Clinical trial NCT02418455
Conditions: Sly Syndrome MPS VII Mucopolysaccharidosis Mucopolysaccharidosis VII
Keywords: MPS 7 Sly Syndrome MPS VII Enzyme Replacement Therapy Rare Disease Mucopolysaccharidosis type 7 Lysosomal Storage Disease Metabolic Disorder
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2015-07-21; Completion date: 2019-03-26
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective was to evaluate the effect of UX003 treatment in pediatric MPS VII participants less than 5 years of age on safety, tolerability, and efficacy as determined by the reduction of urinary glycosaminoglycans (uGAG) excretion.

Detailed description:

Arms: arm 1: UX003 4 mg/kg every other week (QOW). Initial treatment period 48 weeks. Continuation period up to 240 weeks.
Interventions: intervention 1: UX003
Intervention descriptions: intervention 1: solution for intravenous infusion

Protocol documents:
Prot_000.pdf: 
 
Title Page 
 
An Open-label Study of UX003 rhGUS Enzyme Replacement Therapy in MPS 7 
Patients Less than 5 Years Old 
                                       Protocol Number: UX003-CL203 
                                       Original Protocol:  09 January 2015  
                                       Amendment 1:        05 October 2015  
 
 
 
   Amendment 2: 
 07 April 2016 
 
Investigational Product: 
UX003, recombinant human beta-glucuronidase (rhGUS) 
Indication: 
Mucopolysaccharidosis type 7 (MPS 7) 
IND Number: 
123788 
EudraCT Number: 
2015-000104-26 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA  94949 
Sponsor’s Responsible 
Medical Officer: 
Christine Haller, MD 
VP Drug Safety & Pharmacovigilance 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA  USA 94949 
 
 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. 
 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx).  Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited.  By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board /Ethics Committee procedures, to 
obtain written informed consent from potential subjects, or as required by law. 
PPD


Protocol Number:  UX003-CL203  
Amendment 1:  05 OCT 2015  
 
 
 
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Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX003-CL203 Amendment 1 
05 October 2015  
 
Original Protocol UX003-CL203 (dated 09 January 2015) has been modified by 
Amendment 1 to expand the study size and to add or clarify certain procedures. The major 
protocol changes are summarized below:  
1. Overall Study Design and Plan: In Section 7.1 and related sections, the study size 
has been increased from up to 7 subjects to approximately 15 subjects including 
approximately 5 infants with hydrops fetalis. 
Rationale:  Increasing the sample size will provide a more robust assessment of safety 
and efficacy in this patient population. 
2. Study Procedures and Assessments: Several updates have been made to clarify or 
add procedures in Section 7.5. Given the age of the study population and number of 
assessments, if the maximum amount of blood has been taken based on Maximum 
Allowable Blood Volume Guidelines for any subject on any given study visit, some 
assessments will not be required. A provision has been established in the study-
specific Laboratory Manual for details on prioritizing blood draws. Additional 
modifications to study procedures and assessments specified in the protocol text are 
summarized below. 
Urinary and serum GAG: Reference to the NRE as the primary method for 
measuring urinary and serum GAG has been removed from the protocol. 
Rationale: Multiple assays for measuring pathologic accumulation of GAG are 
available. The specific methodology used for evaluating the primary efficacy variable 
will be included in the study Statistical Analysis Plan. 
Functional Development: The protocol has been updated to specify the Bayley 
Scales of Infant and Toddler Development® – Third Edition (Bayley-III) will not be 
administered if the subject has achieved the highest raw score on the instrument, or if, 
based on the clinical judgment of the Investigator, valid and reliable administration is 
not possible at the specified visit. 
Rationale: The protocol previously specified the highest level of age-equivalence on 
the test as a criterion for omitting the Bayley-III assessment; the change to raw score 
provides a more straightforward threshold. The option to withhold assessment based 


Protocol Number:  UX003-CL203  
Amendment 1:  05 OCT 2015  
 
 
 
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Page 3 
on Investigator opinion provides a measure of flexibility thereby avoiding unreliable 
or spurious results due to mitigating factors such as language difficulties or clinical 
condition of the subject.  
Motor Functioning:  A gross motor milestone checklist has been added as an 
additional assessment of motor functioning as a tertiary efficacy variable.  
Rationale: A gross motor milestone checklist was designed to allow for assessment of 
the functional status of the subject requiring limited language interaction and physical 
handling.  
Pulmonary Function Testing:  Pulmonary function assessments have been added to 
the Continuation Period; pulse oximetry measurements will be obtained at 12-week 
intervals. 
Rationale: Continued monitoring of pulmonary function will provide a potential 
measure of maintenance of efficacy. 
Biochemical Markers of Bone Turnover: Assessment of serum markers of bone 
formation and bone resorption including procollagen type 1 N-propeptide (P1NP), 
carboxy-terminal cross-linked telopeptide of type I collagen (CTX-I), bone-specific 
alkaline phosphatase (BALP), and vitamin D will be conducted at Weeks 0 (baseline) 
and 2, then approximately every 8 weeks thereafter for the remainder of the 
Treatment Period (i.e. Weeks 8-48), and every 24 weeks during the Continuation 
Period. 
Rationale: Skeletal abnormalities are characteristic of MPS 7. Measurement of 
biochemical markers of bone turnover may allow the effects of UX003 on skeletal 
tissue to be evaluated.  
Drug Concentration Measurements: Specific time points for collection of PK 
samples have been provided. 
Vital Signs: Procedures for the assessment of vital signs have been clarified. 
Rationale: Vital sign assessments have been clarified to be specific for young 
pediatric subjects. 
3. Reporting and Follow-up of Adverse Drug Events: A new section (Section 8.5.5) 
has been added to provide direction on the reporting requirements for suspected 
unexpected serious adverse reactions (SUSAR) to appropriate Regulatory Authorities 
(including Competent Authorities in all Member States concerned), ECs, and 
Investigators as per local laws and regulations.


Protocol Number:  UX003-CL203  
Amendment 2: 07 APR 2016  
 
 
 
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Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX003-CL203 Amendment 2 
07 April 2016 
 
Protocol Amendment 1 (dated 05 October 2015) has been modified by Amendment 2 to 
remove or clarify certain procedures and update information. The major protocol changes are 
summarized below:  
1. Overall Study Design and Plan:  
• The protocol has been updated to remove reference to availability of commercial 
drug in the subject’s territory as a reason for study termination. In addition “end 
of trial” has been defined in Section 7.5.1 as the last visit of the last subject 
undergoing evaluation in the study. As the planned duration of treatment in this 
study is up to 240 weeks, the end of trial is defined as the Week 240 visit of the 
last subject. In the event the study is terminated by the Sponsor prior to Week 
240, all subjects should complete a termination visit and the date of the last 
termination visit of the last subject would define the end of the trial.  
Rationale: This change and additional clarification were made to align with 
current regulatory guidelines. 
• Revised protocol to allow for Mutation Analysis at any point of the study. 
Rationale: To further characterize the disease manifestations, severity and 
progression of MPS 7, the sponsor aims to determine the specific genetic 
mutation in each patient enrolled if consent is provided for such testing.   
• Clarify the handling of spinal cord compression. 
Rationale: Patients with MPS diseases are at risk for spinal cord compression due 
to disease-related skeletal abnormalities including odontoid hypoplasia and 
vertebral subluxation.  Enzyme replacement therapy may result in increased joint 
flexibility with possible impact on the risk of spinal cord injury.  Additional text 
was added to the protocol to recommend appropriate monitoring and management 
of signs and symptoms of potential spinal cord compression.   
• Removal of serum GAG from the continuation period. 
Rationale: Based on clinical and nonclinical evidence, uGAG is a direct 
pathophysiological and readily measured marker of the MPS disease process and 
a reasonable predictor of treatment effect and clinical benefit. Urine GAG is the 


Protocol Number:  UX003-CL203  
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Page 3 
primary measure of ERT efficacy in MPS disorders and will continue to be 
followed during this continuation period. Multiple assays for measuring 
pathologic accumulation of GAG in urine are now available; supplementary 
assays may be performed. Removal of serum GAG assessments reduces the 
number of required blood draws.  
• Record Retention has been updated to state that all study records must be retained 
for at least 25 years after the end of the clinical trial or in accordance with 
national law. 
Rationale: This administrative change has been made to reflect upcoming changes 
to EU clinical trial regulations and current regulations by other health authorities. 
2. Study Procedures and Assessments:  
• Vital Signs: Procedures for the assessment of vital signs have been clarified. 
Rationale: Vital sign assessments have been clarified to be specific for young 
pediatric subjects. 


Protocol Number:  UX003-CL203  
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2 SYNOPSIS 
TITLE OF STUDY: 
An Open-label Study of UX003 rhGUS Enzyme Replacement Therapy in MPS 7 Patients Less than 
5 Years Old 
PROTOCOL NUMBER: 
UX003-CL203 
STUDY SITES: 
Multicenter; approximately 2-6 sites globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
Mucopolysaccharidosis type 7 (MPS 7, Sly syndrome) is an ultra-rare (< 100 cases currently identified 
worldwide), chronically debilitating, and life-threatening lysosomal storage disease.  It is characterized 
by a deficiency of the lysosomal enzyme beta-glucuronidase (GUS), required for degradation of two 
glycosaminoglycans (GAGs): dermatan sulfate and heparan sulfate, the same substrates accumulated 
in MPS 1 (Hurler syndrome) and MPS 2 (Hunter syndrome).  The GUS deficiency results in 
lysosomal accumulation of GAGs in multiple tissues and organs throughout the body and numerous 
clinical symptoms similar to those observed in MPS 1 and MPS 2.  Some MPS 7 patients present at 
birth with severe edema or non-immune hydrops fetalis and usually die within 2-4 months. 
There are currently no approved treatments for MPS 7.  UX003 (recombinant human 
beta-glucuronidase, rhGUS) is intended as an enzyme replacement therapy (ERT) for the treatment of 
MPS 7.  A Phase 1/2 study has shown that treatment with UX003 can reduce lysosomal storage and 
urinary GAG (uGAG) and is expected to provide clinical benefit; a pivotal Phase 3 study is ongoing.   
Patients with MPS 7 can present as newborns, infants or young children; this Phase 2 study will 
evaluate treatment with UX003 in MPS 7 patients less than 5 years of age. Although young patients 
have the same underlying etiology, the breadth and type of clinical problems can be different, 
including more frequent ascites/edema, cardiac problems, and other severe manifestations.  This study 
will assess the relative safety, pharmacokinetics (PK), and efficacy of UX003 ERT in young patients 
with MPS 7. 
OBJECTIVES: 
Primary Objective: 
The primary objective is to evaluate the effect of UX003 treatment in pediatric MPS 7 subjects less 
than 5 years of age on: 
• 
Safety and tolerability  
• 
Efficacy as determined by the reduction of uGAG excretion 
Secondary Objective: 
The secondary objective is to evaluate the effect of UX003 on growth velocity and 
hepatosplenomegaly. 
 


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Tertiary Objectives: 
Tertiary objectives are to assess PK and evaluate the effect of UX003 on measures of lysosomal 
storage, overall clinical change, cardiac and pulmonary function, bone turnover markers, and 
functional and motor development. 
STUDY DESIGN AND METHODOLOGY: 
UX003-CL203 is an open-label, multicenter, Phase 2 study to assess the safety and efficacy of UX003 
in pediatric MPS 7 subjects. The study seeks to enroll approximately 15 subjects less than 5 years of 
age at the time of informed consent, and will attempt to include approximately 5 infants with hydrops 
fetalis if possible. Subjects with prior exposure to UX003 treatment under an emergency IND may 
also be enrolled at the discretion of the Sponsor. In the initial 48 weeks of treatment, subjects will 
receive UX003 via intravenous (IV) infusion at a dose of 4 mg/kg every other week (QOW). Subjects 
who complete the 48-week study may choose to continue UX003 treatment in the Continuation Period 
up to 240 weeks, or until the subject withdraws consent, the subject is discontinued from the study at 
the discretion of the Investigator or Ultragenyx, or the study is terminated. Figure 2.1 provides a 
schematic of the overall study design. 
Figure 2.1: 
UX003-CL203 Study Schema 
 
NUMBER OF SUBJECTS PLANNED: 
Approximately 15 subjects will be enrolled including approximately 5 subjects with hydrops fetalis. 
Subjects under the age of 5 years at the time of informed consent with a confirmed diagnosis of MPS 7 
will be enrolled. Due to the extremely low prevalence of the disease, the sample size is not based on 
statistical considerations but rather the ability to find qualifying patients.  
Subjects who withdraw or are removed from the study after receiving study drug may be replaced on a 
case-by-case basis, at the discretion of Ultragenyx. 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay, or 
genetic testing 
2. Under 5 years of age at the time of informed consent 
3. Written informed consent of Legally Authorized Representative after the nature of the study has 
been explained, and prior to any research-related procedures 
 


Protocol Number:  UX003-CL203  
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Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Undergone a successful bone marrow or stem cell transplant or has evidence of any degree of 
detectable chimaerism with donor cells 
2. Any known hypersensitivity to rhGUS or its excipients that, in the judgment of the Investigator, 
places the subject at increased risk for adverse effects 
3. Use of any investigational product (drug or device or combination) other than UX003 within 
30 days prior to Screening, or requirement for any investigational agent prior to completion of all 
scheduled study assessments at any time during the study 
4. Has a condition of such severity and acuity, in the opinion of the Investigator, which may not 
allow safe study participation.  For patients with hydrops fetalis, the ongoing interventions to 
manage fluid balance can be continued; if the addition of ERT is considered a fluid-overload risk, 
the individual should be excluded.  
5. Has a concurrent disease or condition that, in the view of the Investigator, places the subject at 
high risk of poor treatment compliance or of not completing the study, or would interfere with 
study participation or affect safety.  Since hydropic patients have a high rate of mortality, the risk 
of death prior to 1 year of age should not be considered sufficient to exclude the patient from the 
study for compliance. 
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
UX003 is a sterile liquid buffered saline formulation of rhGUS at a concentration of 2 mg/mL filled to 
allow withdrawal of a minimal of 5.0 mL deliverable volume and supplied in a 10 mL glass vial. 
UX003 will be administered at a dose of 4 mg/kg QOW by slow IV infusion over approximately 
4 hours.  Infusions will be administered on a rate schedule involving a slower infusion rate initially 
followed by an increase in rate to minimize the potential for infusion associated reactions (IARs); the 
infusion rate may be slowed to manage or reduce IARs. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
No reference therapy will be administered in this study. 
DURATION OF TREATMENT: 
The planned duration of treatment in this study is 48 weeks.  Subjects successfully completing the first 
48 weeks may continue treatment for up to 240 weeks (5 years) or until one of the following occurs: 
the patient withdraws consent, the patient is discontinued from the study at the discretion of the 
Investigator or Ultragenyx, or the study is terminated. 
CRITERIA FOR EVALUATION: 
Safety Assessments: 
Safety will be evaluated by the incidence and frequency of adverse events (AEs) and serious adverse 
events (SAEs), including clinically significant changes from study baseline to scheduled time points 
in: 
• 
Physical examination findings 
• 
Vital signs and weight 
• 
Clinical laboratory evaluations 


Protocol Number:  UX003-CL203  
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• 
Concomitant medications 
• 
IgG antibodies to rhGUS 
• 
Complement C3, C4 and CH50 levels (as indicated) 
Management of Infusion Associated Reactions 
As has been observed in other MPS enzyme therapies, some subjects may experience IARs associated 
with the administration of UX003. Consequently, appropriate measures have been incorporated into 
the study design in order to prevent, monitor and manage potential reactions. These measures include 
prophylactic premedication of subjects with antihistamine, and staged and controlled infusion rates to 
mitigate the potential for infusion reactions.  The protocol also incorporates measures to minimize 
pain and distress, including the optional use of topical anesthetics to ease the pain of placing an IV line 
and the option for an in-dwelling catheter. 
Primary Efficacy Variable: 
• 
Urinary GAG Excretion:  First morning void urine will be evaluated for uGAG concentration and 
normalized to urinary creatinine concentration. 
Secondary Efficacy Variables: 
• 
Growth will be assessed by anthropometric measurements including standing height (length or 
sitting height as applicable), head circumference, and weight. Growth velocity will be calculated 
and compared with pre-treatment growth velocity when available and published normative data 
for age and gender.  
• 
Hepatosplenomegaly:  The volume of the liver and spleen will be determined using ultrasound. If 
an ultrasound is not possible, the liver and spleen should be assessed by physical exam. 
The volume of liver and spleen will be compared to baseline and to normal values if available. 
Ascites will also be assessed.  
Tertiary Efficacy Variables: 
• 
Additional GAG measures including serum GAG and supplementary uGAG assays 
• 
Clinical Global Impression Scale:  Physicians caring for each subject will provide a global 
assessment of change from baseline or change from identification of a new finding using a seven 
point scale ranging from -3 (severe worsening) to +3 (significant improvement).  The Clinical 
Global Impression (CGI) scale will be supported by reported changes in a list of disease-specific 
abnormalities projected to respond to treatment. 
• 
Functional Development will be assessed by the Bayley Scales of Infant and Toddler 
Development® – Third Edition (Bayley-III). 
• 
Motor Functioning will be assessed by a motor development milestone checklist. 
• 
Cardiac Ventricular Mass:  Ventricular mass will be assessed by echocardiogram (ECHO) and 
scored as a z-score relative to normal ventricular mass. Valvular and cardiac function may also be 
evaluated. 
• 
Pulmonary Function:  Pulse oximetry will be used to assess problems in adequate respiration; 
resting O2 saturation will be measured while the subject is breathing room air.   
• 
Biochemical Markers of Bone Turnover (BTMs): Levels of serum markers of bone formation and 
bone resorption will be measured including procollagen type 1 N-propeptide  (P1NP), carboxy-
terminal cross-linked telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase 
(BALP), and vitamin D. 
 


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Pharmacokinetic Parameters derived from Population PK Analysis:  
• 
Area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC0-∞) 
• 
AUC from time zero to the time of last measurable concentration (AUC0-last) 
• 
Maximum plasma concentration (Cmax) 
• 
Time to maximum plasma concentration (Tmax) 
• 
Elimination half-life (t1/2) 
• 
Total clearance of drug after IV administration (CL) 
• 
Apparent volume of distribution based upon the terminal phase (Vdz) 
• 
Apparent volume of distribution at steady-state (Vdss) 
STATISTICAL METHODS: 
Descriptive statistics will be used to summarize the data. For continuous variables, the mean, the 
standard error, median, minimum, and maximum will be provided.  For categorical variables, the 
frequency and percent distributions will be provided.  Two-sided 95% confidence intervals will also 
be presented when appropriate. 
Analyses may be performed at any time during the study at the discretion of the Sponsor. There is no 
unblinding during analysis since it is an open-label study.  
Analysis Sets: 
The full analysis set will consist of all enrolled subjects who receive at least 1 dose of UX003 during 
the study.  
Safety Analysis:   
The primary safety analysis will evaluate the safety of UX003 as measured by the incidence and 
frequency of AEs and SAEs, including clinically significant changes from baseline to scheduled time 
points in safety parameters. The incidence and frequency of AEs will be summarized by System Organ 
Class and Preferred Term, relationship to study drug, and severity. No statistical significance will be 
assessed. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside of reference 
ranges) and/or clinically significant abnormalities after study drug administration will be presented for 
each clinical laboratory measurement.  For each clinical laboratory measurement, descriptive statistics 
will be provided for baseline and all subsequent visits.  Changes from baseline to the post-treatment 
visits will also be provided.  Descriptive statistics of vital signs, imaging assessments, and 
concomitant medications will be provided in a similar manner. 
Changes in findings from baseline physical examinations will be tabulated and listed for each subject 
by examination category.  If there are examination findings that change in more than one subject, these 
will be tabulated in a separate table and expressed as the number of subjects with the change out of the 
total. 
Anti-drug antibody data will be tabulated over the course of the study. The number of subjects 
converting to a positive antibody assay value defined as a titer increase of five-fold or more over 
baseline, and the time of onset of a positive antibody response will be determined.  
Descriptive statistics on the titers achieved and the time of onset of the response will be provided 
(mean, standard deviation, median, range).   
 


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Efficacy Analyses:   
The study is a small open-label study to obtain some clinical efficacy data from a small cohort of these 
ultra-rare patients. A complete hypothesis testing statistical approach is not plausible in this setting, 
but a reasonable approach to assessing for the biologic efficacy of UX003 will be made.   
The primary efficacy analysis will evaluate the mean percent change in uGAG excretion from Week 0 
(Baseline) to Week 48 using the generalized estimating equation (GEE) analysis method.  
For subject(s) previously treated with UX003 under an emergency IND, percent change from initial 
baseline (prior to first dose of UX003) will be used, if the initial baseline data are available. The null 
hypothesis of no change in mean uGAG excretion will be tested. An additional analysis will also be 
performed on the Week 24 time point. 
Secondary analysis on growth and hepatosplenomegaly will be evaluated to compare pretreatment 
with post treatment effects. Growth rate will be compared to historical data from medical records and 
also compared to published normative data for age and gender (if available). Changes in findings from 
baseline for other efficacy variables will be tabulated for each subject. Comparisons of certain efficacy 
variables with published normative data based on age and gender may also be conducted. 
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan. 
 
 


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Protocol Number:  UX003-CL203  
Amendment 2: 07 APR 2016 
 
 
Proprietary and Confidential 
Page 11 
Table 2.2: 
Schedule of Events Continuation Period 
 
 
Abbreviations: Bayley-III = Bayley Scales of Infant Development® – Third Edition, CGI = Clinical Global Impression scale, con-meds = concomitant medications, PK = 
pharmacokinetics, GAG = glycosaminoglycans, ET = early termination 
 
a. 
Screening must take place within 30 days prior to Baseline Visit.  Informed consent/assent must be obtained prior to any Screening procedures. 
b. 
Baseline assessments must be completed within 7 days prior to first dose of study drug, unless otherwise specified. Physical exams and safety labs are the only Screening 
assessments that, if performed within 7 days of the first dose of study drug, may be used for Baseline assessment. Baseline assessments must be performed prior to the infusion if 
scheduled on the same day as the Week 0 visit. 
Assessment 
Continuation Period  
Weeks 50-240 c 
Urinary GAG g 
Every 12 weeks 
Anthropometrics (including weight) h 
Every 12 weeks 
CGI 
Every 12 weeks 
Pulse oximetry 
Every 12 weeks 
Bayley-III 
Every 48 weeks 
Motor Milestone Checklist 
Every 48 weeks 
Echocardiogram i 
Every 48 weeks 
Liver and spleen ultrasound k  
Every 48 weeks 
Adverse events l 
Every 2 weeks 
Concomitant medications and therapies 
Every 2 weeks 
Physical examination m 
Every 12 weeks 
Vital signs n 
Every 2 weeks 
Clinical laboratory tests o 
Every 24 weeks 
Antibodies to rhGUS p 
Every 12 weeks 
Bone  turnover markers 
Every 24 weeks 
Complement C3, C4, CH50 (subjects with IARs)  q, r 
As indicated 
Treatment with UX003 
Every 2 weeks 


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c. 
Visit windows are ± 3 days during the Treatment Period. For major assessment visits (Weeks 12, 24, 36, and 48) and visits during the Continuation Period the window is ± 7 days.  
All assessments scheduled for a treatment day must be completed prior to the infusion on that day. 
d. 
Growth history for height and weight will be collected as part of medical history. Pretreatment measurements of height and weight should be collected from the records if possible to 
assure a pre and post treatment growth rate can be assessed.  Medical history collected at the Baseline visit record any changes in medical history since Screening. 
e. 
Weight to determine appropriate study drug volume for the subsequent visit, and for safety; refer to Pharmacy Manual for instructions on calculating drug dosage and preparation. 
f. 
PK samples will be collected prior to the infusion (pre-dose), 60 minutes after start of infusion, at the end of the infusion, 30-120 minutes post infusion and 4-6 hours post infusion. 
PK samples should not be drawn from the IV line used for administration of study drug. 
g. 
Urinary GAG samples must be collected from first morning urine voids. Urine samples will be collected once at Screening and two times (separate days) during the Baseline Period; 
refer to Laboratory Manual for details.   
h. 
Anthropometric measurements include standing height (or sitting height and recumbent length as appropriate), head circumference and weight.  Anthropometric weight 
measurements may also be used for study drug preparation during the Continuation Period only; refer to Pharmacy Manual for calculating drug dosage and preparation.   
i. 
ECHO performed within three months prior to Baseline visit may be used for baseline provided cardiac ventricular mass can be calculated. 
j. 
If subject requires respiratory support, the type and duration should also be noted. 
k. 
Ultrasound will include assessment of ascites. 
l. 
All AE/SAEs will be recorded from the time the subject signs the consent form until 30 days after the last dose of study drug.  
m. Complete physical examination. If subject has symptoms or signs of  weakness, evaluate for signs of cord compression (e.g., reflexes and moor strength). 
n. 
Vital sign time points on infusion days (at minimum; additional measurements obtained as appropriate) 
Week 0 (Baseline) to Week 12: 15 minutes prior to infusion; every 15 minutes during the infusion; immediately post-infusion; 15, 30 and 60 minutes post-infusion. 
Week 14 to Week 240: 15 minutes prior to infusion; every 60 minutes for the remainder of the infusion;  60 minutes post-infusion. 
o. 
Laboratory samples (blood and urine) are to be collected prior to dosing of study drug.  Clinical laboratory tests are to include hematology, chemistry, and urinalysis. 
p. 
Testing for IgG antibodies directed against rhGUS. Serum sample must be collected before infusion. 
q. 
If maximum amount of blood has been taken based on Maximum Allowable Blood Volume Guidelines for any subject, some assessments are not required; see the Lab Manual for 
details on prioritizing blood draws. 
r. 
If a drug-related IAR has occurred, blood samples for complement C3, C4, and CH50 assessment should be drawn prior to and immediately after the next infusion. 
s. 
If a subject discontinues study treatment or withdraws from the study, every attempt should be made to complete the early termination (ET) visit within 2 weeks of the last dose of 
study drug. Ultrasound, Bayley-III, and motor milestone checklist will not be performed at the ET visit if the assessment was conducted within 1 month of termination.  
t. 
Optional assessment can be performed at a different time-point if total blood volume at week 16 may exceed maximum allowable volume.


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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................4 
3 TABLE OF CONTENTS ...................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................17 
5 
INTRODUCTION .............................................................................................................20 
5.1 Overview of MPS 7...................................................................................................20 
5.2 Enzyme Replacement Therapy for MPS Disorders ..................................................22 
5.3 Brief Overview of UX003 Development ..................................................................23 
5.3.1 
Brief Description of UX003 ........................................................................23 
5.3.1.1 
UX003 Mechanism of Action in MPS7 .......................................24 
5.3.2 
Nonclinical Studies ......................................................................................24 
5.3.3 
Previous Clinical Studies .............................................................................25 
5.4 Summary of Overall Risks and Potential Benefits ....................................................26 
5.5 Study Rationale .........................................................................................................27 
6 STUDY OBJECTIVES ......................................................................................................28 
7 
INVESTIGATIONAL PLAN ............................................................................................29 
7.1 Overall Study Design and Plan .................................................................................29 
7.2 Discussion of Study Design, Including Choice of Control Group ............................29 
7.3 Selection of Study Population ...................................................................................30 
7.3.1 
Inclusion Criteria .........................................................................................30 
7.3.2 
Exclusion Criteria ........................................................................................30 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................31 
7.3.3.1 
Stopping Rules .............................................................................32 
7.4 Treatments .................................................................................................................32 
7.4.1 
Investigational Product ................................................................................32 
7.4.2 
Reference Therapy ......................................................................................32 


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7.4.3 
Study Drug Infusion Procedure ...................................................................33 
7.4.3.1 
Pre-Dose Medication ...................................................................33 
7.4.3.2 
Infusion Procedure .......................................................................33 
7.4.4 
Selection of Doses and Study Duration .......................................................34 
7.4.5 
Method of Assigning Subjects to Treatment Groups ..................................35 
7.4.6 
Blinding .......................................................................................................35 
7.4.7 
Prior and Concomitant Therapy ..................................................................35 
7.4.7.1 
Prohibited Medications ................................................................35 
7.4.7.2 
Permitted Medications .................................................................35 
7.4.8 
Treatment Compliance ................................................................................36 
7.5 Study Procedures and Assessments ..........................................................................36 
7.5.1 
Schedule of Events ......................................................................................36 
7.5.2 
Efficacy Measures .......................................................................................37 
7.5.2.1 
Primary Efficacy Measure:  Urinary GAG Excretion..................37 
7.5.2.2 
Secondary Efficacy Measures ......................................................37 
7.5.2.3 
Tertiary Efficacy Measures ..........................................................38 
7.5.3 
Drug Concentration Measurements .............................................................40 
7.5.4 
Safety Measures & General Assessments ...................................................40 
7.5.4.1 
Medical History ...........................................................................41 
7.5.4.2 
Weight ..........................................................................................41 
7.5.4.3 
Physical Examination...................................................................41 
7.5.4.4 
Vital Signs ....................................................................................41 
7.5.4.5 
Clinical Laboratory Tests for Safety ............................................42 
7.5.4.6 
Antibodies to rhGUS....................................................................43 
7.5.4.7 
Concomitant Medications ............................................................43 
7.5.4.8 
Complement Levels .....................................................................43 
7.5.4.9 
Adverse Events ............................................................................43 


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7.5.5 
Appropriateness of Measures ......................................................................44 
7.6 Statistical Methods and Determination of Sample Size ............................................45 
7.6.1 
Determination of Sample Size .....................................................................45 
7.6.2 
Subject Information .....................................................................................45 
7.6.3 
Populations Analyzed ..................................................................................45 
7.6.4 
Primary Efficacy Endpoint ..........................................................................45 
7.6.5 
Secondary and Tertiary Endpoints and Analyses ........................................46 
7.6.6 
Pharmacokinetic Analyses ..........................................................................46 
7.6.7 
Safety Analyses ...........................................................................................46 
7.6.8 
Analyses ......................................................................................................47 
8 STUDY CONDUCT ..........................................................................................................48 
8.1 Ethics .........................................................................................................................48 
8.1.1 
Institutional Review Board or Ethics Committee ........................................48 
8.1.2 
Ethical Conduct of Study ............................................................................48 
8.1.3 
Subject Information and Consent ................................................................48 
8.2 Investigators and Study Administrative Structure ....................................................49 
8.3 Investigational Product Accountability .....................................................................49 
8.4 Data Handling and Record Keeping .........................................................................50 
8.4.1 
Case Report Forms and Source Documents ................................................50 
8.4.2 
Data Quality Assurance ...............................................................................50 
8.4.3 
Record Retention .........................................................................................51 
8.5 Reporting and Follow-up of Adverse Events ............................................................51 
8.5.1 
Definition of Adverse Events ......................................................................51 
8.5.2 
Severity of Adverse Events .........................................................................52 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................53 
8.5.4 
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting ......................................................53 
8.5.5 
Adverse Drug Reaction Reporting ..............................................................54 


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8.5.6 
Urgent Safety Measures ..............................................................................54 
8.5.7 
Safety Contact Information .........................................................................55 
8.6 Financing and Insurance ...........................................................................................55 
8.7 Publication Policy .....................................................................................................55 
9 REFERENCES ..................................................................................................................56 
10 SIGNATURE PAGE .........................................................................................................61 
 
LIST OF TABLES 
Table 2.1: 
Study UX003- CL203 Schedule of Events ..........................................10 
Table 2.2: 
Schedule of Events Continuation Period .............................................11 
Table 5.2.1: 
Urinary GAG Reduction of > 50% is Likely to Predict Clinical 
Benefit ..................................................................................................23 
Table 7.5.4.5.1: 
Clinical Laboratory Assessments for Safety ........................................42 
 
LIST OF FIGURES 
Figure 2.1: 
UX003-CL203 Study Schema ...............................................................5 
Figure 7.1.1: 
UX003-CL203 Study Schema .............................................................29 
 
 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-last 
area under the plasma concentration-time curve from time zero to the time 
of last measurable concentration 
BALP 
bone-specific alkaline phosphatase 
Bayley-III 
Bayley Scales of Infant and Toddler Development® – Third Edition 
BTM 
bone turnover marker 
BUN 
blood urea nitrogen 
°C 
degrees Celsius 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CGI 
Clinical Global Impression 
CIM6PR 
cation-independent mannose 6-phosphate receptor 
CL 
total clearance of drug after intravenous administration 
Cmax 
maximum plasma concentration 
CRF 
Case Report Form 
CTX-1 
carboxy-terminal cross-linked telopeptide of type I collagen 
EC 
Ethics Committee 
ECHO 
echocardiogram 
EDC 
electronic data capture 
EMLA 
eutectic mixture of local anesthetic 
ERS 
European Respiratory Society 
ERT 
enzyme replacement therapy 
ET 
Early Termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GAG 
Glycosaminoglycan 
GCP 
Good Clinical Practice 
GEE 
Generalized estimating equation 
GGT 
gamma glutamyl transpeptidase 


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GUS 
beta-glucuronidase 
HIPAA 
Health Insurance Portability and Accountability Act 
IAR 
infusion-associated reaction 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IgG 
immunoglobulin G 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS 
mucopolysaccharidosis/mucopolysaccharidoses 
MPS 7 
mucopolysaccharidosis type 7, Sly Syndrome 
MR 
mannose receptor 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
P1NP 
procollagen type 1 N propeptide 
PGI-C 
Physician Global Impression of Change 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
QOW 
every other week 
QW 
every week 
RBC 
red blood cell 
rhGUS 
recombinant human beta-glucuronidase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
t1/2 
half-life 
Tmax 
time to maximum plasma concentration 
uGAG 
urinary glycosaminoglycans 


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US 
United States 
UX003 
Investigational Product/study drug, recombinant human beta-glucuronidase,  
rhGUS 
Vdz 
apparent volume of distribution based upon the terminal phase 
Vdss 
volume of distribution at steady state 
WBC 
white blood cell 
 
 
Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use [ICH] Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 
 
 


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5  INTRODUCTION 
Mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders caused by 
the deficiency of any of the enzymes involved in the stepwise degradation of 
glycosaminoglycans (GAGs). Although many MPS characteristics are similar, each disease is 
a distinct entity arising from deficiency of a specific enzyme. MPS 7 (Sly syndrome) is an 
ultra-rare, chronically debilitating, and life threatening lysosomal storage disease, and one of 
the rarest of the mucopolysaccharidoses. Varying in severity and progression rate, MPS 7 
symptoms may include: abnormal coarsened facies, hepatosplenomegaly, pulmonary disease, 
cardiovascular complications, joint stiffness, short stature, and a skeletal disease known as 
dysostosis multiplex. Most MPS 7 patients die before the second or third decade of life due 
to compounding medical problems. Some MPS 7 patients present at birth with severe edema 
or non-immune hydrops fetalis and usually die within 2-4 months.   
Despite nearly two decades of animal research demonstrating effective treatment with 
enzyme replacement therapy (ERT) in MPS 7 models and the success of ERT in four other 
MPS disorders (MPS 1, MPS 2, MPS 4A and MPS 6), there is no approved treatment 
available for MPS 7. Development in this disease has not proceeded because the extreme 
rarity (less than 100 patients identified worldwide and an estimated incidence rate of less 
than 1 per 250,000 births) and clinical heterogeneity has made it impractical to approach with 
traditional clinical study designs and endpoints.   
UX003 is a formulation of recombinant human beta-glucuronidase (rhGUS), intended as an 
ERT for MPS 7. Ultragenyx has conducted multiple clinical studies to support UX003 
development. Ongoing interventional studies include a Phase 1/2 study to assess safety, 
efficacy, and pharmacokinetics (PK) of UX003 treatment, and a confirmatory randomized 
placebo-controlled Phase 3 study conducted in MPS 7 patients aged 5 – 35 years. 
Additionally, a Phase 3 long-term extension study to assess long-term safety and efficacy for 
patients who complete the phase 3 study or enrolled in other UX003 studies is on-going.  
This study is intended to assess the safety and efficacy of UX003 when administered to MPS 
7 patients less than 5 years of age.   
5.1 
Overview of MPS 7 
MPS 7 (Sly syndrome) is an extremely rare autosomal recessive lysosomal storage disorder 
originally described by William Sly and colleagues in 1973 (Sly et al. 1973). MPS 7 is the 
second rarest of the MPS disorders with fewer than 100 patients identified worldwide and 
also the most heterogeneous of the MPS disorders. MPS 7 is characterized by a deficiency of 
the lysosomal enzyme GUS, which is required for the degradation of two GAGs: dermatan 
sulfate and heparan sulfate. This deficiency results in GAG accumulation in many tissues and 
organs, leading to numerous clinical symptoms similar to those observed for MPS 1 (Hurler 
Syndrome) and MPS 2 (Hunter Syndrome) (Neufeld et al. 2001). 


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MPS 7 genotypes/phenotypes have been studied for many years (reviewed in (Tomatsu et al. 
2009)). A total of 49 unique mutations were identified in a total of 103 mutant alleles found 
in 56 patients, with 9% of the alleles unidentified. Missense mutations account for 78.6% of 
total alleles; the remaining were nonsense mutations, deletions, or splice site mutations, all 
likely leading to a null genotype and severe phenotype. This is a much higher frequency of 
missense mutations than is normally found in other MPS diseases. For example, in MPS 1, 
nearly 70% of alleles are nonsense with two dominant stop mutations accounting for a large 
fraction of all mutations (Scott et al. 1995). 
The clinical course and disease progression of MPS 7 comprises a wide spectrum of severity.  
The most severe form of the disease can uniquely present at birth with hydrops fetalis, a 
severe neonatal condition in which the child retains an enormous amount of fluid throughout 
the body (Vervoort et al. 1996). Infants with hydrops fetalis rarely survive beyond a few 
weeks to a few months of age (Neufeld et al. 2001).   
Patients with severe MPS 7, who are not born with hydrops fetalis, present as infants or 
young children with typical Hurler (MPS 1)-like features (Neufeld et al. 2001). Diagnosis of 
MPS 7 is often made through clinical examination and urine tests for excess 
glycosoaminoglycans excreted in the urine (Sewell et al. 1982). Due to the clinical 
heterogeneity of the disease, it is recommended that GUS activity in all suspected cases of 
lysosomal storage disease be evaluated through enzymatic analysis of leukocytes or 
fibroblasts (Lee et al. 1985). Clinical features include hepatosplenomegaly, pulmonary 
infections,  cardiac problems, corneal clouding, hearing loss, hernias, joint stiffness, short 
stature and dysostosis multiplex.   
Many patients experience progressive pulmonary problems as a result of airway obstruction  
(enlarged adenoids and tonsils, secretions, infections and tracheal abnormalities) leading to 
sleep apnea and pulmonary insufficiency, eventually requiring tracheostomy. Significant 
respiratory restriction combined with frequent recurrent and chronic nasopharyngeal and 
respiratory infections can lead to progressive respiratory compromise and failure (Kakkis et 
al. 1996b); (Neufeld et al. 2001). Heart disease is also common in patients with severe MPS 
7, although it may not develop or manifest until later in life. Valvular insufficiency due to 
thickening and calcification of the valves, arterial lesions of the coronary arteries and 
obstruction of the thoracic aorta like that observed for Hurler syndrome, have been described 
(Kakkis et al. 1996b). In severely affected MPS 7 patients, GAG storage in the coronary 
vessels along with pulmonary insufficiency can lead to cardiomyopathy, cor pulmonale 
and/or death.   
MPS 7 patients generally have a variety of the typical findings of dysostosis multiplex with 
significant variability. This may include odontoid dysplasia with atalantoaxial instability as 
in other MPS disorders. Storage within the synovium and other joint tissues can lead to 
significant restriction of mobility in the hip, shoulder, elbow and knee joints as in other MPS 
disorders. All of these disease complications can result in severe pain or the inability to walk, 
often resulting in the use of a wheelchair. Additional symptoms include hearing loss, 
cataracts, and corneal clouding among others.   


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Life expectancy for most individuals with MPS 7 is into the teenage or young adult years, 
however severe MPS 7 patients may die within the first few years of life or at birth with 
severe hydrops (Vervoort et al. 1996). Mortality is commonly due to cardiovascular or 
respiratory complications. 
5.2 
Enzyme Replacement Therapy for MPS Disorders 
The primary treatment modalities for MPS disorders are ERT and hematopoietic stem cell 
transplantation. Both approaches provide active enzyme to replace the deficiency and confer 
substantial benefit, but are not curative. ERT is now commercially available for MPS1 
(Aldurazyme®, laronidase), MPS 2 (Elaprase®, idursulfase), MPS 4A (Vimizim®, 
elosulfase alfa), and MPS 6 (Naglazym®, galsulfase).  At present, there are no approved 
treatments for MPS 7. Multiple clinical trials have been conducted to establish safety and 
efficacy of ERT in MPS diseases ((Hendriksz et al. 2014); reviewed in (Valayannopoulos et 
al. 2011)). The treatment regimen for ERT involves weekly (QW) or every other week 
(QOW) intravenous (IV) infusions of the recombinant human enzyme.  Many patients treated 
with ERT experience infusion-associated reactions (IARs).  Observed clinical benefits 
include improved walking ability, joint range of motion, improved lung function, decreased 
liver volume, and decreased (but not normalized) uGAG levels. Most MPS patients develop 
antibodies to the recombinant enzyme; in some severely affected MPS 1 patients, antibody 
titer was inversely related to the reduction in uGAG levels (Clarke et al. 2009).   
Clinical study data in the Phase 3 studies of laronidase, idursulfase, galsulfase have 
demonstrated significant predictive value of uGAG levels. The uGAG levels are 
significantly reduced during the first 4-6 weeks of ERT treatment, then reach a plateau 
(Wraith et al. 2004), (Kakkis 2002), (Harmatz et al. 2006); the clinical effect evolves over 
the next 6-12 months. This pattern of uGAG reduction preceding clinical effect is expected 
considering the additional time needed for inflammation and injury to heal and recover 
following the resolution of lysosomal storage, and is consistent with the potential of uGAG 
to predict tissue response.  In the clinical studies, changes in uGAG were able to differentiate 
between effective and less effective dose regimens, with reductions of >50% associated with 
substantial efficacy based on clinical measures (Table 5.2.1). In all cases, uGAG reduction 
≥ 50% was associated with significant clinical benefit.  For idursulfase, the QOW regimen 
showed less than 50% reduction and less efficacy; this difference was detected and predicted 
by the uGAG levels early in the study (Muenzer et al. 2006). For this reason, a measure of 
uGAG should be predictive of changes in lysosomal storage conducive to clinical 
improvement in MPS patients. 


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Table 5.2.1: Urinary GAG Reduction of > 50% is Likely to Predict Clinical Benefit 
Study 
Design 
Dose 
(mg/kg) 
uGAG 
(% Reduction) 
Walk Test 
(m) 
FVC 
 (% predicted) 
Liver Volume 
(% decrease) 
Laronidase for MPS 1 
Phase 3 
(Wraith et al. 
2004) 
RDBPC 
N=45 
0.58 QW 
26 weeks  
- 54.1% 
38.1 
p=0.037 
5.6 
p=0.009 
-18.9 
p=0.009 
Idursulfase for MPS 2 
Phase 3 
(Muenzer et al. 
2006) 
RDBPC 
N=96 
 
 
0.5 QOW  
53 weeks 
- 44.7% 
30.3 
p=.0732 
0.004 
p=0.95 
-24.0 
p<0.0001 
0.5 QW 
53 weeks 
- 52.5% 
44.3 
p=0.00131 
3.45 
p=0.065 
-25.3 
p<0.0001 
Galsulfase for MPS 6 
Phase 3 
(Harmatz et al. 
2006) 
RDBPC 
N=39 
1.0 QW 
24 weeks 
- 75% 
p<0.001 
92* 
p=0.025 
No 
improvement 
Not done 
*12MWT 
 
5.3 
Brief Overview of UX003 Development 
UX003 is intended as an IV ERT for the treatment of MPS 7. A brief overview of existing 
information on UX003 is provided below; a comprehensive review of available data is 
contained in the Investigator’s Brochure (IB) provided by Ultragenyx Pharmaceutical Inc. 
(Ultragenyx), which should be reviewed prior to initiating the study.   
5.3.1 
Brief Description of UX003 
The active pharmaceutical ingredient in UX003, rhGUS, is produced in a genetically 
engineered Chinese hamster ovary cell line that expresses the normal full length human 
GUS protein. The rhGUS protein is synthesized as an 80 kDa monomer with 651 amino 
acids remaining after removal of the 22 amino acid signal peptide (Oshima et al. 1987).  
After glycosylation at four N-linked glycosylation sites at asparagines 173, 272, 420 and 631, 
the apparent molecular weight is 82 kDa for each monomer.  Although usually intact at the 
C-terminus after production, once delivered to the lysosome, proteolysis removes 18 amino 
acids from the C-terminal end to form a 78 kDa monomer (Islam et al. 1993). Biologically, 
purified rhGUS exists as a ~332 kDa homotetramer with two active sites per tetramer. 
The active drug substance is purified using standard chromatography methods and 
formulated for IV administration. 


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5.3.1.1 
UX003 Mechanism of Action in MPS7 
UX003 belongs to a class of ERTs that includes approved products for MPS 1, MPS 2, MPS 
4A, and MPS 6. The active pharmaceutical ingredient in UX003, rhGUS, is a member of the 
lysosomal hydrolase family of enzymes that catalyze breakdown of complex carbohydrates.  
Human GUS catalyzes the hydrolysis of β D-glucuronic acid residues from the non-reducing 
end of heparan sulfate and dermatan sulfate (Vervoort et al. 1996). In vitro and in vivo, 
rhGUS is taken up by cells and tissues by the cation independent mannose 6-phosphate 
receptor (CIM6PR) via the mannose 6-phosphate recognition residues located on the 
enzyme’s N-linked oligosaccharides. Uptake by the CIM6PR occurs in a large number of 
tissues and is important for the maximal effectiveness of the enzyme. The enzyme can also 
be taken up by the mannose receptor (MR) due to some terminal mannose residues located 
on high mannose N-linked oligosaccharides. Clearance by the MR occurs mainly by the cells 
in the reticuloendothelial system: the spleen, Kupffer cells in the liver, and circulating 
macrophages in the plasma. Together, these recognition signals are responsible for the rapid 
clearance and tissue distribution of infused lysosomal enzymes such as rhGUS from the 
circulation.  Both types of delivery can have therapeutic benefit as tissues with the MR also 
manifest substantial GAG storage in the MPS disorders, although the mannose 6-phosphate 
system is sufficient for uptake into all cell types. 
5.3.2 
Nonclinical Studies 
Ultragenyx has conducted a comprehensive nonclinical program to support the chronic QOW 
IV administration of UX003. In addition, the nonclinical pharmacology of recombinant GUS 
has been evaluated in a large number of published studies in vitro and in murine models of 
MPS 7. Studies of potential clinical significance and relevance to this protocol are 
summarized below. Additional details are provided in the IB. 
Nonclinical studies have been completed in MPS 7 mice (including newborns). 
The nonclinical toxicology program includes five studies, including an 8-week 
biodistribution study in tolerant MPS 7 mice, a GLP acute toxicity study in Sprague 
Dawley rats, a 26-week chronic toxicity study in juvenile cynomolgus monkeys, and dose 
range-finding developmental toxicity studies in rabbits and Sprague Dawley rats. At dose 
levels up to 20 mg/kg QOW, no toxicologically-significant findings were related to the 
administration of UX003. These studies support a 5-fold safety factor relative to the 4 mg/kg 
dose planned in this clinical study. The no observed adverse-effect level (NOAEL) for single 
IV dose administration in these studies was 20 mg/kg. 
A large number of studies in MPS 7 mouse models have shown that recombinant GUS 
distributes to many tissues and significantly reduces or prevents lysosomal storage during 
treatment (O'Connor et al. 1998), (Sands et al. 1994), (Sands et al. 1997), (Sands et al. 2001), 
(Vogler et al. 1996), (Vogler et al. 2005). Biodistribution of rhGUS has been seen in many 
tissues affected by MPS 7 including the brain, liver, spleen, heart, kidney, bone and lung 
(Vogler et al. 2005), (Grubb et al. 2008), (Sly et al. 2006).  The reduced lysosomal storage 
following ERT correlates with significant pathologic improvement and clinical benefit, with 


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prolonged effects including dramatic improvements in bone development, growth, cognitive 
ability, hearing, immune function, and survival (Sands et al. 1997), (Sands et al. 2001), 
(Vogler et al. 1996). Additionally, treatment of MPS 7 mice with high doses of rhGUS 
resulted in widespread delivery of enzyme as well as delivery across the blood-brain barrier 
with corresponding reductions in lysosomal storage in nearly all tissues, including the brain. 
The increased enzyme levels and accompanying reduction in lysosomal storage correlated 
with both dose and duration of treatment (Vogler et al. 2005). Histopathologic evaluation of 
tissues from MPS 7 mice showed no pathologic effects related to the enzyme-mediated 
increased clearance of heparan sulfate and dermatan sulfate. 
5.3.3 
Previous Clinical Studies 
The first in-human use of UX003 was sponsored by 
 at the Steven and 
Alexandra Cohen Children's Medical Center of New York under an emergency IND granted 
by the US FDA. A 
 old patient with advanced multi-system MPS 7 including 
respiratory insufficiency was treated with 2 mg/kg rhGUS QOW; the case study and results 
following initial treatment were recently reported (Fox et al. 2014). Through 24 weeks of 
treatment, a decline in uGAG excretion (~ 65%) and a sustained reduction in the size of the 
enlarged liver and spleen have been observed. The data through 52 weeks also show 
improved pulmonary function, oral feeding, and increased activity level. No drug-related 
serious adverse events (SAEs) or IARs have been reported (Fox et al. 2015). 
A second emergency IND was granted to treat a 
 old MPS 7 infant born with severe 
hydrops fetalis (
, New York University School of Medicine). The patient has 
received infusions for 48 weeks; uGAG was reduced by approximately 70% after several 
infusions. No drug-related IARs have occurred in this Investigator sponsored trial.   
An open-label Phase 1/2 study in 3 subjects aged 5, 9, and 25 years is ongoing to assess the 
safety, efficacy, and dose of UX003 in MPS 7 subjects via IV administration QOW for 
36 weeks with provisions for additional treatment during the Continuation Period 
(UX003-CL201; NCT01856218, EudraCT 2013-001152-35). UX003 has been administered 
up to 4 mg/kg in this study. Results through 36 weeks of treatment suggest a reduction in 
uGAG excretion and decreases in liver size relative to baseline at 4 mg/kg, with no SAEs or 
drug-related IARs reported; the most common AEs have been infections and gastrointestinal 
disorders. 
A Phase 3 randomized, placebo-controlled study is being conducted to confirm safety and 
efficacy of UX003 treatment in MPS 7 patients aged 5 – 35 years (UX003-CL301; 
NCT02230566).   
A Phase 3 long-term open-label treatment  extension study to assess long-term safety and 
efficacy of UX003 treatment in MPS 7 patients (UX003-CL202).  
A comprehensive summary regarding previous clinical experience on the use of UX003 is 
provided in the UX003 IB. 
PPD
PPD
PPD
PPD


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5.4 
Summary of Overall Risks and Potential Benefits 
An initial Phase 1/2 study has shown that UX003 can reduce lysosomal storage and uGAG 
and is expected to provide clinical benefit. Data from nonclinical toxicology and safety 
pharmacology studies, along with published data from MPS 7 mouse model studies, provide 
guidance on potential benefits and risks of UX003 treatment. The nonclinical data support 
the safe use of UX003 when dosed at 4 mg/kg (5-fold safety factor). The risk for off-target 
effects is reduced by the extreme specificity of the enzyme and the fact that the mechanism 
of action for GUS is restricted to the lysosome. The enzymatic activity of GUS has a pH 
optimum between 3.5 and 4.5 (data on file). At pH 7 near the pH of plasma, enzymatic 
activity is drastically reduced. Hence, the ability of GUS to degrade heparan sulfate and 
dermatan sulfate outside of the lysosome is limited. 
In addition, an understanding of the benefits and risks associated with ERT for other closely 
related MPS disorders makes it possible to anticipate benefit-risk profile with UX003.  
Clinical trial data and experience with marketed ERT products for the treatment of related 
MPS disorders (MPS 1, MPS 2, MPS 4A, and MPS 6) supports the safety and efficacy of 
MPS ERT as a class. These therapies have been approved and distributed to more than 
40 countries worldwide, with hundreds of patients treated for several years. Laronidase has 
now been marketed for more than 10 years without a significant change in the benefit-risk 
profile. In each of these programs, the reduction in lysosomal storage was demonstrated by 
reductions in liver and spleen size and uGAG excretion. The reduction was associated with 
clinically important changes in mobility, pulmonary function, joint stiffness, and other 
reported findings. 
Studies have also been conducted in MPS 1, MPS 2, MPS 4A, and MPS 6 patients less than 
5 years of age, showing benefit in reducing storage and improving some aspects of disease 
(Wraith et al. 2007), (Giugliani et al. 2014), (Haller et al. 2013), (Lampe et al. 2014). 
Early treatment with ERT can provide important benefits in improving growth, skeletal 
disease and overall clinical outcome (Laraway et al. 2013). 
The most common adverse effects of ERT relate to increased antibody titers and IARs.  
There have been no other consistent adverse effects across the different MPS disorders.  
Though IARs represent the most serious safety concern with ERTs, appropriate measures 
have been incorporated into the design of the current study to prevent, monitor and manage 
potential reactions.  These measures include prophylactic premedication of subjects with 
antihistamine, and staged and controlled infusion rates.  The large fraction of MPS 7 patients 
with missense mutations are expected to exhibit a reduced immune response to ERT due to 
the presence of residual protein, consistent with observations in the tolerant mouse (Sly et al. 
2001) and MPS 1 patients undergoing ERT (Yogalingam et al. 2004).  
The clinical experience with UX003 in pediatric and adult patients with MPS 7 has 
demonstrated a sustained reduction in uGAG levels and clinical improvement. With no 
treatments currently available for this progressive, ultimately-fatal genetic ultra-rare disease, 
a clear medical need exists for a novel disease-modifying approach that holds the potential 


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for altering the clinical course of disease progression. Overall the safety and efficacy data 
from clinical and nonclinical studies in combination with an understanding of the risks 
associated with ERTs for other MPS disorders indicate the benefit-risk ratio of UX003 is 
sufficient to support treatment of pediatric MPS 7 patients less than 5 years of age. 
5.5 
Study Rationale 
MPS 7 is an ultra-rare (< 100 cases currently identified worldwide), chronically debilitating, 
and life-threatening lysosomal storage disease.  Some MPS 7 patients present at birth with 
severe edema or non-immune hydrops fetalis and usually die within 2-4 months. There are 
currently no approved treatments for MPS 7. UX003 is intended as an ERT for the treatment 
of MPS 7. A Phase 1/2 study has shown that treatment with UX003 can reduce lysosomal 
storage and uGAG and is expected to provide clinical benefit; a pivotal Phase 3 study is 
ongoing.   
Patients with MPS 7 can present as newborns, infants or young children; this Phase 2 study 
will evaluate treatment with UX003 in MPS 7 patients less than 5 years of age. Although 
young patients have the same underlying etiology, the breadth and type of clinical problems 
can be different, including more frequent ascites/edema, cardiac problems, and other severe 
manifestations. This study will assess the relative safety, PK, and efficacy of UX003 ERT in 
young patients with MPS 7.   


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6 STUDY OBJECTIVES 
Primary Objective: 
The primary objective is to evaluate the effect of UX003 treatment in pediatric MPS 7 
subjects less than 5 years of age on: 
• Safety and tolerability  
• Efficacy as determined by the reduction of uGAG excretion 
Secondary Objective: 
The secondary objective is to evaluate the effect of UX003 on growth velocity and 
hepatosplenomegaly. 
Tertiary Objectives: 
Tertiary objectives are to assess PK and evaluate the effect of UX003 on measures of 
lysosomal storage, overall clinical change, cardiac and pulmonary function, bone turnover 
markers, and functional and motor development. 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX003-CL203 is an open-label, multicenter, Phase 2 study to assess the safety and efficacy 
of UX003 in pediatric MPS 7 subjects. The study seeks to enroll approximately 15 subjects 
less than 5 years of age at the time of informed consent, and will attempt to include 
approximately 5 infants with hydrops fetalis if possible. Subjects with prior exposure to 
UX003 treatment under an emergency IND may also be enrolled at the discretion of the 
Sponsor. In the initial 48 weeks of treatment, subjects will receive UX003 via IV infusion at 
a dose of 4 mg/kg QOW. Subjects who complete the 48-week study may choose to continue 
UX003 treatment in the Continuation Period up to 240 weeks, or until the subject withdraws 
consent, the subject is discontinued from the study at the discretion of the Investigator or 
Ultragenyx, or the study is terminated. Figure 7.1.1 provides a schematic of the overall study 
design. 
Figure 7.1.1: UX003-CL203 Study Schema 
 
7.2 
Discussion of Study Design, Including Choice of Control Group 
Given the history of ERT in the MPS field, this study is expected to show that UX003 
(rhGUS) can reduce lysosomal storage and improve clinical function in MPS 7 patients less 
than 5 years of age with an acceptable benefit-risk ratio. The population of MPS 7 patients 
less than 5 years of age is very small and heterogeneous; therefore it is not feasible to 
conduct a parallel group or placebo-controlled study to assess safety and efficacy. 
To demonstrate the safety and efficacy of UX003, two interventional studies are being 
conducted in pediatric and adult MPS 7 patients between the ages of 5 and 35 years.   
This study of UX003 has incorporated several elements to make efficient and safe use of a 
variable and vulnerable group of subjects and leverage the extensive existing data and 
lessons learned from other UX003 treatment protocols and approved ERT programs.  
The single-arm, open-label study design provides active treatment to all subjects with this 
extremely rare and serious life-threatening disease, while maintaining appropriate safety and 
efficacy standards in order to gain additional information about UX003 treatment in MPS 7 
patients less than 5 years of age. Once a subject has demonstrated acceptable long-term 
safety and efficacy following the initial 48 weeks of treatment, continuation of UX003 


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treatment will be available. The Continuation Period enables treatment for up to a total of up 
to 240 weeks and has been designed with a reduced frequency of assessments to minimize 
inconvenience and discomfort for the subject.   
7.3 
Selection of Study Population 
The study will be conducted in approximately 15 pediatric MPS 7 subjects. The study seeks 
to enroll subjects under the age of 5 years, and will attempt to include at least 5 infants with 
hydrops fetalis, if possible; subjects with prior exposure to UX003 treatment under an 
emergency IND may also be enrolled at the discretion of the Sponsor. The inclusion criteria 
are structured to enroll subjects with a confirmed diagnosis of MPS 7. To enroll subjects 
most likely to benefit from treatment and demonstrate safety and effectiveness of UX003, 
MPS 7 patients who have undergone successful bone marrow or stem cell transplantation 
will be excluded from the study.   
The Sponsor has taken reasonable measures to ensure the protection and safety of this 
population. Appropriate pediatric expertise will be available at all trial sites, and site 
personnel will be focused on minimizing risk, fear, pain and distress during conduct of the 
study. The protocol incorporates measures to minimize pain and distress including use of 
topical anesthetic to ease the pain of placing an IV line and the option for an in-dwelling 
catheter. Prophylactic premedication of subjects with antihistamine, and staged and 
controlled infusion rates mitigate the potential for IARs.  
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme 
assay, or genetic testing 
2. Under 5 years of age at the time of informed consent 
3. Written informed consent of Legally Authorized Representative after the nature of the 
study has been explained, and prior to any research-related procedures 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Undergone a successful bone marrow or stem cell transplant or has evidence of any 
degree of detectable chimaerism with donor cells 
2. Any known hypersensitivity to rhGUS or its excipients that, in the judgment of the 
Investigator, places the subject at increased risk for adverse effects 


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3. Use of any investigational product (drug or device or combination) other than UX003 
within 30 days prior to Screening, or requirement for any investigational agent prior to 
completion of all scheduled study assessments at any time during the study 
4. Has a condition of such severity and acuity, in the opinion of the Investigator, which may 
not allow safe study participation.  For patients with hydrops fetalis, the ongoing 
interventions to manage fluid balance can be continued; if the addition of ERT is 
considered a fluid-overload risk, the individual should be excluded.  
5. Has a concurrent disease or condition that, in the view of the Investigator, places the 
subject at high risk of poor treatment compliance or of not completing the study, or 
would interfere with study participation or affect safety.  Since hydropic patients have a 
high rate of mortality, the risk of death prior to 1 year of age should not be considered 
sufficient to exclude the patient from the study for compliance.  
7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason.  The Investigator and Ultragenyx also have the right to 
remove subjects from the study.  Ultragenyx must be notified of all subject withdrawals as 
soon as possible.  Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects may be removed from the study for the following reasons: 
• Occurrence of an unacceptable AE 
• An illness that, in the judgment of the Investigator or Ultragenyx, might place the subject 
at risk or invalidate the study  
• At the request of the subject (or legally authorized representative), Investigator, or 
Ultragenyx, for administrative or other reasons 
• Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the case 
report form (CRF).  Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve.  If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified.  All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the Early Termination Visit procedures within 2 weeks of  the last dose of study 
drug. 


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Subjects who withdraw or are removed from the study after receiving study drug may be 
replaced on a case-by-case basis, at the discretion of Ultragenyx. 
7.3.3.1 
Stopping Rules 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs (Section 8.5.3) that represent a change in the nature or an increase in 
frequency of the serious event from their prior medical history or known MPS 7-related 
medical issues will be assessed as to whether the subject will continue on the study.   
The Institutional Review Board (IRB)/Ethics Committee (EC) will be informed should 
unexpected and possibly, probably, or definitely study drug-related SAEs occur. A full 
evaluation of the event will be performed in order to make a decision regarding what actions 
to take, including whether to recommend stopping the study. 
7.4 
Treatments 
UX003 is a sterile liquid buffered saline formulation of rhGUS at a concentration of 
2 mg/mL filled to allow withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL 
glass vial. UX003 will be administered at a dose of 4 mg/kg QOW by slow IV infusion over 
approximately 4 hours. Infusions will be administered on a rate schedule involving a slower 
infusion rate initially followed by an increase in rate to minimize the potential for IARs; the 
infusion rate may be slowed to manage or reduce IARs. Refer to the Pharmacy Manual for 
full details on study drug preparation and administration.   
7.4.1 
Investigational Product 
UX003 (recombinant human beta-glucuronidase, rhGUS) is a multimeric glycoprotein 
produced using a genetically engineered Chinese hamster ovary cell line to secrete the 
human lysosomal enzyme, beta-glucuronidase. The mature form of the enzyme consists of 
651 amino acids. The drug product is formulated at 2 mg/mL rhGUS in UX003 formulation 
buffer (refer to the Pharmacy Manual for buffer excipients). UX003 is supplied as a sterile 
solution for IV administration packaged in single use 10 mL glass vials and is stored at 2 to 
8°C. 
The study drug is manufactured, packaged, and labeled according to current Good 
Manufacturing Practice (cGMP) regulations.   
7.4.2 
Reference Therapy 
The protocol is designed as an open-label active treatment study, therefore no reference 
therapy will be administered in this study.   


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7.4.3 
Study Drug Infusion Procedure 
Study drug (UX003) will be administered QOW by slow IV infusion over a period of 
approximately 4 hours. Subjects will be pre-medicated prior to infusions and study drug will 
be administered on a rate-schedule that minimizes the potential for IARs. The infusion will 
begin at a low rate that will be gradually increased, as tolerated by the subject, until the 
planned maximum rate is reached. 
7.4.3.1 
Pre-Dose Medication 
The subject should fast for a minimum of 1 hour prior to the infusion and for the first 2 hours 
of infusion. If the subject is tolerating the infusion, clear liquids or oral electrolyte solutions 
(e.g. Pedialyte) may be instituted. This requirement may be removed if after 12 weeks of 
treatment, the Investigator feels that the patient is fully tolerating infusions. 
Approximately 30 – 60 minutes prior to each infusion of study drug and after performing 
pre-infusion efficacy assessments, all subjects will be pretreated with an appropriate dose of 
antihistamine medication. Non-sedating antihistamines, such as cetirizine or loratadine, are 
preferred. For subjects who have a history of IARs or other risk factors (e.g. history of 
allergies), a sedating antihistamine (e.g. diphenhydramine or chlorpheniramine) may be 
administered. IV antihistamine (diphenhydramine dihydrochloride) may be used for 
premedication if oral is not acceptable, but the doses should be one-half the usual dose when 
given IV due to a potential increased sensitivity to these agents in MPS patients (Dr. Kakkis, 
personal observations). Antipyretic medications such as ibuprofen or acetaminophen may be 
administered at the discretion of the Investigator. For subjects with IARs, slowing the 
infusion rate is important but additional premedication with agents such as H2 blockers, 
stronger anti-histamines, or glucocorticoids may be considered. 
7.4.3.2 
Infusion Procedure 
The amount of study drug (UX003) will be determined based on the most recent subject 
weight (in kg). The volume of study drug calculated to deliver the correct dose will be 
withdrawn from the vial and aseptically transferred to an infusion bag of normal saline for a 
final 2-3 fold drug dilution. Undiluted UX003 must never be infused. 
PLEASE NOTE FOR PREPARATION OF INFUSION SOLUTIONS:  UX003 (rhGUS) 
is a recombinant protein and is therefore sensitive to bubbles and aggressive mixing that can 
lead to denaturation and loss of enzyme activity. When preparing diluted infusion solutions, 
the product should be withdrawn VERY SLOWLY through a sufficiently large needle 
(18 gauge) to minimize shear and turbulence. When adding study drug solution to an infusion 
bag, this must be done slowly, with liquid to liquid contact and without generating bubbles or 
turbulence; the bags should be rocked gently for mixing. Shaking of vials or infusion bags or 
“volutrols” devices in which aggressive mixing and bubbles can occur are not acceptable. 
Refer to the Pharmacy Manual for complete instructions on calculating drug dosage and 
preparation.  


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Study drug will be administered by slow IV infusion over approximately 4 hours. 
Infusions will be administered on a rate-schedule involving a slower infusion rate initially 
followed by an increase in rate that minimizes the potential for infusion reactions and may be 
slowed to manage or reduce IARs. Refer to the Pharmacy Manual for additional details on 
the infusion rate schedule. Topical eutectic mixture of local anesthetic (EMLA) cream or 
equivalent may be applied to the IV site prior to the infusion to ease the pain of placing an IV 
line. 
A second IV site on the opposite arm from the infusion will be used for the blood samples 
taken for PK analysis. At the discretion of the Investigator, an in-dwelling IV catheter (such 
as a Port-a-Cath® or other brand) may be inserted if there are difficulties in achieving IV 
access for the QOW infusions. If the second IV fails and PK samples cannot be collected 
from the second IV, the main IV line may be use for the post-infusion sampling after flushing 
the line thoroughly with saline. The samples taken through the same line as the infusion 
should be noted on the CRF as being drawn from the same line.  
Equipment necessary for resuscitation must be available during study drug infusion. 
7.4.4 
Selection of Doses and Study Duration 
The planned UX003 dose of 4 mg/kg is based on data from clinical studies in pediatric and 
adult MPS 7 patients, and further supported by nonclinical studies in the MPS 7 mouse 
model and relevant species. The nonclinical data support chronic QOW administration of 
UX003 at dose levels up to 4 mg/kg, providing a 5-fold safety factor.  
The therapeutic ERT doses in prior successful programs for other MPS disorders (0.58, 0.5, 
2 and 1 mg/kg weekly for MPS 1, 2, 4A and 6, respectively) were based on comparable doses 
that exhibited efficacy in their respective animal models. PK data in MPS 1, MPS 2, MPS 4A 
and MPS 6 subjects demonstrate that doses of 0.2 to 2 mg/kg are adequate to achieve 
enzyme concentrations of ~10-207 nM in the circulation.  These enzyme levels are 
approximately 10- to 30-fold the uptake constants (1-7 nM) for the mannose 6 phosphate 
receptor and are believed to saturate delivery of enzyme to the tissues (Kakkis et al. 1994); 
(Kakkis et al. 1996a); (Kakkis et al. 2001); (Dvorak-Ewell et al. 2010). Similar uptake 
constants (1.2-2.6 nM) were obtained in studies with human MPS 7 fibroblast cells in vitro 
(Ultragenyx data). Studies with rhGUS in MPS 7 mice at doses of 4 mg/kg show that serum 
GUS concentrations of >10-fold the uptake constant were readily achieved and demonstrated 
that enzyme was delivered to a variety of important tissues, implying that the efficacious 
dose should be within this range (Grubb et al. 2008). 
The QOW dosing regimen is supported by the long in vitro half-life and increased stability of 
rhGUS compared with other MPS enzymes. Data from the earliest MPS ERT studies showed 
that when human enzymes for MPS 1 or 2 were applied to deficient human fibroblasts, the 
half-life of the enzyme in the lysosome was on the order of 2-5 days (Kakkis et al. 1994); 
(Elaprase 2006) leading to weekly dosing frequency as the optimal choice.  For rhGUS, this 
experiment showed a half-life of about 40 days, which is a substantial increase over MPS 1 


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or MPS 2 enzymes, which are dosed weekly. The rhGUS enzyme is also a more stable 
enzyme than the other MPS enzymes at neutral pH, as it might be exposed to the circulation 
before uptake by lysosomes. Both the increased half-life and stability of rhGUS indicate 
QOW dosing should be adequate in humans. 
Study Duration 
The planned duration of treatment in this study is 48 weeks. Subjects successfully completing 
the first 48 weeks may continue for up to 240 weeks (5 years), or until one of the following 
occurs: the subject withdraws consent, the subject is discontinued from the study at the 
discretion of the Investigator or Ultragenyx, or the study is terminated. 
7.4.5 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number. All subjects will receive active treatment (UX003); there is only one treatment 
group in the study. 
7.4.6 
Blinding 
The study drug will be administered open-label; no study participants will be blinded to study 
treatment. 
7.4.7 
Prior and Concomitant Therapy 
7.4.7.1 
Prohibited Medications 
Subjects may not be enrolled if they have used any investigational product other than UX003 
or investigational medical device within 30 days prior to Screening, or if they require any 
investigational agent prior to completion of all scheduled study assessments. 
The use of genistein is specifically prohibited during study participation. 
7.4.7.2 
Permitted Medications 
Subjects may receive concomitant medications as required. Medications (investigational, 
prescription, over-the-counter, and herbal) and nutritional supplements taken during the 
30 days prior to Screening will be reviewed and recorded at the Screening visit. At the 
Baseline visit, current medications will be recorded. At each visit, any concomitant 
medications added or discontinued during the study should be recorded on the CRF. 
The site personnel should record the following in the CRF: date and time the medication was 
taken, the dose and name of the medication, and the reason the medication was taken. 
Medications administered prior to each infusion of study drug and any non-study therapies 
provided by the Investigator during study participation will be similarly recorded in the CRF. 


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7.4.8 
Treatment Compliance 
Study drug is not to be dispensed to subjects.  Study drug will be administered by IV infusion 
by a qualified health care professional at the clinical site. The date, time, and volume of each 
dose of study drug administered to each subject must be recorded in the dispensing log for 
the study, as well as on the appropriate CRF. 
7.5 
Study Procedures and Assessments 
Informed consent must be obtained prior to any Screening procedures. The Baseline 
(Week 0) visit must take place within 30 days of the Screening visit. Screening assessments 
(physical exam and safety labs) performed within 7 days prior to the first dose of study drug 
may be used for Baseline assessments. Subjects will be treated only after all 
inclusion/exclusion criteria have been confirmed. Baseline assessments must be completed 
within 7 days prior to first dose of study drug, unless otherwise specified. Assessments 
scheduled on the same day as treatment must be performed prior to the infusion.   
Subjects will return to the clinic at 2-week intervals (± 3 days) throughout the 48-week 
Treatment Period for study drug infusion and basic safety measures. Major assessment 
visits (Weeks 12, 24, 36, and 48) are scheduled at 12-week intervals (± 7 days). 
All assessments scheduled for a treatment day must be completed prior to the infusion on that 
day. For subjects who discontinue prior to completing the study, every reasonable effort 
should be made to perform the Early Termination visit procedures within 2 weeks of 
administration of last dose of study drug.   
Following completion of the 48-week Treatment Period, subjects may participate in the 
Continuation Period for up to 240 weeks. Subjects will return to the clinic for UX003 
administration every 2 weeks; additional assessments will be conducted at 12, 24 or 48-week 
intervals (± 7 days).  
7.5.1 
Schedule of Events 
The parameters to be assessed in Study UX003-CL203, along with timing of assessments, are 
provided in the Schedule of Events (Table 2.1 and Table 2.2). Refer to the Study Reference 
Manual for additional details on specific assessments. For any given study visit, if the 
maximum amount of blood has been taken based on Maximum Allowable Blood Volume 
Guidelines for any subject, some assessments are not required; see the Lab Manual for details 
on prioritizing blood draws. 
The end of trial is defined as the last visit of the last subject undergoing evaluation in the 
study. As the planned duration of treatment in this study is up to 240 weeks, the end of trial is 
defined as the Week 240 visit of the last subject. In the event the study is terminated by the 
Sponsor prior to Week 240, all subjects should complete a termination visit and the date of 
the last termination visit of the last subject would define the end of the trial. The termination 


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visit should be completed within 30 days of the last dose of study drug. Efficacy assessments 
performed within 30 days will not be repeated at the termination visit.  
7.5.2 
Efficacy Measures 
The primary efficacy variable in this study, uGAG excretion, will provide a biochemical 
measure of the biological action of UX003. The primary efficacy measure will be supported 
by multiple secondary and tertiary variables to provide an assessment of UX003 efficacy in 
MPS 7 patients less than 5 years of age.   
7.5.2.1 
Primary Efficacy Measure:  Urinary GAG Excretion 
Clinical evidence for the use of uGAG as a relevant primary endpoint is based on nonclinical 
research work over 20 years, clinical disease survey studies, and Phase 3 controlled studies in 
MPS 1, 2 and 6 patients using other ERTs. The results demonstrate a direct relationship 
between disease severity and clinical outcomes with uGAG levels. The studies also 
demonstrate the sensitivity of uGAG to differences in clinical effect within the therapeutic 
range of doses and verified the sustained long-term effects of the ERT. The overall summary 
of these data show that uGAG reductions above a threshold of >50% are associated with 
clinically meaningful changes in clinical parameters in all three MPS ERT programs. 
First morning void urine will be evaluated for uGAG at the time points listed in the schedule 
of events (Table 2.1).  Urine samples will be collected once during Screening Period and on 
two separate days during the Baseline Period (Week 0). Urine samples must be collected 
from first morning voids to assure the urine is adequately concentrated. Samples will be 
evaluated for uGAG concentration and normalized to urinary creatinine concentration.  
Refer to the Laboratory Manual for details on sample collection and processing requirements. 
7.5.2.2 
Secondary Efficacy Measures  
7.5.2.2.1 
Growth 
Growth will be assessed as a secondary efficacy measure to assess changes in growth 
velocity and comparisons to normative data matched for age and gender. Anthropometric 
measurements include standing height (recumbent length or sitting height as appropriate), 
head circumference, and weight, and will be obtained at twelve-week intervals beginning at 
the Baseline visit (Week 0). Every effort should be made to collect standing height. If unable 
to collect standing height, sitting height or length should be collected for that subject.  
Growth velocity will be calculated and compared with pre-treatment growth velocity when 
available. Anthropometric measurements may also be compared to normative reference data 
matched for age and gender. Refer to the Study Reference Manual for additional details on 
anthropometric measurements. 


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7.5.2.2.2 
Hepatosplenomegaly 
The volume of the liver and spleen will be determined using ultrasound and compared with 
normal values for age and gender if available; ascites will also be assessed. Ultrasounds will 
be conducted at the Baseline (Week 0) and Week 12, 24, and 48 (or Early Termination) study 
visits. During the Continuation Period, an ultrasound of the liver and spleen will be 
performed annually (every 48 weeks). If an ultrasound cannot be performed, liver and spleen 
size may be assessed qualitatively by physical exam. Ultrasound will not be performed at the 
ET visit if the assessment was conducted within 1 month of termination.   
7.5.2.3 
Tertiary Efficacy Measures 
The following tertiary efficacy variables will also be evaluated in the study.  Refer to the 
Study Reference Manual for additional details. 
7.5.2.3.1 
Serum and Supplementary Urinary GAG Measures 
Abnormal (pathologic) GAG in the serum will be assessed. One serum sample should be 
collected prior to dosing at the Baseline, Weeks 12, 24, 36, and 48 visits during the 
Treatment Period. . Supplementary assays for uGAG may be performed; samples will be 
collected as described in Section 7.5.2.1. 
7.5.2.3.2 
Clinical Global Impression Scale 
The Clinical Global Impression (CGI) scale was developed for use in National Institute of 
Mental Health-sponsored clinical trials to provide a brief, stand-alone assessment of the 
clinician's view of the patient's global functioning prior to and after initiating a study 
medication (Guy 1976). The CGI provides an overall clinician-determined summary measure 
that takes into account all available information, including knowledge of the patient's history, 
psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
patient's ability to function. The Sponsor has developed an MPS disease-specific and 
age-appropriate version of the CGI (also referred to as the Physician Global Impression of 
Change [PGI-C] in some studies) to be used in this study.  
Physicians caring for each subject will provide a global assessment of change using a seven 
point scale ranging from -3 (severe worsening) to +3 (significant improvement). The CGI 
score will be supported by reported changes relative to baseline or identification of a new 
finding based on a list of disease-specific abnormalities projected to respond to treatment.   
The CGI will be evaluated at the Baseline (Week 0) visit and at 12-week intervals throughout 
the Treatment Period and Continuation Period.  
7.5.2.3.3 
Functional Development 
Functional Development will be assessed by the Bayley Scales of Infant and Toddler 
Development – Third Edition (Bayley-III). The instrument will be administered at Baseline 
(Week 0), and at the Week 24 and 48 (or Early Termination) study visits. During the 


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Continuation Period, the Bayley-III will be completed at 48-week intervals. Bayley-III will 
not be performed at the ET visit if the assessment was conducted within 1 month of 
termination.   
The Bayley-III (Bayley 2006) is a standard series of measurements developed to assess the 
motor (fine and gross), language (receptive and expressive), and cognitive development of 
infants and toddlers, aged 1 month - 42 months. This measure consists of a series of 
developmental play tasks and takes between 45 - 60 minutes to administer. The total raw 
score will be converted into a scaled score and a composite score with percentile rank to 
compare performance to healthy same-age peers. Unless a child has achieved the highest raw 
score on the test, the Bayley-III assessments will continue throughout the study to monitor 
the progress of a child. Additionally, if valid and reliable administration of the instrument is 
not possible based on the clinical judgment of the Investigator, e.g. language difficulties or 
clinical condition of the subject, testing may be omitted at that visit. 
7.5.2.3.4 
Motor Functioning 
A gross motor milestone checklist, developed for use in this trial, will assess gross motor 
functioning and development. The checklist was designed to allow for assessment of the 
functional status of the subject requiring limited language interaction and physical handling. 
See Study Reference Manual for details.  
The checklist will be assessed at Baseline (Week 0), and at the Week 24 and 48 (or Early 
Termination) study visits. During the Continuation Period, the gross motor milestone 
checklist will be completed at 48-week intervals. The checklist will not be completed at the 
ET visit if conducted within 1 month of termination. 
7.5.2.3.5 
Cardiac Ventricular Mass 
Ventricular mass will be assessed by echocardiogram (ECHO) and scored as a z-score 
relative to normal ventricular mass. Valvular and cardiac function may also be evaluated.  
An ECHO performed within three months prior to the Baseline visit may be used for the 
study baseline ECHO provided cardiac ventricular mass can be calculated. ECHO will be 
performed at the Baseline (Week 0) and Week 48 (or Early Termination) study visits.  
During the Continuation Period, ECHO will be assessed annually (every 48 weeks). 
7.5.2.3.6 
Pulmonary Function Testing 
In young patients, traditional pulmonary function testing (i.e. spirometry) is difficult to 
perform, but measuring pulse oximetry can help assess basic problems in adequate 
respiration in the youngest patients Resting O2 saturation will be assessed as a measure of 
pulmonary function while the subject is breathing room air during the Baseline (Week 0) and 
Weeks 12, 24, 36, and 48 (or Early Termination) visits. If the subject requires respiratory 
support, the type and duration should also be noted on the CRF. Pulse oximetry will be 
assessed every 12 weeks during the Continuation Period. 


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7.5.2.3.7 
Biochemical Markers of Bone Turnover  
Biochemical markers of bone turnover (BTMs) will be evaluated as an indicator of changes 
in bone metabolism in response to UX003 treatment. BTMs in serum include procollagen 
type 1 N-propeptide (P1NP), carboxy-terminal cross-linked telopeptide of type I collagen 
(CTX-I), bone specific alkaline phosphatase (BALP) and vitamin D. Serum samples will be 
collected at the Baseline (Week 0) and Week 2, 8, 16, 24, 32, 40 and 48 visits (or Early 
Termination). Bone turnover markers will be assessed at 24-week intervals during the 
Continuation Period. 
7.5.3 
Drug Concentration Measurements 
The concentration of rhGUS in the blood will be measured to characterize the PK of UX003 
following a single dose and multiple doses. Blood samples for PK analysis will be obtained 
at Weeks 0 (Baseline), 24, and 48. PK samples will be collected prior to the infusion (pre-
dose), 60 minutes after start of infusion, at the end of the infusion, 30-120 minutes post 
infusion and 4-6 hours post infusion. 
Samples may be obtained by separate venipunctures, indwelling catheters, peripherally 
inserted central catheter (PICC) line or by combinations of these or other suitable methods. 
The indwelling or PICC line should be managed as prescribed by the clinic procedures. 
Collection and processing instructions can be found in Laboratory Manual. The same IV line 
post-infusion end, may be used if the primary line fails, but extensive saline flushing of the 
line should occur before drawing PK.  
7.5.4 
Safety Measures & General Assessments 
General assessments include medical history, demographics and weight for study drug 
preparation (Section 7.4.3.2). Safety will be evaluated by the incidence, frequency and 
severity of AEs and SAEs, including clinically significant changes from study baseline to 
scheduled time points in vital signs, weight, physical examination, clinical laboratory 
evaluations, and concomitant medications. To assess the immune response to UX003, 
the development of IgG antibodies to rhGUS will be evaluated as indicated in the Schedule 
of Events. Complement C3, C4, and CH50 levels will also be evaluated if a drug-related 
hypersensitivity reaction is suspected. Refer to the Study Reference Manual for additional 
details. 
To further characterize the disease manifestations, severity and progression of MPS 7, 
the sponsor aims to determine the specific genetic mutation in each patient enrolled if 
consent is provided for such testing. This optional assessment can be performed at week 16 
or at different time-point if total blood volume at week 16 may exceed maximum allowable 
volume.   


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7.5.4.1 
Medical History 
A complete medical history will be obtained at the Screening visit. At the Baseline visit, any 
changes in medical history since Screening will be recorded. General medical information 
includes subject demographics (date of birth, ethnicity, and sex) and a history of major 
medical illnesses, diagnoses, and surgeries. Growth history for height and weight will be 
collected. Pretreatment measurements of height and weight should be collected from the 
records if possible to assure a pre and post treatment growth rate can be assessed. MPS7 
treatment history and relevant concomitant medications will be recorded (start date, stop 
date, dose, dose regimen). Medications include prescription, over-the-counter, herbal and 
nutritional supplements. Any relevant concomitant therapy, including physical/occupational 
therapy will be recorded.   
7.5.4.2 
Weight 
During the initial 48-week Treatment Period, weight will be obtained at each visit to 
determine appropriate study drug volume for the subsequent visit, and for safety (refer to 
Pharmacy Manual for instructions on calculating drug dosage). During the Continuation 
Period, weight will be obtained at 12-week intervals (in conjunction with anthropometric 
measurements). Weight will be measured in kilograms using a scale. 
7.5.4.3 
Physical Examination 
Complete physical examinations will be performed at the Screening, Baseline, Week 12, 24, 
36, and 48 study visits (or Early Termination Visit). During the Continuation Period, physical 
examinations will be conducted at 12-week intervals. Physical examinations will include 
assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, 
dermatologic, lymphatic, respiratory, gastrointestinal, genitourinary, neurological, and 
musculoskeletal systems. If the subject exhibits signs or symptoms of weakness or other new 
neurological findings, evaluate for cord compression (e.g. reflexes and motor strength). 
7.5.4.4 
Vital Signs 
Vital signs will include seated systolic blood pressure and diastolic blood pressure measured 
in millimeters of mercury (mm Hg), heart rate in beats per minute, respiration rate in breaths 
per minute, and temperature in degrees Celsius (°C). Vital signs measurements will be 
performed at every visit before any additional assessments are completed. On days when 
study drug is administered, vital signs will be measured as outlined below. 
Week 0 (Baseline) to Week 12, vital signs will be obtained: 
• 15 minutes prior to infusion 
• Every 15 minutes during the infusion 
• Immediately post-infusion 


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• 15, 30, and 60 minutes post-infusion  
Additional measurements should be obtained as appropriate. 
Week 14 to Week 240, vital signs will be obtained: 
• 15 minutes prior to infusion 
• Every 60 minutes for the remainder of the infusion 
• Immediately post-infusion 
• 60 minutes post infusion   
Additional measurements should be obtained as appropriate. 
7.5.4.5 
Clinical Laboratory Tests for Safety 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.4.5.1. 
Clinical laboratory testing for serum chemistry, hematology, and urinalysis will be performed 
at the Screening, Baseline (Week 0), Week 2, 4, and 8 visits. After Week 8, clinical 
laboratory evaluations will be performed every 8 weeks until Week 48 (or Early Termination 
visit). During the Continuation Period, clinical laboratory testing will be performed at 
24-week intervals as indicated in the Schedule of Events (Table 2.1). Blood and urine 
samples will be collected prior to administration of study drug; fasting is not required. 
See Section 7.4.3.1 for infusion related fasting and refer to the Laboratory Manual for 
additional details. 
Table 7.5.4.5.1: 
Clinical Laboratory Assessments for Safety 
Chemistry 
Hematology 
Urinalysis 
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Alkaline phosphatase 
Hemoglobin 
Color 
Amylase 
Mean corpuscular hemoglobin (MCH) 
pH 
Aspartate aminotransferase (AST)) 
MCH concentration (MCHC) 
Specific gravity 
Bilirubin (direct and total) 
Mean corpuscular volume (MCV) 
Ketones 
Blood urea nitrogen (BUN) 
Platelet count 
Protein  
Calcium 
Red blood cell (RBC) count 
Glucose  
Chloride 
Reticulocyte count 
Bilirubin 
Creatinine 
Neutrophil count (absolute and %) 
Nitrite 
Gamma-glutamyl transpeptidase (GGT) 
Lymphocyte count (absolute and %) 
Urobilinogen 
Glucose 
Monocyte count (absolute and %) 
Hemoglobin 
Lactate dehydrogenase (LDH) 
Eosinophil count (absolute and %) 
Creatinine 
Phosphorus 
Basophil count (absolute and %) 
 
Potassium 
White blood cell (WBC) count 
 
Protein (albumin and total) 
WBC differential 
 
Sodium 
 
 


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Subjects who experience a SAE possibly or probably related to study drug or other AE of 
concern may, at the discretion of the Investigator (and/or medical monitor), have additional 
blood samples taken for safety laboratory tests. 
7.5.4.6 
Antibodies to rhGUS 
Prior Phase 3 studies in ERT for MPS have shown that anti-IgG antibodies to the 
recombinant protein do not have a precise relationship to IARs, but the presence of 
antibodies may impact on enzyme distribution and efficacy (Dickson et al. 2008).  
To determine the immunogenicity profile of UX003, testing for IgG antibodies directed 
against rhGUS will take place at Baseline (Week 0) and the Week 8, 16, 24, 32, 40, and 48 
(or Early Termination) visits. During the Continuation Period, anti-drug antibody screening 
will occur at 12-week intervals. Serum samples for antibodies must be collected before 
infusion of study drug.  For subjects with a positive antibody and/or IAR response, further 
laboratory evaluation of the immune response to UX003 (i.e. antibodies and complement) 
may be conducted if warranted. 
7.5.4.7 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at the Screening visit. Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 30 days prior to 
Screening will be reviewed and recorded. At each subsequent visit, change in medications 
since the previous visit will be recorded. A discussion of prohibited and permitted 
medications is provided in Section 7.4.7.  
7.5.4.8 
Complement Levels 
Complement components will be assessed to characterize the immune response following a 
drug-related IAR. For subjects who experience an IAR that is potentially a 
complement-mediated (anaphylactoid) hypersensitivity reaction, blood samples will be 
drawn pre- and immediately post-infusion during the subsequent infusion for measurement of 
the change in C3, C4 and CH50 levels during an infusion. Refer to the Laboratory Manual 
for additional details on sample processing. 
7.5.4.9 
Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent until 30 days 
after the last dose of study drug. The determination, evaluation, reporting, and follow-up of 
AEs will be performed as outlined in Section 8.5. At each visit subjects will be asked about 
any new or ongoing AEs since the previous visit. Assessments of AEs will occur at each 
study visit. 
Clinically significant changes from study baseline in physical examination findings, weight, 
vital signs, and clinical laboratory parameters, will be recorded as AEs or SAEs, if 
appropriate.  


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7.5.5 
Appropriateness of Measures 
The primary efficacy variable in this study, uGAG, is a measure of the underlying 
biochemical defect in MPS 7 patients. Accumulated GAGs and uGAGs are a direct result of 
the genetic enzyme deficiency state. Based on clinical and nonclinical evidence, uGAG is a 
direct pathophysiological and readily measured marker of the MPS disease process and a 
reasonable predictor of treatment effect and clinical benefit. Therefore, if the UX003 restores 
the underlying biochemical block, a reduction of uGAG is expected.   
The additional variables assessed in the program are intended to replicate the clinical 
assessments used in other MPS ERT programs. The clinical assessments in the study employ 
standard measures used in other diseases and conditions that impact the respiratory, cardiac, 
gastrointestinal, skeletal, and central nervous systems. In a multinational study of Laronidase 
in MPS I patients younger than 5 years, clinical responses in liver size and left ventricular 
hypertrophy were observed (Wraith et al. 2007). Pulse oximetry will be conducted to assess 
respiratory compromise, an important component of disease progression and mortality in 
MPS 7 subjects.  ECHO, ultrasound, and anthropometrics are routine, non-invasive 
procedures inflicting minimal pain/distress for the subject, while providing relevant 
indicators of clinical disease phenotype and progression.   
The Bayley-III is useful for assessing the compounded impact of multisystem clinical 
manifestations on the cognitive, motor, and adaptive behavioral development of infants and 
toddlers. In MPS 7, development in these domains is likely to be affected by the 
co-morbidities present in these subjects (McDonald et al. 2010). The Bayley-III may not be 
reliably administered.to all subjects, therefore a motor milestone checklist is also included as 
an assessment of gross motor functioning and development. The checklist developed for this 
trial requires limited language interaction or physical handling and allows for a gross motor 
assessment across all subjects.  
Assessments of serum markers of bone formation and bone resorption were included to 
measure the biochemical markers of bone turnover, which may enable evaluation of the 
effects of UX003 on skeletal tissue. 
Measurements of UX003 drug concentration in blood samples will provide information on 
relevant PK parameters following a single-dose and at steady-state. Where possible, timing 
of assessments has been coordinated with standard safety laboratory tests to minimize risk 
and discomfort and avoid unnecessary sampling. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs, serum 
chemistry and hematology, urinalysis, concomitant medications, and other routine clinical 
and laboratory procedures. In addition, anti-rhGUS IgG antibody levels and complement C3, 
C4 and CH50 levels (as indicated) will be determined as a measure of UX003 
immunogenicity. Since the study population is comprised of pediatric subjects, 
age-appropriate safety and efficacy measures have been incorporated into the study design. 


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7.6 
Statistical Methods and Determination of Sample Size 
The completeness of the data affects the integrity and accuracy of the final study analysis. 
Therefore, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data. Detailed procedures for handling missing, unused, or spurious 
data, along with the detailed method for analyses will be presented in the Statistical Analysis 
Plan (SAP); the information below is intended as a guide to planned analyses. 
The statistical analyses will be reported using summary tables, figures, and data listings. 
All raw data obtained from the CRFs as well as any derived data will be included in data 
listings. All analyses and tabulations will be performed using SAS®. Descriptive statistics 
will be used to summarize the data. For continuous variables, the mean, standard error, 
median, minimum, and maximum will be provided. For categorical variables, the frequency 
and percent distributions will be provided. Statistical tests will be two-sided at the alpha 
=0.05 significance level. Two-sided 95% confidence intervals will also be presented when 
appropriate. The statistical method employed for the analysis of each assessment will be 
defined in more detail in the SAP.  
7.6.1 
Determination of Sample Size 
Approximately 15 subjects will be enrolled including approximately 5 subjects with hydrops 
fetalis. Subjects under the age of 5 years at the time of informed consent with a confirmed 
diagnosis of MPS 7 will be enrolled. Additional subjects previously treated with UX003 
under an emergency IND or similar process may also be enrolled at the discretion of the 
Sponsor. Due to the extremely low prevalence of the disease, the sample size is primarily 
based on the ability to find qualifying patients.  
7.6.2 
Subject Information 
Subject disposition summaries will include the number of subjects, the number of subjects 
receiving study medication, the number of subjects completing the study, and the reasons for 
discontinuation. Demographic variables include age, sex, and race.  
7.6.3 
Populations Analyzed 
The full analysis set will consist of all enrolled subjects who receive at least 1 dose of UX003 
during the study.  
7.6.4 
Primary Efficacy Endpoint 
The study is a small open label study to obtain some clinical efficacy data from a small 
cohort of these ultra-rare patients. A complete hypothesis testing statistical approach is not 
plausible in this setting, but a reasonable approach to assessing for the biologic efficacy of 
UX003 will be made. 


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The primary efficacy analysis will evaluate the mean percent change in uGAG excretion 
from Week 0 (Baseline) to Week 48 using the generalized estimating equation (GEE) 
analysis method.  For subject(s) previously treated with UX003 under an emergency IND, 
percent change from initial baseline (prior to first dose of UX003) will be used, if the initial 
baseline data are available. The null hypothesis of no change in mean uGAG excretion will 
be tested. An additional analysis will also be performed on the Week 24 time point. 
7.6.5 
Secondary and Tertiary Endpoints and Analyses 
Secondary analysis on growth and hepatosplenomegaly will be evaluated to compare 
pretreatment with post treatment effects.  Growth rate will be compared to historical data 
obtained from medical history and records (if available), and also compared to published 
normative data for age and gender. Changes in findings from Baseline for other efficacy 
variables will be tabulated for each subject. Comparisons of certain efficacy variables with 
published normative data based on age and gender may also be conducted.   
7.6.6 
Pharmacokinetic Analyses  
The following PK parameters will be calculated from the plasma concentrations of rhGUS 
measured in these blood samples: 
• Area under the plasma concentration-time curve (AUC) from time zero to infinity 
(AUC0 -∞) 
• AUC from time zero to the time of last measurable concentration (AUC0-last) 
• Maximum plasma concentration (Cmax) 
• Time to maximum plasma concentration (Tmax) 
• Elimination half-life (t1/2) 
• Total clearance of drug after IV administration (CL) 
• Apparent volume of distribution based upon the terminal phase (Vdz) 
• Apparent volume of distribution at steady-state (Vdss) 
7.6.7 
Safety Analyses 
The primary safety analysis will evaluate the safety of UX003 as measured by the incidence, 
frequency and severity of AEs and SAEs, including clinically significant changes from study 
baseline to scheduled time points in: 
• Vital signs and weight 
• Physical examination findings 
• Clinical laboratory evaluations 


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• Concomitant medications 
• IgG antibodies to rhGUS 
• Complement C3, C4 and CH50 levels (as indicated) 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), 
Preferred Term (PT), relationship to study drug, and severity. No statistical significance will 
be assessed. A by-subject listing will be provided for those subjects who experience a SAE, 
including death, or experience an AE associated with early withdrawal from the study or 
study drug treatment. 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside of 
reference ranges) and/or clinically significant abnormalities after study drug administration 
will be presented for each clinical laboratory measurement. For each clinical laboratory 
measurement, descriptive statistics will be provided for study baseline and all subsequent 
visits. Changes from study baseline to the post-treatment visits will also be provided.  
Descriptive statistics of vital signs, imaging assessments for safety, and concomitant 
medications will be provided in a similar manner. 
Changes in findings from study baseline physical examinations will be tabulated and listed 
for each subject by examination category. If there are examination findings that change in 
more than one subject, these will be tabulated in a separate table and expressed as the number 
of subjects with the change out of the total.   
Anti-drug antibody data will be tabulated over the course of the study. The number of 
subjects converting to a positive antibody assay value by increasing titer by five-fold over 
study baseline or more and the time of onset of a positive antibody response will be 
determined. Descriptive statistics on the titers achieved and the time of onset of the response 
will be provided (mean, standard deviation, median, range). For subjects with a positive 
antibody and/or IAR response, further laboratory evaluation of the immune response to 
UX003 (i.e. antibodies and complement) may be conducted as indicated. 
7.6.8 
Analyses 
Analyses may be performed at any time during the study at the discretion of the Sponsor. 
There is no unblinding during these analyses since it is an open-label study.   


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee 
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards", International Conference on Harmonisation 
(ICH) and Good Clinical Practice (GCP) requirements, and applicable laws and local 
regulations. This protocol, any protocol amendments, and the associated informed consent 
forms (ICFs) must be submitted to the IRB/EC for review and must be approved before 
screening of any subject into the study. Study drug may not be shipped to the Investigator 
until Ultragenyx or its designee has received a copy of the letter or certificate of approval 
from the IRB/EC for the protocol and any protocol amendments, as applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/EC and 
Ultragenyx or its designee for review and approval prior to implementation. IRB/EC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety.  In such cases, the chair of the IRB/EC should be notified immediately and the 
amendment forwarded to the IRB/EC for review and approval. 
8.1.2 
Ethical Conduct of Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The Investigator will make every effort to 
assure the study described in this protocol is conducted in full conformance with those 
principles, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, and 
local ethical and regulatory requirements. Should a conflict arise, the Investigator will follow 
whichever law or guideline affords the greater protection to the individual subject.  
The Investigator will also make sure he or she is thoroughly familiar with the appropriate 
administration and potential risks of administration of the study drug, as described in this 
protocol and the IB, prior to the initiation of the study. 
8.1.3 
Subject Information and Consent 
Appropriate forms for documenting written informed consent will be provided by the 
Investigator and reviewed and approved by Ultragenyx or its designee before submission to 
the IRB/EC. Ultragenyx or its designee must receive a copy of the IRB/EC's approval of the 
ICF before the shipment of study drug to the study site. 
It is the Investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The Investigator must explain 


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to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if possible), and his/her legally authorized representative (parent 
or legal guardian) will provide written informed consent for such subjects.   
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The Investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
The date of written informed consent will be documented in each potential subject’s CRF.  
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure 
Each Investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form. All sub-investigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators 
listed on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site to 
perform source document verification. The monitor will verify the Investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging.  
The storage facility must be available for inspection by the study monitor at any time during 
the study.   
A drug accountability record must be maintained for all study drug received, dispensed, 
returned, and/or lost during the study. This record must be kept current and made available to 
the study monitor for inspection. Following the close-out of the study, all unused study drug 


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must be returned to Ultragenyx and/or its designee unless other instructions have been 
provided for final disposition of the study drug.  
8.4 
Data Handling and Record Keeping 
8.4.1 
Case Report Forms and Source Documents 
The Investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject. A validated electronic data capture (EDC) system will be used for entry of the data 
into electronic CRFs. Data must be recorded on CRFs approved by Ultragenyx or its 
designee. All information recorded on CRFs for this study must be consistent with the 
subject's source documentation. 
Initial data entry and any changes to the data will be made only by Ultragenyx-authorized 
users, and data entries and changes will be captured in an electronic audit trail.  
An explanation of any data change should be recorded in the CRF. All data entered in to the 
CRF must be verifiable; therefore, CRFs will be routinely checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records by Ultragenyx or its designee.  
The Investigator must allow direct access to all source documents. 
8.4.2 
Data Quality Assurance 
Monitoring and auditing procedures developed by Ultragenyx and/or its designee will be 
implemented to ensure compliance with FDA/EMA and ICH GCP guidelines.  Ultragenyx's 
designated representative (the monitor) will contact the Investigator and conduct regular 
visits to the study site. The monitor will be expected and allowed to verify the Investigator's 
qualifications, to inspect clinical site facilities, and to inspect study records, including proof 
of IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data. CRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents 
including progress notes, laboratory test reports and other subject records. Instances of 
missing or uninterruptable data will be resolved in coordination with the Investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications by e-mail, telephone, 
facsimile, and/or mail. The Investigator and all other site personnel agree to cooperate fully 
with the monitor and will work in good faith with the monitor to resolve any and all 
questions raised and any and all issues identified by the monitor. 


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The Investigator understands that regulatory authorities, the IRB/EC, and/or Ultragenyx or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least two years after the last approval of a marketing application or for at least 
two years after clinical development of the study drug for the indication being studied has 
been discontinued. The Investigator is required to guaranty access to these documents and to 
cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified and will assist with retention should the 
Investigator/institution be unable to continue maintenance of subject files for the full 
25 years. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 25 years.  
Ultragenyx must be notified and will assist with retention should the Investigator/institution 
be unable to continue maintenance of subject files for the full 25 years. All study records 
must be stored in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) products. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the Investigator or Ultragenyx, places the patient 
or subject at immediate risk of death. It does not include an AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at 
any dose, in the view of either the Investigator or Ultragenyx, results in any of the following 
outcomes:  


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• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE (version 
4.0).  The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions.  
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death or 
are disabling. 
• Death (Grade 5): Events that result in death. 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided.  The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 


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be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious" which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. 
• Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure. 
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs from the time of signing the ICF through 30 days following the last 
dose of study drug, including a clinically significantly abnormal laboratory test result that is 
considered serious, must be reported within 24 hours of knowledge of the event to 
Ultragenyx or its designee. These requirements apply equally to all subjects, regardless of the 
study phase or the at-risk subject's treatment assignment or dosage. All initial SAE reports 
must be followed by detailed descriptions. These should include copies of hospital case 
records and other documents when requested. SAEs will be reported by completing and 
submitting SAE report forms to Ultragenyx or designee.  
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected. 


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All deaths, regardless of causality, from the time of consent through 30 days after last dose of 
study drug must be reported to Ultragenyx or its designee within 24 hours of knowledge.  
8.5.5 
Adverse Drug Reaction Reporting  
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), ECs, and Investigators as per local laws and regulations. 
Fatal and life-threatening SUSARs will be submitted no later than 7-calendar days of first 
knowledge of the event and follow-up information submitted within an additional eight (8) 
days. All other SUSARs will be submitted within 15-calendar days of first knowledge of the 
event.  
Principal Investigators are required to report any urgent safety matters to Ultragenyx or 
designee within 24 hours. Ultragenyx or its designee will inform Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of UX003, major 
safety findings) that may occur during the clinical trial that do not fall within the definition of 
a SUSAR but may affect the safety of subjects participating in the clinical trials, as required, 
in accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from signing the ICF through 30 days following the last dose of study 
drug.  
The Principal Investigator will notify the IRBs/ECs of SAEs and urgent safety matters, in 
accordance with IRB/EC requirements and local laws and regulations. A copy of this 
notification must be provided to Ultragenyx or its designee.  
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory authorities and ECs, as per local laws and regulations.  
8.5.6 
Urgent Safety Measures 
The regulations governing clinical studies state that the Sponsor and Investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the Sponsor and the Investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The Sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
Ethics Committee (EC) is notified at the same time.” The reporting period for urgent safety 
measures is the period from the signing of the ICF through 30 days following the last 


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administration of study drug.  Investigators are required to report any urgent safety measures 
to Ultragenyx within 24 hours. 
8.5.7 
Safety Contact Information 
Drug Safety 
Medical Monitor 
 
   
 
 
 
Christine Haller, M.D. 
Telephone:   
 
Mobile:        
 
e-mail:         
 
 
8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the Investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx and the 
Institution and/or the Investigator. 
PPD
PPD
PPD
PPD


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Tomatsu, S, Montano, AM, Dung, VC, Grubb, JH, and Sly, WS. 2009. "Mutations and 
polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome)." 
Hum.Mutat. 30 (4):511-519. 
Valayannopoulos, V, and Wijburg, FA. 2011. "Therapy for the mucopolysaccharidoses." 
Rheumatology (Oxford) 50 Suppl 5:v49-59. 
Vervoort, R, Islam, MR, Sly, WS, Zabot, MT, Kleijer, WJ, Chabas, A, Fensom, A, Young, 
EP, Liebaers, I, and Lissens, W. 1996. "Molecular analysis of patients with beta-
glucuronidase deficiency presenting as hydrops fetalis or as early 
mucopolysaccharidosis VII." Am.J.Hum.Genet. 58 (3):457-471. 
Vogler, C, Levy, B, Grubb, JH, Galvin, N, Tan, Y, Kakkis, E, Pavloff, N, and Sly, WS. 2005. 
"Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in 
murine mucopolysaccharidosis VII." Proc Natl Acad Sci U S A 102 (41):14777-82. 
 


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Vogler, C, Sands, MS, Levy, B, Galvin, N, Birkenmeier, EH, and Sly, WS. 1996. "Enzyme 
replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis 
type VII: impact of therapy during the first six weeks of life on subsequent lysosomal 
storage, growth, and survival." Pediatr.Res. 39 (6):1050-1054. 
Wraith, JE, Beck, M, Lane, R, van der Ploeg, A, Shapiro, E, Xue, Y, Kakkis, ED, and 
Guffon, N. 2007. "Enzyme replacement therapy in patients who have 
mucopolysaccharidosis I and are younger than 5 years: results of a multinational 
study of recombinant human alpha-L-iduronidase (laronidase)." Pediatrics 120 
(1):e37-46. 
Wraith, JE, Clarke, LA, Beck, M, Kolodny, EH, Pastores, GM, Muenzer, J, Rapoport, DM, 
Berger, KI, Swiedler, SJ, Kakkis, ED, Braakman, T, Chadbourne, E, Walton-Bowen, 
K, and Cox, GF. 2004. "Enzyme replacement therapy for mucopolysaccharidosis I: a 
randomized, double-blinded, placebo-controlled, multinational study of recombinant 
human alpha-L-iduronidase (laronidase)." J Pediatr 144 (5):581-8. 
Yogalingam, G, Guo, XH, Muller, VJ, Brooks, DA, Clements, PR, Kakkis, ED, and 
Hopwood, JJ. 2004. "Identification and molecular characterization of alpha-L-
iduronidase mutations present in mucopolysaccharidosis type I patients undergoing 
enzyme replacement therapy." Hum Mutat 24 (3):199-207. 
 
 


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10 SIGNATURE PAGE 
Protocol Title:  An Open-label Study of UX003 rhGUS Enzyme Replacement Therapy in 
MPS 7 Patients Less than 5 Years Old 
Protocol Number:  UX003-CL203 
I have read Protocol UX003-CL203.  I agree to conduct the study as detailed in this protocol 
and in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all 
applicable regulatory requirements and guidelines.   
 
 
 
 
Investigator Signature 
 
             Date 
 
Printed Name:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accepted for the Sponsor: 
As the Sponsor representative, I confirm that Ultragenyx will comply with all Sponsor 
obligations as detailed in all applicable regulations and guidelines.  I will ensure the 
Investigator is informed of all relevant information that becomes available during the conduct 
of this study.  
 
 
 
 
Christine Haller, MD  
 
 
 
 
 
Date 
VP Drug Safety & Pharmacovigilance 
Ultragenyx Pharmaceutical Inc. 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
Title 
An Open-label Study of UX003 rhGUS Enzyme 
Replacement Therapy in MPS 7 Patients Less than 5 years 
old 
Protocol: 
UX003-CL203 
Investigational Product: UX003, recombinant human beta-glucuronidase (rhGUS) 
Phase: 
2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
 
Author: 
 
Associate Director, Biostatistics 
 
Date: 
22 Dec 2015 
Version Number: 
v1.0 
 
 
 
PPD


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Table of Contents 
1 INTRODUCTION ...............................................................................................................5 
2 STUDY OBJECTIVES ........................................................................................................5 
2.1 Primary ........................................................................................................................5 
2.2 Secondary ....................................................................................................................5 
2.3 Tertiary ........................................................................................................................5 
3 STUDY DESIGN.................................................................................................................5 
3.1 Overall Study Design and Plan ...................................................................................5 
3.2 Determination of Sample Size ....................................................................................6 
3.3 Interim Analysis ..........................................................................................................6 
3.4 Data Monitoring Committee .......................................................................................6 
3.5 Randomization and Blinding Method of Assigning Subjects to Treatment 
Groups .........................................................................................................................6 
4 STUDY CLINICAL OUTCOMES AND COVARIATES ..................................................7 
4.1 Primary Efficacy Variable ..........................................................................................7 
4.2 Secondary Efficacy Variables .....................................................................................7 
4.3 Tertiary Efficacy Variables .........................................................................................7 
4.4 Safety Assessments .....................................................................................................7 
5 DEFINITIONS .....................................................................................................................8 
5.1 Baseline .......................................................................................................................8 
5.2 Fold Increase in uGAG Above Upper Normal Limit .................................................8 
5.3 Growth ........................................................................................................................8 
5.4 Anti-rhGUS Antibody Titer Values ............................................................................9 
5.5 Duration of Exposure to UX003 .................................................................................9 
6 ANALYSIS POPULATIONS .............................................................................................9 
6.1 Full Analysis Set .........................................................................................................9 
7 DATA SCREENING AND ACCEPTANCE ......................................................................9 
7.1 Handling of Missing and Incomplete Data .................................................................9 


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7.2 Missing Date Imputation Rules...................................................................................9 
7.3 Visit Time Windows .................................................................................................11 
7.4 Software ....................................................................................................................11 
8 STATISTICAL METHODS OF ANALYSIS ...................................................................12 
8.1 General Principles .....................................................................................................12 
8.2 Subject Disposition ...................................................................................................12 
8.3 Demographics and Other Baseline Characteristics ...................................................12 
8.4 Medical History.........................................................................................................12 
8.5 Prior and Concomitant Medications .........................................................................12 
8.6 Dosing Summary.......................................................................................................12 
8.7 Efficacy Analyses .....................................................................................................13 
8.7.1 
Primary Efficacy Endpoint ..........................................................................13 
8.7.2 
Secondary Efficacy Endpoints ....................................................................13 
8.7.3 
Other Efficacy Endpoints ............................................................................13 
8.8 Safety Analyses .........................................................................................................14 
8.8.1 
Adverse Events ............................................................................................14 
8.8.2 
Laboratory Parameters ................................................................................14 
8.8.3 
Other Safety Parameters ..............................................................................14 
8.8.4 
Antibodies ...................................................................................................14 
9 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................15 
10 REFERENCES ..................................................................................................................16 
11 APPENDICES ...................................................................................................................17 
 
 
 


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ABBREVIATIONS 
ADA  
anti-drug antibody 
AE 
 
adverse event 
Bayley-III  
Bayley Scales of Infant and Toddler Development® – Third Edition 
CRF 
 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECHO  
echocardiogram  
ERT 
 
Enzyme Replacement Therapy 
GAG  
glycosaminoglycan 
IND 
 
Investigational New Drug (application) 
IV  
 
intravenous 
MedDRA  
Medical Dictionary for Regulatory Activities  
MPS 7  
mucopolysaccharidosis type 7, Sly Syndrome 
PK 
 
pharmacokinetic  
QOW  
every other week 
rhGUS  
beta-glucuronidase  
SAE 
 
serious adverse event 
SAP 
 
Statistical Analysis Plan 
SOC   
system organ class  
TEAE  
treatment emergent adverse event 
uGAG  
urinary glycosaminoglycan 
WHODRUG  World Health Organization Drug  
 
 
 


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1 INTRODUCTION 
The purpose of this statistical analysis plan is to provide details of the statistical analyses that 
have been outlined within the original UX003-CL203 Protocol dated 09 January 2015 
through Protocol Amendment 1 dated 03 October 2015. The data collected in this study will 
evaluate the safety and efficacy of UX003 treatment in pediatric MPS 7 subjects less than 5 
years of age. This SAP does not describe any Pharmacokinetic (PK) data analyses. 
2 STUDY OBJECTIVES 
2.1 
Primary 
The primary objective is to evaluate the effect of UX003 treatment in pediatric MPS 7 subjects less 
than 5 years of age on: 
• Safety and tolerability 
• Efficacy as determined by the reduction of uGAG excretion 
2.2 
Secondary 
The secondary objective is to evaluate the effect of UX003 on growth velocity and 
hepatosplenomegaly. 
2.3 
Tertiary 
Tertiary objectives are to assess PK and evaluate the effect of UX003 on measures of 
lysosomal storage, overall clinical change, cardiac and pulmonary function, bone turnover 
markers, and functional and motor development. 
3 STUDY DESIGN 
As background for the statistical methods presented below, this section provides an overview 
of the study design.  This overview is a summary only.  The protocol is the definitive 
reference for all matters discussed in what follows. 
3.1 
Overall Study Design and Plan 
UX003-CL203 is an open-label, multicenter, Phase 2 study to assess the safety and efficacy 
of UX003 in pediatric MPS 7 subjects less than 5 years of age. UX003 is a formulation of 
recombinant human rhGUS, a human enzyme produced by recombinant DNA methods that 
is intended as an enzyme replacement therapy (ERT) for MPS 7. The study seeks to enroll up 
to 15 subjects less than 5 years of age at the time of signing informed consent, and will 
attempt to include approximately 5 infants with hydrops fetalis if possible. Subjects less than 
5 years of age with prior exposure to UX003 treatment under an emergency IND may also be 
enrolled at the discretion of the Ultragenyx. The inclusion criteria are structured to enroll 
subjects with a confirmed diagnosis of MPS 7. To enroll subjects most likely to benefit from 
treatment and demonstrate safety and effectiveness of UX003, MPS 7 patients who have 


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undergone successful bone marrow or stem cell transplantation will be excluded from the 
study. Subjects who withdraw or are removed from the study after receiving study drug may 
be replaced on a case-by-case basis, at the discretion of Ultragenyx. 
 
Subjects will receive UX003 via intravenous (IV) infusion at a dose of 4 mg/kg every other 
week (QOW). Subjects who complete the 48-week study may choose to continue UX003 
treatment in the Continuation Period up to 240 weeks, or until the subject withdraws consent, 
the subject is discontinued from the study at the discretion of the Investigator or Ultragenyx, 
the study is terminated, or UX003 becomes commercially available.  
Figure 3.1 provides a schematic of the study design. 
Figure 3.1. 
Study Schema 
 
3.2 
Determination of Sample Size 
Approximately 15 subjects will be enrolled including approximately 5 subjects with hydrops 
fetalis. Subjects under the age of 5 years at the time of informed consent with a confirmed 
diagnosis of MPS 7 will be enrolled. Additional subjects previously treated with UX003 
under an emergency IND or similar process may also be enrolled at the discretion of the 
Sponsor. Due to the extremely low prevalence of the disease, the sample size is primarily 
based on the ability to find eligible subjects.  
3.3 
 Interim Analysis 
Analyses may be performed at any time during the study at the discretion of the Sponsor. 
There is no unblinding during these analyses since it is an open-label study. 
3.4 
Data Monitoring Committee 
Safety will be monitored by Ultragenyx on a continual basis. An independent data 
monitoring committee will not be used. 
3.5 
Randomization and Blinding Method of Assigning Subjects to Treatment Groups 
Not applicable.  This is an open label study without randomization of treatment assignment. 


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4 STUDY CLINICAL OUTCOMES AND COVARIATES 
All data are collected according to the schedule of assessments included in the protocol. 
4.1 
Primary Efficacy Variable 
• Urinary GAG Excretion: First morning void urine will be evaluated for uGAG 
concentration and normalized to urinary creatinine concentration. 
4.2 
Secondary Efficacy Variables 
• Growth will be assessed by anthropometric measurements including standing height 
(length or sitting height as applicable), head circumference, and weight. Growth velocity 
will be calculated and compared with pre-treatment growth velocity when available and 
published normative data for age and gender. 
• Hepatosplenomegaly: The volume of the liver and spleen will be determined using 
ultrasound. If an ultrasound is not possible, the liver and spleen should be assessed by 
physical exam. Ascites will also be assessed. 
4.3 
Tertiary Efficacy Variables 
• Additional GAG measures including serum GAG and supplementary uGAG assays 
• Clinical Global Impression Scale: Physicians caring for each subject will provide a global 
assessment of change using a seven point scale ranging from -3 (severe worsening) to +3 
(significant improvement). The Clinical Global Impression (CGI) scale will be supported 
by reported changes in a list of disease-specific abnormalities projected to respond to 
treatment. 
• Functional Development will be assessed by the Bayley Scales of Infant and Toddler 
Development® – Third Edition (Bayley-III). 
• Motor Functioning will be assessed by a gross motor development milestone checklist. 
• Cardiac Ventricular Mass: Ventricular mass will be assessed by echocardiogram 
(ECHO). Valvular and cardiac function may also be evaluated. 
• Pulmonary Function: Pulse oximetry will be used to assess respiratory difficulties; resting 
O2 saturation will be measured while the subject is breathing room air. 
• Biochemical Markers of Bone Turnover (BTMs): Levels of serum markers of bone 
formation and bone resorption will be measured. 
4.4 
Safety Assessments 
Safety will be evaluated by the incidence and frequency of adverse events (AEs) and serious 
adverse events (SAEs), including clinically significant changes from study baseline to 
scheduled time points in: 


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• Vital signs and weight 
• Physical examination findings 
• Clinical laboratory evaluations 
• Concomitant medications 
• Antibodies to rhGUS 
• Complement C3, C4 and CH50 levels (if indicated to characterize the immune response 
following a drug related IAR) 
5 DEFINITIONS 
5.1 
Baseline 
• uGAG baseline is defined as the average of all study assessments prior to or on the date 
of  initiation of treatment with UX003 in this study. For subject(s) previously treated with 
UX003 under an emergency IND, initial baseline will be derived as the average of all 
assessments prior to or on the date of initiation of the initial treatment with UX003. 
• Baseline for growth measurement is defined as the last non-missing study assessment 
prior to the first dose of UX003. For subject(s) previously treated with UX003 under an 
emergency IND, the last assessment prior to the initial UX003 treatment may also be 
used.  
• The baseline for echocardiogram: ECHO performed within three months prior to baseline 
visit may be used as baseline provided cardiac ventricular mass can be calculated. 
• Baseline value for other endpoints is the last non-missing study assessment prior to the 
first dose of UX003 in this study unless otherwise specified.  
5.2 
Fold Increase in uGAG Above Upper Normal Limit 
The fold increase in uGAG above upper limit of normal is the ratio of the uGAG value over 
the uGAG upper limit of normal. If the ratio is less than 1, then it is set as 1. 
5.3 
Growth  
Growth will be assessed by anthropometric measurements.  Z-scores and percentiles will be 
calculated using CDC growth chart (Kuczmarski, 2000). 
Growth velocity of standing height (cm or Z score) may be assessed by a model-based 
approach. A linear regression model for each subject will be built for selected pre-treatment 
(eg., within 2 years prior to Baseline) data and post-treatment data:  
Yt = β0 + β1Xt + εi 


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Where 𝑌𝑌𝑡𝑡 is the standing height (cm) or Z score based on the standing height measured at 
Time t; 𝑋𝑋𝑡𝑡 is the time when standing height is measured;  𝛽𝛽0 is the intercept, 𝛽𝛽1is the slope of 
the regression model; 𝜀𝜀𝑖𝑖 is random error term. 
5.4 
Anti-rhGUS Antibody Titer Values 
 
Subject sera will be tested using a bridging anti-drug antibody (ADA) ELISA to screen for 
antibodies to rhGUS. Samples which are positive in the confirmation assay will then be 
tested in the titer assay giving a titer value, and also be tested with the neutralizing antibody 
assay (NAb). 
5.5 
Duration of Exposure to UX003 
Duration of exposure to UX003 in days in this study is defined as: last date of UX003 
infusion minus first date of UX003 infusion in this study + 14 days 
6 ANALYSIS POPULATIONS 
6.1 
Full Analysis Set 
The full analysis set is defined as all enrolled subjects who received at least 1 dose of UX003 
during the study. 
7 DATA SCREENING AND ACCEPTANCE 
7.1 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and measures with missing item scores. Missing and incomplete data will be identified 
through a review of tables and listings for this study.  Missing and incomplete data will be 
identified for investigation, and possible resolution, by Data Management prior to the study 
database lock.    
In general, missing data will be treated as missing, unless otherwise specified. When a 
change from baseline is assessed, only subjects with a baseline and at least one post-baseline 
measurement will be included in the analysis. 
7.2 
Missing Date Imputation Rules 
For scheduled visit, the visit number will be used for analyses and the missing date will not 
be imputed. 
Missing Date of the Last Dose of Investigational Product 
When the date of the last dose of investigational product is missing for a subject, all efforts 
should be made to obtain the date from the Investigator. If after all efforts are made it is still 
missing, the last visit date will be used as the last dose date. 


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Missing Medical History Related Dates (eg, diagnosis date) or Birth Date 
• If only the day is missing, impute the day to first day of the month. 
• If day and month are missing, impute to January  
• If year is missing, then no imputation will be done, the date will be missing. 
If the imputed medical history related date is earlier than birth date, then birth date will 
be used. 
Missing Date Information for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this study, then impute the month and day of the first dose date in this study. 
o Otherwise, assign ‘January‘  
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
If the imputed start date is earlier than birth date, then birth date will be used. 
Missing Stop Dates 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
• If the resulting end date is after the date of study completion / discontinuation, set the 
imputed end date as the date of study completion / discontinuation. 
Missing Causal Relationship to Investigational Product for Adverse Events 
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of double-blind investigational product, a causality of yes will 


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be assigned. The imputed values for causal relationship to investigational product will be 
used for the incidence summary; the values will be shown as missing in the data listings. 
7.3 
Visit Time Windows 
Table 7.3–1 presents the visit window assigned for scheduled efficacy and safety assessments 
scheduled for every 12 weeks and the corresponding range of treatment days (window) 
during which an actual visit may occur. 
 
Table 7.3–1. Visit Time Windows 
Period 
Visit 
Scheduled Visit Day 
Window 
48-Week 
Treatment Period 
Baseline 
Day 1 
Days ≤ 1 
 
Week 12 
Day 85 
Days [2, 127] 
 
Week 24 
Day 169 
Days [128, 211] 
 
Week 36 
Day 253 
Days [212, 295] 
 
Week 48 
Day 337 
For subjects entered into 
continuation period 
Days [296, start of 
continuation period-1] 
For subjects did not enter into 
continuation period 
Days ≥ 296 
Continuation 
Period 
Weeks 50-240 
Week 60 
Day 421 
Days [start of continuation 
period, 463] 
 
Every 12 Weeks 
Day 84xa+421 
[380+84x,463+84x] 
 
Week 240 
Day 1681 
Days ≥ 1640 
 a 
x=1,2…14  
 
End of Treatment visit for subjects who didn’t complete either the 48-week treatment period 
or the continuation period, and unscheduled visits will be mapped to the closest post baseline 
scheduled visits if the scheduled visits are missing. If there are more than one 
unscheduled/end of study visits mapped to the same window, the one closer to the target day 
will be used. If more than one visits have the equal distance to the target day then the later 
one will be used, if more than one visits on the same day, use the time or the sequence 
number to select the later record. For listings and shift tables, all data points will be included. 
7.4 
Software 
SAS® software version 9.4 or higher will be used to perform most or all statistical analyses. 


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8 STATISTICAL METHODS OF ANALYSIS 
8.1 
General Principles 
Due to the small sample size, all raw data obtained from the Case Report Forms (CRFs) as 
well as any derived data will be included in data listings or graphs.  Descriptive statistics will 
be used to summarize the data. For continuous variables, means, standard deviations, 
medians, minimums, and maximums will be provided. For categorical variables, the counts 
and percentages of subjects in corresponding categories will be provided.  All analysis will 
be based on full analysis set. Statistical tests will be 2-sided at the alpha =0.05 significance 
level. All p-values will be presented as nominal p-values. Summary statistics will be 
provided separately for subjects treated with UX003 under an emergency IND or not. 
Combined summaries will only be provided for uGAG and safety analyses, as prior data to 
initial treatment will be available for uGAG. 
8.2 
Subject Disposition 
The subjects in the full analysis set will be listed. Date of informed consent, the reason for 
treatment discontinuation and study discontinuation will be displayed. 
8.3 
Demographics and Other Baseline Characteristics 
Demographic parameters (e.g., age, sex, race and ethnicity) and other baseline characteristics 
(i.e., initial diagnosis, height and weight) assessed at baseline will be summarized and listed. 
8.4 
Medical History  
Medical history and MPS treatment history will be summarized.  
8.5 
Prior and Concomitant Medications 
The World Health Organization Drug (WHODRUG) dictionary will be used to classify prior 
and concomitant medications. Prior medication is defined as any medication taken prior to 
the first dose of the investigational product in this study. Concomitant medication is defined 
as any medication taken during the study between the day of the first dose of the 
investigational product and the day of the last dose of the investigational product in this 
study. Any medications started after the date of the last dose of the investigational products 
will not be considered concomitant medications. The number and proportion of subjects 
receiving each reported concomitant medication will be summarized by Anatomical 
Therapeutic Chemical (ATC) code and preferred term.  Multiple drug usage by a subject in 
the same category will be counted only once in the summary tables.  
8.6 
Dosing Summary 
The number of infusions and cumulative dose per subject administered and duration of 
exposure to UX003 on this study will be summarized. Treatment compliance calculated as 
received dose divided by expected dose over specified period will also be displayed. 


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8.7 
Efficacy Analyses 
8.7.1 
Primary Efficacy Endpoint 
The primary efficacy analysis will evaluate the mean percent change in uGAG excretion 
from baseline at week 48 using the generalized estimating equation (GEE) analysis method. 
The model will include baseline and visit (up to week 48) as a categorical variable. The 
covariance structure within subjects will be assumed to be exchangeable. For subject(s) 
previously treated with UX003 under an emergency IND, percent change from initial 
baseline will be calculated. 
In addition, the change and percentage change from baseline, fold increase in uGAG 
excretion and number of uGAG responders (defined as ≥ 50% decrease in uGAG excretion 
from baseline) will be presented by visit. 
8.7.2 
Secondary Efficacy Endpoints 
Change from baseline in anthropometric measurements will be summarized by visit, and for 
all subjects (including subject(s) previously treated with UX003 under an emergency IND), 
the last non-missing study assessment prior to the first dose in this study will be used as 
baseline.  
All anthropometric measurements with z scores and percentiles will be listed. Growth 
velocity will be presented for pre-treatment and post-treatment periods, and for the subject(s) 
previously treated with UX003 under an emergency IND the growth velocity will be 
calculated for pre initial UX003 treatment and post initial UX003 treatment. 
 
The change from baseline in liver and spleen size will be summarized by visit.   
8.7.3 
Other Efficacy Endpoints 
The change from baseline for the following parameters will be summarized by visit.  
• Serum GAG measures  
• Functional development: Bayley-III scores: cognitive, language and motor development, 
and social emotions and adaptive behavior  
• Cardiac ventricular mass 
• Pulmonary function: pulse oximetry  
• 
Biochemical markers of bone turnover 
• 
Motor functioning 
For serum GAG excretion, the percentage change form baseline will also be displayed 
The value of CGI will be summarized by visit 


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8.8 
Safety Analyses 
8.8.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs to 
a system organ class (SOC) and a preferred term.  
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose and was not present prior to the first dose in 
this study, or it was present at the first dose but increased in severity during this study.  
Subject incidence of TEAEs will be tabulated by SOC and preferred term. Serious adverse 
events (SAEs), treatment-related TEAEs and treatment-related SAEs will also be 
summarized.  
Detailed listings for all AEs, SAEs, treatment related TEAEs, treatment related SAEs, AEs 
leading to the discontinuation of study drug or discontinuation of study, and death will also 
be generated. The severity will be based on Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. If an AE cannot be graded based on CTCAE, the investigator 
will assign a severity based on 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 
= Death. 
Patterns of Infusion Associated Reactions (IARs) will be specifically evaluated throughout 
the study (see details in Appendix). IARs will be characterized into 4 distinct types based on 
timing of onset relative to the infusion and specific clinical manifestations: anaphylactoid, 
anaphylaxis, urticarial (with or without angioedema), and immune complex. Safety reporting 
of individual AEs will be recorded in parallel. Detailed listings of IARs will be provided. 
8.8.2 
Laboratory Parameters 
Clinical laboratory values (in SI units) and changes from baseline at each assessment time 
point will be summarized for clinical laboratory parameters in hematology, chemistry, 
urinalysis and thyroids panels. Abnormal values will be flagged. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e. outside of 
reference ranges) and/or clinically significant abnormalities after study drug administration 
will be presented by clinical laboratory measurement. 
8.8.3 
Other Safety Parameters 
Other data such as vital signs, physical examination findings, IgG antibodies to rhGUS and 
Complement C3, C4 and CH50 levels with IAR will be summarized as appropriate. 
 
8.8.4 
Antibodies  
Listing of ADA titer levels and neutralizing antibody will be provided by subject and visit. 


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9 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
There are no major changes to the analyses specified in the Protocol Amendment 1 (dated 
05 October 2015)  
 
 


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10 REFERENCES 
Kakkis, ED, Muenzer, J, Tiller, GE, Waber, L, Belmont, J, Passage, M, Izykowski, B, 
Phillips, J, Doroshow, R, Walot, I, Hoft, R, and Neufeld, EF. 2001. "Enzyme-
replacement therapy in mucopolysaccharidosis I." N Engl J Med 344 (3):182-8. 
Kuczmarski RJ, Ogden C, Grummer-Strawn L, et al. CDC Growth Charts: United States. 
Advance Data Report No. 314. NCHS. 2000. 
 
 
 


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11 APPENDICES 
Identification and Timing of IARs 
Hypersensitivity reactions including anaphylaxis, the most severe form, and less severe 
allergic reactions are identified risks from ERT, including potentially ERT with UX003.   
IMPORTANT:  All adverse events occurring from the onset of the study treatment infusion, 
and within four hours following the end of the infusion, regardless of the investigator’s 
assessment of whether or not the event was related to study drug administration will be 
considered an IAR. 
It is expected that the IARs of greatest clinical importance will fall into the category of 
hypersensitivity reactions. Managing severe infusion related reactions requires early signs 
and symptoms to be recognized and well trained clinicians in the management of acute 
events. 
Infusion associated reactions (IARs) may or may not occur in a recognized pattern of 
immune-mediated responses. The following table lists patterns of IARs that have been 
observed: 


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Patterns of IARs 
 
 
Anaphylactoid reactions are the most important severe type of IAR and are caused by 
synchronous complement activation due to IgG1 antibodies to the enzyme and most 
commonly begins during the first hour after the infusion rate is increased. In MPS 7 mice, 
these types of reactions were observed approximately 4-6 weeks after infusions were 
started. The slow rate of infusion for one hour followed by the increased rate of infusion is 
expected to reduce clinical complement-mediated hypersensitivity responses, based on 
studies with laronidase in MPS 1 (Kakkis et al. 2001). 
True anaphylaxis due to an IgE mediated response has not been observed as frequently, but 
still can occur at any time, though it would be expected to be early during the infusion. 
The premedication with an anti-histamine is primarily to minimize IgE mediated histamine 
release and to help mitigate a reaction if one were to occur.  
Urticarial skin reactions with or without angioedema (tongue and throat swelling) is a 
common type of reaction observed often after several months of therapy. This can be 
associated with substantial pruritis and discomfort. Increased premedication and slower 
infusion rates can help. With time, these type of reactions will tend to subside over a period 


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of weeks to months with continued therapy. Airway obstruction is potentially serious in 
patients with MPS who have enlarged tongues, tonsils and adenoids and floppy tracheal 
cartilage, so the appearance of angioedema requires particular care and caution in 
management.   
Immune complex disease can be observed with ERT but is more difficult to discern and 
diagnose primarily because of the delay in onset and variable symptoms. Abdominal pain, 
joint pain/swelling, proteinuria/hematuria, and skin rashes within the 1-5 days after an 
infusion may indicate that the antigen-antibody ratio is close to 1:1 leading to polymerization 
of antigen- antibody complexes, which may precipitate and locally activate complement and 
result in tissue injury.  
IARs may present as described above, or may present with variable signs and symptoms 
alone or in combination. This guide is intended to help investigators evaluate and treat 
subjects who experience an IAR with UX003 ERT.