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
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the long-term safety of UX003 in subjects with MPS 7.

Detailed description:
Participants with MPS 7 who were UX003 treatment-naïve or previously enrolled and treated in a prior clinical study of UX003 (e.g. UX003-CL301 \[NCT02230566\], investigator sponsored trials, expanded access/compassionate use) can enroll into this treatment and extension study provided all eligibility criteria is met for a given participant.

Arms:
arm 1: 4 mg/kg UX003 every other week (QOW)

Interventions: intervention 1: UX003
Intervention descriptions: intervention 1: solution for intravenous (IV) infusion

Protocol document:
Prot_000.pdf: 
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Protocol Number:  UX003-CL202  
Amendment 3:  28 JUL 2016  
 
 
 
Confidential 
Page 2 
 
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 procedures /Ethics Committee, to 
obtain written informed consent from potential subjects, or as required by law.   


 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX003-CL202 Amendment 1 
18 December 2015  
Original Protocol UX003-CL202 (dated 28 October 2014) has been modified by 
Amendment 1 to remove or clarify certain procedures and update information. 
The introductory nonclinical and clinical background information contained within Section 5 
has also been updated for completeness; additional minor edits and typographical corrections 
have also been made. The major protocol changes which impact study design and conduct 
are summarized below:  
1. Administrative and Contact Information: The protocol has been updated to 
provide the EudraCT number (2015-001875-32) for the study. The Medical Monitor 
has been changed to Dr. Christine Haller; contact information for the medical monitor 
and drug safety has been updated (Section 8.5.8). 
2. Study Population:  Inclusion criterion #7 (Section 7.3.1) has been modified to clarify 
UX003 treatment naïve subjects the elevated uGAG excretion must be a minimum of 
2-fold over mean normal levels for age (at baseline). Inclusion criteria # 7 and 8 have 
been combined; UX003 naïve participants must be at least 5 years of age at 
enrollment.   
3. Study Visit Schedule:  The Early Termination Visit is now referred to as the 
Termination Visit. Visit qualifiers have been modified such that if a subject 
withdraws from the study, or if the study is terminated prior to Week 144, the 
termination visit should be completed within 30 days of the last dose of study drug.  
Assessments performed within 30 days of the termination visit will not be repeated 
unless clinically indicated. 
Rationale: The modification clarifies procedures in case the study is terminated early 
by the Sponsor. The 30 day window for assessments eliminates unnecessary testing 
and procedures for subjects. 
4. Study Procedures and Assessments: Several updates have been made to clarify or 
remove procedures in Section 7.5 and the associated Schedule of Events (Table 2.1). 
Language regarding the assessments to be performed throughout this extension study   
has been broadened for applicability to subjects who may enroll from additional 
feeder trials with UX003. In general, efficacy assessments not performed during the 
primary (or feeder) trial will not be required for this long-term treatment and 
extension study; safety assessments will be conducted on all subjects as indicated in 
the protocol. Modifications to specific study procedures and assessments specified in 
the protocol text are summarized below. 


 
Proprietary and Confidential 
Page 3 
Urinary and serum GAG: Serum GAG will no longer be assessed in the study. 
References to the specific methodologies for measurement of GAG in urine and 
serum have been removed from the protocol (Sections 7.5.3 and 7.5.4.2). 
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 
primary measure of ERT efficacy in MPS disorders and will continue to be followed 
during this long-term extension study. 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.  
Weight for Drug Preparation: Weight for drug preparation may now be obtained up 
to 15 days prior to the indicated visit. Weight for drug preparation was removed from 
the Termination Visit procedures (Section 7.5.2.2 and Table 2.1).  
Rationale:  Obtaining weight up to 15 days prior to the indicated visit will provide a 
measure of convenience for study personnel and subjects by enabling the amount of 
study drug to be calculated and adjusted in advance of administration. Weight for 
drug preparation is not required at Termination as no study drug will be administered 
at the visit. 
Biomarkers of Inflammation in Serum: The frequency of serum biomarker 
assessments has been reduced from 12-week intervals to 24-week intervals 
throughout the study. A qualifier has been inserted to perform if indicated based on 
prior studies (Section 7.5.4.2 and Table 2.1). 
Rationale: The utility of assessing of biomarkers of inflammation in understanding 
the action of UX003 in MPS 7 has not been established. An exploratory (pilot) study 
is ongoing to assess biomarkers of inflammation in MPS 7 patients. The 24-week 
interval reduces the frequency of additional blood draws for study participants.   
Physician Clinical Global Impression:  The P-CGI has been removed as an 
assessment in the study. 
Rationale:  Baseline (pre-treatment) P-CGI assessments would have been conducted 
more than 1 year prior to UX003-CL202 enrollment for the majority of study 
subjects; continuing assessments are of limited utility due to likely recall 
inaccuracies. The open-label design of the study also limits objectivity for this 
assessment.   
Hepatosplenomegaly: The frequency of qualitative assessments of the liver and 
spleen has been reduced from 12-week intervals to 48-week intervals except for naïve 
patients (Section 7.5.4.14); the assessment is now specified separately from physical 
examinations in Table 2.1. 


 
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Page 4 
Rationale: The frequency of hepatosplenomegaly assessments has been modified to 
align with the frequency of liver and spleen size assessment (hepatosplenomegaly) in 
other Ultragenyx-sponsored UX003 clinical studies (i.e. 48 weeks). 
5. Reporting and Follow-up of Adverse Drug Events: The following modifications to 
Section 8.5 provide additional guidance and alignment with AE reporting 
requirements, primarily: 
• Additional text was added to clarify that hospitalizations planned prior to 
study enrollment are not considered SAEs (Section 8.5.1).  
• The categories for attributions of AE relatedness to study drug have been 
simplified (Section 8.5.3).  
• A new section (Section 8.5.6) 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), IRBs/ECs, and Investigators as 
per local laws and regulation 
 


Protocol Number:  UX003-CL202  
Amendment 2:  04 MAR 2016  
 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX003-CL202 Amendment 2 
04 March 2016  
Protocol UX003-CL202 Amendment 1 (dated 18 October 2015) has been modified by 
Amendment 2 to remove or clarify certain procedures and update information. The major 
protocol changes that impact study design and conduct are summarized below:  
1. Study Design and Methodology: 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 144 weeks, the end of trial is defined as the Week 144 visit of the 
last subject. In the event the study is terminated by the Sponsor prior to Week 144, 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 in response to a request by 
INFARMED, the Portuguese Competent Authority and to align with current guidelines. 
2. Study Population: Inclusion criterion #2 (Section 7.3.1) has been updated to clarify that 
written informed consent by a legally authorized representative may be provided for 
subjects, including adult subjects, who are intellectually impaired. 
Inclusion criterion #4 has been updated to specify that sexually active subjects must be 
willing to use a highly effective method of contraception. In addition, the list of examples 
of highly effective methods of contraception (Section 7.5.2.6) has been updated to 
remove barrier methods and include bilateral tubal occlusion. 
Inclusion criterion #5 has been updated to remove tubal ligation as a reason that female 
subjects would be considered not of childbearing potential and to clarify the definition of 
those considered not of childbearing potential:  Females considered not of childbearing 
potential include those who have not experienced menarche, are postmenopausal (defined 
as having no menses for at least 12 months) or are permanently sterile due to having 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Rationale: Changes to inclusion criteria were requested by INFARMED, the Portuguese 
Competent Authority. As many patients with MPS 7 have intellectual impairment, the 
change to inclusion criterion #2 will clarify that a legally authorized representative may 
consent on their behalf. Changes to contraception and pregnancy testing language were 
made to align with the Heads of Medicines Agencies Clinical Trial Facilitation Group 
(CTFG) Recommendations related to contraception and pregnancy testing in clinical 
trials. 
3. Pregnancy During Study. Section 7.5.2.6 has been updated to indicate that female 
subjects who become pregnant during the study will be withdrawn from study drug. At 


Protocol Number:  UX003-CL202  
Amendment 2:  04 MAR 2016  
 
 
 
Proprietary and Confidential 
Page 3 
the conclusion of the pregnancy, a decision will be made if the female subject may 
resume study drug based on study treatment risk-benefit evaluation and willingness of the 
subject to comply with the contraceptive requirements. In the event of a pregnancy in the 
partner of a male subject, the male subject may continue with study drug and, as 
previously stated in the protocol, the Investigator must make every effort to follow the 
pregnancy of either subject or partner through resolution of the pregnancy (delivery or 
termination) and report the resolution to Ultragenyx or its designee. 
Rationale: There are no adequate and well-controlled studies in pregnant women using 
UX003 and the effect of study drug on pregnancy and the fetus is unknown. Therefore, 
female subjects who become pregnant will be withdrawn from study drug but will 
continue to be followed on study. Given that MPS 7 is a chronically debilitating and life-
threatening disease, the protocol allows for the potential resumption of therapy at the 
conclusion of pregnancy after a risk-benefit assessment is performed. Male subjects 
whose partners become pregnant will not be removed from study drug because seminal 
transmission of study drug to the fetus is considered highly unlikely. 
4. Record Retention: Section 8.4.3 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. 
 
 


Protocol Number:  UX003-CL202  
Amendment 3:  28 JUL 2016  
 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX003-CL202 Amendment 3 
28 July 2016 
  
Protocol UX003-CL202 Amendment 2 (dated 04 March 2016) has been modified by 
Amendment 3 to clarify certain procedures and update information. The protocol changes are 
summarized below:  
1. Title Page. The title page has been updated to list Paul Harmatz, MD, as the 
Coordinating Investigator. 
Rationale: Ultragenyx nominated Dr. Paul Harmatz, the Principal Investigator at the 
UCSF Benioff Children’s Hospital in Oakland, California, as the Coordinating 
Investigator for this multicenter clinical study. 
2. Pregnancy Testing and Contraception. The description of highly effective methods of 
contraception (Section 7.5.2.6) has been updated to clarify that hormonal contraceptives 
should be associated with the inhibition of ovulation.  
Rationale: Changes to inclusion criteria were requested by INFARMED, the Portuguese 
Competent Authority. 
3. Criteria for Evaluation: Measurement of Anti-Drug Antibody (ADA) Types. ADA 
testing, as one of the safety assessments (primary objective [Section 7.5.2]), has been 
clarified to indicate that clinically significant changes from baseline in levels of all anti-
drug antibodies, not only the immunoglobulin G (IgG) isotype, will be evaluated.  
Rationale: Text was updated to provide clarification that all anti-drug antibodies, not 
only IgG antibodies will be assessed, because it was deemed unclear in Amendment 2. 
This is not a change to the ADA testing. 
4. Serum Biomarkers of Inflammation. Blood for analysis of serum biomarkers of 
inflammation (Section 7.5.4.2) will not be collected after Week 48. 
Rationale: Preliminary results from clinical study UX003-CL201 suggest that analysis of 
serum biomarkers of inflammation did not demonstrate meaningful differences upon 
treatment with UX003; therefore, continuation of this blood collection into the extension 
study was deemed unnecessary. 
5. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2). This test of motor 
proficiency (Section 7.5.4.4) will not be conducted after Week 48.  
Rationale: Continuing to perform the BOT-2 assessments in this open-label extension is 
unlikely to yield informative data. Removal of this test will reduce the burden to subjects 
and investigational sites participating in the study. 


Protocol Number:  UX003-CL202  
Amendment 3:  28 JUL 2016  
 
 
 
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6. Childhood Health Assessment Questionnaire (CHAQ). The person responsible for 
completing the CHAQ has been clarified as the subject’s parent or caregiver 
(Section 7.5.4.12). 
Rationale: Text was updated to clarify the person responsible for completing the CHAQ, 
because the questionnaire was designed to be completed by the subject’s parent or 
caregiver rather than the subject. 
7. Health Assessment Questionnaire (HAQ). The mode of administration of the HAQ and 
the persons permitted to complete the HAQ have been clarified (Section 7.5.4.12).  
Rationale: Text was updated to clarify that the HAQ may be administered to the subject 
via interview if the subject is deemed unable to complete a paper questionnaire. 
Also dependent on the ability of the subject, a parent or caregiver may complete the 
HAQ. 
8. Record Retention. Section 8.4.3 Record Retention was updated to clarify the 
responsibilities of the Investigator, Institution, and Ultragenyx with regard to record 
retention.  
Rationale: Text was updated to clarify that it is not the explicit responsibility of 
Ultragenyx to assist with records retention. 
 
 


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2 SYNOPSIS 
TITLE OF STUDY:  
A Long-Term Open-Label Treatment and Extension Study of UX003 rhGUS Enzyme Replacement 
Therapy in Subjects with MPS 7 
PROTOCOL NUMBER: 
UX003-CL202 
STUDY SITES: 
Multi-center; multi-national; approximately 12 sites globally 
PHASE OF DEVELOPMENT: 
Phase 3 
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 the 
glycosaminoglycans (GAGs): dermatan sulfate (DS), chondroitin-6-sulfate (CS) and heparan sulfate 
(HS). The GUS deficiency results in lysosomal accumulation of GAGs in multiple tissues and organs 
throughout the body and numerous clinical signs and symptoms as a result of tissue damage and organ 
dysfunction. There are currently no approved treatments for MPS 7.   
UX003 (recombinant human beta glucuronidase, rhGUS) is intended as a long-term enzyme 
replacement therapy (ERT) for the treatment of MPS 7 via intravenous (IV) administration. 
Ultragenyx is conducting this treatment and extension study to assess the long-term safety and efficacy 
of UX003 treatment in subjects with MPS 7. Subjects with MPS 7 who are UX003 treatment-naïve or 
have been previously enrolled and treated with UX003 in other clinical studies or programs are 
eligible for enrollment. 
The study will continue for up to 144 weeks or until one of the following occurs: the subject 
withdraws consent and discontinues from the study, the subject is discontinued from the study at the 
discretion of the Investigator or Ultragenyx, or the study is terminated.   
OBJECTIVES:  
The primary objective of the study is to evaluate: 
• Long-term safety of UX003 in subjects with MPS 7. 
The secondary objective of the study is to evaluate: 
• Long-term efficacy of UX003 in reducing urinary GAG (uGAG) substrate in subjects with 
MPS 7. 
Other objectives of the study are to evaluate: 
• Measures of lysosomal storage including hepatosplenomegaly 
• Measures of other clinical and functional outcomes, including pulmonary function, walking 
distance, shoulder flexion, fine motor function, gross motor function, climbing stairs, visual 
acuity, and cardiac size and function, and a composite Multi-Domain Responder Index (MDRI), 


Protocol Number:  UX003-CL202 
Amendment 3:  28 JUL 2016  
 
 
Confidential 
Page 6 
as applicable per subject status.  
• Growth, as defined by impact on general health and assessed by changes in height (or length) and 
weight growth velocity. 
• Subject-reported disability and quality of life, and fatigue, as indicated. 
• Subject or parent/caregiver global assessment of change and impact on activities of daily living, 
as indicated. 
• If an individualized clinical response (ICR) endpoint was defined for a subject from a previous 
UX003 study, the ICR may continue to be followed. 
STUDY DESIGN AND METHODOLOGY:  
This is a multi-center, multinational, open-label treatment and extension study in subjects with MPS 7.  
The study will assess long-term safety and efficacy of UX003 treatment and will continue for up to 
144 weeks or until one of the following occurs: the subject withdraws consent and discontinues from 
the study, the subject is discontinued from the study at the discretion of the Investigator or Ultragenyx, 
or the study is terminated. 
Subjects with MPS 7 who are UX003 treatment-naïve or previously enrolled and treated in a prior 
clinical study of UX003 may have the option to enroll into this treatment and extension study provided 
all eligibility criteria have been met for a given subject.  Subjects with MPS 7 who were enrolled in 
either an Ultragenyx sponsored study (e.g., UX003-CL301) or non-Ultragenyx sponsored clinical 
studies (e.g., Investigator sponsored trials (ISTs), expanded access/compassionate use) may be eligible 
for enrollment. Those subjects enrolling from a previous UX003 study should have a reasonable 
benefit-risk assessment from their primary study as determined by the Investigator, in order to 
continue with long-term therapy in this extension study. To be enrolled, subjects need to meet all 
inclusion/exclusion criteria. 
All subjects will receive 4 mg/kg UX003 every other week (QOW) unless data from prior studies 
define a different dose either for that subject or the use of UX003 in general.  
As has been observed with other MPS ERTs, some subjects may experience infusion-associated 
reactions (IARs) with the administration of UX003. Thus, prophylactic antihistamine will be 
administered prior to each study drug infusion. Antipyretic pretreatment may also be given at the 
Investigator’s discretion. To minimize the potential for IARs, infusions will initially be administered 
on a slower rate schedule followed by an increase in rate.  Infusion rate may be slowed to manage or 
reduce IARs. 
Safety will be monitored throughout the study based on physical examinations, clinical laboratory 
analyses, and reporting of adverse events (AEs) and serious adverse events (SAEs).    
Evaluations of efficacy, including uGAG levels, 6-minute walk test (6MWT), pulmonary function 
testing, shoulder flexion, visual acuity, and fine and gross motor function will be performed according 
to the Schedule of Events (Table 2.1 and Section 7.5) if age appropriate and subject is able to perform. 
Additional assessments will be performed, as indicated, to assess serum biomarkers of inflammation, 
3-minute stair climb test (3MSCT), hepatosplenomegaly, growth velocity, cardiac size and function, 
ICR endpoint (if appropriate), patient-reported outcomes, and subject/parent/caregiver global 
impression of change. The termination visit should be completed by all subjects who do not complete 
the Week 144 end of study visit. The termination 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. If the termination visit occurs after Week 48, blood for serum biomarkers of 


Protocol Number:  UX003-CL202 
Amendment 3:  28 JUL 2016  
 
 
Confidential 
Page 7 
inflammation will not be collected and BOT-2 assessments will not be conducted. 
NUMBER OF SUBJECTS PLANNED:  
Approximately 20 subjects with a confirmed diagnosis of MPS 7, who are UX003 treatment-naïve or 
were previously treated with UX003 in either an Ultragenyx-sponsored study or a non-Ultragenyx 
sponsored study (e.g., IST). 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION:  
Individuals eligible to participate in this study must meet all of the following inclusion criteria: 
1. Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay 
or genetic testing. 
2. Willing and able to provide written, signed informed consent or, in the case of subjects under 
the age of 18 (or 16 years, depending on the region) or subjects who are intellectually 
impaired, provide written assent (if required) and written informed consent by a legally 
authorized representative after the nature of the study has been explained, and prior to any 
research-related procedures. 
3. Willing to comply with all study procedures. 
4. Sexually active subjects must be willing to use a highly-effective method of contraception 
while participating in the study and for 30 days following the last dose. 
5. Females of childbearing potential must have a negative pregnancy test at Baseline and be 
willing to have additional pregnancy tests during the study. Females considered not of 
childbearing potential include those who have not experienced menarche, are postmenopausal 
(defined as having no menses for at least 12 months without an alternative medical cause) or 
are permanently sterile due to having hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. 
6. For UX003 treatment-naïve subjects only, apparent clinical signs of lysosomal storage disease 
as judged by the Investigator, including at least one of the following: enlarged liver and 
spleen, joint limitations, airway obstruction or pulmonary problems, limitation of mobility 
while still ambulatory. 
7. For UX003 treatment-naïve subjects only, at least 5 years old at time of enrollment and with 
elevated uGAG excretion at a minimum of 2-fold over the mean normal levels for age (at 
baseline). 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. If enrolled in a prior UX003 clinical study, the subject experienced safety-related event(s) in 
the prior UX003 clinical study that, in the opinion of the Investigator and sponsor, precludes 
resuming UX003 treatment. 
2. Undergone a successful bone marrow or stem cell transplant or has any degree of detectable 
chimaerism with donor cells. 
3. Presence or history of any hypersensitivity to rhGUS or its excipients that, in the judgment of 
the Investigator, places the subject at increased risk for adverse effects. 
4. Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at any 


Protocol Number:  UX003-CL202 
Amendment 3:  28 JUL 2016  
 
 
Confidential 
Page 8 
time during the study. 
5. Other than the use of UX003, use of any investigational product (drug or device or 
combination) within 30 days prior to Baseline, or requirement for any investigational agent 
prior to completion of all scheduled study assessments. 
6. Presence of a condition of such severity and acuity that, in the opinion of the Investigator, 
warrants immediate surgical intervention or other treatment or may not allow safe study 
participation. 
7. Concurrent disease or condition, or laboratory abnormality 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 introduce additional safety concerns. 
INVESTIGATIONAL PRODUCT(S), DOSE, AND MODE OF ADMINISTRATION:  
UX003 is a sterile liquid buffered saline formulation of rhGUS that contains enzyme at a concentration 
of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL 
glass vial. UX003 will be administered 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.  
REFERENCE THERAPY(IES), 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 up to 144 weeks or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued from the 
study at the discretion of the Investigator or Ultragenyx, or the study is terminated. 
CRITERIA FOR EVALUATION: 
Primary Objective: 
Safety will be evaluated in all subjects by the incidence and frequency of AEs and SAEs, including 
clinically significant changes from baseline to scheduled time points in: 
• 
Physical examination findings 
• 
Vital signs and weight 
• 
Echocardiogram (ECHO) findings 
• 
Clinical laboratory evaluations 
• 
Concomitant medications 
• 
Antibodies to rhGUS 
• 
Complement C3, C4 and CH50 levels (as indicated) 
Adverse Physiology Related Group Safety Reporting 
Adverse Physiology Related Group (APRG) reporting is a novel method synthesizing safety symptoms 
into multi-domain physiology related groups to capture IAR information. APRG reporting will be used 
to detect adverse physiologies that might be expressed variably within and between subjects in a study 


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based on known patterns of adverse physiologies, such as anaphylactoid reactions. This reporting is 
related to IARs only and standard AE reporting will still be conducted in addition to the APRG.  
Management of Infusion Associated Reactions (IARs) 
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 IARs. 
Secondary Objective: 
• 
Urinary GAG excretion:  First morning void urine will be evaluated for uGAG concentration 
and normalized to urinary creatinine concentration. 
Other Objectives: 
For the purposes of this study, efficacy assessments listed below which were not performed during the 
primary or feeder study will generally not be required for this long-term treatment and extension 
study; safety measures will be assessed in all subjects. UX003-naïve subjects will be required to 
complete all of the following assessments (as appropriate). 
• 
Biomarkers of inflammation in serum: Blood samples will be collected through Week 48 to 
evaluate levels of biomarkers of inflammation and response to treatment. 
• 
Six Minute Walk Test (6MWT):  The total distance walked (meters) in a six-minute period 
will be measured.  The percent of predicted normal distance walked based on published 
normative data will also be determined. 
• 
Bruininks-Oseretsky Test of Motor Proficiency (BOT-2):  This test of motor proficiency will 
be administered through Week 48 to evaluate treatment-related changes in four domains 
assessing both fine and gross motor function: fine motor precision, manual dexterity, balance, 
running speed and agility.  The test may be modified and tests omitted to accommodate the 
needs of the subject. 
• 
Three Minute Stair Climb Test (3MSCT):  The number of stairs climbed within a three-minute 
period will be assessed. 
• 
Pulmonary function testing (spirometry): Spirometry will be administered to subjects who do 
not require invasive ventilatory support or have a tracheostomy.  Pulmonary function variables 
include forced vital capacity (FVC) and maximum voluntary ventilation (MVV). 
• 
Shoulder flexion maximum range of motion:  Goniometry will be used to measure (in degrees) 
the maximum passive shoulder range of motion in both flexion and extension and compared to 
known normal standards for age. 
• 
Growth (anthropometric): Growth will be assessed by anthropometric measurements including 
standing height (or recumbent length or sitting height if applicable) and weight. Growth 
velocity will be calculated and compared with pre-treatment growth velocity when available. 
• 
Visual acuity will be measured using a standard eye chart and recorded for each eye 
independently. 
• 
Multi-domain responder index (MDRI): consisting of the six-minute walk test (6MWT), the 
Bruininks-Oseretsky Test of Motor Proficiency (BOT-2; fine motor and gross motor function), 


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forced vital capacity (FVC), shoulder flexion, and visual acuity. 
• 
Individualized Clinical Response (ICR): Will only be assessed for subjects previously 
enrolling from the Ultragenyx-sponsored MPS 7 Phase 3 clinical study UX003-CL301 where 
an outcome of interest was previously selected from the possible clinical outcome measures, 
the same ICR identified in the primary (or feeder) study may continue to be followed in this 
study. 
• 
Scoring of Impactful Clinical Problems: The three most impactful clinical problems as 
reported by the subject/parent/caregiver during the Clinical Problem Evaluation will be 
scored on a Likert scale.  For UX003 treatment-naïve subjects, the initial Clinical Problem 
Evaluation will occur at the Baseline visit. For subjects enrolling from the Ultragenyx-
sponsored MPS 7 Phase 3 clinical study UX003-CL301, the Clinical Problems identified 
during the UX003-CL301 Randomization visit will continue to be scored throughout this 
study. 
• 
Subject-reported disability, quality of life, and fatigue:  The MPS Health Assessment 
Questionnaire, Childhood Health Assessment Questionnaire (CHAQ), or Health Assessment 
Questionnaire (HAQ) will be administered to evaluate treatment-related changes in self-care 
and mobility activities of daily living. The age-appropriate Pediatric Quality of Life 
Multidimensional Fatigue Scale (Peds QL-Multidimensional Fatigue Scale) will be 
administered to evaluate treatment-related changes in fatigue. 
• 
Subject/Parent/Caregiver Clinical Global Impression (CGI) scale:  Subjects or 
parents/caregivers will provide a global assessment of change using a CGI scale. In addition, 
subjects or parents/caregivers will provide narratives of their perception of how treatment has 
impacted the subject’s ability to complete activities of daily living.   
• 
Hepatosplenomegaly:  Liver and spleen measurements will be assessed by physical exam.  
• 
Cardiac ventricular mass/function:  Ventricular mass will be assessed by ECHO and scored as 
a z-score relative to normal ventricular mass. Evaluation of valvular function and cardiac 
function will be made primarily for safety purposes. 
STATISTICAL METHODS:  
The Full Analysis Set will consist of all subjects who were received at least 1 dose of investigational 
product. Both safety and efficacy analysis will be based on Full Analysis Set. Continuous variables 
will be summarized by number of subjects and mean, standard deviation (SD), median, minimum, and 
maximum values. Categorical variables will be summarized by number and percentage of subjects. 
Safety Analysis  
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), severity, and relationship to UX003 treatment. 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 will be presented for each clinical laboratory 
measurement. 


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uGAG and Other Efficacy Analyses  
Urinary GAG percent reduction from pre-treatment baseline and changes from pre-treatment baseline 
for other clinical efficacy endpoints will be summarized with descriptive statistics. The percentage 
change from pre-treatment baseline in uGAG will be tested using the GEE method. The GEE model 
will include baseline and time as categorical variables.  
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan (SAP). 
 


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Table 2.1: 
Schedule of Events 
 
 
Treatment / Assessment Period b,c 
Baseline a,b 
First 48 Weeks of Treatment 
Treatment Weeks 50 - 144 
Termination 
Visit z  
0 
Every 2 
Weeks 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Every 2 
Weeks 
Every 12 
Weeks d 
Every 24 
Weeks e 
Every 48 
Weeks f 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history g 
X 
 
 
 
 
 
 
 
 
 
 
ICR identification (only for 
UX003-CL301 subjects) h  
X 
 
 
 
 
 
 
 
 
 
 
Weight for drug preparation i 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
Clinical Problem Evaluation j 
X 
 
 
X 
 
X 
 
 
X 
 
X 
UX003 Treatment 
X 
X 
 
 
 
 
X 
 
 
 
 
Safety Assessments 
Physical examination k 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
Vital signs l 
X 
X 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory tests m 
X 
 
 
 
 
X 
 
 
 
X 
X 
Urine pregnancy test n 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
Antibodies to rhGUS o 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Complement C3, C4, CH50 
(for subjects with IARs) p 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
 
 
 
X 
 
 
 
X 
Adverse events q 
X 
X 
 
 
 
 
X 
 
 
 
X 
Efficacy Assessments 
Urinary GAG r 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 


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Treatment / Assessment Period b,c 
Baseline a,b 
First 48 Weeks of Treatment 
Treatment Weeks 50 - 144 
Termination 
Visit z  
0 
Every 2 
Weeks 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Every 2 
Weeks 
Every 12 
Weeks d 
Every 24 
Weeks e 
Every 48 
Weeks f 
 
Serum biomarkers of 
inflammation 
X 
 
 
X 
 
X 
 
 
 
 
X 
6MWT, 3MSCT s 
X 
 
 
X 
 
X 
 
 
X 
 
X 
BOT-2 s 
X 
 
 
X 
 
X 
 
 
 
 
X 
Spirometry t 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Goniometry u 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anthropometrics v 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
Visual acuity (eye chart) 
X 
 
 
X 
 
X 
 
 
X 
 
X 
MPS HAQ, CHAQ/HAQ, Peds 
QL w 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Subject/Parent/Caregiver CGIx 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Liver and spleen assessment y 
X 
 
 
 
 
X 
 
 
 
X 
X 
Echocardiogram  
X 
 
 
 
 
X 
 
 
 
X 
X 
Abbreviations:  CGI = clinical global impression, ICR = Individual Clinical Response, IAR = infusion-associated reaction, GAG = glycosaminoglycan, 
6MWT = Six-Minute Walk Test, BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency (Second Edition), 3MSCT = Three-Minute Stair Climb Test, 
CHAQ = Childhood Health Assessment Questionnaire, MPS HAQ = Mucopolysaccharidosis Health Assessment Questionnaire, Peds QL = Pediatric Quality 
of Life Inventory™, rhGUS = recombinant human beta-glucuronidase, GAG = glycosaminoglycans 
 
a. 
For subjects enrolling from UX003-CL301, the Baseline Visit will be conducted in conjunction with the UX003-CL301 Week 48 study visit to avoid 
treatment disruption. Subjects enrolling from an Ultragenyx-sponsored clinical study: efficacy, ECHO and clinical laboratory assessments performed 
during the final or End of Treatment visit from the primary study may be used as baseline assessments if performed within 30 days of study baseline 
visit as indicated in Section 7.5. Assessment of antibodies to rhGUS (e.g.,Week 46 rhGUS assessment in UX003-CL301) may be used as baseline 
assessments if performed within 30 days of study Baseline Visit. Any listed assessments not performed during the primary study final visit must be 


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performed before the first study drug infusion. Unless otherwise specified, Baseline assessments must be completed within 30 days prior to the first dose 
of study drug.  For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored clinical study, initial baseline safety and 
efficacy assessments as indicated in Section 7.5 will be performed within 30 days of the study baseline visit as indicated in Section 7.5.  Refer to Study 
Reference Manual for additional details. 
b. For all subjects, assessments scheduled on the same day as treatment must be completed prior to the infusion. 
c. 
Visit windows are ± 3 days and for major assessment visits (Weeks 12, 24, 36, 48 and every 24 weeks thereafter), the window is ± 7 days.   
d. Actual study weeks for every-12-week visits = Weeks 60, 72, 84, 96, 108, 120, 132, 144. 
e. 
Actual study weeks for every-24-week visits = Weeks 72, 96, 120, 144. 
f. 
Actual study weeks for every-48-week visits = Weeks 96, 144. 
g. Medical history will be collected for all subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored study (e.g., Investigator 
sponsored trials (ISTs), expanded access/compassionate use).  For subjects enrolled in UX003-CL301 or other Ultragenyx sponsored study, their 
previously reported medical history will carry over to this study. 
h. The ICR will only be identified for subjects enrolling from the MPS 7 Phase 3 Ultragenyx sponsored study UX003-CL301.   
i. 
Weight for drug preparation may be obtained up to 15 days prior to indicated visit (e.g. Weeks 10, 22, 34, and 46 visits). 
j. 
For UX003 treatment-naïve subjects the three most impactful clinical problems reported by the subject/parent/caregiver will be identified and scored at 
the Baseline visit. These clinical problems will continue to be scored throughout this study.  For subjects enrolling from the MPS 7 Phase 3 Ultragenyx 
sponsored study UX003-CL301, the three most impactful clinical problems reported by the subject/parent/caregiver during the UX003-CL301 
randomization visit will continue to be scored throughout this study. 
k. Physical examinations are to include neurologic examination and evaluation of the presence or absence of corneal clouding.  If subject complains of leg 
weakness or fatigue, evaluate for signs of cord compression (e.g., leg reflexes and motor strength). 
l. 
On infusion days, vital signs will be measured at a minimum of: immediately (<30 minutes) before the infusion, at least every 30 minutes for the first 
hour of infusion, at least every hour for the remainder of the infusion and immediately (<30 minutes) after the infusion.  Additional measurements 
should be obtained as appropriate. 
m. 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.  Laboratory samples for safety performed within 30 days prior to Baseline may be used for the study baseline. 
n. For women of childbearing potential only.  A serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test result. 
o. Testing for any antibodies directed against rhGUS. Antibody sample must be collected before infusion. 
p. If a drug-related IAR has occurred, C3, C4 and CH50 samples should be drawn prior to and immediately after the end of infusion at the subsequent 
infusion. 
q. For subjects enrolling from an Ultragenyx-sponsored clinical trial, all AEs will be recorded from the time the subject signs the informed consent and 
completes the End of Treatment visit in the primary study until 30 days after the last dose of study drug.  For subjects who are treatment naïve or who 
are enrolling from a non-Ultragenyx-sponsored clinical trial, all AEs will be recorded from the time the subject signs the informed consent until 30 days 
after the last dose of study drug.   
r. 
Urine samples must be collected from first morning voids.  


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s. 
The 6MWT, 3MSCT and BOT-2 assessments may be conducted over a span of two days with each test performed once. The preferred order is to 
perform the 6MWT and 3MSCT on separate days. If performed on the same day, the 6MWT should be done before the 3MSCT. The subject’s resting 
heart rate must return to baseline between assessments.  
t. 
Pulmonary function testing may be omitted for subjects with tracheostomies. If performed on the same day, pulmonary function testing should be done 
before the 6MWT and 3MSCT. The subject’s resting heart rate must return to baseline between assessments.    
u. The highest value of three shoulder flexion and extension range of motion measurements for each side will be reported. 
v. Anthropometric measurements include standing height and weight. If standing height cannot be obtained, recumbent length or sitting height will be 
determined.  
w. The MPS HAQ or HAQ/CHAQ should be performed for UX003 treatment-naïve subjects and subjects enrolling from the MPS 7 Phase 3 Ultragenyx 
sponsored study UX003-CL301. The MPS HAQ will be administered to all age groups. The CHAQ should be performed for pediatric subjects only 
(<14 years old). The HAQ should be performed for subjects ≥14 years old.  Subjects will consistently complete the same questionnaire (HAQ or 
CHAQ) administered at baseline for the duration of the study regardless of whether their age changes from 13 to 14 during the study.  The age-
appropriate version of the PedsQL multidimensional fatigue module will be administered throughout the study. For subjects enrolling from previous 
clinical trial with UX003, these subject-reported outcome measures will only be administered if they were previously performed in their primary (or 
feeder) study. 
x. As part of the subject/parent/caregiver clinical global impression assessment, subjects/parents/caregivers will be asked to provide narratives of how 
treatment has impacted the subject’s ability to complete activities of daily living. 
y. Liver and spleen size will be assessed qualitatively by physical examination.  
z. 
The termination visit should be completed by all subjects who do not complete the Week 144 end of study visit. The termination 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. 
AEs ongoing at 30 days following the last dose of study drug should have a comment in the source document by the Investigator that the event has 
recovered, recovered with sequelae, or stabilized. If the termination visit occurs after Week 48, blood for serum biomarkers of inflammation will not be 
collected and BOT-2 assessments will not be conducted.


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3 TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................16 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................21 
5 INTRODUCTION .............................................................................................................24 
5.1 Overview of MPS 7...................................................................................................24 
5.2 Enzyme Replacement Therapy for MPS Disorders ..................................................26 
5.3 Brief Overview of UX003 Development ..................................................................27 
5.3.1 
Brief Description of UX003 ........................................................................27 
5.3.1.1 
UX003 Mechanism of Action in MPS 7 ......................................28 
5.3.2 
Nonclinical Studies ......................................................................................28 
5.3.3 
Clinical Studies ............................................................................................29 
5.4 Summary of Overall Risks and Potential Benefits ....................................................30 
5.5 Study Rationale .........................................................................................................31 
6 STUDY OBJECTIVES ......................................................................................................32 
7 INVESTIGATIONAL PLAN ............................................................................................33 
7.1 Overall Study Design and Plan .................................................................................33 
7.2 Discussion of Study Design ......................................................................................34 
7.2.1 
Adverse Physiology Related Group Safety Reporting ................................34 
7.2.2 
Urinary GAG Excretion ..............................................................................34 
7.2.3 
Multi-domain Responder Index ...................................................................35 
7.3 Selection of Study Population ...................................................................................35 
7.3.1 
Inclusion Criteria .........................................................................................36 
7.3.2 
Exclusion Criteria ........................................................................................36 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................37 


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7.3.3.1 
Stopping Rules .............................................................................38 
7.4 Treatments .................................................................................................................38 
7.4.1 
Identity of Investigational Product ..............................................................38 
7.4.2 
Study Drug Infusion Procedure ...................................................................38 
7.4.2.1 
Pre-Dose Medication ...................................................................39 
7.4.2.2 
Infusion Procedure .......................................................................39 
7.4.3 
Selection of Doses in the Study ...................................................................40 
7.4.4 
Prior and Concomitant Therapy ..................................................................41 
7.4.4.1 
Prohibited Medications ................................................................41 
7.4.4.2 
Permitted Medications .................................................................41 
7.4.5 
Treatment Compliance ................................................................................42 
7.5 Study Procedures and Assessments ..........................................................................42 
7.5.1 
Schedule of Events ......................................................................................42 
7.5.2 
Safety Assessments (Primary Objective) ....................................................43 
7.5.2.1 
Medical History ...........................................................................44 
7.5.2.2 
Weight ..........................................................................................44 
7.5.2.3 
Physical Examination...................................................................45 
7.5.2.4 
Vital Signs ....................................................................................45 
7.5.2.5 
Clinical Laboratory Tests for Safety ............................................45 
7.5.2.6 
Pregnancy Testing ........................................................................46 
7.5.2.7 
Antibodies to rhGUS....................................................................47 
7.5.2.8 
Complement Levels .....................................................................48 
7.5.2.9 
Concomitant Medications ............................................................48 
7.5.2.10 
Adverse Events ............................................................................48 
7.5.2.11 
Adverse Physiology Related Group Reporting ............................49 
7.5.3 
Urinary GAG Excretion (Secondary Objective) .........................................49 
7.5.4 
Other Efficacy Measures .............................................................................49 


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7.5.4.1 
Multi-domain Responder Index ...................................................50 
7.5.4.2 
Serum Biomarkers of Inflammation ............................................50 
7.5.4.3 
Six Minute Walk Test ..................................................................50 
7.5.4.4 
Bruininks-Oseretsky Test of Motor Proficiency ..........................51 
7.5.4.5 
Three Minute Stair Climb Test ....................................................51 
7.5.4.6 
Pulmonary Function Testing ........................................................52 
7.5.4.7 
Goniometry ..................................................................................53 
7.5.4.8 
Anthropometrics ..........................................................................53 
7.5.4.9 
Visual Acuity ...............................................................................53 
7.5.4.10 
Individual Clinical Response .......................................................54 
7.5.4.11 
Scoring of Impactful Clinical Problems ......................................54 
7.5.4.12 
Subject-Reported Disability, Quality of Life, and Fatigue ..........55 
7.5.4.13 
Clinical Global Impression ..........................................................56 
7.5.4.14 
Hepatosplenomegaly ....................................................................57 
7.5.4.15 
Cardiac Ventricular Mass ............................................................57 
7.5.5 
Appropriateness of Measurements ..............................................................57 
7.6 Statistical Methods and Determination of Sample Size ............................................58 
7.6.1 
Sample Size .................................................................................................58 
7.6.2 
Analysis Populations ...................................................................................59 
7.6.3 
Statistical Principles ....................................................................................59 
7.6.4 
Demography, Baseline Characteristics, and Disposition ............................59 
7.6.5 
Efficacy endpoints .......................................................................................59 
7.6.6 
Safety Analyses ...........................................................................................59 
7.6.6.1 
Adverse Events ............................................................................60 
7.6.6.2 
Clinical Laboratory Evaluations ..................................................60 
7.6.6.3 
Vital Signs ....................................................................................60 
7.6.6.4 
Exposure ......................................................................................60 


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7.6.7 
Interim Analyses ..........................................................................................60 
7.6.8 
Data Monitoring Committee .......................................................................60 
8 STUDY CONDUCT ..........................................................................................................61 
8.1 Ethics .........................................................................................................................61 
8.1.1 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................61 
8.1.2 
Ethical Conduct of Study ............................................................................61 
8.1.3 
Subject Information and Consent ................................................................61 
8.2 Investigators and Study Administrative Structure ....................................................62 
8.3 Investigational Product Accountability .....................................................................63 
8.4 Data Handling and Record Keeping .........................................................................63 
8.4.1 
Case Report Forms and Source Documents ................................................63 
8.4.2 
Data Quality Assurance ...............................................................................63 
8.4.3 
Record Retention .........................................................................................64 
8.5 Reporting and Follow-up of Adverse Events ............................................................64 
8.5.1 
Definition of Adverse Events ......................................................................64 
8.5.2 
Severity of Adverse Events .........................................................................65 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................66 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................67 
8.5.4.1 
General .........................................................................................67 
8.5.5 
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting ......................................................67 
8.5.5.1 
Pregnancy Reports .......................................................................68 
8.5.6 
Adverse Drug Reaction Reporting ..............................................................68 
8.5.7 
Urgent Safety Measures ..............................................................................69 
8.5.8 
Safety Contact Information .........................................................................69 
8.6 Financing and Insurance ...........................................................................................69 
8.7 Publication Policy .....................................................................................................69 


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9 REFERENCES ..................................................................................................................70 
10 SIGNATURE PAGE .........................................................................................................75 
 
List of Tables 
Table 2.1: 
Schedule of Events ...............................................................................12 
Table 5.2.1: 
Urinary GAG Reduction of > 50% is Likely to Predict Clinical 
Benefit ..................................................................................................27 
Table 7.5.2.5.1: 
Clinical Laboratory Assessments .........................................................46 
 


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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
3MSCT 
Three-Minute Stair Climb Test 
6MWT 
Six-Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
APRG 
Adverse Physiology Reporting Group 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
BOT-2 
Bruininks-Oseretsky Test of Motor Proficiency 2nd Edition 
BUN 
blood urea nitrogen 
°C 
degrees Celsius 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CHAQ 
Childhood Health Assessment Questionnaire 
CIM6PR 
cation-independent mannose 6-phosphate receptor 
CRF 
Case Report Form 
CS 
chondroitin-6-sulfate 
DS 
dermatan sulfate 
EC 
Ethics Committee 
ECHO 
echocardiogram 
EDC 
electronic data capture 
EMLA 
eutectic mixture of local anesthetic 
ERS 
European Respiratory Society 
ERT 
enzyme replacement therapy 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
GUS 
beta-glucuronidase 


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HAQ 
Health Assessment Questionnaire 
HIPAA 
Health Insurance Portability and Accountability Act 
HS 
heparan sulfate 
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 
ICR 
Individualized Clinical Response  
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IST 
Investigator sponsored trial 
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 
MDRI 
MID 
Multi-domain responder index 
minimally important difference 
MIP-1alpha 
macrophage inflammatory protein 1 alpha 
MPS 
MPS 1 
MPS 2 
mucopolysaccharidosis/mucopolysaccharidoses 
mucopolysaccharidosis type 1, Hurler Syndrome 
mucopolysaccharidosis type 2, Hunter Syndrome 
MPS 7 
mucopolysaccharidosis type 7, Sly Syndrome 
MPS HAQ 
Mucopolysaccharidosis Health Assessment Questionnaire 
MVV 
maximum voluntary ventilation 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
No observed adverse effect level  
PedsQL 
Pediatric Quality of Life Inventory™ 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
QOW 
every other week 


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QW 
weekly 
RBC 
red blood cell 
rhGUS 
recombinant human beta-glucuronidase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to maximum plasma concentration 
TNF-alpha 
tumor necrosis factor-alpha 
uGAG 
urinary glycosaminoglycans 
US 
United States 
UX003 
Investigational Product/study drug, recombinant human beta-glucuronidase,  
rhGUS 
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. 
Primary (or feeder) study is defined as the Ultragenyx-sponsored study a subject completed 
immediately prior to enrollment in this long-term treatment and extension study. The terms 
“primary study” and “feeder study” may be used interchangeably in the protocol. 
“Study baseline” is defined as the baseline visit of this long-term treatment and extension 
study (UX003-CL202). 
“Pre-treatment baseline” is defined as the baseline visit in the primary study (e.g., 
UX003-CL301) or the visit and/or assessment performed just prior to treatment with UX003. 


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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 of the characteristics are similar among the 
mucopolysaccharidoses, 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. In more severely affected 
MPS 7 patients, there may be developmental delay as well. Most MPS 7 patients die before 
the second or third decade of life due to compounding medical problems. 
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), MPS 7 patients do not have an 
approved treatment available.  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 3 clinical studies to date in support of UX003 
development. A retrospective study (UX003-CL001) reviewed medical records of patients 
with MPS 1, 2, and 6 to evaluate the long-term impact of ERT products (Aldurazyme®, 
Elaprase®, and Naglazyme®) on total urinary GAG (uGAG) excretion and formally analyze 
the relationship of uGAG to the major clinical manifestations of MPS disorders. Prospective, 
interventional studies include an initial Phase 1/2 study (UX003-CL201) assessing safety, 
efficacy, and pharmacokinetics (PK) of UX003; a Phase 2 study (UX003-CL203) in patients 
under 5 years old, and a pivotal safety and efficacy Phase 3 study (UX003-CL301). 
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 the GAGs: dermatan 
sulfate (DS), chondroitin-6 sulfate (CS), and heparan sulfate (HS). 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 mutations 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 comprise 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 non-immune hydrops fetalis frequently 
present as infants or young children with clinical signs and symptoms including 
hepatosplenomegaly, pulmonary infections, cardiac problems, corneal clouding, hearing loss, 
hernias, joint stiffness and short stature (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).  
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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Patients with an intermediate form of MPS 7 have features similar to the more severe form of 
the disease but may present later and have less developmental delay and less rapid disease 
progression. At the attenuated end of the spectrum, MPS 7 patients can present as adults with 
a less severe physical disease (de Kremer et al. 1992). There are also some patients that 
present with an attenuated form at adolescence with a wide spectrum of abnormalities, but no 
mental retardation or corneal clouding (Kakkis et al. 1996b), (Neufeld et al. 2001).   
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 MPS 1 
(Aldurazyme®, laronidase), MPS 2 (Elaprase®, idursulfase), MPS 4A (Vimizim™ 
(elosulfase alfa), and MPS 6 (Naglazyme®, 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 (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, galsulfase and idursulfase 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 uGAG’s potential as a 
predictor of 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. UX003, the drug product in this clinical trial, is a 
sterile liquid buffered saline formulation of rhGUS that contains enzyme at a concentration 
of 2 mg/mL in a 10 mL glass vial filled to allow the withdrawal of a 5.0 mL deliverable 
volume. 


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5.3.1.1 UX003 Mechanism of Action in MPS 7 
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 glycosaminoglycans: DS, CS, and HS (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 
enzyme replacement is distributed 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). 


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The reduced lysosomal storage following ERT correlates with significant pathologic 
improvement and clinical benefit, with 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 HS and DS. 
5.3.3 Clinical Studies 
The first in-human use of UX003 was sponsored by Dr. Joyce Fox and Steven and Alexandra 
Cohen Children's Medical Center of New York under an emergency IND granted by the 
FDA. A 12-year-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. 2015). 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). The patient elected to continue UX003 
treatment. 
A second emergency IND was granted to treat a 4-month old MPS 7 infant born with severe 
non-immune hydrops fetalis (Dr. Heather Lau, New York University School of Medicine). 
The patient has received infusions for approximately 1 year; uGAG was reduced by at least 
70% after several infusions. No drug-related IARs have occurred in this Investigator-
sponsored trial (IST). The patient was subsequently enrolled in the Phase 2 study 
(UX003-CL203) described below.   
The clinical development program for UX003 rhGUS ERT consists primarily of the 
following studies, in addition to Study UX003-CL202: 
• An open-label Phase 1/2 study to assess the safety, efficacy, and dose of UX003 in 
pediatric and adult MPS 7 patients via IV administration QOW for 36 weeks with up 
to an additional 36 weeks treatment during the Continuation Period (UX003-CL201; 
NCT01856218 followed by ongoing long-term treatment at 4 mg/kg QOW) 
• A randomized, placebo-controlled, blind-start, single-crossover Phase 3 study to 
assess the efficacy and safety of UX003 in pediatric and adult MPS 7 patients via IV 
administration QOW for 48 weeks (UX003-CL301; NCT02230566) 


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• An open-label Phase 2 study of UX003 in MPS 7 patients less than 5 years old 
(UX003-CL203; NCT02418455) 
Available efficacy and safety data in humans is provided in the IB. 
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 up to 4 mg/kg as an IV infusion and support a 5-fold 
safety factor relative to the 4 mg/kg dose. 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 GAGs 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 the benefit-risk profile with UX003.  
Clinical trial data and experience with marketed ERT products for the treatment of related 
MPS disorders 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 
subjects 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. 
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 patients with 
antihistamine, and staged and controlled infusion rates. The large fraction of MPS 7 patients 
with missense mutations may result in a reduced immune response to ERT since residual 
protein in the tolerant mouse (Sly et al. 2001) and also in MPS 1 humans undergoing ERT is 
associated with reduced immune responses (Yogalingam et al. 2004).  
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 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 


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the risks associated with ERTs for other MPS disorders indicate the benefit-risk ratio of 
UX003 is sufficient to support clinical development for the treatment of MPS 7. 
5.5 
Study 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 GUS, required for degradation of 
the GAGs: DS, CS and HS. The GUS deficiency results in lysosomal accumulation of GAGs 
in multiple tissues and organs throughout the body and numerous clinical signs and 
symptoms as a result of tissue damage and organ dysfunction. There are currently no 
approved treatments for MPS 7.   
UX003 (recombinant human beta glucuronidase, rhGUS) is intended as a long-term ERT for 
the treatment of MPS 7 via IV administration. Ultragenyx is conducting this treatment and 
extension study to assess the long-term safety and efficacy of UX003 treatment in subjects 
with MPS 7. Subjects with MPS 7 who are UX003 treatment-naïve or have been previously 
enrolled and treated with UX003 in other clinical studies or programs are eligible for 
enrollment. 
The study will continue for up to 144 weeks or until one of the following occurs: the subject 
withdraws consent and discontinues from the study, the subject is discontinued from the 
study at the discretion of the Investigator or Ultragenyx, or the study is terminated.    


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6 STUDY OBJECTIVES 
The primary objective of the study is to evaluate: 
• Long-term safety of UX003 in subjects with MPS 7 
The secondary objective of the study is to evaluate: 
• Long-term efficacy of UX003 in reducing uGAG substrate in subjects with MPS 7 
Other objectives of the study are to evaluate: 
• Measures of lysosomal storage including hepatosplenomegaly 
• Measures of other clinical and functional outcomes, including pulmonary function, 
walking distance, shoulder flexion, fine motor function, gross motor function, climbing 
stairs, visual acuity, and cardiac size and function, and a composite Multi-Domain 
Responder Index (MDRI), as applicable per subject status  
• Growth, as defined by impact on general health and assessed by changes in height (or 
recumbent length) and weight growth velocity 
• Subject-reported disability and quality of life, and fatigue, as indicated 
• Subject or parent/caregiver global assessment of change and impact on activities of daily 
living, as indicated 
• If an individualized clinical response (ICR) endpoint was defined for a subject from a 
previous UX003 study, the ICR may continue to be followed 
 
 


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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This is a multi-center, multinational, open-label treatment and extension study in subjects 
with MPS 7. The study will assess long-term safety and efficacy of UX003 treatment and 
will continue for approximately 144 weeks or until one of the following occurs: the subject 
withdraws consent and discontinues from the study, the subject is discontinued from the 
study at the discretion of the Investigator or Ultragenyx, or the study is terminated. 
Subjects with MPS 7 who are UX003 treatment-naïve or previously enrolled and treated in a 
prior clinical study of UX003 may have the option to enroll into this treatment and extension 
study provided all eligibility criteria have been met for a given subject. Subjects with MPS 7 
who were enrolled in either an Ultragenyx sponsored study (e.g., UX003-CL301) or 
non-Ultragenyx sponsored clinical studies (e.g., ISTs, expanded access/compassionate use) 
may be eligible for enrollment. Those subjects enrolling from a previous UX003 study 
should have a reasonable benefit-risk assessment from their primary study as determined by 
the Investigator, in order to continue with long-term therapy in this extension study. To be 
enrolled, subjects need to meet all inclusion/exclusion criteria. 
All subjects will receive 4 mg/kg UX003 QOW unless data from prior studies define a 
different dose either for that subject or the use of UX003 in general.  
As has been observed with other MPS ERTs, some subjects may experience 
infusion-associated reactions (IARs) with the administration of UX003. Thus, prophylactic 
antihistamine will be administered prior to each study drug infusion. Antipyretic pretreatment 
may also be given at the Investigator’s discretion. To minimize the potential for IARs, 
infusions will initially be administered on a slower rate schedule followed by an increase in 
rate. Infusion rate may be slowed to manage or reduce IARs. 
Safety will be monitored throughout the study based on physical examinations, clinical 
laboratory analyses, and reporting of adverse events (AEs) and SAEs.    
Evaluations of efficacy, including uGAG levels, 6-minute walk test (6MWT), pulmonary 
function testing, shoulder flexion, visual acuity, and fine and gross motor function will be 
performed according to the Schedule of Events (Table 2.1 and Section 7.5) if age appropriate 
and subject is able to perform. Additional assessments will be performed, as indicated, to 
assess serum biomarkers, 3-minute stair climb test (3MSCT), hepatosplenomegaly, growth 
velocity, cardiac size and function, ICR endpoint (if appropriate), patient-reported outcomes, 
and subject/parent/caregiver global impression of change. 
The termination visit should be completed by all subjects who do not complete the Week 144 
end of study visit. The termination 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 


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termination visit. If the termination visit occurs after Week 48, blood for serum biomarkers 
of inflammation will not be collected and BOT-2 assessments will not be conducted. 
7.2 
Discussion of Study Design 
This open-label treatment and extension study in subjects with MPS 7 will further establish 
the long-term safety and efficacy profile of QOW infusions of UX003 (rhGUS) at a dose of 
4 mg/kg. 
7.2.1 Adverse Physiology Related Group Safety Reporting 
In this study, in addition to standard AE collection and laboratory evaluations, safety 
assessments will also include Adverse Physiology Related Group (APRG) reporting, a novel 
method synthesizing safety symptoms into multi-domain physiology related groups.  
APRG reporting provides the opportunity to detect variable adverse physiologies that might 
be expressed variably within and between subjects in a study. For example, anaphylactoid 
reactions are common IARs in ERT programs, and have a set pattern of specific symptoms 
and timing of reactions. During treatment, soon after the acceleration of the infusion, 
fever/chills, tachycardia/lower blood pressure, respiratory distress or desaturation, and 
abdominal pain/nausea/spontaneous smooth muscle contraction may occur. This is one 
example of a set of symptoms associated with a complement-mediated IAR. Symptoms 
may occur to varying degrees or be reported differently depending on the observer. 
Pre-set associated symptoms for adverse physiologies like anaphylactoid/complement 
mediated IARs, will help drive the assessment of the IARs in a more precise way, and assure 
the IAR is reported accurately. IAR findings will be recorded and tracked within the case 
report form (CRF) for likely APRGs, to enhance the detection of the common pattern of 
IARs. 
7.2.2 Urinary GAG Excretion 
The extensive research conducted on MPS disorders provides significant relevant scientific 
data that allows for the qualification of uGAG as a biomarker that is reasonably likely to 
predict clinical benefit. The disease process and mechanism of action for UX003 in MPS 7 
are well understood and data from other MPS disorders with comparable ERTs have 
established that uGAG is a direct pathophysiological marker of the disease process and 
uGAG is a reasonable predictor of treatment effect and clinical benefit in MPS disorders 
(Section 5.2). Considering the evidence on qualification of uGAG as a relevant biomarker for 
MPS disorders, the similarity of MPS 7 to other MPS disorders, and the critical nature of this 
disease, which is too rare to be easily studied in traditional study designs with clinical 
endpoints, uGAG is reasonable for use as an important endpoint in a pivotal study of ERT in 
MPS 7. 


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7.2.3 Multi-domain Responder Index 
In traditional clinical study design, efficacy is typically established based on one limited 
measure in one dimension of a complex multi-system clinical disease. For the subject, the 
total impact of therapy is an integration of the effects on all important clinical domains. 
Particularly in rare disease studies with heterogeneous populations, single clinical endpoints 
may not adequately cover the breadth of disease or capture enough data. Novel approaches to 
combine independent multi-domain analyses assure that the broader basis for efficacy can be 
assessed without the complexity of trying to construct qualified composite endpoints.  
Proof of concept for this approach in MPS programs was demonstrated using a meta-analysis 
of data from three MPS ERT Phase 3 clinical programs (Signorovitch 2011). The results 
demonstrated a combination analysis of three clinical endpoints predicted subject-reported 
treatment benefit better than each endpoint alone. 
A multi-domain responder index (MDRI) has been incorporated into the study design to 
provide an assessment of UX003 efficacy across a broad spectrum of clinical characteristics 
commonly observed in MPS 7 subjects. The minimal important difference (MID) for each 
variable will be defined and each subject scored for response to each variable. 
7.3 
Selection of Study Population 
The study will be conducted in approximately 20 MPS 7 subjects who are UX003 treatment-
naïve or were previously treated with UX003 in either an Ultragenyx-sponsored clinical 
study or a non-Ultragenyx sponsored clinical study. The inclusion criteria are structured to 
enroll UX003 treatment-naïve subjects with a confirmed diagnosis of MPS 7, presenting with 
clinical characteristics of lysosomal storage disease, and subjects previously treated with 
UX003 that have had a reasonable benefit-risk assessment from their primary study as 
determined by the Investigator, in order to continue with long-term therapy in this treatment 
and extension study. To enroll subjects most likely to benefit from long-term treatment and 
demonstrate safety and efficacy of UX003, MPS 7 subjects 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.  
Subjects with MPS 7 who are UX003 treatment naïve or have been enrolled and treated in a 
previous UX003 clinical study are eligible for this long-term treatment and extension study. 
Subjects who were reported to have safety-related events in a previous UX003 clinical study 


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that, in the opinion of the Investigator and sponsor, preclude resuming UX003 treatment will 
also be excluded. 
7.3.1 Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following inclusion 
criteria: 
1. Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme 
assay or genetic testing. 
2. Willing and able to provide written, signed informed consent, or in the case of subjects 
under the age of 18 (or 16 years, depending on the region) or subjects who are 
intellectually impaired, provide written assent (if required) and written informed consent 
by a legally authorized representative after the nature of the study has been explained, 
and prior to any research-related procedures. 
3. Willing to comply with all study procedures. 
4. Sexually active subjects must be willing to use a highly effective method of contraception 
while participating in the study and for 30 days following the last dose. 
5. Females of childbearing potential must have a negative pregnancy test at Baseline and be 
willing to have additional pregnancy tests during the study. Females considered not of 
childbearing potential include those who have not experienced menarche, are 
postmenopausal (defined as having no menses for at least 12 months without an 
alternative medical cause) or are permanently sterile due to having hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy.  
6. For UX003 treatment-naïve subjects only, apparent clinical signs of lysosomal storage 
disease as judged by the Investigator, including at least one of the following: enlarged 
liver and spleen, joint limitations, airway obstruction or pulmonary problems, limitation 
of mobility while still ambulatory. 
7. For UX003 treatment-naïve subjects only, aged 5 years and older and elevated uGAG 
excretion at a minimum of 2-fold over mean normal levels for age (at baseline). 
 
7.3.2 Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. If enrolled in a prior UX003 clinical study, the subject experienced a safety-related event 
in a prior UX003 clinical study that, in the opinion of the Investigator and sponsor, 
precludes resuming UX003 treatment. 
2. Undergone a successful bone marrow or stem cell transplant or has any degree of 
detectable chimaerism with donor cells. 


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3. Presence or history of any hypersensitivity to rhGUS or its excipients that, in the 
judgment of the Investigator, places the subject at increased risk for adverse effects. 
4. Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at 
any time during the study. 
5. Use of any investigational product (drug or device or combination) other than UX003 
within 30 days prior to Baseline, or requirement for any investigational agent prior to 
completion of all scheduled study assessments. 
6. Presence of a condition of such severity and acuity that, in the opinion of the Investigator, 
warrants immediate surgical intervention or other treatment or may not allow safe study 
participation. 
7.  Concurrent disease or condition, or laboratory abnormality 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 introduce additional 
safety concerns. 
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. 
Female subjects who become pregnant will be withdrawn from study drug (refer to 
Section 7.5.2.6). 
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, 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 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 


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the last dose given, their etiology should be identified and Ultragenyx should be notified.  
All unscheduled tests must be reported to Ultragenyx immediately. 
The termination visit should be completed by all subjects who do not complete the Week 144 
end of study visit. The termination 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. If the termination visit occurs after Week 48, blood for serum biomarkers 
of inflammation will not be collected and BOT-2 assessments will not be conducted. 
7.3.3.1 Stopping Rules 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related serious adverse events (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 IRB/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 
Approximately 20 subjects may be dosed QOW for up to 144 weeks. All subjects will 
receive 4 mg/kg UX003 QOW unless data from prior studies define a different dose either 
for that subject or the use of UX003 in general. 
7.4.1 Identity of 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 Investigational Brochure or Pharmacy Manual for details about 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 Good Manufacturing 
Practice (GMP) regulations.   
7.4.2 Study Drug Infusion Procedure 
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 


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begin at a low rate that will be gradually increased, as tolerated by the subject, until the 
planned maximum rate is reached. 
Refer to the Study Reference Manual for additional details on study drug infusion 
procedures.  
7.4.2.1 Pre-Dose Medication 
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.  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, or 
steroids may be considered. 
7.4.2.2 Infusion Procedure 
The amount of UX003 will be determined based on 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. 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. 
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. 
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. 


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Equipment necessary for resuscitation must be available during study drug infusion. 
7.4.3 Selection of Doses in the Study 
The planned UX003 dose of 4 mg/kg is based on doses examined in an ongoing Phase 2 
clinical study in MPS 7 subjects, 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, with a relative 5-fold safety factor.  
The pharmacologic studies in the MPS 7 mouse showed that both 2 mg/kg and 4 mg/kg were 
effective doses with only a few tissues or cell types such as osteocytes responding better at 
4 mg/kg versus 2 mg/kg. Safety was the same at all doses. 
The Phase 1/2 study (UX003-CL201) in MPS 7 subjects evaluated UX003 administered at 
doses of 1, 2, and 4 mg/kg QOW. Preliminary results suggest the percent reduction in urinary 
GAG excretion is greatest with the 4 mg/kg dose with mean reductions of approximately 
60% observed, while the reductions at 2 mg/kg were in the 40-50% range. Additionally, 
during the forced dose titration process, the reductions in uGAG observed at 4 mg/kg 
lessened when subjects returned to the 2 mg/kg dose, suggesting a decrease in efficacy.  
These changes in uGAG exceeded an absolute difference of 10% and were of sufficient 
magnitude to consider the 4 mg/kg dose a more appropriate dose. In the clinical studies of 
ERT for other MPS disorders, 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.  Infusions at 4 mg/kg in 3 subjects in the UX003-CL201 
study for 8 weeks showed no safety issues, and there have been no drug-related IARs at any 
dose to date. Therefore, the 4 mg/kg dose appears to be well tolerated at this time.  
The therapeutic ERT doses in prior successful programs for other MPS disorders (0.58, 0.5 
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 ~10-27 nM in the circulation. These enzyme levels are 
approximately 10- to 30-fold the uptake constants (1-2.7 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). 
A higher dose is needed to provide the same rhGUS molar concentration as other MPS 
enzymes, since rhGUS enzyme has two active sites per tetramer and the molecular 
weight (332 kDa tetramer) is approximately 4-fold higher compared to the other MPS 
enzymes. The equivalent number of moles of enzyme active sites would require about two 


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times the efficacious dose for other MPS enzymes on a mass or milligram basis. 
Therefore, approximately 1-4 mg/kg UX003 is estimated to achieve the same molar 
concentration of active enzyme. 
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 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. 
All subjects may receive up to 144 weeks of UX003 treatment. The treatment duration is 
sufficient to assess long-term safety and provide sufficient insight on sustained clinical 
effects and improvements in pediatric, adolescent, and adult efficacy of UX003 treatment in 
MPS 7 subjects. 
7.4.4 Prior and Concomitant Therapy 
7.4.4.1 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 Baseline, 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. 
7.4.4.2 Permitted Medications 
Subjects may receive concomitant medications as required.   
For subjects enrolling from an Ultragenyx-sponsored clinical trial, medications 
(investigational, prescription, over-the-counter, and herbal) and nutritional supplements 
reported as ongoing at the primary study’s End of Treatment visit and any new medications 
taken prior to Baseline will be reviewed and recorded at the Baseline visit. Any enrolling 
subject who had an early termination in the primary study will have their baseline 
concomitant medications collected in the same manner as a subject who is treatment naïve or 
enrolling from a non-Ultragenyx sponsored study (see following paragraph). 
For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored 
clinical trial, medications (investigational, prescription, over-the-counter, and herbal) and 


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nutritional supplements taken during the 30 days prior to Baseline will be reviewed and 
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. 
7.4.5 Treatment Compliance 
UX003 is not to be dispensed to subjects. UX003 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 
7.5.1 Schedule of Events 
Informed consent must be obtained prior to any study procedures. Subjects will be enrolled 
only after inclusion/exclusion criteria have been confirmed.  
For subjects previously enrolled in the Ultragenyx-sponsored MPS 7 Phase 3 clinical study 
UX003-CL301, the Baseline Visit will be conducted in conjunction with the UX003-CL301 
Week 48 study visit to avoid treatment disruption. Data collected at the UX003-CL301 
Week 48 visit may serve as the Baseline data for this study. All additional Baseline 
assessments (not included in the UX003-CL301 Week 48 assessments), other than UX003 
treatment, must also be completed prior to determination of eligibility. Following 
confirmation of eligibility, subjects will receive their first study drug infusion in this study 
and will return for assessments according to the Schedule of Events (Table 2.1). 
For subjects enrolling from other Ultragenyx sponsored clinical studies, clinical outcome 
assessments including efficacy, echocardiogram (ECHO) and clinical laboratory tests 
performed during the final, or End of Treatment, visit from the primary (or feeder) study may 
be used as baseline assessments for this study if performed within 30 days of the Baseline 
visit as specified below.  
Subjects enrolling from an Ultragenyx sponsored clinical study who had an early termination 
in their primary (or feeder) study will have their baseline assessments collected in the same 
manner as a subject who is treatment naïve or enrolling from a non-Ultragenyx sponsored 
study (see following paragraph). 


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For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored 
clinical study, initial baseline safety and efficacy assessments will be performed within 
30 days of the Baseline visit. All assessments scheduled on the same day as UX003 treatment 
must be performed prior to the first study drug infusion for this treatment and extension 
study.  
For all subjects, Baseline study visits should be conducted at a primary site from an 
Ultragenyx sponsored clinical study.  Following the Baseline visit, subjects may return to 
their primary, or Baseline, study site for all safety assessments, efficacy assessments, and 
infusions every 24 weeks through the end of study. Alternatively, the 24-week visits may be 
performed at the subject’s local site if feasible. All other clinic visits, including assessments 
and infusions, may be performed at the subject’s local site as appropriate. 
Subjects will return to the clinic at 2-week intervals (± 3 days) for study drug infusion and 
basic safety measures. Subjects will have assessment of uGAG levels and physical exams at 
12-week intervals. Major assessment visits are scheduled at 24-week intervals (± 7 days) 
through the end of study.  
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 144 weeks, the end of trial is 
defined as the Week 144 visit of the last subject. In the event the study is terminated by the 
Sponsor prior to Week 144, 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 
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. If the termination visit 
occurs after Week 48, blood for serum biomarkers of inflammation will not be collected and 
BOT-2 assessments will not be conducted. 
The parameters to be assessed in Study UX003-CL202, along with timing of assessments, 
are provided in the Schedule of Events (Table 2.1). All assessments scheduled on the same 
day as a UX003 treatment day must be completed prior to the infusion on that day. 
Where caregiver assessments are required, the same individual should complete the 
assessment for consistency of reporting, when possible. Refer to the Study Reference Manual 
for additional details on specific assessments. 
7.5.2 Safety Assessments (Primary Objective) 
For the purposes of this study, all safety assessments will be performed on all subjects 
entering from a prior study with UX003, unless otherwise specified. UX003-naïve subjects 
will be required to complete all applicable (age- and ability-appropriate) study assessments as 
indicated in Table 2.1.   
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 


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signs, weight, physical examination, clinical laboratory evaluations, and concomitant 
medications. Evaluation of valvular function and cardiac function by ECHO will be made 
primarily for safety purposes.   
APRG reporting is a novel method synthesizing safety symptoms into multi-domain 
physiology related groups. APRG reporting has been incorporated into the study design to 
detect adverse physiologies that might be expressed variably within and between subjects in 
a study. 
To assess the immune response to UX003, the development of any antibodies to rhGUS, and 
complement C3, C4, and CH50 levels will also be evaluated if a drug-related hypersensitivity 
reaction is suspected.  Pregnancy testing (or pregnancy of partner, if needed) will also be 
conducted.   
7.5.2.1 Medical History 
For subjects continuing treatment from a previous Ultragenyx sponsored study, 
general medical history information obtained during the primary (or feeder) study (e.g., 
UX003-CL301) will carry over to this study. The general medical history includes subject 
demographics (date of birth, ethnicity, and sex) and a history of major medical illnesses, 
diagnoses, surgeries and confirmation of MPS 7 diagnosis. To ensure all medical histories 
are complete and current, any enrolling subject who had an early termination in the primary 
study will have any changes or new information since their discontinuation in the primary 
study recorded. 
For subjects who are treatment naïve or who enroll from a non-Ultragenyx sponsored study, 
a complete medical history is to be completed prior to the Baseline visit, or at the 
Baseline visit prior to first study treatment, to ensure subject meets all eligibility criteria. 
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 
(or recumbent length) and weight will be collected. MPS 7 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. 
7.5.2.2 Weight 
Weight will be obtained at Baseline, and at every 12 weeks as needed to determine 
appropriate study drug volume. Weight for drug preparation may be obtained up to 15 days 
prior to the indicated visit (e.g. Weeks 10, 22, 34, and 46 visits).Weight will be measured in 
kilograms using a scale. 


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7.5.2.3 Physical Examination 
Complete physical examinations will be performed at Baseline then every 12 weeks until the 
end of study visit (or termination visit). A physical examination performed at the primary 
(or feeder) study End of Treatment visit or within 30 days prior to Baseline may be used for 
the study baseline.  
Physical examinations will include assessments of general appearance; head, eyes, ears, nose, 
and throat; the cardiovascular, dermatologic, lymphatic, respiratory, gastrointestinal, 
genitourinary, and musculoskeletal systems. Physical examinations are to include neurologic 
examination and evaluation of the presence or absence of corneal clouding. If subject 
complains of leg weakness or fatigue, evaluate for signs of cord compression (e.g. leg 
reflexes and motor strength). 
7.5.2.4 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 will be administered, vital signs will be measured within 30 minutes before the 
infusion, at least every 30 minutes for the first hour of infusion, at least every hour for the 
remainder of the infusion, and within 30 minutes after the infusion. Additional measurements 
should be obtained as appropriate. Refer to the Study Reference Manual for additional details 
on vital sign assessments. 
7.5.2.5 Clinical Laboratory Tests for Safety 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.2.5.1. 
Clinical laboratory testing will be performed at the Baseline visit and at 48-week intervals as 
indicated in the Schedule of Events (Table 2.1). Clinical laboratory tests performed at the 
primary (or feeder) study End of Treatment visit or within 30 days prior to Baseline may be 
used for the study baseline. Blood and urine samples will be collected prior to administration 
of study drug; fasting is not required. Refer to the Laboratory Manual for additional details. 


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Table 7.5.2.5.1: 
Clinical Laboratory Assessments 
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 
 
 
 
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. 
7.5.2.6 Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests at the Baseline visit 
and every 12 weeks throughout the study (and at the Termination visit). Female subjects with 
a positive pregnancy test at Baseline will not be enrolled in the study. Females who have not 
experienced menarche will not undergo pregnancy testing. Should a female subject 
experience menarche during the course of the study, the subject will be considered a female 
subject of childbearing potential and undergo urine pregnancy testing per the Schedule of 
Events (Table 2.1). 
Additional pregnancy tests will be performed at any visit in which pregnancy status is in 
question. A serum pregnancy test will be performed in the event of a positive or equivocal 
urine pregnancy test result, or can be performed if pregnancy test by urine is not feasible. 
Pregnancy in subject or partner must be reported (Section 7.5.2.6.1); pregnant subjects will 
be withdrawn from study drug. At the conclusion of the pregnancy, a decision will be made if 
the female subject may resume study drug based on study treatment risk-benefit evaluation 
and willingness of the subject to comply with the contraceptive requirements. In the event of 
a pregnancy in the partner of a male subject, the male subject may continue with study drug.   


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Experience with UX003 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby that are currently unknown. Sexually active male and female 
subjects of childbearing potential or with partners of child-bearing potential must consent to 
use a highly effective method of contraception during and for 30 days following the last dose 
of study drug. Examples of highly effective methods include: 
• Established use of hormonal contraceptives, such as the birth control pill, injection or 
implant, associated with inhibition of ovulation 
• Intrauterine device (IUD) or intrauterine system (IUS), a small device with hormones that 
goes inside the uterus 
• Bilateral tubal occlusion 
• Male sterilization, also called vasectomy  
• True abstinence which means not having sex because subject chooses not to 
7.5.2.6.1 
Pregnancy in Subject or Partner 
Pregnancies in subjects or partners must be reported within 24 hours of knowledge of the 
event to Ultragenyx or its designee. The Investigator must make every effort to follow the 
pregnancy of either subject or partner through resolution of the pregnancy (delivery or 
termination) and report the resolution to Ultragenyx or its designee. In the event of a 
pregnancy in the partner of a subject, the Investigator should make every effort to obtain the 
female partner’s consent for release of protected health information. Refer to the Study 
Reference Manual for details on the reporting procedures to follow in the event of pregnancy. 
7.5.2.7 Antibodies to rhGUS 
Prior Phase 3 studies in ERT for MPS have shown that 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 antibodies directed against rhGUS will take place at the 
Baseline visit, and every 24 weeks through the end of trial (or termination) visit. Testing for 
rhGUS antibodies performed at the primary (or feeder) study End of Treatment visit or 
within 30 days prior to Baseline may be used for the study baseline.  Serum samples for 
antibodies must be collected before infusion of study drug. Refer to the Laboratory Manual 
for additional details on sample processing. 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. 


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7.5.2.8 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. 
7.5.2.9 Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at the Baseline visit.   
For subjects enrolling from an Ultragenyx-sponsored clinical trial, medications 
(investigational, prescription, over-the-counter, and herbal) and nutritional supplements 
reported as ongoing at primary study’s End of Treatment visit and any new medications 
taken prior to Baseline will be reviewed and recorded at Baseline visit. Any enrolling subject 
who had an early termination in the primary study will have their baseline concomitant 
medications collected in the same manner as a subject who is treatment naïve or enrolling 
from a non-Ultragenyx sponsored study (see following paragraph). 
For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored 
clinical trial, medications (investigational, prescription, over-the-counter, and herbal) and 
nutritional supplements taken during the 30 days prior to Baseline will be reviewed and 
recorded. 
At each subsequent visit, change in medications since the previous visit will be recorded.  
A discussion of prior and concomitant medications is provided in Section 7.4.4. 
7.5.2.10 Adverse Events 
For subjects enrolling from an Ultragenyx-sponsored clinical trial, all AEs will be recorded 
from the time the subject signs the informed consent for this extension study and completion 
of the End of Treatment visit in the primary study until 30 days after the last dose of study 
drug. Adverse events reported as ongoing at the primary study’s End of Treatment visit and 
any new AEs prior to Baseline will be reviewed and recorded at Baseline visit. Any enrolling 
subject who had an early termination in the primary study will have their baseline AE 
information collected in the same manner as a subject who is treatment naïve or enrolling 
from a non-Ultragenyx sponsored study (see following paragraph). 
For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored 
clinical trial, all AEs will be recorded from the time the subject signs the informed consent 
until 30 days after the last dose of study drug.   


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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, vital 
signs, and clinical laboratory parameters, will be recorded as AEs or SAEs, if appropriate. 
7.5.2.11 Adverse Physiology Related Group Reporting 
APRG is an approach to safety reporting for common expected AEs that have a set of 
symptoms all related to an adverse physiologic pathway. Patterns of IARs will be specifically 
evaluated throughout the study. 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.  
Refer to the Study Reference Manual for additional details on APRG reporting.  
7.5.3 Urinary GAG Excretion (Secondary Objective) 
Results of prior non-clinical and clinical work 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. 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 Baseline then every 12 weeks 
throughout the study (or termination visit). A uGAG assessment performed at the primary 
(or feeder) study End of Treatment visit or within 30 days prior to Baseline may be used for 
the study baseline. Urine samples must be collected from first morning voids to assure the 
urine is adequately concentrated. Refer to the Laboratory Manual for details on sample 
collection and processing requirements. Supplementary assays for uGAG may be performed. 
Urinary GAG excretion will provide a biochemical measure of the biological action of 
UX003. These assessments will be supported by other efficacy measures, including a 
multi-domain responder index to provide an assessment of UX003 efficacy in MPS 7 
subjects. 
7.5.4 Other Efficacy Measures 
Other efficacy assessments, including a multi-domain clinical responder index, will be used 
to assess clinical changes following UX003 treatment.  In general, other efficacy assessments 
will be performed only if they were performed in the primary (or feeder) study. 
Efficacy assessments not performed during the primary (or feeder study) will not be required 


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for this long-term treatment and extension study, unless otherwise specified. UX003-naïve 
subjects will be required to complete all applicable (age- and ability-appropriate) study 
assessments as indicated in Table 2.1.   
7.5.4.1 Multi-domain Responder Index 
Single clinical endpoints may not adequately cover the breadth of disease. Novel approaches 
to combine independent multi-domain analyses assure that the broader basis for efficacy can 
be assessed. The MDRI consisting of 6MWT, FVC, shoulder flexion, visual acuity, and 
BOT-2 (fine motor and gross motor), provides an assessment of UX003 efficacy across a 
broad spectrum of clinical characteristics commonly observed in MPS 7 subjects. The MID 
for each variable will be defined and each subject scored for each variable. 
For subjects enrolling from prior clinical studies with UX003, the MDRI will only be 
evaluated if the clinical outcomes described above were previously assessed in their primary 
(or feeder) study.   
7.5.4.2 Serum Biomarkers of Inflammation 
Blood samples will be collected at the Baseline, Week 24, and Week 48 visits for assessment 
of biomarkers of inflammation in serum using established quantitative methods, if indicated 
based on prior work. If the termination visit occurs after Week 48, blood for serum 
biomarkers of inflammation will not be collected. An inflammation biomarker assessment 
performed at the primary (or feeder) study End of Treatment visit or within 30 days prior to 
Baseline may be used for the study baseline. The inflammatory biomarkers may include, but 
not be limited to, the following:  tumor necrosis factor-alpha (TNF-alpha) and macrophage 
inflammatory protein 1 alpha (MIP-1alpha). 
7.5.4.3 Six Minute Walk Test 
Subjects who cannot walk may omit the 6MWT. Some subjects may be too young and/or 
physically impaired to reliably perform the test, the test performance at the Baseline visit will 
be used to determine feasibility for naïve subjects. The 6MWT may not be performed at 
subsequent study visits if the subject is unable to reliably or safely perform the test at 
Baseline. Subjects enrolling from an Ultragenyx sponsored study (e.g., UX003-CL301) will 
continue to perform the 6MWT if evaluated during the primary/feeder study. The 6MWT 
will be administered to appropriate subjects once per test day to appropriate subjects during 
the Baseline visit, then every 24 weeks thereafter (or at termination visit). A 6MWT 
performed at the primary (or feeder) study End of Treatment visit or within 30 days prior to 
Baseline may be used for the study baseline assessment.    
For subjects enrolling from prior clinical studies with UX003, the 6MWT will only be 
administered if previously performed in their primary (or feeder) study. A 6MWT performed 
within 30 days prior to Baseline may be used for the study baseline assessment.   


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The 6MWT will be conducted based on American Thoracic Society guidelines (ATS 2002).  
Subjects will be instructed to walk the length of a pre-measured course for 6 consecutive 
minutes. If applicable, the use of any walking aids in the performance of the 6MWT will be 
noted. Refer to the Study Reference Manual for detailed instructions on conducting the 
6MWT. 
The 6MWT and 3MSCT should be performed on separate days, if possible. If performed on 
the same day, the 6MWT should be done before the 3MSCT; the subject’s resting heart rate 
must return to baseline between assessments. 
The total distance walked (meters) following the six minute period will be recorded; an 
interim measurement will also be obtained following the first two minutes of the 6MWT.  
The total time spent walking during the test will be recorded. The percent of predicted 
normal distance walked will also be determined based on published normative data (Geiger 
et al. 2007), (Gibbons et al. 2001).  
7.5.4.4 Bruininks-Oseretsky Test of Motor Proficiency 
The Bruininks-Oseretsky Test of Motor Proficiency – 2nd Edition (BOT-2) is a standardized, 
norm-referenced test of fine and gross motor skills for children (≥ 4 years of age) and young 
adults (Bruininks et al. 2005). Four subtests of the BOT-2 will be administered to evaluate 
treatment-related changes in fine motor proficiency and gross motor function: fine motor 
precision, manual dexterity, balance, running speed and agility. The test may be modified 
and tests omitted to accommodate the needs of the subject. The BOT-2 will be assessed at the 
Baseline, Week 24, and Week 48 visits. If the termination visit occurs after Week 48, BOT-2 
assessments will not be conducted. A BOT-2 assessment performed at the primary (or feeder) 
study End of Treatment visit or within 30 days prior to Baseline may be used for the study 
baseline assessment.  
For subjects enrolling from previous clinical studies with UX003, the BOT-2 will only be 
administered if previously performed in their primary (or feeder) study. A BOT-2 performed 
within 30 days prior to Baseline may be used for the study baseline assessment. 
7.5.4.5 Three Minute Stair Climb Test 
The 3MSCT (Zech et al. 2011) will be used to assess functional power via stair climbing 
capacity.  Subjects who cannot climb stairs may omit this test. Some subjects may be too 
young and/or physically impaired to reliably perform the test, the test performance at the 
Baseline visit will be used to determine feasibility for naïve subjects. The 3MSCT may 
not be performed at subsequent study visits if the subject is unable to reliably or safely 
perform the test at Baseline. Subjects enrolling from an Ultragenyx sponsored study 
(e.g., UX003-CL301) will continue to perform the 3MSCT if evaluated during the 
primary/feeder study.  The 3MSCT will be administered to appropriate subjects during the 
Baseline visit, then every 24 weeks thereafter (or at termination visit). A 3MSCT assessment 


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performed at the primary (or feeder) study End of Treatment visit or within 30 days prior to 
Baseline may be used for the study baseline assessment. 
For subjects enrolling from previous clinical studies with UX003, the 3MSCT will only be 
administered if previously performed in their primary (or feeder) study. A 3MSCT performed 
within 30 days prior to Baseline may be used for the study baseline assessment. 
The 3MSCT will be administered once per indicated visit by a licensed physical therapist. 
Oxygen saturation will be measured before and after the test using a pulse oximeter.  
The subject will be asked to stand at the foot and center of the stairs and climb the stairs upon 
command. Use of any available stair railing will be allowed if preferred by the subject.  
The number of stairs climbed within a three minute period will be recorded.  
The 6MWT (Section 7.5.4.3) and 3MSCT should be performed on separate days, if possible.  
If performed on the same day, the 6MWT should be done before the 3MSCT. The subject’s 
resting heart rate must return to baseline between assessments.   
7.5.4.6 Pulmonary Function Testing 
Spirometry will not be conducted on subjects who require invasive ventilatory support or 
have a tracheostomy.  Invasive ventilation is defined as any form of ventilatory support 
applied with the use of an endotracheal tube. Spirometry will be administered in accordance 
with ATS/ERS guidelines (ATS/ERS 2002) to appropriate subjects during the Baseline visit, 
then every 24 weeks thereafter (or at termination visit). Spirometry performed at the primary 
(or feeder) study End of Treatment visit or within 30 days prior to Baseline may be used for 
the study baseline. If performed on the same day, spirometry should be done before the 
6MWT and 3MSCT. The subject’s resting heart rate must return to baseline between 
assessments.    
For subjects enrolling from prior clinical studies with UX003, Spirometry will only be 
administered if previously performed in their primary (or feeder) study. Spirometry 
performed within 30 days prior to Baseline may be used for the study baseline assessment.  
Pulmonary function variables include forced vital capacity (FVC) and maximum voluntary 
ventilation (MVV). The percent predicted values will be calculated after testing using 
published normative data (Wang et al. 1993), (Eigen et al. 2001), (Hankinson et al. 1999).  
If standing height cannot be obtained, an estimate of standing height may be used to derive 
the height measurement required to calculate percent predicted values. 


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7.5.4.7 Goniometry 
The maximum passive shoulder range of motion in both flexion and extension will be 
measured in degrees using a goniometer. Shoulder flexion will be the evaluable measure.  
The highest value of three shoulder flexion and extension range of motion measurements for 
each side will be reported and compared to known normal standards for age. Goniometry will 
be performed during the Baseline visit, then every 24 weeks thereafter (or at termination 
visit). A shoulder flexion, or goniometry, assessment performed at the primary (or feeder) 
study End of Treatment visit or within 30 days prior to Baseline may be used for the study 
baseline. 
For subjects enrolling from previous clinical studies with UX003, goniometry will only be 
administered if they were previously performed in their primary (or feeder) study.  
Goniometry performed within 30 days prior to Baseline may be used for the study baseline 
assessment. 
7.5.4.8 Anthropometrics 
Growth will be assessed from anthropometric measurements (standing height [or recumbent 
length, if applicable] and weight) at 12-week intervals beginning at the Baseline visit to 
Week 24, then every 24 weeks thereafter (or at termination visit). Every effort should be 
made to collect standing height when appropriate. If unable to collect standing height, sitting 
height should be collected for that subject. Growth velocity will be calculated and compared 
with pre-treatment growth velocity when available.   
7.5.4.9 Visual Acuity 
Visual acuity will be measured (corrected and uncorrected) using a standard eye chart and 
recorded for each eye independently. For this study, visual acuity will be assessed at the 
Baseline visit, then every 24 weeks thereafter (or at termination visit). A visual acuity 
assessment performed at the primary (or feeder) study End of Treatment visit or within 
30 days prior to Baseline may be used for the study baseline. 
For subjects enrolling from previous clinical studies with UX003, visual acuity assessments 
will only be administered if they were previously performed in their primary (or feeder) 
study. A visual acuity assessment performed within 30 days prior to Baseline may be used 
for the study baseline assessment. 


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7.5.4.10 Individual Clinical Response 
The ICR may provide a specific assessment of the ability of UX003 to impact the most 
important clinical manifestation of MPS 7 for a given subject. 
For subjects who were previously treated in the Ultragenyx-sponsored MPS 7 Phase 3 
clinical study UX003-CL301 and had an ICR assigned, that same ICR may be followed in 
this long-term treatment and extension study. If applicable, the ICR will be identified during 
the Baseline visit and then assessed every 24 weeks thereafter (or at termination visit).  
During the previous Ultragenyx sponsored MPS 7 Phase 3 clinical study UX003-CL301, the 
physician will have queried the subject or parent/caregiver about signs and symptoms 
of MPS 7 that interfere most with the subject’s daily life (Clinical Problem Evaluation). 
Answers will have been mapped to an appropriate clinical outcome measure. For example, 
difficulty walking could map to the 6MWT; breathing problems to FVC; trouble 
manipulating small objects to BOT-2 fine motor function; difficulty with balance or agility to 
BOT-2 gross motor function; reduced joint mobility to shoulder flexion maximum range of 
motion; and tiredness/fatigue to the PedsQL-multidimensional fatigue scale.  
The determination of the ICR in Ultragenyx study UX003-CL301 will have been based on, 
but not limited to: 1) the specific concerns that the subject/parent/caregiver has reported; 
2) the ability of the subject to reliably complete the assessment; and 3) the extent of 
impairment measured in the outcome of interest and will take into consideration 
developmental, cognitive, and behavioral factors observed at both the Screening and 
Randomization (Week 0) visits. The clinical outcome ranked with the highest impact on daily 
life that can be reliably completed by the subject and meets a threshold level of impairment 
will be selected as the ICR for that subject. The Investigator will be responsible for defining 
the ICR for each subject in consultation with an independent clinical consultant during 
previous study, UX003-CL301.   
For subjects that have not participated in the UX003-CL301 study, the ICR endpoint will not 
be defined in this study. 
7.5.4.11 Scoring of Impactful Clinical Problems 
The three most impactful clinical problems as reported by the subject or parent/caregiver 
during the Clinical Problem Evaluation may be identified and scored on a Likert scale.  
The Likert scale will be administered during the Baseline visit, then every 24 weeks 
thereafter (or at termination visit).     
For UX003 treatment-naïve subjects, the initial Clinical Problem Evaluation will occur at the 
Baseline visit.  For subjects previously enrolled in the Ultragenyx-sponsored MPS 7 Phase 3 
clinical study UX003-CL301, the Clinical Problems identified during the UX003-CL301 
Randomization visit will continued to be scored throughout this study. For these subjects the 


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Clinical Problem scores rated at the primary (or feeder) study End of Treatment visit or 
within 30 days prior to Baseline may be used for the study baseline.  
This assessment will not be evaluated for subjects enrolling from previous clinical studies, 
other than UX003-CL301 noted above (e.g. ISTs, expanded access/compassionate use). 
Refer to the Study Reference Manual for more details of the scoring. 
7.5.4.12 Subject-Reported Disability, Quality of Life, and Fatigue 
For UX003 treatment-naïve subjects and subjects enrolling from the MPS 7 Phase 3 
Ultragenyx sponsored study (i.e., UX003-CL301), subject-reported disability and pain will 
be assessed by the MPS Health Assessment Questionnaire (MPS HAQ), and either 
Childhood Health Assessment Questionnaire (CHAQ) or Health Assessment Questionnaire 
(HAQ) (as appropriate for subject age). These subject-reported outcome measures will be 
administered to evaluate treatment-related changes in self-care and mobility activities of 
daily living including feeding, dressing, bathing, grooming, tooth brushing, toileting, 
mobility, walking and stair climbing.   
For subjects enrolling from previous clinical studies with UX003, these subject-reported 
outcome measures will only be administered if they were previously performed in their 
primary (or feeder) study. Subject-reported outcome measures performed within 30 days 
prior to Baseline may be used for the study baseline assessment.   
Age-appropriate questionnaires will be completed at the Baseline visit, then every 24 weeks 
thereafter (or at termination visit). For subjects enrolling from the MPS 7 Phase 3 
Ultragenyx sponsored study (i.e., UX003-CL301), subject-reported outcome assessments 
performed at the primary (or feeder) study End of Treatment visit or within 30 days prior to 
Baseline may be used for the study baseline.    
The MPS HAQ will be administered to all age groups. Subjects will consistently 
complete the same questionnaire (HAQ or CHAQ) administered at baseline for the duration 
of the study regardless of whether their age changes from 13 to 14 during the study. 
The age-appropriate version of the PedsQL multidimensional fatigue module will be 
administered throughout the study.   
MPS Health Assessment Questionnaire:  The MPS HAQ was developed to assess the 
self-care and mobility skills of subjects with MPS 1.  As MPS 7 shares many similar 
features with MPS 1, use of the MPS HAQ in this study should provide important 
information on the functional independence of MPS 7 subjects. The questionnaire includes 
self-care (eating/drinking, dressing, bathing, grooming, tooth brushing, and toileting) and 
mobility domains (dexterity, mobility, walking, stair climbing, and gross motor skills).  
Caregiver assistance items are also included to assess the extent to which assistance is 
required for the performance of activities related to the self-care and mobility domains.  


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The mode of administration will be based on subject ability. If possible, the subject should 
complete the questionnaire, or this may be done via interview. If not feasible for the subject 
to provide this information, it may be completed by a parent or caregiver. The same person 
should complete the questionnaire throughout the course of the study.   
Childhood Health Assessment Questionnaire:  The CHAQ was initially developed to 
assess health status in children with juvenile rheumatoid arthritis (Singh et al. 1994).  
The instrument consists of 30 items in the Disability Index comprising 8 subscales:  dressing, 
grooming, arising, eating, walking, reach, grip, and activities; pain is indicated on a sliding 
scale. Higher scores reflect greater disability. The CHAQ should be administered for 
pediatric subjects only (˂14 years old). The subject’s parent or caregiver should complete the 
CHAQ, and the same person should complete the questionnaire throughout the course of the 
study. 
Health Assessment Questionnaire:  The full HAQ is among the first PRO instruments 
initially designed to represent a model of subject-oriented outcome assessment (Bruce et al. 
2005). The HAQ disability and pain scales (Fries et al. 1982) have been extensively validated 
and employed in a variety of diseases and conditions. There are 20 items in 8 categories that 
represent a comprehensive set of functional activities – dressing, rising, eating, walking, 
hygiene, reach, grip, and usual activities. The HAQ should be administered for subjects 
≥14 years old. The mode of administration will be based on subject ability. If possible, the 
subject should complete the questionnaire, or this may be done via interview. If not feasible 
for the subject to provide this information, it may be completed by a parent or caregiver. 
The same person should complete the questionnaire throughout the course of the study. 
Fatigue: Subject-reported fatigue will be assessed by the Pediatric Quality of Life 
Inventory™ (PedsQL)-Multidimensional Fatigue Scale. The PedsQL multidimensional 
fatigue scale is a specific module of the PedsQL™ designed to measure fatigue in subjects 
aged 2 and above (Varni et al. 1999), (Varni et al. 2001). The 18-item scale is comprised of 
three subscales: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue 
(6 items).  The age-appropriate version of the PedsQL will be completed by the subject or 
caregiver.  
7.5.4.13 Clinical Global Impression 
The CGI provides an overall measure that takes into account the subject's history, 
psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
subject's ability to function. 
Subjects or parents/caregivers will provide a global assessment of change using a seven point 
scale ranging from -3 (severe worsening) to +3 (significant improvement). This global 
assessment will be accompanied by narratives from the subjects or parents/caregivers on their 
perception of how treatment has impacted the subjects’ ability to perform activities of daily 
living.   


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For UX003 treatment-naïve subjects and subjects enrolling from the MPS 7 Phase 3 
Ultragenyx sponsored study UX003-CL301, the Subject/Parent/Caregiver CGI will be 
evaluated at the Baseline visit, then every 24 weeks thereafter (or at termination visit).    
For subjects enrolling from the MPS 7 Phase 3 Ultragenyx sponsored study UX003-CL301, 
CGIs performed at the primary (or feeder) study End of Treatment visit or within 30 days 
prior to Baseline may be used for the study baseline assessment.   
For subjects enrolling from clinical studies with UX003 other than UX003-CL301, the 
Subject/Parent/Caregiver CGI will only be administered if previously performed in their 
primary (or feeder) study. CGIs performed within 30 days prior to Baseline may be used for 
the study baseline assessment.   
7.5.4.14 Hepatosplenomegaly 
Liver and spleen size will be assessed qualitatively by physical examination at 48-week 
intervals (or at Termination Visit). 
Refer to the Study Reference Manual for more detail. 
7.5.4.15 Cardiac Ventricular Mass 
Ventricular mass will be assessed by ECHO and scored as a z-score relative to normal 
ventricular mass. Evaluation of valvular function and cardiac function will be made primarily 
for safety purposes. ECHO will be performed at the Baseline visit, then every 48 weeks 
thereafter (or at termination visit).   
An ECHO performed at the primary (or feeder) study End of Treatment visit or within 
30 days prior to the Baseline visit may be used for the Baseline assessment provided cardiac 
ventricular mass can be calculated. 
7.5.5 Appropriateness of Measurements 
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 antibody levels and complement C3, C4 
and CH50 levels will be determined (as indicated) as a measure of the immune response to 
UX003 treatment. 
Urinary GAG is a measure of the underlying biochemical defect in MPS 7 subjects.  
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 


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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. Spirometry, goniometry, ECHO, 
visual acuity, 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 6MWT, BOT-2, and 3MSCT are useful for assessing the compounded impact of 
multisystem clinical manifestations on the performance of activities of daily living. In 
MPS 7, performance on these tests is likely to be affected by the pulmonary, cardiovascular, 
and musculoskeletal morbidity present in these subjects (McDonald et al. 2010). 
Spirometry will be conducted to assess respiratory compromise, an important component of 
disease progression and mortality in MPS 7 subjects. Where possible, additional 
subject-reported outcomes were included to assess functional disability and activities of daily 
living (e.g., MPS HAQ, CHAQ/HAQ, PedsQL, and CGI). Other efficacy assessments, 
including a multi-domain clinical responder index enable a composite analysis of clinical 
changes. 
The ICR is a measure of each subject’s response to treatment that is selected based on the 
relevance of the outcome measure to concerns that the subject/parent/caregiver has reported, 
the subject’s ability to complete clinical outcome assessment reliably, and the extent of 
impairment for that individual. The ICR enables evaluation of the clinical benefit of 
UX003 by assessing change in a pre-specified individualized clinical outcome that is deemed 
most relevant for each subject and then determining an overall response rate for the study 
population. For subjects who were previously treated in an Ultragenyx sponsored study 
(i.e., UX003-CL301) and had an ICR assigned, that same ICR may be followed in this 
long-term treatment and extension study. 
7.6 
Statistical Methods and Determination of Sample Size 
7.6.1 Sample Size 
Approximately 20 subjects with a confirmed diagnosis of MPS 7, who were previously 
treated with UX003 in either an Ultragenyx-sponsored study or a non-Ultragenyx sponsored 
study, or UX003 treatment-naïve subjects at least 5 years old at the time of informed consent 
with a confirmed diagnosis of MPS 7 will be enrolled into this study. Hence, there is not a 
formal sample size calculation and justification.  


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7.6.2 Analysis Populations 
Full Analysis Set: The full analysis set will consist of all subjects who receive at least 1 dose 
of investigational product. 
7.6.3 Statistical Principles 
Continuous variables will be summarized by number of subjects and mean, standard 
deviation (SD), median, minimum, and maximum values. Categorical variables will be 
summarized by number and percentage of subjects. Statistical tests will use 2-sided 
alpha =0.05 significance level. Two-sided 95% confidence intervals will also be presented 
Safety and Efficacy analysis will all be based on Full Analysis Set using observed data. 
Missing values will not be imputed, unless otherwise specified. 
The analyses planned in this protocol will be expanded in the UX003-CL202 SAP. The SAP 
will be approved prior to the database lock. Any deviations from the analyses described in 
the protocol and SAP will be noted in the final clinical study report (CSR).  
The statistical analyses will be reported using summary tables, figures, and data listings.  . 
All analyses and tabulations will be performed using SAS®. All raw data obtained from the 
CRFs as well as any derived data will be included in data listings. 
7.6.4 Demography, Baseline Characteristics, and Disposition 
Demographics (age, sex, and race) and other baseline disease characteristics will be 
summarized using descriptive statistics.  
The number of subjects enrolled, treated, and completed will be summarized. 
Subject discontinuation from the study, and from treatment, will each be summarized 
including reason for discontinuation. 
7.6.5 Efficacy endpoints  
The percentage change from pre-treatment baseline in uGAG and changes from 
pre-treatment baseline for other efficacy endpoints will be described across subjects in terms 
of the mean and standard deviation. The percentage change from pre-treatment baseline in 
uGAG will be tested using the GEE method. The GEE model will include baseline and time 
as categorical variables.   
7.6.6 Safety Analyses 
The following safety measures in this study will be summarized: 
• Incidence and frequency of AEs, treatment related AEs,  and SAEs 


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• Clinically significant changes from baseline in vital signs, weight, physical examination 
findings, ECHO and clinical laboratory tests 
• Concomitant medications 
• UX003 antibodies 
• Complement C3, C4 and CH50 levels (as indicated) 
7.6.6.1 Adverse Events 
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, Preferred 
Term (PT), relationship to study drug, and severity. All reported AEs with onset during the 
treatment (i.e. treatment-emergent AEs) will be included in the analysis. Special attention 
will be given to those subjects who died, discontinued treatment due to an AE, or 
experienced a SAE (e.g., summaries, listings, and narrative preparation may be provided, as 
appropriate). 
7.6.6.2 Clinical Laboratory Evaluations 
Clinical laboratory data will be summarized by the type of laboratory test. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and at each 
scheduled time point.  The frequency and percentage of subjects who experience abnormal 
clinical laboratory results (i.e., outside of reference ranges) and/or clinically significant 
abnormalities will be presented for each clinical laboratory measurement. A listing of 
subjects with any markedly abnormal laboratory results will be provided.  
7.6.6.3 Vital Signs 
Vital signs will be summarized and listed by individual subject. Summaries of vital signs 
data over time and changes from Baseline over time will be provided. 
7.6.6.4 Exposure 
Exposure to UX003 will be summarized using the number of doses and total amount of drug 
administered to each subject during the study. 
7.6.7 Interim Analyses 
No interim analyses are planned for this study. 
7.6.8 Data Monitoring Committee 
There will not be a Data Monitoring Committee used in this study. 


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8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 Institutional Review Board (IRB) or Ethics Committee (EC)  
The IRB/EC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, "Institutional Review Boards."  This protocol, any protocol amendments, the 
associated informed consent forms (ICFs), and the informed consent procedures must be 
submitted to the IRB/EC for review and must be approved before the enrollment of any 
subject into the study. Investigational Product 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 Assembly General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The Investigator will make every effort 
that 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 Investigational Product, as 
described in this protocol and the Investigator's Brochure, 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 Investigational Product 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 


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the study have been fully explained to each potential subject. The Investigator must explain 
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. 
Receipt 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 (SDV). The monitor will verify the Investigator's 
ongoing qualifications, to inspect clinical site facilities, and to inspect study records, 
including proof of EC/IRB review, with the stipulation that subject confidentiality will be 
maintained in accordance with local and federal regulations, including HIPAA requirements.   
A Coordinating Investigator will be identified for multicenter trials. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data.  
The Coordinating Investigator will read and sign the Clinical Study Report (CSR). 


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8.3 
Investigational Product Accountability 
While at the clinical site, Investigational Product must be stored in a secure limited access 
location at controlled temperature as described in the Investigator’s Brochure 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 Investigational Product 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 
Investigational Product must be returned to Ultragenyx and/or its designee unless other 
instructions have been provided for final disposition of the Investigational Product.  
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 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, 


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including 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 with the study site 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. 
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 2 years after the last approval of a marketing application or for at least 
2 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 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. 


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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:  
• Death 
• A life-threatening adverse event 
• 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 subject 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. 


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• 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 
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. 


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8.5.4 Adverse Event Reporting to Ultragenyx 
8.5.4.1 General 
All AEs (i.e. any new or worsening in severity or frequency of a pre-existing condition) with 
an onset after the subject signs consent for study participation must be promptly documented 
on the AE eCRF via the EDC system. The Principal Investigator is responsible for evaluating 
all AEs, obtaining supporting documents, and ensuring documentation of the event is 
adequate. Details of the AE must include severity, relationship to study drug, duration, and 
outcome.  
For subjects enrolling from an Ultragenyx-sponsored clinical trial, all AEs will be recorded 
from the time the subject signs the informed consent for this extension study and completion 
of the End of treatment visit in the primary study until 30 days after the last dose of study 
drug. Adverse events reported as ongoing at primary study’s End of treatment visit and any 
new AEs prior to Baseline will be reviewed and recorded at Baseline visit. Any enrolling 
subject who had an early termination in the primary study will have their baseline AE 
information collected in the same manner as a subject who is treatment naïve or enrolling 
from a non-Ultragenyx sponsored study (see following paragraph). 
For subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored 
clinical trial, all AEs will be recorded from the time the subject signs the informed consent 
until 30 days after the last dose of study drug.   
In addition, the Investigator should report any AE that occurs after this time period that is 
believed to have a reasonable possibility of being associated with study drug.  
AEs ongoing at 30 days following the last dose of study drug should have a comment in the 
source document by the Investigator that the event has recovered, recovered with sequelae, or 
stabilized.  
8.5.5 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.  


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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. 
All deaths, regardless of causality, from the time of consent through 30 days after last dose of 
study drug must be reported as an SAE to Ultragenyx or its designee within 24 hours of 
knowledge.  
The Investigator also must notify the IRB/EC of the occurrence of the SAE, in writing, as 
soon as is practicable and in accordance with local law. A copy of this notification must be 
provided to Ultragenyx or its designee. 
8.5.5.1 Pregnancy Reports 
Reported pregnancy of a subject or a subject’s partner, while participating in this study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. Pregnancy associated SAEs will be processed and submitted, as required, as per the 
SAE reporting process. 
8.5.6 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), IRBs/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, or as otherwise required per local laws and regulations. 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 its 
designee within 24 hours. Ultragenyx or its designee will inform Regulatory Authorities, 
IRBs/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 


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Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J 
Cardiopulm.Rehabil. 21 (2):87-93. 
Grubb, JH, Vogler, C, Levy, B, Galvin, N, Tan, Y, and Sly, WS. 2008. "Chemically modified 
beta-glucuronidase crosses blood-brain barrier and clears neuronal storage in murine 
mucopolysaccharidosis VII." Proc.Natl.Acad.Sci.U.S.A 105 (7):2616-2621. 
Hankinson, JL, Odencrantz, JR, and Fedan, KB. 1999. "Spirometric reference values from a 
sample of the general U.S. population." Am.J Respir Crit Care Med 159 (1):179-187. 
Harmatz, P, Giugliani, R, Schwartz, I, Guffon, N, Teles, EL, Miranda, MC, Wraith, JE, 
Beck, M, Arash, L, Scarpa, M, Yu, ZF, Wittes, J, Berger, KI, Newman, MS, Lowe, 
AM, Kakkis, E, and Swiedler, SJ. 2006. "Enzyme replacement therapy for 
mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, 
multinational study of recombinant human N-acetylgalactosamine 4-sulfatase 
(recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension 
study." J.Pediatr. 148 (4):533-539. 
Islam, MR, Grubb, JH, and Sly, WS. 1993. "C-terminal processing of human beta-
glucuronidase. The propeptide is required for full expression of catalytic activity, 
intracellular retention, and proper phosphorylation." J Biol Chem. 268 (30):22627-
22633. 
Kakkis, ED. 2002. "Enzyme replacement therapy for the mucopolysaccharide storage 
disorders." Expert Opin Investig Drugs 11 (5):675-85. 
Kakkis, ED, Matynia, A, Jonas, AJ, and Neufeld, EF. 1994. "Overexpression of the human 
lysosomal enzyme alpha-L-iduronidase in Chinese hamster ovary cells." Protein Expr 
Purif 5 (3):225-32. 
Kakkis, ED, McEntee, MF, Schmidtchen, A, Neufeld, EF, Ward, DA, Gompf, RE, Kania, S, 
Bedolla, C, Chien, SL, and Shull, RM. 1996a. "Long-term and high-dose trials of 
enzyme replacement therapy in the canine model of mucopolysaccharidosis I." 
Biochem Mol Med 58 (2):156-67. 


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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. 
Kakkis, ED, and Neufeld, EF. 1996b. "The Mucopolysaccharidoses." In Principles of Child 
Neurology, edited by Berg BO, 1141-1165. New York: McGraw-Hill. 
Lee, JE, Falk, RE, Ng, WG, and Donnell, GN. 1985. "Beta-glucuronidase deficiency. A 
heterogeneous mucopolysaccharidosis." Am.J.Dis.Child 139 (1):57-59. 
McDonald, A, Steiner, R, Kuehl, K, and Turbeville, S. 2010. "Clinical utility of endurance 
measures for evaluation of treatment in patients with mucopolysaccharidosis VI 
(Maroteaux-Lamy syndrome)." J Pediatr Rehabil.Med 3 (2):119-127. 
Muenzer, J, Wraith, JE, Beck, M, Giugliani, R, Harmatz, P, Eng, CM, Vellodi, A, Martin, R, 
Ramaswami, U, Gucsavas-Calikoglu, M, Vijayaraghavan, S, Wendt, S, Puga, AC, 
Ulbrich, B, Shinawi, M, Cleary, M, Piper, D, Conway, AM, and Kimura, A. 2006. "A 
phase II/III clinical study of enzyme replacement therapy with idursulfase in 
mucopolysaccharidosis II (Hunter syndrome)." Genet.Med 8 (8):465-473. 
Neufeld, EF, and Muenzer, J. 2001. "The Mucopolysaccharidoses." In The Metabolic and 
Molecular Bases of Inherited Disease, edited by CR Scriver, AL Beaudet, WS Sly 
and D Valle, 3421-3452. New York: McGraw-Hill. 
O'Connor, LH, Erway, LC, Vogler, CA, Sly, WS, Nicholes, A, Grubb, J, Holmberg, SW, 
Levy, B, and Sands, MS. 1998. "Enzyme replacement therapy for murine 
mucopolysaccharidosis type VII leads to improvements in behavior and auditory 
function." J.Clin.Invest 101 (7):1394-1400. 
Oshima, A, Kyle, JW, Miller, RD, Hoffmann, JW, Powell, PP, Grubb, JH, Sly, WS, Tropak, 
M, Guise, KS, and Gravel, RA. 1987. "Cloning, sequencing, and expression of cDNA 
for human beta-glucuronidase." Proc.Natl.Acad.Sci.U.S.A 84 (3):685-689. 
Sands, MS, Vogler, C, Kyle, JW, Grubb, JH, Levy, B, Galvin, N, Sly, WS, and Birkenmeier, 
EH. 1994. "Enzyme replacement therapy for murine mucopolysaccharidosis type 
VII." J.Clin.Invest 93 (6):2324-2331. 
Sands, MS, Vogler, C, Torrey, A, Levy, B, Gwynn, B, Grubb, J, Sly, WS, and Birkenmeier, 
EH. 1997. "Murine mucopolysaccharidosis type VII: long term therapeutic effects of 
enzyme replacement and enzyme replacement followed by bone marrow 
transplantation." J.Clin.Invest 99 (7):1596-1605. 
Sands, MS, Vogler, CA, Ohlemiller, KK, Roberts, MS, Grubb, JH, Levy, B, and Sly, WS. 
2001. "Biodistribution, kinetics, and efficacy of highly phosphorylated and non-


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phosphorylated beta-glucuronidase in the murine model of mucopolysaccharidosis 
VII." J.Biol.Chem. 276 (46):43160-43165. 
Scott, HS, Bunge, S, Gal, A, Clarke, LA, Morris, CP, and Hopwood, JJ. 1995. "Molecular 
genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological 
implications." Hum.Mutat. 6 (4):288-302. 
Sewell, AC, Gehler, J, Mittermaier, G, and Meyer, E. 1982. "Mucopolysaccharidosis type 
VII (beta-glucuronidase deficiency): a report of a new case and a survey of those in 
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Treatments. Boston, Massachusetts. 
Singh, G, Athreya, BH, Fries, JF, and Goldsmith, DP. 1994. "Measurement of health status in 
children with juvenile rheumatoid arthritis." Arthritis Rheum 37 (12):1761-9. 
Sly, WS, Quinton, BA, McAlister, WH, and Rimoin, DL. 1973. "Beta glucuronidase 
deficiency: report of clinical, radiologic, and biochemical features of a new 
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Sly, WS, Vogler, C, Grubb, JH, Levy, B, Galvin, N, Tan, Y, Nishioka, T, and Tomatsu, S. 
2006. "Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice 
defines roles for the mannose 6-phosphate and mannose receptors." 
Proc.Natl.Acad.Sci.U.S.A 103 (41):15172-15177. 
Sly, WS, Vogler, C, Grubb, JH, Zhou, M, Jiang, J, Zhou, XY, Tomatsu, S, Bi, Y, and Snella, 
EM. 2001. "Active site mutant transgene confers tolerance to human beta-
glucuronidase without affecting the phenotype of MPS VII mice." 
Proc.Natl.Acad.Sci.U.S.A 98 (5):2205-2210. 
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." 
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Varni, JW, Seid, M, and Kurtin, PS. 2001. "PedsQL 4.0: reliability and validity of the 
Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and 
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Varni, JW, Seid, M, and Rode, CA. 1999. "The PedsQL: measurement model for the 
pediatric quality of life inventory." Med.Care 37 (2):126-139. 


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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-
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"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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replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis 
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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. 
Zech, A, Steib, S, Sportwiss, D, Freiberger, E, and Pfeifer, K. 2011. "Functional muscle 
power testing in young, middle-aged, and community-dwelling nonfrail and prefrail 
older adults." Arch.Phys.Med Rehabil. 92 (6):967-971. 
 
 


PPD
PPD

SAP_001.pdf: 
Study Number: UX003-CL202 
Statistical Analysis Plan 
08 Mar 2016, Version 1.0 
Approval Form for Statistical Analysis Plan 
Protocol Number: 
UX003-CL202 
Protocol Title: 
A Long-Term Open-Label Treatment and Extension Study ofUX003 
rhGUS Enzyme Replacement Therapy in Subjects with MPS 7 
Status: 
vl.O 
Proprietary and Confidential 
PPD


Study Number: UX003-CL202 
Statistical Analysis Plan 
08 Mar 2016, Version 1.0 
Approval Form for Statistical Analysis Plan 
Protocol Number: 
UX003-CL202 
Protocol Title: 
A Long-Term Open-Label Treatment and Extension Study ofUX003 
rhGUS Enzyme Replacement Therapy in Subjects with MPS 7 
Status: 
vl.O 
Senior Management Review: 
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PPD


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STATISTICAL ANALYSIS PLAN 
 
Title 
A Long-Term Open-Label Treatment and Extension Study 
of UX003 rhGUS Enzyme Replacement Therapy in 
Subjects with MPS 7 
Protocol: 
UX003-CL202 
Investigational Product: 
UX003, recombinant human beta-glucuronidase (rhGUS) 
Phase: 
3 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
Associate Director, Biostatistics 
 
Date: 
08 Mar 2016 
Version Number: 
1.0 
 
 
 
PPD


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Table of Contents 
1 
INTRODUCTION ...............................................................................................................6 
2 STUDY OBJECTIVES ........................................................................................................7 
2.1 Primary ........................................................................................................................7 
2.2 Secondary ....................................................................................................................7 
2.3 Other............................................................................................................................7 
3 STUDY DESIGN.................................................................................................................8 
3.1 Overall Study Design and Plan ...................................................................................8 
3.2 Study Duration ............................................................................................................8 
3.3 Determination of Sample Size ....................................................................................8 
3.4 Interim Analysis ..........................................................................................................9 
3.5 Data Monitoring Committee .......................................................................................9 
3.6 Randomization and Blinding ......................................................................................9 
4 STUDY CLINICAL OUTCOMES....................................................................................10 
4.1 Safety Assessments ...................................................................................................10 
4.2 Efficacy Variables .....................................................................................................10 
5 DEFINITIONS ...................................................................................................................12 
5.1 Baseline .....................................................................................................................12 
5.2 Fold increase in uGAG above upper normal limit ....................................................12 
5.3 Multidomain responder index ...................................................................................12 
5.4 Fatigue MID score ....................................................................................................14 
5.5 Growth Velocity ........................................................................................................14 
5.6 Percent predicted Six-Minute Walk Tests ................................................................14 
5.7 Anti-rhGUS Antibody Titer Values ..........................................................................15 
5.8 Duration of exposure to UX003 ................................................................................15 
6 ANALYSIS POPULATIONS ...........................................................................................16 
7 DATA SCREENING AND ACCEPTANCE ....................................................................17 


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7.1 Handling of Missing and Incomplete Data ...............................................................17 
7.2 Missing Date Imputation Rules.................................................................................17 
7.3 Visit Time Windows .................................................................................................18 
7.4 Software ....................................................................................................................19 
8 STATISTICAL METHODS OF ANALYSIS ...................................................................20 
8.1 General Principles .....................................................................................................20 
8.2 Subject Disposition ...................................................................................................20 
8.3 Demographics and Other Baseline Characteristics ...................................................20 
8.4 Medical History.........................................................................................................20 
8.5 Prior and Concomitant Medications .........................................................................20 
8.6 Dosing Summary.......................................................................................................21 
8.7 Efficacy Analyses .....................................................................................................21 
8.8 Safety Analyses .........................................................................................................22 
8.8.1 
Adverse Events ............................................................................................22 
8.8.2 
Laboratory Parameters ................................................................................23 
8.8.3 
Other Safety Parameters ..............................................................................23 
8.8.4 
Antibodies ...................................................................................................23 
9 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................24 
10 REFERENCES ..................................................................................................................25 
11 APPENDICES ...................................................................................................................27 
 
LIST OF TABLES 
Table 5.3.1: 
Definition of the Minimal Important Difference for multi-
domain responder analysis ...................................................................12 
Table 7.3.1: 
Visit Time Windows ............................................................................19 
Table 11.1.1: 
Schedule of Events ...............................................................................27 
 
 


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ABBREVIATIONS 
2MWT   
Two Minute Walk Test  
3MSCT 
Three Minute Stair Climb Test  
6MWT 
Six Minute Walk Test 
ADA  
anti-drug antibody 
AE 
 
adverse event 
APRG  
Adverse Physiology Related Group  
BOT-2  
Bruininks-Oseretsky Test of Motor Proficiency  
CGI 
 
Clinicians’s Global Impression  
CHAQ  
Childhood Health Assessment Questionnaire 
CRF 
 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC   
Data Monitoring Committee 
ECHO  
echocardiogram  
ERT 
 
Enzyme Replacement Therapy 
FEV1  
forced expiratory volume in one second 
FVC  
forced vital capacity 
GAG  
glycosaminoglycan 
GEE 
 
Generalized Estimating Equation  
 
HAQ  
Health Assessment Questionnaire 
ICR 
 
Individualized Clinical Response  
IV  
 
intravenous 
ITT 
 
Intent to Treat  
MedDRA  
Medical Dictionary for Regulatory Activities  
MPS 7  
mucopolysaccharidosis type 7, Sly Syndrome 
MVV1  
maximum voluntary ventilation in one minute 
PK 
 
Pharmacokinetic  
rhGUS  
Recombinant Human Beta-Glucuronidase 
SAE 
 
serious adverse event 
SAP 
 
Statistical Analysis Plan 
SOC   
system organ class  


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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-CL202 Protocol dated 28 October 2014 
through Protocol Amendment version 1.0 dated 18 December 2015. The data collected in this 
study will evaluate the long-term safety and efficacy of UX003 treatment in subjects with 
Mucopolysaccharidoses type 7 (MPS 7). This SAP does not describe any Pharmacokinetic 
(PK) data analyses. 


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2 STUDY OBJECTIVES 
2.1 
Primary 
The primary objective is to evaluate the long-term safety of UX003 in subjects with MPS 7. 
2.2 
Secondary 
The secondary objective is to evaluate the long-term efficacy of UX003 in reducing urinary 
glycosaminoglycans (uGAG) in subjects with MPS 7. 
2.3 
Other 
Other objectives are to evaluate: 
• Measures of lysosomal storage including hepatosplenomegaly  
• Measures of other clinical and functional outcomes, including pulmonary function, 
walking distance, shoulder flexion, fine motor function, gross motor function, climbing 
stairs, visual acuity, and cardiac size and function, and a composite Multi-Domain 
Responder Index (MDRI), as applicable per subject status.  
• Growth, assessed by changes in height (or length) and weight growth velocity. 
• Subject-reported disability and quality of life, and fatigue, as indicated. 
• Subject or parent/caregiver global assessment of change and impact on activities of daily 
living, as indicated.  
• If an individualized clinical response (ICR) endpoint was defined for a subject from a 
previous UX003 study, the ICR may continue to be followed. 


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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-CL202 is a multi-center, multi-national, open-label treatment and extension study in 
subjects with MPS 7. The study will assess long-term safety and efficacy of UX003 
treatment and will continue for approximately 144 weeks, or until the study drug is 
commercially available in the subject’s local territory, or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the Investigator or Ultragenyx, or the study is terminated. 
Subjects with MPS 7 who are UX003 treatment-naïve or previously enrolled and treated in a 
prior clinical study of UX003 may have the option to enroll into this treatment and extension 
study provided all eligibility criteria have been met for a given subject.  Subjects with MPS 7 
who were enrolled in either an Ultragenyx sponsored study (e.g., UX003-CL301) or 
non-Ultragenyx sponsored clinical studies (e.g., Investigator sponsored trials (ISTs), 
expanded access/compassionate use) may be eligible for enrollment. Those subjects enrolling 
from a previous UX003 study should have a reasonable benefit-risk assessment from their 
feeder study as determined by the Investigator, in order to continue with long-term therapy in 
this extension study.  
All subjects will receive 4 mg/kg UX003 every other week (QOW) unless data from prior 
studies define a different dose either for that subject or the use of UX003 in general.  
3.2 
Study Duration 
The planned duration of treatment in this study is up to 144 weeks, or until the study drug is 
commercially available in the subject’s local territory, or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the Investigator or Ultragenyx, or the study is terminated. 
The schedule of events is shown in Appendix 1. 
3.3 
Determination of Sample Size 
Up to 20 subjects with a confirmed diagnosis of MPS 7, who were previously treated with 
UX003 in either an Ultragenyx-sponsored study (rollover subjects) or a non-Ultragenyx 
sponsored study (IST subjects) as well as UX003 treatment-naïve subjects will be enrolled 
into this study. Hence, there is not a formal sample size calculation and justification. 


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3.4 
Interim Analysis 
After the first 8 rollover subjects from 301 complete the Week 12 assessment, an analysis 
will be conducted to support filing. 
Additional analyses may be performed during the study at the discretion of the Sponsor. 
There is no unblinding during these analyses since it is an open-label study. 
3.5 
Data Monitoring Committee 
Safety in this open-label study will be monitored by Ultragenyx. An independent data 
monitoring committee will not be used. 
3.6 
Randomization and Blinding  
All subjects received UX003 on an open-label basis. Randomization, blinding and 
stratification factors are not needed for this study design.  


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4 STUDY CLINICAL OUTCOMES  
4.1 
Safety Assessments 
Safety will be evaluated by the incidence, frequency and severity of AEs and serious adverse 
events (SAEs), including clinically significant changes from study baseline to scheduled time 
points in vital signs, weight, physical examination, clinical laboratory evaluations, and 
concomitant medications.  
APRG safety reporting is a novel method that captures symptoms and their timing, allowing 
the diagnostic synthesis of infusion related events into one of several multi-domain 
physiology related groups to capture infusion-associated reaction (IAR) information. APRG 
reporting has been incorporated into the study design to detect adverse physiologies that 
might be expressed variably within and between subjects in a study. 
To assess the immune response to UX003, the development of IgG antibodies to rhGUS, and 
complement C3, C4, and CH50 levels only be drawn if an IAR occurs will also be evaluated 
as indicated. Pregnancy testing (or pregnancy of partner, if needed) will also be conducted. 
4.2 
Efficacy Variables 
• Urinary GAG Excretion: First morning void urine will be evaluated for uGAG 
concentration  
• Biomarkers of inflammation in serum: Blood samples will be collected to evaluate levels 
of biomarkers of inflammation and response to treatment. 
• Six Minute Walk Test (6MWT):  The total distance walked (meters) in a six minute 
period  
• Bruininks-Oseretsky Test of Motor Proficiency (BOT-2):  This test of motor proficiency 
will be administered to evaluate treatment-related changes in four domains assessing both 
fine and gross motor function: fine motor precision, manual dexterity, balance, running 
speed and agility. The test may be modified and tests omitted to accommodate the needs 
of the subject.  
• Three Minute Stair Climb Test (3MSCT):  The number of stairs climbed within a three 
minute period. 
• Pulmonary function testing: Spirometry will be administered to subjects who do not 
require invasive ventilatory support or have a tracheostomy. Pulmonary function 
variables include forced vital capacity (FVC) and maximum voluntary ventilation 
(MVV).   
• Shoulder flexion maximum range of motion:  Goniometry will be used to measure 
(in degrees) the maximum passive shoulder range of motion in both flexion and 
extension. 


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• Growth (anthropometric): Growth will be assessed by anthropometric measurements 
including standing height (or recumbent length or sitting height if applicable) and weight.  
• Visual acuity: will be measured using a standard eye chart and recorded for each eye 
independently.  
• Multi-domain Responder Analysis (MDRI): The multi-domain responder analysis will 
consider the scoring as described in Section 5.3.  
• Individualized Clinical Response (ICR): Will only be assessed for subjects previously 
enrolling from the Ultragenyx-sponsored MPS 7 Phase 3 clinical study UX003-CL301 
where an outcome of interest was previously selected from the possible clinical outcome 
measures, the same ICR identified in the feeder study may continue to be followed in this 
study. 
• Scoring of Impactful Clinical Problems: The three most impactful clinical problems as 
reported by the subject/parent/caregiver during the Clinical Problem Evaluation will be 
scored on a Likert scale.  For UX003 treatment-naïve subjects, the initial Clinical 
Problem Evaluation will occur at the Baseline visit. For subjects enrolling from the 
Ultragenyx-sponsored MPS 7 Phase 3 clinical study UX003-CL301, the Clinical 
Problems identified during the UX003-CL301 Randomization visit will continue to be 
scored throughout this study. 
• Subject-reported disability, health related quality of life, and fatigue:  The MPS Health 
Assessment Questionnaire, Childhood Health Assessment Questionnaire (CHAQ), or 
Health Assessment Questionnaire (HAQ) will be administered to evaluate treatment-
related changes in self-care and mobility activities of daily living. The age-appropriate 
Pediatric Quality of Life Multidimensional Fatigue Scale (Peds QL-Multidimensional 
Fatigue Scale) will be administered to evaluate treatment-related changes in fatigue. 
• Subject/Parent/Caregiver Clinical Global Impression (CGI) scales: Subjects or 
parents/caregivers will provide a global assessment of change using a CGI scale. In 
addition, subjects or parents/caregivers will provide narratives of their perception of how 
treatment has impacted the subject’s ability to complete activities of daily living. 
• Hepatosplenomegaly:  Liver and spleen measurements will be assessed by physical exam.   
• Cardiac ventricular mass/function: Ventricular mass will be assessed by echocardiogram 
(ECHO) and scored as a z-score relative to normal ventricular mass.  


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5 DEFINITIONS 
5.1 
Baseline 
Naïve subjects: 
• uGAG baseline is defined as the average of all assessments prior to or on the date of the 
first dose of UX003 in this study. Baseline value for other endpoints is the last non-
missing assessment prior to or on the date of the first dose of UX003 in this study.  
IST subjects: 
• uGAG baseline is the average of all assessments prior to or on the date of the initiation of 
the initial treatment with UX003. 
• Baseline value for other endpoints is the last non-missing assessment prior to or on the 
date of first dose of UX003 in this study.  
Rollover subjects: 
• The baseline (efficacy and safety) defined in feeder study will be used for this study.  
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 1. 
5.3 
Multidomain responder index   
The multidomain responder score will be calculated as the total score across the following six 
domains (6MWT, FVC%pred, Shoulder flexion, Visual acuity, and BOT-2 fine motor and 
BOT-2 gross motor) (Table 5.3.1). 
Table 5.3.1: 
Definition of the Minimal Important Difference for multi-domain responder 
analysis 
 
Domain 
Minimal important difference (MID) 
References 
6MWT 
23 meter AND 10% change from 
baseline 
(Redelmeier et al. 1997), (Puhan et al. 2008), 
(du Bois et al. 2011), (Mathai et al. 2012), 
(Wraith et al. 2004), (Clarke et al. 2009), 
(Muenzer et al. 2006), (Harmatz et al. 2006), 
(BioMarin 2013) 
FVC%pred 
5% absolute change or 10% relative 
change from baseline in FVC%pred 
(Wraith et al. 2004), (Muenzer et al. 2006), 
(BioMarin 2013) 
Shoulder flexion 
20 degree change of passive shoulder 
range of motion 
(Wraith et al. 2004), (Harmatz et al. 2006), 
(Clarke et al. 2009), (Okuyama et al. 2010) 


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Domain 
Minimal important difference (MID) 
References 
Visual acuity 
3 lines (corrected, both eyes) 
(Arch-Ophthalmol 1999); (Ferris et al. 1982), 
(Reeves et al. 1993) 
BOT-2 fine motor 
Fine Motor Precision: change of 0.72 
Manual Dexterity: change of 1.47 
(Wuang et al. 2009)  
BOT-2 gross motor 
Balance: 0.57 
Running speed and agility:0.59 
(Wuang et al. 2009) 
 
To compute the multi-domain responder index, changes over time in each domain variable 
will be scored and classified as follows.  In general, if the change is equal or greater than one 
minimal clinically important difference (MID), the score of +1 is provided.  If changed 
negatively by one MID or greater, the score is -1.  If there is no clinically significant change 
(>-1.0 to <1.0 MID), the score is 0.   Furthermore: 
• For 6MWT distance, the score +1 will be assigned when there is an increase of 23 meters 
or more AND a greater than 10% increase from baseline are observed, while the score -1 
will be assigned when there is a decrease of 23 meters or more and a decrease of 10% or 
more from baseline are observed.  Otherwise the score for this domain is 0. 
• For FVC%pred, the score +1 will be assigned when a 5% absolute increase or 10% relative 
increase from baseline, while the score -1 will be assigned when a 5% absolute decrease 
or 10% relative decrease from baseline. Otherwise the score for this domain is 0. 
• For visual acuity, the score +1 will be assigned when both eyes, corrected, have 3 lines or 
more improvement in visual acuity scales, while the score -1 will be assigned when both 
eyes, corrected, declined 3 lines or more in visual acuity scales.  Otherwise the score for 
this domain is 0.  One line of improvement is defined as -0.10 of change in LogMAR 
scale. 
• For shoulder flexion domain where there are two tests to evaluate MID: the score +1 will 
be assigned when at least one side (left or right) range of motion improves at least one 
MID or more where the other side does not decline for more than one MID.  The score -1 
will be assigned when both shoulder range of motion decline for more than one MID.  
Otherwise the score will be set as 0. 
• For BOT-2 fine motor and gross motor domains where there are two tests to evaluate 
MID: the score +1 will be assigned when at least one test improves at least one MID or 
more where the other test does not decline for more than one MID.  The score -1 will be 
assigned when both tests decline for more than one MID.  Otherwise the score will be set 
as 0.  The scaled score from BOT-2 is used to evaluate MID. 
The integration of benefit will occur by summing the responses, positive, negative or zero, 
across all domain variables to derive the subject-specific multi-domain responder index.   


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If a subject is unable to reliably or safely perform a particular assessment at a visit, that 
domain will be scored as 0 for that visit.   
5.4 
Fatigue MID score 
The MID score +1 will be assigned if ≥10 points increase from baseline in fatigue total score. 
The MID score -1 will be assigned if ≥10 points reduction from baseline in fatigue total 
score. Otherwise the MID score is 0.  
5.5 
Growth Velocity 
Growth will be assessed by anthropometric measurements of height.  Z-scores and 
percentiles will be calculated using CDC growth chart (Kuczmarski, 2000), and for both 
historical (up to 2 years) and on study anthropometric measurements for males ≤18 years and 
females ≤15 at informed consent of this study. 
Growth velocity will be assessed by a model-based approach. A linear regression model for 
each subject will be built for selected pre-treatment data and post-treatment data:  
Yt = β0 + β1Xt + εi 
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. 
5.6 
Percent predicted Six-Minute Walk Tests 
To calculate the percent predicted 6MWT value, the following formulas will be applied 
(Geiger et al. 2007) for subjects aged <20 years old at informed consent of this study 
𝐹𝐹𝐹𝐹𝐹𝐹 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀: 𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
196.72 + (39.81 ∗𝐴𝐴𝐴𝐴𝐴𝐴) −(1.36 ∗𝐴𝐴𝐴𝐴𝐴𝐴2) + (132.28 ∗𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡) ∗100 
 
𝐹𝐹𝐹𝐹𝐹𝐹 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹: 𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
188.61 + (51.50 ∗𝐴𝐴𝐴𝐴𝐴𝐴) −(1.86 ∗𝐴𝐴𝐴𝐴𝐴𝐴2) + (86.10 ∗𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡) ∗100 
 
Where: 
Xi = The percent predicted 6MWT result at time i for subject X 
X0i = The 6MWT (m) result at time i for subject X 
 
To calculate the percent predicted 6MWT value, the following formulas will be applied 
(Gibbons et al. 2001) for subjects aged  ≥ 20 years old 15 at informed consent of this study: 
𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
868.8 −(2.99 ∗𝐴𝐴𝐴𝐴𝐴𝐴) + (74.7 ∗𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊) ∗100 


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Where: 
Xi = The percent predicted 6MWT result at time i for subject X 
X0i = The 6MWT (m) result at time i for subject X 
The age and height measured at corresponding visit will be used to calculate percent 
predicted 6MWT value.  
5.7 
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). 
5.8 
Duration of exposure to UX003 
Duration of exposure to UX003 in days in this is defined as: last date of UX003 infusion – 
first date of UX003 infusion in this study + 14 days. 


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6 ANALYSIS POPULATIONS 
Full Analysis Set: consists of all enrolled subjects who receive at least one dose of 
investigational product in this study.  
l ultra~Y?
I 


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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 scales or measures with missing item scores. Missing and incomplete data will be 
identified by Data Management through a review of tables and listings for this study and 
investigated for possible resolution 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. 
Assessments performed on unscheduled/end of treatment visits can be mapped to scheduled 
visits (based on target days of the scheduled visits), if the scheduled visits are missing 
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. 
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: 


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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 
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. 


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Table 7.3.1: 
Visit Time Windows 
Period 
Visit 
Scheduled Visit Day 
Window 
First 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 
Treatment  
Weeks 50-240 
Week 60 
Day 421 
Days [start of continuation 
period, 463] 
 
Every 12 Weeks 
Day 84xa+421 
[380+84x,463+84x] 
 
Week 144 
Day 1009 
Days ≥ 968 
a x=1,2…6 
 
Termination visit for subjects who didn’t complete the study, 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 visit has 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 
All analysis will be performed based on full analysis set, and summaries will be presented 
overall and for naïve, IST and rollover subjects separately. The statistical analyses will be 
reported using summary tables, figures, and data listings.  Statistical tests will be 2-sided at 
the alpha =0.05 significance level. All p-values will be presented as nominal p-values.  
Continuous variables will be summarized with means, standard deviations, medians, 
minimums, and maximums.  Categorical variables will be summarized by counts and by 
percentages of subjects in corresponding categories. All raw data obtained from the CRFs as 
well as any derived data will be included in data listings.  
8.2 
Subject Disposition 
The subjects in the full analysis set will be summarized. The reasons for study 
discontinuation will be summarized. 
8.3 
Demographics and Other Baseline Characteristics 
For rollover subjects, demographic parameters (e.g., age, sex, race and ethnicity) and other 
baseline characteristics (i.e., initial diagnosis, height and weight) measured at baseline of the 
feeder study will be used. For naïve subjects or IST subjects, demographic and other baseline 
characteristics measured at the baseline of this study will be used. 
8.4 
Medical History 
Medical and MPS treatment history will be summarized. Medical and MPS treatment history 
for rollover subjects are recorded in the feeder study. 
8.5 
Prior and Concomitant Medications 
The latest World Health Organization Drug (WHODRUG) dictionary will be used to classify 
prior and concomitant medications.  
For rollover subjects, prior medication will be defined as any medication taken before the 
first dose in the feeder study. For naïve and IST subjects, prior medication will be 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.  
The number and proportion of subjects receiving each reported prior and concomitant 
medication will be summarized by Anatomical Therapeutic Chemical (ATC) code and 
preferred term.  Multiple uses by a subject of the same drug will be counted only once in the 
summary tables.  


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8.6 
Dosing Summary 
The number of infusions and cumulative dose and duration of exposure to UX003 per subject 
in this study will be summarized. Treatment compliance will be displayed. 
8.7 
Efficacy Analyses 
Because the primary objective of this study is to evaluate the long-term safety, the efficacy 
parameters will not be grouped into primary or secondary categories. 
The percent change in uGAG excretion will be analyzed using the generalized estimating 
equation (GEE) method. Model will include baseline a covariate and visit (in this study) as a 
factor. The covariance structure within subjects will be assumed to be exchangeable.  
Descriptive statistics will be presented by assessment time point for observed and change 
from baseline for the following other efficacy parameters.  
• Biomarkers of inflammation in serum 
• 6MWT and the percent predicted 6MWT value 
• BOT-2 
• 3MSCT 
• Pulmonary function testing (eg., FVC, FEV and MVV1) 
• Shoulder range of motion (goniometry) in extension and flexion by shoulder and the 
average of the right and left shoulders. 
• Visual acuity  
• Fatigue 
• MPS HAQ 
• CHAQ 
• HAQ 
• Scoring of impactful clinical problems 
• Cardiac ventricular mass 
Descriptive statistics will be presented by assessment time point for the following other 
efficacy parameters.  
• MDRI 
• Fatigue MID 
• Subject/Parent/Caregiver CGI scales 
• Hepatosplenomegaly 


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For growth, anthropometric measurements with z scores and percentiles will be summarized 
by historical time point and on study visit. For naïve subjects, the slopes of growth velocities 
will be summarized for pre (historical up to 2 years and baseline data) and post (baseline and 
post treatment data) treatment periods. For IST subjects, the growth velocities will be 
calculated for pre-initial UX003 treatment (up to 2 years) and post-initial UX003 treatment. 
For rollover subjects, the growth velocities will be calculated for pre first treatment in the 
feeder study (up to 2 years) and post first treatment in the feeder study. 
For ICR, whether a positive change, according to the MID criteria, has occurred in the pre-
specified ICR will be assessed. The percentage of subjects achieving an ICR MID will be 
calculated for the rollover subjects and presented by assessment time point. 
8.8 
Safety Analyses 
8.8.1 
Adverse Events 
The latest Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
AEs to a system organ class (SOC) and 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 in this study, and was not present prior to the 
first dose in this study, or it was present at the first dose in this study but increased in severity 
during the 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, and death will also be generated. The severity will be based on 
Common Terminology Criteria for Adverse Events (CTCAE). 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 related to AE. 
Patterns of Infusion Associated Reactions (IARs) will be specifically evaluated throughout 
the study. 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. 


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8.8.2 
Laboratory Parameters 
Clinical laboratory values (in SI units) and changes from baseline at each assessment time 
point will be summarized for laboratory parameters in hematology, chemistry and urinalysis. 
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 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 
18 December 2015)  
 
 


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10 REFERENCES 
Arch-Ophthalmol. 1999. "Photodynamic therapy of subfoveal choroidal neovascularization 
in age-related macular degeneration with verteporfin: one-year results of 2 
randomized clinical trials--TAP report. Treatment of age-related macular 
degeneration with photodynamic therapy (TAP) Study Group." Arch Ophthalmol 117 
(10):1329-45. 
BioMarin. 2013. "Vimizim (elosulfase alfa) for the treatment of Mucopolysaccharidosis 
Type IVA (Morquio A Syndrome)." Briefing Document for the Endocrinologic and 
Metabolic Drugs Advisory Committee (19 November 2013). 
Clarke, LA, Wraith, JE, Beck, M, Kolodny, EH, Pastores, GM, Muenzer, J, Rapoport, DM, 
Berger, KI, Sidman, M, Kakkis, ED, and Cox, GF. 2009. "Long-term efficacy and 
safety of laronidase in the treatment of mucopolysaccharidosis I." Pediatrics 123 
(1):229-40. 
du Bois, RM, Weycker, D, Albera, C, Bradford, WZ, Costabel, U, Kartashov, A, Lancaster, 
L, Noble, PW, Sahn, SA, Szwarcberg, J, Thomeer, M, Valeyre, D, and King, TE, Jr. 
2011. "Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and 
minimal clinically important difference." Am J Respir Crit Care Med 183 (9):1231-7. 
Ferris, FL, 3rd, Kassoff, A, Bresnick, GH, and Bailey, I. 1982. "New visual acuity charts for 
clinical research." Am J Ophthalmol 94 (1):91-6. 
Geiger, R, Strasak, A, Treml, B, Gasser, K, Kleinsasser, A, Fischer, V, Geiger, H, 
Loeckinger, A, and Stein, JI. 2007. "Six-minute walk test in children and 
adolescents." J Pediatr 150 (4):395-9, 399. 
Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J 
Cardiopulm.Rehabil. 21 (2):87-93. 
Harmatz, P, Giugliani, R, Schwartz, I, Guffon, N, Teles, EL, Miranda, MC, Wraith, JE, 
Beck, M, Arash, L, Scarpa, M, Yu, ZF, Wittes, J, Berger, KI, Newman, MS, Lowe, 
AM, Kakkis, E, and Swiedler, SJ. 2006. "Enzyme replacement therapy for 
mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, 
multinational study of recombinant human N-acetylgalactosamine 4-sulfatase 
(recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension 
study." J.Pediatr. 148 (4):533-539. 
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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Mathai, SC, Puhan, MA, Lam, D, and Wise, RA. 2012. "The minimal important difference in 
the 6-minute walk test for patients with pulmonary arterial hypertension." Am J 
Respir Crit Care Med 186 (5):428-33. 
Muenzer, J, Wraith, JE, Beck, M, Giugliani, R, Harmatz, P, Eng, CM, Vellodi, A, Martin, R, 
Ramaswami, U, Gucsavas-Calikoglu, M, Vijayaraghavan, S, Wendt, S, Puga, AC, 
Ulbrich, B, Shinawi, M, Cleary, M, Piper, D, Conway, AM, and Kimura, A. 2006. "A 
phase II/III clinical study of enzyme replacement therapy with idursulfase in 
mucopolysaccharidosis II (Hunter syndrome)." Genet.Med 8 (8):465-473. 
Okuyama, T, Tanaka, A, Suzuki, Y, Ida, H, Tanaka, T, Cox, GF, Eto, Y, and Orii, T. 2010. 
"Japan Elaprase Treatment (JET) study: idursulfase enzyme replacement therapy in 
adult patients with attenuated Hunter syndrome (Mucopolysaccharidosis II, MPS II)." 
Mol Genet Metab 99 (1):18-25. 
Puhan, MA, Mador, MJ, Held, U, Goldstein, R, Guyatt, GH, and Schunemann, HJ. 2008. 
"Interpretation of treatment changes in 6-minute walk distance in patients with 
COPD." Eur Respir J 32 (3):637-43. 
Redelmeier, DA, Bayoumi, AM, Goldstein, RS, and Guyatt, GH. 1997. "Interpreting small 
differences in functional status: the Six Minute Walk test in chronic lung disease 
patients." Am J Respir Crit Care Med 155 (4):1278-82. 
Reeves, BC, Wood, JM, and Hill, AR. 1993. "Reliability of high- and low-contrast letter 
charts." Ophthalmic Physiol Opt 13 (1):17-26. 
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. 
Wuang, YP, and Su, CY. 2009. "Reliability and responsiveness of the Bruininks-Oseretsky 
Test of Motor Proficiency-Second Edition in children with intellectual disability." Res 
Dev Disabil 30 (5):847-55. 


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11 APPENDICES 
Appendix 1  Schedule of Events 
Table 11.1.1: Schedule of Events 
 
 
Treatment / Assessment Period b,c 
Baseline a,b 
First 48 Weeks of Treatment 
Treatment Weeks 50 - 144 
Termination 
Visit z  
0 
Every 2 
Weeks 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Every 2 
Weeks 
Every 12 
Weeks d 
Every 24 
Weeks e 
Every 48 
Weeks f 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history g 
X 
 
 
 
 
 
 
 
 
 
 
ICR identification (only for 
UX003-CL301 subjects) h  
X 
 
 
 
 
 
 
 
 
 
 
Weight for drug preparationi 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
Clinical Problem Evaluationj 
X 
 
 
X 
 
X 
 
 
X 
 
X 
UX003 Treatment 
X 
X 
 
 
 
 
X 
 
 
 
 
Safety Assessments 
Physical examination k 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
Vital signs l 
X 
X 
 
 
 
 
X 
 
 
 
X 
Clinical laboratory tests m 
X 
 
 
 
 
X 
 
 
 
X 
X 
Urine pregnancy test n 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
Antibodies to rhGUS o 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Complement C3, C4, CH50 
(for subjects with IARs) p 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment / Assessment Period b,c 
Baseline a,b 
First 48 Weeks of Treatment 
Treatment Weeks 50 - 144 
Termination 
Visit z  
0 
Every 2 
Weeks 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
Every 2 
Weeks 
Every 12 
Weeks d 
Every 24 
Weeks e 
Every 48 
Weeks f 
 
Concomitant medications 
X 
X 
 
 
 
 
X 
 
 
 
X 
Adverse events q 
X 
X 
 
 
 
 
X 
 
 
 
X 
Efficacy Assessments 
Urinary GAG r 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
Serum biomarkers of 
inflammation 
X 
 
 
X 
 
X 
 
 
X 
 
X 
6MWT, BOT-2, 3MSCT s 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Spirometry t 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Goniometry u 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anthropometrics v 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
Visual acuity (eye chart) 
X 
 
 
X 
 
X 
 
 
X 
 
X 
MPS HAQ, CHAQ/HAQ, Peds 
QL w 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Subject/Parent/Caregiver CGIx 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Liver and spleen assessment y 
X 
 
 
 
 
X 
 
 
 
X 
X 
Echocardiogram  
X 
 
 
 
 
X 
 
 
 
X 
X 
Abbreviations:  CGI = clinical global impression, ICR = Individual Clinical Response, IAR = infusion-associated reaction, GAG = glycosaminoglycan, 
6MWT = Six-Minute Walk Test, BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency (Second Edition), 3MSCT = Three-Minute Stair Climb Test, 
CHAQ = Childhood Health Assessment Questionnaire, MPS HAQ = Mucopolysaccharidosis Health Assessment Questionnaire, Peds QL = Pediatric Quality 
of Life Inventory™, rhGUS = recombinant human beta-glucuronidase, GAG = glycosaminoglycans 


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a. 
For subjects enrolling from UX003-CL301, the Baseline Visit will be conducted in conjunction with the UX003-CL301 Week 48 study visit to avoid 
treatment disruption. Subjects enrolling from an Ultragenyx-sponsored clinical study: efficacy, ECHO and clinical laboratory assessments performed 
during the final or End of Treatment visit from the feeder study may be used as baseline assessments if performed within 30 days of study baseline visit 
as indicated in Section 7.5. Any listed assessments not performed during the feeder study final visit must be performed before the first study drug 
infusion. Unless otherwise specified, Baseline assessments must be completed within 30 days prior to the first dose of study drug.  For subjects who are 
treatment naïve or who are enrolling from a non-Ultragenyx sponsored clinical study, initial baseline safety and efficacy assessments as indicated in 
Section 7.5 will be performed within 30 days of the study baseline visit as indicated in Section 7.5.  Refer to Study Reference Manual for additional 
details. 
b. For all subjects, assessments scheduled on the same day as treatment must be completed prior to the infusion. 
c. 
Visit windows are ± 3 days and for major assessment visits (Weeks 12, 24, 36, 48 and every 24 weeks thereafter), the window is ± 7 days.   
d. Actual study weeks for every-12-week visits = Weeks 60, 72, 84, 96, 108, 120, 132, 144. 
e. 
Actual study weeks for every-24-week visits = Weeks 72, 96, 120, 144. 
f. 
Actual study weeks for every-48-week visits = Weeks 96, 144. 
g. Medical history will be collected for all subjects who are treatment naïve or who are enrolling from a non-Ultragenyx sponsored study (e.g., Investigator 
sponsored trials (ISTs), expanded access/compassionate use).  For subjects enrolled in UX003-CL301 or other Ultragenyx sponsored study, their 
previously reported medical history will carry over to this study. 
h. The ICR will only be identified for subjects enrolling from the MPS 7 Phase 3 Ultragenyx sponsored study UX003-CL301.   
i. 
Weight for drug preparation may be obtained up to 15 days prior to indicated visit (e.g. Weeks 10, 22, 34, and 46 visits). 
j. 
For UX003 treatment-naïve subjects the three most impactful clinical problems reported by the subject/parent/caregiver will be identified and scored at 
the Baseline visit. These clinical problems will continue to be scored throughout this study.  For subjects enrolling from the MPS 7 Phase 3 Ultragenyx 
sponsored study UX003-CL301, the three most impactful clinical problems reported by the subject/parent/caregiver during the UX003-CL301 
randomization visit will continue to be scored throughout this study. 
k. Physical examinations are to include neurologic examination and evaluation of the presence or absence of corneal clouding.  If subject complains of leg 
weakness or fatigue, evaluate for signs of cord compression (e.g., leg reflexes and motor strength). 
l. 
On infusion days, vital signs will be measured at a minimum of: immediately (<30 minutes) before the infusion, at least every 30 minutes for the first 
hour of infusion, at least every hour for the remainder of the infusion and immediately (<30 minutes) after the infusion.  Additional measurements 
should be obtained as appropriate. 
m. 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.  Laboratory samples for safety performed within 30 days prior to Baseline may be used for the study baseline. 
n. For women of childbearing potential only.  A serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy test result. 
o. Testing for IgG antibodies directed against rhGUS. Antibody sample must be collected before infusion. 
p. If a drug-related IAR has occurred, C3, C4 and CH50 samples should be drawn prior to and immediately after the next infusion. 


Study Number:  UX003-CL202  
Statistical Analysis Plan,  
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q. For subjects enrolling from an Ultragenyx-sponsored clinical trial, all AEs will be recorded from the time the subject signs the informed consent and 
completes the End of Treatment visit in the feeder study until 30 days after the last dose of study drug.  For subjects who are treatment naïve or who are 
enrolling from a non-Ultragenyx-sponsored clinical trial, all AEs will be recorded from the time the subject signs the informed consent until 30 days 
after the last dose of study drug.   
r. 
Urine samples must be collected from first morning voids.  
s. 
The 6MWT, 3MSCT and BOT-2 assessments may be conducted over a span of two days with each test performed once. The preferred order is to 
perform the 6MWT and 3MSCT on separate days. If performed on the same day, the 6MWT should be done before the 3MSCT. The subject’s resting 
heart rate must return to baseline between assessments.  
t. 
Pulmonary function testing may be omitted for subjects with tracheostomies. If performed on the same day, pulmonary function testing should be done 
before the 6MWT and 3MSCT. The subject’s resting heart rate must return to baseline between assessments.    
u. The highest value of three shoulder flexion and extension range of motion measurements for each side will be reported. 
v. Anthropometric measurements include standing height and weight. If standing height cannot be obtained, recumbent length or sitting height will be 
determined.  
w. The MPS HAQ or HAQ/CHAQ should be performed for UX003 treatment-naïve subjects and subjects enrolling from the MPS 7 Phase 3 Ultragenyx 
sponsored study UX003-CL301. The MPS HAQ will be administered to all age groups. The CHAQ should be performed for pediatric subjects only 
(<14 years old). The HAQ should be performed for subjects ≥14 years old.  Subjects will consistently complete the same questionnaire (HAQ or 
CHAQ) administered at baseline for the duration of the study regardless of whether their age changes from 13 to 14 during the study.  The age-
appropriate version of the PedsQL multidimensional fatigue module will be administered throughout the study. For subjects enrolling from previous 
clinical trial with UX003, these subject-reported outcome measures will only be administered if they were previously performed in their feeder study. 
x. As part of the subject/parent/caregiver clinical global impression assessment, subjects/parents/caregivers will be asked to provide narratives of how 
treatment has impacted the subject’s ability to complete activities of daily living. 
y. Liver and spleen size will be assessed qualitatively by physical examination.  
z. 
If a subject withdraws from the study, or if the study terminated prior to Week 144, the termination visit should be completed within 30 days of the last 
dose of study drug.  Assessments performed within 30 days of the termination visit will not be repeated unless clinically indicated.