An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) Capsules in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy
Phase: PHASE2
Conditions: GNE Myopathy, Hereditary Inclusion Body Myopathy (HIBM)
Sponsor: Ultragenyx Pharmaceutical Inc

 
An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of 
Sialic Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) 
Capsules in Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy 
                                    
                                    Protocol Number: 
 
UX001-CL202 
                                    Original Protocol: 
 
01 March 2013 
                                    Amendment 1: 
 
02 October 2013 
                                    Amendment 2: 
 
17 December 2014 
                                    Amendment 3: 
 
07 October 2015 
                                    Amendment 4: 
 
17 June 2016  
 
Investigational Product: 
Sialic Acid-Extended Release Tablets (SA-ER)/Sialic Acid-
Immediate Release Capsules (SA-IR) 
Indication: 
GNE myopathy, also known as Hereditary Inclusion Body 
Myopathy (HIBM), Distal Myopathy with Rimmed Vacuoles 
(DMRV), or Nonaka Disease 
IND/EudraCT Number: 
109,334 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA  94949 
Sponsor’s Responsible 
Medical Officer: 
 MD 
Vice President, Clinical Sciences  
 
 
Coordinating Investigator: Professor Yoseph Caraco, MD  
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), and 
applicable regulatory requirements. 
 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary and is 
the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx).  Unauthorized disclosure, reproduction, transmission, 
or use of this document or information is strictly prohibited.  By accepting this document, the recipient agrees that 
the information it contains will not be disclosed without written authorization from Ultragenyx, except to the extent 
required to satisfy Institutional Review Board /Ethics Committee procedures, to obtain written informed consent 
from potential subjects, or as required by law. 

Protocol Number:  UX001-CL202 
Protocol Amendment 4 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 4 
17 June 2016 
 
 
The Protocol Amendment 3 of UX001-CL202 (dated 07 October 2015) has been modified by 
Amendment 4 to incorporate a number of changes based on additional information acquired 
since the beginning of the study.  The major changes to the protocol impacting the conduct of 
the study are summarized below.  Additional changes have also been made to provide 
supportive background information and rationale for the proposed changes (along with minor 
edits for consistency and clarity) but are not detailed in this summary. 
1. The Month 36 visit was defined as the end of study visit. In addition, this amendment 
now provides subjects the opportunity to enroll in the UX001-CL302, an ongoing 
extension study. These changes affected the synopsis, Table 2.2, and Sections 7.1 and 
7.5.1. This amendment also clarifies that the Termination Visit is not required for 
subjects who are rolling over to the UX001-CL302 extension study, but is required 
for subjects who terminate study participation early or who decide not to participate 
in the UX001-CL302 extension study. 
Rationale: The changes were made to clarify the end of study visit, clarify which 
subjects are required to complete the Termination Visit, and to provide subjects in the 
current study the opportunity to enroll in the UX001-CL302 extension study.  
2. 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. 
3. Updates were made to Section 7.4.2, Identity of Study Drug.  
Rationale: These changes were made for clarification. 
4. A change was made to Section 8.5.4, Adverse Event Reporting to Ultragenyx.  
Rationale: This change was made to be consistent with the current Ultragenyx 
template language regarding this topic. 
 

Protocol Number:  UX001-CL202 
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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 3 
07 October 2015 
 
 
The Protocol Amendment 2 of UX001-CL202 (dated 17 December 2014) has been modified 
by Amendment 3 to incorporate a number of changes based on additional information 
acquired since the beginning of the study.  The major changes to the protocol impacting the 
conduct of the study are summarized below.  Additional changes have also been made to 
provide supportive background information and rationale for the proposed changes (along 
with minor edits for consistency and clarity) but are not detailed in this summary. 
1. Part IV was added to change the formulation from sialic acid immediate release 
(SA-IR) to SA extended release (SA-ER). The SA-IR dose formulation has been 
removed. This change affects multiple sections of the protocol synopsis and body of 
the protocol, including the Schedule of Events (Table 2.2), Study Rationale 
(Section 5.4), Study Objectives (Section 6), Investigational Plan (Section 7), and 
Treatments (Section 7.4). 
Rationale: By the 4th day of dosing in a nonclinical study conducted in dogs, AUC for 
free SA was similar between the immediate and extended release formulations. In 
addition, a review of population data for Month 12 of Part III in the current study 
confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. 
Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by 
taking SA-ER.  
2. Updated Section 8.5.1 (Definition of Adverse Events) with the following text: “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.” 
Rationale: Updated for clarification of the SAE definition. 
3. Updated Sections 8.5.4 with new text related to reporting of adverse events. 
Rationale: Updated to align with other Ultragenyx protocols. 
4. Updated safety contact information (Section 8.5.5). 
Rationale: Updated to inform proper reporting of serious adverse events. 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 2 
17 December 2014 
 
 
The Protocol Amendment 1 of UX001-CL202 (dated 02 October 2013) has been modified by 
Amendment 2 to incorporate a number of changes based on additional information acquired 
since the beginning of the study.  The major changes to the protocol impacting the conduct of the 
study are summarized below.  Additional changes have also been made to provide supportive 
background information and rationale for the proposed changes (along with minor edits for 
consistency and clarity) but are not detailed in this summary. 
1. Sponsor’s Responsible Medical Officer and associated Medical Monitor contact 
information (Section 8.5.6) have been updated to: 
, MD 
2. Part III was added to the study design to allow for the reduction of the dose from 12g/day 
to 6g/day for a majority of participating subjects. This change affects multiple sections of 
the protocol synopsis and body of the protocol, including the Schedule of Events 
(Table 2.2), Study Rationale (Section 5.4), Study Objectives (Section 6), Investigational 
Plan (Section 7), and Treatments (Section 7.4). 
Rationale: This change is based on a review of the data for the rollover subjects from the 
parent study UX001-CL201 who had been receiving 12g/day in Part II of this extension 
study.  The data analysis suggests that an improvement of at least 15% in either the UEC 
or the LEC after 6 months of treatment with 12g/day SA represents a response that is 
suggestive of an added benefit from the higher dose.  The small subset of rollover 
subjects who meet these criteria, along with the ongoing naïve subjects, will have the 
option to remain on the 12g/day dose for the remainder of the study. 
3. The statistical methods were updated (synopsis and Section 7.6). 
Rationale: The statistical methods were updated to reflect the changes to the study design 
described in change #2 and to clarify which analyses populations were used for the Part 
II interim analyses. 
4. The protocol was updated to include a coordinating investigator. The coordinating 
investigator was identified on the cover page of the protocol and the selection process and 
responsibilities of the coordinating investigator are discussed in Investigators and Study 
Administrative Structure (Section 8.2).  

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Rationale: Identification of a coordinating investigator is required by the European 
Union.   
5. Prohibited Medications (Section 7.4.4.1) was updated by removing the text stating that 
urine will be analyzed to detect the presence of ManNAc.  
Rationale: This text was removed for clarification as this study procedure was only 
performed in Part I. 
6. Updated pregnancy text in Section 7.5.4.10. 
 
Rationale: This text was updated to match the current protocol template text. 
 
 

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CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX001-CL202 Amendment 1 
02 October 2013 
 
 
The Original Protocol 01 version of UX001-CL202 (dated 01 March 2013) has been 
modified by Amendment 1 to incorporate a number of changes based on additional 
information acquired since the beginning of the study.  The majority of changes were 
predicated by a complete analysis and review of pharmacokinetic (PK), pharmacodynamic 
(PD), clinical efficacy, and safety results from the 24-week placebo-controlled, double-blind 
Treatment Period of the UX001-CL201 Phase 2 clinical trial.  The major changes to the 
protocol impacting the conduct of the study are summarized below.  Additional changes have 
also been made to provide supportive background information and rationale for the proposed 
changes (along with minor edits for consistency and clarity) but are not detailed in this 
summary.  
1. Indication:  GNE Myopathy is now the preferred term used in the protocol for the 
indication.  The majority of references to HIBM have been replaced with GNE 
Myopathy. 
2. Sponsor’s Responsible Medical Officer and associated contact information has been 
changed to 
 MD PhD. 
3. Overall Study Design and Plan. 
The study will now be conducted in two parts.  Part I of the study will provide additional 
information on the long-term safety and efficacy of 6g/day dose of SA-ER as initially 
designed, except the maximum treatment duration on 6g SA-ER has been shortened to 
approximately 12 weeks.  The Part I Termination Visit will also serve as the Baseline 
Visit for Part II of the study. 
Part II of the study will assess the long-term safety and efficacy of an increased SA dose 
(12g/day).  In this phase, SA treatment will be administered in the form of SA-ER tablets 
and sialic acid immediate release (SA-IR) capsules.  Beginning with the Part II-Baseline 
Visit, all subjects currently enrolled in Part I will crossover to the SA-ER/SA-IR dosing 
regimen.  An additional 10 GNE Myopathy subjects will be enrolled into Part II of the 
study.  The additional subjects will provide an assessment of 12g/day SA-ER/SA-IR 
treatment in treatment-naïve subjects able to walk at least 200 meters (and < 80% 
predicted) in a screening 6 Minute Walk Test (6MWT).   Throughout the Part II 
Treatment Period, all subjects will be administered three 500 mg SA-ER tablets and three 

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500 mg SA-IR capsules orally four times per day (QID), in the morning, afternoon, early 
evening, and at bedtime (qHS), for a total dose of 12g/day.   
Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, 
and function, and changes in exploratory serum biomarkers will be performed according 
to the Schedule of Events specific to each phase of the study (Table 2.1 and Table 2.2).  
If reasonable efficacy and safety are demonstrated during an interim analysis following 6 
months of treatment, the subjects will continue treatment for up to 36 months.  A Part II 
Termination Visit will be conducted 4 weeks after subjects receive their last dose of study 
drug. 
Rationale:  The modification of study design was predicated on results of planned PK, 
PD, clinical efficacy, and safety analyses following the 24-week placebo-controlled 
Treatment Period in the UX001-CL201 Phase 2 clinical study, wherein SA-ER treatment 
was administered at two dose levels, 3g and 6g SA-ER/day.  The goal of the Week 24 
interim analysis was to identify the dose that provides the best risk-benefit profile.  
The results show that the highest dose (6g/day SA-ER) provided sustained exposure, a 
modest clinical efficacy signal, and acceptable safety profile.   
The clinical efficacy data showed dose-dependent improvement in muscle strength 
relative to placebo in some muscle groups, particularly in the upper extremities at the 
6g/day SA-ER dose. These changes were statistically significant or trended towards 
significance, and were more pronounced in subjects that had greater walking ability at 
baseline, a predefined subset.  Other clinical endpoints (e.g. weighted arm lift test) did 
not reveal measureable changes at the Week 24 interim assessment.  Creatine kinase 
(CK) levels showed a trend to improvement in the 6g/day SA-ER dose group compared 
with placebo.  Overall, SA-ER appeared to be well tolerated with no serious adverse 
events observed in either dose group. 
Based on data from the Week 24 analysis following the placebo-controlled Treatment 
Period, the 6g/day SA-ER dose level appears to be at the lower end of the effective range, 
while 3g/day SA-ER had almost no effect.  An additional analysis of safety and efficacy 
data will be conducted at the end of the Treatment Continuation Period in UX001-CL201 
Phase 2 clinical study to evaluate whether the observed treatment effect is sustained or 
increased over a longer 48-week period. However, additional clinical benefit is not 
expected.   
In summary, the Week 24 interim data show a modest positive clinical efficacy signal 
and acceptable safety profile at the 6g/day dose suggesting the potential to optimize the 
therapeutic index by increasing SA exposure.  Therefore, investigation into optimizing 
the risk-benefit profile of SA substrate replacement by examining higher SA doses is 
warranted. 
 

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4. Investigational Product and Treatment.   
Part II of the study will assess the safety and efficacy of 12g/day SA-ER/SA-IR treatment 
for 6 months.  If reasonable efficacy and safety are demonstrated, the subjects will 
continue SA-ER/SA-IR treatment for up to 36 months. 
The SA-ER/SA-IR study drugs administered in Part II of the study will consist of SA-ER 
tablets, each containing 500 mg of SA active ingredient in an extended release 
formulation, and SA-IR capsules, each containing 500 mg of SA active ingredient.  
During the Part II Treatment Period, the 12g total daily SA-ER/SA-IR dose will be 
administered by the oral route and will be divided into a QID regimen: three SA-ER 
tablets (1.5g SA-ER) and three SA-IR capsules (1.5g SA-IR) taken in the morning, 
afternoon, early evening, and qHS.  If tolerability issues arise, the dose may be 
temporarily stepped down until symptoms resolve. 
Rationale:  Since successful use of SA replacement therapy in humans is believed to 
depend upon optimized exposure to the compound, an increased dose will be examined in 
Part II of the study.  Although administration of more extended release tablets could be 
utilized, data in canines suggests that administration of immediate release SA in 
combination with the SA-ER will maximize absorption in the GI tract. Therefore, Part II 
will examine safety and efficacy of an increased dose level combining immediate release 
SA (SA-IR) with SA-ER. 
The SA-ER/SA-IR dose and regimen for Study UX001-CL202 was selected based on the 
apparent detectable treatment effect at the highest dose and the association of higher SA 
serum levels with better improvement in strength, suggesting that a higher dose might be 
useful.  PK data from canine studies suggest that adding immediate release SA was the 
most effective way to increase SA, and higher doses of SA should be safe.  Supportive 
information is summarized below: 
• Dose effect at 6g only.  Interim results from UX001-CL201 suggest the 6g SA-ER 
dose level appears to be at the lower end of the effective range since a clinical 
efficacy signal was observed but 3g SA-ER had almost no effect.   
• The SA level correlates with treatment effect based on HHD.  The Week 24 
interim data imply a positive PD signal and acceptable safety profile suggesting the 
potential to optimize the therapeutic index by increasing SA exposure.   
• Canine studies show that immediate release most effective way to increase SA.  
Studies in normal canines showed that more than proportional increases in absorption 
of SA are possible if an immediate release formulation was mixed with an extended 
release formulation.  The concept is that the immediate release product enhances 
stomach absorption which is not well utilized by extended release formulated tablets. 
• QID therapy should support higher SA levels.  Since SA-IR is rapidly cleared, a 
QID dosing regimen is predicted to provide optimized continuous exposure to SA.  

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Administration of a 12g total daily dose of SA would therefore be divided into 4 
equal doses of 3g each (1.5g SA-ER + 1.5g SA-IR), representing only a 50% increase 
for each dose. 
• Safety of very high SA doses.  In a chronic toxicology study in rats, the NOAEL was 
2000 mg/kg SA, which provides a safety margin of approximately 1.4-fold for the 
proposed 12g/day dose level.  In a 6 month oral toxicity study in dogs, the NOAEL 
was 2000 mg/kg SA, which provides a safety margin of approximately 5-fold for the 
human 12g/day dose level.   
• Single doses of 6g SA-ER given in one dose, were well tolerated.  In the Phase 1 
PK and tolerability study, 6g SA-ER was administered to GNE Myopathy subjects in 
a single oral dose and was well tolerated with no SAEs observed. 
5. Study Objectives. 
The safety objectives in Part II of the study have been modified to evaluate the safety of 
12g/day SA in the treatment of GNE Myopathy subjects over a 6 month period.  
The clinical efficacy objectives of the study remain unchanged, except to reflect the 
change in investigational product to SA-ER/SA-IR.  An additional exploratory objective 
has been added to determine whether 12g /day of SA-ER/SA-IR administered as 
1.5g/1.5g four times per day is superior to prior treatment with 6g/day of SA-ER therapy 
administered as 2g three times per day in GNE Myopathy subjects.  
Rationale:  The objectives of the study have been revised to delineate specific aims for 
Part I and Part II of the study.  The change is in agreement with the overall study design 
and treatment regimens. 
6. Selection of Study Population and Sample Size. 
The sample size has been increased to enroll an additional 10 treatment naïve GNE 
Myopathy subjects into Part II of the study. 
Rationale:  Approximately 46 subjects currently enrolled in the study have completed a 
minimum of 48-weeks SA-ER treatment as part of study UX001-CL201 and Part I of this 
study.  Part II of the study will be the first time GNE Myopathy subjects will be treated 
with 12g/day SA-ER/SA-IR.  Therefore, 10 additional subjects will be enrolled to assess 
safety and clinical efficacy of the higher 12 g/day dose level in a treatment naïve 
population.  

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7. Inclusion Criteria. 
The first inclusion criterion was modified to: 
• Enrollment in, and successful completion of the UX001-CL201 protocol OR 
(for 10 treatment naïve subjects): 
o Have a confirmed diagnosis of GNE Myopathy 
o Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT 
(orthotics and assistive devices allowed) 
o No prior history of treatment with SA or MaNAc 
Rationale:   The modified criterion aids in defining the study population, which consists 
primarily of GNE Myopathy subjects who completed the UX001-CL201 Phase 2 clinical 
study, but also defines requirements for the enrollment of additional treatment naïve 
subjects.  The diagnosis and age range for the treatment naïve subjects are the same as 
requirements for continuing subjects.  The ability to walk at least 200 meters during the 
6MWT was an enrollment target for 60% of subjects in the UX001-CL201 protocol.  
Since the strongest clinical efficacy signal in the Week 24 interim analysis was observed 
in this subset of GNE Myopathy subjects, Part II of this study will seek to enroll 
additional subjects most likely to obtain clinical benefit from treatment.  
8. Schedule of Events.   
For clarity, the Schedule of Events has been separated into two distinct tables.  The visit 
schedule and assessments to be conducted during Part I of the study are presented in 
Table 2.1.  The visit schedule and assessments to be conducted during Part II of the study 
are presented in Table 2.2.   
Rationale:  Specific assessments may differ depending on the phase of the study (i.e. Part 
I or Part II).  Evaluations of safety, changes in clinical endpoints such as muscle strength, 
mobility, and function, PK, and changes in exploratory serum biomarkers will be 
performed according to the Schedule of Events specific to each phase of the study.   
9. Exploratory Efficacy Measures.    
Exploratory efficacy assessments will be conducted as indicated in the Schedule of 
Events for Parts I and II of the study (Table 2.1 and Table 2.2, respectively).  However, 
samples to assess serum protein biomarkers (other than CK) will not be obtained in Part 
II of the study. 
Rationale:  Results from a panel of serum biomarkers at the Week 24 interim analysis of 
the Phase 2 study (UX001-CL201) were ambiguous.  Therefore, serum protein 
biomarkers will not be assessed in Part II of the study to avoid subjecting study 
participants to unnecessary procedures.  CK levels in serum will be assessed in both Parts 

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I and II of the study since a positive, dose-dependent decrease in serum CK levels was 
observed in UX001-CL201. 
10. Safety Measures & Procedures.   
A detailed medical history, including a GNE Myopathy-specific medical history will be 
obtained at the Part II Screening/Baseline Visit for newly enrolled subjects only.  
There are no changes to safety measures, only revised timing of assessments.  
Safety assessments will be conducted as indicated in the Schedule of Events for Parts I 
and II of the study (Table 2.1 and Table 2.2, respectively). 
Rationale:  For continuing subjects, the Medical History information obtained during the 
UX001-CL201 study will carry over to the current treatment extension study.  
Similar information must be obtained for the treatment naïve subjects who will enroll 
directly into Part II of the study. 
Stopping Rules. 
Specific language regarding stopping rules (Section 7.3.3.1) has been modified as 
follows: 
“If two subjects develop the same unexpected Grade 3 AE that is possibly or probably 
related to study drug or any subject develops an unexpected Grade 4 AE that is possibly 
or probably related to study drug, enrollment of new subjects will may be suspended until 
a thorough evaluation can be performed.”  
Rationale:  Interim results following a 24-week Treatment Period with SA-ER are now 
available and provide a profile of expected AEs; no SAEs have been reported to date in 
the ongoing study.   Should unexpected Grade 3 and 4 AEs occur as detailed above, a full 
clinical evaluation will performed by the medical monitor, principal investigators, and the 
Data Monitoring Committee (DMC) as detailed in the protocol.  Following the full 
evaluation, an informed decision can be made whether to suspend enrollment or stop the 
study. 

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Safety Contact Information. 
The safety contact information for Ultragenyx (Biosoteria/Dohmen Safety) has been 
updated. 
11. Drug Concentration Measurements. 
Free SA in the urine will be measured in Part I of the study only.  Free SA trough levels 
will be assessed in serum during Parts I and II of the study.  There will be no assessments 
of free SA in the urine during Part II of the study. 
Rationale:  Results of PK assessments at the Week 24 interim analysis of the Phase 2 
study (UX001-CL201) suggest serum SA measurement is more reliable than urine for 
characterizing trough levels of SA.  Therefore, urine PK parameters will not be assessed 
in Part II of the study to avoid subjecting study participants to unnecessary procedures.   
12. Statistical Methods. 
An interim analysis will be conducted when the last subject has completed the Month 6 
Visit of the Part II Treatment Period.  For Part II efficacy evaluation of the continuing 
subjects, change from baseline of Part II to Month 6 assessment at 12g/day SA-ER/SA-IR 
dose will be determined and compared with the improvement observed during the first 
6 months of treatment with 6g/day SA-ER dose and to the rate of change observed with 
placebo or 3g treatments during the first 6 months of the study.  The 10 additional 
treatment naïve subjects will be evaluated for change from their baseline visit to Month 6 
assessment at 12g/day SA-ER/SA-IR dose compared with placebo, 3 g and 6 g treatments 
for 24 weeks in subjects that walk more than 200m at baseline in the 6MWT.  
Rationale:  Changes to the planned statistical analysis are consistent with the modified 
study design to assess the efficacy and tolerability of the higher dose of sialic acid.  
The planned interim analysis following 6-months treatment with SA-ER/SA-IR will 
provide an initial assessment of safety and efficacy.  If reasonable safety and efficacy are 
demonstrated, subjects will continue therapy for up to 36 months.  Full details of planned 
analysis will be presented in the Statistical Analysis Plan for UX001-CL202. 

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2 SYNOPSIS 
TITLE OF STUDY: 
An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of Sialic 
Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) Capsules in 
Patients with GNE Myopathy or Hereditary Inclusion Body Myopathy 
PROTOCOL NUMBER: 
UX001-CL202 
STUDY SITES: 
Four sites, globally 
PHASE OF DEVELOPMENT: 
Phase 2 
RATIONALE: 
GNE myopathy or hereditary inclusion body myopathy (HIBM) is a rare and severely debilitating 
disease caused by a defect in the biosynthetic pathway for sialic acid (SA).  Substrate replacement of 
SA in an extended release formulation (SA-ER; also termed Ace-ER) is a potential therapeutic 
strategy based on evidence from relevant in vivo models, supported by pharmacokinetic (PK) 
characterization in a Phase 1 clinical study, and stabilization in muscle strength in a Phase 2 
randomized controlled trial (UX001-CL201).  The interim data from the Phase 2 study implied a 
positive clinical efficacy signal and acceptable safety profile suggesting the potential to optimize the 
therapeutic index by increasing SA exposure.  Since successful use of SA replacement therapy in 
humans is believed to depend upon optimized exposure to the compound, an increased dose was 
suggested.  Although administration of more extended release tablets could be utilized, data in canines 
suggest that administration of immediate release SA (SA-IR) in combination with the SA-ER will 
maximize absorption in the GI tract. Therefore a study testing an increased dose level combining 
SA-IR with SA-ER was proposed.   
Subjects completing the 48-week study (UX001-CL201) were eligible to continue treatment under this 
open-label extension protocol.  Additional GNE Myopathy subjects have been enrolled to assess the 
safety and efficacy of SA-ER/SA-IR in a treatment naïve population. 
Ultragenyx is conducting this study (UX001-CL202) in four parts:  Part I of the study will provide 
additional information on the long-term safety and efficacy of 6g/day SA-ER; Part II of the study will 
assess the long-term safety and efficacy of 12g/day SA (comprised of 1.5g of SA-ER and 1.5g of 
SA-IR treatment 4 times per day). Parts III and IV will provide long-term safety and efficacy data on 
both 6 and 12g/day SA (both SA-ER/SA-IR [Part III] and SA-ER [Part IV]).  Part III was added based 
on a review of individual subject data for the rollover subjects from the parent study UX001-CL201 at 
Month 6. The data analysis suggested that a small subset of subjects received an added benefit from 
the higher dose (defined as at least a 15% increase in either the UEC or LEC).  The rollover subjects 
who met these criteria, along with the ongoing naïve subjects, had the option to remain on the 12g/day 
dose for the remainder of the study. Part IV was added to change the formulation from SA-IR to 
SA-ER. The SA-IR dose formulation has been removed based on data showing that by the 4th day of 
dosing in a nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 

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and extended release formulations. In addition, a review of population data for Month 12 of Part III in 
the current study confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. Therefore, no 
further SA-IR will be administered after the initiation of Part IV; patients currently on 12g/day may 
continue receiving the 12g/day dose, if desired, by taking SA-ER. 
Patients who elect to decrease from 12g/day to 6g/day may be allowed to do so upon Sponsor 
approval. 
OBJECTIVES: 
 
The safety objectives of the study are to: 
• Evaluate additional long-term safety of SA-ER treatment of GNE Myopathy subjects previously 
treated with SA-ER at dose of 6g/day (Part I) 
• Evaluate the safety of 12g/day SA (delivered by 1.5g of SA-ER tablets and 1.5g of SA-IR 
capsules 4 times per day) in the treatment of GNE Myopathy subjects (Part II) over a 6 month 
treatment period. 
• Evaluate the safety of SA treatment at both 6g/day and 12g/day (Part III [SA-ER/SA-IR] and 
Part IV [SA-ER]). 
 
The clinical objectives of the study are to: 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on muscle strength as 
measured by hand-held dynamometry (HHD) 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on mobility, strength, 
and function using a series of physical performance measures 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on functional disability 
using an interview-based questionnaire.  
 
The exploratory objectives of the study are to: 
• Evaluate the effect of SA treatment on serum biomarkers of sialylation in GNE Myopathy 
subjects (Part I) 
• Determine whether 12g /day SA-ER/SA-IR administered 1.5g/1.5g four times per day is superior 
to prior treatment with SA-ER in GNE Myopathy subjects (Part II) 
o Determine whether a subset of subjects have additional benefit on the higher dose 
treatment. 
STUDY DESIGN AND METHODOLOGY: 
This open-label extension study of will assess the long-term safety and efficacy of SA treatment over a 
period of approximately 36 months, or until marketing approval or program termination by 
Ultragenyx. Subjects who complete the study will be eligible to enroll into UX001-CL302 open-label 
extension study.  In Part I of the study, approximately 46 subjects will be enrolled following 
successful completion of the UX001-CL201 study.  The Baseline visit will be conducted in 
conjunction with the UX001-CL201 Week 48 study visit to avoid treatment disruption.  Enrollment 
will take place after all UX001-CL201 Week 48 study assessments have been completed and the 
investigator has determined the subject meets all eligibility criteria.  Data collected at the 

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UX001-CL201 Week 48 visit will serve as the Baseline data for Part I of this protocol.  Following the 
signing of informed consent at the Baseline visit, each subject will be dispensed a 6-week supply of 
study drug.  Throughout the Part I Treatment Period of the study, all subjects will continue to take four 
500 mg SA-ER tablets orally three times per day (TID), in the morning, early evening, and at bedtime 
(qHS), for a total dose of 6g/day.  The Part I Termination Visit will also serve as the Baseline Visit for 
Part II of the study. 
Beginning with the Part II-Baseline Visit, all subjects currently enrolled in Part I will crossover to the 
SA-ER/SA-IR dosing regimen.  Approximately 10 GNE Myopathy subjects will be enrolled into Part 
II of the study.  The additional subjects will provide an assessment of SA-ER/SA-IR treatment in SA 
naïve subjects able to walk at least 200 meters (and < 80% predicted) in a screening 6 Minute Walk 
Test (6MWT).   
Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, and function, 
and changes in exploratory serum biomarkers will be performed according to the Schedule of Events 
specific to each phase of the study (Table 2.1 and Table 2.2).  A Termination Visit will be conducted 
4 weeks after subjects receive their last dose of study drug (last dose of study drug received at Month 
36). For subjects who are eligible and choose to participate in the UX001-CL302 open-label extension 
study, the Month 36 Visit is considered the end of study visit and the Termination Visit is not required. 
Any subject who discontinues the current study early or is ineligible or decides not to participate in the 
UX001-CL302 open-label extension study is required to have a Termination Visit 4 weeks after their 
last dose of study drug, as per Schedule of Events. Efficacy data analyses will be conducted at the end 
of the Treatment Period, although interim analyses may be performed at the discretion of Ultragenyx. 
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).  An independent 
Data Monitoring Committee (DMC) will review safety information periodically an on an ad hoc basis 
as outlined in the DMC charter, which is maintained separately from this protocol. 
NUMBER OF SUBJECTS PLANNED: 
Up to 46 subjects previously treated in the UX001-CL201 study will be enrolled.  Approximately 
10 subjects, naïve to SA and MaNAc treatment, will be enrolled directly into Part II of the study. 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
 
Individuals eligible to participate in this study must meet all of the following criteria: 
• 
Enrollment in, and successful completion of the UX001-CL201 protocol OR  
(for 10 treatment naïve subjects): 
O Have a confirmed diagnosis of GNE Myopathy 
O Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT (orthotics 
and assistive devices allowed)  
o No prior history of treatment with SA or MaNAc  
• 
Must be willing and able to provide written, signed informed consent after the nature of the study 
has been explained, and prior to any research-related procedures 
• 
Must be willing and able to comply with all study procedures  
• 
Sexually active subjects must be willing to use an acceptable method of contraception while 

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participating in the study 
• 
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 been in menopause for at least two years, or have had tubal 
ligation at least one year prior to Baseline, or who have had total hysterectomy. 
 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
• 
Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at any time 
during the study 
• 
Use of any investigational product (other than SA-ER tablets) to treat GNE Myopathy 
• 
Ingestion of N-acetyl-D-mannosamine (ManNAc) or similar SA-producing compounds  
• 
Has had any hypersensitivity to SA or its excipients that, in the judgment of the investigator, 
places the subject at increased risk for adverse effects 
• 
Have any co-morbid conditions, including unstable major organ-system disease(s) that in the 
opinion of the investigator, places the subject at increased risk of complications, interferes with 
study participation or compliance, or confounds study objectives.  
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
Part I:  The investigational product will consist of SA-ER tablets, each containing 500 mg of SA active 
ingredient in an extended release formulation.  During the Part I Treatment Period, the 6000 mg (6g) 
total daily SA-ER dose will be administered by the oral route and will be divided into a TID regimen:  
four tablets in the morning, four tablets in the early evening, and four SA-ER tablets qHS.  
Part II:  Each dose of SA-ER/SA-IR will consist of SA-ER tablets, each containing 500 mg of SA 
active ingredient in an extended release formulation and SA-IR capsules, each containing 500 mg of 
SA active ingredient.  During the Part II Treatment Period, the 12,000 mg (12g) total daily SA dose 
will be administered by the oral route and will be divided into a QID regimen:  three SA-ER tablets 
(1.5g SA-ER) and three SA-IR capsules (1.5g SA-IR) taken in the morning, afternoon, early evening, 
and qHS.  If tolerability issues arise, the dose may be temporarily stepped down until symptoms 
resolve. 
Part III:  12g/day dose – Each dose of SA-ER/SA-IR will consist of SA-ER tablets, each containing 
500 mg of SA active ingredient in an extended release formulation and SA-IR capsules, each 
containing 500 mg of SA active ingredient.  During the Part III Treatment Period, the 12,000 mg (12g) 
total daily SA dose will be administered by the oral route and will be divided into a TID or QID 
regimen. If tolerability issues arise, the dose may be temporarily stepped down until symptoms 
resolve.  
6g/day dose – Each dose of SA-ER will consists of tablets, each containing 500 mg of SA active 
ingredient in an extended release formulation.  During the Treatment Period, the 6000 mg (6g) total 
daily SA-ER dose will be administered by the oral route and will be divided into a TID regimen. 
Part IV: 6g/day dose and 12g/day dose – Each dose of SA-ER will consists of tablets, each containing 
500 mg of SA active ingredient in an extended release formulation.  During the Treatment Period, the 
6g total daily SA-ER dose will be administered by the oral route and will be divided into a TID 

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regimen. The 12g total daily SA-ER dose will be administered by the oral route and will be divided 
into a TID or QID regimen. 
All doses should be taken with food (i.e. within 30 minutes following a meal or snack). 
DURATION OF TREATMENT: 
The Part I Treatment Period will be up to approximately 12 weeks (3 months) in duration.  The Part II, 
Part III, and Part IV Treatment periods will be up to 36 months in duration.  The total duration of the 
study will be up to 40 months.  
CRITERIA FOR EVALUATION: 
Efficacy: 
Efficacy will be evaluated by continued improvement in clinical assessments.  Efficacy assessments 
may differ depending on the phase of the study (i.e. Part I, Part II, Part III, or Part IV).   For Part I 
efficacy evaluation, results from the last pre-treatment assessment from UX001-CL201 will be 
compared with the last post-treatment assessment for the Part I Treatment Period as listed in the 
Schedule of Events (Table 2.1), with efficacy conclusions based on change since SA-ER treatment 
initiation.   
An interim analysis will be conducted when a majority of subjects have completed the Month 6 Visit 
of the Part II Treatment Period.  For Part II efficacy evaluation of the continuing subjects, change from 
baseline of Part II to Month 6 assessment at 12g/day SA-ER/SA-IR dose will be determined and 
compared with the improvement observed during the first 6 months of treatment with 6 g/day SA-ER 
dose, and to the rate of change observed with placebo or 3g treatments during the first 6 months of the 
study.  The changes from baseline of the treatment-naïve subjects will be evaluated over time.   
In addition, changes in muscle strength over the entire treatment period of subjects who started with 
6g/day and 3g/day will be evaluated and compared to the projected values of subjects who received 
placebo for the first 24 weeks of treatment in UX001-CL201. 
Clinical Efficacy Measures: 
• 
Hand-Held Dynamometry:  Muscle strength based on the maximum voluntary isometric 
contraction (MVIC) against a hand-held dynamometer will be measured in the following muscle 
groups: gross grip, pinch, shoulder abductors, elbow flexors, elbow extensors, hip abductors, hip 
adductors, hip flexors, hip extensors, knee flexors and knee extensors.  The total force (kg) will be 
measured as well as the percent of predicted normal force based on age, gender, height and weight 
(where applicable). 
• 
Six-Minute Walk Test:  The total distance walked (meters) in a six minute period will be 
measured as well as the percent of predicted normal distance based on age and gender.   
• 
Walking Speed Test:  The time required to walk 25 feet (7.62 meters) will be assessed at a 
comfortable and a maximum gait speed.  The total number of seconds required for each speed will 
be recorded.  Individual subject performance will also be compared to healthy peers based on 
normative data. 
• 
Weighted Arm Lift Test:  The number of times the subject can raise a 1 kg weight above the head 
in a 30-second period will be recorded.  The test will be performed bilaterally. 
• 
HIBM Functional Activities Scale:  The total score, as well as subscale scores for mobility, 
self-care, and upper extremity function on an interview-administered functional disability measure 
will be recorded. 

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Exploratory Efficacy Measures: 
• 
Serum protein markers:  Serum specimens will be evaluated to assess potential use as biomarkers 
of sialylation.  
• 
Creatine kinase levels in serum will be assessed as a potential biomarker for muscle injury 
Safety: 
Safety will be evaluated by the incidence and frequency of AEs and SAEs, including clinically 
significant changes from Baseline to scheduled time points in:  
• 
Vital signs 
• 
Neurological and physical examination results 
• 
Laboratory evaluations 
• 
Interval history:  reported symptoms of increasing muscle weakness or pain, incidence of falls 
STATISTICAL METHODS: 
Details of the planned interim analysis, safety and efficacy analyses will be provided in a statistical 
analysis plan maintained separately from this protocol. 
Interim Analysis: 
An Interim analysis will be conducted when a majority of subjects have completed the Month 6 Visit 
during the Part II Treatment period. 
Efficacy Analyses: 
Efficacy data analyses will be conducted at the end of the 6-month Treatment Period with 
SA-ER/SA-IR, when all subjects have completed 12 months of participation, and at the end of the 
36 month Treatment Period.  The treatment naïve subjects will be studied as a separate subgroup. 
Clinical efficacy analyses will include:  1) Muscle strength as measured by HHD, and reported as 
force in kg and percent of predicted normal, 2) Walking ability as measured by the 6MWT, and 
reported as distance in meters and percent of predicted normal, 3) Walking speed as measured by the 
walking speed test, which will be reported in seconds and percent of predicted normal for each 
walking speed, 4) Arm raising ability as measured by the weighted arm lift test, which will be 
reported as the total number of completed repetitions, and 5) Functional disability as measured by the 
HIBM-FAS, which will be reported as a total score and subscale scores for mobility, self-care, and 
upper extremity function with lower scores associated with greater disability.   
For those clinical evaluations with repeated assessments (i.e., HHD, 6MWT, and the walking speed 
and weighted arm lift tests), the analysis will be performed using a repeated measures analysis. 
A full accounting of the analyses for Parts III and IV of the study will be provided in the Statistical 
Analysis Plan.   
Safety Analyses: 
All subjects who receive study drug will be included in the safety analysis.  Safety will be evaluated 
on the incidence and frequency of AEs and SAEs, and clinically significant change in vital signs, 
laboratory test results, or physical examinations.  Safety data will be periodically reviewed by the 
DMC.  

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Table 2.1: 
Schedule of Events (Part I) 
a Potential subjects for the Part I Treatment Period will be baselined at the UX001-CL201 Week 48 study visit. Study drug 
will be dispensed only after UX001-CL202 consent has been signed and all study procedures have been performed. 
b For Week 6 and 12 visits, the window is ± 0 days. 
c The Part I Termination Visit will also serve as the Part II Baseline Visit.  For subjects who discontinue prior to completing 
the study, the Termination Visit will be considered an Early Termination Visit; every reasonable effort should be made to 
perform the Termination Visit procedures within four weeks of discontinuation.  
d Interval history will include any signs, symptoms, or events (e.g., falls) experienced by the subject since the prior study 
visit that are not related to study procedure(s) performed at prior study visits or study drug.  Interval history may include 
exacerbation or improvement in existing medical conditions (including the clinical manifestations of GNE Myopathy) that 
might interfere with study participation, safety, and/or positively or negatively impact performance of functional 
assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor 
administration technique and assess qualitative changes in function.  Subject identity will be protected by blurring out the 
facial area in the video.  
g Trough levels of free SA in serum and free and total SA in urine. 
h Adverse Events will be collected after subject signs Informed Consent form. 
ASSESSMENTS AND EVENTS 
PART I TREATMENT PERIOD b 
(weeks) 
PART I TERM 
VISIT c 
 
BASELINE a 
6 
12 
 
INFORMED CONSENT 
X 
 
 
 
INTERVAL HISTORY d 
X 
 
 
X 
VITAL SIGNS 
X 
 
 
X 
HEIGHT AND WEIGHT 
X 
 
 
X 
PHYSICAL EXAM e 
X  
 
 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY (HHD) f 
X 
 
 
X 
6 MINUTE WALK TEST  
(6MWT) f 
X 
 
 
X 
WALKING SPEED TEST f 
X 
 
 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
 
X 
HIBM-FAS 
X 
 
 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
 
 
X 
SERUM PROTEIN MARKERS 
X 
 
 
X 
FREE SERUM SA LEVELS g 
X 
 
 
X 
FREE AND TOTAL URINE SA LEVELS g 
X 
 
 
X 
CBC, CHEMISTRY, URINALYSIS 
X 
 
 
X 
PREGNANCY TEST 
X 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
X 
X 
X 
TREATMENT DISPENSED 
X 
X 
X 
 

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Table 2.2: 
Schedule of Events (Parts II, III, and IV) 
ASSESSMENTS AND EVENTS 
PARTS II, III, AND IV TREATMENT PERIOD b 
(months) 
TERM 
VISIT c 
 
SCREENING/
BASELINE a 
1 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36k 
 
INFORMED CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL/INTERVAL HISTORYd 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
VITAL SIGNS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HEIGHT AND WEIGHT 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PHYSICAL EXAM e 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
NEUROLOGICAL EXAM 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
EFFICACY MEASURES 
HAND-HELD DYNAMOMETRY 
(HHD) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
6 MINUTE WALK TEST 
(6MWT) f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WALKING SPEED TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
WEIGHTED ARM LIFT TEST f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HIBM-FAS 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
CLINICAL LABORATORY TESTS 
CREATINE KINASE 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
FREE SERUM SA LEVELS g 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
CBC, CHEMISTRY 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
PREGNANCY TEST 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
ADVERSE EVENTS 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONCOMITANT MEDICATIONS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DISPENSE STUDY DRUG i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TREATMENT COMPLIANCE j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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a The Part I Termination Visit also serves as the Parts II, III, and IV Baseline Visit for continuing subjects.  SA naïve subjects enter directly into Part II of the study 
(Screening/Baseline Visit for these subjects). Study drug will be dispensed only after UX001-CL202 (Parts II, and III, and IV) consent has been signed. 
b The Month 1 Visit window is ± 1 week.  For all other Visits the window is ± 14 days. For Part III and Part IV transitions, subjects will be asked to return to the clinic (may be an 
unscheduled visit) within 5 weeks from IRB/EC approval, to discuss their dosing and to consent.  
c The Termination Visit occurs four weeks after subjects receive their last dose.  For subjects who discontinue prior to completing the study, the Termination Visit will be 
considered an Early Termination Visit; every reasonable effort should be made to perform the Termination Visit procedures within four weeks of discontinuation.  The 
Termination Visit is not required for subjects who are eligible and choose to participate in the UX001-CL302 open-label extension study, but must be completed for any subject 
who terminates study participation early or is ineligible or decides not to participate in the extension study.  
d For SA naïve subjects, medical history (including a detailed GNE Myopathy disease-specific history) will be reviewed at the Screening/Baseline visit.  Interval history for all 
subjects will include any signs, symptoms, or events (e.g., falls) experienced by the subject since the prior study visit that are not related to study procedure(s) performed at prior 
study visits or study drug.  Interval history may include exacerbation or improvement in existing medical conditions (including the clinical manifestations of GNE Myopathy) that 
might interfere with study participation, safety, and/or positively or negatively impact performance of functional assessments. 
e The physical examinations at all study visits will be complete. 
f Portions of the HHD, 6MWT, walking speed and weighted arm lift testing sessions may be videotaped to monitor administration technique and assess qualitative changes in 
function.  Subject identity will be protected by blurring out the facial area in the video.  
g Trough levels of free SA in serum. 
h Adverse Events will be collected after subject signs Informed Consent form. 
i Study drug will be dispensed at scheduled treatment visits; additional study drug will be shipped directly to subjects between visits on a monthly basis.  
j Phone calls will be placed to each subject at least once between each study visit to assess treatment compliance with the dosing regimen.  Additional telephone contacts with the 
subject may be placed as needed. 
k Subjects who complete this study and are eligible may enroll in the UX001-CL302 open-label extension study. The Month 36 Visit is considered the end of study visit for 
subjects who are eligible and chose to participate in the open label extension study.  

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3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................3 
3 TABLE OF CONTENTS ...................................................................................................12 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................16 
5 INTRODUCTION .............................................................................................................19 
5.1 Overview of the Disease ...........................................................................................20 
5.2 Brief Overview of the Development of the Product .................................................22 
5.2.1 
Brief Description of the Investigational Product .........................................23 
5.2.2 
Nonclinical Studies ......................................................................................24 
5.2.3 
Previous Clinical Studies .............................................................................25 
5.3 Summary of Overall Risks and Potential Benefits ....................................................26 
5.4 Study Rationale .........................................................................................................27 
6 STUDY OBJECTIVES ......................................................................................................28 
7 INVESTIGATIONAL PLAN ............................................................................................29 
7.1 Overall Study Design and Plan .................................................................................29 
7.2 Discussion of Study Design, Including Choice of Control Group ............................30 
7.3 Selection of Study Population ...................................................................................31 
7.3.1 
Inclusion Criteria .........................................................................................32 
7.3.2 
Exclusion Criteria ........................................................................................33 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................33 
7.3.3.1 
Stopping Rules .............................................................................34 
7.4 Treatments .................................................................................................................34 
7.4.1 
Treatments Administered ............................................................................34 
7.4.2 
Identity of Study Drugs ...............................................................................35 
7.4.2.1 
Investigational Product ................................................................35 
7.4.3 
Selection of Doses and Study Duration .......................................................36 

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7.4.4 
Prior and Concomitant Therapy ..................................................................38 
7.4.4.1 
Prohibited Medications ................................................................38 
7.4.4.2 
Permitted Medications .................................................................38 
7.4.5 
Treatment Compliance ................................................................................39 
7.5 Study Procedures and Assessments ..........................................................................39 
7.5.1 
Schedule of Events ......................................................................................39 
7.5.2 
Clinical Efficacy Measures .........................................................................40 
7.5.2.1 
Hand-held dynamometry .............................................................40 
7.5.2.2 
Six Minute Walk Test ..................................................................40 
7.5.2.3 
Walking Speed Test .....................................................................41 
7.5.2.4 
Weighted Arm Lift Test ...............................................................41 
7.5.2.5 
HIBM Functional Activities Scale ...............................................42 
7.5.3 
Exploratory Efficacy Measures ...................................................................42 
7.5.4 
Safety Measures & General Assessments ...................................................42 
7.5.4.1 
Medical History ...........................................................................42 
7.5.4.2 
Interval History ............................................................................42 
7.5.4.3 
Vital Signs ....................................................................................43 
7.5.4.4 
Height and Weight Evaluations ...................................................43 
7.5.4.5 
Physical Examination...................................................................43 
7.5.4.6 
Neurological Examination ...........................................................43 
7.5.4.7 
Clinical Laboratory Tests .............................................................44 
7.5.4.8 
Adverse Events ............................................................................45 
7.5.4.9 
Concomitant Medications ............................................................45 
7.5.4.10 
Pregnancy Testing ........................................................................45 
7.5.4.11 
Pregnancy in Subject or Partner ...................................................45 
7.5.5 
Drug Concentration Measurements .............................................................46 
7.5.6 
Appropriateness of Measures ......................................................................46 

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7.6 Statistical Methods and Determination of Sample Size ............................................47 
7.6.1 
Clinical and Exploratory Efficacy Measures ...............................................47 
7.6.1.1 
Clinical Efficacy Analyses ...........................................................47 
7.6.2 
Safety Measures ..........................................................................................49 
7.6.3 
Data Monitoring Committee .......................................................................50 
7.6.4 
Determination of Sample Size .....................................................................50 
8 STUDY CONDUCT ..........................................................................................................51 
8.1 Ethics .........................................................................................................................51 
8.1.1 
Institutional Review Board or Ethics Committee ........................................51 
8.1.2 
Ethical Conduct of Study ............................................................................51 
8.1.3 
Subject Information and Consent ................................................................51 
8.2 Investigators and Study Administrative Structure ....................................................52 
8.3 Investigational Product Accountability .....................................................................52 
8.4 Data Handling and Record Keeping .........................................................................53 
8.4.1 
Case Report Forms and Source Documents ................................................53 
8.4.2 
Data Quality Assurance ...............................................................................53 
8.4.3 
Record Retention .........................................................................................54 
8.5 Reporting and Follow-up of Adverse Events ............................................................54 
8.5.1 
Definition of Adverse Events ......................................................................54 
8.5.2 
Severity of Adverse Events .........................................................................55 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................56 
8.5.4 
Adverse Event Reporting to Ultragenyx .....................................................56 
8.5.4.1 
General .........................................................................................56 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, 
and Requirements for Immediate Reporting ................................57 
8.5.4.3 
Urgent Safety Reporting ..............................................................57 
8.5.4.4 
Adverse Drug Reaction Reporting ...............................................58 
8.5.4.5 
Pregnancy in Subject or Partner ...................................................58 

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8.5.5 
Safety Contact Information .........................................................................59 
8.6 Financing and Insurance ...........................................................................................59 
8.7 Publication Policy .....................................................................................................59 
9 REFERENCES ..................................................................................................................60 
10 SIGNATURE PAGE .........................................................................................................63 
 
List of Tables 
Table 2.1: 
Schedule of Events (Part I) ....................................................................9 
Table 2.2: 
Schedule of Events (Parts II, III, and IV) ............................................10 
Table 7.5.4.7.1: 
Clinical Laboratory Assessments .........................................................44 
 
List of Figures 
Figure 5.1.1: 
The Sialic Acid Biosynthetic Pathway ................................................22 
 

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
6MWT 
Six Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CMP-SA 
cytosine monophosphate-sialic acid 
CRF 
Case Report Form 
CSR 
clinical study report 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
DMRV 
EC 
distal myopathy with rimmed vacuoles 
Ethics Committee 
ELISA 
enzyme-linked immunosorbent assay 
EMG 
electromyography 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GNE 
glucosamine (UDP-N-acetyl)-2-epimerase 
GNE-DMP 
GNE Myopathy Disease Monitoring Program 
GNE/MNK 
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase 
hERG 
human ether-à-go-go-related gene 
HHD 
hand-held dynamometry 
HIBM 
hereditary inclusion body myopathy 
HIBM-FAS 
HIBM Functional Activities Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
informed consent form 

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ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IVIG 
intravenous immune globulin 
LDH 
lactate dehydrogenase 
ManNAc 
N-acetyl-D-mannosamine 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP9 
matrix metallopeptidase 9 
MRC 
Medical Research Council 
MUAP 
polyphasic muscle unit action potential 
MVIC 
maximum voluntary isometric contraction 
NANA 
N-acetylneuraminic acid 
NCAM 
neural cell adhesion molecule 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
qHS 
at the time of sleep (i.e., at bedtime) 
QID 
four times per day 
RBC 
red blood cell 
SA 
sialic acid 
SAE 
serious adverse event 
SA-ER 
Sialic Acid-Extended Release 
SA-IR 
Sialic Acid Immediate Release 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
TID 
three times per day 
US 
United States 
WBC 
white blood cell 

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Definition of Terms 
Investigational Product is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use” (from International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use [ICH] Harmonised Tripartite Guideline E6: Guideline for Good Clinical Practice).  
The terms “Investigational Product” and “study drug” may be used interchangeably in the 
protocol. 

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5 INTRODUCTION 
Sialic Acid-Extended Release (SA-ER, UX001; also termed Ace-ER) is an extended release 
formulation of sialic acid (SA, also known as N-acetylneuraminic acid or NANA) intended 
as a substrate replacement therapy for GNE myopathies.  GNE myopathy, hereditary 
inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), and 
Nonaka disease are all different names of the same disorder, which is caused by a defect in 
the biosynthetic pathway for SA.  For the purposes of this protocol, GNE Myopathy will be 
used as the term for this disorder. 
Patients with GNE Myopathy cannot produce sufficient SA in muscle tissues; consequently 
glycoproteins and glycolipids in affected patients are not appropriately sialylated.  
In humans, GNE Myopathy is a severe progressive myopathy with onset usually in affected 
patients 18-30 years of age.  Initial diagnosis is followed by progressive loss of muscle 
strength, distal to proximal, which ultimately leads to loss of ambulation in 10-20 years.  
By replacing SA substrate, sialylation should be restored on key target glycoproteins and 
glycolipids and should lead to restoration of biochemical function, improved muscle 
physiology, and improved clinical function.   
The scientific rationale for this substrate replacement therapy is primarily based on the nature 
of the underlying genetic disease and on the work of Malicdan and colleagues, who 
demonstrated oral SA replacement therapy can be effective in restoring biochemical function 
with higher levels of sialylation in a relevant HIBM mouse model (Malicdan et al. 2009).  
The improved biochemical function in treated mice resulted in reduced or absent HIBM 
pathology, prevented clinical signs of muscle disease, and improved survival (Malicdan et al. 
2009). 
SA has a short half-life in the circulation.  Rapid clearance makes it difficult to use as a 
therapeutic replacement substrate in which a steady and constant supply of SA is required for 
use in glycoprotein and glycolipid synthesis.  The SA-ER formulation is expected to provide 
more stable blood levels of SA without spikes or troughs over the 24 hour cycle in humans 
when dosed three or four times per day (TID or QID).  Continuous exposure is likely an 
important step in assuring adequate sialylation during peak periods of synthesis, particularly 
during the night when maximal muscle growth and repair occur. 
The safety of SA has been evaluated in studies of chronic treatment of HIBM mice and in 
toxicology studies in multiple species of normal animals.  Data from these studies, 
summarized in the Investigator’s Brochure (IB), established a reasonable safety profile for 
SA and allow the determination of a no observed adverse effect level (NOAEL), setting the 
stage for the translation of this work to human GNE Myopathy patients.   
The SA-ER formulation was evaluated in a Phase 1 pharmacokinetic (PK) study to assess 
safety and exposure after a single dose and seven days of repeat dosing in SA-deficient GNE 
Myopathy subjects.  Data from this study suggests SA-ER is well tolerated by subjects with 
GNE Myopathy at single and multiple doses up to 6g/day, and sustained levels of SA in 

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blood and urine are achieved.  The TID dosing interval is sufficient to maintain trough levels 
of SA above background. 
A Phase 2 randomized, double-blind study has been performed to evaluate the safety and 
pharmacodynamic (PD) effects of SA-ER at two dose levels (6g/day and 3g/day) over 
48 weeks, including a 24-week placebo-controlled Treatment Period followed by a 24-week 
Treatment Continuation period on SA-ER.  Interim results from the 24-week placebo 
controlled Treatment Period implied a clinical efficacy signal and acceptable safety profile 
suggesting the potential to optimize the therapeutic index by increasing SA exposure.   
Part I of the study will provide treatment continuation for subjects completing the 
aforementioned Phase 2 study and elicit additional information on the long-term safety and 
efficacy of 6g/day SA-ER.  Parts II, III, and IV of the study will assess the long-term safety 
and efficacy of 12g/day SA-ER/SA-IR or SA-ER treatment (1.5g/1.5g TID or QID) and the 
long-term safety and efficacy of 6g/day SA-ER treatment (1.5g TID) for up to 36 months.   
Ultragenyx is also sponsoring a GNE Myopathy-Disease Monitoring Program 
(GNEM-DMP), a novel registry/natural history study to obtain data on the disease 
characteristics of GNE Myopathy and its progression.   
5.1 
Overview of the Disease 
GNE Myopathy was first described by Argov and Yarom in 1984 in a group of affected 
Iranian Jews in Israel (Argov et al. 1984).  The patients showed progressive muscle weakness 
and atrophy, and rimmed vacuoles on biopsy.  Since that time, a variety of GNE Myopathy 
patients have been identified worldwide, including those of Italian, Japanese, Thai, Indian, 
American and African origin (Huizing et al. 2009).  The clinical course is similar among 
these populations, and includes disease onset usually after age 20  years (mean 26 years, 
range 15–40 years; (Nalini et al. 2010); (Nonaka et al. 2005); (Sadeh et al. 1993); (Sunohara 
et al. 1989) though it can be symptomatic earlier. 
Patients often have foot drop due to tibialis anterior weakness as a first sign of GNE 
Myopathy; general weakness is usually more pronounced peripherally, which then 
progresses proximally.  Both weakness and atrophy are noted in muscles, with some fatty 
replacement infiltration as the disease advances.  In many patients, there is a curious relative 
sparing of the quadriceps for unknown reasons.  The forearm flexors and axial musculature 
may become more involved over time.  The rate of progression is gradual and variable 
between patients over a 10–20 year period leading to a wheelchair-bound state in a mean of 
12 years (Nonaka et al. 2005).  The ocular, pharyngeal and respiratory muscles are relatively 
spared clinically though they may show some abnormal pathology in some patients (Argov et 
al. 1984).  A representative example of disease progression was chronicled in Japanese 
patients over a decade (Sunohara et al. 1989) and showed the Medical Research Council 
(MRC) scale of manual motor assessment scores on a five point scale declining over a 
decade or so in three patients.  Disease progression is not rapid compared with some 

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myopathies but ultimately the level of function becomes severely compromised and 
equivalent to quadriplegia.  
Other clinical or physiological evaluations of GNE Myopathy patients show a variable 
number of abnormalities, all consistent with the myopathic pathologic process.  Unlike other 
myopathies, blood creatine kinase (CK) activities are only mildly elevated or remain in the 
normal range (22/58 patients reported by three publications had two-times or higher 
elevations; (Sadeh et al. 1993); (Mizusawa et al. 1987); (Sunohara et al. 1989) but evaluation 
of CK may still be useful as a marker for GNE Myopathy.  The mouse model of HIBM 
showed elevated CK levels that improve substantially on treatment (Malicdan et al. 2009).  
The decline in muscle bulk and function is substantial but the time course of decline may be 
sufficiently slow as to not cause acute CK elevations as observed in other disorders, such as 
Duchenne muscular dystrophy. 
Electromyography (EMG) in GNE Myopathy patients is abnormal, with spontaneous 
fibrillations consistent with denervation.  A myopathic pattern (polyphasic muscle unit action 
potentials [MUAPs]) consistent with denervation is observed, however nerve conduction is 
generally normal (Sadeh et al. 1993); (Mizusawa et al. 1987).  Conducting EMG in clinical 
programs is very difficult as there are substantial difficulties with differences in operators 
and inconsistencies of findings. 
Imaging studies of the muscle by computed tomography (CT) scan (Sadeh et al. 1993); 
(Mizusawa et al. 1987) or magnetic resonance imaging (Huizing et al. 2009) show substantial 
and diffuse abnormalities to muscle structure with significant fat infiltration in affected 
muscles but the quadriceps have more normal appearance (Huizing et al. 2009).  Many 
muscles have limited muscle tissue left, which could impact the potential for optimal 
treatment and substantial disease reversal in advanced patients.  
All GNE myopathies (HIBM, DMRV and Nonaka disease) are caused by defects in the 
GNE gene encoding the enzyme for the first step of the SA biosynthetic pathway 
(Figure 5.1.1).  The GNE gene codes for the bifunctional enzyme glucosamine 
(UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE/MNK) (Eisenberg et al. 
2001); (Jay et al. 2009).  The enzyme is the rate-controlled and regulated first step in the 
biosynthesis of the SA that is required for the complete glycosylation of many glycoproteins 
and glycolipids. 
Studies in tissues and mouse models have shown that the deficiency of SA production in 
GNE Myopathy is a key factor in the disease state, though the exact pathophysiologic effect 
of decreased sialylation on glycoproteins or glycolipids is still debated.  Sialylation is 
decreased in the most credible experiments and effects on proteins like neural cell adhesion 
molecule (NCAM) or on proteases like neprilysin, have been proposed (Malicdan et al. 
2008); (Broccolini et al. 2009).  NCAM is essential for muscle enervation and is 
hyposialylated in GNE Myopathy (Ricci et al. 2006).  The pattern of spontaneous fibrillation 
of denervation in GNE Myopathy may be consistent with a pathophysiological role for 
NCAM hyposialylation (Broccolini et al. 2009).  NCAM hyposialylation was used recently 

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to identify atypical GNE Myopathy patients with GNE mutations among a cohort of 
myopathy patients (Broccolini et al. 2010).  Another model involves a hyposialylation effect 
on neprilysin, an endopeptidase for hydrophobic proteins.  The accumulation of unfolded 
proteins and amyloid is consistent with neprilysin being deficient (Malicdan et al. 2008).  
When hyposialylated, neprilysin is less stable and less active, potentially leading to the 
accumulation of unfolded, undigested proteins in vacuoles (Broccolini et al. 2008).  
Among glycolipids, GM3 is also decreased in GNE Myopathy but the role this glycolipid 
plays in the biology of the disease is not clear (Paccalet et al. 2010).  Even with these 
limitations as to the specific pathophysiological role of sialylation, analyses of sialylation of 
these muscle components should still be useful in assessing the PD effects of substrate 
replacement therapy. 
Figure 5.1.1: The Sialic Acid Biosynthetic Pathway 
 
Although no proven pathway for the effect of hyposialylation in GNE Myopathy has been 
demonstrated conclusively, the pathology and data suggest that some combination of 
pathophysiologies is likely and that human skeletal muscle is prone to these problems 
because of normally lower expression levels of GNE/MNK.  In any case, replacement with 
either N-acetyl-D-mannosamine (ManNAc), which is located downstream of the block in 
GNE/MNK, or SA itself can restore CMP-SA synthesis and subsequent sialylation of 
proteins and lipids (Figure 5.1.1).  The GNE/MNK protein may have other functions, but the 
substrate replacement work to date shows that its role in the synthesis of SA is its dominant 
role in the muscle cell and SA deficiency is at the core of the cause of this disease. 
5.2 
Brief Overview of the Development of the Product 
A brief overview of existing information is provided below; a comprehensive review of the 
data is contained in the IB provided by Ultragenyx Pharmaceutical Inc. (Ultragenyx), which 
should be reviewed prior to initiating the study. 

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SA as an active ingredient was produced from N-acetylglucosamine using an enzyme 
catalyzed process.  The active ingredient was subjected to a series of nonclinical 
pharmacology and toxicology studies conducted by Ultragenyx; evaluation of the active 
ingredient also included some data from prior published work on SA toxicology.  
The NOAEL for the product was determined to be 2000 mg/kg in dogs and rats.  SA-ER, the 
extended release formulation of SA to be used in the study, was developed to enhance the PK 
of the product due to its rapid clearance from the body.   
Following clearance of an Investigational New Drug (IND) submission by the United States 
(US) Food and Drug Administration (FDA), a Phase 1 study of SA-ER was conducted.  
Over a range of single or multiple day doses from 650 - 6,000 mg/day no safety problems 
were identified, and PK analysis showed acceptable absorption of the product with a PK 
curve that covered about 8-16 hours.  Repeat dosing for one week with dose levels from 
1,950-6000 mg/day showed that trough levels could be maintained above the background 
level, as expected for a sustained release formulation.  
A Phase 2 randomized, placebo-controlled study has been performed to evaluate the safety 
and PD effects of SA-ER at two dose levels (6g/day and 3g/day).  The study consisted of a 
24-week placebo-controlled Treatment Period, followed by an additional 24-week Treatment 
Extension period with all subjects on the investigational product.  The interim 24-week data 
from the Phase 2 study suggested a positive clinical efficacy signal and acceptable safety 
profile indicating the potential to optimize the therapeutic index by increasing SA exposure.   
5.2.1 
Brief Description of the Investigational Product 
SA (also known as N-acetylneuraminic acid or NANA) intended as a substrate replacement 
therapy for GNE Myopathy, which is caused by a defect in the de novo biosynthesis of sialic 
acid.  The choice of an extended release formulation is based on the fact that SA has a short 
half-life in the circulation and its rapid clearance makes it difficult to use as a therapeutic 
replacement substrate in which a steady and constant supply of SA is needed.  SA-ER was 
developed to improve the stability of exposure to SA and allow more appropriate dosing and 
efficient substrate replacement. 
SA-ER 500 mg tablets are white to off-white, uncoated or film-coated, extended release, oval 
tablets that are designed for oral administration.  The tablet formulation contains 
approximately 43.3% active pharmaceutical ingredient in a mixed polymer matrix developed 
for extended release of SA over 24 hours.  Tablets are manufactured by a formulation process 
using wet aqueous granulation; the blend is then dried and compressed into tablets.  
Film-coated tablets are coated with Opadry II, a non-functional aqueous film coating.  
SA-ER 500 mg tablets are 1,150 mg in total weight. 
Since successful use of SA replacement therapy in humans is believed to depend upon 
optimized exposure to the compound, an increased dose was examined in Part II of this 
extension study.  Although administration of more extended release tablets could have been 
utilized, data in canines suggested that administration of immediate release SA in 

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combination with the SA-ER would maximize absorption in the GI tract. Therefore a study 
testing an increased dose level combining immediate release SA (SA-IR) with SA-ER was 
proposed in Amendment 1. Amendment 2 allows for subjects to receive either 6g/day or 
12g/day based on the data collected and analyzed from Part II. Refer to Section 7.2 for 
additional details and rationale for the dose reduction in Part III.  
SA-IR 500mg capsules are naturally colored, size 000, immediate release, hard gelatin 
capsules designed for oral administration.  The capsule formulation contains approximately 
93.5% active pharmaceutical ingredient.  Manufacturing consists of dry blending followed by 
filling into capsules.  SA-IR capsules have a fill weight of approximately 535 mg and a total 
weight of approximately 698 mg. 
5.2.2 
Nonclinical Studies 
Published in vivo studies in the HIBM mouse model have shown that replacement by SA can 
reduce muscle weakness and atrophy, improve muscle pathology and function, and restore 
sialylation in muscle (Malicdan et al. 2009).  The rational basis for the use of SA as a therapy 
in GNE Myopathy is primarily dependent on these results.  Key safety pharmacology, PK, 
and toxicology studies to support the use of SA in treating GNE Myopathy are summarized 
below; additional details may be found in the IB.   
Safety pharmacology:  Ultragenyx conducted the core battery of safety pharmacology 
studies of SA that are recommended by ICH guidelines.  These studies consisted of in vitro 
human ether-à-go-go-related gene (hERG) channel inhibition, neurobehavior in rats, and 
respiratory and cardiovascular evaluations in dogs after oral administration of SA.  SA did 
not show any potential for QT prolongation in the hERG assay at concentrations as high as 
6 x 10-3 mole/L.  There were no adverse effects on neurobehavior in rats or on respiratory 
and cardiovascular function in dogs at oral SA doses as high as 2000 mg/kg. 
PK study in dogs:  Ultragenyx conducted a multiple-dose, cumulative dosing, PK study in 
dogs to assess exposure following administration of SA-ER and the SA-ER/SA-IR treatment 
combination.  Each dog was administered SA-ER (200 mg/kg/day; human dose equivalent 
100 mg/kg/day) TID throughout the study duration (12 days).  Following 4 days of SA-ER 
treatment, SA-IR (100 mg/kg/day) TID was added to SA-ER treatment.  Following 4 days of 
SA-ER/SA-IR treatment, the SA-IR dose was increased to 200 mg/kg/day.  The highest dose 
level of SA-ER/SA-IR was equivalent to a human dose of 200 mg/kg/day.  The area under 
the curve (AUC) during the 8-hr dosing window increased proportionally to the dose of 
SA-IR, suggesting the administration of SA in extended-release and immediate-release forms 
can improve overall absorption of SA-ER and increase free SA levels up to 3X in the serum.   
Overall SA-ER/SA-IR was well tolerated in this study.        
Chronic toxicology studies in rats and dogs:  In an oral 6-month rat study, there were no 
treatment-related effects on clinical condition, body weight, food consumption, 
ophthalmology, clinical pathology (hematology, blood chemistry, and urinalysis) and in 
pathologic evaluations (gross, organ weight, and histopathology).  The no observed adverse 

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effect level (NOAEL) in this study was 2000 mg/kg which is equivalent to approximately a 
17 g daily human dose.  This provides a safety margin of approximately 1.4–fold over the 
proposed highest dose (12g/day) in the Phase 2 UX001-CL201 Study.  The 9-month oral 
toxicity study in dogs did not show any adverse effects on clinical condition, body weight, 
food consumption ophthalmology, electrocardiography, clinical pathology (hematology, 
blood chemistry, and urinalysis) and in pathologic evaluations (gross, organ weight, and 
histopathology). The NOAEL in this study was 2000 mg/kg which is equivalent to a 60 g 
daily human dose. This provides a safety margin of approximately 5–fold over the proposed 
highest dose (12g/day) proposed in the Phase 2 UX001-CL201 Study.  
Reproductive and developmental toxicology studies in rats and rabbits: To date, 
reproductive and developmental toxicity studies at oral doses as high as 2000 mg/kg/day 
have not shown any adverse effects on fertility of male or female rats, or treatment-related 
effects on pregnant females or embryo-fetal development parameters in rats and rabbits.  
5.2.3 
Previous Clinical Studies 
Key results from studies to support the use of SA in treating GNE Myopathy are summarized 
below; additional details may be found in the IB.   
Phase 1 PK and Safety (UX001-CL101):  “A Phase 1 Study to Evaluate the Safety and 
Pharmacokinetics of Single and Repeat Doses of Sialic Acid Extended-Release (SA-ER) 
Tablets in Patients with Hereditary Inclusion Body Myopathy (HIBM)”.   
The study was conducted in 28 subjects who received single and multiple doses to assess 
the PK and safety of SA-ER.  Subjects received SA-ER tablets orally at one of five dose 
levels in the single dose phase, and one of four levels in the repeat dose phase.  Each of the 
28 enrolled subjects were sequentially assigned to a specific dose level and received two 
single-dose exposures at that same dose level (fasted and fed).  The low dose cohorts were 
filled before assigning higher dose cohorts.  The subjects were then assigned to receive one 
repeat-dose regimen.  The lower dose repeat-dose cohorts are being filled before proceeding 
to higher repeat-dose levels.   Dose levels are as follows: 
• single doses:  650 mg (n = 6), 1,950 mg (n = 6), 2,925 mg (n = 6), 4,875 mg (n = 4), 
6000 mg (n=6). 
• multiple dosing:  650 mg TID (1,950 mg/day; n = 8), 975 mg TID (2,925 mg/day; n = 8), 
1,625 mg TID (4,875 mg/day; n = 6), 2000 mg TID (6000 mg/day; n = 6). 
Safety evaluations have not shown any significant drug-associated safety problems.  
Preliminary PK analyses show that the drug is absorbed with some variation in humans.  
Multi-day dosing has shown increased and sustained blood levels of free SA over a 24 hour 
cycle, consistent with expectations for an extended release formulation.   

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Phase 2 PK, PD and Safety (UX001-CL201):  “A Phase 2 Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Study to Evaluate the Dose and Pharmacodynamic 
Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients with GNE Myopathy or 
Hereditary Inclusion Body Myopathy”. 
A Phase 2 randomized, placebo-controlled study has been performed to evaluate the safety 
and PD effects of SA-ER at two dose levels (3g and 6g/day).  The study consists of a 
24-week placebo-controlled Treatment Period, followed by an additional 24-week Treatment 
Continuation Period whereby all subjects receive active treatment.  A planned analysis was 
conducted following completion of the 24-week placebo-controlled Treatment Period; the 
goal was to identify the dose that provides the best risk-benefit profile.   
Results of planned PK, PD, clinical efficacy, and safety analyses following the 24-week 
placebo-controlled Treatment Period showed dose-dependent improvement in muscle 
strength relative to placebo, particularly in the upper extremities at the 6g SA-ER dose. 
These changes were statistically significant or trended towards significance, and were more 
pronounced in subjects that had greater walking ability at baseline, a predefined subset.  
Other clinical endpoints did not reveal changes at this Week 24 interim assessment.  
CK levels showed a trend to improvement in the 6g SA-ER dose group compared with 
placebo.  SA-ER appeared to be well tolerated with no serious adverse events (SAEs) 
observed in either dose group.  As expected, the highest dose (6g/day SA-ER) provided a 
sustained exposure, a clinical efficacy signal, and acceptable safety profile.   
GNE Myopathy-Disease Monitoring Program:  A natural history study collecting data on 
the disease characteristics and its progression is also in progress.   
5.3 
Summary of Overall Risks and Potential Benefits 
Since SA is a normal body compound with native pathways for degradative metabolism and 
rapid renal clearance, there is no evidence or expectation of a significant safety issue with SA 
replacement therapy at this time.  Data from nonclinical and clinical studies to date suggest 
SA-ER administered alone or with SA-IR does not pose any significant safety risks that can 
be identified at this time.  Toxicology or adverse pharmacology findings were not observed 
in SA-treated animals; at very high doses, osmotic diarrhea may be observed in treated dogs.  
Interim safety results following a 24-week Treatment Period in a completed Phase 2 study 
(UX001-CL201), suggested an increase in diarrhea and GI symptoms relative to placebo.  
No correlation was observed between the GI events and free SA serum levels suggesting the 
frequency of GI events does not appear to be dose dependent.    
In patients with GNE Myopathy, replacement of the substrate SA has the potential to restore 
normal sialylation of muscle glycoproteins and glycolipids, which could improve the 
function of muscle and limit the loss of muscle strength.  It is not clear how much the effects 
of GNE Myopathy are reversible or if and how fast reversal of muscle disease might occur.  
The data in the HIBM mouse model suggest that over a one year period, substantial 
beneficial effects on the pathology of the disease are possible.  However, it is not clear 

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whether advanced disease can improve, as opposed to preventing progression of existing 
disease.  If the therapy has an effect comparable to that observed by Sparks and colleagues 
using intravenous immune globulin (IVIG) as a source of SA (Sparks et al. 2007), then the 
benefit to GNE Myopathy patients in improving muscle strength and function might be 
substantial.  In clinical studies conducted to date, the highest dose (6g/day SA-ER) provided 
a sustained exposure, a clinical efficacy signal, and acceptable safety profile.  Overall the 
risk-benefit ratio appears to be favorable based on the excellent safety record to date, and the 
potential benefit observed in nonclinical and clinical studies. 
5.4 
Study Rationale 
GNE myopathy or HIBM is a severe progressive metabolic myopathy caused by a defect in 
the biosynthetic pathway for sialic acid (SA).  Substrate replacement of SA is a potential 
therapeutic strategy based on evidence from relevant in vivo models, supported by PK 
characterization in a Phase 1 clinical study, and improvement in muscle strength from a 
Phase 2 randomized controlled trial.  The first study showed some efficacy at the 6g dose 
level but not at 3g, indicating the dose level may be at the low end of the dose response 
curve.  The interim data implied a clinical efficacy signal and acceptable safety profile 
suggesting the potential to optimize the therapeutic index by increasing SA exposure.  
Since successful use of SA replacement therapy in humans is believed to depend upon 
optimized exposure to the compound, an increased dose was suggested.  Although 
administration of more extended release tablets could be utilized, data in canines suggests 
that administration of immediate release SA (SA-IR) in combination with the SA-ER will 
maximize absorption in the GI tract. Therefore a study testing an increased dose level 
combining SA-IR with SA-ER is proposed. 
Subjects completing the 48-week UX001-CL201 study are eligible to continue treatment 
under this open-label extension protocol testing an increased dose of SA.  Additional GNE 
Myopathy subjects will be enrolled to assess the safety and efficacy of SA-ER/SA-IR in a 
treatment-naïve population.  Ultragenyx is conducting this study in four parts:  Part I of the 
study will provide additional information on the long-term safety and efficacy of 6g/day 
SA-ER; Part II of the study will assess the safety and efficacy of 12g/day of SA (comprised 
of 1.5 g of SA-ER / 1.5 g of SA-IR treatment QID).  Part III of the study reduces the dose 
from 12g/day to 6g/day for subjects who did not show additional benefit at 12g/day; 
however, treatment-naïve subjects and a small subset of rollover subjects will be invited to 
remain on the higher dose of 12g/day (described in Section 7.2).  Part IV was added to 
change the formulation from SA-IR to SA-ER. The SA-IR dose formulation has been 
removed based on data showing that by the 4th day of dosing in a nonclinical study conducted 
in dogs, AUC for free SA was similar between the immediate and extended release 
formulations. In addition, a review of population data for Month 12 of Part III in the current 
study confirmed that 12g/day SA-IR did not appear to provide any additional benefit 
compared with 6g/day SA-ER, although some individual patients may have improved. 
Therefore, no further SA-IR will be administered after the initiation of Part IV; patients 
currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking SA-ER. 

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6 STUDY OBJECTIVES 
The safety objectives of the study are to: 
• Evaluate additional long-term safety of SA-ER treatment of GNE Myopathy subjects 
previously treated with SA-ER at dose of 6g/day (Part I) 
• Evaluate the safety of 12g /day SA (delivered by 1.5g of SA-ER tablets and 1.5g of 
SA-IR capsules 4 times per day) in the treatment of GNE Myopathy subjects (Part II) 
over a 6 month treatment period 
• Evaluate the safety of SA treatment at both 6g/day and 12 g/day (Part III [SA-ER/SA-IR] 
and Part IV [SA-ER]).   
The clinical objectives of the study are to: 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on muscle 
strength as measured by hand-held dynamometry (HHD) 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on mobility, 
strength, and function using a series of physical performance measures 
• Evaluate the long-term effect of SA treatment of GNE Myopathy subjects on functional 
disability using an interview-based questionnaire.  
The exploratory objectives of the study are to: 
• Evaluate the effect of SA-ER treatment on serum biomarkers of sialylation in GNE 
Myopathy subjects (Part I)  
• Determine whether 12g/day SA-ER/SA-IR administered 1.5g/1.5g four times per day is 
superior to prior treatment with SA-ER in GNE Myopathy subjects (Part II) 
o Determine whether a subset of subjects has additional benefit on the higher dose 
treatment. 

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7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
This open-label extension study of will assess the long term safety and efficacy of SA 
treatment over a period of approximately 36 months, or until marketing approval or program 
termination by Ultragenyx.  In Part I of the study, approximately 46 subjects will be enrolled 
following successful completion of the UX001-CL201 study.  The Baseline visit will be 
conducted in conjunction with the UX001-CL201 Week 48 study visit to avoid treatment 
disruption.  Enrollment will take place after all UX001-CL201 Week 48 study assessments 
have been completed and the investigator has determined the subject meets all eligibility 
criteria.  Data collected at the UX001-CL201 Week 48 visit will serve as the Baseline data 
for Part I of this protocol.  Following the signing of informed consent at the Baseline visit, 
each subject will be dispensed a 6-week supply of study drug.  Throughout the Part I 
Treatment Period of the study, all subjects will continue to take four 500 mg SA-ER tablets 
orally three times per day (TID), in the morning, early evening, and at bedtime (qHS), for a 
total dose of 6g/day.  The Part I Termination Visit will also serve as the Baseline Visit for 
Part II of the study. 
Beginning with the Part II-Baseline Visit, all subjects currently enrolled in Part I will 
crossover to the SA-ER/SA-IR dosing regimen.  Approximately 10 treatment naïve GNE 
Myopathy subjects will be enrolled into Part II of the study.  The additional subjects will 
provide an assessment of SA-ER/SA-IR treatment in SA naïve subjects able to walk at 
least 200 meters (and < 80% predicted) in a screening 6 Minute Walk Test (6MWT).   
Throughout the 36-month Part II Treatment Period, all subjects will be administered 1.5g 
SA-ER and 1.5g SA-IR orally four times per day (QID), in the morning, afternoon, early 
evening, and qHS, for a total SA dose of 12g/day.  
Part III of the study reduces the SA dose from 12g/day to 6g/day for subjects who did not 
show additional benefit at 12g/day at the interim analysis; however, treatment naïve subjects 
and a small subset of rollover subjects who showed a potential efficacy benefit will be 
invited to remain on the higher dose of 12g/day. Part III will assess the long-term safety 
and efficacy of 12g/day SA-ER/SA-IR treatment for the duration of the study for the subjects 
who stay on the higher dose in Part III and will provide additional information on the 
long-term safety and efficacy of 6g/day SA-ER for the remaining subjects.  
Part IV was added to change the formulation from SA-IR to SA-ER. The SA-IR dose 
formulation has been removed based on data showing that by the 4th day of dosing in a 
nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 
and extended release formulations. In addition, a review of population data for Month 12 of 
Part III in the current study confirmed that 12g/day SA-IR did not appear to provide any 
additional benefit compared with 6g/day SA-ER, although some individual patients may have 
improved. Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking 
SA-ER.   

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Evaluations of safety, changes in clinical endpoints such as muscle strength, mobility, and 
function, and changes in exploratory serum biomarkers will be performed according to 
the Schedule of Events specific to each phase of the study (Table 2.1 and Table 2.2).  
A Termination Visit will be conducted 4 weeks after subjects receive their last dose of study 
drug (last dose of study drug received at Month 36).  For subjects who are eligible and 
choose to participate in the UX001-CL302 open-label extension study, the Month 36 Visit is 
considered the end of study visit and the Termination Visit is not required. Any subject who 
discontinues the current study early or is ineligible or decides not to participate in the 
UX001-CL302 extension study is required to have a Termination Visit 4 weeks after their 
last dose of study drug, as per Schedule of Events. Efficacy data analyses will be conducted 
at the end of the 36-month Treatment Period, although interim analyses may be performed at 
the discretion of Ultragenyx. 
Safety will be monitored throughout the study based on physical examinations, clinical 
laboratory analyses, and reporting of adverse events (AEs) and SAEs.  An independent Data 
Monitoring Committee (DMC) will review safety information periodically an on an ad hoc 
basis as outlined in the DMC charter, which is maintained separately from this protocol. 
7.2 
Discussion of Study Design, Including Choice of Control Group 
Part I of the study will focus on evaluating the long-term safety of 6g/day SA-ER treatment 
in GNE Myopathy subjects continuing SA-ER treatment as an extension of the 48-week, 
Phase 2 UX001-CL201 clinical study.  Part I of the study will also explore long-term effects 
of SA-ER on clinical measures of muscle strength, mobility, function, disability and 
health-related quality of life.  Exploratory evaluations of the effects of SA-ER on serum 
biomarkers will be performed in Part I of the study only.  
Since Part I of the study is designed as an open-label extension designed to continue SA-ER 
treatment for subjects successfully completing the Phase 2 UX001-CL201 study, the study 
size and population are therefore restricted to said individuals.  In UX001-CL201, safety and 
efficacy of SA-ER was examined in a randomized, double-blind study at two dose levels and 
compared to placebo treatment control.  The current study design is not powered to assess 
statistically significant comparisons between treatment groups.  Instead, the study population 
for Part I is intended to provide additional long-term safety data following maintenance 
treatment with 6g/day SA-ER.   Since all subjects will receive the same treatment, 
randomization or blinding of study drug is not necessary.  
The Week 24 interim data from the Phase 2 UX001-CL201 study implied a positive PD 
signal and acceptable safety profile suggesting the potential to optimize the therapeutic index 
by increasing SA exposure.  Therefore, investigation into optimizing the risk-benefit profile 
of SA substrate replacement by examining higher SA doses is warranted.  Part II of the study 
will assess the long-term safety and efficacy of an increased SA dose (total 12g/day) for up to 
12 months.  In this phase, SA treatment will be in the form of SA-ER tablets and immediate 
release capsules (SA-IR) to maximize absorption from the GI tract based on data obtained 
from nonclinical studies in canines.  Continuing subjects will terminate Part I of the study 

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following approximately 12 weeks of treatment with 6g/day SA-ER and continue on to 
Part II of the study by crossing over to an increased daily SA dose of 12g/day.  Since Part II 
of the study will be the first time GNE Myopathy subjects will be treated with the 
SA-ER/SA-IR investigational product, approximately 10 GNE Myopathy subjects will be 
enrolled to assess long-term safety and clinical efficacy of SA-ER/SA-IR in a treatment naïve 
population. 
An interim analysis was conducted after 6 months of treatment with SA-ER/SA-IR; the 
results of this interim analysis have led to the establishment of Part III of the study.  Part III 
will provide long-term safety and efficacy data on both 6 and 12g/day SA.  This change is 
based on a review of individual subject data for the rollover subjects from the parent study 
UX001-CL201. The data analysis suggests that a small subset of subjects received an added 
benefit from the higher dose (defined as at least a 15% increase in either the UEC or LEC).  
The rollover subjects who met these criteria, along with the ongoing naïve subjects, had the 
option to remain on the 12g/day dose for the remainder of the study. 
Part IV was added to change the formulation from SA-IR to SA-ER. The SA-IR dose 
formulation has been removed based on data showing that by the 4th day of dosing in a 
nonclinical study conducted in dogs, AUC for free SA was similar between the immediate 
and extended release formulations. In addition, a review of population data for Month 12 of 
Part III in the current study confirmed that 12g/day SA-IR did not appear to provide any 
additional benefit compared with 6g/day SA-ER, although some individual patients may have 
improved. Therefore, no further SA-IR will be administered after the initiation of Part IV; 
patients currently on 12g/day may continue receiving the 12g/day dose, if desired, by taking 
SA-ER.  
Patients who elect to decrease from 12 g/day to 6 g/day may be allowed to do so upon 
Sponsor approval.  
The 36-month treatment duration is intended to evaluate the long-term safety and efficacy of 
SA.  While the lack of a control group may introduce difficulties in discerning natural disease 
progression from treatment effectiveness, due to the progressive debilitative nature of the 
disease, a placebo-controlled study of this duration is not feasible 
7.3 
Selection of Study Population 
The study will be conducted in adult patients who have previously demonstrated mutations in 
the gene for the GNE/MNK enzyme leading to a diagnosis of GNE myopathy (variously 
termed HIBM, DMRV, or Nonaka disease).  These patients are unable to synthesize 
endogenous SA, which leads to muscle weakness and atrophy.  Consequently, this is the 
relevant population for testing SA replacement therapy to determine if exogenous SA leads 
to improved protein and lipid sialylation and stabilized or improved muscle structure and 
performance.  The majority of the study population will consist of approximately 46 GNE 
Myopathy subjects who successfully completed UX001-CL201 and may or may not have 

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been previously exposed to SA-ER.  Approximately 10 GNE Myopathy subjects who are SA 
and MaNAc-treatment naïve will be enrolled into Part II of the study. 
The inclusion/exclusion criteria from the UX001-CL201 study inherently define the study 
population for subjects in Part I of the study, since successful completion of UX001-CL201 
is requisite for enrollment in this study.   The previous study was designed to allow for the 
enrollment of patients with a broad spectrum of physical disability, with at least 60% of 
enrolled subjects having residual lower extremity strength and function sufficient to walk 
≥ 200 meters in the 6MWT.  Enrolling patients across the spectrum of disease severity as 
subjects allowed the study to fully explore the safety and efficacy profile of SA-ER and 
inform the design of future studies.  However, it should be noted that subjects unable to 
complete UX001-CL201 would not be eligible for this extension study, potentially 
introducing population bias toward subjects experiencing favorable safety and efficacy 
following up to 48 weeks treatment with SA-ER. 
For the additional treatment naïve subjects enrolled into Part II of the study, the diagnosis 
and age range are the same as requirements for continuing subjects.  This subgroup will be 
restricted to GNE Myopathy subjects with the ability to walk at least 200 meters during the 
6MWT.  Since the strongest clinical efficacy signal was observed in this subset of GNE 
Myopathy subjects participating in the UX001-CL201 study, this protocol was designed to 
enroll those subjects most likely to obtain clinical benefit from study treatment. 
7.3.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
• Enrollment in and successful completion of the UX001-CL201 protocol OR 
(for 10 treatment naïve subjects): 
o Have a confirmed diagnosis of GNE Myopathy 
o Aged 18 -65 years of age, inclusive 
o Able to walk ≥ 200 meters and < 80% of predicted normal during the 6MWT 
(orthotics and assistive devices allowed) 
o No prior history of treatment with SA or MaNAc 
• Must be willing and able to provide written, signed informed consent after the nature of 
the study has been explained, and prior to any research-related procedures 
• Must be willing and able to comply with all study procedures  
• Sexually active subjects must be willing to use an acceptable method of contraception 
while participating in the study 
• 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 been in menopause for at least two years, 

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or have had tubal ligation at least one year prior to Baseline, or who have had total 
hysterectomy. 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
• Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at 
any time during the study 
• Use of any investigational product (other than SA-ER tablets) to treat GNE Myopathy 
• Ingestion of ManNAc or similar SA producing compounds  
• Has had any hypersensitivity to SA or its excipients that, in the judgment of the 
investigator, places the subject at increased risk for adverse effects 
• Have any co-morbid conditions, including unstable major organ-system disease(s) that in 
the opinion of the Investigator, places the subject at increased risk of complications, 
interferes with study participation or compliance, or confounds study objectives. 
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 principal investigators and Ultragenyx also have the 
right to remove subjects from the study.  Subjects may be removed from the study for the 
following reasons: 
• Occurrence of an unacceptable AE 
• An illness that, in the judgment of the principal investigator or Ultragenyx, might 
invalidate the study or place the subject at risk 
• At the request of the subject, principal investigator, or Ultragenyx, whether for 
administrative or other reasons 
• Protocol deviation or unreliable behavior 
If the reason for removal of a subject from the study is an AE, the AE and any related test or 
procedure results will be recorded in the source documents and transcribed onto the Case 
Report Form (CRF).  Each clinically significant abnormal laboratory value or other clinically 
meaningful abnormality should be followed until the abnormality resolves or until a decision 
is made that it is not likely to resolve.  If such abnormalities do not return to normal within 
30 days after the last dose given, their etiology should be identified and Ultragenyx should be 
notified.  All unscheduled tests must be reported to Ultragenyx immediately. 
If a subject discontinues from the study prematurely, every reasonable effort should be made 
to perform the (Early) Termination Visit procedures within four weeks of discontinuation. 

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Subjects who withdraw or are removed from the study after receiving study drug may not 
re-enter the study. 
7.3.3.1 
Stopping Rules 
A DMC will be constituted for Study UX001-CL202 and will act in an advisory capacity to 
Ultragenyx to monitor the safety of SA-ER/SA-IR in subjects who participate in the study 
(see Section 7.6.3).  The DMC may provide advice to Ultragenyx in any determination of 
whether study enrollment should be paused or if the study should be halted. 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE).  If two subjects develop the same unexpected Grade 3 
AE that is possibly or probably related to study drug or any subject develops an unexpected 
Grade 4 AE that is possibly or probably related to study drug, enrollment of new subjects 
may be suspended until a thorough evaluation can be performed.  Should these AEs occur, a 
full clinical evaluation will be performed by the medical monitor, principal investigators, and 
DMC in order to make a decision regarding what actions to take, including whether to 
suspend or resume enrollment, or recommend stopping the study after Institutional Review 
Board (IRB)/Ethics Committee (EC) review.  The recommendations from the medical 
monitor and investigators will be forwarded to the IRB/EC for review and approval. 
7.4 
Treatments 
7.4.1 
Treatments Administered 
The SA-ER investigational product will consist of tablets containing 500 mg of SA active 
ingredient in an extended release formulation.  In Part I of the study, the 6000 mg (6g) total 
daily SA-ER dose will be self-administered by the oral route and will be divided into a three 
TID regimen; all subjects will self-administer four 500 mg tablets in the morning, four tablets 
in the early evening, and four SA-ER tablets qHS.  
The SA-IR investigational product will consist of capsules containing 500 mg of SA active 
ingredient in an immediate release formulation.  In Part II of the study, the 12,000 mg (12g) 
total daily SA dose will be self-administered by the oral route and will be divided into a QID 
regimen; all subjects will self-administer three 500 mg tablets (1.5g SA-ER) and three 
500 mg capsules (1.5g SA-IR) in the morning, afternoon, early evening, and qHS.  
In Part III of the study, for those subjects on the 12g/day dose, each dose of SA-ER/SA-IR 
will consist of SA-ER tablets, each containing 500 mg of SA active ingredient in an extended 
release formulation and SA-IR capsules, each containing 500 mg of SA active ingredient.  
During the Treatment Period, the 12,000 mg (12g) total daily SA dose will be administered 
by the oral route and will be divided into a TID or QID regimen. If tolerability issues arise, 
the dose may be temporarily stepped down until symptoms resolve.  
In Part III of the study, for those subjects on the 6g/day dose, each dose of SA-ER will 
consists of tablets, each containing 500 mg of SA active ingredient in an extended release 

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formulation.  During the Treatment Period, the 6000 mg (6g) total daily SA-ER dose will be 
administered by the oral route and will be divided into a TID regimen. 
Part IV: 6g/day dose and 12g/day dose – Each dose of SA-ER will consists of tablets, each 
containing 500 mg of SA active ingredient in an extended release formulation.  During the 
Treatment Period, the 6g total daily SA-ER dose will be administered by the oral route and 
will be divided into a TID regimen. The 12g total daily SA-ER dose will be administered by 
the oral route and will be divided into a TID or QID regimen. 
Subjects will be instructed to take all study medication with food in the morning, the 
afternoon, early evening, and/or qHS (i.e. within 30 minutes following a meal or snack).   
7.4.2 
Identity of Study Drugs 
The study drugs for protocol UX001-CL202 are white, oval, SA-ER tablets and naturally 
colored, size 000, hard gelatin SA-IR capsules for oral administration.  No animal-derived 
products are used in the manufacture of the tablets.  Where bovine gelatin is used for 
production of gelatin capsules, it is in compliance with pharmaceutical regulatory statutes. 
The study drugs were manufactured, packaged, and labeled according to Good 
Manufacturing Practice (GMP) regulations. 
Study drug tablets will be packaged in bottles.  Each bottle will contain 168 tablets or 
capsules, equivalent to 2 weeks of study drug supply.  During Part I, subjects will receive an 
approximate 6 week supply at the Baseline and Week 6 visits.  For Week 6 and Week 12 
visits, the visit window is ± 0 days.  For the duration of the study, subjects will be instructed 
to return all unused study drug to the next visit.   
Study drug will be dispensed at in-clinic visit. Additional drug may be shipped to subjects by 
the investigative site in between scheduled clinic visits.   
Bottles will be labeled with the study number (UX001-CL202).  The bottle will display the 
protocol number (UX001-CL202), the name and city, state, and zip code of the study sponsor 
(Ultragenyx Pharmaceutical Inc.), the storage conditions, expiration date, and the statement 
"Caution: New Drug – Limited by Federal (US) Law to Investigational Use".   
7.4.2.1 
Investigational Product 
SA-ER 500 mg tablets are white to off-white, extended release, oval tablets intended for oral 
administration.  The tablet formulation contains approximately 43.3% active pharmaceutical 
ingredient in a mixed polymer matrix developed for extended release of SA over 24 hours.  
Tablets are manufactured by a formulation process using wet aqueous granulation; the blend 
is then dried and compressed into tablets.  SA-ER 500 mg tablets are 1150 mg in total 
weight. 
SA-IR 500mg capsules are naturally colored, size 000, immediate release, hard gelatin 
capsules designed for oral administration.  The capsule formulation contains approximately 

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93.5% active pharmaceutical ingredient.  Manufacturing consists of dry blending followed by 
filling into capsules.  SA-IR capsules have a fill weight of approximately 535 mg and a total 
weight of approximately 698 mg. 
7.4.3 
Selection of Doses and Study Duration 
Part I - SA-ER Treatment Period:  In Part I of this Phase 2 open label extension study, 
SA-ER will be administered orally TID for a total dose of 6000 mg/day (6g SA-ER).  
The SA-ER dose and regimen for Study UX001-CL202 was selected based on the following 
information: 
• Analyses of SA PK in the Phase 1 study UX001-CL101 indicate that orally administered 
doses of SA-ER at 2000 - 6000 mg/day divided into TID dosing is effectively absorbed in 
humans, and multiple day dosing at doses up to 6000 mg/day achieves steady, increased 
levels of free SA in the serum with some individual variation. 
• In the Phase 1 study, single oral doses of SA-ER at up to 6g SA-ER and seven days of 
treatment at up to 6g/day have been administered without any significant drug-associated 
safety problems. 
• Malicdan and colleagues have demonstrated that 20 mg/kg/day SA given orally as 
replacement therapy effectively prevented disease in a mouse model of HIBM (Malicdan 
et al. 2009).  Using the allometric scaling method suggested by the US FDA (FDA 
Guidance for Industry 2005), the human equivalent dose is 12.5 times higher; a mouse 
dose of 20 mg/kg/day is equivalent to a human dose of 1.6 mg/kg/day. 
• Toxicology studies have identified the NOAEL to be 2000 mg/kg in dogs and rats, far 
above the proposed human dose level of 6g/day SA-ER in Part I of the study. 
• TID dosing in conjunction with an extended release formulation is able to achieve steady 
increased levels of SA over the 24 hour cycle. 
• To date, no SAEs have been observed from an ongoing Phase 2 randomized, 
placebo-controlled study evaluating the safety and PD effects of 3g/day and 6g/day 
SA-ER.   
Based on these data, the 6g/day total daily dose selected for Part I of the Phase 2 extension 
study is deemed reasonable.  The use of doses above that tested in preclinical mouse models 
accounts for species-specific differences in absorption and/or biological activity.  Based on 
Phase 1 clinical data, steady state SA levels are achieved with TID dosing:  in the morning, 
early evening, and qHS.  The qHS dose is particularly important to assure coverage during 
the night.   
Part II - SA-ER/SA-IR Treatment Period:  Successful use of SA replacement therapy in 
humans is believed to depend upon optimized exposure to the compound.  Interim results 
from the UX001-CL201 study suggest an increased dose of therapy is warranted.  In Part II 
of this Phase 2 open label extension study, 12g SA will be administered orally via 1.5g of 

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SA-ER tablets and 1.5g SA-IR capsules, QID.  The SA-ER/SA-IR dose and regimen for 
Study UX001-CL202 was selected based on the following additional information: 
• Dose effect at 6g only.  Interim results from UX001-CL201 suggest the 6g SA-ER dose 
level appears to be at the lower end of the effective range since a clinical efficacy signal 
was observed but 3g SA-ER had almost no effect.   
• The SA level correlates with treatment effect based on HHD.  The Week 24 interim 
data imply a positive PD signal and acceptable safety profile suggesting the potential to 
optimize the therapeutic index by increasing SA exposure.   
• Canine studies show that immediate release most effective way to increase SA.  
Studies in normal canines showed that more than proportional increases in absorption of 
SA are possible if an immediate release formulation was mixed with an extended release 
formulation.  The concept is that the immediate release product enhances stomach 
absorption which is not well utilized by extended release formulated tablets. 
• QID therapy should support higher SA levels.  Since SA-IR is rapidly cleared, a QID 
dosing regimen is predicted to provide optimized continuous exposure to SA.  
Administration of a 12g total daily dose of SA would therefore be divided into 4 equal 
doses of 3g each (1.5g SA-ER + 1.5g SA-IR), representing only a 50% increase for each 
dose. 
• Safety of very high SA doses.  In a chronic toxicology study in rats, the NOAEL was 
2000 mg/kg SA, which is provides a safety margin of approximately 1.4-fold for the 
proposed 12g/day dose level.  In a 6 month oral toxicity study in dogs, the NOAEL was 
2000 mg/kg SA, which provides a safety margin of approximately 5-fold for the human 
12g/day dose level.   
• Single doses of 6g SA-ER given in one dose were well tolerated.  In the Phase 1 PK 
and tolerability study, 6g SA-ER was administered to GNE Myopathy subjects in a single 
oral dose and was well tolerated with no SAEs observed. 
Based on these data, the 12g/day total daily dose selected for Part II of the Phase 2 extension 
study is deemed reasonable.  Results of nonclinical studies in canines suggest the 
administration of SA in extended-release and immediate-release form can improve overall 
absorption of SA-ER and increase free SA levels in the serum.  Although administration of 
more extended release tablets could be utilized, data in canines suggests that administration 
of SA-ER/SA-IR will maximize absorption in the GI tract. 
Part III – 12g/day SA-ER/SA-IR or 6g/day SA-ER Treatment Period:  This change is based 
on a review of individual subject data for the rollover subjects from the parent study 
UX001-CL201. The data analysis suggests that a small subset of subjects received an added 
benefit from the higher dose.  The rollover subjects who meet these criteria, along with the 
ongoing naïve subjects, will have the option to remain on the 12g/day dose for the remainder 
of the study. 

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Part IV – 12g/day SA-ER or 6g/day SA-ER Treatment Period: Part IV was added to change 
the formulation from SA-IR to SA-ER. The SA-IR dose formulation has been removed based 
on data showing that by the 4th day of dosing in a nonclinical study conducted in dogs, AUC 
for free SA was similar between the immediate and extended release formulations. 
In addition, a review of population data for Month 12 of Part III in the current study 
confirmed that 12g/day SA-IR did not appear to provide any additional benefit compared 
with 6g/day SA-ER, although some individual patients may have improved. Therefore, no 
further SA-IR will be administered after the initiation of Part IV; patients currently on 
12g/day may continue receiving the 12g/day dose, if desired, by taking SA-ER.  
Study Duration:  The maximum treatment duration for Part I of the study will be 12 weeks 
to allow crossover to Part II of the study.  The Parts II, III, and IV treatment durations of 
approximately 36 months enables a long-term assessment of the safety and efficacy of 
SA-ER/SA-IR and SA-ER in subjects with GNE Myopathy. 
7.4.4 
Prior and Concomitant Therapy 
7.4.4.1 
Prohibited Medications 
Patients may not be enrolled if they have used any investigational product (other than SA-ER 
tablets) or investigational medical device prior to Baseline, or if they require any 
investigational agent prior to completion of all scheduled study assessments.  Ingestion of 
ManNAc, SA, or related metabolites; IVIG; or anything that can be metabolized to produce 
SA in the body is prohibited during the 60 days prior to Baseline and throughout the study.  
If ManNAc, SA or other substrate was used more than 60 days prior to Baseline, the time 
period of use, the compound used, and the dose and dose regimen should be recorded in the 
subject’s history.  If a patient has been on substrate replacement therapy in the past, the 
investigator must consider the potential confounding effects of this therapy before enrolling 
the patient as a subject in the study. 
IT IS ESSENTIAL THAT THE SUBJECT COMMIT TO NOT INGESTING ManNAc 
OR SIMILAR OTHER SA-PRODUCING COMPOUNDS DURING THE CONDUCT 
OF THIS STUDY AS IT COULD CONFOUND THE INTERPRETATION OF 
RESULTS.   
7.4.4.2 
Permitted Medications 
Other than the medications specifically prohibited in this document, subjects may receive 
concomitant medications as required.  Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during the 60 days prior to 
Baseline will be reviewed and recorded.  At the Baseline visit, current medications will be 
recorded.  If a subject takes any medication other than SA-ER during study treatment, the 
subject should record the date and time the medication was taken, the name of the 
medication, and the reason the medication was taken in the drug administration diary; this 
data will be recorded in the subject’s CRF. 

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Any non-study therapies received during study participation will be similarly recorded in the 
subject’s medical record and CRF. 
7.4.5 
Treatment Compliance 
Subjects will be asked to maintain a record of self-administration in a drug accountability 
diary; the diary will be reviewed at each study visit.  Subjects will be instructed to return all 
unused study drug to the next visit.  Drug accountability diaries will be collected by site 
personnel at the clinic visits.  Site personnel will maintain a record of all medication 
dispensed to each subject and all unused medication returned to the site. In Parts II, III, and 
IV of the study, site personnel will make periodic calls to subjects to ensure treatment 
compliance. 
7.5 
Study Procedures and Assessments 
7.5.1 
Schedule of Events 
The Part I Baseline Visit will be conducted in conjunction with the UX001-CL201 Week 48 
study visit to avoid treatment disruption.  Enrollment will take place after all UX001-CL201 
Week 48 study assessments have been completed and the investigator has determined the 
subject meets all eligibility criteria.  Data collected at the UX001-CL201 Week 48 visit will 
serve as the Baseline data for Part I of this study.  Following the signing of informed consent 
at the Part I Baseline visit, each subject will be dispensed study drug and will return for 
assessments according to the Part I Schedule of Events (Table 2.1).   
For subjects continuing treatment during Part I, the Part II Baseline Visit will be conducted in 
conjunction with the Part I Termination Visit.  Additional treatment-naïve subjects will be 
enrolled directly into Part II of the study, with screening and baseline assessments taking 
place at the Part II Baseline Visit.  Following the signing of informed consent at the Part II 
Baseline visit, each subject will be dispensed study drug and will return for assessments 
according to the Schedule of Events (Table 2.2).   
The Termination Visit occurs four weeks after subjects receive their last dose of the study 
(last dose of study drug received at Month 36).  The Termination Visit is not required for 
subjects who are eligible and choose to participate in the extension study, but must be 
completed for any subject who terminates study participation early or decides not to 
participate in the UX001-CL302 open-label extension study. For subjects who discontinue 
prior to completing the study, the Termination Visit will be considered an Early Termination 
Visit; every reasonable effort should be made to perform the Termination Visit procedures 
within four weeks of discontinuation. 
The parameters to be assessed in Study UX001-CL202, along with timing of assessments for 
each part of the study, are provided in the Schedule of Events (Table 2.1 and Table 2.2).  

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7.5.2 
Clinical Efficacy Measures 
The clinical efficacy measures in this study will evaluate muscle strength, mobility and 
function using the evaluations detailed below.  Assessments will be conducted as indicated in 
the Schedule of Events (Table 2.1 and Table 2.2, respectively).  Portions of the tests may be 
videotaped to monitor test administration and assess for qualitative changes in function 
(e.g., gait).  Subject identity will be protected by blurring the facial area in the video(s).  
Refer to the Clinical Evaluator Manual for additional details on clinical efficacy measures. 
7.5.2.1 
Hand-held dynamometry 
In Part I of the study, HHD testing will be performed at the Baseline and Part I Termination 
Visits, to assess muscle strength.  For continuing subjects, the assessment at the Part I 
Termination Visit will serve as the baseline assessment for Part II of the study.  HHD testing 
in Parts II, III, and IV of the study will be performed at Baseline (for treatment naïve 
subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  Formal training will be 
conducted with the licensed physical therapists administering the HHD testing to standardize 
technique and minimize variability.  The maximum voluntary isometric contraction (MVIC) 
against a dynamometer will be used to measure strength in the following muscle groups:  
shoulder abductors, elbow flexors, elbow extensors, hip abductors, hip adductors, hip flexors, 
hip extensors, knee flexors and knee extensors.  A hand dynamometer will be used to assess 
gross grip strength and a pinch dynamometer will be used to assess pinch strength.  
Each effort will last approximately three seconds with a slow build to a maximum voluntary 
force.  Strength in the elbow flexors and elbow extensors will be measured with the subject 
lying in a supine position on an examination table.  Strength in the hip extensors will be 
measured with the subject leaning over an examination table in a prone position.  All other 
muscle groups will be tested with the subject in a sitting position.  All measurements will be 
taken bilaterally.  The administrator will attempt to obtain two force values within 
approximately 15% of each other for each muscle group.  Testing positions may be altered 
at the discretion of the administrator to improve the reliability of the test.  The total force 
(in kg) will be recorded at the time of test administration.  The highest force value collected 
for each muscle group will be used for data analysis.  The percent of predicted normal values 
will be calculated after the testing using published normative data (Mathiowetz et al. 1985); 
(NIMS 1996); (Bohannon 1997b); (Bohannon et al. 2006); (Peters et al. 2011). 
7.5.2.2 
Six Minute Walk Test  
In Part I of the study, the 6MWT (Solway et al. 2001) will be administered at Baseline and 
the Part I Termination Visits to assess walking ability.  For continuing subjects, the 
assessment at the Part I Termination Visit will serve as the baseline assessment for Part II of 
the study.  In Parts II, III, and IV of the study, the 6MWT will be administered at Baseline 
(for treatment naïve subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  
The 6MWT will be administered by a licensed physical therapist in accordance with 
American Thoracic Society (ATS) guidelines (ATS 2002).  Blood pressure, heart rate and 
self-reported Borg scale dyspnea and fatigue ratings will be recorded before and after the test 

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administration.  ATS guidelines require a subject to have a pre-test resting heart rate of less 
than 120 beats/minute, systolic blood pressure of less than 180 mm Hg and diastolic blood 
pressure of less than 100 mm Hg to ensure safety.  Subjects who meet the safety criteria will 
be instructed to walk the length of a pre-measured 20 meter course for six consecutive 
minutes.  Traffic cones will be used to standardize the distance in hallways longer than 
20 meters.  The subject will walk laps around the cones until the six minute time period has 
expired.  However, the test will not be interrupted and the subject will continue to walk for 
the 6-minute duration of the test.  Instructions and encouragement will be given according to 
the script provided in the ATS guidelines.  The distance walked at the end of six minutes 
will be recorded in meters at the time of test administration.  The percent of predicted 
normal values will be calculated after the testing using published normative data (Gibbons et 
al. 2001). 
7.5.2.3 
Walking Speed Test 
In Part I of the study, the walking speed test will be administered at Baseline and the Part I 
Termination Visits to assess gait speed.  In Parts II, III, and IV of the study, the walking 
speed test will be administered at Baseline (for treatment naïve subjects), Months 3, 6, 12, 
18, 24, 30, 36 and Termination Visits.  The test will be administered twice by a licensed 
physical therapist, once at a comfortable speed and once at a maximum speed.  Subjects will 
be instructed to walk the length of a pre-measured 25 foot (7.62 meter) course.  Traffic cones 
or tape on the floor will be used to standardize the distance.  Subjects will have a few feet at 
the beginning and the end of the 25 foot course to allow for acceleration and deceleration.  
For the comfortable speed test, subjects will be instructed to walk at their normal pace.  
For the maximum speed test, subjects will be instructed to walk as fast as they safely can 
without running.  The total number of seconds required to complete the test for each speed 
will be recorded in seconds at the time of test administration.  Subject performance relative to 
peers will be calculated after the testing using published normative data (Bohannon 1997a).  
7.5.2.4 
Weighted Arm Lift Test 
In Part I of the study, the weighted arm lift test (Agarwal et al. 2006) will be administered at 
Baseline and the Part I Termination Visits, to assess upper limb function.  In Parts II, III, and 
IV of the study, the weighted arm lift test will be administered at Baseline (for treatment 
naïve subjects), Months 3, 6, 12, 18, 24, 30, 36 and Termination Visits.  The test will be 
administered by a licensed physical therapist.  The subject will be asked to sit in a chair 
holding a 1 kg barbell with the shoulder adducted, the elbow in full flexion and the forearm 
in supination.  On command, the subject will be asked to lift the arm above the head until the 
elbow is fully extended, then to lower the arm back to the starting position.  The subject will 
be asked to repeat the action at a comfortable pace according to their own rhythm for the 
30 second duration of the test.  The test will be performed bilaterally and the final score will 
be the mean of the total number of completed repetitions from both arms.  The number of 
completed repetitions from each arm and the mean score will be recorded at the time of test 
administration.   

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7.5.2.5 
HIBM Functional Activities Scale 
In Part I of the study, the HIBM Functional Activities Scale (HIBM-FAS) will be 
administered at the Baseline and Part I Termination Visits, to assess functional disability.  
For continuing subjects, the assessment at the Part I Termination Visit will serve as the 
baseline assessment for Part II of the study.  Additional HIBM-FAS assessments in Parts II, 
III, and IV of the study will be performed at Baseline (for treatment naïve subjects), Months 
6, 18, 36 and Termination Visits.  The scale is being developed specifically for patients with 
GNE myopathy (HIBM) based on feedback received from affected individuals on the impact 
of the disease on their function.  Items in the scale assess the subject’s ability to 
independently perform various activities of living that involve self-care, mobility and use of 
the upper and lower extremities.  The scale will be administered in an interview format by a 
licensed physical therapist and scored after the testing. 
7.5.3 
Exploratory Efficacy Measures 
Additional novel exploratory biomarkers of sialylation and muscle injury may also be 
evaluated to explore the possible best methodology to monitor GNE Myopathy disease.  
Candidate biomarkers present in serum may include: 
• CK levels 
• Neural cell adhesion molecule (NCAM) measured using an ELISA assay and/or 
immunoblot assay to characterize the NCAM types present.  
• Other biomarkers of muscle injury and remodeling, including MMP9 and microRNAs 
Assessment of serum protein markers will only be conducted in Part I of the study.  In Parts 
II, III, and IV of the study, CK levels will be the only exploratory efficacy measure assessed.   
7.5.4 
Safety Measures & General Assessments 
7.5.4.1 
Medical History 
For continuing subjects, the medical history information obtained during the UX001-CL201 
study will carry over to this study.  A detailed medical history, including a GNE 
Myopathy-specific medical history, will be obtained at Screening/Baseline Visit for new 
subjects entering the study (i.e. treatment naïve individuals).  The medical history will solicit 
information on any prior or existing medical conditions that might interfere with study 
participation or safety.  This medical history should elicit all major illnesses, diagnoses, and 
surgeries to date.  
7.5.4.2 
Interval History 
Each interval history is intended to record any signs, symptoms, or events (e.g., falls) 
experienced by the subject since the prior study visit that are not related to study procedure(s) 
performed at prior study visits or study drug.  Interval history may include exacerbation or 

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improvement in existing medical conditions (including the clinical manifestations of GNE 
Myopathy) that might interfere with study participation, safety, and/or positively or 
negatively impact performance of functional assessments.  Interval history may identify 
under-reported AEs, and will be collected at the study visits indicated in the Schedule of 
Events (Table 2.1 and Table 2.2). 
7.5.4.3 
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 study visits indicated in the Schedule of Events (Table 2.1 and Table 2.2).   
7.5.4.4 
Height and Weight Evaluations 
Measurements of height and weight will be collected on each subject using a stadiometer and 
a scale by the physical therapist administering the performance testing.  Height and weight 
data will be used to evaluate each subject’s muscle strength and function using published 
normative data where available. 
7.5.4.5 
Physical Examination 
In Part I of the study, complete physical examinations will be performed at the Baseline and 
Part I Termination Visits.  For continuing subjects, findings in the Part I Termination Visit 
will serve as the Part II baseline assessment.  In Parts II, III, and IV of the study, a complete 
physical examination will be performed at Baseline (for treatment naïve subjects), Months 6, 
18, 36 and the Termination Visits.  Physical examinations will include assessments of 
general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, 
lymphatic, respiratory, gastrointestinal, genitourinary, musculoskeletal, neurologic systems 
(at designated visits where a complete neurological examination is not performed).  
Other body systems may be examined and symptoms of increasing muscle weakness and 
pain will be recorded.  The presence of changes in muscle pain or weakness should be 
evaluated carefully by a complete neurologic exam when these changes are reported by 
subjects.  The specific muscle location and pain should be noted.  Clinically significant 
changes from Baseline will be recorded as AEs.   
7.5.4.6 
Neurological Examination 
In Part I of the study, a neurological examination will be performed at the Baseline and Part I 
Termination Visits.  For continuing subjects, findings in the Part I Termination Visit will 
serve as the Part II baseline assessment.  In Parts II, III, and IV of the study, a neurological 
examinations will be performed at Baseline (for treatment naïve subjects), Months 6, 18, 36 
and the Termination Visits.  The neurological examination will include assessments of 
cognition, cranial nerves, motor function, coordination and gait, reflexes, and sensory 
function.   

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7.5.4.7 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study are listed in Table 7.5.4.7.1; 
the time points for these evaluations are indicated in the Schedule of Events (Table 2.1 and 
Table 2.2).  Fasting is not required.  Refer to the central laboratory manual for additional 
details. 
Table 7.5.4.7.1: 
Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Special Assessments 
Alanine 
aminotransferase 
(ALT/SGPT) 
Hematocrit 
Appearance 
Free serum SA 
Alkaline phosphatase 
Hemoglobin 
Color 
Serum pregnancy test 
(if positive urine 
pregnancy test) 
Amylase 
MCH concentration (MCHC) 
pH 
 
Aspartate 
aminotransferase 
(AST/SGOT) 
Mean corpuscular hemoglobin 
(MCH) 
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 
 
Cholesterol (total) 
WBC differential 
Nitrite 
 
Creatine kinase (CK) 
Neutrophil count (absolute and 
%) 
Urobilinogen 
 
Creatinine 
Lymphocyte count (absolute and 
%) 
Hemoglobin 
 
Gamma-glutamyl 
transpeptidase (GGT) 
Monocyte count (absolute and 
%) 
Creatinine 
 
Glucose, non-fasting 
Eosinophil count (absolute and 
%) 
 
 
Lactate dehydrogenase 
(LDH) 
Basophil count  
(absolute and %) 
 
 
Lipase 
White blood cell (WBC) count 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Protein (albumin and 
total) 
 
 
 
Sodium 
 
 
 
Triglycerides 
 
 
 
 
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. 

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7.5.4.8 
Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent until 30 days 
after the last dose of study drug or, if applicable, until the date the subject signs the informed 
consent for the open-label extension study, UX001-CL302, whichever occurs sooner.  
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 every study visit. 
7.5.4.9 
Concomitant Medications 
Concomitant medications will be reviewed and recorded at each study visit.  A discussion of 
concomitant medications is provided in Section 7.4.4. 
7.5.4.10 Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests as specified in the 
Schedule of Events (Table 2.1 and Table 2.2).  Female patients with a positive pregnancy test 
at Baseline do not meet eligibility criteria for enrollment and will not be enrolled in the 
study.  Females considered not of childbearing potential include those who have had total 
hysterectomy, have been in menopause for at least two years, or have had tubal ligation at 
least one year prior to Baseline. 
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.  
Experience with UX001 in pregnant women is limited. The study drug may involve risks to a 
pregnant female or unborn baby which are currently unknown.  Participants of child‐bearing 
potential or with partners of child bearing potential who have not undergone a bilateral 
salpingo‐oophorectomy and are sexually active must consent to use a highly effective method 
of contraception as determined by the site investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug.  Examples of highly 
effective methods of contraception include oral hormonal contraceptives, patch hormonal 
contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical 
hysterectomy, vasectomy, tubal ligation or true abstinence (when this is in line with the 
preferred and usual lifestyle of the subject), which means not having sex for the duration 
specified above because the subject chooses not to.  
7.5.4.11 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 

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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. 
7.5.5 
Drug Concentration Measurements 
Blood samples for the measurement of trough levels of free serum SA will be drawn at the 
time points shown in the Schedule of Events (Table 2.1 and Table 2.2); samples will be 
obtained from the subjects during blood draws for clinical laboratory samples.  
Urine samples for measurement of free serum SA will be collected during Part I of the study 
only.  The time elapsed from the last dose of study drug should be noted.  SA, the active 
study drug in UX001-CL202, occurs naturally in the human body, both through de novo 
synthesis and via the diet.  Consequently, the free serum SA level should reflect, but will not 
be a quantitative measure, of circulating study drug.  Refer to the central laboratory manual 
for details on the drug concentration measurements. 
7.5.6 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study include clinical changes in muscle 
strength, and subject mobility, and function.  The clinical assessments in the study 
employ standard performance measures used in other neuromuscular diseases and 
conditions that cause muscle weakness and impaired function.  Based on the work of Aitkens 
(Aitkens et al. 1989), the study will focus on quantitative muscle testing.  The strength of a 
set of muscle groups in the upper and lower extremities will be assessed by HHD, a form of 
quantitative muscle testing that uses a device with a strain gauge to measure force during a 
MVIC (Sisto et al. 2007) .  Walking ability will be assessed using the 6MWT test, a 
commonly used test of endurance used in clinical trials for various indications that has served 
as the basis for many product approvals.   In addition, an interview-based measure designed 
to evaluate disability in GNE Myopathy patients (HIBM-FAS) will be administered in this 
study to further validate the instrument. 
Exploratory measures will attempt to identify changes in serum biomarkers in Part I of the 
study.  Serum NCAM may be evaluated to provide some estimate of the sialylation of 
NCAM in the regenerating muscle, albeit at low levels in the circulation.  Other biomarkers 
of muscle injury (e.g., MMP9 and microRNAs) may also be assessed.  However, interim data 
from the UX001-CL201 study suggests the results may be of limited value; therefore, 
exploratory serum protein markers will not be assessed in Parts II, III, and IV of the study.   
Serum CK level will be assessed as a measure of muscle injury throughout the study; a 
positive dose-dependent decrease in serum CK levels was observed in the UX001-CL201 
Week 24 analysis.  Unlike other myopathies, CK activities are mildly elevated or in the 
normal range for these patients; 22/58 patients reported by three publications had two-times 
or higher elevations (Sadeh et al. 1993); (Mizusawa et al. 1987); (Sunohara et al. 1989).  
The mouse model of HIBM showed elevated CK levels that improved substantially on 
treatment (Malicdan et al. 2009).  Given the modest CK levels in patients, it is unclear if this 

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is a universally evaluable endpoint in humans, however in the mouse model, the data on 
reduced CK levels during SA treatment was compelling (Malicdan et al. 2009).   
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, neurological 
examination, vital signs, serum chemistry, and other routine clinical and laboratory 
procedures.  In addition, symptoms of increasing muscle weakness and pain which are 
characteristic of myopathy will be recorded. 
7.6 
Statistical Methods and Determination of Sample Size 
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection, 
and to avoid missing data.  In particular the endurance measures will be performed in 
duplicate using standard and consistent methodology.  The detailed method for analyses will 
be presented in the Statistical Analysis Plan (SAP); the information below is intended as a 
guide to planned analyses.  
7.6.1 
Clinical and Exploratory Efficacy Measures 
The clinical evaluation measures in this study are: 
• Improvement in quantitative muscle strength as measured by HHD. 
• Improvement in mobility, strength and gross motor function as measured by the 6MWT 
and walking speed and weighted arm lift tests. 
• Improvement in functional disability as measured by the HIBM-FAS. 
The exploratory efficacy measures in this study will involve evaluation of novel biomarkers 
of sialylation and muscle injury.  The exploratory efficacy measures may include: 
• Improvement in serum biomarkers of muscle injury, including CK. 
• Improvement in other serum biomarkers of muscle injury, sialylation, and remodeling, 
including MMP9 (metalloproteinase level) and specific microRNAs associated with 
muscle disease. 
Serum biomarkers of sialylation will be evaluated as exploratory analyses in Part I of the 
study only.  Serum CK levels will be evaluated in Parts I, II, III, and IV of the study.   
7.6.1.1 
Clinical Efficacy Analyses 
All subjects with any post-dose data will be included in the intent-to-treat (ITT) efficacy 
analysis.   
Efficacy will be evaluated by continued improvement in clinical assessments.  Efficacy 
assessments may differ depending on the phase of the study (i.e., Part I, Part II, Part III, or 

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Part IV). For Part I efficacy evaluation, results from the last pre-treatment assessment from 
UX001-CL201 will be compared with the last post-treatment assessment for the Part I 
Treatment Period as listed in the Schedule of Events (Table 2.1), with efficacy conclusions 
based on change since SA-ER treatment initiation.  An interim analysis will be conducted 
when a majority of subjects have completed the Month 6 Visit of the Part II Treatment 
Period.  For Part II efficacy evaluation of the continuing subjects, change from baseline of 
Part II to Month 6 assessment at 12g/day SA-ER/SA-IR dose will be determined and 
compared with the improvement observed during the first 6 months of treatment with 6 g/day 
SA-ER dose, and to the rate of change observed with placebo or 3g treatment during the first 
6 months of the study.   
The changes from baseline of the treatment-naïve subjects will be evaluated over time. 
Potential comparisons of the changes from baseline to Month 6 will be performed for the 
6MWT, UE, and LE between the naïve group versus the placebo and 6g/day treatment 
groups for the first 24 weeks of treatments in subjects able to walk more than 200m at 
baseline.  In addition, changes in muscle strength over the entire treatment period of subjects 
who started with 6g/day and 3g/day will be evaluated and compared to the projected values 
of subjects who received placebo for the first 24 weeks of treatment in UX001-CL201. 
A full accounting of the analyses for Parts III and IV of the study will be provided in the 
Statistical Analysis Plan.  
For those clinical evaluations with repeated assessments (i.e., HHD, 6 MWT, walking speed 
and weighted arm lift tests) the analysis will be performed using a repeated measures 
analysis.  An exchangeable variance-covariance structure will be used.  The final treatment 
effect estimate based on this model will be the estimated treatment difference at Month 36.  
The purpose of including data from assessments prior to Month 36 is to increase the 
precision of the estimated variance, while using categorical effects of time-by-treatment to 
avoid modeling assumptions.  
Muscle strength as measured by HHD will be reported as force in kg and percent of predicted 
normal force based on age, gender, height and weight (where applicable).  Changes in force 
and percent of predicted normal force will be assessed for gross grip, pinch, shoulder 
abductors, elbow flexors, elbow extensors, hip abductors, hip adductors, hip flexors, hip 
extensors, knee flexors, and knee extensors.  Individual muscle groups will also be compared 
to assess individual muscle changes. 
Walking ability as measured by the 6MWT will be reported as distance in meters and percent 
of predicted normal based on age and gender.  Changes in distance and percent of predicted 
normal will be assessed.  The proportion of subjects with a normal percent predicted distance 
walked (i.e., a percent predicted distance walked of ≥ 80%) at each time point may be 
tabulated.  The relationship between 6MWT results and other and efficacy outcomes may 
also be explored. 

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Walking speed as measured by the 25 feet walk test will be reported in seconds and percent 
of predicted normal for each walking speed.  Changes in the number of seconds and percent 
of predicted normal for each speed from Baseline will be assessed. 
Arm raising ability as measured by the weighted arm lift test will be reported as the total 
number of completed repetitions.  Changes from Baseline in repetitions between the 
treatment arms will be assessed. 
Functional disability as measured by the HIBM-FAS will be reported as a total score and 
subscale scores for mobility, self-care, and upper extremity function, with lower scores 
associated with greater disability.  Changes in the total score will be assessed. 
7.6.2 
Safety Measures 
The safety measures in this study are: 
• Incidence and frequency of AEs and SAEs 
• Clinically significant changes from baseline in vital signs, physical and neurological 
examination findings and laboratory evaluations 
• Interval history, including reported symptoms of increasing muscle weakness or pain, and 
incidence of falls 
The analyses of safety will include all subjects who receive any study drug at any time during 
the study and provide any post-treatment safety information.  Safety data will be periodically 
reviewed by the DMC.  
For the safety analysis, the incidence and frequency of AEs and SAEs will be evaluated.  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), 
Preferred Term (PT), relationship to study drug, and severity for each treatment group.  
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. 
Clinical laboratory data will be summarized by the type of laboratory test.  The frequency 
and percentage of subjects who experience abnormal clinical laboratory results (i.e., outside 
of reference ranges) and/or clinically significant abnormalities after study drug 
administration will be presented for each clinical laboratory measurement.  For each clinical 
laboratory measurement, descriptive statistics will be provided for Baseline and all 
subsequent post-treatment scheduled visits.  Changes from Baseline to the post-treatment 
visits will also be provided.  Descriptive statistics of vital signs, imaging assessments, and 
concomitant medications will also be provided in a similar manner. 
The SAP will provide additional details on the planned statistical analysis. 

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7.6.3 
Data Monitoring Committee 
A DMC will be constituted for Study UX001-CL202 and will act in an advisory capacity to 
Ultragenyx to monitor the safety of SA-ER/SA-IR in subjects who participate in the study.  
The DMC may: 
• Review plans for data monitoring. 
• Evaluate the progress of the trial, study data quality, timeliness, subject recruitment, 
accrual and retention, subjects’ risk versus potential benefit, and other factors that could 
affect the study outcome. 
• Consider relevant information that may have an impact on the safety of the participants or 
the ethics of the study 
• Make other recommendations to Ultragenyx concerning continuation, termination or 
other modifications of the study based on their observations of the study. 
7.6.4 
Determination of Sample Size  
Approximately 46 subjects may be enrolled in Part I of this open-label extension study.  
Sample size is limited to the number of subjects enrolled in the Phase 2 safety and efficacy 
study, UX001-CL201.  As Part I of the study is intended to evaluate of the long-term safety 
of 6g/day SA-ER in subjects with GNE Myopathy, and ascertain the long-term effect of 
SA-ER treatment on muscle strength, mobility, and functional disability, the sample size is 
deemed reasonable to satisfy Part I study objectives.   
Approximately 10 treatment-naïve subjects will be enrolled into Part II of the study.  
This subset of treatment naïve GNE Myopathy subjects will provide additional safety and 
efficacy information following treatment with SA-ER/SA-IR. 
The study design is open-label with all subjects receiving the same treatment.  Therefore, the 
study is not powered to assess statistically significant comparisons.  Instead, the sample size 
is intended to provide the maximum amount of long-term safety and efficacy data for the 
investigational product. 

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

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to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. 
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.  The monitor will verify the investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator has been identified for this trial.  The Coordinating Investigator 
is 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 reads and signs the Clinical Study Report (CSR). 
8.3 
Investigational Product Accountability 
While at the clinical site, study drug must be stored in a secure limited access location at 
controlled temperature as described in the IB and according to product packaging.  
The storage facility must be available for inspection by the study monitor at any time during 
the study.   

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

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

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

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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. 
• Not Related:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt.  That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 
with the onset of the event and the exposure to study drug and/or a causal relationship is 
considered biologically implausible. 
• Possibly Related:  This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been produced 
by a number of other factors. 
• Probably Related:  This category applies to an AE that is likely related to the 
investigational agent/procedure.  That is, the AE has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, follows a known or 
suspected pattern of response, and is strongly associated with study drug exposure. 
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 preexisting condition) with 
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.  
All AEs will be collected from the time the subject signs the informed consent through 
30 days following the last dose of study drug, or, if applicable, until the date the subject signs 
the informed consent for the open-label extension study, UX001-CL302, whichever occurs 
sooner. In addition for those subjects choosing not to enroll in UX001-CL302, the 
Investigator should report any AE that occurs more than 30 days following the last dose of 
study drug that is believed to have a reasonable possibility of being associated with study 
drug.  
AEs ongoing after the defined follow-up period stated in the paragraph above should have a 
comment in the source document by the Investigator that the event has recovered, recovered 
with sequelae, or stabilized.   

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8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Any SAE that occurs at any time during the study, 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. 
The reporting requirement for SAEs is from the time of signing of the ICF through 30 days 
following the last study drug administration.  
SAEs will be reported by completing and submitting SAE report forms to Ultragenyx or its 
designee. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. 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. 
A death occurring during the study, during the per-protocol follow-up period, or within 
30 days after stopping treatment with the study drug must be reported to Ultragenyx or its 
designee within 24 hours of knowledge of the death whether or not it is considered 
treatment-related.  
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 IRB/EC requirements and local law. A copy of 
this notification must be provided to Ultragenyx or its designee.    
8.5.4.3 
Urgent Safety Reporting 
The regulations governing clinical studies state that the sponsor and investigator are required 
to take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subjects, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union (EU) 
Clinical Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the 
occurrence of any new event relating to the conduct of the trial or the development of the 
investigational medicinal product where that new event is likely to affect the safety of the 
subjects, the sponsor and the investigator shall take appropriate urgent safety measures to 
protect the subjects against any immediate hazard. The sponsor shall forthwith inform the 
competent authorities of those new events and the measures taken and shall ensure that the 
Ethics Committee (EC) is notified at the same time.”  The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. Investigators are required to report any urgent safety measures to Ultragenyx 
within 24 hours. 

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8.5.4.4 
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), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional eight (8) days. All other SUSARs will be submitted within 15-calendar days of 
first knowledge of the event.  
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
Ethics Committees, and Investigators of any events (e.g. change to the safety profile of 
UX001, 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 the signing of the ICF through 30 days following 
the last dose of study drug. 
The investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee.  
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and Ethics Committees, as per local laws and regulations. 
8.5.4.5 
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 reporting period for pregnancies is the period from 
the signing of the ICF through 30 days following the last dose of study drug. 
Reported pregnancy of a subject or a subject’s partner, while participating in the study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. 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. 
Pregnancy-associated SAEs will be processed and submitted, as necessary, as per the 
SUSAR reporting process (Section 8.5.4.4). 

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