosing in Part B no 
sooner than 4 weeks after the subject’s last dose in Part A. 
In Part B, dose or dosing frequency (eg, QOW or QW) modifications may be 
considered by the Sponsor after consultation with the SRC. 
Subjects who received doses of either 0.3 mg/kg or 1 mg/kg during Part A may 
escalate to the next higher dose of SBC-103 considered to be safe by the 
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Sponsor and SRC with their first dose in Part B or at any time thereafter.  
Subjects who received doses of 0.3 in Part A may be considered for a second 
dose escalation to 3 mg/kg at any time during Part B provided that they have 
tolerated at least 2 doses of 1 mg/kg in Part B. 
Part C (Therapy at 5 and/or 10 mg/kg) Dosing Schedule 
Only subjects who meet eligibility criteria for Part C will continue SBC-103 
therapy in Part C.  Subjects will initiate SBC-103 therapy in Part C at either 5 or 
10 mg/kg based upon a randomized assignment.  SBC-103 will be administered 
IV QOW (infusions must be administered at least 10 days apart) until Study 
Week 156.  Intra-subject dose escalation from 5 to 10 mg/kg based on all 
available safety, PK, and PD/efficacy data may not occur without prior written 
approval from the Sponsor.  Dose reductions may be considered for safety and 
tolerability at any time in Part C. 
Reference Therapy 
There is no standard reference therapy against which the investigational product 
is being compared. 
Criteria for 
Evaluation –  
Primary Endpoint  
Primary Endpoint 
The primary endpoint of this study is safety and tolerability of SBC-103 in 
subjects with MPS IIIB.  The safety assessments will include the following: 
• 
Incidence of AEs, serious adverse events (SAEs), and 
infusion-associated reactions (IAR)s; 
• 
Changes from baseline in clinical laboratory tests (hematology, serum 
chemistry, and urinalysis) and CSF findings (cell counts, glucose, and 
protein); 
• 
Changes from baseline in 12-lead electrocardiograms (ECGs) ; 
• 
Changes in vital signs during and post-infusion, relative to pre-infusion 
values; 
• 
Physical examination findings; 
• 
Use of concomitant medications/therapies; 
• 
Assessment of anti-drug antibodies (ADAs), including seroconversion 
rate, time to seroconversion, and ADA titer by time point, peak ADA 
titer, and ADA titer status (positive/negative), and the effect of ADAs on 
the safety of SBC-103, including the relationship between ADA-positive 
subjects and the incidence of IARs. 
Criteria for 
Evaluation –  
Secondary and 
Exploratory 
Endpoints  
Secondary Endpoints 
The secondary endpoints of this study are baseline and post-treatment measures 
of the following assessments: 
• PK profile of SBC-103 after single and multiple doses: 
o Maximum observed serum concentration (Cmax) 
o Time to reach Cmax (Tmax) 
o Area under the concentration-time-curve from time 0 to the last 
measurable time point (AUClast) 
o Area under the concentration-time-curve extrapolated to infinity 
(AUC∞) 
o Half-life (T1/2) 
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o Clearance (CL) 
o Volume of distribution at terminal phase (Vz) 
o Accumulation ratio (Rac) 
• 
Effects of SBC-103 treatment on the onset, magnitude, and reversibility 
of changes in levels of total HS in CSF, serum, and urine.  
• 
Neurocognitive and developmental function as determined by the scores 
on the Vineland-II and, as appropriate to the subject’s age, the BSID-III 
or KABC-II, Bruininks-Oseretsky Test of Motor Proficiency, Second 
Edition, Brief Form (BOT-2 Brief Form), and Children’s 
Communication Checklist, Second Edition (CCC-2). 
• 
Brain structure as determined by the relative proportion of grey and 
white matter volume and indices of microstructural integrity as assessed 
by MRI of the brain. 
• 
Effect of temporary interruption of SBC-103 therapy (between Parts A 
and B) on safety, tolerability, and select PD/efficacy markers. 
Exploratory Endpoints 
Exploratory endpoints in this study include measures to examine the onset, 
magnitude, and reversibility of changes in exploratory biomarkers, SBC-103 
concentration in CSF, MPS IIIB disease characteristics, symptoms, and QOL 
after IV administration of SBC-103:  
• 
Biomarkers: 
o Change in non-reducing end (NRE) HS derivatives in CSF, serum, 
and urine 
o Changes in serum ferritin and chitotriosidase 
o Changes in CSF-disease related biomarkers including but not limited 
to, hepatocyte growth factor (HGF), calbindin D, Tau, pTau, 
amyloid β, albumin, Immunoglobulin G (IgG), glutamic acid, and 
glycine 
o Changes in glutamic acid and glycine in relation to plasma 
(carrier-mediated excitatory amino acids that are markers of 
transport function) 
o Changes in CSF/serum albumin index (CSF-AI)   
o Changes in IgG index ( [CSF/serum IgG ratio] / [ CSF-AI] )   
o Changes in inflammatory markers in serum 
• 
Disease characteristics, symptoms, and QOL  
o Assessment of sleep disorders or dysfunction as determined by the 
Children's Sleep Habits Questionnaire (CSHQ)  
o Assessment of behavior as determined by the Sanfilippo Behavior 
Rating Scale (SBRS) 
o Assessment of subjective QOL as determined by the Short Form 
Health Survey for Children (SF-10)  
o Assessment of caregiver QOL as determined by the Zarit Burden 
Interview (ZBI) 12-item short form  
o Coarsening of features by Facial Dysmorphology Novel Analysis 
(FDNA)  
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• 
Additional blood or urine biomarkers of interest that are identified 
during the course of this study based on emerging data from the 
scientific literature or the Sponsor’s MPS IIIB development program (if 
there is sufficient sample volume and if local regulations permit). 
• 
Assessment of genes that may contribute to and/or modify the disease 
phenotype via a DNA sample (where local regulations permit and 
subject to discretionary approval from each center’s Institutional Review 
Board [IRB]/Independent Ethics Committee [IEC] and the 
consent/assent of the subject [and/or consent of the subject’s parent or 
legal guardian]). 
Statistical Methods 
General Considerations 
Descriptive summary statistics will be provided for demographics, disposition 
and dose exposure.  Number and percentage of subjects who discontinued from 
the study, along with reasons for discontinuations will be tabulated and 
described in listings. 
Continuous data will be summarized using descriptive statistics (number of 
subjects, mean, standard deviation, median, minimum, and maximum) and, 
where appropriate, graphic representation and two-sided 95% confidence 
intervals (CI); categorical data will be summarized by sample size, proportions, 
and two-sided 95% CIs. 
The sample size of approximately 9 subjects is based on clinical and not 
statistical consideration and is considered sufficient to provide PK, safety, and 
PD/efficacy data to inform dose and regimen selection for additional clinical 
studies.   
Analysis Datasets 
The full analysis set (FAS), defined as all subjects who have received any 
amount of SBC-103 and from whom informed consent has been obtained, will 
be used to summarize PK, PD, and efficacy data. 
The safety analysis set, which is the same population as the FAS, will be used 
to summarize all safety and tolerability data. 
Safety Analysis 
Descriptive statistics will be computed for safety parameters, as appropriate.  
Number and percentage of subjects who discontinued from the study because of 
AEs, will be tabulated across dose cohorts; severity and frequency of AEs and 
SAEs will also be tabulated across dose cohorts.  All other safety data will be 
provided in listings.  Baseline, within study, end-of-study, and change from 
baseline in physical examination findings, ECG, clinical laboratory values, and 
vital signs will be summarized by dose cohort.  
The proportion of subjects with measurable antibodies to SBC-103 will be 
displayed.  In addition, IARs will be tabulated by cohort and overall.  
Medications to treat IARs, including any medications for pretreatment, will also 
be presented by cohort and over the entire study period.  SBC-103 infusions in 
which the rate was slowed or discontinued due to IARs will be detailed in a 
separate data listing. 
Further statistical evaluations will be applied for select endpoints, if warranted.  
All baseline data and safety data collected during the study will be listed for 
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each subject. 
Safety analyses may be performed for Parts A, B, C, and/or all 3 study parts (ie, 
the entire study).  Details for the analyses will be provided in the SAP. 
Pharmacokinetic Analysis  
PK analysis will be performed using non-compartmental analysis method.  
Graphs of PK concentration over time will be generated for each subject and 
also for all subjects in a dose group.  Serum PK parameter (Cmax, Tmax, AUClast, 
AUC∞, T1/2, CL, Vz, and Rac) assessments will be summarized for each subject, 
as well as for each dose group.  SBC-103 concentration in CSF will be 
summarized at available time points.  Additional analysis of PK data, including 
assessment of the impact of ADA, may be performed as appropriate.   
Pharmacokinetic analyses may be performed for Parts A, B, C, and/or all 
3 study parts (ie, the entire study).  Further details will be provided in the PK 
section of the statistical analysis plan (SAP). 
Pharmacodynamic/Efficacy Analyses  
Parameters describing total HS and exploratory disease-related biomarkers 
including NRE HS derivatives, will be provided in listings and may be 
tabulated as described previously. 
Parameters describing disease characteristics, symptoms, and quality of life of 
subjects with MPS IIIB, including neurodegeneration (MRI), CSF-AI, 
neurocognitive and QOL (Vineland-II, BSID-III, KABC-II, BOT-2 Brief Form, 
CSHQ, CCC-2, SBRS, SF-10, ZBI 12-item) will be provided in listings and 
may be tabulated as appropriate.  
PD, disease characteristics, symptoms, and QOL outcomes analyses will be 
summarized.  Observed measurements and changes or percent changes from 
baseline in HS and NRE HS derivatives and disease related biomarkers will be 
summarized overall and by dosing regimen for each time point.  Change in 
relative proportion of grey and white matter volume and microstructural 
integrity will be summarized.   
Graphs of actual values and changes over time may be created as appropriate.   
Parameters describing facial features of subjects with MPS IIIB will be 
provided in listings and may be tabulated as appropriate.  
Pharmacodynamic/efficacy analyses will be performed for Parts A and C, 
and/or all 3 study parts (ie, the entire study).  Further details of the pre-specified 
analyses will be provided in the SAP. 
Summaries of Data Prior to Study Completion     
Interim data will be summarized for presentation to regulatory authorities or to 
the scientific community to facilitate discussions and obtain input on late phase 
study designs. 
For some of these summaries, CIs may be computed.  Additional details of the 
pre-specified statistical analyses will be provided in a separate SAP. 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ADA 
Anti-drug antibody(ies) 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUClast 
Area under the concentration-time-curve from time 0 to the last 
measureable time point 
AUC∞ 
Area under the concentration-time-curve extrapolated to infinity 
BBB 
Blood brain barrier 
BMI 
Body mass index 
BOT-2 Brief Form 
Bruininks-Oseretsky Test of Motor Proficiency, Second 
Edition, Brief Form 
BP 
Blood pressure 
BSID-III 
Bayley Scales of Infant and Toddler Development, Third 
Edition 
BUN 
Blood urea nitrogen 
CCC-2 
Children’s Communication Checklist, Second Edition 
CDC 
Centers for Disease Control 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum observed serum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CSF-AI 
Cerebrospinal fluid/serum albumin index 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
Clinical study report 
CT 
Computed tomography 
DNA 
Deoxyribonucleic acid 
DQ 
Developmental quotient 
ECG 
Electrocardiograms 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FDNA 
Facial Dysmorphology Novel Analysis 
GAG 
Glycosaminoglycan(s) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HED 
Human equivalent dose 
HFA 
Height-for-age 
HGF 
Hepatocyte growth factor 
HS 
Heparan sulfate 
IAR 
Infusion-associated reaction 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IT 
Intrathecal(ly) 
IV 
Intravenous(ly) 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition  
LSDs 
Lysosomal storage disorders 
M6PR 
Mannose-6-phosphate receptor 
MCH 
Mean corpuscular hemoglobin;  
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mL 
Milliliter 
MMR 
Macrophage mannose receptor 
MPS 
MPS I 
Mucopolysaccharidosis(ses) 
Mucopolysaccharidosis I 
MPS II 
Mucopolysaccharidosis II 
MPS IIIB, Sanfilippo B 
Mucopolysaccharidosis III, type B 
MRI 
Magnetic resonance imaging 
NAGLU 
Alpha-N-acetylglucosaminidase 
NOAEL 
No-observed-adverse-effect level 
NRE 
Non-reducing end 
NVI 
Non verbal index 
PAD 
Pharmacologically active dose 
PD 
Pharmacodynamic(s) 
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Abbreviation 
Definition 
PDCO 
Pediatric Committee 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QOL 
Quality of life 
QOW 
Every other week 
QW 
Every week 
Rac 
Accumulation ratio 
rhNAGLU 
Recombinant human alpha-N-acetylglucosaminidase 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBRS 
Sanfilippo Behavior Rating Scale 
SDTM 
Study data tabulation model 
SF-10 
Short Form Health Survey for Children  
sMRI 
Structural magnetic resonance imaging 
SOA 
Schedule of assessments 
SRC 
Safety Review Committee 
T1/2
 
Half-life 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
Tmax 
Time to reach Cmax 
ULN 
Upper limit of normal 
US 
United States 
Vineland-II 
Vineland Adaptive Behavior Scales, Second Edition 
Vz 
Volume of distribution at terminal phase 
WFA 
Weight-for-age 
WFH 
Weight-for-height 
ZBI 
Zarit Burden Interview 12-item short form 
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TABLE OF CONTENTS 
1 
INTRODUCTION.......................................................................................................... 24 
1.1 
Background ........................................................................................................ 24 
1.1.1 
Mucopolysaccharidosis Type IIIB ........................................................ 24 
1.1.2 
Medical Rationale for Enzyme Replacement Therapy for 
MPS IIIB ............................................................................................... 25 
1.2 
Investigational Medicinal Product (SBC-103)................................................. 26 
1.3 
Nonclinical Data ................................................................................................. 26 
1.4 
Clinical Data ....................................................................................................... 28 
1.4.1 
Data for SBC-103 ................................................................................. 28 
1.4.2 
Assessment of Neurodegeneration by Structural and 
Diffusion MRI....................................................................................... 31 
1.5 
Dose Rationale and Risk/Benefits ..................................................................... 33 
1.5.1 
Study Dose Rationale............................................................................ 33 
1.5.2 
Risk/Benefit Assessment ...................................................................... 35 
2 
Study Objectives............................................................................................................. 39 
2.1 
Primary Objective .............................................................................................. 39 
2.2 
Secondary Objectives......................................................................................... 39 
2.3 
Exploratory Objectives ...................................................................................... 39 
3 
INVESTIGATIONAL PLAN ....................................................................................... 40 
3.1 
Overall Design and Plan of the Study .............................................................. 40 
3.1.1 
Part A (Initial Therapy)......................................................................... 42 
3.1.2 
Part B (Therapy at 1 and/or 3 mg/kg) ................................................... 47 
3.1.3 
Part C (Therapy at 5 and/or 10 mg/kg) ................................................. 47 
3.2 
Rationale for Study Design ............................................................................... 51 
3.3 
Rationale for Dose and Escalation Timing ...................................................... 52 
3.3.1 
Rationale for Dose Escalation in Part A (Initial Therapy) .................... 52 
3.3.2 
Rationale for Intra-Patient Dose Escalation in Part B 
(Therapy at 1 and/or 3 mg/kg) .............................................................. 52 
3.3.3 
Rationale for Additional Dose Escalation in Part C (Therapy 
at 5 and/or 10 mg/kg) ............................................................................ 53 
3.4 
Study Endpoints ................................................................................................. 53 
3.4.1 
Primary Endpoint .................................................................................. 53 
3.4.2 
Secondary Endpoints ............................................................................ 53 
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3.4.3 
Exploratory Endpoints .......................................................................... 54 
4 
Study Population ............................................................................................................ 56 
4.1 
Target Population .............................................................................................. 56 
4.2 
Number of Subjects............................................................................................ 56 
4.3 
Eligibility Criteria .............................................................................................. 56 
4.3.1 
Inclusion Criteria .................................................................................. 56 
4.3.2 
Exclusion Criteria ................................................................................. 57 
4.3.3 
Qualifications for Participation in Part B (Therapy at 1 
and/or 3 mg/kg) ..................................................................................... 57 
4.3.4 
Qualifications for Participation in Part C (Therapy at 5 
and/or 10 mg/kg) ................................................................................... 58 
4.4 
Concomitant Medications and Treatments ..................................................... 58 
4.5 
Discontinuation of Subjects ............................................................................... 58 
4.5.1 
Premature Withdrawal from Study Participation.................................. 58 
4.5.2 
Procedures for Discontinuation ............................................................ 59 
4.6 
Subject Replacement Policy .............................................................................. 59 
4.7 
Subject Re-screening ......................................................................................... 59 
5 
Study Procedures ........................................................................................................... 60 
5.1 
Study Assessments ............................................................................................. 60 
5.1.1 
Informed Consent/Assent ..................................................................... 60 
5.1.2 
Subject Eligibility ................................................................................. 60 
5.1.3 
Medical History .................................................................................... 60 
5.1.4 
Demographic Information..................................................................... 61 
5.1.5 
Physical Examination ........................................................................... 61 
5.1.6 
Height and Weight ................................................................................ 61 
5.1.7 
Vital Signs and Electrocardiogram ....................................................... 61 
5.1.8 
Neurocognitive, Developmental and Quality of Life (QOL) 
Assessments .......................................................................................... 62 
5.2 
Clinical Laboratory Assessments ..................................................................... 66 
5.2.1 
Routine Assessments and Biomarkers .................................................. 66 
5.2.2 
Facial Dysmorphology Novel Analysis ................................................ 72 
5.2.3 
General Anesthesia/Sedation ................................................................ 73 
5.2.4 
Structural and Diffusion MRI ............................................................... 73 
5.2.5 
Telephone Calls .................................................................................... 74 
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6 
Study Treatments ........................................................................................................... 75 
6.1 
Treatments Administered ................................................................................. 75 
6.1.1 
Dose Adjustments ................................................................................. 75 
6.2 
Stopping Rules .................................................................................................... 75 
6.2.1 
Stopping Rules in Individual Subjects .................................................. 75 
6.2.2 
Stopping Rules for Multiple Subjects ................................................... 77 
6.3 
Description of SBC-103 ..................................................................................... 77 
6.4 
Method for Assigning Subjects to Treatment Groups ................................... 77 
6.5 
Storage and Disposition of SBC-103 ................................................................ 77 
6.5.1 
Receipt of Drug Supplies ...................................................................... 77 
6.5.2 
Storage .................................................................................................. 78 
6.5.3 
Disposition ............................................................................................ 78 
6.6 
Preparation and Administration of Study Drug ............................................. 78 
6.6.1 
Preparation of Study Drug .................................................................... 78 
6.6.2 
Administration of Study Drug .............................................................. 78 
6.7 
Randomization and Blinding of SBC-103 ........................................................ 79 
6.8 
Destruction of SBC-103 ..................................................................................... 79 
7 
Assessment of Safety ...................................................................................................... 80 
7.1 
Adverse Events and Laboratory Abnormalities ............................................. 80 
7.1.1 
Clinical Adverse Events........................................................................ 80 
7.1.2 
Laboratory Test Abnormality ............................................................... 81 
7.1.3 
Adverse Events of Special Interest (Infusion-Associated 
Reactions) ............................................................................................. 82 
7.2 
Handling of Safety Parameters ......................................................................... 84 
7.2.1 
Serious Adverse Events and Infusion-Associated Reactions 
(Immediately reportable to the Sponsor) .............................................. 84 
7.2.2 
Adverse Event Reporting Period .......................................................... 84 
7.2.3 
Treatment and Follow-up of Adverse Events ....................................... 84 
7.2.4 
Follow-up of Abnormal Laboratory Test Values ................................. 84 
7.2.5 
Pregnancy.............................................................................................. 84 
7.3 
Recording of Adverse Events ............................................................................ 85 
7.4 
Reporting of Serious Adverse Events, Infusion-Associated 
Reactions and Unanticipated Problems ........................................................... 85 
7.4.1 
Investigator Reporting: Notifying the Sponsor ..................................... 85 
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7.4.2 
Investigator Reporting: Notifying the IRB/IEC.................................... 86 
7.4.3 
Sponsor Reporting: Notifying Regulatory Authorities ......................... 86 
7.4.4 
Sponsor Reporting: Notifying Participating Investigators.................... 87 
7.5 
Independent Safety Review Committee (SRC) ............................................... 87 
8 
Statistical Plan ................................................................................................................ 88 
8.1 
General Considerations ..................................................................................... 88 
8.2 
Determination of Sample Size ........................................................................... 88 
8.3 
Analysis Sets ....................................................................................................... 88 
8.3.1 
Full Analysis Set ................................................................................... 88 
8.3.2 
Safety Analysis Set ............................................................................... 88 
8.4 
Safety Analysis ................................................................................................... 88 
8.5 
Pharmacokinetic Analysis ................................................................................. 89 
8.6 
Pharmacodynamic/Efficacy Analyses .............................................................. 89 
8.7 
Summaries of Data Prior to Study Completion .............................................. 89 
9 
Subject Data Handling and Record Keeping .............................................................. 90 
9.1 
Confidentiality .................................................................................................... 90 
9.2 
Source Documents .............................................................................................. 90 
9.3 
Case Report Forms ............................................................................................ 90 
9.4 
Records Retention .............................................................................................. 90 
10 
Study Monitoring, Auditing, and Inspecting ............................................................... 91 
10.1 
Study Monitoring Plan ...................................................................................... 91 
10.2 
Auditing and Inspecting .................................................................................... 91 
11 
Ethical Considerations................................................................................................... 92 
12 
Clinical Study Report and Data Disclosure ................................................................. 93 
13 
References ....................................................................................................................... 94 
14 
Appendices ...................................................................................................................... 99 
14.1 
Appendix A: Schedule of Study Assessments (Part A, Initial 
Therapy)............................................................................................................ 100 
14.2 
Appendix B: Schedule of Study Assessments (Part B, Therapy at 1 
and/or 3 mg/kg – Year 1) ................................................................................. 103 
14.3 
Appendix C: Schedule of Study Assessments (Part B, Therapy at 
1 and/or 3 mg/kg – Years 2-3, as applicable) ................................................. 105 
14.4 
Appendix D: Schedule of Study Assessments (Part C, Therapy at 
5 and/or 10 mg/kg) ........................................................................................... 111 
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14.5 
Appendix E:  NGLU-CL02 Neurocognitive, Developmental and 
QOL Assessments............................................................................................. 121 
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LIST OF TABLES IN THE TEXT 
Table 1: 
Preliminary Serum Pharmacokinetic Results (Study NGLU-CL02) ............................... 31 
Table 2: 
Predicted Safety Margins at Clinical Doses of 5 and 10 mg/kg QOW ............................ 35 
Table 3: 
Part A (Initial Therapy) Dose Cohorts ............................................................................. 42 
Table 4: 
Clinical Laboratory Tests ................................................................................................. 68 
Table 5: 
PK Sampling in Part A (Initial Therapy) ......................................................................... 70 
Table 6: 
PK Sampling in Part B (Therapy at 1 and/or 3 mg/kg) .................................................... 71 
Table 7: 
PK Sampling in Part C (Therapy at 5 and/or 10 mg/kg) .................................................. 71 
Table 8: 
Assessment of Causality .................................................................................................. 81 
Table 9: 
Guidelines for the Management of IARs ......................................................................... 83 
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LIST OF FIGURES IN THE TEXT 
Figure 1: 
Study Schematic for Part A (Initial Therapy), Part B (Therapy at 1 and/or 
3 mg/kg), and Part C (Therapy at 5 and/or 10 mg/kg) ..................................................... 41 
Figure 2: 
Planned Staggered Subject Treatment and Dose Escalation Schedule for the 
First Four Doses of SBC-103 in Part A (Initial Therapy) ................................................ 44 
Figure 3: 
Planned Subject Treatment and Dose Escalation Schedule in Part C (Therapy 
at 5 and/or 10 mg/kg) ....................................................................................................... 50 
 
 
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1 INTRODUCTION 
This document is a protocol for a human research study.  This study will be conducted according 
to Good Clinical Practice (GCP), as defined by the International Council for Harmonisation 
(ICH) and the ethical principles underlying European Union (EU) Directives 2001/20/EC and 
2005/28/EC; the United States (US) Code of Federal Regulations (CFR), Title 21, Parts 50 and 
312 (21 CFR 50, 21 CFR 312); and all applicable government regulations and institutional 
research policies and procedures. 
1.1 Background 
1.1.1 Mucopolysaccharidosis Type IIIB 
The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by 
a deficiency of enzymes catalyzing the degradation of glycosaminoglycans (GAGs, also known 
as mucopolysaccharides).  The majority of LSDs share a propensity for a chronic and 
progressive disease course with multi-system involvement, although each MPS may present with 
unique clinical features (Neufeld, 2012, The Metabolic and Molecular Bases of Inherited 
Disease).  The type III MPS, referred to as Sanfilippo syndromes, are clinically very similar and 
demonstrate somatic complications that are commonly observed in the other MPS; however, 
MPS III is also characterized by severe degeneration of the central nervous system (CNS) which 
dominates the clinical picture (Heron, 2011, Am J Med Genet A; Neufeld, 2012, The Metabolic 
and Molecular Bases of Inherited Disease).  The MPS III syndromes are all characterized by the 
accumulation of heparan sulfate (HS) due to mutations in 1 of the 4 enzymes required for the 
degradation of HS.  Heparan N-sulfatase is deficient in type A, alpha-N-acetylglucosaminidase 
(NAGLU) in type B, acetyl-CoA:alpha-glucosaminide acetyltransferase in type C, and N-acetyl 
glucosamine 6-sulfatase in type D.  
MPS IIIB, also known as Sanfilippo B syndrome (OMIM #252920), is a very rare LSD 
associated with significant morbidity and mortality in affected subjects.  Birth prevalence 
estimates for MPS IIIB, based on the available literature and defined as the number of diagnosed 
cases per 100,000 live births over 1 year, range from 0.12 - 0.78 per 100,000 (Nelson, 1997, 
Hum Genet; Poorthuis, 1999, Hum Genet; Nelson, 2003, Am J Med Genet; Pinto, 2004, Eur J 
Hum Genet; Baehner, 2005, J Inherit Metab Dis; Heron, 2011, Am J Med Genet A).  Regional 
variances may exist with respect to prevalence or the relative proportion of MPS IIIB to the other 
MPS subtypes.  The disease is caused by mutations in the NAGLU gene.  MPS IIIB patients 
typically have a normal to near-normal development during the first 2 years of life, followed by a 
slowing and full stagnation of development at around 3 to 4 years, and finally regression of 
cognitive capabilities.  Patients usually become fully dependent on care early in their teenage 
years.  Death typically occurs at the end of the second or the beginning of the third decade of 
life.  However, as with other LSDs, a broader spectrum of disease severity may exist.  An 
attenuated form of MPS IIIB has been described in a Dutch cohort of patients in which the 
progression of some disease manifestations appears to be slower, but progression still occurs 
with loss of functions such as speech and walking (Valstar, 2010, J Inherit Metab Dis; Wijburg, 
2013, Acta Paediatr).  Patients with the attenuated phenotype may have a stable intellectual 
disability for many years.  These patients also appear to have a longer preservation of motor 
functions and may live into adulthood (Valstar, 2011, Orphanet J Rare Dis). 
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There are currently no safe or effective therapies for the treatment of MPS IIIB.  Supportive 
therapies are used in an attempt to mitigate some of the effects of the disease.  Options for 
management of clinical symptoms are limited, and include the use of CNS medications to control 
seizures, behavioral problems, and sleep problems. 
1.1.2  Medical Rationale for Enzyme Replacement Therapy for MPS IIIB 
The medical rationale of enzyme replacement therapy (ERT) and specifically, the potential 
medical benefit of intravenously (IV) administered recombinant enzyme for MPS IIIB are 
supported by the successful use of ERT with favorable benefit/risk profiles to treat other LSDs; 
nonclinical data demonstrating the benefit of substrate reduction in the CNS on CNS 
manifestations in LSDs including the MPS III syndromes; and nonclinical data demonstrating the 
ability of IV administered SBC-103, a recombinant human alpha-N-acetylglucosaminidase 
(rhNAGLU), to reduce substrate levels in the liver and the brain in the MPS IIIB animal model.   
ERT has been used successfully to treat a number of LSDs with favorable benefit/risk 
profiles.  The successful treatment of Gaucher’s 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 ERT for LSDs (Barton 1990, 
Proc Natl Acad Sci USA; Barton 1991, N Engl J Med).  The scientific concepts established by 
these initial studies have now been extended to a broad range of disorders including: Pompe 
disease (van der Beek 2006, Acta Neurol Belg), Fabry disease (Wilcox 2004, Am J Hum Genet), 
MPS I (Wraith 2004, J Pediatr), and MPS II (Muenzer 2007, Mol Genet Metabol).  As a result, 
there is now extensive clinical experience with long-term ERT in subjects with LSDs (Desnick 
2012, Annu Rev Genomics Hum Genet). 
Early intervention with IV administered ERT in other LSDs with CNS manifestations in sibling 
pair studies appears to modify disease progression.  In MPS II, 2 siblings, aged 3 years and 
4 months, respectively, initiated treatment by IV administration of the ERT idursulfase and 
outcomes were compared (Tajima 2013, Mol Genet Metab).  At the start of treatment, the older 
brother showed typical neurodegenerative features of MPS II, including intellectual 
disability.  After 34 months of treatment with idursulfase, his somatic disease was stable or 
improved; however, he continued to decline cognitively.  By comparison, after 32 months of 
treatment with idursulfase, his younger brother manifested only exudative otitis media, but 
remained free from most of the somatic features that appeared in his brother at the same age.  Of 
relevance to considerations for MPS IIIB, although the younger brother’s developmental quotient 
trended downward over time to just below the normal range, his intellectual disability at 3 years 
of age was not as severe as the brother who started treatment later. 
Nonclinical studies with a variety of experimental therapeutic modalities have demonstrated that 
substrate reduction in the CNS in LSDs, including the MPS III syndromes, is accompanied by 
improvements in CNS manifestations (Kim 2009, Eur J Neurosci; Ou 2014, Mol Genet Metab; 
Higuchi 2012, Mol Genet Metab).  In addition, brain NAGLU enzyme levels required to 
maintain normal phenotype in wild type or heterozygote carriers are substantially lower (>50×) 
than enzyme activity levels in normal liver (Li 1999, Proc Natl Acad Sci USA).  Furthermore, 
nonclinical studies with SBC-103 have demonstrated that IV administration of SBC-103 reduces 
substrate levels in both systemic tissues (liver/kidney) and in the brain in the MPS IIIB animal 
model (Leavitt 2013, LDN WORLD Conference). 
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In summary, this knowledge and the precedent established for other LSDs, provide rationale that 
ERT with SBC-103 may benefit patients with MPS IIIB.  Developing a more complete 
understanding of the pharmacokinetics (PK), and pharmacodynamics (PD)/efficacy of SBC-103 
via this study will further inform the dose and regimen selection for future studies of SBC-103 as 
an ERT for MPS IIIB, a disease with devastating CNS complications. 
1.2 Investigational Medicinal Product (SBC-103) 
SBC-103, rhNAGLU, is manufactured using transgenic Gallus, produced in egg white.  
SBC-103 is a highly purified recombinant human enzyme intended to be used as ERT for the 
treatment of MPS IIIB.   
The rhNAGLU transgene encodes the same amino acid sequence as reported for the native 
human enzyme (Weber 1996, Hum Mol Genet; Zhao 1996, Proc Natl Acad Sci USA).  Purified 
rhNAGLU is a glycoprotein that contains up to 7 potential N-linked glycosylation sites.  Specific 
glycans, including mannose-6-phosphate containing glycans, are thought to be critical for 
biodistribution and uptake of SBC-103 into the lysosomes of key target cells involved in 
pathogenesis of the disease.  NAGLU catalyzes the hydrolysis of N-acetylglucosamine 
(GlcNAc)alpha(1-4))n to (GlcNAc alpha(1-4))n-1 and 2-(acetylamino)-2-deoxy-beta-D-
glucopyranose.  
SBC-103 is supplied as an aqueous solution which is essentially free of visible foreign 
particulate matter. 
1.3 Nonclinical Data 
In vitro studies with SBC-103 using NAGLU-deficient human fibroblasts have demonstrated 
efficient mannose-6 phosphate dependent cellular uptake with correction of intracellular enzyme 
deficiency.  In addition, mannose receptor-mediated uptake of SBC-103 by cells of macrophage 
lineage has also been demonstrated. 
Several nonclinical studies demonstrated a reduction in total HS in NAGLU-deficient mice 
following IV administration of SBC-103 (4-6 repeated doses), with doses ranging from 0.3 to 
27 mg/kg for up to 6 weeks in duration.  The results demonstrated dose-dependency.  Reductions 
in HS concentrations were accompanied by increases in measured NAGLU concentration.  
Following SBC-103 administration, clinical signs such as lethargy and ataxia were observed.  
The majority of the observations occurred after the third or fourth dose.  These observations were 
not considered to be directly related to pharmacological effect of SBC-103.  In these studies, 
hypersensitivity reactions, which were sometimes fatal, were attributed to the repeat IV 
administration of a human recombinant protein to a heterologous species (SBC103-P004, 
SBC103-P007, SBC103-P009, SBC103-P010) and are consistent with published literature 
(Hovland 2007, Toxicol Pathol; Flaherty 2012, Toxicological Sciences; Finkelman 2007, 
J Allergy Clin Immunol; Khodoun 2011, PNAS).  Pretreatment with diphenhydramine was used 
to minimize the effects, but did not completely block the reactions.  This finding is consistent 
with the existence of 2 distinct pathways of anaphylaxis in mice; either by Immunoglobulin E 
(IgE) mediated histamine release from mast cells or by Immunoglobulin G (IgG) mediated PAF 
release from macrophages (Finkelman 2007, J Allergy Clin Immunol). 
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In the study SBC103-P010, the potential for CNS uptake and activity following IV 
administration of SBC-103 was evaluated in NAGLU-deficient mice.  These mice were 
administered 0.3, 1, 3, 5 or 10 mg/kg of SBC-103 once every week (QW) for 4 weeks.  A 
statistically significant decrease in HS was demonstrated in both brain and liver following IV 
dosing with a pharmacologically active dose (PAD; the lowest dose tested with the intended 
pharmacologic activity) established at a dose level of 3 mg/kg (0.075 mg dose for a 25 gram 
mouse) IV in the brain and 0.3 mg/kg (0.0075 mg dose) in the liver (SBC103-P010). 
Consistent with ICH guidelines (ICH S6 [Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals and Addendum to ICH6, Preclinical Safety Evaluation 
of Biotechnology-Derived Pharmaceuticals S6(R1)]), the potential toxicity of SBC-103 was 
evaluated in 2 species, the Sprague-Dawley rat (4 weeks) and the Cynomolgus monkey (4 weeks 
and 3 months).  Since monkeys of 0.5-3 years of age corresponds to a human child of 2-12 years 
(Barrow 2007, FDA News; Tassisnari 2013, Wiley), and the MPS IIIB patient population 
includes children, juvenile Cynomolgus monkeys were studied in the 3-month toxicology study 
of SBC-103.  The monkey is considered the most relevant species for the toxicological 
assessment of SBC-103. 
The potential toxicity of SBC-103 was evaluated in Sprague-Dawley rats following repeated IV 
doses of SBC-103 (1, 3, or 10 mg/kg) QW for 4 weeks with a 2-week recovery period 
(SBC103-T007).  Overall, the IV administration of SBC-103 QW at a dose of 10 mg/kg resulted 
in transient clinical observations of decreased activity, decreased muscle tone and/or prostration 
generally after the third and fourth doses.  Microscopically, findings of minimal to mild 
inflammation were observed in the liver at all doses and in the heart and lungs of individual 
animals at 10 mg/kg.  Most of these findings showed partial reversibility at the end of the 
recovery period.  The incidence of anti-SBC-103 IgG antibodies in samples collected at study 
termination was 100% in SBC-103 treated animals (irrespective of the dose), and no 
anti-SBC-103 antibody formation was detected in any control animals.  Based on the observed 
vascular/perivascular inflammation in the heart and lungs in the Sprague-Dawley rat, a 
no-observed-adverse-effect level (NOAEL) was established at a dose level of 3 mg/kg. 
The potential toxicity of SBC-103 was evaluated in Cynomolgus monkeys following repeated IV 
doses of SBC-103 (1, 3, 10, or 20 mg/kg) QW for 4 weeks with a 2-week recovery period 
(SBC103-T008).  There were no changes in clinical observations, macroscopic, organ weight, or 
microscopic findings that were considered SBC-103-related.  The incidence of anti-SBC-103 
IgG antibodies in samples collected at study termination was ~80% in SBC-103 treated animals 
(irrespective of the dose), and no anti-SBC-103 antibody formation was detected in any control 
animals.  The administration of SBC-103 at these IV dose levels was well-tolerated.  
Consequently, the NOAEL in this study was considered to be 20 mg/kg QW. 
The potential toxicity of SBC-103 was also evaluated in juvenile Cynomolgus monkeys 
following repeated IV doses at QW dose levels of 3 and 10 mg/kg or at an every other week 
(QOW) dose level of 20 mg/kg during a 3-month dosing period with a 4-week recovery period 
(SBC103-T009).  There were no SBC-103-related mortalities and no macroscopic, organ weight, 
or microscopic changes that were considered SBC-103 related.  Transient clinical signs were 
noted; however, there were no correlating findings in any of the other parameters evaluated.  The 
transient clinical signs included, but were not limited to, decreased activity, hunched posture, 
lying on side, abnormal gait, uncoordination, excessive scratching/cage manipulation and/or 
repetitive behavior.   
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The presence of anti-SBC-103 IgG antibodies was confirmed in 87%, 60%, and 87% animals in 
the 3 mg/kg, 10 mg/kg, and 20 mg/kg dose groups, respectively, and no animals in the control 
group were confirmed positive for anti-SBC-103 antibody.  Antibody titers did not increase with 
dose level administered.  Consequently, the NOAELs were considered to be 10 mg/kg QW and 
20 mg/kg QOW in this study. 
Overall, the findings in 2 different toxicology species and data from a NAGLU disease model at 
relevant IV doses suggest a hypersensitivity reaction to a foreign protein with some species 
differences.  This is generally supported by the high incidence of anti-SBC-103 IgG antibodies in 
SBC-103 treated animals across species, and laboratory/clinical indicators of inflammation.  
While this is consistent with previous studies, it should be noted that, nonclinical studies are not 
predictive of potential immunogenicity in humans (Garcia 2007, Mol Genet Metab; Hemsley 
2007, Mol Genet Metab; McVie-Wylie 2008, Mol Genet Metab; Hovland 2007, Toxicol Pathol; 
Flaherty 2012, Toxicological Sciences; Finkelman 2007, J Allergy Clin Immunol; Khodoun 
2011, PNAS; Brinks 2011, Pharm Res; Ponce 2009, Reg Toxicol Pharmacol).  Additionally, it is 
important to note that, SBC-103 administered IV at high doses resulted in microscopic findings 
in both the rat and Cynomolgus monkey in numerous tissues presumably reflecting exaggerated 
hypersensitivity reaction to a human protein. 
Refer to the Investigator’s Brochure for further information regarding the nonclinical studies 
with SBC-103. 
1.4 Clinical Data 
1.4.1 Data for SBC-103 
As this is a first-in-human study, no clinical data for SBC-103 were available when this study 
was planned and initiated. 
As described in Section 3.1, subjects in Part A receive IV infusions of SBC-103 at 1 of 3 doses 
(0.3, 1, or 3 mg/kg) QOW for 24 weeks followed by a 4-week temporary interruption of therapy 
prior to re-initiating therapy at Week 28 in Part B.  Modifications to dose or dosing frequency for 
individual subject(s) is permitted in Part B with the intent of treating subjects with the lowest 
potentially efficacious dose that is safe and tolerable.  
As of 20 November 2015, preliminary data were available for all subjects enrolled in this study, 
including approximately 20 to 40 weeks (~11 to 20 QOW doses) of preliminary safety data, and 
preliminary PK and PD data through Week 12 (~7 QOW doses).   
These data are briefly summarized below.  However, it should be noted that these are 
preliminary data from an ongoing study and an open database, and therefore, are subject to 
change based on data review, reconciliation, and/or auditing.  
As described in Section 3.1.1, approximately 9 subjects were to be enrolled in this study across 
3 dose cohorts (n=3/cohort) with a provision to permit enrollment of additional subjects if more 
than 3 subjects in a cohort had entered Screening and were eligible to participate in the study.  A 
total of 11 subjects were sequentially enrolled in this study into Cohort 1 (0.3 mg/kg, n=3), 
Cohort 2 (1 mg/kg, n=4), or Cohort 3 (3 mg/kg, n=4).  All subjects had a confirmed diagnosis of 
MPS IIIB and documented developmental delay with onset before 6 years of age.  The majority 
of subjects enrolled in this study are 
  The age range across all 
patients at study entry was 
 and the mean (SD) age was 7.5 (2.82) years for 
subjects in the 0.3 mg/kg dose cohort, 6.6 (4.54) years for subjects in the 1 mg/kg dose cohort, 
and 4.5 (2.10) years for subjects in the 3 mg/kg dose cohort.   
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As of 20 November 2015, all 3 subjects in Cohort 1 have completed Part A of the study and have 
received between 5 and 7 doses of SBC-103 at 1.0 mg/kg QOW in Part B; all 4 subjects in 
Cohort 2 have completed Part A and 2 of these subjects have received 2 doses at 3.0 mg/kg 
QOW in Part B; and the 4 subjects in Cohort 3 have completed between 20 and 24 weeks of 
Part A at 3.0 mg/kg.  
1.4.1.1 Preliminary Safety Data 
Preliminary safety data as of 20 November 2015, which corresponds to at least 20 and up 
40 weeks on study, demonstrate that IV infusions of SBC-103 at 0.3, 1, or 3 mg/kg administered 
QOW appear overall to be safe and well tolerated. 
While 10 subjects (90.9%) experienced a total of 80 treatment-emergent adverse events 
(TEAEs)
1, the majority of the events were assessed by the investigator as mild in intensity 
(75/80, 93.8%) and as either unlikely related or unrelated to study drug (71/80, 88.8%). The most 
common AEs (occurring in ≥2 subjects) were pyrexia, vomiting, diarrhoea, cough, rhinorrhoea, 
erythema, and dermatitis diaper; with the exception of pyrexia, none of these was considered by 
the investigator to be related to treatment with SBC-103. 
A total of 9 AEs (11.2%) occurring in 5 subjects (45.5%) were considered by the investigator to 
be related or possibly related to treatment with SBC-103; the majority of these (7/9 events) were 
infusion associated reactions (IARs), which are commonly observed with other enzyme 
replacement therapies (Desnick 2012, Ann Rev Genomics Hum Genet; Fabrazyme® prescribing 
information, 2010; Aldurazyme® prescribing information, 2013; Elaprase® prescribing 
information, 2013; Naglazyme® prescribing information, 2013).  The IARs occurred in 
3 subjects and included 4 events of pyrexia and 1 event each of tachycardia, hypertension, and 
chills.  These events were all non-serious, mild in intensity, and resolved without sequelae.  
These IARs were treated with oral anti-pyretics and/or antihistamines and, for some events, 
infusion rate was slowed as per the protocol specified guidelines for the management of IARs.  
None of the subjects needed extended pre-medication to continue receiving SBC-103.  Anti-drug 
antibody status is under evaluation. 
There have been no deaths or life-threatening events, no discontinuations due to AEs, and no 
severe AEs. Three (3) treatment-emergent serious adverse events (TESAEs) (staphylococcal 
bacteraemia, bacteraemia, and pyrexia) were reported in 1 subject (9.1%) 
 all 
3 TESAEs were assessed by the investigator as mild or moderate in intensity and unrelated to 
study drug, and all 3 resolved without sequelae. 
One (1) subject 
 met the protocol specified criterion to pause dosing with SBC-103 
based on confirmed elevations (≥2 × upper limit of normal [ULN]) in aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) (see Section 6.2.1); this is briefly described below.  No 
other subjects met any of the criteria requiring that SBC-103 dosing be paused. 
 
 
1 Any adverse event (AE) that occurred after the first dose of SBC-103 is considered a treatment-emergent adverse 
event (TEAE). 
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In addition to AEs, serum chemistry, liver function tests, hematology, coagulation, and urinalysis 
parameters were assessed at scheduled visits; vital signs were also measured and physical 
examinations were performed at scheduled visits.  As of the data cut-off date, there were no 
apparent dose-related trends nor any apparent trends over time indicative of potential toxicity of 
SBC-103. 
1.4.1.2 Preliminary Pharmacokinetic and Pharmacodynamic Data 
Preliminary Pharmacokinetic Results 
Preliminary PK data through a data cut-off date of 09 October 2015 are available, and summary 
statistics for select PK parameters are presented in Table 1.  
Exposure to SBC-103 increased in a dose proportional manner across the doses tested (0.3, 1, 
and 3 mg/kg) based on the maximum observed serum concentration (Cmax) and the area under the 
concentration-time-curve from time 0 to the last measureable time point (AUClast) on Day 0 and 
at Week 12.  Power analyses, in which the Ln AUClast PK exposure was regressed against Ln 
Dose (0.3 to 3 mg/kg) across all subjects yielded a β value of 1.075 (95% CI: 0.865-1.29) at Day 
0 following single dose (first dose) administration and 0.804 (95% CI: 0.537-1.07) at Week 12 
following multiple dose administration QOW.  These values were 1.12 (95% CI: 0.893-1.35) at 
Day 0 and 0.855 (95% CI: 0.617-1.10) at Week 12 for Cmax. 
The mean half-life (T1/2) for SBC-103 increased from 0.14 to 0.29 hours and was independent of 
dose and time (Table 1).  As shown in Table 1, accumulation (Cmax and AUClast) was observed at 
Weeks 12 and 24 in the 0.3 and 1 mg/kg dose cohorts.  In contrast, no accumulation was 
observed at Week 12 in the 3 mg/kg dose group (Rac=0.95 to 0.99).   
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Table 1: 
Preliminary Serum Pharmacokinetic Results (Study NGLU-CL02) 
Parametera 
0.3 mg/kg 
(N=3) 
1 mg/kg 
(N=4) 
3 mg/kg 
(N=4) 
n 
Mean (SD) 
CV% 
n 
Mean (SD) 
CV% 
n 
Mean (SD) 
CV% 
AUClast 
(ng•h/mL) 
Day 0 
3 
440 (94) 
22% 
4 
1862 (374) 
20% 
4 
5538 (2448) 
44% 
Week 12 
3 
782 (58) 
7.4% 
4b 
2789 (725) 
26% 
3b 
5299 (2659) 
50% 
Week 24 
3 
630 (149) 
24% 
1 
2703 
NA 
ND 
ND 
ND 
Cmax 
(ng/mL) 
Day 0 
3 
250 (38) 
16% 
4 
1073 (199) 
19% 
4 
3617 (1960) 
54% 
Week 12 
3 
433 (29) 
6.6% 
4b 
1571 (493) 
31% 
3b 
3231 (1315) 
41% 
Week 24 
3 
333 (30) 
9% 
1 
1424 
NA 
ND 
ND 
ND 
T1/2 
(h) 
Day 0 
1 
0.29 
NA 
3 
0.22 (0.04) 
19% 
3 
0.14 (0.04) 
28% 
Week 12 
2 
0.21 (0.05) 
22% 
4b 
0.27 (0.13) 
48% 
2b 
0.28 (0.16) 
59% 
Week 24 
1 
0.19  
NA 
1 
0.28 
NA 
ND 
ND 
ND 
Rac for 
Cmax 
Week 12 
3 
1.77 (0.39) 
22% 
3b 
1.53 (0.29) 
18.8% 
3b 
0.95 (0.61) 
63.5% 
Week 24 
3 
1.34 (0.13) 
9.5% 
1 
1.53 
NA 
ND 
ND 
ND 
Rac for 
AUClast 
Week 12 
3 
1.81 (0.25) 
14% 
3b 
1.59 (0.11) 
7.0% 
3b 
0.99 (0.68) 
68% 
Week 24 
3 
1.44 (0.17) 
12.0% 
1 
1.64 
NA 
ND 
ND 
ND 
 
 
Mean 
Range 
 
Mean 
Range 
 
Mean 
Range 
Tmax 
(h) 
Day 0 
3 
1.08 
0.5-2.25 
4 
1.63  
1.5-2.0 
4 
1.25 
0.5-1.5 
Week 12 
3 
1.67 
1.5-2.00 
4b 
1.25 
1.5-1.5 
3b 
2.00 
0.5-2.5 
Week 24 
3 
1.75 
1.5-2.25 
1 
2.00 
NA 
ND 
ND 
ND 
Key:  NA = not applicable for CV% because N<3; ND = not determined (due to ongoing sample analysis, serum levels of 
SBC-103 were not available as of the data cut-off [09 October 2015] for the PK analysis). 
a PK parameters were estimated using PhoenixTM WinNonlin® (Version 6.4).Nominal time was used for computation. 
b Subject 
 was enrolled in Cohort 3 and received 3 mg/kg on Day 0.  However, due an unrelated SAE (see 
Section 1.4.1.1), 
 was not dosed at Weeks 2, 4, or 6, and 
 resumed dosing at 1 mg/kg and received 1 mg/kg at Weeks 8 
and 12.  This subject was, therefore, included in the 1 mg/kg group at Week 12. 
 
Preliminary Pharmacodynamic Results 
Preliminary PD data through a data cut-off date of 30 October 2015 are available. At doses up to 
3 mg/kg QOW, decreases in heparan sulfate in cerebrospinal fluid (CSF) were directionally 
consistent and moderately correlated with increased serum SBC-103 exposure (Pearson 
correlation coefficient R=0.5831 for Cmax and 0. 5968 for AUClast). Across all 3 dose levels, the 
maximum observed HS reduction from baseline was 16.5% in CSF and 68.8% in serum.  
1.4.2 Assessment of Neurodegeneration by Structural and Diffusion MRI 
Neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, and multiple system 
atrophy are characterized by slow progressive loss of neurons in the CNS, which leads to deficits 
in specific brain functions.  Neurodegenerative diseases usually extend over a decade, and the 
actual onset of neurodegeneration may precede clinical manifestations by many years.  MPS III 
is also a neurodegenerative disorder, and it shares similar characteristics with the more 
traditional neurodegenerative diseases.  
In recent years, multimodal neuroimaging has become the most widely used approach to 
evaluating the pathophysiology of the diseased brain.  The aim is to quantify the single or 
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combined weight of magnetic resonance imaging (MRI) parameters to describe 
neurodegenerative processes.  Measurement of MRI parameters sensitive to complementary 
tissue characteristics (eg, volume atrophy, iron deposition, and microstructural damage) has great 
potential for evaluating pathological changes in neurologic/psychiatric diseases.  Structural and 
diffusion MRI can provide indices of grey and white matter volume reductions and 
microstructural and white matter connection integrity, and may be used to assess 
neurodegeneration.   
Structural magnetic resonance imaging (sMRI) obtains high resolution structural images that are 
useful for brain morphometry investigation.  In sMRI scans, two types of brain tissue - grey 
matter and white matter - are clearly perceptible and distinguishable.  Thus, sMRI allows for 
simultaneous analysis of these two tissues, which have most often been analyzed separately in 
studies of both healthy and diseased brain (Preuss 2005, Schizophr Res; Mitelman 2007, 
Neuroimage; Hazlett 2008, Schizophr Res).  This is an important advance, given the complex 
relationship between grey and white matters.  Grey matter is composed predominantly of cell 
bodies, while white matter is composed mainly of axons connecting cell bodies; both tissues are 
highly integrated within cerebral cortex and subcortical structures, and it has been proposed that 
spatial expansion of one could be associated with contraction of the other (Pfefferbaum 1994, 
Arch Neurol; Cicchetti 2006, Ann N Y Acad Sci).  Therefore, it is reasonable to expect that 
morphometric changes in one tissue may result in, or be related to, disturbance of the other 
(Xu 2012, Neurol Res Int). 
Diffusion MRI is routinely employed for the diagnosis and management of stroke and other 
diseases (eg, tumors, multiple sclerosis, and epilepsy).  Diffusion MRI is a quantitative imaging 
technique that is sensitive to changes in the microstructure of tissues, meaning that it is 
influenced by alterations in cell packing, cell size and membrane permeability to water.  Most 
biomarkers derived by this modality are therefore sensitive to subtle alterations in tissue structure 
and are good biomarker candidates for early detection of pathological changes and for 
monitoring subtle changes over time.  Accordingly, diffusion MRI has proven useful for 
obtaining information about the underlying mechanisms of neurodegenerative disorders (eg, 
Alzheimer’s disease and other dementias, Parkinson’s disease, Huntington’s disease, 
amyotrophic lateral sclerosis, hereditary ataxias), and has potential utility to confirm diagnoses 
and predict prognoses and therapeutic response in patients with neurodegenerative disease.   
A structural and diffusion MRI will, therefore, be performed at baseline to assess 
neurodegeneration prior to treatment with SBC-103 and will also be used as a comparison to 
evaluate changes after extended treatment with SBC-103. 
In addition, blood brain barrier (BBB) integrity will be assessed by calculating the CSF/serum 
albumin index (CSF-AI).  The BBB partly prevents proteins from peripheral blood from entering 
the brain and the CSF, resulting in markedly lower concentrations of proteins in CSF than in 
serum (Davson 1969, The Cerebrospinal Fluid. Handbook of Neurochemistry).  Albumin in CSF 
originates in the serum as it is synthesized only in the liver (Fishman 1980, Adv Neurol).  The 
relationship between the concentration of albumin in CSF and serum, that is the CSF-AI, is the 
most common method for evaluating BBB function (Ganrot 1974, Clin Chem; Tibbling 1977, 
Scan J Clin Lab Invest). 
The Sponsor has conducted a non-interventional/observational study in patients with MPS IIIB 
entitled Evaluation of Blood Brian Barrier Integrity and Structural Abnormalities in MPS IIIB 
Patients Using Multimodal Magnetic Resonance Imaging (Study NGLU-CL01, Data on File).  In 
this study, BBB integrity and structural brain abnormalities were evaluated in 5 MPS IIIB 
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patients using CSF-AI and multimodal MRI.  Top-line data indicate that in MPS IIIB patients, 
there is evidence of mild BBB leakage based on the CSF-AI findings; these findings are reflected 
in the absence of clear evidence for BBB leakage on MRI.  MRI volumetric measurements 
showed global and tissue-specific atrophy in these patients.  
1.5 Dose Rationale and Risk/Benefits 
1.5.1 Study Dose Rationale 
1.5.1.1 Defining a Pharmacologically Active Dose 
Extended treatment with an ERT is generally required to offer any benefit for a chronic disease 
such as MPS IIIB, and in a pediatric population such as this, it is important to provide some 
prospect for benefit with the investigational treatment.  Therefore, this study was designed to 
support chronic dosing for an extended period of time and to allow for intra-patient dose 
escalation based on evidence of biological activity.  Because of the profound neurocognitive 
abnormalities that dominate the clinical presentation of patients with MPS IIIB, HS reduction in 
CSF is considered to be an important predictor of potential clinical efficacy in these patients, and 
therefore, an important PD endpoint representative of biological activity.   
However, there is no precedence in MPS IIIB for the magnitude of reduction of HS in the CNS 
that will be required for efficacy.  Based on a combination of data including: the size of systemic 
substrate reduction with other IV enzyme replacement therapies in MPS I (Clarke 2009, 
Pediatrics) and MPS II (Muenzer 2006, Genet Med), reduction of CSF substrate from 
intrathecally (IT) administered ERT in a related disease, MPS IIIA (Breen 2013, www.ashg.org), 
and the degree of reduction of HS in the brain in the NAGLU mouse model experiments 
(SBC-103 IB), an estimated substrate reduction of ~40% in the CSF in humans is considered to 
be a reasonable target to identify a pharmacologically active and potentially efficacious clinical 
dose of SBC-103. 
1.5.1.2 Part A (Initial Therapy):  Dose Selection Rationale 
Part A of this study is an open label, dose escalation study of 3 dose levels of SBC-103 (0.3, 1, 
and 3 mg/kg) administered by IV infusion QOW for 24 weeks.  For a 7-year-old MPS IIIB 
patient weighing approximately 30 kg, the 3 dose levels of SBC-103 (0.3, 1, and 3 mg/kg) would 
equate to total doses of 9 mg, 30 mg, and 90 mg, respectively (Centers for Disease Control 
[CDC] Clinical Growth Charts, NGLU-CL01 Data on File). 
The dose scaling across species for SBC-103 has used body weight.  This is based on reviews of 
the approach taken for therapeutic proteins (Tang 2004, J Pharm Sci; Mahmood 2004, J Pharm 
Sci), particularly enzyme replacement therapies such as Elaprase®.  
The selection of 0.3 mg/kg as the starting dose of SBC-103 in Part A was based on:  the 
NOAELs in the 3-month juvenile Cynomolgus monkey study and in the 4-week Sprague-Dawley 
rat study when SBC-103 was administered as an IV infusion, along with the pharmacologic 
effects observed in the NAGLU-deficient nonclinical mouse model of MPS IIIB and PK/PD 
modeling of nonclinical data.  
In the Sprague-Dawley rat, the NOAEL was defined as 3 mg/kg based on the observed 
vascular/perivascular inflammation in the heart and lungs; this represents a 10-fold margin over 
the proposed starting dose (0.3 mg/kg) on a mg/kg basis.  Transient clinical signs attributable to 
SBC-103 infusions were observed at a dose of 10 mg/kg, generally after the third and fourth 
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doses (see Section 1.3).  Given the frequent presence of anti-SBC-103 antibodies, these likely 
reflect hypersensitivity to the administration of a human protein to a rat.   
In the juvenile Cynomolgus monkey study, which is considered the most relevant study to 
support studying SBC-103 in the MPS IIIB pediatric population, the NOAEL was defined as 
10 mg/kg QW and 20 mg/kg QOW.  This represents a 33- and 66-fold margin over the proposed 
starting dose (0.3 mg/kg) on a mg/kg body weight basis.  
Pharmacological effects were seen in a highly relevant nonclinical mouse model of MPS IIIB 
(NAGLU-deficient) with IV bolus doses of SBC-103.  These mice were administered 0.3, 1, 3, 5 
or 10 mg/kg of SBC-103 QW for 4 weeks (SBC103-P010).  Total HS in the brain was reduced 
following IV administration at 3 mg/kg dose, thus establishing the PAD at 3 mg/kg IV (human 
equivalent dose [HED] = 3 mg/kg based on body weight).  HS in the liver was reduced following 
IV administration at the 0.3 mg/kg establishing the PAD in the liver at 0.3 mg/kg (HED = 0.3 
mg/kg based on body weight).  Brain NAGLU enzyme levels required to maintain normal 
phenotype in wild type or heterozygote carriers are substantially lower (>50×) than enzyme 
activity levels in normal liver and soluble GAG (microgram/mg dry tissue) levels are several fold 
higher in the liver than in the brain (Li, 1999, Proc Natl Acad Sci USA).   
The above data from the NGLU-deficient mouse model, PK modeling, and toxicology data as 
well as affinity data for SBC-103 binding to the macrophage mannose receptor (MMR) and 
mannose-6-phosphate receptor (M6PR) support the 0.3 mg/kg starting dose and the QOW dosing 
frequency in this study.  Based on these data, the planned starting dose of 0.3 mg/kg was 
expected to provide possible therapeutic effect in this Phase 1/2 study.  The increment between 
doses in this study is approximately 3-fold, allowing for the assessment of initial safety, 
tolerability, PK and PD/efficacy in MPS IIIB patients across a 10-fold range of doses on a mg/kg 
basis (0.3, 1 and 3 mg/kg). 
1.5.1.3 Part B (Therapy at 1 and/or 3 mg/kg):  Dose Selection Rationale 
As described in Section 3.1.2, after review of safety, tolerability, and treatment response data in 
Part A, dose modification for individual subjects is permitted in Part B; this allows for either 
dose escalation to 1 and/or 3 mg/kg or reductions to 1 or 0.3 mg/kg based on safety and 
tolerability and the greatest potential for benefit.  
1.5.1.4 Part C (Therapy at 5 and/or 10 mg/kg):  Dose Selection Rationale 
Preliminary PD data through Week 12 showed that while decreases in heparan sulfate in CSF 
were moderately correlated with increased serum PK exposure (AUClast and Cmax), the maximum 
HS reduction in CSF across all 3 doses was 16.5%, which did not reach  the target reduction of 
~40% (see Section 1.5.1.1).  Greater systemic reduction in substrate was observed following 
administration of SBC-103; the maximum HS reduction in serum observed across all 3 doses 
was 68.8%, which is consistent with systemic reductions observed for other ERTs.  In addition, 
the initial safety profile of SBC-103 indicates that it appears to be safe and well tolerated in 
patients with MPS IIIB (see Section 1.4.1.1).  
In the NAGLU-deficient mouse model, SBC-103 administered QW as IV bolus doses of 0.3, 1, 
3, 5, or 10 mg/kg for 4 weeks resulted in decreases in HS in the liver and brain, and while near 
maximal HS decreases were observed in the liver at doses ≥1 mg/kg, HS levels in the brain 
continued to decrease with each increasing dose (SBC103-P010). Furthermore, similar 
reductions in HS (brain and liver) were observed in the NAGLU-deficient mouse model 
regardless of administration regimen (ie, IV bolus QW, IV bolus QOW, or IV infusion QOW) 
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(SBC103-P010; SBC103-P013). Therefore, it is reasonable to expect that greater reductions of 
HS in CSF may be expected at increased dose levels in this clinical study. Dose escalation above 
3 mg/kg in Part C will explore whether substrate reduction in the CNS can be increased with 
higher doses (5 and 10 mg/kg) or whether maximal clearance from the CNS has been achieved, 
thus allowing for identification of doses for extended therapy in this study and for future clinical 
development that will ensure the greatest potential for clinical benefit. 
Therefore, based on the availability of the initial clinical data as well as existing toxicokinetic 
and toxicology data from the 3-month juvenile Cynomolgus monkey study, new human PK and 
PK/PD modelling were performed to predict exposure-based safety margins at doses of 5 and 
10 mg/kg QOW.  As shown in Table 2, scenarios were modelled using 2 sets of assumptions: 
(1) that exposure remains dose proportional; and (2) that exposure is dose disproportional as was 
observed in the juvenile monkey toxicology study.  A starting dose of 5 mg/kg QOW in Part C 
has a projected exposure safety margin of ~6-fold (based on PK exposure) and a dose safety 
margin of 4.  This dose level should provide information on whether or not additional HS 
reduction in CSF can be achieved with greater doses.  If the initial doses at 5 mg/kg are tolerated, 
the 10 mg/kg dose, which has a projected exposure-based safety margin of ~2- to 3-fold (based 
on PK exposure) and a dose safety margin of 2, will also be evaluated (see Section 3.1.3 for a 
summary of the Part C study design). 
Table 2: 
Predicted Safety Margins at Clinical Doses of 5 and 10 mg/kg QOW 
Dose  
(mg/kg, QOW) 
AUClast  
(ng•h/mL) 
Exposure-Based Safety Margina 
Dose Safety 
Marginb 
Dose 
Proportionalc 
Dose  
Disproportionald 
Dose 
Proportionalc 
Dose 
Disproportionald 
 
5 
 
9,515 
 
6.1 
 
4.0 
10 
 
19,030 
31,742 
3.0 
1.8 
2.0 
a Calculated as SBC-103 exposure (AUClast = 58,000 ng•h/mL) on Day 85 in the 3-month juvenile monkey toxicology study 
(SBC103-T009) at the NOAEL dose (20 mg/kg QOW) / predicted SBC-103 exposure (AUClast ) at Week 12 in humans 
b Dose margin = NOAEL dose (20 mg/kg) in the 3-month juvenile monkey toxicology study (SBC103-T09) / SBC-103 
proposed human dose 
c Predicted based on the dose proportionality as observed from 0.3 to 3 mg/kg QOW up to Week 12 in this clinical study. 
d Predicted based on a greater than dose proportional increase (5.56-fold) from 3 to 10 mg/kg and a less than dose proportional 
increase (1.6-fold) from 10 to 20 mg/kg in AUClast observed at Day 85 in the3-month juvenile monkey toxicology 
(SBC103-T009) 
 
1.5.2 Risk/Benefit Assessment 
As discussed in Section 1.1.1, MPS IIIB is a very rare disease that is associated with significant 
morbidity and mortality in affected subjects.  Currently, there are no safe or effective therapies 
for MPS IIIB.  
Part A (Initial Therapy) 
The initial benefit/risk assessment of SBC-103 for this study was based on data from nonclinical 
studies.  Data from safety and toxicity studies conducted in the Sprague-Dawley rat and 
Cynomolgus monkey (including a 3-month study in juvenile monkeys) demonstrated that 
SBC-103 administered IV was generally well tolerated at the doses planned in Parts A and B of 
this study.  Minimal/mild microscopic findings were noted in the liver in some animals, and 
these changes appear to be limited and were seen at doses higher than planned in this study. 
Clinical observations such as decreased activity, drowsiness/sluggishness, decreased muscle 
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tone, abnormal gait, and repetitive behavior were noted generally after the third or fourth dose of 
SBC-103.  These observations were transient and not correlated with any other parameters 
evaluated.  These findings along with anti-SBC-103 IgG antibodies are suggestive of 
hypersensitivity, which is not unexpected when administering a recombinant human protein to a 
heterologous species.  It should be noted that, nonclinical studies are not predictive of potential 
immunogenicity of humans (Brinks 2011, Pharm Res; Ponce 2009, Reg Toxicol Pharmacol).  
Subjects in this clinical study will be monitored closely to identify any potential safety concerns, 
including monitoring liver parameters and antibody development.  See Sections 5.2 and 6.2 for 
more details regarding laboratory assessments and subject stopping rules.   
Extensive clinical experience with approved ERTs for other LSD indications is also relevant for 
risk evaluation of SBC-103.  The main AEs associated with administration of approved ERTs 
(including but not limited to Cerezyme®, VPRIV®, Fabrazyme®), are related to IARs 
(Cerezyme® prescribing information, 2011; VPRIV® prescribing information, 2013; 
Fabrazyme® prescribing information, 2010; Desnick 2012, Annu Rev Genomics Hum Genet).  
The observed IARs are usually mild and can be managed by changes in infusion rate and/or the 
administration of anti-pyretics and anti-histamines.  While severe infusion reactions, including 
anaphylaxis and SAEs related to ERT administration rarely occur, medications and equipment 
for the treatment of hypersensitivity reactions will be available for immediate use.  They include, 
but are not limited to, oxygen, acetaminophen, antihistamines (eg, diphenhydramine, parenteral 
and oral), corticosteroids, epinephrine (adrenaline), and cardiopulmonary resuscitation devices.  
Anti-drug antibodies (ADA) have also been reported with approved ERTs and may be associated 
with altered response to treatment and/or increased risk of IARs.  
As described in Section 1.1.2 and Section 1.3, pharmacologic activity has been observed 
following IV infusion of SBC-103 in NAGLU-deficient mice including increased enzyme 
activity and reduction of the accumulated substrate (HS).  Although examination of the effects of 
long-term IV dosing on CNS manifestations in the mouse model has not been possible because 
of clinical symptoms related to the apparent hypersensitivity, there is a substantial body of data 
linking substrate reduction in brain tissue in MPS IIIB and other MPS disorders with 
improvements in CNS manifestations (Calias 2012, PLoS One; Hemsley 2009, Int J Clin 
Pharmacol Ther). 
The design of this first-in-human study is based on in vivo pharmacology data from a relevant 
disease model supporting the potential for CNS activity following IV administration 
(SBC103-P004, SBC103-P007, SBC103-P009, SBC103-P010), with supportive information 
from in vivo pharmacology data in a relevant disease model supporting the potential for CNS 
activity following IV/IT administration (SBC-103 P011); tissue specific differences in NAGLU 
enzyme levels required to maintain normal phenotype (Li 1999, Proc Natl Acad Sci USA); 
positron emission tomography (PET)/computed tomography (CT) investigations of the PK of 
radiolabeled SBC-103 in non-human primates (IV administration and IT administration) 
indicating access to the CNS following IV administration (SBC103-K004), and PK modeling 
data and affinity data for SBC-103 binding to MMR and M6PR.  
As described in Section 1.1.2, early IV administration of enzyme to an MPS II patient partially 
stabilized cognitive function and prevented the somatic complications seen in his affected older 
brother who started treatment later in life (Tajima 2013, Mol Genet Metab).  There is extensive 
clinical evidence supporting the safety of ERT with known AEs for which to monitor.  
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Part B (Therapy at 1 and/or 3 mg/kg) and Part C (Therapy at 5 and/or 10 mg/kg) 
It is anticipated that extended dosing of SBC-103 may have beneficial effects on disease activity, 
including the neurologic manifestations of MPS IIIB, and it is important to provide the pediatric 
patient population with this disease the greatest prospect of direct benefit in this clinical study by 
evaluating extended therapy at doses that are both safe and have the potential to reach the 
identified target for pharmacologic activity and potential efficacy (see Section 1.5.1.1).  Thus, 
Parts B and C provide for subjects to receive extended therapy and also permit periodic review of 
ongoing safety, PK, and PD data.  Periodic data review permits continued assessment of 
potential benefit and risk based on clinical data and may be used to guide dose modification 
accordingly (escalation or de-escalation, as appropriate). 
Furthermore, the data provided from the study will guide and inform the design of future clinical 
studies. 
1.5.2.1 Risk Assessment for Selected Study Procedures 
In addition to potential risks associated with Investigational Medicinal Product (IMP) 
administration, this study entails procedures that incur incremental risks that are critical for a 
thorough evaluation of the effects of SBC-103 on MPS IIIB.  Given the devastating 
complications associated with MPS IIIB and the inability to obtain important disease relevant 
information using other approaches, the risks are considered to be acceptable in this patient 
population. 
Anesthesia 
Disease progression in subjects with MPS IIIB is associated with cognitive decline and 
behavioral disturbances.  Conscious subjects will not be able to comply with study assessment 
requirements, including maintenance of appropriate positioning during MRI and lumbar 
puncture.  Thus subjects will receive general anesthesia prior to, and during the MRI procedure 
(and lumbar puncture, as appropriate).  Sedation of children is associated with risks of 
hypoxemia, inadequate sedation, and failed sedation.  General anesthesia is a safe alternative to 
facilitate MRI scans in children perceived to be at increased risk for sedation-related AEs as for 
those with a history of failed sedation (Malviya 2000, Br J Anaesth). 
Lumbar Puncture 
A lumbar puncture is necessary to determine if SBC-103 administration is able to reduce HS 
within the CNS.  A subject may experience discomfort or bruising of the skin at the site where 
the needle was inserted (similar to blood collection).  Mild headache is reported in less than 10% 
of cases.   
In rare instances, more severe headaches may occur, which usually respond quickly to treatment 
with over-the-counter pain relievers.  A very rare occurrence is infection from the sample 
collection itself.  The risk for such infection is less than that of a regular blood draw.  
Subjects will receive general anesthesia prior to the lumbar puncture, if clinically appropriate.  
See above regarding risks associated with anesthesia. 
Magnetic Resonance Imaging 
The primary risks of MRI in patients with MPS IIIB are those associated with the administration 
of anesthesia and the potential interference of MRI with metallic foreign objects in the body.  
Subjects will be screened by MRI personnel, according to local guidelines, for any medical 
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contraindications to MRI, including the presence of metallic foreign bodies in the brain or eye or 
cardiac pacemaker.  See above regarding risks associated with anesthesia. 
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2 STUDY OBJECTIVES 
2.1 Primary Objective 
• 
To evaluate the safety and tolerability of IV administration of SBC-103 in subjects 
with mucopolysaccharidosis III, type B (MPS IIIB, Sanfilippo B) with evaluable 
signs or symptoms of developmental delay. 
2.2 Secondary Objectives 
• 
To characterize the PK profile of SBC-103 administered IV. 
• 
To determine the effects of SBC-103 administered IV on the levels, onset and 
magnitude of changes in total HS in CSF, serum, and urine. 
• 
To evaluate the PD/efficacy of doses of SBC-103 administered IV as measured by 
neurocognitive and developmental function and change in brain structures. 
• 
To evaluate the impact of temporary interruption of SBC-103 therapy (between 
Parts A and B) on safety, tolerability, and select PD/efficacy markers, including the 
reversibility of changes in levels of total HS in CSF, serum, and urine.  
2.3 Exploratory Objectives 
• 
To examine the onset, magnitude, and reversibility of changes in exploratory 
biomarkers, SBC-103 concentration in CSF, MPS IIIB disease characteristics, 
symptoms, and quality of life (QOL) after IV administration of SBC-103. 
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3 INVESTIGATIONAL PLAN 
3.1 Overall Design and Plan of the Study 
This study is designed to evaluate the safety and tolerability of IV administration of SBC-103 for 
the treatment of MPS IIIB.  Approximately 9 subjects at approximately 4 centers are expected to 
participate in this study.  As illustrated in Figure 1, this study will be conducted in 3 parts: Part A 
(Initial therapy), Part B (Therapy at 1 and/or 3 mg/kg), and Part C (Therapy at 5 and/or 
10 mg/kg).  All subjects who participate in Part A may continue SBC-103 dosing in Part B if 
they qualify for continued dosing (see Section 4.3.3), and all subjects participating in Part B are 
eligible for dose escalation in Part C providing that the criteria in Section 4.3.4 are met. 
As indicated in Figure 1, the total duration of the study is approximately 164 weeks.  This 
includes a Screening period that will last up to 4 weeks, 156 weeks of therapy with SBC-103, 
4 weeks of time off therapy (between Weeks 24 - 28) , and a 4-week follow-up period after the 
last dose is administered.  
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Figure 1: 
Study Schematic for Part A (Initial Therapy), Part B (Therapy at 1 and/or 3 mg/kg), and Part C (Therapy at 
5 and/or 10 mg/kg) 
 
a In Part A, the SRC will review data as described in Section 3.1.1.1.  
b Subjects will have 4 weeks in between their last dose in Part A and their first dose in Part B instead of the 2 weeks that occurs with QOW dosing.  
c Subjects who meet qualifying criteria may re-initiate therapy in Part B (see Section 4.3.3); dosing in Part B will continue until necessary regulatory and ethics 
committee review and approval (where required) are obtained for each site to dose escalate in Part C and the subject meets the qualifying criteria to begin 
dosing in Part C. 
d In Parts B and C, the SRC will review aggregate safety data as described in Section 7.5. 
e Subjects who meet qualifying criteria may dose escalate in Part C (see Section 4.3.4); in Part C, the SRC will also review data as described in Section 3.1.3.1. 
 
 
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3.1.1 Part A (Initial Therapy) 
In Part A, following completion of the screening assessments to confirm study eligibility, 
approximately 9 subjects will be treated in 1 of 3 different dosing cohorts (0.3, 1, or 3 mg/kg).  
In the event that more than 3 subjects in a cohort have entered Screening and are determined to 
be eligible to participate in the study, an additional subject may be dosed with SBC-103 within 
the intended dose cohort.  This will be acceptable provided the following conditions are met: 
1) the SRC has met and approved the continued dosing of the 1st subject in the cohort and the 
first dose of the 2nd subject and 2) the Sponsor has reviewed safety information of the 2nd subject 
in the cohort and has approved the 3rd patient to be dosed. 
Each subject in each cohort will be dosed sequentially with SBC-103 administered by IV 
infusion QOW for 24 consecutive weeks.  See Table 3 and Figure 1.  
Table 3: 
Part A (Initial Therapy) Dose Cohorts 
Dose 
Cohort # 
Dose of SBC-103a 
Dosing Regimen 
Sample Sizeb 
1 
0.3 mg/kg 
QOW for 24 weeks 
n=3 
2 
1 mg/kg 
QOW for 24 weeks 
n=3 
3 
3 mg/kg 
QOW for 24 weeks 
n=3 
a Intra-patient dose escalation is not planned during Part A.  
b Enrollment of an additional subject in a cohort may occur as described above.  
 
Details regarding the maximum planned dose, dose adjustments, and stopping rules in the event 
of poor tolerability are provided in Section 6.1 and Section 6.2. 
Safety, PK and PD/efficacy assessments will be performed in all subjects as noted in the 
Schedule of Assessments (SOA) for Part A, detailed in Section 14.1 (Appendix A).  All subjects 
will be monitored in an in-patient setting for safety and tolerability for at least 24 hours 
following the first dose of SBC-103.  To evaluate safety, follow-up phone calls will be made to 
each subject (or the subject’s parent or caregiver) within 24 hours after the subject’s second, 
third, and fourth doses in Part A (Weeks 2, 4 and 6, respectively).  
After receiving SBC-103 QOW for 24 consecutive weeks, subjects will have a 4-week temporary 
interruption of therapy prior to being considered for participation in Part B.   
If a subject will not participate in Part B of the study, an additional follow-up phone call will be 
made 4 weeks after the subject’s last administered dose in Part A unless the subject has a 
scheduled follow-up visit. 
3.1.1.1 Criteria for Dosing and Cohort Dose Escalation in Part A 
As illustrated in Figure 2, the decision to continue dosing in the 1st subject in the 1st, 2nd, and 
3rd cohorts will be made by the Sponsor based on SRC recommendations after review of 24-hour 
safety data from that subject and available safety data from all other subjects. 
The decision to initiate dosing in the 2nd subject of each cohort will be made by the Sponsor 
based on SRC recommendations after review of 24-hour safety data from Subject 1 in the same 
cohort and available safety data from all other subjects. 
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The decision to initiate dosing in the 3rd subject of each cohort will be made by the Sponsor 
based on 24-hour safety data from Subject 2 in the same cohort and available safety data from all 
other subjects. 
As described in Figure 2, the decision to escalate into the next dose cohort will be made by the 
Sponsor based on SRC recommendations after review of safety data from the 1st subject who 
completes the first 4 doses in the dose cohort, 24-hour safety data after the first dose from the 
3rd subject of the same cohort, and available safety data from all other subjects. 
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Figure 2: 
Planned Staggered Subject Treatment and Dose Escalation Schedule for the First Four Doses of SBC-103 in 
Part A (Initial Therapy) 
 
(continued on next page) 
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(continued on next page) 
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3.1.2 Part B (Therapy at 1 and/or 3 mg/kg) 
Subjects who meet qualifying criteria may commence Part B (Therapy at 1 and/or 3 mg/kg) after 
completing Part A, and after the SRC and Sponsor have evaluated an individual subject’s 
available safety data and has deemed it acceptable for that subject to initiate continued therapy in 
Part B.  Only subjects who meet eligibility criteria for Part B will re-initiate SBC-103 dosing in 
Part B.  Refer to Section 4.3.3.  Eligible subjects may re-initiate SBC-103 dosing in Part B no 
sooner than 4 weeks after the subject’s last dose in Part A.   
In Part B, dose or dosing frequency (eg, QOW or QW) modifications may be considered by the 
Sponsor after consultation with the SRC, based on a review of safety, tolerability and treatment 
response data. With the intent of treating patients with the lowest dose that is safe and tolerable 
and which has potential for efficacy, dose modification (either an increase to 1 or 3 mg/kg, or a 
decrease to 0.3 or 1 mg/kg) may be proposed for individual subject(s) after evaluation of the 
safety and tolerability data as well as biomarker and treatment response data after 24 weeks of 
study participation.  
Dose modifications will not be considered until Part B of the study, except for instances where a 
dose reduction is required for reasons of safety and tolerability.  Subjects who receive doses of 
0.3 mg/kg in Part A may be considered for a second dose escalation to 3 mg/kg at any time 
during Part B provided that they have tolerated at least 2 doses of 1 mg/kg in Part B.  
Details regarding the maximum planned dose to be evaluated, dose adjustments, and stopping 
rules in the event of poor tolerability are provided in Section 6.1 and Section 6.2. 
Safety, PK, and PD/efficacy assessments will be conducted at regular intervals throughout Part B 
as specified in the SOA for Part B.  See Sections 14.2 and 14.3 (Appendix B and Appendix C).   
Subjects who have received and tolerated at least 4 doses of SBC-103 QOW at 3 mg/kg may be 
considered for participation in Part C (see Section 3.1.3 and Section 4.3.4). Subjects will 
continue to be dosed in Part B of the study until necessary regulatory and ethics committee 
review and approval (where required) are obtained for each site to dose escalate in Part C. 
Subjects who are unable to tolerate at least 4 doses of SBC-103 at 3 mg/kg will continue to be 
dosed at the highest tolerable dose in Part B until study completion. 
If a subject prematurely discontinues, a follow-up call will be made 4 weeks after the subject’s 
last administered dose in Part B unless the subject has a scheduled follow-up visit. 
3.1.3 Part C (Therapy at 5 and/or 10 mg/kg) 
Subjects who meet eligibility criteria for Part C (see Section 4.3.4) may begin Part C at their next 
scheduled visit provided that regulatory and ethics committee review and approval (where 
required) have been obtained for at their study site and the criteria for dosing in Section 3.1.3.1 
are met.  Part C is a randomized, open-label assessment of SBC-103 at doses of 5 or 10 mg/kg 
administered IV.  Subjects will be randomized such that at least 1 subject from each cohort 
assigned in Part A will receive SBC-103 at 5 mg/kg and at least 1 subject from each cohort 
assigned in Part A will receive SBC-103 at 10 mg/kg.  Thus each of the assigned dose levels 
from Part A will be represented in each of the 2 dose levels being studied in Part C.  Treatment 
in Part C will continue through Week 156 of the study. 
Details regarding the maximum planned dose, dose adjustments, and stopping rules in the event 
of poor tolerability are provided in Section 6.1 and Section 6.2. 
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Safety, PK and PD/efficacy assessments will be performed in all subjects as noted in the SOA 
for Part C, detailed in Section 14.4 (Appendix D).  To minimize unnecessary risk and burden to 
subjects, the following study assessments in Part B may be used as baseline assessments for 
Part C in lieu of repeating the assessment prior to the first dose in Part C:   
• An MRI performed within 8 weeks prior to Day 0 in Part C (Day 0C) may be used as the 
baseline assessment for Part C in lieu of performing an MRI on Day 0C. 
• Neurocognition testing performed within 8 weeks prior to Day 0C may be used as the 
baseline assessment for Part C in lieu of performing neurocognition testing on Day 0C. 
• A lumbar puncture performed within 4 weeks prior to Day 0C may be used as the 
baseline assessment for Part C in lieu of performing a lumbar puncture on Day 0C. 
In addition, because individual subjects may reach Week 156 of the study at unique study visits 
in Part C, the following assessments in Part C may be used as the end-of-treatment assessment in 
lieu of repeating the assessment at Study Week 156: 
• An MRI performed within 8 weeks prior to Study Week 156 may be used as the final 
assessment for Part C in lieu of performing an MRI at Study Week 156. 
• Neurocognition testing performed within 8 weeks prior to Study Week 156 may be used 
as the final assessment for Part C in lieu of performing neurocognition testing at Study 
Week 156. 
• A lumbar puncture performed within 4 weeks prior to Study Week 156 may be used as 
the final assessment for Part C in lieu of performing a lumbar puncture at Study 
Week 156. 
These assessments are also noted on the SOA for Part C. 
To provide complete safety data for SRC review (described in Section 3.1.3.1 below), the 
following subjects will be monitored in an in-patient setting for safety and tolerability as follows: 
• The first subject to receive SBC-103 at 5 mg/kg will be monitored for at least 24 hours 
after administration of the first 5 mg/kg dose. 
• The first subject to receive SBC-103 at 10 mg/kg will be monitored for at least 24 hours 
after administration of the first 10 mg/kg dose. 
If a subject discontinues participation from Part C of the study, an additional follow-up phone 
call will be made 4 weeks after the subject’s last administered dose in Part C unless the subject 
has a scheduled follow-up visit. 
3.1.3.1 Criteria for Dosing in Part C 
The first subject who is eligible to dose escalate in Part C (see Section 4.3.4) and who is 
randomized to receive 5 mg/kg in Part C will be the first subject dosed in Part C; in the event that 
>1 subject is eligible at the same time, subjects will be dosed sequentially based on subject 
identification number (eg, Subject [Site #]-003 would be dosed before Subject [Site #]-005).  As 
shown in Figure 3, the decision to continue dosing this subject and to start dosing the remaining 
4 subjects at 5 mg/kg will be made by the Sponsor based on SRC recommendations after review 
of 24-hour safety data from the first subject dosed at 5 mg/kg.  The remaining subjects 
randomized to the 5 mg/kg dose group may be dosed in parallel providing they meet all 
eligibility criteria to participate in Part C.   
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The decision to dose the first subject at 10 mg/kg will be made by the Sponsor based on SRC 
recommendations after review of safety data from 1 subject who completes the first 2 doses at 
5 mg/kg, and review of all available safety data from any other subjects who have received at 
least 1 dose of SBC-103 at 5 mg/kg (Figure 3).  Similar to initiation of dosing at the 5 mg/kg 
dose level, the first subject to receive the 10 mg/kg dose will be the first eligible subject to dose 
escalate in Part C who is randomized to the 10 mg/kg group; in the event that >1 subject is 
eligible at the same time, subjects will be dosed sequentially based on subject identification 
number.  The decision to dose the remaining 5 subjects at 10 mg/kg will be made by the Sponsor 
based on SRC recommendations after review of 24-hour safety data from the first subject dosed 
at 10 mg/kg.  The remaining subjects randomized to the 10 mg/kg dose group may be dosed in 
parallel providing they meet all eligibility criteria to dose escalate in Part C.   
Intra-subject dose escalation from 5 to 10 mg/kg based on all available safety, PK, and 
PD/efficacy data may not occur without prior written approval from the Sponsor.  Dose 
reductions may be considered for safety and tolerability at any time in Part C. 
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Figure 3: 
Planned Subject Treatment and Dose Escalation Schedule in Part C (Therapy at 5 and/or 10 mg/kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2 Rationale for Study Design 
This study will be conducted in 3 parts: Part A (Initial therapy), Part B (Therapy at 1 and/or 
3 mg/kg), and Part C (Therapy at 5 and/or 10 mg/kg).  Part A is designed to assess the safety, 
tolerability, PK, and PD/efficacy of 3 escalating doses of SBC-103 dosed QOW over 24 weeks. 
As this is the first-in-human study, 24-hour in-patient safety monitoring following the first dose 
for each subject and SRC and/or Sponsor review of safety data have been incorporated into 
Part A to minimize risk and to monitor subject safety (see Section 3.1.1.1).  Following Part A 
and prior to entering Part B, subjects will have a 4-week period of time off therapy (instead of 
the usual 2 weeks between doses that occurs with QOW dosing) in order to assess the impact of 
treatment interruption on safety, tolerability, and select PD markers, including the assessment of 
reversibility of any observed on-therapy changes in HS. 
In light of the pediatric patient population intended for enrollment, it is important (and often 
required by regulation) to provide some prospect for benefit with the investigational treatment. 
For an enzyme replacement therapy for a chronic disease such as MPS IIIB, extended treatment 
is generally required to offer any prospect of benefit. Therefore, Part B is designed to assess the 
safety, tolerability, PK, and PD/efficacy of chronic dosing for an extended period of time and to 
allow for intra-patient dose modification based on available data.  Prior to commencing Part B, 
the SRC will review all available safety data from a specific cohort and any safety data available 
from other cohorts to determine the demonstration of an acceptable safety and tolerability profile 
to support extended therapy (see Section 7.5). Additionally, in Part B, the SRC will continue to 
provide oversight of subject safety through periodic reviews of safety data. Ad-hoc reviews of 
safety data will be performed by the SRC on an as-needed basis in the event of emerging safety 
signals of clinical concern in one or more subjects, including subjects who meet pre-defined 
stopping rules (see Section 6.2). 
Part C (added with Amendment 6 based on preliminary safety and PK/PD data from Parts A and 
B) is designed to assess the safety, tolerability, PK, and PD/efficacy of SBC-103 at 5 and 10 
mg/kg over at least 24 weeks as well as to assess the effects on chronic dosing. Intrasubject dose 
modification is permitted in Part C (based on data review and Sponsor agreement) with the intent 
to treat subjects with the lowest potentially efficacious dose that is safe and tolerable. Because 
dose escalation occurs in Part C, 24-hour in-patient safety monitoring following the first dose for 
each subject and SRC and/or Sponsor review of safety data have been incorporated into Part C to 
minimize risk and to monitor subject safety (see Section 3.1.3.1). Additionally, in Part C, the 
SRC will continue to provide oversight of subject safety through periodic reviews of safety data. 
Ad-hoc reviews of safety data will be performed by the SRC on an as-needed basis in the event 
of emerging safety signals of clinical concern in one or more subjects, including subjects who 
meet pre-defined stopping rules (see Section 6.2). 
To provide the greatest likelihood of benefit, subjects are permitted to enter Part C as soon as 
necessary regulatory and ethics committee review and approval (where required) has been 
obtained and the subject meets the qualifying criteria to begin dosing in Part C (see 
Section 4.3.4).  Therefore, each subject’s duration of treatment and assessments in Part B may 
vary.  Once a subject enters Part C, the study visit schedule is reset to Day 0 Part C (Day 0C) to 
ensure that the visit days/assessments correspond to the same number of infusions of SBC-103 
for each subject.  All study visits in Part C will be scheduled relative to Day 0C to allow for a 
more meaningful assessment of the PK and PD/efficacy profile of the 5 and 10 mg/kg doses. In 
addition, subjects will be randomized such that at least 1 subject from each cohort assigned in 
Part A will receive SBC-103 at 5 mg/kg and at least 1 subject from each cohort assigned in 
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Part A will receive SBC-103 at 10 mg/kg.  Thus each of the assigned dose levels from Part A 
will be represented in each of the 2 dose levels being studied in Part C. 
There are emerging compelling data on the advantages of earlier treatment with ERTs in other 
MPS subtypes particularly with regard to impact on disease manifestations which are eventually 
irreversible (Tajima 2013, Mol Genet Metab; Gabrielli 2010, Pediatrics; McGill 2010, Clin 
Genet; Furujo 2011, Mol Genet Metab).  Given the inevitable neurodegenerative manifestations 
of MPS IIIB, early intervention is an important consideration to avoid irreversible disease 
progression and, therefore, pediatric subjects have been included in this study. 
Data from a nonclinical disease model (NAGLU deficient mice) demonstrate reductions in brain 
HS and increases in brain enzyme activity following IV dosing of SBC-103.  Evaluating the 
accumulation of HS in the CSF via lumbar puncture in this clinical study will provide important 
insights into the utility of SBC-103 therapy administered IV. 
Important manifestations of MPS IIIB disease include developmental and cognitive delay and 
regression as well as sleep and behavior disturbances.  This study includes periodic assessments 
to evaluate any changes in these parameters after treatment with SBC-103 administered by IV 
infusion.  As noted in Section 1.4.2, structural and diffusion MRI can provide indices of grey and 
white matter volume reductions and microstructural and white matter connection integrity.  For 
these reasons, structural and diffusion MRI will be used to assess neurodegeneration and any 
changes after treatment with SBC-103 administered by IV infusion.  Blood-brain-barrier 
integrity will also be evaluated by measuring CSF-AI. 
Information regarding the safety and tolerability of each dosing cohort, along with PK/PD data, 
will be used to guide any additional dose escalation in this study as well as to support the 
selection of doses and dose scheduling for subsequent studies.   
3.3 Rationale for Dose and Escalation Timing 
3.3.1 Rationale for Dose Escalation in Part A (Initial Therapy) 
Considering the potential for immunogenicity with a protein product, evaluation of the safety and 
tolerability following multiple rather than single doses prior to escalation is important.  Most 
clinical observations in nonclinical studies occurred by the fourth dose (see Section 1.3).  
Therefore, In Part A, the decision to escalate into the next dosing cohort (from Cohort 1 to 
Cohort 2 and from Cohort 2 to Cohort 3) will be made by the Sponsor, based on SRC 
recommendations after review of safety data from the first subject who completes the first 4 
QOW doses in the dose cohort and 24-hour safety data from Subject 3 in the same dose cohort.  
Intra-patient dose escalation is not planned for Part A. 
3.3.2 Rationale for Intra-Patient Dose Escalation in Part B (Therapy at 1 and/or 
3 mg/kg) 
Based on the experience with neurodegenerative diseases, it is anticipated that clinical response 
to treatment may not be observed sooner than 6 months after initiating treatment with 
SBC-103.  Therefore, evaluation of safety and tolerability data as well as biomarker and response 
to treatment data will take place after 24 weeks of treatment in Part A.  With the intent of treating 
patients with the lowest dose that is safe and tolerable and which has potential for efficacy, dose 
escalation may be proposed for individual subject(s) at any time in Part B as described in 
Section 3.1.2 and Section 6.1.   
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3.3.3 Rationale for Additional Dose Escalation in Part C (Therapy at 5 and/or 
10 mg/kg) 
Preliminary available clinical safety, PK, and PD data (see Section 1.4.1) from this study 
together with existing toxicokinetic and toxicology data from the juvenile Cynomolgus monkey 
study provide a safety margin (see Section 1.5.1.4) that supports dose escalation to 5 and 
10 mg/kg in Part C.  Given the available safety data from Parts A and B and the prior SBC-103 
exposure in these patients, 24-hour safety data from 1 subject at each dose are considered 
appropriate to permit the expansion of each dose cohort, and data from 1 subject who completes 
the first 2 doses at 5 mg/kg is considered appropriate to initiate dosing at 10 mg/kg. 
In addition, ongoing safety and PD data from Part C will be reviewed on an ongoing basis to 
guide further dose selection (ie, escalation from 5 to 10 mg/kg or reduction from 10 to 5 mg/kg) 
in this study with the goal of treating patients at the lowest dose that is likely to demonstrate 
clinical benefit while also being safe and tolerable.  
3.4 Study Endpoints 
3.4.1 Primary Endpoint 
The primary endpoint of this study is safety and tolerability of SBC-103 in subjects with 
MPS IIIB.  The safety assessments will include the following: 
• 
Incidence of AEs, SAEs, and IARs; 
• 
Changes from baseline in clinical laboratory tests (hematology, serum chemistry, and 
urinalysis) and CSF findings (cell counts, glucose, and protein); 
• 
Changes from baseline in 12-lead electrocardiograms (ECGs); 
• 
Changes in vital signs during and post-infusion, relative to pre-infusion values; 
• 
Physical examination findings; 
• 
Use of concomitant medications/therapies; 
• 
Assessment of ADAs, including seroconversion rate, time to seroconversion, and 
ADA titer by time point, peak ADA titer, and ADA titer status (positive/negative), 
and the effect of ADAs on the safety of SBC-103, including the relationship between 
ADA-positive subjects and the incidence of IARs. 
3.4.2 Secondary Endpoints 
The secondary endpoints of this study are baseline and post-treatment measures of the following 
assessments: 
• 
PK profile of SBC-103 after single and multiple doses: 
• 
Maximum observed serum concentration (Cmax) 
• 
Time to reach Cmax (Tmax) 
• 
Area under the concentration-time-curve from time 0 to the last measurable time 
point (AUClast) 
• 
Area under the concentration-time-curve extrapolated to infinity (AUC∞) 
• 
Half-life (T1/2) 
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• 
Clearance (CL) 
• 
Volume of distribution at terminal phase (Vz) 
• 
Accumulation ratio (Rac) 
• 
Effects of SBC-103 treatment on the onset, magnitude, and reversibility of changes in 
levels of total HS in CSF, serum, and urine.  
• 
Neurocognitive and developmental function as determined by the scores on Vineland 
Adaptive Behavior Scales, Second Edition (Vineland-II) and, as appropriate to the 
subject’s age, the Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III) or Kaufman Assessment Battery for Children, Second Edition (KABC-II), 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form (BOT-2 
Brief Form), and Children’s Communication Checklist, Second Edition (CCC-2). 
• 
Brain structure as determined by the relative proportion of grey and white matter volume 
and indices of microstructural integrity as assessed by MRI of the brain. 
• 
Effect of temporary interruption of SBC-103 therapy (between Parts A and B) on safety, 
tolerability, and select PD/efficacy markers.  
3.4.3 Exploratory Endpoints 
Exploratory endpoints in this study include measures to examine the onset, magnitude, and 
reversibility of changes in exploratory biomarkers, SBC-103 concentration in CSF, MPS IIIB 
disease characteristics, symptoms, and QOL after IV administration of SBC-103: 
• 
Biomarkers: 
• 
Change in non-reducing end (NRE) HS derivatives in CSF, serum, and urine 
• 
Changes in serum ferritin and chitotriosidase 
• 
Changes in CSF-disease related biomarkers including but not limited to, hepatocyte 
growth factor (HGF), calbindin D, Tau, pTau, amyloid β, albumin, IgG, glutamic acid, 
and glycine 
• 
Changes in glutamic acid and glycine in relation to plasma (carrier-mediated excitatory 
amino acids that are markers of transport function) 
• 
Changes in CSF/serum albumin index (CSF-AI). 
• 
Changes in IgG index ( [CSF/serum IgG ratio] / [ CSF-AI] )  
• 
Changes in inflammatory markers in serum 
• 
Disease characteristics, symptoms, and QOL 
• 
Assessment of sleep disorders or dysfunction as determined by the Children's Sleep 
Habits Questionnaire (CSHQ) 
• 
Assessment of behavior as determined by the Sanfilippo Behavior Rating Scale (SBRS) 
• 
Assessment of subjective QOL as determined by the Short Form Health Survey for 
Children (SF-10) 
• 
Assessment of caregiver QOL as determined by the Zarit Burden Interview (ZBI) 12-item 
short form 
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• 
Coarsening of features by Facial Dysmorphology Novel Analysis (FDNA) 
• 
Additional blood or urine biomarkers of interest that are identified during the course of 
this study based on emerging data from the scientific literature or the Sponsor’s MPS IIIB 
development program (if there is sufficient sample volume and if local regulations 
permit). 
• 
Assessment of genes that may contribute to and/or modify the disease phenotype via a 
DNA sample (where local regulations permit and subject to discretionary approval from 
each center’s Institutional Review Board [IRB]/Independent Ethics Committee [IEC] and 
the consent/assent of the subject [and/or consent of the subject’s parent or legal 
guardian]). 
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4 STUDY POPULATION 
4.1 Target Population 
The target population for this study is male and female subjects with documented MPS IIIB who 
are greater than or equal to 2 years old but less than 12 years old.  
4.2 Number of Subjects 
Approximately 9 subjects with MPS IIIB are planned to be treated in this study.  All subjects 
may enter Part B if they meet eligibility criteria described in Section 4.3.3, and once the site has 
received approval to escalate to doses of 5 and 10 mg/kg, subjects may enter Part C if they meet 
eligibility criteria described in Section 4.3.4. 
4.3 Eligibility Criteria 
4.3.1 Inclusion Criteria  
A subject who meets all of the following inclusion criteria will be eligible to participate in this 
study: 
1. Has a definitive diagnosis of MPS IIIB, as determined by either of the following: 
a. Documented deficiency in NAGLU enzyme activity ≤10% of the mean value in normal 
individuals (Heron, 2011, Am J Med Genet A) based on test results from a central 
laboratory at Screening. 
OR 
b. Documented functionally-relevant mutations in both alleles of the NAGLU gene based 
on historical test results from a local laboratory (if available) or results from the central 
laboratory at Screening. 
1. Greater than or equal to 2 years old and less than 12 years old at the time of written informed 
consent, and has an age equivalent of ≥1 year on the Vineland-II. 
2. Has documented developmental delay with onset before 6 years of age, as defined by: 
a. Cognitive delay evaluated by BSID-III or KABC-II. 
OR 
b. Language delay, plateauing or regression of language skills as determined by the 
Investigator and confirmed by the Vineland-II (communication domain) administered at 
Screening (eg, subject uses isolated words, associated words such as two-word 
combination, sentences, poor or reduced language and/or language difficult to 
understand). 
3. Subject or subject’s parent or legal guardian (if applicable) consents to participate in the 
study and provides informed consent prior to any study procedures being performed.  If the 
subject is of minor age; he/she is willing to provide assent where required per local 
regulations, and if deemed able to do so. 
4. Female subjects who are of childbearing potential at the time of consent or who become of 
childbearing potential during participation on study (a) must have a negative urine pregnancy 
test at Screening, (b) cannot be breast feeding, and (c) must consent to use a highly reliable 
method of birth control (expected failure rate less than 5% per year) for the duration of the 
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study and for 30 days after last dose of SBC-103.  Women may be considered of 
non-childbearing potential if they have not started their menses or are surgically sterile (ie, 
total hysterectomy or bilateral salpingo-oophorectomy). 
5. Male subjects must consent to use a highly reliable method of birth control (expected failure 
rate less than 5% per year) during any sexual contact with females of childbearing potential 
while participating in the study and for 30 days following discontinuation from this study 
even if he has undergone a successful vasectomy.  
6. Willingness and ability to comply with protocol requirements to the extent that may be 
expected of a subject with cognitive impairment. 
4.3.2 Exclusion Criteria 
A subject who meets any of the following exclusion criteria will be ineligible to participate in 
this study: 
1. Received treatment with gene therapy at any time, or any investigational drug (including 
high dose genistein > 150 mg/kg/day), or device intended as a treatment for MPS IIIB 
within 30 days prior to Screening, or is currently being treated in another study that 
involves an investigational drug or device.  
2. Has any internal or non-removable external metal items that may present a safety risk for 
study assessments that utilize magnetic fields, or any other medical condition or 
circumstance in which an MRI is contraindicated according to local institutional policy. 
3. Previous hematopoietic stem cell or bone marrow transplant. 
4. Known or suspected hypersensitivity to anesthesia or the use of a sedative is 
contraindicated for any other reason. 
5. History of poorly controlled seizure disorder. 
6. A bleeding disorder, or any other medical condition or circumstance in which a lumbar 
puncture (for collection of CSF) is contraindicated according to local institutional policy. 
7. Known hypersensitivity to eggs.  Subjects at high risk for food allergy that may include 
eggs should be tested according to local guidelines.   
8. Other medical conditions or co-morbidities (eg, ALT or AST > 3x ULN, confirmed by 
repeat testing, analyzed centrally or locally and based on the standardized reference range 
provided in the central laboratory manual), or other markers of clinically significant liver 
dysfunction (eg, elevated bilirubin, [with the exception of patients with confirmed 
Gilberts Disease] confirmed by repeat testing, or elevated prothrombin time 
[PT]/International normalized ratio [INR] confirmed by repeat testing analyzed centrally 
or locally and based on the standardized reference range provided in the central 
laboratory manual) which in the opinion of the Investigator, in consultation with the 
Sponsor, would interfere with study compliance, or confound data interpretation. 
4.3.3 Qualifications for Participation in Part B (Therapy at 1 and/or 3 mg/kg) 
Subjects are eligible for continued SBC-103 dosing in Part B if they do not meet any Exclusion 
criteria listed above and if they meet the following: 
1. Completion of Part A with no unmanageable study drug toxicity;  
2. Continue to meet Section 4.3.1 Inclusion Criteria items 4-7; and 
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3. SRC and Sponsor have reviewed the subject’s safety data from Part A and have deemed 
it acceptable for the subject to re-initiate dosing in Part B. 
4.3.4   Qualifications for Participation in Part C (Therapy at 5 and/or 10 mg/kg) 
Subjects are eligible for continued SBC-103 dosing at a higher dose (5 or 10 mg/kg QOW) in 
Part C if they do not meet any Exclusion criteria listed above and if they: 
1. Have completed at least 4 doses of 3 mg/kg in either Part A or Part B with no 
unmanageable study drug toxicity; and 
2. Continue to meet Section 4.3.1 Inclusion Criteria items 4-7. 
4.4 Concomitant Medications and Treatments 
Concomitant medications include prescription and over-the-counter medications, prophylactic 
and therapeutic vaccines, herbal medications, vitamins, and dietary/nutritional supplements, as 
well as any investigational medications the subject may have received.  Concomitant treatments 
include diagnostic, palliative, or interventional procedures (eg, hematopoietic stem cell 
transplant, bone marrow transplant). 
At the Screening visit, information on all medications and treatments received by the subject 
within the preceding 4 weeks will be recorded in the case report form (CRF).  Thereafter, 
reasonable efforts will be made to ascertain all changes in concomitant medications and 
treatments from Screening until the subject completes the safety follow-up phone call.  Particular 
attention will be given to any changes in the dose or dosing regimen of genistein or melatonin, 
antihistamines, chloral hydrate, benzodiazepines, thioridazine, carbamazepine, and sodium 
valproate.  Note that subjects who are on a stable dosing regimen for any of the listed 
medications at the time of Screening, including a low dose of genistein (≤ 150 mg/kg/day), 
should remain on the dosing regimen during the study.  Dose adjustments or discontinuation of 
these medications should occur only when there is a clear medical reason and should be 
pre-approved by the Sponsor.  Information on all concomitant medications and treatments will be 
recorded in the CRF and will include the name of the medication (brand or generic) or therapy, 
reason for use, start date, stop date, dose, route of administration (if applicable), and frequency of 
administration. 
4.5 Discontinuation of Subjects 
4.5.1 Premature Withdrawal from Study Participation 
Subjects have the right to withdraw from the study at any time for any reason, without prejudice 
to further treatment.  
The Investigator and Sponsor also have the right to withdraw subjects from the study at any time.  
Specific reasons for discontinuation may include, but are not restricted to, the following: 
• Intercurrent illness 
• Adverse events, including severe infusion reactions 
• Pregnancy 
• Protocol deviation or non-compliance 
• Termination of the study by the Sponsor  
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4.5.2 Procedures for Discontinuation 
If a subject discontinues at any time after being dosed with SBC-103 (excluding ineligibility for 
Part B), all efforts should be made to have the subject complete follow-up visit procedures, 
including End of Study/Early Withdrawal Visit per SOA (refer to Section 14).  All subjects who 
withdraw 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. 
When a subject fails to return for scheduled assessments, the following efforts should be made to 
contact him/her (this would generally apply to the parent/caregiver) to determine a reason for the 
failure to return: three phone attempts, including the date and time, to be documented in the 
subject’s chart.  If there is no response to the telephone calls, a certified letter should be sent.  
After these efforts have been exhausted, a subject should be identified as lost to follow-up.  
4.6 Subject Replacement Policy 
Subjects who discontinue prior to administration of SBC-103 will be replaced.  Subjects who 
discontinue for reasons other than medically important adverse event(s) considered related to the 
administration of SBC-103 may be replaced after discussion between the Sponsor and the SRC. 
4.7 Subject Re-screening 
Subjects who were unable to complete all Screening procedures within the 28-day screening 
window may be re-screened.  The subject will be re-consented and screening procedures will be 
repeated at the discretion of the Investigator after discussion with the Medical Monitor.  
 
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5 STUDY PROCEDURES 
5.1 Study Assessments 
A Schedule of Study Assessments (SOA) is presented in Section 14.1 (Appendix A) for Part A 
(Initial Therapy), in Sections 14.2 and 14.3 (Appendices B and C) for Part B (Therapy at 
1 and/or 3 mg/kg), and in Section 14.4 (Appendix D) for Part C (Therapy at 5 and/or 10 mg/kg).  
Unless otherwise specified, all study assessments described in the following sections are 
applicable to Parts A, B, and C of this study.  The SOA provides detailed information regarding 
the time points for all of these assessments. 
5.1.1 Informed Consent/Assent 
The subject (or the subject's parent or legal guardian) will be given a consent form as well as a 
verbal explanation of the study, including information about the study procedures, and will have 
all questions adequately addressed.  The subject (or the subject's parent or legal guardian) must 
sign and date a consent form that has been approved by the appropriate IRB/IEC before 
screening procedures are initiated, and will be given a copy of the signed and dated informed 
consent form.  In addition, age and comprehension-appropriate assent will be obtained from 
subjects below the age of consent, as required by local regulations.   
5.1.2 Subject Eligibility 
All subjects will be assessed for eligibility against the inclusion and exclusion criteria described 
in Section 4.3. All eligibility assessments are to be completed prior to the commencement of any 
Day 0 procedure (ie, any invasive procedures, including general anesthesia or sedation, lumbar 
puncture and MRI). Sites are requested to provide documentation/confirmation of eligibility to 
the Sponsor, which is subject to Sponsor review and agreement. 
In Part B, all subjects will also be assessed to determine whether they qualify for re-initiation of 
SBC-103 dosing as described in Section 4.3.3, and subjects will be permitted to enter Part C 
(expanded dose escalation) if they meet the criteria in Section 4.3.4. 
5.1.3 Medical History 
A complete medical history will be obtained for each subject at Screening, including (but not 
limited to) the following:  
• Historical results of NAGLU enzyme activity testing and genetic mutation analysis, as 
applicable; 
• Presence (and date of onset, if known) of the following clinical manifestations or 
disorders as applicable: 
o Cognitive delay/difficulties 
o Abnormal facial features (flat nasal bridge, enlarged lips, enlarged mouth and 
tongue, abnormal thickening/darkening/coarseness of eyebrows) 
o Hepatomegaly 
o Language delay/difficulties, or regression of language skills  
o Abnormal behaviors (hyperactivity, aggressiveness, irritability, endangering 
behaviors) 
o Autism spectrum disorder 
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o Epilepsy 
o Motor function delay/difficulties, including loss of independent walking 
o Sleep disturbances (settling difficulties, early awakening, complete reversal of 
day-night rhythm, obstructive sleep apnea) 
o Ear-nose-throat problems (recurrent ear infections, adenoidectomy or 
tonsillectomy, grommets, documented history of hearing loss) 
In addition, a family medical history will be obtained, documenting the number of siblings and 
the medical status of each sibling, including the presence of abnormalities suggestive of 
MPS IIIB.  Where NAGLU enzyme activity or genetic testing has confirmed the presence of 
MPS IIIB in additional family members, data will be collected on relationship, age of diagnosis, 
medical complications, and, if applicable, cause of death. 
Refer to Section 4.4 for details on collection of medication history and concomitant 
medications/treatments. 
5.1.4 Demographic Information 
The following demographic information will be collected at Screening: date of birth, gender, 
race, and ethnicity.  If local regulations do not allow a full date of birth to be collected, the birth 
date will be reported to the extent allowed (eg, month and year or year only). 
5.1.5 Physical Examination 
Complete, age-appropriate physical examinations will be performed by the Investigator or 
qualified designee at the time points specified in the SOA.  These examinations will include an 
assessment of the subject’s general appearance; skin; head, eyes, ears, nose, throat and head 
circumference; heart; lungs; abdomen; extremities/joints; and neurological status.  Abnormal 
findings will be recorded in the CRF. 
5.1.6 Height and Weight 
Height and weight will be measured at the time points specified in the SOA.  Weight-for-age 
(WFA), weight-for-height (WFH), height-for-age (HFA), and body mass index (BMI)-for age 
will be derived during data analysis, and percentiles or z-scores will be determined for each of 
these derived parameters by standardization to age- and gender-appropriate CDC growth charts. 
5.1.7 Vital Signs and Electrocardiogram 
Vital signs, including pulse rate, respiratory rate, systolic and diastolic blood pressure (BP), and 
body temperature will be taken at the time points specified in the SOA.  In addition, a baseline 
blood pressure measurement should be taken in triplicate prior to administration of SBC-103 at 
screening or prior to SBC-103 administration on either Day 0 in Part A or the subject’s the next 
scheduled infusion.  The baseline BP measurement should be done as follows: 
• Ensure the subject is relaxed or distracted. 
• Obtain 3 separate BP measurements. 
o The same arm should be used for each reading. 
o The right arm is preferred for these repeat BP measurements for consistency and 
comparison with standard tables and, because of the possibility of coarctation of 
the aorta, which might lead to false (low) readings in the left arm. 
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o Each reading should be taken on the same day >15 minutes apart. 
o The same suitable equipment should be used for each reading. 
• Each measurement should be recorded in the subject’s source records and in the CRF  
On Day 1 in Part A, vital signs will be taken prior to hospital discharge.  During dosing visits 
vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 
15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of 
the infusion.  Vital signs should also be obtained after the lumbar puncture is completed as per 
the standard of care.  In Part B, the duration of post-infusion vital signs monitoring may be 
shortened to 1 hour starting with Week 54, provided that there is no occurrence of IARs during 
the infusion.  In Part C, the duration of post-infusion vital signs monitoring may be shortened to 
1 hour starting with Week 26 of Part C, provided that there is no occurrence of IARs during the 
infusion. 
Every effort will be made to collect a 12-lead ECG during the time points specified in the SOA; 
12-lead ECGs will be collected in triplicate during Part A of the study only.  ECGs will be 
reviewed by the Investigator, or designee, and any abnormalities will be specified as clinically 
significant or not clinically significant.  
Due to the behavioral issues typical of subjects with MPS IIIB, ECG assessments may not be 
able to be completed, but should be attempted whenever possible.   
5.1.8 Neurocognitive, Developmental and Quality of Life (QOL) Assessments 
Neurocognitive, developmental and QOL assessments are presented in Section 14.5 
(Appendix E) and will be performed at time points specified in the SOA.  BSID-III and/or 
KABC-II, and BOT-2 Brief Form are administered to the subject.  All other assessments are 
administered to the parent or caregiver. 
The investigator or designee should use clinical judgement to decide whether subject hearing or 
vision problems may preclude developmental testing.  Assessment of vision and hearing may be 
collected from medical history, parent report and/or based on evaluation during Screening 
physical exam.  
Assessments to be performed will include the Vineland-II, BSID-III and/or KABC-II, BOT-2 
Brief Form, CCC-2, CSHQ, SBRS, ZBI 12-item, and the SF-10.  The Vineland-II, BSID-III or 
KABC-II and BOT-2 Brief Form should be administered face to face by appropriately qualified 
professionals.  Assessments may be conducted over more than 1 day.  
The selection of the appropriate neurocognitive test instrument administered to the child is 
normally dependent on the calendar age of the child.  However, since MPS IIIB patients are 
likely to show delayed development, the choice of test instrument at the Screening visit will be 
based on a subject’s Vineland-II age equivalent (developmental age) assessed using the survey 
interview form.  The BSID-III will be administered to subjects with a mean Vineland-II 
age-equivalent of < 3 years 6 months, and the KABC-II, BOT-2 Brief Form, and CCC-2 will be 
administered to subjects with a Vineland-II age-equivalent of ≥ 3 years 6 months.  
During the initial administration of the BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 at 
Screening, if the test administrator determines that the chosen test instrument appears unfit for 
the subject, he/she may switch to the alternate test instrument. However, after the Screening visit, 
the KABC-II should be first attempted. If the subject appears to be failing the KABC-II, they 
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may revert to the BSID-III. If the subject passes the BSID-III, the KABC-II should be continued. 
See Sections 5.1.8.2 and 5.1.8.3 for details.  
5.1.8.1 Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) 
The Vineland-II supports the diagnosis of cognitive and developmental disabilities in subjects 
from birth through age 90 years.  The Vineland-II assesses a subject’s abilities across 5 domains: 
communication, daily living skills, socialization, motor skills, and maladaptive behaviors.  In this 
study, all sections except for the critical items in the Maladaptive Behavior domain will be used.  
Standardized scores, percentile ranks, and adaptive levels are provided for each domain, as well 
as for an adaptive behavior composite measure.  Additionally, the Vineland-II allows for 
determination of V-scale scores, adaptive levels, and age equivalents for subdomains of each of 
the 5 adaptive behavior domains.  Administration of the Vineland-II Survey Interview Form with 
the parent/caregiver takes approximately 20 to 60 minutes.  
The Vineland overall adaptive behavior composite (mean domain age equivalent) will be 
calculated based on all age equivalent scores for the sub-domains under communication, daily 
living skills and socialization, both including and excluding motor skills.  Maladaptive behavior 
is not included in this calculation. A developmental quotient (DQ) will also be calculated as: (age 
equivalent / calendar age) × 100; DQ will also be calculated both including and excluding the 
motor domain. 
5.1.8.2 Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III) 
The BSID-III has been validated for children aged less than 3.5 years and takes approximately 
25 to 60 minutes to administer (Connolly 2012, Pediatr Phys Ther).  The test is administered to 
the subject and was designed to identify young children with development delays.  The BSID-III 
assesses developmental function across 5 domains: cognition; language (expressive and 
receptive); motor (fine and gross motor functioning); and social, emotional, and adaptive 
behavior. 
In this study, cognition, language, and motor functioning will be assessed.  The social, 
emotional, and adaptive behavior domains are not being used due to overlap with the Vineland 
scale.  The mean domain age equivalent will be calculated based on all age equivalent scores for 
the sub-tests, and mean overall age equivalent will be calculated based on all domain age 
equivalent scores.  A DQ will also be calculated as:  (age equivalent / calendar age) × 100. 
Switching from BSID-III to the KABC-II 
At the Screening visit, a child may perform better than expected based on the Vineland-II test.  If 
the score on the first subdomain (cognition) is higher or equal to 79, the KABC-II should be used 
in combination with BOT-2 and CCC-2.  
During future study visits, the KABC-II should be attempted first.  If the subject appears to be 
failing the KABC-II, they may revert to the BSID-III.  If the subject passes the BSID-III, the 
KABC-II should be continued at this visit when practical and subject compliance allows. 
5.1.8.3 Kaufman Assessment Battery for Children, Second Edition (KABC-II) 
The KABC-II has been validated for children aged 3 to 18 years and takes approximately 35 to 
70 minutes to administer (Malda 2010, Assessment).  The test is administered to the subject and 
was designed to identify strengths and weaknesses in cognitive ability and mental processing.  
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The KABC-II is comprised of 18 subtests, although not all subtests are required to be 
administered, and is typically used in conjunction with other cognitive or neuropsychological 
assessments. 
Order of completion of the sub-tests by MPS IIIB Subjects 
Children with MPS IIIB may not be able to complete all subtests, due to a limited attention span 
and behavioral problems.  Therefore, only completion of the non-verbal index (NVI) battery, as 
appropriate for the developmental age of the child, is required to be completed.  Other skills 
(language and motor skills) will be assessed by the CCC-2 and BOT-2 Brief Form, respectively.  
Priority should be given to the most informative domains, the required NVI tests and the BOT-2 
Brief Form.  The CCC-2 is completed by the parents.  After completion of the NVI and BOT-2 
Brief Form, the rater can complete the optional domains in order of importance, and thus, 
relevance.  The NVI and BOT-2 Brief Form should be administered first.  The optional domains 
include Sequential/Gsm, Simultaneous/Gv, Learning/Glr, Planning/Gf (only for developmental 
ages 7-18 years), and Knowledge/Gc. 
Switching from KABC-II to the BSID-III 
At the Screening visit, a child may perform poorer than expected on the KABC-II.  In this case 
the BSID-III should be used.  It is likely that these children will have started with the NVI 
subtests for children 3-5 years.  The first tests for the NVI are Conceptual thinking and Face 
recognition.  If the raw scores for both these first two tests are ≤5 then the KABC-II should be 
discontinued and the BSID-III should be used.  
During future study visits, the KABC-II should be attempted first.  If the subject appears to be 
failing the KABC-II, they may revert to the BSID-III.  If the subject passes the BSID-III, the 
KABC-II should be continued at this visit when practical and subject compliance allows. 
 
5.1.8.4 Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief 
Form (BOT-2 Brief Form) 
The BOT-2 Brief Form is an individually administered test that uses engaging, goal-directed 
activities to measure a wide array of motor skills in children aged 4 through 21 years (Bruininks 
2010, NCS).  The BOT-2 Brief Form contains 12 items to assess fine motor precision, fine motor 
integration, manual dexterity, bilateral coordination, balance, running speed and agility, upper-
limb coordination and strength.  The BOT-2 Brief Form will be administered to subjects who are 
also completing the KABC-II and takes approximately 20 minutes to complete. 
If the subject does not obtain any points in the first two tasks, the motor scales of the BSID-II 
should be used, even if the subject's cognition was assessed by KABC-II. 
5.1.8.5 Children’s Communication Checklist, Second Edition (CCC-2) 
The CCC-2 is a 70-item questionnaire that was designed to rate aspects of communication in 
children including speech vocabulary, sentence structure, and social language skills.  Within the 
two domains of language and pragmatics, the following sub-domains are evaluated: speech, 
syntax, semantics, coherence, initiation, scripted language, context, nonverbal communication, 
social relations, and interests (Volden 2010, Am I Speech Lang Pathol).  The CCC-2 takes 
approximately 5 to 15 minutes to administer to the parent/caregiver and has been validated for 
use in children between the ages of 4 to 16 years.  In this study, the CCC-2 will be administered 
to parents/caregivers who are assessed by the KABC-II in order to get an estimation of language 
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and communication development of the subject.  Since language development assessment is 
already part of the BSID-III, the CCC-2 should not be completed by parents/caregivers of the 
children who are assessed by BSID-III. 
5.1.8.6 Children’s Sleep Habits Questionnaire, (CSHQ) 
The CSHQ is a comprehensive, parent-reported screening survey that has been validated for 
children aged 4 to 10 years (Owens 2000, Sleep); however, it will be completed, if possible, for 
all subjects treated in the study.  The design of the CSHQ is based on common clinical symptom 
presentations of the most prevalent pediatric diagnoses as described in the International 
Classification of Sleep Disorders (Thorpy 1990, American Sleep Disorder Association).  The 
CSHQ takes approximately 20 minutes to complete and consists of 45 questions administered 
across 8 sleep-wake functions including bedtime resistance, sleep onset delay, sleep duration, 
sleep anxiety, night awakenings, sleep-disordered breathing, parasomnias, and daytime 
sleepiness. 
5.1.8.7 Sanfilippo Behavior Rating Scale (SBRS) 
The SBRS is a parent-reported assessment developed at the University of Minnesota specifically 
to assess patients with Sanfilippo Syndrome or MPS III disease.  The SBRS assesses 
communication and expression as well as behavior and is administered as 3 sections.  The initial 
assessment includes Section I (Communication), Section II (Temper Tantrums) and Section III 
(Behavior), which evaluates 15 areas of function that are important for or unique to children with 
Sanfilippo Syndrome.  The 96 questions included in the initial assessment will take 
approximately 45 minutes to complete.  The follow-up assessments that will be completed in 
Parts B and C include a specific follow-up version of Section I, II and III of the SBRS.  This 
section will assess if there have been any changes since the last visit (increased, stayed the same, 
decreased).  It will take approximately 45 minutes for the parent to complete the 96 questions 
during the follow-up assessments. 
5.1.8.8 12-item Zarit Burden Interview (ZBI) 
The 12-item ZBI is a caregiver self-report measure that is used to evaluate levels of stress for 
caregivers of subjects with Alzheimer’s or other forms of dementia.  The 12-item ZBI, validated 
for use in cross-sectional, longitudinal and interventional studies (Bédard 2001, Gerontologist), 
represents a truncated form of the original 22-item ZBI thus enabling easier administration.  The 
assessment takes approximately 5 minutes to complete and measures the caregiver’s overall level 
of burden enabling physicians to identify caregivers who may be at high risk of developing 
physical and/or emotional problems.  
5.1.8.9 10-item Short Form Health Survey for Children (SF-10) 
The SF-10 is a parent-completed survey that contains 10 questions adapted from the Child 
Health Questionnaire and takes less than 5 minutes to complete.  The SF-10 has been validated 
in children aged 5 to 18 years (Zhang 2008, Health Qual Life Outcomes); however, it will be 
completed, if possible, for all subjects treated in the study under the age of 5.  The SF-10 
provides coverage across a wide range of domains, and is scored to produce physical and 
psychosocial health summary measures.  The survey provides a quick and efficient means to 
measure health status.  Due to its brevity, the SF-10 can be easily integrated and administered 
within a broader assessment, and is particularly applicable to large-scale child population 
surveys. 
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5.2 Clinical Laboratory Assessments 
5.2.1 Routine Assessments and Biomarkers 
A list of all clinical laboratory tests that will be performed is provided in Table 4; the time points 
for sample collection are specified in the SOA.  Central lab reference ranges will be used 
throughout the study, including in the event that labs are analyzed locally.  All attempts should 
be made to draw lab samples for central lab analysis when samples are needed for local analysis. 
Blood will be collected for standard hematology and serum chemistry (including coagulation 
parameters). 
During Screening, if a subject’s ALT or AST is greater than 3 × ULN; or a subject has elevated 
bilirubin or PT/INR, confirmatory testing will be completed.  Confirmatory testing may be 
completed locally or by the central lab, however results will be based on the standardized 
reference ranges provided in the central laboratory manual for this study.  Abnormal safety labs 
at Screening can be repeated within 1 to 2 weeks.  The difference between these two pre-
treatment values for each abnormal lab should differ by <20% in each subject.  
Efforts should be made by the Investigator to review subject medical history, concomitant 
medications and health status so that a clear explanation for the elevation is established.  The 
Investigator, in consultation with the Sponsor, shall make a determination of subject eligibility 
based on review of Exclusion Criteria #8.  
During the study, after treatment with SBC-103, in the event that a subject’s ALT or AST are 2× 
ULN (when baseline ALT or AST were within normal limits) or 3× ULN (when baseline ALT or 
AST was greater than 1.5× ULN), or when a subject has an elevation in bilirubin or PT/INR a 
confirmatory test should be completed at the earliest possible time point, but not later than the 
next scheduled visit.  Upon positive confirmation of the elevated transaminases as described 
above, dosing will be paused until AST and ALT have  returned to baseline or to study nadir 
(nadir values may be confirmed by additional lab sampling at the discretion of the investigator, 
using the same lab for analysis of each sample), or normalized if the baseline level was within 
normal limits.  See Section 6.2.1 for stopping rules. 
Every effort will be made to collect urine for urinalysis testing.  If urine can be collected, a urine 
pregnancy test will be performed for females of child-bearing potential.  If a urine sample is not 
able to be provided, a serum pregnancy test will be performed.  
Blood will also be collected for determination of NAGLU enzyme activity and NAGLU gene 
mutation analysis.  A sample will be obtained at Screening for measurement of NAGLU enzyme 
activity by a central laboratory, irrespective of whether historical enzyme activity results are 
available from a local laboratory.  A sample will be collected for determination of NAGLU 
genotype, only if a historical result is not available from the study central laboratory.  If 
available, historical NAGLU enzyme activity and genotyping data from the local laboratory will 
also be recorded in the CRF. 
Serum, and where possible, urine, will be collected for analysis of MPS IIIB substrate (total HS) 
and other disease-related exploratory biomarkers including NRE HS derivatives.  CSF will be 
collected via lumbar puncture for analysis of total HS and other disease-related exploratory 
biomarkers including NRE HS derivatives.  All efforts will be made to obtain a blood sample to 
evaluate serum albumin and serum IgG at the same time as the CSF sample, as reflected in the 
SOA.  The CSF-AI will be calculated as the CSF albumin (mg/mL) / serum albumin (g/L).  IgG 
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index will be calculated as the ([CSF/serum IgG ratio] / [ CSF-AI]).  Refer to Section 5.2.1.4 for 
details regarding the lumbar puncture.  
A specific sample for exploratory biomarker analysis is being collected in this study; however, 
remaining blood and urine samples collected in this study may also be used to analyze additional 
biomarkers of potential clinical interest, if there is sufficient sample and where local regulations 
permit.  As subjects with MPS IIIB may be incontinent, urine samples for routine assessments 
and biomarkers may not be able to be collected, but should be attempted whenever possible. 
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 Committee for Medicinal 
Products for Human Use (CHMP) and Pediatric Committee (PDCO) guidance 
(EMEA/536810/2008, adopted 25 June 2009), the blood laboratory tests will be ranked by tier.  
Per individual, the study-related blood loss should not exceed 3% of the total blood volume 
during a period of four weeks and should not exceed 1% at any single time.  The total volume of 
blood is estimated at 80 to 90 mL/kg body weight; 3% corresponds to about 2.4 to 2.7 mL blood 
per kg body weight.   
Only Tier 1 assessments (see Table 4) are considered mandatory and all efforts should be made 
to collect these samples in all subjects.  Samples for the Tier 2 or Tier 3 assessments will be 
collected if permitted based on the blood or CSF volume threshold for a subject’s weight, as well 
as the subject’s clinical status.   
All tests will be performed by a central laboratory with the exception of the urine pregnancy test 
(or serum pregnancy test if the urine cannot be collected), CSF routine findings, and (as of 
23 March 2015) all coagulation panels, which will be done locally. 
Clinical laboratory samples will be stored by the Sponsor or designee in a secure and controlled 
environment until analysis, and will be destroyed by the Sponsor or designee after all worldwide 
obligations have been met, or sooner if required by local regulations.  
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of clinical laboratory samples. 
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Table 4: 
Clinical Laboratory Tests 
Lab Panel 
Tier 
Matrix 
Tests 
Hematology 
1 
Whole Blood 
White blood cell count; red blood cell count; hemoglobin; hematocrit; 
MCV, MCH, MCHC; platelet count; neutrophil; lymphocytes; 
monocytes; eosinophils; basophils; 
Serum Chemistry 
1 
Serum 
ALT, AST, alkaline phosphatase, GGT, albumin, total bilirubin, serum 
electrolytes (sodium, potassium, chloride, calcium, magnesium, 
phosphorus), glucose, creatinine, bicarbonate, total protein, BUN 
Coagulation 
1 
Plasma c 
PT, INR c 
Urinalysis 
N/A 
Urine 
pH, clarity, color, specific gravity, glucose, ketones, blood, protein, 
nitrite, and leukocytes (microscopic examination will only be done if 
urinalysis is positive for blood, nitrite, or leukocytes, or if protein is 
>1+) 
Pregnancy testa 
N/A 
Urine 
 
MPS IIIB 
Diagnostics 
1 
Dried blood spot 
NAGLU enzyme activity 
1 
Dried blood spot   
NAGLU gene mutation analysis 
PK 
1  
Serum 
PK profile 
PK 
3 
CSF 
SBC-103 concentration 
ADA 
1 
Serum 
Anti-SBC-103 Antibody (IgM,  IgG and IgE).  Subjects who 
experience a moderate or severe IAR should have a serum sample 
collected for ADA during the next study visit (≥ 4 days after the IAR) 
prior to the infusion. 
Biomarkers 
1 
Serum 
HS (total and NRE) 
2 
Serum 
Ferritin and chitotriosidase 
2 
Plasma 
Glutamic acid and glycine 
2 
Serum 
IgG, inflammatory markers, and exploratory biomarkers 
N/A 
Urine 
HS (total and NRE) 
1 
CSF 
HS (total and NRE) 
2 
CSF 
HGF, calbindin D, Tau, pTau, amyloid β, albumin, IgG, glutamic acid 
and glycine 
1 
CSF/Serumb 
CSF/Serum Albumin Index (CSF-AI) and IgG index ([CSF/serum IgG 
ratio] / [ CSF-AI]) 
2 
CSF c 
Routine findings (cell counts, glucose, protein)c 
DNA Sampled 
2 
Whole blood 
 
Serum Tryptase 
If clinically 
indicated 
Serum 
Subjects who experience a moderate or severe IAR should have a 
serum sample collected for analysis of 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. 
Key: ADA = anti-drug antibodies; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; CSF = cerebrospinal fluid; DNA = deoxyribonucleic acid; GGT = gamma-glutamyl transpeptidase; HGF = hepatocyte 
growth factor; HS = heparan sulfate; IAR = infusion-associated reaction; IgE = immunoglobulin E; IgG = immunoglobulin G; 
IgG index = immunoglobulin G index;  IgM = immunoglobulin M; INR= international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; N/A = not 
applicable; NRE = non-reducing end; NAGLU = alpha-N-acetylglucosaminidase; PK = pharmacokinetics; PT = prothrombin 
time. 
Unless specified in the SOA, the laboratory tests apply to Part A (Initial Therapy), Part B (Therapy at 1 and/or 3 mg/kg), 
and Part C (Therapy at 5 and/or 10 mg/kg). 
a Test performed by a local laboratory for all female subjects of child-bearing potential.  If a urine sample is not able to be 
provided, a serum pregnancy test will be performed by a local laboratory. 
b Ensure that serum albumin is collected at each time point a CSF sample is collected. If a serum chemistry is not scheduled at 
the same study visit, a serum albumin should be drawn. 
c Test performed by a local laboratory. 
d  Performed only where local regulations permit and consent is received from the subject or the subject’s parent or legal 
guardian. 
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5.2.1.1 DNA Sample 
Where local regulations permit and subject to discretionary approval from each center’s IRB/IEC 
and the consent of the subject (and/or consent of the subject's parent or legal guardian), a whole 
blood sample will be collected from each subject for DNA extraction.  
DNA sequences, including both the protein-coding sequences and the noncoding sequences 
involved in transcriptional and translational regulation and other biological functions, will be 
analyzed by the Sponsor for genetic modifications that may contribute to and/or modify the 
disease phenotype or rate of progression of MPS IIIB.  Such DNA sequences, that may be 
investigated include: 
• NAGLU; 
• Genes coding for other proteins involved in HS biology that may contribute to and/or 
modify the disease phenotype of MPS IIIB. 
DNA samples will be stored by the Sponsor, or designee, in a secure and controlled environment 
until analysis, and will be destroyed by the Sponsor after all worldwide obligations have been 
met, or sooner if required by local regulations.  
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples. 
5.2.1.2 Exploratory Biomarkers 
Blood samples for serum isolation will be obtained at the time points specified in the SOA for 
exploratory analyses to identify and evaluate disease-related biomarkers, where local regulations 
and blood volume threshold permits.  A specific sample for exploratory biomarker analysis is 
being collected in this study; however, remaining blood and/or urine samples collected in this 
study may also be used to analyze additional biomarkers of potential clinical interest, if there is 
sufficient sample and where local regulations permit.  These samples will be used to identify 
baseline disease and dynamic markers that will help the Sponsor to better understand the 
pathogenesis of MPS IIIB and related comorbidities and response to treatment.  Given the rarity 
of MPS IIIB, the definitive list of analytes remains to be determined.   
Collection of samples for exploratory biomarker analysis will be subject to discretionary 
approval from each center’s IRB/IEC and the specific written consent of the subject or the 
subject’s parent or legal guardian.  This section of the protocol only applies if approval for 
collection of these additional samples has been granted by the IRB/IEC and consent is provided 
by the subject (or the subject’s parent or legal guardian). 
Samples will be stored by the Sponsor, or designee, in a secure and controlled environment until 
analysis, and will be destroyed by the Sponsor or designee after all worldwide obligations have 
been met, or sooner if required by local regulations.  Biomarker assays will be performed by a 
central laboratory or, as appropriate, by academic research laboratories with expertise in the 
analysis of specific biomarkers. 
Refer to the laboratory manual for further details regarding the collection, processing, and 
storage of these samples.   
5.2.1.3 Pharmacokinetic Assessments 
As described in Table 5 (Part A), Table 6 (Part B), and Table 7 (Part C) and the SOA, blood 
samples will be collected to determine SBC-103 serum concentrations using an enzyme-based 
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PK assay.  PK samples collected concurrently with vital sign assessments will be taken prior to 
collection of blood pressure on the non-infusion arm.  PK samples collected at all other time 
points will be taken at least 5 minutes following deflation of the blood pressure cuff.  PK 
samples should not be taken from the same extremity where the infusion catheter is in place. 
CSF samples for determination of SBC-103 concentration in the CSF may also be collected from 
subjects if CSF volume limitations based on subject’s age and weight have not been exceeded. 
Table 5: 
PK Sampling in Part A (Initial Therapy) 
 
Day 0 
Week 12 
Week 24 
Pre-infusion (within 30 minutes) 
X 
X 
X 
During Infusion 
 
 
 
30 minutes (±5 minutes) 
X 
X 
X 
90 minutes (±5 minutes)a 
X 
X 
X 
120 minutes/End of Infusionb 
(±5 minutes) 
X 
X 
X 
After Completion of Infusion 
 
 
 
15 minutes (±2 minutes) 
X 
X 
X 
30 minutes (±5 minutes) 
X 
X 
X 
60 minutes (±5 minutes) 
X 
X 
X 
90 minutes (±5 minutes) 
X 
X 
X 
120 minutes (±5 minutes) 
X 
X 
X 
4 hours (±5 minutes) 
X 
X 
X 
6 hours (±5 minutes) 
 
X 
 
8 hours (±15 minutes) 
X 
  
X 
12 hours (±15 minutes) 
X 
 
X 
24 hours (±15 minutes)a 
X 
 
X 
aTime points may be omitted, if necessary, to avoid exceeding blood volume limitations. 
bAfter the infusion bag has been emptied, but prior to the flush. 
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Table 6: 
PK Sampling in Part B (Therapy at 1 and/or 3 mg/kg) 
 
Week 52 
Week 78 
Week 104 
Week 130 
Week 156 
Pre-infusion (within 30 minutes) 
X 
 
X 
 
X 
During Infusion 
 
 
 
 
 
30 minutes (±5 minutes) 
X 
  
X 
  
X 
90 minutes (±5 minutes)a 
X 
X  
X 
X  
X 
120 minutes/End of Infusionb 
(±5 minutes) 
X 
  
X 
  
X 
After Completion of Infusionc 
 
 
 
 
 
30 minutes (±5 minutes) 
X 
  
X 
  
X 
120 minutes (±5 minutes) 
X 
  
X 
  
X 
4 hours (±15 minutes) 
X 
  
X 
  
X 
6 hours (±15 minutes) 
X 
 
X 
 
X 
aTime point may be omitted, if necessary, to avoid exceeding blood volume limitations. 
bAfter the infusion bag has been emptied, but prior to the flush. 
cTime is relative to the end of the infusion, not the end of the flush. 
Note:  Subjects may enter Part C at any time point during Part B, therefore not all weeks in Part B may be applicable. 
Table 7: 
PK Sampling in Part C (Therapy at 5 and/or 10 mg/kg) 
 
Day 0 
Wk 12 
Wk 24 
Wk 52 
Wk 78 
Wk 104 
Wk 130 or  
End-of-Tx Visita 
Pre-infusion (within 30 min.) 
X 
X 
X 
X 
X 
X 
X 
During Infusion 
 
 
 
 
 
 
 
30 minutes (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
90 minutes (±5 minutes)b 
X 
X 
X 
X 
X 
X 
X 
120 minutes/End of Infusionc 
(±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
After Completion of Infusiond 
 
 
 
 
 
 
 
15 minutes (±2 minutes) 
X 
X 
X 
X 
X 
X 
X 
30 minutes (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
60 minutes (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
90 minutes (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
120 minutes (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
4 hours (±5 minutes) 
X 
X 
X 
X 
X 
X 
X 
6 hours (±15 minutes) 
X 
X 
X 
X 
X 
X 
X 
Key:  min. = minutes; Tx = treatment; Wk = Week 
aWeek 130 in Part C or the subject’s end-of-therapy visit (ie, Week 156 of the study or early termination visit) 
bTime point may be omitted, if necessary, to avoid exceeding blood volume limitations. 
cAfter the infusion bag has been emptied, but prior to the flush. 
dTime is relative to the end of the infusion, not the end of the flush. 
 
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5.2.1.4 Lumbar Puncture (Cerebrospinal Fluid) 
Lumbar punctures will be performed for the collection of CSF at the time points specified in the 
SOA. The coagulation laboratory panel should be collected within 48 hours prior to performing 
the lumbar puncture, and the results should be available prior to sedating/anesthetizing the 
subject or performing the lumbar puncture. At Day 0, the lumbar puncture (including the 
initiation of sedation/anesthesia) shall not commence until the site receives the coagulation 
results, confirms that a subject continues to meet eligibility, and provides such documentation to 
the Sponsor for review and agreement. For all other lumbar punctures during the study, the 
procedure (including the initiation of sedation/anesthesia) will not commence until the site 
receives these results and confirms that it is safe for the subject to receive anesthesia/sedation 
and the lumbar puncture. This documentation should be filed as part of the subject’s file and 
does not need to be reviewed by the Sponsor before the procedure. To facilitate this process, all 
coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to 
the central laboratory for analysis. 
The lumbar puncture may be performed under general anesthesia, if clinically appropriate, or 
under light sedation and will be performed as per local practices by a qualified professional in 
accordance with local institutional procedures.  The first 10 mL of CSF will be collected and 
mixed gently to avoid gradient effects.  The actual volume may be adjusted based on subject age 
or size and local institutional guidelines.  If CSF volume is limited, the analysis of CSF HS (total 
and NRE) should be prioritized as noted in Table 4. 
Routine CSF findings will also be documented (eg, cell counts, glucose, and protein levels), and 
MPS IIIB substrate (HS) and other exploratory CSF biomarkers will be analyzed (see Table 4 for 
details). 
Per the SOA, collection of serum chemistry will not always coincide with the collection of CSF.  
In order to measure the CSF-AI at each possible time point, a serum albumin sample should be 
collected at time points where a serum chemistry sample is not being collected at the same day as 
the CSF sample.  After the lumbar puncture is completed, the subject should be observed as per 
institution standard practice.  Vital signs should be obtained prior to discharge.  Any AEs or 
changes to concomitant medications should also be assessed.  
5.2.2 Facial Dysmorphology Novel Analysis  
Facial photographs will be obtained for Facial Dysmorphology Novel Analysis (FDNA) at the 
time points specified in the SOA.  This technology enables automatic detection and evaluation of 
subtle cranio-facial dysmorphology associated with multiple rare diseases, by processing and 
analyzing standard 2-dimensional (2D) facial photos.  The FDNA system uses proprietary 
computer algorithms to recognize and describe subtle craniofacial malformations (out of a list of 
clinically relevant anatomical facial features) in mathematical terms.  A ranked score, 
representing the probability of the genetic syndrome, is produced based on analysis of the 
severity of the facial alterations relative to variations in a normal population, as well as 
recognition of the face “gestalt” associated with certain rare diseases.  FDNA offers potential as 
a tool for screening large populations for MPS IIIB, which may enable wider and earlier 
diagnosis of MPS IIIB patients, as well as providing a means for monitoring progression of 
disease in patients diagnosed with MPS IIIB.  This study will evaluate FDNA technology as a 
means to evaluate both clinical characteristics and course of disease progression in MPS IIIB.  
FDNA assessment will be optional based on subject/parent consent to participate.  A 
subject/caregiver may refuse this assessment and still participate in this study.  Once a 
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subject/caregiver consents to this assessment, all attempts should be made to collect data at each 
study time point. 
5.2.3 General Anesthesia/Sedation 
Subject compliance and maintenance of appropriate and stable positioning in the MRI is 
complicated due to the anticipated behavior disturbances characteristic of MPS IIIB subjects.  A 
key advantage of general anesthesia is that it minimizes any potential for stress or anxiety during 
the procedure and is independent of a subject’s ability to cooperate, which is critical with MPS 
IIIB subjects.  The whole process, including preparation and scan time, is more predictable, and 
the scan quality will benefit as a result of the subject being immobilized.   
Thus, subjects will receive general anesthesia prior to the MRI procedure.  In principle all types 
of general anesthesia techniques can be used as long as the subject is kept asleep during the MRI 
procedure.  The decision should depend on comorbidities, anatomy and fasting status in the 
individual case and the procedures and practices of the institution.  In clinical practice and in 
earlier studies with subjects with MPS III, propofol sedation was used together with a laryngeal 
mask to guarantee a secure airway and to not unnecessarily prolong the procedure.  The IV 
properties of propofol make it an ideal anesthetic for subjects undergoing imaging 
assessments.  An IV anesthetic without endotracheal intubation allows for careful titration of 
sedation to achieve a clinical effect.  Propofol provides the ability to titrate an anesthetic level 
rapidly and maintain stable drug concentrations during the procedure, thus ensuring that 
anaesthesia is administered in a timely and consistent manner.  Recovery from this type of 
anaesthesia is rapid and not accompanied by nausea or vomiting.  Often the anesthetic can be 
delivered allowing the subject to breathe spontaneously.  Competency of airway is accomplished 
by the insertion of a laryngeal mask airway which allows ventilation of the subject in the cases 
required.  Appropriate local procedures should be utilized under supervision of a pediatric 
anesthesiologist, however, in subjects aged 2 - 10 years, a dose of 100 mcg/kg/min will be 
sufficient to keep the subject asleep with no movement during the scan.  If the subject has an IV 
in place, then a bolus of 2-10 mg/kg (depending on age) can be given initially, followed by a 
continuous infusion of propofol.  If no IV is in place, then anesthesia can be induced with an 
inhalative narcotic such as halothane or sevoflurane (with N20 and oxygen), and IV can be 
inserted, and then continuous infusion of propofol started (Schulte-Uentrop 2010, Curr Opin 
Anaesthesiol). 
As indicated in Section 5.2.1.4, if clinically appropriate, lumbar punctures may also be 
performed under general anesthesia in accordance with local institutional procedures.  When 
applicable, the lumbar puncture should be performed just prior to or after the MRI.  Lumbar 
puncture, when not performed alongside the MRI, may also be performed under light sedation. 
If clinically indicated, subjects may also receive general anesthesia or sedation for central line 
placement for long-term vascular access, in accordance with institutional guidelines.  When 
possible, the procedure to place the central line should be performed while the subject is already 
anesthetized or sedated for another study procedure. 
5.2.4 Structural and Diffusion MRI 
MRI will be performed at time points specified in the SOA.   
High-resolution whole-brain T1-weighted and T2-weighted images will be acquired in order to 
enable measurements of brain volume and relative volumes of grey and white matter. 
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Whole-brain diffusion MRI will also be acquired with multiple diffusion sensitization 
orientations, b value ≥ 1000 s/mm2.  This will enable measurement of diffusion tensor 
parameters, including mean diffusivity (mean apparent diffusion coefficient) and fractional 
anisotropy, as well as anatomical connectivity mapping.  
The estimated total scan time will be approximately 5-10 minutes for structural MRI sequences 
and 15 minutes for diffusion MRI sequences.  All imaging scans will be read centrally.  Detailed 
instructions on image acquisition and analysis will be provided in the Imaging Manual.   
5.2.5 Telephone Calls 
A follow-up telephone call will be made to each subject (or the subject’s parent or caregiver) 
within 24 hours after each of the subject’s second, third, and fourth doses (Week 2, Week 4, and 
Week 6, respectively) in Part A to assess AEs.   
If the subject does not participate in Part B or in Part C of the study, an additional follow up 
telephone call will be made to the subject (or the subject’s parent or caregiver) to assess AEs and 
concomitant medications at least 4 weeks after the subject’s last administered dose in either 
Part A or Part B unless the subject has a scheduled follow-up visit.   
If the subject participates in Part C of the study, a follow-up telephone call will be made to the 
subject (or the subject’s parent or caregiver) to assess AEs and concomitant medications at least 
4 weeks after the subject’s last dose of SBC-103 administered under this protocol unless the 
subject has a scheduled follow-up visit. 
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6 STUDY TREATMENTS 
6.1 Treatments Administered 
Part A (Initial Therapy) 
In Part A, all subjects in each dosing cohort (0.3 mg/kg, 1 mg/kg, 3 mg/kg) will receive SBC-103 
administered by IV infusion QOW for 24 consecutive weeks.  Infusions must be administered at 
least 10 days apart. All study visits will be scheduled relative to Day 0. 
Part B (Therapy at 1 and/or 3 mg/kg) 
For eligible subjects, dosing in Part B may not be re-initiated sooner than 4 weeks and no greater 
than 4 weeks and 3 days after the last dose administered in Part A (See SOA).  Subjects who 
received doses of either 0.3 mg/kg or 1 mg/kg during Part A may escalate to the next higher dose 
of SBC-103 considered to be safe by the Sponsor and SRC with their first dose in Part B or at 
any time thereafter.  Subjects who received doses of 0.3 mg/kg in Part A may be considered for a 
second dose escalation to 3 mg/kg at any time during Part B provided that they have tolerated at 
least 2 doses of 1 mg/kg in Part B (see Section 3.1.2). 
In Part B, if a subject misses ≥ 3 consecutive infusions, additional assessments will be required 
prior to resuming dosing, including safety labs (hematology, chemistry, coagulation, urinalysis 
and pregnancy test, where applicable), and serum and urine HS.  If ≥ 6 consecutive infusions are 
missed, additional assessments, including lumbar puncture for CSF collection, may be required 
prior to resuming dosing as determined by the Sponsor in consultation with the investigator.  The 
next scheduled lumbar puncture would not be necessary if ≤ 2 months have elapsed since the 
previous lumbar puncture. 
Part C (Therapy at 5 and/or 10 mg/kg) 
Dosing in Part C may start as soon as a subject is eligible (Section 4.3.4) and according to the 
schema outlined in Section 3.1.3.  Therefore, each subject’s duration of treatment and 
assessments in Part B may vary.  Once a patient is dose escalated in Part C, the study visit 
schedule is reset to Day 0 Part C (Day 0C).  In Part C, subjects will be randomized such that at 
least 1 subject from each cohort assigned in Part A will receive SBC-103 at 5 mg/kg and at least 
1 subject from each cohort assigned in Part A will receive SBC-103 at 10 mg/kg.  Thus each of 
the assigned dose levels from Part A will be represented in each of the 2 dose levels being 
studied in Part C.  Infusions must be administered at least 10 days apart.  All study visits in 
Part C will be scheduled relative to Day 0C. 
6.1.1 Dose Adjustments  
The maximum planned dose to be evaluated in this study is 10 mg/kg administered by IV 
infusion.  In the event of poor tolerability at any time during the study the dose may be reduced 
or paused.  If a subject cannot tolerate the lowest dose (0.3 mg/kg QOW) despite measures taken 
to manage any IARs or other significant safety events, the subject will be discontinued from 
treatment.  See Section 7.1.3 for guidelines for diagnosis and management of IARs and 
Section  6.2 for stopping rules for individual and multiple patients.  
6.2   Stopping Rules  
6.2.1 Stopping Rules in Individual Subjects  
During Part A (Initial Therapy), Part B (Therapy at 1 and/or 3 mg/kg), and Part C (Therapy at 
5 and/or 10 mg/kg), subjects who experience a severe IAR, a serious or severe AE that is 
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considered related to SBC-103, or a significant elevation in specific laboratory values will have 
SBC-103 dosing paused based on the rules described below. 
For IARs:  
• Subjects who develop a severe IAR, as defined in Section 7.1.3, must stop treatment until 
their information is reviewed by the SRC.  Dosing with alterations to the infusion 
regimen (eg, pretreatment or slowing the rate of infusion) may resume once the SRC and 
the Sponsor approve.  
• Subjects with mild or moderate IARs can continue receiving SBC-103 in the study.  The 
SRC or Sponsor may recommend alterations to the infusion regimen (eg, pretreatment or 
slowing the rate of infusion).  
For all other AEs (ie, AEs that are not characterized as IARs): 
• Any event considered related to SBC-103 which is either serious or severe will result in 
pausing additional dosing in an individual subject.  The SRC and the Sponsor will review 
the data and will resume dosing only after review and agreement.  
• Subjects with mild or moderate non-serious AEs can continue receiving SBC-103 in the 
study.  
For Laboratory Values: 
• Dosing will be paused based on confirmed elevations in AST or ALT under the following 
circumstances:  
• In the event that a subject’s AST or ALT is greater than or equal to 2 times the ULN 
(when baseline ALT or AST was within normal limits) 
• In the event that a subject’s AST or ALT is greater than or equal to 3 times the ULN 
(if baseline ALT or AST greater than 1.5 ULN). 
Dosing will only resume after AST or ALT have returned to baseline or to study nadir 
(nadir values may be confirmed by additional lab sampling at the discretion of the 
investigator, using the same lab for analysis of each sample), or normalized if the 
baseline level was within normal limits.  
The subject should be restarted at a reduced dose.  For example, if a subject was 
receiving a dose of 10 mg/kg, he/she would be restarted at 5 mg/kg; subjects receiving 
5 mg/kg would be restarted at 3 mg/kg; etc.  In the event that the subject was receiving a 
dose of 0.3mg/kg, he/she may resume at the 0.3 mg/kg dose only after AST or ALT have 
returned at least to baseline or to study nadir (nadir values may be confirmed by 
additional lab sampling at the discretion of the investigator, using the same lab for 
analysis of each sample), or normalized if the baseline level was within normal limits.   
If after resuming treatment at the lower dose, the ALT or AST elevation recurs at greater 
than or equal to 2 times the ULN (for those with ALT or AST within normal limits at 
baseline) or 2 times the baseline value (for those with abnormal ALT or AST at baseline) 
study drug should be stopped and not resumed.  Dosing will be paused based on 
confirmed elevations in AST or ALT with accompanying elevations in the following 
o Confirmed bilirubin greater than 1.5 times ULN 
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o Confirmed INR increase of 0.2 
o Eosinophilia (more than 5%), rash or fever  
If these bilirubin and INR values normalize (and the independent SRC believes that it is 
safe to do so), the subject may resume dosing on a lower dose of the study drug (eg, those 
on a 3 mg/kg would resume dosing at 1 mg/kg, those on a 0.3 mg/kg dose would resume 
the 0.3 mg/kg dose).  However, in this scenario, if a subject develops recurrent elevations 
in AST or ALT (with or without elevations in total bilirubin or INR), the drug should be 
stopped and not resumed. 
Subjects whose rise in LFTs is accompanied by eosinophilia (more than 5%), rash or 
fever should not be restarted on the study drug.   
6.2.2 Stopping Rules for Multiple Subjects  
At any time during this study, if 2 or more subjects experience the same (or similar) event 
considered related to SBC-103 which is either serious or severe, or any 1 subject experiences a 
life-threatening AE considered to be related to SBC-103, dosing will be paused for all subjects 
treated at that dose or higher.  The SRC and the Sponsor will review the subject(s) data and 
dosing will resume only after review and agreement.  Detailed information regarding the 
composition of the SRC, the safety data to be reviewed, and the data review process will be 
included in the SRC charter. 
At any time during this study, the SRC or Sponsor may request a pause in dosing of all subjects 
based on review of reported events and all available data.  Dosing will resume only after the 
review of data and agreement to do so by the SRC and Sponsor. 
6.3 Description of SBC-103 
The reference document for SBC-103 is the Investigator Brochure.  SBC-103 must be 
administered under close supervision of the Investigator, or designee. 
The study drug will be provided in a 10-mL glass vial containing approximately 10.5 mL 
(including 5% overfill) of a buffered solution of SBC-103 at a concentration of 2 mg/mL.  The 
study drug contains no preservatives and vials are single use only.  
6.4 Method for Assigning Subjects to Treatment Groups 
In Part A, subjects will be treated sequentially as described in Section 3.1.1.  In Part B, if they 
qualify, subjects will re-initiate treatment with SBC-103 as described in Section 6.1.  In Part C, 
subjects will be randomized such that at least 1 subject from each cohort assigned in Part A will 
receive SBC-103 at 5 mg/kg and at least 1 subject from each cohort assigned in Part A will 
receive SBC-103 at 10 mg/kg.  Thus each of the assigned dose levels from Part A will be 
represented in each of the 2 dose levels being studied in Part C. 
6.5 Storage and Disposition of SBC-103 
6.5.1 Receipt of Drug Supplies 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment.  It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory.  Any damaged or unusable SBC-103 in a given shipment will be documented in the 
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study files.  The Investigator must notify study Sponsor of any damaged or unusable study 
treatments that were supplied to the Investigator’s site. 
6.5.2 Storage 
All SBC-103 vials must be stored at a controlled temperature of 2-8°C.  Vials should not be 
frozen and should be protected from light during storage.   
The infusion bag or syringe containing SBC-103 diluted in 0.9% saline should be prepared 
immediately before infusion.  Dilution should occur under controlled and validated aseptic 
conditions.  The prepared diluted infusion bag (or syringe) may be stored at room temperature 
(20°C to 25°C) for no more than 8 hours, although it is preferable that prepared solution be used 
within 4 hours of dilution.  Shaking or other forms of agitation of vials or infusion bags should 
be avoided.  Refer to the IMP Manual for detailed instructions.  
6.5.3 Disposition 
The Investigator or designee (eg, a licensed pharmacist) will be responsible for maintaining 
accurate records for all supplies used.  Opened vials of SBC-103 containing residual volume will 
be stored at room temperature for SBC-103 accountability.  Following SBC-103 accountability, 
the Sponsor will provide authorization to the Investigator to return or destroy any remaining 
investigational product as instructed. 
Under no circumstances will SBC-103 be used other than as directed in the protocol.  Refer to 
the IMP Manual for additional details. 
6.6 Preparation and Administration of Study Drug 
6.6.1 Preparation of Study Drug 
Dose preparation and administration should be performed using sterile, non-pyrogenic 
disposable materials including, but not restricted to syringes, needles, transfer tubing and 
stopcocks.   
The infusion bag (or syringe) containing SBC-103 should be prepared just prior to the start of IV 
infusion.  It is preferable that the prepared diluted infusion is used within 4 hours of dilution, 
although it may be stored at room temperature for up to 8 hours. 
Prior to preparation of the infusion, the vials of study drug should 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.  SBC-103 is a protein and should be not be shaken but should be 
handled and mixed gently to prevent foaming. 
The subject’s most recent protocol-scheduled weight measurement, 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 IV infusion.  Study drug will be diluted in 0.9% saline for injection.    
Refer to the IMP Manual for detailed instructions regarding the preparation of the IV infusion.  
6.6.2 Administration of Study Drug 
All infusions must be administered under close supervision of the Investigator, or designee. 
Study drug should not be infused with other products in the same infusion tubing, as the 
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compatibility of SBC-103 in solution with other products has not been evaluated.  It is 
recommended that all infusions of study drug be administered using in-line filtration with a low 
protein binding 0.2 micron filter.  
The recommended duration of the infusion is 2 hours at a constant rate.  The protocol allows for 
a change in rate should the patient experience an IAR.  At the discretion of the investigator and 
in consultation with the sponsor, in circumstances such as a prior IAR or other like situations 
where patient safety is a concern, an extended duration of infusion or a variable rate is 
acceptable.  If the infusion is not well tolerated, the infusion rate may be decreased or interrupted 
as noted in Section 7.1.3 and Section 6.2.  All changes to infusion rate must be carefully 
recorded in the CRF, including the start and stop time of each rate change. 
Refer to the IMP Manual for detailed instructions on the administration of SBC-103. 
6.7 Randomization and Blinding of SBC-103 
This is an open label study with no requirement for blinding. 
In Part C, subjects will be randomized such that at least 1 subject from each cohort assigned in 
Part A will receive SBC-103 at 5 mg/kg and at least 1 subject from each cohort assigned in 
Part A will receive SBC-103 at 10 mg/kg.  Thus each of the assigned dose levels from Part A 
will be represented in each of the 2 dose levels being studied in Part C.  As noted in 
Section 1.4.1, a total of 11 subjects are enrolled in this study; 5 of these will be randomized to 
receive 5 mg/kg QOW and 6 will be randomized to receive 10 mg/kg QOW. 
Details of the randomization will be provided in a randomization specification document, which 
will be maintained by the Sponsor.   
6.8 Destruction of SBC-103 
If any unused study drug material is remaining upon completion of the study, the material will be 
returned to the Sponsor or designee or destroyed only after the Sponsor or designee has 
performed final drug accountability and provided written authorization for the return or 
destruction of study drug.  Refer to the IMP Manual for further instructions. 
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7 ASSESSMENT OF SAFETY 
The methods for collecting safety data are described below.  All personnel involved with the 
study must ensure they are familiar with the content of this section. 
7.1 Adverse Events and Laboratory Abnormalities 
7.1.1 Clinical Adverse Events  
An AE is any untoward medical occurrence in a subject, which does not necessarily have to have 
a causal relationship with the administration of a study drug.  An AE can therefore be any 
unfavorable and unintended sign, symptom or disease temporally associated with the use of the 
study drug, 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 in the AE page of the CRF.   
The Investigator will assess the severity, causality (relationship to study drug), and seriousness 
of each AE. 
Severity: The Investigator will assess the severity of all AEs/SAEs as mild, moderate, or severe, 
based on the following definitions, developed from Clinical Data Interchange Standards 
Consortium (CDISC) Study Data Tabulation Model (SDTM) standard terminology v3.1.1). 
• Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of 
daily living.  
• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research participant. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.  
Causality: AEs will be assessed as not related, unlikely related, possibly related, or related to 
study drug.  Table 8 provides general guidance on the assessment of causality.  For data 
reporting purposes, AEs assessed as not related or unlikely related will be classified as unrelated 
to study drug, and AEs assessed as possibly related or related will be classified as related to 
study drug.  Assessment of causality should be based on the Investigator’s medical judgment and 
the observed symptoms associated with the event.  
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Table 8: 
Assessment of Causality 
Relationship to Study Drug 
Criteria for Judgment 
Related 
Reasonable temporal relationship of the clinical event to study 
drug 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 study drug 
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 study drug 
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.  
An SAE is any AE that is or leads to any of the following:  
• Death. 
• Immediately life threatening.  An adverse event is considered “life threatening” if, in the 
view of either the investigator or Sponsor, its occurrence places the subject at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Congenital anomaly/birth defect. 
• 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 above. 
All SAEs and IARs must be reported to the Sponsor as described in Section 7.4.1. 
7.1.2 Laboratory Test Abnormality 
Laboratory test results will be recorded, or appear on the laboratory reports submitted directly 
from the central laboratory.  Out of range laboratory test values should not be reported as AEs 
unless they are considered to be clinically significant abnormalities by the Investigator. 
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7.1.3 Adverse Events of Special Interest (Infusion-Associated Reactions) 
IARs will be considered AEs of special interest.  Any AE that occurs during the infusion or 
within 4 hours after the infusion is completed and is assessed by the Investigator as at least 
possibly related to study drug will be designated as an IAR for this study.  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 reaction.  
These supplies include, but are not limited to, oxygen, acetaminophen, antihistamines (eg, 
diphenhydramine, parenteral and oral), 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, cardiac arrhythmias, dyspnea, wheezing, stridor, hypotension or 
hypertension.  
General guidelines for the diagnosis and management of IARs are provided in Table 9.  These 
guidelines are not intended to be comprehensive.  The Investigator should use clinical judgement 
in the management of IARs in individual subjects participating in this study.  In the case of a 
severe life-threatening reaction, current medical standards for emergency treatment are to be 
followed. 
 
 
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Table 9: 
Guidelines for the Management of IARs 
Symptoms 
Action 
Mild Reaction 
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% 
• 
Increase infusion time in accordance with 
institutional standard of care  
• 
Administer oral anti-pyretic and/or antihistamine 
• 
Once the event has resolved, the infusion should 
continue at reduced rate for a minimum of 
30 minutes before infusion is increased to 75% of 
original rate 
• 
Decrease infusion rate by a further 25% if 
symptoms persist 
• 
If symptoms continue despite rate reduction, stop 
infusion 
• 
Pre-treat with oral antihistamine and antipyretic 
prior (approx. 1.5 hours) to next infusion  
• 
eg, diphenhydramine 25-50 mg by mouth and 
acetaminophen 650 mg by mouth 
Moderate Reaction 
• 
Hyperemia (flushing) 
• 
Chest discomfort 
• 
Itching and/or raised urticarial rash 
• 
Severe headache 
• 
Gastrointestinal symptoms, vomiting, diarrhea, 
abdominal cramping 
• 
Stop infusion 
• 
Give antihistamine intravenously and consider IV 
steroids in accordance with institutional standard of 
care 
• 
Give any prescribed inhaler treatment if 
appropriate 
• 
Collect serum for analysis of 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. 
• 
Pre-treat with oral antihistamine and antipyretic 
prior to next infusion 
• 
Skin testing may be considered 
Severe Reaction 
• 
Clinically significant cardiovascular effects 
(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 intramuscular injection of epinephrine 
(adrenaline)  
• 
Give antihistamines intravenously and steroids 
intravenously 
• 
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 
SRC has completed review of the IAR, and any 
other relevant safety data (Section 6.2) 
 
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7.2 Handling of Safety Parameters 
7.2.1 Serious Adverse Events and Infusion-Associated Reactions (Immediately 
reportable to the Sponsor) 
All SAEs and all IARs (serious and non-serious), 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). 
The definition and reporting requirement are in accordance with ICH Guideline for Clinical 
Safety Data Management, Definitions and Standards for Expedited Reporting (Topic E2, 1995). 
7.2.2 Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from signature of 
the informed consent to the end of the study treatment follow-up.  Adverse events 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 following the last administration of study 
treatment.  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 immediately and followed up until they have returned to baseline values and/or an 
adequate explanation of the abnormality is found.  If a clear explanation is established, it should 
be recorded.  All subject showing possible drug-induced liver injury should be evaluated by a 
hepatologist for other causes of elevated hepatic function tests and followed until all 
abnormalities return to normal or baseline, or are deemed not to be related to the study drug.  
See Sections 5.2.1 and 6.2.1 regarding pausing rules for subjects with significantly elevated 
transaminases.  
7.2.5 Pregnancy 
Female subjects who are of childbearing potential at the time of consent or who become of 
childbearing potential during participation on study must agree to use a highly reliable method of 
birth control (expected failure rate less than 5% per year) for the duration of the study and for 
30 days after the last dose of SBC-103.  
Male subjects and their partners, must be using a highly reliable method of birth control 
(expected failure rate less than 5% per year) for the duration of the study and for 30 days after 
the last dose of SBC-103.  
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A female subject must immediately inform the Investigator if she becomes pregnant during the 
study and must not receive further SBC-103 infusions.  Pregnancies occurring up to 90 days after 
the completion of the last infusion must be reported to the Investigator.  The Investigator must 
report all pregnancies to the Sponsor within 24 hours of notification.  The Investigator should 
counsel the subject discussing the risks of continuing with the pregnancy and the possible effects 
on the fetus.  Monitoring of the subject should continue until conclusion of the pregnancy. 
Pregnancy occurring in the partner of a subject participating in the study within 90 days of 
completion of the last infusion must also be reported to the Investigator and Sponsor.  The 
partner should be counseled and followed as described above. 
7.3 Recording of Adverse Events 
At each contact with the subject (and the subject’s parent or caregiver), 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 
CRF.  All clearly related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded under one diagnosis.  
Adverse events will be recorded from the time of signing of the informed consent until 
completion of the last scheduled visit, ie, the follow-up visit.  Adverse events 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 
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 CRF.  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 or possibly 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 SBC-103, causality assessment and outcome of the event will be recorded for each AE. 
7.4 Reporting of Serious Adverse Events, Infusion-Associated Reactions and 
Unanticipated Problems 
Investigators and the Sponsor must conform to the AE reporting timelines, formats and 
requirements of the various entities to which they are responsible.  (§13 GCP-V; Detailed 
guidance on the collection, verification and presentation of AE/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, IECs or IRBs, and Investigators as required by 
local regulations. 
All SAEs and 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. 
7.4.1 Investigator Reporting: Notifying the Sponsor 
Periodic Safety reporting to regulatory authorities will be done by the Sponsor according to 
national and local regulations.  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 
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after the Investigator’s first knowledge of the event.  To report such events, an SAE/IAR form 
must be completed by the Investigator and sent within 24 hours.  The Investigator will keep a 
copy of this SAE/IAR form on file at the study site.  
The Investigator will provide any additional information within 24 hours of becoming aware of 
this information.  This should include a copy of the completed SAE or IAR form, and any other 
information that will assist with 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 after the Investigator’s becomes aware of this information.  
Report SAEs and IARs by fax to: 
 
 
 
 
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 receipt will be kept in the Investigator’s study file. 
7.4.3 Sponsor Reporting: Notifying Regulatory Authorities 
The Sponsor is required to report certain study events in an expedited manner to the US Food 
and Drug Administration (FDA), the European Medicine Agency, and to all country Regulatory 
Authorities where the study is being conducted.  The following describes the safety reporting 
requirements by timeline for reporting and associated type of event: 
• Immediately and within 7 calendar days 
o Any suspected adverse reaction that is: associated with the use of the study drug, 
unexpected, and fatal or life threatening.   
o Follow-up information must be reported in the following 8 calendar days. 
• Immediately and within 15 calendar days 
o Any suspected adverse reaction that is: associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening. 
o Any finding from tests in laboratory animals that suggest a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
o Any event in connection with the conduct of the study or the development of the 
IMP that may affect the safety of the study subjects. 
o Follow-up information must be reported within 15 calendar days 
The Sponsor will comply with all additional local safety reporting requirements, as applicable.  
Periodic safety reporting to competent authorities will be done by the Sponsor or designee 
according to national and local regulations. 
PPD Pharmacovigilance Fax 
EU 
 
US 
 
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PPD


NGLU-CL02 Protocol Amendment 7 
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7.4.4 Sponsor Reporting: Notifying Participating Investigators 
It is the responsibility of the Sponsor or designee to immediately notify all participating 
Investigators of any 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 Independent Safety Review Committee (SRC) 
Part A (Initial Therapy), Part B (Therapy at 1 and/or 3 mg/kg), and Part C (Therapy at 5 and/or 
10 mg/kg) 
It will be the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  Additional oversight of the subject safety in the study will be provided by an 
independent SRC composed of individuals with pertinent medical expertise, who will serve in 
advisory capacity to the Sponsor, to provide an additional level of scrutiny to minimize the 
chance that clinical study participants are exposed to unreasonable or unnecessary risks.  The 
SRC will provide additional oversight for safety through periodic and ad-hoc reviews of safety 
data.  The specific activities and composition of the SRC will be outlined in the SRC Charter 
which will be ratified during the initial meeting, prior to commencement of dosing of the study 
subjects.  The SRC will be tasked with ongoing review of safety data in order to advise the 
Sponsor regarding continued dosing and dose escalation decisions for the study.  These safety 
monitoring functions and the oversight of such activities will be distinct from the requirement for 
study review and IRB/IEC approvals. 
Core members of the SRC will not participate in the study as Investigators or sub-investigators, 
as members of any team otherwise participating in the study, or in any other capacity that may 
compromise their privileged activities on the SRC.  Neither members of the SRC nor their 
immediate family members will have a direct financial interest in the Sponsor or an interest that 
is dependent of the outcome of the study.  To be considered for SRC membership, all candidates 
must disclose all actual or potential conflicts of interest, including any financial interest in, or 
research activity on a competing product.  SRC members will be compensated at an appropriate 
market rate for time spent reviewing, discussing, and attending the meetings.  The Sponsor will 
also reimburse SRC members for any out-of-pocket travel expenses required for attendance at 
the meetings.  Aside from the above, SRC members will receive no additional compensation for 
their membership on the committee as outlined in the SRC Charter. 
Part B (Therapy at 1 and/or 3 mg/kg) and Part C (Therapy at 5 and/or 10 mg/kg) 
The SRC will perform a review of each subject’s available safety data prior to the start of Part B 
for each subject.  The SRC will also conduct periodic reviews (at least every 6 months during the 
first year and annually thereafter) of aggregate safety data as indicated in the SRC Charter.   
Ad-hoc reviews of safety data will be performed on an as-needed basis in the event of emerging 
safety signals of clinical concern in one or more subjects, including subjects who meet the pre-
defined stopping rules for study treatment (see Section 6.2).  Additionally the Sponsor will 
review the PD/efficacy every 6 months during the first year and at least annually thereafter to 
confirm the appropriateness of continued dosing. 
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8 STATISTICAL PLAN 
8.1 General Considerations 
Descriptive summary statistics will be provided for demographics, disposition and dose 
exposure.  Number and percentage of subjects who discontinued from the study, along with 
reasons for discontinuations will be tabulated and described in listings. 
Continuous data will be summarized using descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) and, where appropriate, graphic 
representation and two-sided 95% confidence intervals (CI); categorical data will be summarized 
by sample size, proportions, and two-sided 95% CIs. 
8.2 Determination of Sample Size 
The sample size of approximately 9 subjects is based on clinical and not statistical consideration 
and is considered sufficient to provide PK, safety, and PD/efficacy data to inform dose and 
regimen selection for additional clinical studies. 
8.3 Analysis Sets 
8.3.1 Full Analysis Set 
The full analysis set (FAS), defined as all subjects who have received any amount of SBC-103 
and from whom informed consent has been obtained, will be used to summarize PK, PD, and 
efficacy data. 
8.3.2 Safety Analysis Set 
The safety analysis set, which is the same population as the FAS, will be used to summarize all 
safety and tolerability data.   
8.4 Safety Analysis  
Safety analyses may be performed for Parts A, B, C, and/or all 3 study parts (ie, the entire study). 
Descriptive summaries of data will be presented overall for all treated subjects and by dose 
group, as appropriate.  Details of these analyses, including how baseline values are defined, will 
be specified in the statistical analysis plan (SAP).   
Descriptive statistics will be computed for safety parameters, as appropriate.  Number and 
percentage of subjects who discontinued from the study because of AEs, will be tabulated across 
dose cohorts; severity and frequency of AEs and SAEs will also be tabulated across dose cohorts.  
All other safety data will be provided in listings.  Baseline, within study, end-of-study, and 
change from baseline in physical examination findings, ECG, clinical laboratory values, and vital 
signs will be summarized by dose cohort.  
The proportion of subjects with measurable antibodies to SBC-103 will be displayed.  In 
addition, IARs will be tabulated by cohort and overall.  Medications to treat IARs, including any 
medications for pretreatment, will also be presented by cohort and over the entire study period.  
SBC-103 infusions in which the rate was slowed or discontinued due to IARs will be detailed in 
a separate data listing. 
Further statistical evaluations will be applied for select endpoints, if warranted.  All baseline data 
and safety data collected during the study will be listed for each subject. 
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8.5 Pharmacokinetic Analysis  
PK analysis will be performed using non-compartmental analysis.  Graphs of PK concentration 
over time will be generated for each subject and also for all subjects in a dose group.  Serum PK 
parameter (Cmax, Tmax, AUClast, AUC∞, T1/2, CL, Vz, and Rac) assessments will be summarized for 
each subject, as well as for each dose group.  SBC-103 concentration in CSF will be summarized 
at available time points.  Additional analysis of PK data, including assessment of the impact of 
ADA, may be performed as appropriate.   
Pharmacokinetic analyses may be performed for Parts A, B, C, and/or all 3 study parts (ie, the 
entire study).  Further details will be provided in the PK section of the SAP. 
8.6 Pharmacodynamic/Efficacy Analyses 
Pharmacodynamic/efficacy analyses will be performed for Parts A and C, and/or all 3 study parts 
(ie, the entire study). Descriptive summaries of data will be presented overall for all treated 
subjects and by dose group, as appropriate.  Details of these analyses, including how baseline 
values are defined, will be specified in the SAP.   
Parameters describing total HS and exploratory disease-related biomarkers including NRE HS 
derivatives, will be provided in listings and may be tabulated as described previously. 
Parameters describing disease characteristics, symptoms, and QOL of subjects with MPS IIIB, 
including neurodegeneration (MRI), CSF-AI, neurocognitive and QOL (Vineland-II, BSID-III, 
KABC-II, BOT-2 Brief Form, CSHQ, CCC-2, SBRS, SF-10, ZBI 12-item) will be provided in 
listings and may be tabulated as appropriate.  
PD, disease characteristics, symptoms, and QOL outcomes analyses will be summarized.  
Observed measurements and changes or percent changes from baseline in HS and NRE HS 
derivatives and disease related biomarkers will be summarized overall and by dosing regimen for 
each time point.  Change in relative proportion of grey and white matter volume and 
microstructural integrity will be summarized.   
Graphs of actual values and changes over time may be created as appropriate.   
Parameters describing facial features of subjects with MPS IIIB will be provided in listings and 
may be tabulated as appropriate.  
8.7 Summaries of Data Prior to Study Completion 
Interim data will be summarized for presentation to regulatory authorities or to the scientific 
community to facilitate discussions and obtain input on late phase study designs. 
For some of these summaries, CIs may be computed.  Additional details of the pre-specified 
statistical analyses will be provided in a separate SAP. 
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9 SUBJECT DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of applicable local regulations. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  Source 
data are contained in source documents.  Examples of these original documents and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments. 
The MRI images plus auxiliary information will be stored locally but also transmitted to the 
Sponsor in Digital Imaging and Communications in Medicine format for potential further 
internal analyses and for generation of illustrative images.  
9.3 Case Report Forms 
Required data for this study will be captured on CRFs via electronic data capture unless 
otherwise specified in this document.  Except for data points for which the protocol  indicate that 
the CRF may serve as source documentation, data are to be obtained from the subject’s source 
documents and then entered into the CRF by authorized personnel.  Clinical data that are not 
recorded on the CRF 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 for SBC-103 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 SBC-103.  These documents should 
be retained for a longer period if required by the local legislation requirements or 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 (eg, diagnostic laboratory), 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 (or their designee), government regulatory bodies, and quality assurance groups of 
all study-related documents (eg, source documents, regulatory documents, data collection 
instruments, study data).  The Investigator will ensure the capability for inspections of applicable 
study-related facilities (eg, diagnostic laboratory). 
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 in accordance with international standards of GCP (ICH, EU 
Directives 2001/20/EC and 2005/28/EC, and US 21CFR50 and 21CFR312), as well as all other 
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 applicant and 
a copy of this decision will be provided to the Sponsor before commencement of this study.  The 
IRB/IEC will be requested to provide a list of IRB/IEC members.  A member who is affiliated 
with the Sponsor should not participate in voting on the IRB/IEC opinion. 
Each subject (or the subject’s parent or legal guardian) will be given a consent form describing 
this study and providing sufficient information to allow the subject (or the subject’s parent or 
legal guardian) to make an informed decision about the subject’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 (or a subject’s parent or legal guardian), using the 
IRB/IEC-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject (or 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 (if applicable) 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 DATA DISCLOSURE 
A clinical study report (CSR) will be produced upon completion of the study.  A coordinating 
Investigator will be designated to review and sign the completed CSR.  
Information about this study will be posted on the http://clinicaltrials.gov and 
https://www.clinicaltrialsregister.eu websites and, where applicable, on other websites required 
by the local regulatory authorities of participating countries. 
It is intended that the results from this research will be submitted to a peer-reviewed medical 
publication, once the study is completed. 
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Leavitt M, Xu H, Canty D, Quinn AG. 2013 LDN WORLD conference. Biochemical Evidence Of The 
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14 APPENDICES 
 
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14.1 Appendix A: Schedule of Study Assessments (Part A, Initial Therapy)  
Schedule of Study Assessments 
 
Part A:  Initial Therapy 
Time 
Off 
Assessments 
Screening 
Day 0*** 
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days)* 
-28 to 0** 
-4 to 0 
 
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG (Triplicate2) 
X 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
FDNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI 12-item, SF-103 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
NAGLU Enzyme Activity4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NAGLU Genotype5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA Sample6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Serum 
Chemistry (including 
Coagulation7), Urinalysis8 
X 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Pregnancy Test (Urine)9 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan 
Sulfate (Total and NRE)10 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum Ferritin and 
Chitotriosidase11 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Plasma Glutamic Acid and 
Glycine11 
X 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum Biomarkers 
(Exploratory, including IgG 
and Inflammatory Markers) 
 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Blood Pharmacokinetic 
Profile12 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SBC-103 ADA13 
 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
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Schedule of Study Assessments 
 
Part A:  Initial Therapy 
Time 
Off 
Assessments 
Screening 
Day 0*** 
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days)* 
-28 to 0** 
-4 to 0 
 
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
±5  
 
General 
Anesthesia/Sedation14 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Lumbar Puncture7,14,15 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Heparan Sulfate (Total and 
NRE) in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF14 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Glutamic Acids and Glycine 
in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Routine Findings  
(Cell Counts, Glucose, 
Protein) in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
SBC-103 in CSF 
 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Structural and Diffusion 
MRI14 
 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
SBC-103 Dosing 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call16 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Part B Eligibility 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events17 
CONTINUOUS 
Concomitant Medications18 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; 
FDNA = Facial Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; MRI = 
magnetic resonance imaging; NAGLU = alpha-N-acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for 
Children; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart.  
**  Subjects who are unable to complete all Screening procedures within 28-day window may be re-screened. See Section 4.7. 
***  Day 0 assessments may be completed over 5 days (starting on Day -4) provided that all eligibility assessments are completed prior to the commencement of any Day 0 procedure (ie, any 
invasive procedures, including general anesthesia or sedation, lumbar puncture, and MRI). Subjects will be monitored for at least 24 hours in an in-patient setting at the Day 0 visit. 
Documentation/confirmation of eligibility must be provided to the Sponsor and is subject to Sponsor review and agreement. At Day 0, the lumbar puncture (including the initiation of 
sedation/anesthesia) shall not commence until the site receives the coagulation results, confirms that a subject continues to meet eligibility, and provides such documentation to the Sponsor for 
review and agreement. 
XP  Assessments to be performed pre-dose. 
1.  Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.  On Day 1, vital signs will be obtained prior to discharge.  Vital signs will be obtained after any lumbar puncture as per site standard of care.  In addition, a baseline blood pressure 
measurement should be taken in triplicate at screening or prior to SBC-103 administration on either Day 0 in Part A or the subject’s next scheduled infusion (see Section 5.1.7). 
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2.  12-lead ECGs should be collected in triplicate (within 5 minutes), when possible during Part A of the study only. 
3.  If the identical assessment(s) were previously administered, historical results should be recorded.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be 
administered in-person by an appropriately qualified professional.   
4.  NAGLU enzyme activity will be assessed by a central laboratory at Screening, irrespective of whether historical enzyme activity results are available from a local laboratory.   
5.  DNA sample for NAGLU genotype is required to confirm Diagnosis of MPS IIIB when a historical result is not available from the study central lab.  
6.  Performed where local regulations permit and subject to discretionary approval from each center's IRB/IEC and the consent/assent of the subject (and/or consent of the subject's parent or legal 
guardian).   
7.  The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
8.  If samples are taken within 3 days of Day 0, samples do not need to be repeated on Day 0. However, a Day 0 serum sample for albumin should be collected at the same time as the CSF collection, to 
enable calculation of CSF-AI. Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples 
for central lab analysis when samples are needed for local analysis. 
9.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
10.  If serum or urine heparan sulfate is collected within 7 days of Day 0, it does not need to be repeated at Day 0. All attempts should be made to collect a urine sample for heparan sulfate. 
11.  If serum ferritin, chitotriosidase and amino acid panel is collected within 7 days of Day 0, it does not need to be repeated at Day 0.  
12. Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
13.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
14.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically indicated, 
subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the procedure to place 
the central line should be performed while the subject is already anesthetized or sedated for another study procedure. During study visits where CSF is collected that do not coincide with a serum 
chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the lumbar puncture is completed, the subject should be observed as per institution 
standard practice.   
15.  Subjects should be observed following the lumbar puncture as per institution standard practice. Vital signs, adverse events and concomitant medications should be assessed before the subject is 
discharged from the site. 
16.  A follow-up telephone call will be made to the subject (or the subject's parent or caregiver) within 24 hours of the 2nd, 3rd , and 4th doses in Part A, and after the last dose of SBC-103 administered in 
the study (Week 24 or Early Termination) unless the subject has a scheduled follow-up visit. 
17.  All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
18.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
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14.2 Appendix B: Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – Year 1)  
Schedule of Study Assessments 
 
Part B:  Therapy at 1 and/or 3 mg/kg (Weeks 28 through 52) 
Assessments 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Week 38 
Week 40 
Week 42 
Week 44 
Week 46 
Week 48 
Week 50 
Week 52 
Visit Window (Days)* 
+3  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Height and Weight 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG  
 
 
 
 
X 
 
 
 
 
 
 
 
X 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vineland-II , BSID-III, KABC-II, 
BOT-2 Brief Form, CSHQ, 
CCC-2, SBRS, ZBI 12-item, 
SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology, Serum Chemistry 
(including Coagulation3), 
Urinalysis4 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Pregnancy Test (Urine)5 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
Serum and Urine Heparan Sulfate 
(Total and NRE) 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Serum Ferritin and Chitotriosidase 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Exploratory Serum Biomarkers, 
including IgG, Inflammatory 
markers 
XP 
 
 
 
XP 
 
 
 
XP 
 
 
 
XP 
Serum Pharmacokinetic Profile6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 ADA7 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
General Anesthesia/Sedation8 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Lumbar Puncture3,8,9 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Heparan Sulfate (Total and NRE) 
in CSF 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Calbindin D, HGF, Tau, pTau, 
Amyloid β, Albumin, IgG in CSF 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Glutamic Acids and Glycine in 
CSF 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Routine Findings (Cell Counts, 
Glucose, Protein) in CSF 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
SBC-103 in CSF 
XP 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Structural and Diffusion MRI8 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
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Schedule of Study Assessments 
 
Part B:  Therapy at 1 and/or 3 mg/kg (Weeks 28 through 52) 
Assessments 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Week 38 
Week 40 
Week 42 
Week 44 
Week 46 
Week 48 
Week 50 
Week 52 
Visit Window (Days)* 
+3  
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior 
Scales, Second Edition; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional.  
3. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
4.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
5.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
8.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
9.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the lumbar 
puncture is completed, the subject should be observed as per institution standard practice. 
10.  All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
11.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
 
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14.3 Appendix C: Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – Years 2-3, as 
applicable)  
Schedule of Study Assessments 
Part B:  Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk  54 / 
Wk 106 
Wk 56 / 
Wk 108 
Wk 58 / 
Wk110 
Wk 60 / 
Wk 112 
Wk 62 / 
Wk 114 
Wk 64/ 
Wk 116 
Wk 66/ 
Wk 118 
Wk 68/ 
Wk 120 
Wk 70/ 
Wk 122 
Wk 72/ 
Wk 124 
Wk 74/ 
Wk 126 
Wk 76/ 
Wk 128 
Wk 78/ 
Wk 130 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG  
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI 12-item, SF-102 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology, Serum 
Chemistry (including 
Coagulation3), Urinalysis4 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Pregnancy Test (Urine)5 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan 
Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum Ferritin and 
Chitotriosidase  
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Plasma Glutamic Acid and 
Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Exploratory Serum 
Biomarkers, including IgG, 
Inflammatory markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
Serum Pharmacokinetic 
Profile6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBC-103 ADA7 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General 
Anesthesia/Sedation8 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Lumbar Puncture3,8,9 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Heparan Sulfate (Total and 
NRE) in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
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Schedule of Study Assessments 
Part B:  Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk  54 / 
Wk 106 
Wk 56 / 
Wk 108 
Wk 58 / 
Wk110 
Wk 60 / 
Wk 112 
Wk 62 / 
Wk 114 
Wk 64/ 
Wk 116 
Wk 66/ 
Wk 118 
Wk 68/ 
Wk 120 
Wk 70/ 
Wk 122 
Wk 72/ 
Wk 124 
Wk 74/ 
Wk 126 
Wk 76/ 
Wk 128 
Wk 78/ 
Wk 130 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Glutamic Acids and Glycine 
in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
SBC-103 in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
Structural and Diffusion 
MRI7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone call10 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events11 
CONTINUOUS 
Concomitant Medications12 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; D = day; ECG = electrocardiogram; FDNA = 
Facial Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior 
Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0; Infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional.  
3. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
4.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
5.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate-to-severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
8.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
9.  During study visits where CSF is will be collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
10.  A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
11. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
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12.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
 
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Schedule of Study Assessments 
Part B:  Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk 80/ 
Wk 132 
Wk 82/ 
Wk 134 
Wk 84/ 
Wk 136 
Wk 86/ 
Wk 138 
Wk 88/ 
Wk 140 
Wk 90/ 
Wk 142 
Wk 92/ 
Wk 144 
Wk 94/ 
Wk 146 
Wk 96/ 
Wk 148 
Wk 98/ 
Wk 150 
Wk 100/ 
Wk 152 
Wk 102/ 
Wk 154 
Wk 104/ 
Wk 156  
(End of 
Tx/ Early 
Term) 
Week 
160 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Physical Examination 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI 12-item, SF-
102 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology, Serum 
Chemistry (including 
Coagulation3), 
Urinalysis4 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Pregnancy Test (Urine)5 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan 
Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Ferritin and 
Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Plasma Glutamic Acid 
and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Exploratory Serum 
Biomarkers, including 
IgG, Inflammatory 
markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
 
Serum Pharmacokinetic 
Profile6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SBC-103 ADA7 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General 
Anesthesia/Sedation8 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Lumbar Puncture3,8,9 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Heparan Sulfate (Total 
and NRE) in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Calbindin D, HGF, Tau, 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
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NGLU-CL02 Protocol Amendment 7 
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Schedule of Study Assessments 
Part B:  Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk 80/ 
Wk 132 
Wk 82/ 
Wk 134 
Wk 84/ 
Wk 136 
Wk 86/ 
Wk 138 
Wk 88/ 
Wk 140 
Wk 90/ 
Wk 142 
Wk 92/ 
Wk 144 
Wk 94/ 
Wk 146 
Wk 96/ 
Wk 148 
Wk 98/ 
Wk 150 
Wk 100/ 
Wk 152 
Wk 102/ 
Wk 154 
Wk 104/ 
Wk 156  
(End of 
Tx/ Early 
Term) 
Week 
160 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
pTau, Amyloid β, 
Albumin, IgG in CSF 
Glutamic Acids and 
Glycine in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Routine Findings (Cell 
Counts, Glucose, Protein) 
in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
SBC-103 in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
 
Structural and Diffusion 
MRI7 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call10 
 
 
 
 
 
 
 
 
 
 
 
 
 
X19 
Adverse Events11 
CONTINUOUS 
Concomitant 
Medications12 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; term = termination; Tx = treatment; 
Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Starting at Week 54, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional.  
3. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
4.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
5.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
8.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
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NGLU-CL02 Protocol Amendment 7 
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procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
9.  During study visits where CSF is will be collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
10. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.  
11. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
12.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.  
 
 
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14.4 Appendix D: Schedule of Study Assessments (Part C, Therapy at 5 and/or 10 mg/kg) 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 1 through 26) 
Assessments 
Wk 1C 
D0C 
Wk 1C 
D1C* 
Wk  
2C  
Wk 
4C 
Wk 
6C 
Wk 
8C 
Wk 
10C 
Wk 
12C 
Wk 
14C 
Wk 
16C 
Wk 
18C 
Wk 
20C 
Wk 
22C 
Wk 
24C 
Wk 
26C 
Visit Window (Days)** 
±5 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Part C Informed Consent/Assent 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part C Eligibility Assessment 
XP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG  
XP 
 
XP 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
FDNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vineland-II, BSID-III, KABC-II, BOT-2 BF, CSHQ, 
CCC-2, SBRS, ZBI 12-item, SF-102,3 
XP,3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology, Serum Chemistry (including Coagulation4), 
Urinalysis5 
XP 
X 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Pregnancy Test (Urine)6 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum Ferritin and Chitotriosidase 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Plasma Glutamic Acid and Glycine 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum Pharmacokinetic Profile7 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
SBC-103 ADA8 
XP 
 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General Anesthesia/Sedation9 
XP 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Lumbar Puncture4,9,10,11 
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Heparan Sulfate (Total and NRE) in CSF 
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Calbindin D, HGF, Tau, pTau, Amyloid β, Albumin, 
IgG in CSF 
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Glutamic Acids and Glycine in CSF 
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein)  
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
SBC-103 in CSF 
XP,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
 
Structural and Diffusion MRI9,12 
XP,12 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
 
SBC-103 Dosing 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events13 
CONTINUOUS 
Page 111 of 121 
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NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 1 through 26) 
Assessments 
Wk 1C 
D0C 
Wk 1C 
D1C* 
Wk  
2C  
Wk 
4C 
Wk 
6C 
Wk 
8C 
Wk 
10C 
Wk 
12C 
Wk 
14C 
Wk 
16C 
Wk 
18C 
Wk 
20C 
Wk 
22C 
Wk 
24C 
Wk 
26C 
Visit Window (Days)** 
±5 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Concomitant Medications14 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 BF  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third 
Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior 
Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
The Week 1C Day 1C visit applies only to the first subject at each dose level. 
** All study visits will be scheduled relative to Week 1 Day 0 in Part C; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Starting at Week 26C, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care.   
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing. 
3. Neurocognition testing performed within 8 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessments on Day 0C. 
4. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
9.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice.   
11. A lumbar picture performed within 4 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessment on Day 0C. 
12.  An MRI obtained within 8 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessment on Day 0C. 
13. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
14. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
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NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 28 through 52) 
STUDY WEEK from Part A Day 0 
 
Wk 
156 
Wk 
160 
Part C Visit 
Wk 
28C 
Wk 
30C 
Wk 
32C 
Wk 
34C 
Wk 
36C 
Wk 
38C 
Wk 
40C 
Wk 
42C 
Wk 
44C 
Wk 
46C 
Wk 
48C 
Wk 
50C 
Wk 
52C 
End of 
Tx 
Follow
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG  
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X3 
 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Pregnancy Test (Urine)6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Ferritin and Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Plasma Glutamic Acid and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Pharmacokinetic Profile7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
SBC-103 ADA8 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General Anesthesia/Sedation9 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP 
 
Lumbar Puncture4,9,10,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Heparan Sulfate (Total and NRE) in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Glutamic Acids and Glycine in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein)  
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
SBC-103 in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Structural and Diffusion MRI9,12 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP,12 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Page 113 of 121 
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DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION FROM ALEXION 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive 
Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose 
1.  Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care.   
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing.   
3. Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
9.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice.  
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
12.  An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.   
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
15.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
 
Page 114 of 121 
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DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION FROM ALEXION 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 54 through 78 and Weeks 106 through 130) 
STUDY WEEK from Part A Day 0 
 
Wk 
156 
Wk 
160 
Part C Visit 
Wks 
54C  
Wks 
56C  
Wks 
58C  
Wks 
60C  
Wks 
62C  
Wks 
64C  
Wks 
66C 
Wks 
68C 
Wks 
70C 
Wks 
72C 
Wks 
74C 
Wks 
76C 
Wks 
78C 
End of 
Tx 
Follow
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X3 
 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Pregnancy Test (Urine)6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Ferritin and Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Plasma Glutamic Acid and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Pharmacokinetic Profile7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
SBC-103 ADA8 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General Anesthesia/Sedation9 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP 
 
Lumbar Puncture4,9,10,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Heparan Sulfate (Total and NRE) in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Glutamic Acids and Glycine in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein)  
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
SBC-103 in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Structural and Diffusion MRI9,12 
 
 
 
 
 
 
 
 
 
 
 
 
 
XP,12 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Page 115 of 121 
ALEXION PHARMACEUTICALS, INC.  PROPRIETARY AND CONFIDENTIAL: 
DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION FROM ALEXION 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive 
Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care.   
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing.  
3. Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
9.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit 
12.  An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.   
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
15.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
Page 116 of 121 
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DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION FROM ALEXION 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 80 through 104) 
STUDY WEEK from Part A Day 0 
 
Wk 
156 
Wk 
160 
Assessments  
Part C Visit 
Week 
80C  
Week 
82C  
Week 
84C 
Week 
86C  
Week 
88C  
Week 
90C  
Week 
92C  
Week 
94C 
Week 
96C 
Week 
98C 
Week 
100C 
Week 
102C 
Week 
104C 
End of 
Tx 
Follow
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Physical Examination 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
XP 
 
Height and Weight 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG  
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X3 
 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Pregnancy Test (Urine)6 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
XP 
 
Serum and Urine Heparan Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Ferritin and Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Plasma Glutamic Acid and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Pharmacokinetic Profile7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
SBC-103 ADA8 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
 
XP 
 
General Anesthesia/Sedation9 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP 
 
Lumbar Puncture4,9,10,11 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
Heparan Sulfate (Total and NRE) in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
Glutamic Acids and Glycine in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein)  
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
SBC-103 in CSF 
 
 
 
 
 
XP 
 
 
 
 
 
 
XP 
XP,11 
 
Structural and Diffusion MRI9, 12 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP,12 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Page 117 of 121 
ALEXION PHARMACEUTICALS, INC.  PROPRIETARY AND CONFIDENTIAL: 
DO NOT COPY OR DISTRIBUTE WITHOUT PERMISSION FROM ALEXION 


NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive 
Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care.   
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing.  
3. Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
9.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice.   
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
12.  An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.   
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
15.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
 
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NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Schedule of Study Assessments 
Part C:  Therapy at 5 and/or 10 mg/kg (Weeks 54 through 78 and Weeks 106 through 130) 
STUDY WEEK from Part A Day 0 
 
Wk 
156 
Wk 
160 
Part C Visit 
Wks 
106C 
Wks  
108C 
Wks  
110C 
Wks 
112C 
Wks 
114C 
Wks 
116C 
Wks 
118C 
Wks 
120C 
Wks 
122C 
Wks 
124C 
Wks 
126C 
Wks  
128C 
Wks 
130C 
End of 
Tx 
Follow
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Physical Examination 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Height and Weight 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
XP 
XP 
 
FDNA 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X3 
 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Pregnancy Test (Urine)6 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
Serum and Urine Heparan Sulfate (Total and NRE) 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Ferritin and Chitotriosidase 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Plasma Glutamic Acid and Glycine 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
 
 
 
XP 
 
 
 
XP 
 
 
 
 
XP 
XP 
 
Serum Pharmacokinetic Profile7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
SBC-103 ADA8 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
XP 
 
General Anesthesia/Sedation9 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP 
 
Lumbar Puncture4,9,10,11 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Heparan Sulfate (Total and NRE) in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Glutamic Acids and Glycine in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein)  
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
SBC-103 in CSF 
 
 
 
 
 
 
XP 
 
 
 
 
 
XP 
XP,11 
 
Structural and Diffusion MRI9,12 
 
 
 
 
 
 
 
 
 
 
 
 
 
XP,12 
 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
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NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N-
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive 
Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart.  
XP  Assessments to be performed pre-dose. 
1.  Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care.   
2.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing.  
3. Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4. The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.  Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.  If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.  In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion.  
9.  Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10.  During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit 
12.  An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit.   
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary.  
15.  Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF.   
 
 
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NGLU-CL02 Protocol Amendment 7 
January 21, 2016 
 
14.5 Appendix E:  NGLU-CL02 Neurocognitive, Developmental and QOL 
Assessments 
Assessment* 
Administered to 
Special Instructions 
Vineland-II 
Parent/Caregiver 
Must be administered prior to the other 
developmental tests at Screening (ie, BSID-
III, KABC-II, BOT-2, CCC-2)  
Administered in-person 
BSID-III1 
Subject 
 
  
At Screening, administered to subjects with 
Vineland-II age equivalent of <3 years, 6 
months) 
Administered in-person  
KABC-II1 
Subject 
 
At Screening, administered to subjects with 
Vineland-II age equivalent of ≥3 years, 6 
months Administered in-person  
BOT-2 Brief 
Form2 
Subject 
Administered only to subjects who complete 
the KABC-II. 
CCC-22 
Parent/Caregiver 
 
Administered only to subjects completing the 
KABC-II. 
ZBI, 12-item 
Parent/Caregiver 
 
SF-10 
Parent/Caregiver 
 
SBRS 
Parent/Caregiver 
 
CSHQ 
Parent/Caregiver 
 
* All neurocognitive, developmental and QOL assessments are administered during the Screening visit.  
Assessments can be performed over multiple days. 
1Either the BSID-III or KABC-II will be administered to the subject depending on the mean age equivalent 
determined by the Vineland-II at Screening.  Refer to supplemental instructions provided to each site regarding 
when to switch the BSID-III or KABC-II. 
2Administered only to subjects completing the KABC-II 
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SAP_001.pdf: 
A Phase I/II Open Label Study in MPS IIIB Subjects to 
Investigate the Safety, Pharmacokinetics, and 
Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously 
 
 
Unique Protocol ID:  
 
 
 
NGLU-CL02 
NCT Number:  
 
 
 
 
NCT02324049 
EudraCT Number:  
 
 
 
2013-003400-39 
Date of Statistical Analysis Plan: 
01 September 2017 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Alexion Pharmaceuticals, Inc. 
 
 
STATISTICAL ANALYSIS PLAN FOR 
CLINICAL STUDY REPORT (CSR) 
 
 
 
PROTOCOL NUMBER: NGLU-CL02 
 
A Phase I/II Open Label Study in MPS IIIB Subjects to 
Investigate the Safety, Pharmacokinetics, and 
Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously  
 
 
 
 
Author: 
 
Date: 01 Sep 2017 
Version: 1.0 
PPD


PPD


PPD


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
2. TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................3 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................7 
4. 
DESCRIPTION OF THE PROTOCOL .......................................................................9 
4.1. 
Changes from Analyses Specified in the Protocol .......................................................9 
4.1.1. 
Primary Objective .......................................................................................................10 
4.1.2. 
Secondary Objectives .................................................................................................10 
4.1.3. 
Exploratory Objectives ...............................................................................................10 
4.1.4. 
Assessments / Parameters Included in Analysis .........................................................10 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................10 
5. 
DEFINITIONS ...........................................................................................................11 
5.1. 
Efficacy .......................................................................................................................11 
5.1.1. 
Primary Endpoint(s) ....................................................................................................11 
5.1.2. 
Secondary Endpoints ..................................................................................................11 
5.1.2.1. 
Pharmacokinetic (PK) Parameters ..............................................................................11 
5.1.2.2. 
Pharmacodynamic (PD) Parameters ...........................................................................11 
5.1.3. 
Tertiary Endpoints ......................................................................................................11 
5.1.4. 
Other Efficacy Endpoints ...........................................................................................11 
5.1.4.1. 
Exploratory Endpoints ................................................................................................11 
5.2. 
Safety ..........................................................................................................................11 
5.2.1. 
Adverse Events (AEs) .................................................................................................11 
5.2.2. 
Vital Signs ..................................................................................................................12 
5.2.3. 
Laboratory Assessments .............................................................................................12 
5.2.4. 
Other Safety Assessments of Special Interest ............................................................12 
5.2.4.1. 
Anti-Drug Antibodies (ADA) .....................................................................................12 
5.2.4.2. 
ECG ............................................................................................................................12 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) ...........................................13 
6.1. 
Full Analysis Set (FAS) ..............................................................................................13 
6.2. 
Per Protocol (PP) Set ..................................................................................................13 
6.3. 
Safety Set ....................................................................................................................13 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
6.4. 
Other Sets ....................................................................................................................13 
7. 
STATISTICAL ANALYSIS ......................................................................................14 
7.1. 
Study Patients .............................................................................................................14 
7.1.1. 
Disposition of Patients ................................................................................................14 
7.1.2. 
Protocol Deviations ....................................................................................................14 
7.1.3. 
Demographics, Disease Characteristics and History ..................................................14 
7.1.3.1. 
Demographics .............................................................................................................14 
7.1.3.2. 
Disease Characteristics ...............................................................................................15 
7.1.3.3. 
Medical / Surgical History and Baseline Physical Examination ................................15 
7.1.4. 
Prior and Concomitant Medications / Therapies ........................................................15 
7.2. 
Efficacy Analyses .......................................................................................................15 
7.2.1. 
Primary Analysis ........................................................................................................15 
7.2.1.1. 
Handling of Dropouts or Missing Data ......................................................................15 
7.2.1.2. 
Subgroup Analysis ......................................................................................................15 
7.2.1.3. 
Multicenter Studies .....................................................................................................15 
7.2.1.4. 
Hypothesis Testing and Significance Level ...............................................................15 
7.2.1.5. 
Sensitivity Analyses ....................................................................................................15 
7.2.2. 
Secondary Analyses ....................................................................................................15 
7.2.2.1. 
Neurocognitive and Developmental Assessments ......................................................16 
7.2.2.2. 
MRI Findings ..............................................................................................................16 
7.2.2.3. 
Blood Brain Barrier (BBB) Integrity Assessments ....................................................16 
7.2.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................16 
7.2.3. 
Tertiary Analyses ........................................................................................................16 
7.2.4. 
Other Efficacy Analyses .............................................................................................16 
7.2.5. 
Exploratory Analyses ..................................................................................................16 
7.3. 
Safety Analyses ..........................................................................................................16 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure .............................................16 
7.3.2. 
Adverse Events (AEs) .................................................................................................17 
7.3.2.1. 
Overall Summary of Adverse Events .........................................................................17 
7.3.2.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) ..................18 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship ...........................................................18 
7.3.2.4. 
AEs and SAEs by SOC, PT, and Severity ..................................................................18 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events .....................................18 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
7.3.3. 
Other Safety ................................................................................................................19 
7.3.3.1. 
Analyses for Laboratory Tests ....................................................................................19 
7.3.3.2. 
Vital Signs ..................................................................................................................19 
7.3.3.3. 
Other Safety Parameters of Special Interest ...............................................................19 
8. 
REFERENCES ...........................................................................................................20 
9. 
APPENDICES ............................................................................................................21 
9.1. 
Schedule of Study Assessments..................................................................................21 
9.1.1. 
Schedule of Study Assessments (Part A, Initial Therapy) ..........................................22 
9.1.2. 
Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – Year 
1) .................................................................................................................................25 
9.1.3. 
Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – 
Years 2-3, as applicable) .............................................................................................27 
9.1.4. 
Schedule of Study Assessments (Part C, Therapy at 5 and/or10 mg/kg) ...................33 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP .....................43 
9.3. 
Sample Size, Power, and Randomization ...................................................................43 
9.3.1. 
Sample Size and Power ..............................................................................................43 
9.3.2. 
Randomization ............................................................................................................43 
9.4. 
Technical Specifications for Derived Variables .........................................................43 
9.4.1. 
Baseline Definition .....................................................................................................43 
9.4.2. 
Visit Windows ............................................................................................................44 
9.4.3. 
Imputation of Partial Dates .........................................................................................44 
9.5. 
Additional details on Statistical Methods ...................................................................45 
 
 
 
 
 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
LIST OF TABLES 
Table 1: 
Abbreviations and acronyms ........................................................................................7 
 
 
 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this SAP.  
Table 1: 
Abbreviations and acronyms 
Abbreviation or acronym 
Explanation 
ADA  
Anti-drug antibodies  
AE  
Adverse event(s)  
AESI 
Adverse events of special interest 
ATC 
Anatomical therapeutic chemical 
BBB  
Blood brain barrier  
BOT-2  
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition  
BSID-III  
Bayley Scales of Infant and Toddler Development, Third Edition  
CCC-2  
Children’s Communication Checklist, Second Edition  
CSF  
Cerebrospinal fluid  
CSF-AI  
Cerebrospinal fluid/serum albumin index  
CSHQ  
Children’s Sleep Habits Questionnaire  
CSP 
Clinical study protocol 
CSR 
Clinical study report 
ECG  
Electrocardiogram  
eCRF 
Electronic case report form 
FAS 
Full Analysis Set 
FDNA  
Facial Dysmorphology Novel Analysis  
HGF  
Hepatocyte growth factor  
HS  
Heparan sulfate  
IAR  
Infusion-associated reaction  
ICH  
International Conference on Harmonization  
IgG  
Immunoglobulin G  
IMP  
Investigational Medicinal Product  
IV  
Intravenous(ly)  
KABC-II  
Kaufman Assessment Battery for Children, Second Edition  
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS IIIB  
Mucopolysaccharidosis III, type B  
MRI  
Magnetic resonance imaging  
NAGLU  
Alpha-N-acetylglucosaminidase  
NRE  
Non-reducing end  
NVI  
Non-verbal index  
PD  
Pharmacodynamic(s)  
PK  
Pharmacokinetic(s)  
PT  
Preferred Term  
QOW 
Once every other week  
Rel Day 
Relative study day 
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SBRS  
Sanfilippo Behavior Rating Scale  
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SF-10  
10-item Short Form Health Survey for Children  
SI 
International system of units 
MRI  
Magnetic resonance imaging  
SOA  
Schedule of Assessments  
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
Abbreviation or acronym 
Explanation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
US  
United States (of America)  
Vineland-II  
Vineland Adaptive Behavior Scales, Second Edition  
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI  
Zarit Burden Interview 12-item short form  
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
4. 
DESCRIPTION OF THE PROTOCOL 
Study NGLU-CL02, A Phase I/II Open Label Study in MPS IIIB Subjects to Investigate the 
Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered 
Intravenously, is an open label, 3-part Phase I/II study designed to evaluate the safety, 
tolerability, pharmacokinetics, and pharmacodynamics/efficacy of intravenous (IV) 
administration of SBC-103 in subjects with mucopolysaccharidosis III, type B (MPS IIIB, 
Sanfilippo B) with evaluable signs or symptoms of developmental delay.  
Study NGLU-CL02 is conducted in 3 parts: Part A (Initial therapy at 0.3, 1, or 3 mg/kg), Part B 
(Extended Therapy at 1 and/or 3 mg/kg), and Part C (Extended Therapy at 5 and/or 10 mg/kg).   
Part A is designed to assess the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD)/efficacy of 3 escalating doses of SBC-103 dosed once every other week 
(QOW) over 24 weeks.   
Part B is designed to assess the safety, tolerability, PK, and PD/efficacy of chronic dosing for an 
extended period of time and to allow for intra-subject dose modification based on available data.  
Following Part A and prior to entering Part B, subjects will have a 4-week period of time off 
therapy (instead of the usual 2 weeks between doses that occurs with QOW dosing) in order to 
assess the impact of treatment interruption on safety, tolerability, and select PD/efficacy markers, 
including the assessment of reversibility of any observed on-therapy changes in heparan sulfate 
(HS).   
Part C (added with Amendment 6 and based on preliminary safety and PK/PD data from Parts A 
and B) is designed to assess the safety, tolerability, PK, and PD/efficacy of SBC-103 at 5 and 
10 mg/kg QOW, as well as to assess the effects on chronic dosing.  Subjects will be followed on 
Part C until the end of the treatment period at 156 weeks (a period of between 90 and 110 
weeks). Intra-subject dose modification is permitted in Part C (based on data review and Sponsor 
agreement) with the intent to treat subjects with the lowest potentially efficacious dose that is 
safe and tolerable.  
The protocol can be referenced for additional details. The Part C Schedule of Assessments 
(SOA) is attached in Appendix 9.1.4 of this Statistical Analysis Plan (SAP). 
On 11 Jul 2017, Alexion decided to stop the clinical development program with SBC-103.  A 
clinical study report (CSR) will detail the final demographic, disposition, exposure, and safety 
data of each study. 
4.1. 
Changes from Analyses Specified in the Protocol 
The data analyses, data summaries and data presentations specified for the NGLU-CL02 CSR 
represent a reduced subset of the overall total data analyses, data summaries, and data 
presentations described in the NGLU-CL02 final approved Clinical Study Protocol (CSP) 
version (Amendment 7, 21 January 2016) for the full study.  Only demographic, disposition, 
safety and exposure data will be used to create data summaries and listings for the reduced subset 
of the CSP specified full study parameters presented by Part C dose assignment (5 or 10 mg/kg 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
QOW) and overall (5 and 10 mg/kg QOW combined).  Only the assessments/parameters 
specified in Section 4.1.4 will be included. 
4.1.1. 
Primary Objective 
The primary objective of this CSR SAP is to evaluate the safety and tolerability of IV 
administration of SBC-103 in subjects with mucopolysaccharidosis III, type B (MPS IIIB, 
Sanfilippo B) with evaluable signs and symptoms. 
4.1.2. 
Secondary Objectives 
No secondary objectives will be addressed in this SAP. 
4.1.3. 
Exploratory Objectives 
No exploratory objectives will be addressed in this SAP. 
4.1.4. 
Assessments / Parameters Included in Analysis  
• 
Demographics 
• 
Disposition 
• 
Use of Prior and Concomitant Medications (Listing only) 
• 
Treatment Exposure, Dosing Administration and Infusion Summary (Listings only) 
• 
Treatment Emergent Adverse Events (TEAEs) 
• 
Treatment Emergent Serious Adverse Events (TESAEs) 
• 
Infusion Associated Reactions (IAR) 
• 
Anti-drug Antibody (ADA) Assay and Titer Results  
• 
Laboratory Parameters: Hematology, Chemistry, Urinalysis, including Coagulation, 
Renal Function, and Liver Function (Listings only).  
• 
Lumbar Puncture:  CSF Findings and CSF-AI Ratio (listings only)  
• 
Vital Signs (listing only) 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Not applicable. 
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5. 
DEFINITIONS 
5.1. 
Efficacy  
5.1.1. 
Primary Endpoint(s) 
The primary objective is to evaluate the safety and tolerability of IV administration of SBC-103, 
and as such, there is no primary efficacy endpoint. 
5.1.2. 
Secondary Endpoints 
Analyses of secondary efficacy endpoints will not be included in the CSR.  
5.1.2.1. 
Pharmacokinetic (PK) Parameters 
Analyses of PK data will not be included in the CSR. 
5.1.2.2. 
Pharmacodynamic (PD) Parameters 
Analyses of PD or PK/PD data, including HS, will not be included in the CSR. 
5.1.3. 
Tertiary Endpoints 
Not applicable. 
5.1.4. 
Other Efficacy Endpoints 
5.1.4.1. 
Exploratory Endpoints 
Analyses of exploratory endpoints will not be included in the CSR. 
5.2. 
Safety 
The primary endpoint of this study is the safety and tolerability of SBC-103 in subjects with 
MPS IIIB.  The safety assessments will include the following: 
• 
Incidence of treatment emergent adverse events (TEAEs), treatment emergent serious 
adverse events (TESAEs), and infusion-associated reactions (IARs) which are adverse 
events of special interest (AESI). 
• 
Incidence of anti-drug antibodies (ADA) including ADA titer by time point, peak ADA 
titer, and ADA titer status (positive/negative), and the effect of ADAs on the safety of 
SBC-103, including the relationship between ADA-positive subjects and the incidence of 
IARs. 
5.2.1. 
Adverse Events (AEs) 
Adverse events are defined in Protocol Section 7.1. Also refer to Appendix 9.4.3 of this SAP for 
special handling of AE partial dates.  Any AE that occurs after the first dose of SBC-103 in Part 
A is considered a treatment emergent adverse event (TEAE).  AEs will be summarized 
cumulatively over the entire study and separately for Part C. 
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5.2.2. 
Vital Signs 
Vital signs will be provided in a listing.  The following vital signs were recorded at the times in 
Parts A, B and C as specified in Appendix 9.1: systolic and diastolic blood pressure (millimeters 
of mercury (mmHg)), heart rate (beats/minute), respiratory rate (breaths/minute), and 
temperature (degrees Celsius (°C) or degrees Fahrenheit (°F)). 
5.2.3. 
Laboratory Assessments 
Serum chemistry, hematology, urinalysis including coagulation, renal function, liver function, 
CSF, and assessment of ADAs related testing will be performed as per the SOA. Details on 
specific laboratory assessment timing in Parts A, B and C are provided in Appendix 9.1.  All 
laboratory results will be provided in listings.   
5.2.4. 
Other Safety Assessments of Special Interest 
5.2.4.1. 
Anti-Drug Antibodies (ADA) 
Patients will be monitored for the development of antibody production against SBC-103 at the 
times specified in the Part C SOA (Appendix 9.1.4).  Serum will be collected and analyzed for 
the presence of ADA, and if positive, further analyzed for titer, and characterization of response 
(e.g., positive/negative). 
5.2.4.2. 
ECG 
Analyses of electrocardiogram (ECG) data will not be included in the CSR. 
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Statistical Analysis Plan 
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6. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
The following analysis sets will be used for the presentation and analysis of the data for the CSR.  
For further information on the processing of patient data utilized in creating the following study 
population analysis dataset(s)/subset(s) and baselines, please see Appendix 9.4.1. 
 
6.1. 
Full Analysis Set (FAS) 
Not applicable. 
6.2. 
Per Protocol (PP) Set 
Not applicable. 
6.3. 
Safety Set 
The Safety Analysis Set, defined as all patients for whom informed consent has been obtained, 
who have a confirmed diagnosis of MPS IIIB, and who have received any amount of SBC-103, 
will be used to summarize all safety and tolerability data.  
6.4. 
Other Sets 
Not applicable. 
 
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Statistical Analysis Plan 
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{01 Sep 2017, Version 1.0} 
7. 
STATISTICAL ANALYSIS 
All output will be sorted and labeled according to the International Conference on 
Harmonization (ICH) recommendations, and formatted to the appropriate page size(s).  
For the analyses covered by this SAP, data analysis and presentation for this study is primarily 
descriptive in nature; therefore, no inferential analyses are planned. Selected data will be 
presented in by-patient data listings and summarized in tables across patients if appropriate.  
Descriptive summaries will be presented for treated subjects overall and by dose assignment, as 
appropriate.  Continuous data will be summarized using descriptive statistics including number 
of patients, mean, standard deviation (SD), median, minimum, maximum, Lower quartile (25th 
percentile) Q1, and Upper quartile (75th percentile) Q3; categorical data will be summarized by 
counts and proportions. No formal statistical hypothesis testing will be performed. 
For this analysis, information will be displayed by the Part C dose assignment as follows: 
SBC-103 5 mg/kg – QOW and SBC-103 10 mg/kg – QOW.  All data listings that contain an 
evaluation date will contain a relative study day (Rel Day).  Pre-treatment and on-treatment 
study days are numbered relative to the day of the first dose of study drug which is designated as 
Relative Day 1. The preceding day is Day -1, the day before that is Day -2, etc. The last day of 
study drug is designated with an “L” (e.g., Day 14L). 
7.1. 
Study Patients 
7.1.1. 
Disposition of Patients 
Patient enrollment and disposition including number of patients screened, enrolled, dosed, and 
percentage of patients who discontinued from the study, along with reasons for discontinuations 
will be tabulated and described in listings.  
7.1.2. 
Protocol Deviations 
Analyses of protocol deviations will not be included in the CSR. 
7.1.3. 
Demographics, Disease Characteristics and History 
7.1.3.1. 
Demographics 
Demographic and baseline characteristics will be summarized descriptively.  Age at study entry 
(years), gender, race, ethnicity, baseline weight, baseline height and baseline Body Mass Index 
(BMI) will be summarized.  Listings will also be provided. 
 
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7.1.3.2. 
Disease Characteristics 
 
Disease characteristics will not be included in the CSR.  
 
7.1.3.3. 
Medical / Surgical History and Baseline Physical Examination 
Medical/surgical history and physical examination data will not be included in the CSR.   
7.1.4. 
Prior and Concomitant Medications / Therapies 
All medications and treatments received by the patient during the study or within the preceding 4 
weeks will be collected.  Any medication or treatment received after the first dose of SBC-103 
will be considered concomitant.  Medications will be mapped to a generic term using the current 
Alexion version of World Health Organization (WHO) Drug Dictionary (WHO-DD).  
Medications will be classified using the Anatomical Therapeutic Chemical (ATC) classification 
system.  All prior and concomitant medications/therapies will be provided in listings.   
7.2. 
Efficacy Analyses 
7.2.1. 
Primary Analysis 
As stated above, the primary objective of this study is to evaluate the safety and tolerability of IV 
administration of SBC-103, and as such, there is no primary efficacy endpoint or analysis. 
7.2.1.1. 
Handling of Dropouts or Missing Data 
Partial dates will be handled as detailed in Appendix 9.4.3 including details for calculating 
calendar or chronological age, as necessary.  Missing data will be handled as detailed below for 
each measure. 
7.2.1.2. 
Subgroup Analysis 
Not applicable. 
7.2.1.3. 
Multicenter Studies 
Four centers are participating in this study and the number of subjects at each center by 
assignment is not large enough to produce meaningful summaries by center; therefore analyses 
by center will not be performed. Data from all sites will be pooled together. 
7.2.1.4. 
Hypothesis Testing and Significance Level 
Data analysis and/or presentation for this study are primarily descriptive in nature; therefore, no 
inferential analyses are planned and p-values will not be provided.   
7.2.1.5. 
Sensitivity Analyses 
Not applicable. 
7.2.2. 
Secondary Analyses 
Analyses of secondary endpoints will not be included in the CSR. 
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7.2.2.1. 
Neurocognitive and Developmental Assessments 
Analyses of neurocognitive and developmental assessments will not be included in the CSR. 
7.2.2.2. 
MRI Findings 
Analyses of MRI findings will not be included in the CSR. 
7.2.2.3. 
Blood Brain Barrier (BBB) Integrity Assessments 
CSF/serum albumin index (CSF-AI) assessments of BBB integrity will be provided in listings. 
7.2.2.4. 
Pharmacokinetic and Pharmacodynamic Analyses 
7.2.2.4.1. Pharmacokinetic Analyses 
Analyses of pharmacokinetic (PK) data will not be included in the CSR. 
7.2.2.4.2. Pharmacodynamic Analyses 
Analyses of pharmacodynamic (PD) data will not be included in the CSR. 
7.2.3. 
Tertiary Analyses 
Not applicable. 
7.2.4. 
Other Efficacy Analyses 
Not applicable. 
7.2.5. 
Exploratory Analyses  
No exploratory analyses will be included in the CSR.   
7.3. 
Safety Analyses 
As stated above in Section 5.2, the primary objective of this study is the safety and tolerability of 
SBC-103 in subjects with MPS IIIB. Descriptive statistics will be computed for specified safety 
parameters using the Safety Analysis Set, as appropriate, including treatment emergent adverse 
events (TEAEs), treatment emergent serious adverse events (TESAEs), and infusion-associated 
reactions (IARs) which are adverse events of special interest (AESI). The incidence of anti-drug 
antibodies (ADA) including ADA titer by time point, peak ADA titer, ADA titer status 
(positive/negative), neutralizing antibodies, and the relationship between ADA-positivity and the 
incidence of IARs will be presented. 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure 
Dosing administration information will be listed by patient number, Part C dose assignment, and 
visit and will present details on confirmation of SBC-103 administration, reasons SBC-103 was 
not administered, total # of vials used, target dose (mg/kg), and dose concentration (mg/mL).  
Exposure to study drug (SBC-103) related information will be listed by patient number, Part C 
dose assignment and visit. The stop/start dates/times, total actual volume of drug infused (mL), 
infusion rate (mL/hr), type of infusion (dosing or saline flush), rate reduction percentage 
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compared to previous infusion rate, and information on any modification to the infusion 
including reason for modification will be presented in the listings.   
7.3.2. 
Adverse Events (AEs) 
Information will be summarized on all AEs that began at any time from the date of first study 
dose in Part A through the last procedure at the last study visit. Adverse events will be classified 
by the study Investigator into one of the following relations to study drug: not related, unlikely 
related, possibly related or related to study drug. For reporting purposes, “related” events will 
include all AEs assessed by the Investigator as: possibly related, or related to study drug. 
All AEs captured in the eCRF will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding system and displayed in tables and data listings using System 
Organ Class (SOC) and Preferred Term (PT).  All AEs will be coded using the MedDRA, 
version 13.1 or higher. 
Severity of AEs will be graded on a 3-point scale (mild, moderate and severe) based on the 
definitions, developed from Clinical Data Interchange Standards Consortium (CDISC) Study 
Data Tabulation Model (SDTM) standard terminology v3.1.1 (see Protocol Section 7.1.1).  
Adverse event incidence will be reported based on the concept of treatment emergence for the 
purposes of this analysis. Any AE that occurs after the first dose of SBC-103 in Part A is 
considered a treatment emergent adverse event (TEAE) for this study.  
Adverse events are summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given AE. 
The number of events, as well as the number and percentage of patients with a TEAE, will be 
summarized by Part C dose assignment and overall, cumulatively over the entire study and 
separately for Part C. 
7.3.2.1. 
Overall Summary of Adverse Events 
An overall summary of TEAEs and treatment-emergent SAEs (TESAEs) will include summaries 
of events (n) and number of patients with events (n, %). 
Within each summary category (TEAEs, TESAEs) the following subcategories will also be 
summarized, as appropriate: 
• At Least 1 TEAE 
• At Least 1 Severe TEAE 
• At Least 1 Related TEAE (possibly related or related to study drug) 
• At Least 1 TEAE Leading to Withdrawal / Discontinuation from the Study 
• At Least 1 IAR 
• At Least 1 Serious TEAE 
  Additionally, the number and percentage of patients who died on study will be presented. 
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Statistical Analysis Plan 
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7.3.2.2. 
AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT) 
The number of TEAEs and the number and percentage of patients with events will be 
descriptively summarized and presented by SOC and PT.  Patients are counted once in each SOC 
and PT. Percentages will be based on the total number of treated patients by Part C dose 
assignment and overall for each visit assessed. 
The number of Serious TEAE’s and the number and percentage of patients with events will be 
descriptively summarized and presented by PT.  Patients are counted once in each PT.  
Percentages will be based on the total number of treated patients by Part C dose assignment and 
overall for each visit assessed. 
All AEs will be presented in by-patient listings. 
7.3.2.3. 
AEs and SAEs by SOC, PT, and Relationship 
Individual patient AE/SAE data for Relationship to Study Drug and Relationship to Study 
Procedures is presented in the by-patient AE listings. 
7.3.2.4. 
AEs and SAEs by SOC, PT, and Severity 
 
Individual patient AE/SAE data for severity is presented by-patient AE listings. 
 
7.3.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events 
Deaths and other SAE’s will be identified by the data presented in the by-patient listings of AEs. 
7.3.2.5.1    Other Significant Adverse Events 
Procedure-related AEs will be identified by the relationship to study procedures data presented in 
the by-patient listings of AEs.  
7.3.2.5.2.   Infusion-Associated Reactions 
 
Infusion-associated reactions (IARs) will be considered AEs of special interest (AESIs). An AE 
will be considered an IAR if it meets either of the following criteria: 
• 
The Investigator checks “Yes” to the question “Is AE an IAR?” on the AE eCRF. 
• 
The AE (diagnosis and/or symptom) occurs between the start of the infusion up to 4 
hours after the infusion and is assessed by the Investigator as at least possibly related to 
Investigational Medicinal Product (IMP). 
Note that several AEs may be associated with 1 IAR observed with SBC-103 administration; 
each AE is captured as a separate event. The number and percentage of patients who experience 
any IAR and the number of IARs reported over the course of the study will be summarized. Any 
patient who experiences an IAR is only counted once regardless of the number of associated 
events. Patients may be counted more than once if IARs occur on more than 1 dosing day. 
Summaries of AEs that comprise an IAR will be displayed by MedDRA PT. Each patient will be 
counted only once within each PT. 
A by-patient data listing of all AEs will be presented. 
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7.3.3. 
Other Safety 
7.3.3.1. 
Analyses for Laboratory Tests 
The clinical laboratory data include hematology, chemistry, urinalysis (including coagulation, 
renal function and liver function), CSF findings and CSF-AI ratio.  All clinical laboratory data 
will be listed.  
Clinical laboratory values by time of assessment will be expressed in International System of 
units (SI units) in data listings. Unscheduled lab test results will also be presented in the data 
listings. Abnormal lab values will be flagged with “H”/“L” or “HIGH”/“LOW” for out of range 
values, and an asterisk for clinical significance in the data listings. 
Patient data for clinical laboratory data will be presented in listings by Part C dose assignment, 
patient number and visit.   
7.3.3.2. 
Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
and body temperature. A listing of vital signs will be presented by patient number, vital sign 
parameter, vital sign value, and visit. 
7.3.3.3. 
Other Safety Parameters of Special Interest 
7.3.3.3.1. Antidrug Antibody (ADA) 
Assays testing for screening, confirmed, neutralizing ADA will be performed and ADA titers 
will be measured for neutralizing antibodies. For this analysis, confirmed ADA assay results will 
be descriptively presented by ADA status (Positive, Negative) as the proportion of patients, n 
(%), with measurable confirmed antibodies to SBC-103 by Part C dose assignment and overall 
for each assessed visit.  Neutralizing antibodies for confirmed positive cases will also be 
presented.   
ADA titer result statistics will be descriptively presented by ADA status, visit, Part C dose 
assignment and overall. 
The number and percentage of patients with Infusion-Association Reactions (IARs) adverse 
events by MedDRA System Organ Class, Preferred Term, and ADA positivity will be presented 
along with the number of IAR events.  If a patient experienced more than one event in a given 
SOC, that patient is counted once for that SOC.  If a patient experienced more than one event 
with a given PT, that patient is counted only once for that PT. 
7.3.3.3.2. ECG 
Analyses of ECG data will not be included in the CSR. 
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8. 
REFERENCES 
 
 
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9. 
APPENDICES 
 
9.1. 
Schedule of Study Assessments 
 
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Statistical Analysis Plan 
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9.1.1. 
Schedule of Study Assessments (Part A, Initial Therapy) 
 
Schedule of Study Assessments 
Part A: Initial Therapy 
Time 
Off 
Assessments 
Screening 
Day 0*** 
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days)* 
-28 to 0** 
-4 to 0 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Informed Consent/Assent 
X 
Inclusion/Exclusion Criteria 
X 
Medical History/ 
Demography 
X 
Physical Examination 
X 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (Triplicate2) 
X 
XP 
XP 
XP 
FDNA 
X 
X 
Vineland-II , BSID-III, KABC-II, 
BOT-2 Brief Form, CSHQ, 
CCC-2, SBRS, ZBI 12-item, 
SF-103 
X3 
XP 
NAGLU Enzyme Activity4 
X 
NAGLU Genotype5 
X 
DNA Sample6 
X 
Hematology, Serum 
Chemistry (including 
Coagulation7), Urinalysis8 
X 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)9 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulfate (Total and NRE)10 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase11 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine11 
X 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum Biomarkers 
(Exploratory, including IgG 
and Inflammatory Markers) 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Blood Pharmacokinetic 
Profile12 
X 
X 
X 
SBC-103 ADA13 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
 
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Statistical Analysis Plan 
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Schedule of Study Assessments 
Part A: Initial Therapy 
Time 
Off 
Assessments 
Screening 
Day 0*** 
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 
20 
Week 
22 
Week 
24 
Week 
26 
Visit Window (Days)* 
-28 to 0** 
-4 to 0 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
General 
Anesthesia/Sedation14 
XP 
XP 
XP 
Lumbar Puncture7,14,15 
XP 
XP 
XP 
Heparan Sulfate (Total and 
NRE) in CSF 
XP 
XP 
XP 
Calbindin D, HGF, Tau, pTau, 
Amyloid β, Albumin, IgG in 
CSF14 
XP 
XP 
XP 
Glutamic Acids and Glycine 
in CSF 
XP 
XP 
XP 
Routine Findings 
(Cell Counts, Glucose, 
Protein) in CSF 
XP 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
XP 
Structural and Diffusion 
MRI14 
XP 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call16 
X 
X 
X 
X 
Part B Eligibility 
Assessment 
X 
Adverse Events17 
CONTINUOUS 
Concomitant Medications18 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; 
FDNA = Facial Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; MRI = magnetic 
resonance imaging; NAGLU = alpha-N-acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II 
= Vineland Adaptive Behavior Scales, Second Edition; ZBI = Zarit Burden Interview, 12-item. 
* 
All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart. 
** 
Subjects who are unable to complete all Screening procedures within 28-day window may be re-screened. See Section 4.7. 
***   Day 0 assessments may be completed over 5 days (starting on Day -4) provided that all eligibility assessments are completed prior to the commencement of any Day 0 procedure (ie, any invasive 
procedures, including general anesthesia or sedation, lumbar puncture, and MRI). Subjects will be monitored for at least 24 hours in an in-patient setting at the Day 0 visit. 
Documentation/confirmation of eligibility must be provided to the Sponsor and is subject to Sponsor review and agreement. At Day 0, the lumbar puncture (including the initiation of 
sedation/anesthesia) shall not commence until the site receives the coagulation results, confirms that a subject continues to meet eligibility, and provides such documentation to the Sponsor for 
review and agreement. 
XP    Assessments to be performed pre-dose. 
1.   Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.  On Day 1, vital signs will be obtained prior to discharge.  Vital signs will be obtained after any lumbar puncture as per site standard of care.  In addition, a baseline blood pressure 
measurement should be taken in triplicate at screening or prior to SBC-103 administration on either Day 0 in Part A or the subject’s next scheduled infusion (see Section 5.1.7). 
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2.   12-lead ECGs should be collected in triplicate (within 5 minutes), when possible during Part A of the study only. 
3.   If the identical assessment(s) were previously administered, historical results should be recorded.  The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered 
in-person by an appropriately qualified professional. 
4.   NAGLU enzyme activity will be assessed by a central laboratory at Screening, irrespective of whether historical enzyme activity results are available from a local laboratory. 
5.   DNA sample for NAGLU genotype is required to confirm Diagnosis of MPS IIIB when a historical result is not available from the study central lab. 
6.   Performed where local regulations permit and subject to discretionary approval from each center's IRB/IEC and the consent/assent of the subject (and/or consent of the subject's parent or legal 
guardian). 
7.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
8.   If samples are taken within 3 days of Day 0, samples do not need to be repeated on Day 0. However, a Day 0 serum sample for albumin should be collected at the same time as the CSF collection, to 
enable calculation of CSF-AI. Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for 
central lab analysis when samples are needed for local analysis. 
9.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
10. If serum or urine heparan sulfate is collected within 7 days of Day 0, it does not need to be repeated at Day 0. All attempts should be made to collect a urine sample for heparan sulfate. 
11. If serum ferritin, chitotriosidase and amino acid panel is collected within 7 days of Day 0, it does not need to be repeated at Day 0. 
12. Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
13. In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to the 
infusion. 
14. Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically indicated, 
subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the procedure to place the 
central line should be performed while the subject is already anesthetized or sedated for another study procedure. During study visits where CSF is collected that do not coincide with a serum chemistry 
sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
15. Subjects should be observed following the lumbar puncture as per institution standard practice. Vital signs, adverse events and concomitant medications should be assessed before the subject is 
discharged from the site. 
16. A follow-up telephone call will be made to the subject (or the subject's parent or caregiver) within 24 hours of the 2nd, 3rd , and 4th doses in Part A, and after the last dose of SBC-103 administered in the 
study (Week 24 or Early Termination) unless the subject has a scheduled follow-up visit. 
17. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
18. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
Proprietary and Confidential                                                                                                                       Page 24 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
9.1.2. 
Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – Year 1) 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Weeks 28 through 52) 
Assessments 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Week 38 
Week 40 
Week 42 
Week 44 
Week 46 
Week 48 
Week 50 
Week 52 
Visit Window (Days)* 
+3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
1 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
FDNA 
X 
Vineland-II , BSID-III, KABC-II, 
BOT-2 Brief Form, CSHQ, 
CCC-2, SBRS, ZBI 12-item, SF-
102 
X 
Hematology, Serum Chemistry 
(including Coagulation3), 
Urinalysis4 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)5 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate 
(Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers, 
including IgG, Inflammatory 
markers 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile6 
X 
SBC-103 ADA7 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation8 
XP 
XP 
XP 
Lumbar Puncture3,8,9 
XP 
XP 
XP 
Heparan Sulfate (Total and NRE) 
in CSF 
XP 
XP 
XP 
Calbindin D, HGF, Tau, pTau, 
Amyloid β, Albumin, IgG in CSF 
XP 
XP 
XP 
Glutamic Acids and Glycine in 
CSF 
XP 
XP 
XP 
Routine Findings (Cell Counts, 
Glucose, Protein) in CSF 
XP 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
XP 
Structural and Diffusion MRI8 
XP 
 
 
Proprietary and Confidential                                                                                                                       Page 25 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Weeks 28 through 52) 
Assessments 
Week 28 
Week 30 
Week 32 
Week 34 
Week 36 
Week 38 
Week 40 
Week 42 
Week 44 
Week 46 
Week 48 
Week 50 
Week 52 
Visit Window (Days)* 
+3 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events10 
CONTINUOUS 
Concomitant Medications11 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- acetylglucosaminidase; 
NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior 
Scales, Second Edition; ZBI = Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart. XP    
Assessments to be performed pre-dose. 
1.   Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional. 
3.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject to 
receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
4.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
5.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
8.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject 
should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
9.   During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the lumbar 
puncture is completed, the subject should be observed as per institution standard practice. 
10. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
11. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 26 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
9.1.3. 
Schedule of Study Assessments (Part B, Therapy at 1 and/or 3 mg/kg – Years 2-3, as applicable) 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk 54 / 
Wk 106 
Wk 56 / 
Wk 108 
Wk 58 / 
Wk110 
Wk 60 / 
Wk 112 
Wk 62 / 
Wk 114 
Wk 64/ 
Wk 116 
Wk 66/ 
Wk 118 
Wk 68/ 
Wk 120 
Wk 70/ 
Wk 122 
Wk 72/ 
Wk 124 
Wk 74/ 
Wk 126 
Wk 76/ 
Wk 128 
Wk 78/ 
Wk 130 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
FDNA 
X 
Vineland-II , BSID-III, KABC-II, 
BOT-2 Brief Form, CSHQ, 
CCC-2, SBRS, ZBI 12-item, 
SF-102 
X 
Hematology, Serum 
Chemistry (including 
Coagulation3), Urinalysis4 
XP 
XP 
XP 
Pregnancy Test (Urine)5 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulfate (Total and NRE) 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic Acid and 
Glycine 
XP 
XP 
XP 
Exploratory Serum 
Biomarkers, including IgG, 
Inflammatory markers 
XP 
XP 
XP 
Serum Pharmacokinetic 
Profile6 
X 
SBC-103 ADA7 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anesthesia/Sedation8 
XP 
XP 
Lumbar Puncture3,8,9 
XP 
XP 
Heparan Sulfate (Total and 
NRE) in CSF 
XP 
XP 
Calbindin D, HGF, Tau, 
pTau, Amyloid β, Albumin, 
IgG in CSF 
XP 
XP 
 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 27 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
Assessments 
Wk 54 / 
Wk 106 
Wk 56 / 
Wk 108 
Wk 58 / 
Wk110 
Wk 60 / 
Wk 112 
Wk 62 / 
Wk 114 
Wk 64/ 
Wk 116 
Wk 66/ 
Wk 118 
Wk 68/ 
Wk 120 
Wk 70/ 
Wk 122 
Wk 72/ 
Wk 124 
Wk 74/ 
Wk 126 
Wk 76/ 
Wk 128 
Wk 78/ 
Wk 130 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Glutamic Acids and Glycine 
in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) in 
CSF 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
Structural and Diffusion 
MRI7 
Telephone call10 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events11 
CONTINUOUS 
Concomitant Medications12 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; D = day; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- 
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior 
Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0; Infusions must be administered at least 10 days apart. 
XP    Assessments to be performed pre-dose. 
1.   Vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 2 hours after completion of the 
infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional. 
3.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the 
subject to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to 
the central 
laboratory for analysis. 
4.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis 
when samples are needed for local analysis. 
5.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate-to-severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
8.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If 
clinically indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When 
possible, the procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is 
completed, the subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is 
discharged from the site. 
9.   During study visits where CSF is will be collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
10. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
Proprietary and Confidential                                                                                                                       Page 28 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
11. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
12. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
 
 
 
Assessments 
Wk 80/ 
Wk 132 
Wk 82/ 
Wk 134 
Wk 84/ 
Wk 136 
Wk 86/ 
Wk 138 
Wk 88/ 
Wk 140 
Wk 90/ 
Wk 142 
Wk 92/ 
Wk 144 
Wk 94/ 
Wk 146 
Wk 96/ 
Wk 148 
Wk 98/ 
Wk 150 
Wk 100/ 
Wk 152 
Wk 102/ 
Wk 154 
Wk 104/ 
Wk 156 
(End of 
Tx/ Early 
Term) 
Week 
160 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
FDNA 
X 
Vineland-II , BSID-III, 
KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, 
SBRS, ZBI 12-item, SF- 
102 
X 
Hematology, Serum 
Chemistry (including 
Coagulation3), 
Urinalysis4 
XP 
XP 
XP 
Pregnancy Test (Urine)5 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan 
Sulfate (Total and NRE) 
XP 
XP 
XP 
Serum Ferritin and 
Chitotriosidase 
XP 
XP 
XP 
Plasma Glutamic Acid 
and Glycine 
XP 
XP 
XP 
Exploratory Serum 
Biomarkers, including 
IgG, Inflammatory 
markers 
XP 
XP 
XP 
Serum Pharmacokinetic 
Profile6 
X 
SBC-103 ADA7 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General 
Anesthesia/Sedation8 
XP 
XP 
Lumbar Puncture3,8,9 
XP 
XP 
Heparan Sulfate (Total 
and NRE) in CSF 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 29 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
Calbindin D, HGF, Tau, 
XP 
XP 
Proprietary and Confidential                                                                                                                       Page 30 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part B: Therapy at 1 and/or 3 mg/kg (Years 2 and 3, as applicable prior to Part C) 
 
 
 
Assessments 
Wk 80/ 
Wk 132 
Wk 82/ 
Wk 134 
Wk 84/ 
Wk 136 
Wk 86/ 
Wk 138 
Wk 88/ 
Wk 140 
Wk 90/ 
Wk 142 
Wk 92/ 
Wk 144 
Wk 94/ 
Wk 146 
Wk 96/ 
Wk 148 
Wk 98/ 
Wk 150 
Wk 100/ 
Wk 152 
Wk 102/ 
Wk 154 
Wk 104/ 
Wk 156 
(End of 
Tx/ Early 
Term) 
Week 
160 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
pTau, Amyloid β, 
Albumin, IgG in CSF 
Glutamic Acids and 
Glycine in CSF 
XP 
XP 
Routine Findings (Cell 
Counts, Glucose, Protein) 
in CSF 
XP 
XP 
SBC-103 in CSF 
XP 
XP 
Structural and Diffusion 
MRI7 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call10 
X19 
Adverse Events11 
CONTINUOUS 
Concomitant 
Medications12 
CONTINUOUS 
Key: ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, 
Third Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- 
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; term = termination; Tx = treatment; 
Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0; infusions must be administered at least 10 days apart. 
XP    Assessments to be performed pre-dose. 
1.   Starting at Week 54, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional. 
3.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the 
subject to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to 
the central laboratory for analysis. 
4.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis 
when samples are needed for local analysis. 
5.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
6.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
7.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
     8.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically indicated,  
           subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
Proprietary and Confidential                                                                                                                       Page 31 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
          procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the subject should be  
           observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
9.   During study visits where CSF is will be collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
10. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
11. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
12. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 32 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
9.1.4. 
Schedule of Study Assessments (Part C, Therapy at 5 and/or10 mg/kg) 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 1 through 26) 
Assessments 
Wk 1C 
D0C 
Wk 1C 
D1C* 
Wk 
2C 
Wk 
4C 
Wk 
6C 
Wk 
8C 
Wk 
10C 
Wk 
12C 
Wk 
14C 
Wk 
16C 
Wk 
18C 
Wk 
20C 
Wk 
22C 
Wk 
24C 
Wk 
26C 
Visit Window (Days)** 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Part C Informed Consent/Assent
XP 
Part C Eligibility Assessment 
XP 
Physical Examination 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
XP 
XP 
XP 
XP 
FDNA 
X 
X 
Vineland-II, BSID-III, KABC-II, BOT-2 BF, CSHQ, CCC-2, 
SBRS, ZBI 12-item, SF-102,3 
XP,3 
X 
Hematology, Serum Chemistry (including Coagulation4), 
Urinalysis5 
XP 
X 
XP 
XP 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and Glycine 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile7 
X 
X 
X 
SBC-103 ADA8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation9 
XP 
XP 
XP 
4,9,10,11 
Lumbar Puncture 
XP,11 
XP 
XP 
Heparan Sulfate (Total and NRE) in CSF 
XP,11 
XP 
XP 
Calbindin D, HGF, Tau, pTau, Amyloid β, Albumin, 
IgG in CSF 
XP,11 
XP 
XP 
Glutamic Acids and Glycine in CSF 
XP,11 
XP 
XP 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein) 
XP,11 
XP 
XP 
SBC-103 in CSF 
XP,11 
XP 
XP 
Structural and Diffusion MRI9,12 
XP,12 
XP 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events13 
CONTINUOUS 
 
Proprietary and Confidential                                                                                                                       Page 33 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 1 through 26) 
Assessments 
Wk 1C 
D0C 
Wk 1C 
D1C* 
Wk 
2C 
Wk 
4C 
Wk 
6C 
Wk 
8C 
Wk 
10C 
Wk 
12C 
Wk 
14C 
Wk 
16C 
Wk 
18C 
Wk 
20C 
Wk 
22C 
Wk 
24C 
Wk 
26C 
Visit Window (Days)** 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Concomitant Medications14 
CONTINUOUS 
Key:  ADA = anti-drug antibodies; BOT-2 BF = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third 
Edition; CCC-2 = Children’s Communication Checklist, Second Edition;  CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial 
Dysmorphology Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- 
acetylglucosaminidase; NRE = non-reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Vineland-II = Vineland Adaptive Behavior Scales, 
Second Edition; Wk = week; ZBI = Zarit Burden Interview, 12-item. 
*    The Week 1C Day 1C visit applies only to the first subject at each dose level. 
**  All study visits will be scheduled relative to Week 1 Day 0 in Part C; infusions must be administered at least 10 days apart. 
XP    Assessments to be performed pre-dose. 
1.   Starting at Week 26C, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing. 
3.   Neurocognition testing performed within 8 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessments on Day 0C. 
4.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the 
subject to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to 
the central 
laboratory for analysis. 
5.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis 
when samples are needed for local analysis. 
6.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
9.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If 
clinically indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When 
possible, the procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is 
completed, the subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is 
discharged from the site. 
10. During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar picture performed within 4 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessment on Day 0C. 
12. An MRI obtained within 8 weeks prior to Day 0 in Part C may be used as the Day 0C baseline in lieu of repeating the assessment on Day 0C. 
13. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
14. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
Proprietary and Confidential                                                                                                                       Page 34 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 28 through 52) 
STUDY WEEK from Part A Day 0 
Wk 
156 
Wk 
160 
Part C Visit 
Wk 
28C 
Wk 
30C 
Wk 
32C 
Wk 
34C 
Wk 
36C 
Wk 
38C 
Wk 
40C 
Wk 
42C 
Wk 
44C 
Wk 
46C 
Wk 
48C 
Wk 
50C 
Wk 
52C 
End of 
Tx 
Follow 
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
XP 
XP 
FDNA 
X 
X 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
X 
X3 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and Glycine 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile7 
X 
X 
SBC-103 ADA8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation9 
XP 
XP 
XP 
Lumbar Puncture4,9,10,11 
XP 
XP 
XP,11 
Heparan Sulfate (Total and NRE) in CSF 
XP 
XP 
XP,11 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
XP,11 
Glutamic Acids and Glycine in CSF 
XP 
XP 
XP,11 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein) 
XP 
XP 
XP,11 
SBC-103 in CSF 
XP 
XP 
XP,11 
Structural and Diffusion MRI9,12 
XP 
XP,12 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call13 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 35 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third Edition; 
CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial Dysmorphology Novel 
Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- acetylglucosaminidase; NRE = non-reducing 
end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = 
Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart. XP    
Assessments to be performed pre-dose 
1.   Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered 
prior to dosing. 
3.   Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject 
to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
9.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the 
subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10. During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
12. An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
15. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 36 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 54 through 78 and Weeks 106 through 130) 
STUDY WEEK from Part A Day 0 
Wk 
156 
Wk 
160 
Part C Visit 
Wks 
54C 
Wks 
56C 
Wks 
58C 
Wks 
60C 
Wks 
62C 
Wks 
64C 
Wks 
66C 
Wks 
68C 
Wks 
70C 
Wks 
72C 
Wks 
74C 
Wks 
76C 
Wks 
78C 
End of 
Tx 
Follow 
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
XP 
XP 
FDNA 
X 
X 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
X 
X3 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and Glycine 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile7 
X 
X 
SBC-103 ADA8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation9 
XP 
XP 
XP 
Lumbar Puncture4,9,10,11 
XP 
XP 
XP,11 
Heparan Sulfate (Total and NRE) in CSF 
XP 
XP 
XP,11 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
XP,11 
Glutamic Acids and Glycine in CSF 
XP 
XP 
XP,11 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein) 
XP 
XP 
XP,11 
SBC-103 in CSF 
XP 
XP 
XP,11 
Structural and Diffusion MRI9,12 
XP,12 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call13 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 37 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third 
Edition; CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial Dysmorphology 
Novel Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- acetylglucosaminidase; NRE = non-
reducing end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = 
week; ZBI = Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart. 
XP    Assessments to be performed pre-dose. 
1.   Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered prior 
to dosing. 
3.   Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the 
subject to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to 
the central laboratory for analysis. 
5.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis 
when samples are needed for local analysis. 
6.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
9.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If 
clinically indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When 
possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the 
subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the 
site. 
10. During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit 
12. An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
15. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
Proprietary and Confidential                                                                                                                       Page 38 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 80 through 104) 
STUDY WEEK from Part A Day 0 
Wk 
156 
Wk 
160 
Assessments 
Part C Visit 
Week 
80C 
Week 
82C 
Week 
84C 
Week 
86C 
Week 
88C 
Week 
90C 
Week 
92C 
Week 
94C 
Week 
96C 
Week 
98C 
Week 
100C 
Week 
102C 
Week 
104C 
End of 
Tx 
Follow 
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
XP 
XP 
FDNA 
X 
X 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
X 
X3 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and Glycine 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile7 
X 
X 
SBC-103 ADA8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation9 
XP 
XP 
XP 
Lumbar Puncture4,9,10,11 
XP 
XP 
XP,11 
Heparan Sulfate (Total and NRE) in CSF 
XP 
XP 
XP,11 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
XP,11 
Glutamic Acids and Glycine in CSF 
XP 
XP 
XP,11 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein) 
XP 
XP 
XP,11 
SBC-103 in CSF 
XP 
XP 
XP,11 
Structural and Diffusion MRI9, 12 
XP 
XP,12 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call13 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
Proprietary and Confidential                                                                                                                       Page 39 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third Edition; 
CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial Dysmorphology Novel 
Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- acetylglucosaminidase; NRE = non-reducing 
end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = 
Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart. XP    
Assessments to be performed pre-dose. 
1.   Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered prior to 
dosing. 
3.   Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject 
to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
9.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the 
subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10. During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After the 
lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
12. An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
15. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
 
 
Proprietary and Confidential                                                                                                                       Page 40 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
Schedule of Study Assessments 
Part C: Therapy at 5 and/or 10 mg/kg (Weeks 54 through 78 and Weeks 106 through 130) 
STUDY WEEK from Part A Day 0 
Wk 
156 
Wk 
160 
Part C Visit 
Wks 
106C 
Wks 
108C 
Wks 
110C 
Wks 
112C 
Wks 
114C 
Wks 
116C 
Wks 
118C 
Wks 
120C 
Wks 
122C 
Wks 
124C 
Wks 
126C 
Wks 
128C 
Wks 
130C 
End of 
Tx 
Follow 
-up 
Visit Window (Days)* 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Physical Examination 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Height and Weight 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
XP 
XP 
FDNA 
X 
X 
Vineland-II , BSID-III, KABC-II, BOT-2 Brief 
Form, CSHQ, CCC-2, SBRS, ZBI 12-item, SF-102,3 
X 
X3 
Hematology, Serum Chemistry (including 
Coagulation4), Urinalysis5 
XP 
XP 
XP 
XP 
Pregnancy Test (Urine)6 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
Serum and Urine Heparan Sulfate (Total and NRE) 
XP 
XP 
XP 
XP 
Serum Ferritin and Chitotriosidase 
XP 
XP 
XP 
XP 
Plasma Glutamic Acid and Glycine 
XP 
XP 
XP 
XP 
Exploratory Serum Biomarkers including IgG and 
Inflammatory Markers 
XP 
XP 
XP 
XP 
Serum Pharmacokinetic Profile7 
X 
X 
SBC-103 ADA8 
XP 
XP 
XP 
XP 
XP 
XP 
XP 
General Anesthesia/Sedation9 
XP 
XP 
XP 
Lumbar Puncture4,9,10,11 
XP 
XP 
XP,11 
Heparan Sulfate (Total and NRE) in CSF 
XP 
XP 
XP,11 
Calbindin D, HGF, Tau, pTau, Amyloid β, 
Albumin, IgG in CSF 
XP 
XP 
XP,11 
Glutamic Acids and Glycine in CSF 
XP 
XP 
XP,11 
Routine Findings in CSF 
(Cell Counts, Glucose, Protein) 
XP 
XP 
XP,11 
SBC-103 in CSF 
XP 
XP 
XP,11 
Structural and Diffusion MRI9,12 
XP,12 
SBC-103 Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call13 
X 
Adverse Events14 
CONTINUOUS 
Concomitant Medications15 
CONTINUOUS 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
 
 
Key:  ADA = anti-drug antibodies; BOT-2 Brief Form  = Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, Brief Form; BSID-III = Bayley Scales of Infant and Toddler Development, Third Edition; 
CCC-2 = Children’s Communication Checklist, Second Edition; CSF = cerebrospinal fluid; CSHQ = Children’s Sleep Habits Questionnaire; ECG = electrocardiogram; FDNA = Facial Dysmorphology Novel 
Analysis; HGF = hepatocyte growth factor; IgG = immunoglobulin G; KABC-II = Kaufman Assessment Battery for Children, Second Edition; NAGLU = alpha-N- acetylglucosaminidase; NRE = non-reducing 
end; SBRS = Sanfilippo Behavior Rating Scale; SF-10 = 10-item Short Form Health Survey for Children; Tx = treatment; Vineland-II = Vineland Adaptive Behavior Scales, Second Edition; Wk = week; ZBI = 
Zarit Burden Interview, 12-item. 
*    All study visits will be scheduled relative to Day 0 in Part C; infusions must be administered at least 10 days apart. XP    
Assessments to be performed pre-dose. 
1.   Starting at Week 26, vital signs will be taken pre-dose (within approximately 30 minutes), approximately every 15 minutes during infusion and approximately every 15 minutes for 1 hour after 
completion of the infusion, provided there is no occurrence of IARs during the infusion.   Vital signs will be obtained after any lumbar puncture as per site standard of care. 
2.   The Vineland-II, BSID-III or KABC-II, BOT-2 Brief Form, and CCC-2 should be administered in-person by an appropriately qualified professional; where possible, the test should be administered prior 
to dosing. 
3.   Neurocognition testing performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessments at the Study Week 156 Visit. 
4.   The coagulation laboratory panel should be collected within 48 hours prior to performing the lumbar puncture, and the results should be available prior to sedating/anesthetizing the subject or 
performing the lumbar puncture. The procedure (including the initiation of sedation/anesthesia) will not commence until the site receives these results and confirms that it is safe for the subject 
to receive anesthesia/sedation and the lumbar puncture.  To facilitate this process, all coagulation panels (as of 23 March 2015) will be drawn and analyzed locally rather than sent to the central 
laboratory for analysis. 
5.   Central lab reference ranges will be used throughout the study, including in the event that labs are analyzed locally. All attempts should be made to draw lab samples for central lab analysis when 
samples are needed for local analysis. 
6.   If a urine sample is not able to be provided, a serum pregnancy test will be performed by a local laboratory. 
7.   Refer to Section 5.2.1.3 for directions and timing of PK sampling. 
8.   In addition to time points indicated, obtain a sample for ADA determination anytime subject experiences a moderate or severe IAR during the next study visit (≥ 4 days after the IAR) and prior to 
the infusion. 
9.   Lumbar puncture and MRI procedures may be performed under general anaesthesia or light sedation, as clinically appropriate in accordance with local institutional procedures. If clinically 
indicated, subjects may also receive general anesthesia or sedation for central line placement for long-term vascular access, in accordance with institutional guidelines. When possible, the 
procedure to place the central line should be performed while the subject is already anesthetized or sedated for another study procedure. After the lumbar puncture is completed, the 
subject should be observed as per institution standard practice.  Vital signs, adverse events and concomitant medications should be assessed before the subject is discharged from the site. 
10. During study visits where CSF is collected that do not coincide with a serum chemistry sample per the SOA, a serum albumin should be collected in order to assess CSF-AI Index. After 
the lumbar puncture is completed, the subject should be observed as per institution standard practice. 
11. A lumbar puncture performed within 4 weeks prior to the Study Week 156 Visit may be used as the last assessment in lieu of repeating the assessment at the Study Week 156 Visit 
12. An MRI performed within 8 weeks prior to the Study Week 156 Visit may be used as the last visit assessment in lieu of repeating the assessment at the Study Week 156 Visit. 
13. A telephone call will be made 4 weeks after the last dose received of SBC-103 after Week 156 End of Treatment or after the Early Termination visit. 
14. All AEs should be followed until they have returned to baseline values or stabilized or until the Investigator and Sponsor or designee agree that follow-up is no longer necessary. 
15. Information on all medications and treatments received by the subject within the 4 weeks preceding the Screening visit through the final visit will be recorded in the CRF. 
 
 
Proprietary and Confidential                                                                                                                       Page 42 of 45 
 


Alexion Pharmaceuticals, Inc. 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
9.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Not applicable. 
9.3. 
Sample Size, Power, and Randomization 
9.3.1. 
Sample Size and Power 
The sample size of approximately 9 subjects is based on clinical and not statistical consideration 
and is considered sufficient to provide PK, safety, and PD/efficacy data to inform dose and 
regimen selection for additional clinical studies. 
9.3.2. 
Randomization 
Parts A and B were open label and non-randomized with no requirement for blinding. 
In Part C, subjects are randomized such that at least 1 subject from each dose assignment in Part 
A received SBC-103 at 5 mg/kg and at least 1 subject from each dose assignment in Part A 
received SBC-103 at 10 mg/kg.  Thus each of the assigned dose levels from Part A is represented 
in each of the 2 dose levels being studied in Part C.   
 
As noted in the CSP Section 1.4.1, a total of 11 subjects enrolled in this study; 5 of these 
randomized to receive 5 mg/kg QOW and 6 randomized to receive 10 mg/kg QOW. 
Details of the randomization are provided in a randomization specification document, which is 
maintained by the Sponsor. 
9.4. 
Technical Specifications for Derived Variables  
9.4.1. 
Baseline Definition 
Baseline is defined as the value closest and prior to the first administration of SBC-103 on the 
first day of dosing. Once a subject enters Part C, the study visit schedule is reset to Week 1 Day 
0 Part C (WK1C D0C) to ensure that the visit days/assessments correspond to the same number 
of infusions of SBC-103 for each subject. All study visits in Part C will be scheduled relative to 
WK1C D0C to allow for a more meaningful assessment of the PK and PD/efficacy profile of the 
5 and 10 mg/kg doses. The first day of dosing is Day 0 in the SOA and will be considered 
Relative Study Day 1 in order to construct CDISC compliant datasets.  Analyses will use the 
assessments based on the Day 0 visit per the eCRF.  Part C baseline is defined as the value of the 
last assessment performed at the visit closest and prior to the first administration of SBC-103 on 
the first day of dosing in Part C at 5 mg/kg or 10 mg/kg. 
Subjects will begin Part C at varying time points.  For some subjects, the Part C Baseline 
(WK1C D0C) visit will occur at the same time as, and will be equivalent to the 12 Month (Week 
52) On-Study visit.  Subjects that escalated into Part C prior to the 12 Month (Week 52) On-
Study visit will have a Part C Baseline (WK1C D0C) visit only.  Finally, subjects who escalated 
into Part C after the 12 Month (Week 52) On-Study visit, their Part C Baseline (WK1C D0C) 
visit will be a separate visit from their 12 Month (Week 52) On-Study visit and will occur at the 
visit closest and prior to the first administration of SBC-103 at the escalated 5 or 10 mg/kg dose.  


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
To minimize unnecessary risk and burden to subjects, the following study assessments in Part B 
may be used as baseline assessments for Part C in lieu of repeating the assessment prior to the 
first dose in Part C: 
• An MRI performed within 8 weeks prior to Day 0 in Part C (WK1C D0C) may be used 
as the baseline assessment for Part C in lieu of performing an MRI on Day 0C (WK1C 
D0C). 
• Neurocognitive and developmental testing performed within 8 weeks prior to Day 0 in 
Part C (WK1C D0C) may be used as the baseline assessment for Part C in lieu of 
performing neurocognitive and developmental testing on Day 0C (WK1C D0C). 
• A lumbar puncture performed within 4 weeks prior to Day 0 in Part C (WK1C D0C) 
may be used as the baseline assessment for Part C in lieu of performing a lumbar 
puncture on Day 0C (WK1C D0C). 
To ensure that all assessments are properly summarized, an analysis flag will be created to 
indicate each Part C baseline assessment. 
9.4.2. 
Visit Windows 
It is expected that all visits will occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the eCRF even if the assessment is outside of the 
visit window. In data listings, the relative day of all visits will also be presented. 
9.4.3. 
Imputation of Partial Dates 
For descriptive analysis purposes, partial dates will be imputed for some calculations (e.g. time 
to, and duration of, etc.). For calculation of time of laboratory test from diagnosis, partial dates 
will be handled as follows.  Date of diagnosis must be imputed from age at diagnosis and date of 
birth (DOB).  Date of diagnosis will be defined as DOB + age at diagnosis.  If DOB contains 
partial dates, date of diagnosis will be defined as imputed DOB + age at diagnosis. Time from 
diagnosis will be calculated from imputed date of diagnosis.  
For other analyses, partial dates will be handled by the following imputation methods: 
• Imputations for ages (in months): If birthdate is not missing, Age = (Assessment date - birth 
date)/30.4375. If only birth year and month are available, Age = (Assessment year- birth 
year)*12 + (assessment month-birth month). If only birth year is available then a “midpoint 
date” of July 1 will be used for an imputed birth date; using July 1 of the birth year, Age = 
(Assessment date – imputed birth date)/30.4375.  If the birth date is completely missing, Age 
= (age in years from eCRF*12) for Baseline (add the appropriate number of months for any 
follow-up assessments). 
• AE Start Date Imputation: The earliest possible date will be imputed for start date of AEs. If 
the day of the month is missing, the day will be set to the first day of the month. If the day 
and month are both missing, the day and month will be assumed to be January 1. 
• AE End Date Imputation: The latest possible date will be imputed for end date of AEs. If the 
day of the month is missing, the day will be set to the last day of the month. If the day and 
month are both missing, the day and month will be assumed to be December 31. 
Proprietary and Confidential                                                                                                                       Page 44 of 45 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
{Protocol: NGLU-CL02 21 Jan 2016 (Amendment 7)} 
{01 Sep 2017, Version 1.0} 
• Midpoint Imputation:  For all other partial dates, a “midpoint date” will be imputed.  If the 
day of the month is missing, the day will be set to the fifteenth (15th) day of the month.  If 
the day and month are both missing, the day and month will be assumed to be July 1. 
• Should the date created with these imputation rules place it outside the possible range of 
values established by complete, known dates (such as the birth date, death date, ICF date for 
study procedures), the closest known date will be used.  In the case of date imputations for 
age calculations, the age as reported on the eCRF will be used as a reference to ensure the 
calculated age is appropriate. 
For reporting purposes, a month will be defined as 30.4375 days (rounded and displayed to 1 
decimal place) and a year defined as 365.25 days (rounded and displayed to 2 decimal places). 
9.5. 
Additional details on Statistical Methods 
Not applicable. 
Proprietary and Confidential                                                                                                                       Page 45 of 45