Conditions: Glycogen Storage Disease Type III
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the safety of UX053 in adults with Glycogen Storage Disease Type III (GSD III).

Detailed description:
This study is a phase 1/2 first-in-human (FIH), study to evaluate the safety, tolerability, and pharmacokinetic (PK) of a single ascending dose (SAD) and repeat doses (RD) of UX053 in patients with GSD III. The SAD cohorts will be open-label (OL). There will be two types of RD cohorts, an open-label (OL-RD) and a randomized, double-blind (DB), and placebo-controlled (DB-RD).

Arms:
arm 1: Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker. arm 2: Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker. arm 3: Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker. arm 4: Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker. arm 5: Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker. arm 6: Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.

Interventions: intervention 1: UX053 intervention 2: Placebo intervention 3: Antipyretic intervention 4: H2 Blocker intervention 5: H1 Blocker
Intervention descriptions: intervention 1: mRNA-based biologic intervention 2: consists of the same components as the formulation buffer for UX053 intervention 3: participants will receive oral premedication prior to infusion intervention 4: participants will receive oral premedication prior to infusion intervention 5: participants will receive oral premedication prior to infusion

Protocol document:
Prot_000.pdf: 
1 
Confidential 
1.
TITLE PAGE
A Phase 1/2 First-in-human, Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Single Ascending Doses and Repeat  
Doses of UX053 in Patients with GSD III  
Original Protocol: 20 Jan 2021 
Amendment 1: 24 March 2021 
Amendment 1.1 (UK-specific): 07 September 2021 
Amendment 2: 01 October 2021  
Amendment 2.1 (US-specific): 01 October 2021 *(see Table 16) 
Amendment 2.2 (UK-specific): 01 October 2021  
Amendment 2.3 (US-specific): 03 January 2022 
Amendment 3.1 (US-specific): 14 July 2022 
Brief Title: 
First-in-human Study of UX053 in Patients with GSD III 
Product number: 
UX053 
Indication: 
Glycogen Storage Disease Type III (GSD III) 
IND Number:  
027233 
EudraCT Number: 
2021-000903-19 
Sponsor:  
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA 94949 
USA 
Sponsor’s Responsible Medical 
Monitor: 
 
This trial will be performed in compliance with the protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements and guidelines. 
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 prior written authorization from Ultragenyx, except to the 
extent required to satisfy Institutional Review Board/Independent Ethics Committee procedures, to obtain written 
informed consent from potential subjects, or as required by law.  
PPD


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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX053-CL101 Amendment 3.1 (US-specific) 
14 July 2022 
Protocol UX053-CL101 Amendment 2.3 (dated 03 January 2022) has been modified by Amendment 3.1 (US-specific). 
Amendment 3.1 is considered to be substantial. Minor edits and typographical corrections have also been made. Changes impacting 
study design and/or conduct are summarized below. In addition to the sections described below where changes occurred, relevant 
updates were made to the Synopsis. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4.4 Potential Benefits; 
Section 5.5 Risk Minimization; 
Section 7.1 Study Design; Section 7.1.3 
Rationale for Study Design; 
Section 7.1.4 Dose Rationale; 
Section 7.2.1 Duration of Subject 
Participation; Section 8.1 Inclusion 
Criteria; Section 8.2 Exclusion Criteria; 
Section 8.5 Screening Requirements; 
Section 9 Interventions; Section 9.1.2 
Preparation and Administration; 
Section 9.3 Nutrition Management; 
Section 9.7 Treatment Compliance; 
Section 9.8.1 Treatment Assignment; 
Section 9.8.2; nearly all subsections of 
Section 10 Assessments; Section 11.1 
Sample Size Determination; 
Section 11.2 Analysis Sets; 
Section 11.3.1 General Principles; 
Section 11.6 Anti-drug Antibody 
Analyses; Section 11.7 Efficacy 
Analyses; Section 11.11 Planned 
Analyses; Figure 1 UX053-CL101 
Study Design; Schedule of Events 
Table 4, Table 5, and Table 6; Schedule 
of PK Assessments Table 8; Appendix 2 
Subjects who complete the 90-day safety follow-up in 
the Single Ascending Dose (SAD) cohorts can elect to 
enter into open-label repeat dose (OL-RD) cohorts to 
receive an additional 4 doses of open-label UX053 
administered every 4 weeks (Q4W). These subjects 
will be rescreened for participation in the OL-RD 
cohorts prior to redosing; eligibility can be combined 
with assessments at the SAD Day 90 Visit. During 
rescreening for OL-RD cohorts, subjects will be 
assessed for status of diet optimization and stability 
based on nutrition data collected during participation in 
SAD cohorts and rescreening for OL-RD cohorts.  
Reflecting this change, there are now 2 sets of RD 
cohorts: the previously included randomized, 
double-blind, placebo-controlled RD (DB-RD) cohorts 
and the newly added OL-RD cohorts.  
Initiation of OL-RD cohorts runs in parallel with 
initiation of DB-RD cohorts, guided by Data 
Monitoring Committee (DMC) review. The timing of 
the DMC reviews was updated to reflect this. A new 
schedule of events table was added to indicate the 
timing of assessments for the OL-RD cohorts and the 
Schedule of pharmacokinetic (PK) Assessments 
Table 8 was updated to reflect the addition of OL-RD 
cohorts treated Q4W.  
The optimal dose interval for UX053 is not known. 
Allowing subjects who participated in SAD cohorts to 
enroll in OL-RD cohorts will allow for the investigation 
of safety, PK, and pharmacodynamic (PD) effects of 
repeat dosing of UX053 with a Q4W dosing regimen. 
The Q2W regimen is expected to be the maximum 
frequency of dosing based on nonclinical studies, and a 
less frequent dosing regimen may be possible based on 
PK data in humans.  
Section 10.5.1 Controlled Fasting 
Challenge 
Section 10.5.1 was added to reflect the addition of a 
controlled fasting challenge (CFC) as an optional 
assessment for subjects in RD cohorts.  
To assess if CFC is useful to identify a clinically 
significant improvement in glycemic status with UX053 
treatment.  
Section 7.1 Study Design 
A schematic illustrating nutrition optimization and 
stabilization requirements during screening for the 
DB-RD cohorts was added.  
To clarify the nutrition optimization and stabilization 
requirements by cohort. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1 Inclusion Criteria; 
Section 8.2 Exclusion Criteria; 
Section 9.6 Restricted or Prohibited 
Medications, Devices, and Procedures 
One new inclusion criterion and 1 new exclusion 
criterion were added to allow rescreening of subjects 
from the SAD cohorts as they enter the OL-RD cohorts 
(noted above). Existing eligibility criteria that referred 
to RD cohorts were edited to specify how the criteria 
apply to the new OL-RD cohorts.  
The newly added inclusion criterion is: For subjects 
rescreening into OL-RD cohorts, after treatment with 
UX053 in a SAD cohort, subjects must meet the 
following criteria: 
a. 
If a significant rise in ALT occurs after the prior 
dose, ALT should show a decreasing trend 
toward the subject’s baseline value 
b. Total bilirubin is within normal limits  
c. 
Platelets are within normal limits 
d. INR is within normal limits 
The additional exclusion criterion is: For subjects 
rescreening into OL-RD cohorts, any of the following 
after treatment with UX053 in a SAD cohort [are 
excluded]: 
e. 
New or worsening symptoms of liver disease 
(including new or worsening hepatomegaly) 
along with any increase in transaminase levels 
f. 
Receipt of any blood product administration 
(eg, packed red blood cells, platelet, fresh frozen 
plasma) for management of consumptive 
coagulopathy  
g. An ALT level that is ≥ 8x ULN and > 2x the 
subject’s baseline value in the absence of an 
alternative explanation 
Subjects who receive a single dose of UX053 are no 
longer treatment naïve. Subject-level dose interruption 
criteria were adapted for the purpose of redosing these 
subjects in the OL-RD cohorts.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 Study Design 
All SAD cohorts will consist of at least 2 subjects. 
Previously, Cohorts 1S and 2S had 2 subjects each and 
Cohort 3S and Cohort 4S had 3 subjects each.  
The text indicating that subjects will be added in blocks 
of 4 was removed.  
Safety data from at least 2 subjects are required for the 
decision to proceed with the next cohort(s). If further 
characterization of safety, PK, and PD at a given dose 
level is desired, individual subjects may be added to 
SAD cohorts as needed. 
Section 5.4.1.1 Potential Risks Identified 
from Nonclinical Studies; Section 7.1 
Study Design; Section 7.1.4 Dose 
Rationale; Section 9 Interventions 
Dose escalation plans were clarified. Ultragenyx aims 
to test at least 3 dose levels of UX053. Dose levels for 
each cohort may be altered depending on safety, PK, 
and PD findings from prior cohorts. If needed to 
evaluate safety and dose-response relationship 
additional cohorts may be added to test doses up to 
0.30 mg/kg.  
Cohorts 4S and 4R, in which subjects are to receive 
single or multiple doses of UX053 at 0.30 mg/kg, 
respectively, are now optional.  
All cohorts beyond Cohort 1S are contingent on 
supportive safety, PK, and PD data from prior cohorts. 
Based on preliminary data from Cohort 1S and 
nonclinical PK/PD modeling, it is unlikely that doses as 
high as 0.30 mg/kg will be needed for maximum 
biological effect. 
Section 7.1.2 Number of Subjects; 
Section 11.1 Sample Size Determination 
The total number of subjects included in the study was 
updated to approximately 18, reflecting 6 planned 
subjects in Cohorts 1S, 2S, and 3S and 12 planned 
subjects in Cohorts DB-1R, DB-2R, and DB-3R. 
Additional subjects may be added to SAD or RD 
cohorts for further characterization of safety.  
The updated total number of subjects reflects the 
changes in study design.  
Section 7.1 Study Design 
Reference to the Pharmacy Manual regarding guidance 
on dose reductions was removed. If a subject in a RD 
cohort (either DB or OL) develops a treatment-
emergent adverse event (TEAE)/serious TEAE ≥ Grade 
3 that is considered by the Investigator to be related to 
study drug or an intolerable TEAE in a RD cohort, any 
further study drug administration and any subject-level 
dose reductions should be discussed with the Medical 
Monitor.  
Investigators should not redose subjects who have 
experienced UX053-related TEAEs until after 
discussion with the Medical Monitor.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 Study Design; Schedule of 
Events Table 4 and Table 6  
Text was edited to clarify that telephone calls regarding 
the use of continuous glucose monitoring (CGM) and 
handheld glucometer (HHG) devices will occur as 
needed, outside of scheduled study visits.  
To clarify the timing of telephone calls related to CGM 
and HHG data collection.  
Section 7.1 Study Design 
Text was added to clarify that subjects within a given 
RD cohort can be dosed simultaneously. After 
initiation of repeat dosing, subjects will follow a Q2W 
(DB-RD cohorts) or Q4W (OL-RD cohorts) dosing 
regimen.  
To clarify the interval between dosing subjects within 
RD cohorts.  
Section 8.1 Inclusion Criteria 
The italicized text was added to the following inclusion 
criterion “Willing and able to provide access to 
medical records surrounding medical treatment that 
occurred prior to enrollment and during the study.”  
To ensure complete capture of relevant safety data.  
Section 8.2 Exclusion Criteria; 
Section 9.6 Restricted or Prohibited 
Medications, Devices, and Procedures 
The exclusion criterion “Planned surgery, including 
dental surgeries, during the SAD Period for subjects in 
Part 1 or prior to Week 10 of the RD Period for 
subjects in Part 2” was updated to “Planned surgery, 
including dental surgeries, during the study.” This text 
was also updated in the section regarding restricted 
procedures.  
To simplify for greater clarity.  
Section 10.4.4.4 Nutrition Diary; 
Schedule of Events Table 4 and Table 6 
For all cohorts, nutrition diary recordings will now be 
recorded at least 3 consecutive days per week through 
Screening and for the 3 consecutive days in the week 
leading up to each subsequent visit. 
To reduce subject burden.  
Schedule of Events Table 6  
Assessments for serum CK-M/B, troponin I, and CK, 
and plasma BNP were added at Weeks 2, 4, 6, and 8 
for the DB-RD cohorts. The assessment for plasma 
BNP was removed from ISV.  
ToAssessments were added to facilitate evaluation of 
potential PD effects on heart and skeletal muscle. The 
assessment for plasma BNP is no longer performed at 
ISV, but can be performed during screening (Nutrition 
Optimization Visits [NOVs] and Stabilization Visit 
[STV]) at the discretion of the Investigator.  
Schedule of Events Table 4 and Table 6; 
Appendix 3  
Assessments for urine beta hydroxybutyrate and whole 
blood for RNA analysis were removed for all cohorts.  
To reduce subject burden.   


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Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 6  
Assessments for urine beta hydroxybutyrateThe 
physical exam and weight assessment was added to 
Weeks 3, 5removed from Week 12, 24, and 736 for the 
DB-RD cohorts.  
To facilitate evaluation of potential PD effects on 
ketosis.To reduce subject burden.   
Schedule of Events Table 4  
The Day 42 Visit was removed for the SAD cohort.  
To reduce subject burden.  
Schedule of Events Table 6  
Assessment of serum ketones was removed at Week 9 
for the DB-RD cohorts. Serum ketones was also 
changed to capillary ketones for DB-RD cohorts. Also 
for the DB-RD cohorts, ketones are no longer assessed 
at the NOV (previously optional per discretion of the 
Investigator) and Weeks 1, 12, 24, and 36.  
Assessment of serum ketones is not required at 
WeekNOV, and Weeks 1, 9, 12, 24, and 36 for the DB-
RD cohorts. The assessment of capillary ketones instead 
of serum ketones for RD cohorts aligns with the addition 
of an optional CFC for RD cohorts.  
Schedule of Events Table 6 
The schedule of events tables for the RD cohorts 
reflects that the imaging assessments (liver magnetic 
resonance imaging [MRI], magnetic resonance 
spectroscopy [MRS], FibroScan or ultrasound 
elastography) can occur throughout rescreening (OL-
RD) or screening (DB-RD). Imaging assessments were 
also removed for the DB-RD EOS III W48/ET Visit.  
To reduce subject burden.  
Section 8.3.2 Subject-level Redosing 
and Stopping Criteria; Section 9.1.1 
Premedications; Section 9.1.2 
Preparation and Administration; 
Section 9.1.3 Clinical Observation and 
Supportive Care; Section 9.5 Rescue 
Medications; Section 11.4 Safety 
Analyses  
Infusion-associated reaction (IAR) was changed to 
infusion-related reaction (IRR) throughout the 
protocol.  
The use of IRR better aligns with Medical Dictionary 
for Regulatory Activities (MedDRA) terminology.  
Schedule of Events Table 6  
Prothrombin time/international normalized ratio 
(PT/INR) will be assessed at all scheduled study visits 
in the Treatment and Follow-up Period for the DB-RD 
cohorts. 
To facilitate early detection of consumptive 
coagulopathy and liver injury, both are a potential risk 
of UX053. 


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Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 6; 
Section 10.5.5; Appendix 3   
Assessments for plasma glucose tetrasaccharide (Glc4) 
were removed from the study and the heading title for 
Section 10.5.5 was changed from “Limit Dextrins” to 
“Glucose Tetrasaccharide.”  
Assessments for urine Glc4 were added at Weeks 3, 4, 
5, 6, 7, and 9 for DB-RD cohorts.  
Plasma Glc4 is no longer required, and removal of this 
assessment will reduce subject burden. The timing of 
urine Glc4 was changed to improve temporal resolution 
of this PD biomarker. 
Schedule of Events Table 6 
Section 10.5.7 Exploratory Future Use 
Blood Cell Pellet, Serum, and Plasma 
Collection. 
The row titled “Blood Cell Pellet for Future Use” in all 
schedule of events tables was removed, and the row 
Serum & Plasma for Future use” was updated to 
include white blood cells (WBC) and red blood cells 
(RBC). Similar language changes were made in 
Section 10.5.7.  
To align language between region-specific protocols. 
There is no operational change as a result of this 
language change.  
Table 7 Schedule of Vital Sign 
Assessments 
Table 7 Schedule of Vital Sign Assessments across 
SAD and RD cohorts was consolidated and simplified 
to reflect consistency in vital sign assessments.  
The schedule of vital sign assessments on infusion visits 
is the same for all infusions, regardless of cohort.  
Section 8.3.2 Subject-level Redosing 
and Stopping Criteria 
“Safety labs will be obtained at Weeks 1, 3, 5, 7, and 9 
of the RD Period, corresponding to 1 week after each 
dose of study drug” was removed from Section 8.3.2 
Subject-level Redosing and Stopping Criteria.  
This information is not appropriate for this section.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4.2 Potential Risks of 
Premedication; Section 5.5 Risk 
Minimization; Section 7.1.4 Dose 
Rationale; Section 8.3.2 Subject-level 
Redosing and Stopping Criteria; 
Section 9.1.1 Premedications; 
Section 9.5 Rescue Medications 
Text was added throughout relevant sections to 
reiterate guidance from Table 11, noting that 
epinephrine should be administered if a subject 
develops an IRR that meets diagnostic criteria for 
anaphylaxis. For all other hypersensitivity reactions ≥ 
Grade 2 in severity suspected to be due to immune 
activation, dexamethasone should e the initial rescue 
medication.  
Text was added to Section 9.5 to account for rescue 
medications in the event of severe consumptive 
coagulopathy and profound complement activation. 
Also in this section, text was updated to clarify that 
premedication and rescue medication selection will be 
based on the nature of the reactions being observed and 
the risks of such medications. As previously noted in , 
the following text was added to Section  and Section : 
“Additional treatment, including a complement 
inhibitor (such as eculizumab) may be considered.” 
To provide additional clarity on the use of rescue 
medications in the event of potential risks of UX053 
treatment.  
Section 11.2 Analyses Sets 
The terminology regarding the analyses sets was 
updated. The Safety Analysis Set will include all 
enrolled subjects, defined as subjects deemed eligible 
for treatment at D0 in the SAD cohorts, and those 
randomized in the DB-RD cohorts, and those who 
continue into OL-RD cohorts from SAD cohorts. A Per 
Protocol (PP) Analysis Set, consisting of subjects who 
complete the study without major protocol deviations 
that could compromise PD or efficacy assessments may 
be analyzed as described in the Statistical Analysis 
Plan (SAP). The PK Analysis Set is a subset of subjects 
in the Safety Analysis Set who have at least 1 
evaluable investigational product (IP) concentration. 
The PK Analysis Set will be used for the analysis of 
PK endpoints. 
Changes were made to align with the SAP.  


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Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 4  
Footnote a in the SAD cohort’s schedule of events 
table was updated to indicate that there must be a 
minimum of 10 days between any assessments that are 
measured at both the Screening and the Baseline Visit.  
To provide clarification regarding the timing required 
between assessments taken at the Screening and 
Baseline Visit for SAD cohorts.  
Section 10.4.1.1 Liver Magnetic 
Resonance Imaging; Section 10.4.1.2 
Liver Magnetic Resonance Spectroscopy 
Study Reference Manual was changed to Study 
Imaging Manual.  
Instructions related to liver MRI and MRS are provided 
in the Study Imaging Manual.  
Schedule of Events Table 4 and Table 6; 
Section 10.4.1.1 Liver Magnetic 
Resonance Imaging  
If feasible, quantitation of glycogen using nuclear 
overhauser enhancement (glycoNOE) (Zhou et al., 
2020) of the liver, may be collected at the time of the 
liver MRI/MRS. 
GlycoNOE may provide additional insight into changes 
in glycogen content in the liver.  
Section 8.1 Inclusion Criteria 
The word “fertile” was removed from the following 
entry criterion “Females of childbearing potential must 
have a negative pregnancy test at screening (and 
rescreening, as applicable) and be willing to have 
additional pregnancy tests during the study. Subjects of 
childbearing potential or fertile males who are sexually 
active with partners of childbearing potential must 
consent to use a highly effective contraceptive method, 
as described in Appendix 4, from the Period following 
the signing of the informed consent through 30 days 
after last dose of study drug.” 
Assessment of fertility for males in this study is not 
conducted.  
Section 5.5 Risk Minimization; 
Section 7.1.4 Dose Rationale; 
Section 9.1.2 Preparation and 
Administration; Schedule of Events 
Table 8 
As noted in the prior amendment, the study drug 
infusion rate schedule may require modification, 
including lengthening of total infusion time, to 
minimize the risk of IRRs in individual subjects. Text 
regarding slowing the infusion rate was edited and 
added in Section 7.1.4 and Section 9.1.2. Reflecting 
this adaptive design, the following text was added as a 
footnote to Table 8: “If the total infusion time is 
extended beyond 4 hours, a blood sample should be 
collected at the new end of infusion (EOI) time. If the 
new EOI time overlaps with a prespecified time point, 
sampling should continue at the next scheduled time 
point” 
The rate of infusion of study drug may be adjusted to 
minimize the risk of IRRs.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 Study Design 
Text was added defining a stable diet as remaining 
within the nutritional guidelines for adults with GSD 
III based on expert recommendations.  
To clarify the definition of a stable diet.  
Section 7.1 Study Design 
The following text was removed “Mean weekly protein 
intake < 20% of total calorie intake and mean weekly 
FDUERK\GUDWHLQWDNHRIWRWDOFDORULHLQWDNHIRU
subjects will be considered protocol deviations, 
notwithstanding temporary changes to diet due to 
illness. The classification of such deviations will be 
determined by the magnitude, frequency, and duration 
of excursions beyond the specified guidelines.”  
There is no need to call out specific examples of 
protocol deviations, and a definition of stable diet was 
added separately.  
Section 10.4.4.3 GNE Myopathy 
Functional Activities Scale Expanded 
Version 
The GNE Myopathy Functional Activities Scale 
(GNEM-FAS) will no longer be scored by the 
clinician. The clinician will administer the assessment 
and provide the raw values for Ultragenyx to score.  
To reflect the change in scoring of the GNEM-FAS. 
Section 7.1 Study Design 
Text was added indicating that a future amendment 
may occur to add an open-label extension after an 
interim review of safety, PK, and PD data.  
This text was added to reflect potential future changes to 
the protocol.  
Section 8.2 Exclusion Criterion  
 
  
 
  
Section 8.2 Exclusion Criterion 
In the following sentence within exclusion criterion 10, 
“asymptomatic cardiomyopathy” was updated to “mild 
cardiomyopathy:” “Asymptomatic cardiomyopathy and 
left ventricular hypertrophy (LVH) are allowed.  
New York Heart Association (NYHA) Function 
Capacity II and below are allowed, not just 
asymptomatic cardiomyopathy.  
Title Page  
A brief study title was added to the title page. The 
study title was also edited.  
Updated per recent regulatory guidance. and to reflect 
changes in this amendment (ie, addition of an open-label 
cohort). 
CCI
CCI


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6 Objectives and Endpoints 
Reflecting the addition of a Q4W dosing regimen, the 
secondary endpoint was updated to “PK parameters of 
AGL mRNA and ATX95, which may include Tmax, 
Cmax, AUClast, AUCinf, AUCtau (RD cohorts only), RAUC 
(RD cohorts only), Tlast, T1/2, CL, Vss” 
The secondary endpoint was updated to reflect that both 
Q2W and Q4W dosing regimens will be evaluated.  
Section 5.4.2 Potential Risks of 
Premedication; Section 7.1 Study 
Design; Section 7.1.4 Dose Rationale; 
Section 8.3.2 Subject-level Redosing 
and Stopping Criteria; Section 9.1.1 
Premedications; Section 9.1.3 Clinical 
Observation and Supportive Care; 
Section 9.5 Rescue Medications 
The sentence “If dexamethasone (or equivalent) is used 
as a rescue medication, premedication with 
dexamethasone (or equivalent) should be considered 
for all subjects’ subsequent infusions” was updated to 
“If dexamethasone (or equivalent) is used as a rescue 
medication, premedication with dexamethasone (or 
equivalent) should be considered for that subject’s 
subsequent infusions after discussion with the Medical 
Monitor.” Similar edits were made in sections that 
referenced this guidance.  
Subjects may have different sensitivities, requiring an 
individualized assessment for the use of additional 
premedication.  
Schedule of Events Table 4 and Table 6; 
Section 10.4.3.1 Creatine Kinase and 
Myoglobin Section 10.4.3.2; Calf 
Magnetic Resonance Spectroscopy; 
Section 10.5.3 Serum Biotinidase; 
Appendix 3 
Serum myoglobin, serum biotinidase, and calf MRS 
were removed from the study for all cohorts.  
To reduce subject burden, assessments for these 
exploratory PD endpoints were removed.  
Schedule of Events Table 6 
The Week 12, 24, and 36 Visits for DB-RD cohorts 
were changed to be conducted at home. As a result, 
Fibroscan or ultrasound elastography will be conducted 
at Week 10 instead of Week 12; and GNEM-FAS, 
Patient-reported Outcomes Measurement Information 
System (PROMIS), and handheld dynamometry 
(HHD) will be assessed at Week 10, and not at Weeks 
12, 24, and 36.  
To reduce subject burden.  
Appendix 5  
Text regarding Data Protection, Anonymization, and 
Security in Appendix 5, was updated to reflect the 
latest regulatory guidance.  
Updated per regulatory guidance and for clarity.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.5 Risk Minimization 
Text regarding the collection of safety labs in 
Section 5.5 Risk Minimization was updated to align 
with the schedule of events.  
To correct and align protocol text with the schedule of 
events.  
 


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2. 
SYNOPSIS  
Sponsor: Ultragenyx Pharmaceutical Inc. (Ultragenyx) 
Ultragenyx Product: UX053 
Title: A Phase 1/2 First-in-human, Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Single Ascending Doses and Repeat Doses of UX053 in Patients with GSD 
III  
Development Phase: Phase 1/2  
Introduction  
UX053 is an mRNA-based biologic that is being developed for the treatment of Glycogen 
Storage Disease Type III (GSD III). The purpose of this first-in-human (FIH) trial is to 
investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy 
of UX053 in adults with GSD III.  
Objectives and Endpoints 
Table 1: 
Primary and Secondary Endpoints 
OBJECTIVES 
ENDPOINTS 
Primary  
 
Evaluate the safety of UX053 in adults with GSD III 
The incidence and severity of TEAEs, serious TEAEs, 
and related TEAEs in the SAD and RD cohorts 
Secondary  
 
Characterize the PK of UX053 in adults with GSD III 
PK parameters of AGL mRNA and ATX95, which may 
include Tmax, Cmax, AUClast, AUCinf, AUCtau (RD cohorts 
only), RAUC (RD cohorts only), Tlast, T1/2, CL, Vss  
AGL, amylo-Į-1,6-glucosidase 4-alpha-glucanotransferase; AUC, area under the concentration-time curve; AUCinf, 
AUC from time 0 to infinity; AUClast, AUC from time 0 to the last measurable concentration; AUCtau, AUC from 
time 0 to end of dosing period; CL, clearance; Cmax, maximum observed concentration; PK, pharmacokinetics; 
RAUC, accumulation ratio (calculated as AUC after repeat dose / AUC after a single dose); RD, Repeat Dose; 
SAD, Single Ascending Dose; T1/2, half life; TEAE, treatment-emergent adverse events; Tlast, time of last 
measurable concentration; Tmax, time of maximum observed concentration; Vss, volume of distribution at steady 
state. 
Tertiary
 
and exploratory objectives 
 
 and their corresponding endpoints are provided in the Statistical Analysis 
Plan (SAP).  
Study Design 
UX053-CL101 is a phase 1/2 FIH study to evaluate the safety, tolerability, and PK of single 
ascending dose (SAD) and repeat doses (RD) of UX053 in patients with GSD III (Figure 1). 
The SAD cohorts will be open label (OL). There will be 2 types of RD cohorts: 1) OL-RD and 
2) randomized, double-blind (DB), and placebo-controlled RD (referred to as DB-RD). 
Treatment-naïve subjects enter the SAD and DB-RD cohorts. Subjects in the SAD cohorts who 
complete the SAD 90-day Follow-up Period can enter OL-RD cohorts. Details for each of these 
cohorts are described below. 
CCI
CCI


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Figure 1: 
UX053-CL101 Study Design 
Note: Additional subjects may be included in any cohort at the discretion of Ultragenyx. Dose levels for any cohort may be reduced depending on safety findings 
from prior cohorts. Additional cohort(s) at dose levels between 0.05 mg/kg to 0.3 mg/kg may also be included pending review of safety data.  
1RWH'RVHHVFDODWLRQLVJXLGHGE\UHYLHZRIDQGZHHNVRIVDIHW\GDWDIRUWKH6$'DQG5'FRKRUWVUHVSHFWLYHO\ Higher dose cohorts may not be 
initiated, depending on safety and PD findings from prior cohorts, as determined by Ultragenyx (with input from the DMC for the RD cohorts. 
DB, randomized double-blind placebo-controlled; OL, open-label; Q2W, every 2 weeks; Q4W, every 4 weeks; RD, Repeat Dose; SAD, Single Ascending Dose 


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Single Ascending Dose Cohorts 
The SAD cohorts evaluate safety and PK of single doses of UX053 in treatment-naïve subjects. 
All subjects in the SAD cohorts will undergo a Screening Visit prior to their Baseline Visit. 
There are 3 planned SAD cohorts, each consisting of at least 2 subjects, all of whom will receive 
open-label UX053 (Figure 1). The planned dose escalation will proceed from 0.05 mg/kg in 
Cohort 1S, to 0.10 mg/kg in Cohort 2S, and to 0.20 mg/kg in Cohort 3S. An independent Data 
Monitoring Committee (DMC) will review at least 2 weeks of safety data for at least 2 subjects 
within a SAD cohort and the cumulative data from all subjects in prior dosing cohorts 
(when applicable) before deciding to proceed with the next SAD cohort.  
Each subject in the SAD cohorts will be followed for a Follow-up Period of 90 days after dosing. 
At the SAD Day 90 Visit, marking completion of the Follow-up Period, subjects can be 
rescreened for entry into the OL-RD cohorts described below.  
Open-Label Repeat Dosing Cohorts (Extension for SAD Cohorts) 
The OL-RD cohorts serve as a short-term extension for subjects who participated in a SAD 
cohort. The OL-RD cohorts evaluate the safety and PK of 4 additional OL doses of UX053 in 
subjects who received a single dose of UX053 in a SAD cohort and completed the 90-day 
Follow-up Period. Subjects from the SAD cohorts are rescreened for participation in the OL-RD 
cohorts; eligibility for additional dosing in the OL-RD cohorts can be combined with 
assessments at the SAD Day 90 Visit.  
During rescreening, a nutrition assessment will be completed at an Initial Screening Visit (ISV) 
to determine if the subject’s diet meets the nutritional guidelines for adults with GSD III based 
on expert recommendations (Table 2). OL-RD subjects will proceed through rescreening as 
shown in Figure 2 based on whether they meet these nutritional guidelines. 
Table 2: 
Nutrition Guidelines for Adults with GSD III 
High protein intake with a target of ≥ 25% of total calories  
Low complex carbohydrates intake with a target of < 50% of total calories 
Minimal intake of simple sugars 
Avoidance of fasting 
Consideration of high-protein bedtime snack or a high-protein formula for overnight enteral feeding 
Based on expert guidelines (Kishnani et al., 2010) 
The first day of the ISV (which may coincide with the SAD Day 90 Visit) is followed by 
3 consecutive days of nutrition diary collection. If a subject’s diet during participation in a SAD 
cohort meets nutritional guidelines, and continues to do so at the ISV, the subject can proceed 
directly to the OL-RD Nutrition Stabilization Visit (STV) as soon as the ISV assessments are 
completed. 
If the subject’s diet does not meet nutritional guidelines, a Nutrition Optimization Visit (NOV) is 
performed. At this visit, nutritional counseling is provided to the subject on dietary changes 
needed to comply with GSD III-specific nutrition guidelines (Table 2). Nutrition diary and 
continuous glucose monitor (CGM) data will be reviewed by the Investigator and safety 


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laboratory tests may be obtained at the discretion of the Investigator. After 1 week of nutrition 
optimization (approximately 2 weeks after the ISV), the subject proceeds to the STV (occurring 
approximately 2 weeks before the subject’s OL-RD Baseline/Week 0 Visit) and thereafter 
maintains a stable diet as defined by the nutritional guidelines for GSD III (Table 2) for the 
remainder of the study. If an OL-RD subject is unable to achieve an optimized diet, they are still 
eligible to proceed to the STV. The reason for the inability to achieve an optimized diet should 
be documented and the subject should make no substantial nutrition changes for the remainder of 
the study. 
For selected sites and subjects, the OL-RD STV includes an optional controlled fasting challenge 
(CFC). Prior to the CFC, a morning cortisol is obtained between 6 and 9 am. The CFC is 
conducted during the subject’s stay in the hospital, usually overnight, but can be conducted 
during the day. For the same sites and subjects, another optional CFC occurs at the Week 16 
Visit; only subjects who completed the optional CFC at STV complete the CFC at Week 16. 
Additional details regarding the CFC are in Section 10.5.1.  
Beginning with the OL-RD Baseline/Week 0 Visit, subjects in the OL-RD cohorts will receive 
4 additional OL doses of UX053 Q4W at the same or lower dose than they received in the SAD 
cohorts, based on ongoing assessment of safety data.  


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Figure 2: 
Rescreening Schematic for OL-RD Cohorts 
CFC, controlled fasting challenge; EOS, End of Study; ISV, Initial Screening Visit; NOV, Nutrition Optimization Visit(s); OL, open-label; RD, repeat dose; 
SAD, single ascending dose; STV, Stabilization Visit.  


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Randomized, Double-Blind, and Placebo Controlled Cohorts 
The DB-RD cohorts will evaluate the safety and PK of 5 doses of UX053 or placebo in 
treatment-naïve subjects. All DB-RD subjects will participate in a Screening Period 
(approximately 8 to 12 weeks) (Figure 3), in which subjects will be screened for study eligibility 
and assessed for the need to optimize their diet based on nutrition guidelines for adults with GSD 
III based on expert recommendations (Table 2). Within the first 2 weeks after the ISV, the 
Investigator will review nutrition diary data to determine if nutrition optimization is needed. If 
nutrition optimization is not needed, the STV occurs in clinic approximately 2 weeks after the 
ISV, and the Baseline/Week 0 Visit occurs approximately 4 weeks after the STV to demonstrate 
6 weeks of nutrition stability. 
If nutrition changes are needed, a 2- to 4-week period of nutrition optimization will be performed 
to comply with GSD III-specific nutrition guidelines (Table 2). In this situation, the first NOV 
occurs as a phone visit approximately 2 weeks after the ISV. During nutrition optimization, 
NOV phone visits occur weekly or more frequently as needed; nutrition diary and CGM data are 
reviewed; and safety laboratory tests may be obtained at the discretion of the Investigator. 
Nutritional counseling is provided to the subject. When the Investigator determines that the 
subject has achieved nutritional optimization the STV is performed. 
The Baseline/Week 0 Visit occurs as least 6 weeks after the STV. Due to the staggered nature of 
the cohorts (described below), a subject may be in nutrition stabilization for longer than 6 weeks 
before their Baseline Visit; in such instances, the total duration of the Screening Period may 
exceed 12 weeks. Nutrition guidance and monitoring for this study was established with 
available health authority guidance, and greater detail is available in the Study Reference 
Manual. 
After the STV, no substantial nutrition changes should be made through the remainder of the 
study, notwithstanding temporary changes due to illness. 
For selected sites and subjects, the DB-RD STV includes an optional controlled fasting challenge 
(CFC). Prior to the CFC, a morning cortisol is obtained between 6 and 9 am. The CFC is 
conducted during the subject’s stay in the hospital, usually overnight, but can be conducted 
during the day. For the same sites and subjects, another optional CFC occurs at the Week 10 
Visit; only subjects who completed the optional CFC at STV complete the CFC at Week 10. 
Additional details regarding the CFC are in Section 10.5.1.  


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Figure 3: 
Screening Schematic for the DB-RD Cohorts 
CFC, controlled fasting challenge; DB, double blind; ISV, Initial Screening Visit; NOV, Nutrition Optimization Visit(s); RD, repeat dose; STV, Stabilization 
Visit.  


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In DB-RD cohorts, treatment-naive subjects will be randomized 3:1 to UX053 or placebo in 
ascending dose cohorts (4 subjects per cohort) (Figure 1). DB-RD subjects will receive study 
drug every 2 weeks (Q2W); a total of 5 doses of study drug are planned. The planned dose levels  
are 0.05 mg/kg in cohort DB-1R, 0.10 mg/kg in cohort DB-2R, and 0.20 mg/kg in cohort DB-3R.  
Initiation of RD Cohorts (Both OL-RD and DB-RD) 
Initiation of RD cohorts is as follows:  
• Initiation of Cohort DB-1R and OL-1R will be guided by DMC review of at least 
2 weeks of safety data from at least 2 Cohort 2S subjects and any available data from 
all subjects in prior and ongoing cohorts.  
• Initiation of Cohort OL-2R and DB-2R will be guided by DMC review of either 1) at 
least 6 weeks of safety data from at least 4 subjects within Cohort DB-1R or 2) at 
least 12 weeks of safety data from at least 3 subjects within Cohort OL-1R 
(whichever is available first). In both of these scenarios, all available data from all 
subjects in prior and ongoing cohorts will also be reviewed.  
• Initiation of Cohort OL-3R and Cohort DB-3R will be guided by DMC review of 
either 1) at least 6 weeks of safety data from at least 4 subjects within Cohort DB-2R 
or 2) at least 12 weeks of safety data from at least 3 subjects within Cohort OL-2R 
(whichever is available first). In both of these scenarios, all available data from all 
subjects in prior and ongoing cohorts will also be reviewed.  
Cohort- and Subject-level Dose Selection and Modification for All Cohorts (SAD, OL-RD, and 
DB-RD)  
At any time Ultragenyx may decide not to initiate a planned dose cohort. Dose levels for each 
cohort may be altered depending on safety, PK, and/or PD findings from prior cohorts. If needed 
to evaluate safety and dose-response relationships, additional cohorts may be added to test doses 
up to 0.30 mg/kg or additional subjects may be added to a cohort at the discretion of Ultragenyx 
to further characterize safety, PK, and PD effects, with input from the DMC. In every case, the 
safety of a single dose will be evaluated prior to repeat doses at the same dose level.  
If a subject in an RD cohort develops a treatment-emergent adverse event (TEAE)/serious TEAE 
≥ Grade 3 that is considered by the Investigator to be related to study drug or an intolerable 
TEAE, subject-level dose reductions are allowed in consultation with the Medical Monitor. 
Ultragenyx will notify the DMC immediately if any subject experiences an event that satisfies 
subject-level stopping criteria (Section 8.3.2) or study-level stopping criteria (Section 8.3.3).  
Glucose and Nutrition Data Collection by Study Subjects 
At the Screening Visit for the SAD cohorts and ISV for the DB-RD cohorts, all subjects will 
receive CGM and handheld glucometer (HHG) devices and will be trained on the proper use of 
these devices. Subjects will also be trained on completion of the nutrition diary during screening. 
Subjects entering the OL-RD cohorts do not need to be retrained if compliance was acceptable 
during participation in the SAD cohorts. When CGM data is being collected, all subjects will 
connect their CGM and HHG devices to a study-provided laptop weekly and upload CGM and 
HHG data. At remote visits, in conjunction with assessments performed by a home health nurse, 


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the site will contact subjects by telephone or videoconference to confirm the CGM device is 
properly in use and data was uploaded; answer any questions regarding or help troubleshoot 
(if necessary) CGM device use; and review CGM data, HHG data (when applicable), and 
nutrition diary entries; outside of scheduled visits, these telephone calls will occur as needed. At 
in-clinic visits, a conversation between the site and the subject should occur to ensure CGM 
compliance and troubleshoot if needed.  
Drug Administration, Dose Interval, and Blinding 
UX053 will be administered as an intravenous (IV) infusion over the course of at least 4 hours, 
with a slower rate of infusion for the first hour to minimize the risk of hypersensitivity or 
anaphylactoid-type reactions (refer to the Pharmacy Manual for additional infusion details) 
(Table 3 and Section 9). The infusion rate may be slowed to minimize the risk of infusion-related 
reactions (IRRs) in individual subjects. 
Premedication and Rescue Medication  
All subjects, including those treated with placebo, will receive premedication at least 1 hour prior 
to the infusion, consisting of oral paracetamol/acetaminophen (500 mg) or ibuprofen (400 to 
800 mg), an H2 blocker (eg, famotidine 20 mg or equivalent dose of another H2 blocker), and an 
H1 blocker (eg, cetirizine 10 mg or equivalent dose of another H1 blocker). For the 
premedication, paracetamol/acetaminophen is preferred over ibuprofen.  
At the discretion of the Investigator, with input from Ultragenyx and the DMC, and based on the 
emerging safety profile of UX053, additional premedications and rescue medications may be 
used to reduce the risk and severity of immune reactions in RD cohorts. Premedication and 
rescue medication selection will be based on the nature of the reactions being observed and the 
risks of such medications in patients with GSD III.  
If a subject develops an IRR that meets diagnostic criteria for anaphylaxis (Section 8.3.3), 
epinephrine should be administered as initial rescue medication. For all other hypersensitivity 
reactions ≥ Grade 2 in severity suspected to be due to immune activation, dexamethasone should 
be the initial rescue medication.  The Medical Monitor must be notified if any rescue medication 
is used.  
If dexamethasone (or equivalent) is used as a rescue medication, premedication with 
dexamethasone (or equivalent) should be considered for that subject’s subsequent infusions after 
discussion with the Medical Monitor. 
Section 8.3.2 provides subject-level redosing criteria, stopping criteria, and additional 
instructions on how to proceed in the event of an IRR. 
Subjects will have cardiorespiratory monitoring throughout the infusions and will stay overnight 
for visits in which they receive study drug and be observed in an inpatient or observational unit 
for 24 hours after the end of each infusion. Prior to discharge, all the following criteria must be 
met: 
● All scheduled study assessments have been completed. 
● No evidence of vital sign instability or clinical instability in the opinion of the 
investigator. 
● Any signs or symptoms of potential IRRs are resolving or resolved. 


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Guidance on signs and symptoms that subjects should be vigilant for upon discharge and how to 
proceed in the event that these signs and symptoms manifest are provided in Section 9.1.4. 


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Table 3: 
Study Investigational Product, Premedication, and Rescue Medication  
Interventiona 
 
UX053 
Placebo 
Paracetamol/ 
acetaminophen or 
ibuprofenb 
H1 blocker; 
cetirizine or 
equivalent 
H2 blocker; 
famotidine or 
equivalent 
Dexamethasone or 
equivalentc 
Dose 
Formulation 
Ampule 
Ampule 
Tablet 
Tablet 
Tablet 
Ampule  
Unit Dose 
Strength(s) / 
Dosage Level(s) 
0.05, 0.10, and 0.20 
single dose during 
in SAD cohorts and 
Q2W or Q4W in RD 
cohortsd  
- 
500 mg 
(paracetamol 
/acetaminophen); 
400-800 mg 
(ibuprofen) 
10 mg for cetirizine 
20 mg for 
famotidine 
10 mg for IV 
dexamethasone 
Route of 
Administration 
IV infusion 
IV infusion 
Oral 
Oral 
Oral 
IV infusion 
Use 
Experimental 
Placebo 
Premedicatione 
Premedicatione 
Premedicatione 
Rescue medication, 
or premedication for 
subsequent infusions 
if used as rescue 
medication 
previously 
a Regardless of assigned treatment (UX053 or placebo), all subjects in the DB-RD cohort will also be asked to maintain a diet based on expert recommendations 
for adults with GSD III throughout the study (Table 2). 
b Paracetamol/acetaminophen is preferred over ibuprofen.  
c Dexamethasone should be the first-in-line rescue medication; alternative or additional rescue medications are allowed, if necessary, at the discretion of the 
Investigator. The Medical Monitor must be notified if any rescue medication is used. 
d Additional cohort(s) at dose levels between 0.05 mg/kg to 0.30 mg/kg may also be included pending review of safety data. 
e Premedications will be administered to all subjects, including subjects receiving placebo. At the discretion of the Investigator, with input from Ultragenyx and 
the DMC, and based on the emerging safety profile of UX053, additional premedications and rescue medications may be used to reduce the risk and severity 
of immune reactions in subjects in RD cohorts. Premedication and rescue medication selection will be based on the nature of the reactions being observed and 
the risks of such medications in patients with GSD III. 
DB, double-blind; DMC, Data Monitoring Committee; GSD, Glycogen Storage Disease; IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; RD, 
Repeat Dose; SAD, Single Ascending Dose. 
 
  


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In each SAD cohort, subjects will be dosed sequentially with review of safety laboratory data 
from the 24-hour time point prior to dosing of the next subject. Within SAD cohorts, dosing of 
individual subjects will occur at a minimum interval of 72 hours. For example, the second 
subject in a cohort receives their first dose after a minimum of 72 hours after the first subject in 
the same cohort received their first dose. Subjects within a given RD cohort can be dosed 
simultaneously. After the first dose, DB-RD subjects maintain a Q2W dosing regimen and 
OL-RD subjects maintain a Q4W dosing regimen.  
Subjects may receive COVD-19 vaccines during participation in the study. To facilitate 
discrimination of UX053 IRRs and adverse effects of vaccine administration, vaccines should 
not be administered within 48 hours after the most recent administration of UX053 and until 
safety labs obtained have been reviewed and the subject has been assessed for any possible 
hypersensitivity reaction to the most recent dose of UX053 (Section 9.1.6). 
For the DB-RD cohort, the subjects, Investigators, and site staff will be blinded to the treatment. 
Due to the difference in the opacity of UX053 and placebo, an unblinded pharmacist will prepare 
the investigational product (IP) and an unblinded nurse will prepare the infusion before masking 
the infusion syringe and tubing with colored covers.  
The full schedules of events for the SAD, OL-RD and DB-RD, cohorts are listed in Table 4, 
Table 5, and Table 6, respectively. Additional details regarding the timing of assessments before, 
during, and following treatment infusion are provided in Table 7 for vital signs and Table 8 for 
PK samples.  
Although they are eligible, it is expected that few patients with GSD IIIb, IIIc, or IIId will enroll. 
Subjects with GSD IIIb/c/d will participate in all assessments, including muscle imaging and 
function tests, and will be included in all safety analyses. Sensitivity analyses for cardiac and 
skeletal muscle endpoints may exclude patients with GSD IIIb/c/d as described in the SAP.  
Future protocol amendments may occur to include pediatric subjects with GSD III or the addition 
of an open-label extension for all subjects after an interim review of safety, PK, and PD data.
Number of Sites: Approximately 10 sites globally will participate. 
Number of Subjects: Approximately 18 adult subjects are planned to be enrolled. Additional 
subjects may be enrolled to further characterize safety.  
Population: 
Each subject must meet the inclusion criteria listed below at screening (ISV for DB-RD cohorts) 
or rescreening (OL-RD cohorts) and baseline (Day 0 for SAD cohorts or Week 0 in all RD 
cohorts), as applicable, to be enrolled in the study: 
1. Confirmed diagnosis of GSD III (all subtypes) based on pathogenic mutations in the 
amylo-α-1,6-glucosidase 4-alpha-glucanotransferase (AGL) gene on both alleles or 
glycogen debranching enzyme (GDE) deficiency based on biopsy of liver, muscle, or 
fibroblasts  
2. History of any of the following:  
a. Severe hypoglycemia, defined as neuroglycopenia (eg, altered mental status, seizure, 
dizziness, slurred speech, blurry vision, abnormal behavior, perioral paresthesia,  


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requiring intervention by a caregiver) or blood glucose < 54 mg/dL (3 mmol/L) 
within the last year 
b. ≥ 2 incidents of symptomatic hypoglycemia (defined as blood glucose < 70 mg/dL 
[3.9 mmol/L] if measured at the time of symptoms) within the last year, despite 
nutrition management 
c. Ongoing liver injury, defined as alanine aminotransferase (ALT) > 2.5x the upper 
limit of normal (ULN) within the last year 
3. For treatment-naïve subjects (SAD and DB-RD cohorts), alanine aminotransferase (ALT) 
≤ 5x the upper limit of normal (ULN) during the 3 months prior to the Baseline Visit.  
4. Males or females ≥ 18 years of age  
5. For subjects enrolling into DB-RD cohorts, willing and able to demonstrate nutrition 
stability based on nutrition guidelines for adults with GSD III (Table 2)  
6. Willing and able to provide access to medical records surrounding medical treatment that 
occurred prior to enrollment and during the study  
7. Willing and able to provide written informed consent, or in the case of adult subjects with 
cognitive limitation, provide written assent (if required) and written informed consent by 
a legally authorized representative after the nature of the study has been explained and 
prior to any test procedures or assessments  
8. Females of childbearing potential must have a negative pregnancy test at screening 
(and rescreening, as applicable) and be willing to have additional pregnancy tests during 
the study. Subjects of child-bearing potential or males who are sexually active with 
partners of child-bearing potential must consent to use a highly effective contraceptive 
method, as described in Appendix 4, from the Period following the signing of the 
informed consent through 30 days after last dose of study drug 
9. For subjects rescreening into OL-RD cohorts after treatment with UX053 in a SAD 
cohort, subjects must meet the following criteria: 
a. If a significant rise in ALT occurs after the prior dose, ALT should show a decreasing 
trend toward the subject’s baseline value 
b. Total bilirubin is within normal limits  
c. Platelets are within normal limits 
d. International normalized ratio (INR) is within normal limits 
Each subject must not meet the exclusion criteria listed below at screening (ISV for DB-RD 
cohorts) and baseline (Day 0 for SAD cohorts or Week 0 in all RD cohorts), as applicable, to be 
enrolled in the study: 
1. History of liver transplant, including hepatocyte cell therapy/transplant, or active listing 
for liver transplant  
2. History of cirrhosis, or presence of any of the following: 
a. Total bilirubin ≥ 1.3 mg/dL and INR ≥ 1.3 
b. Evidence of portal hypertension, including, but not limited to the following symptoms 
splenomegaly, ascites, thrombocytopenia, esophageal varices, or history of hepatic 
encephalopathy 


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c. Model for End Stage Liver Disease (MELD) score > 12 
3. Current Hepatitis B or C infection or history of chronic Hepatitis B or C infection 
4. Severe renal impairment defined as a glomerular filtration rate (GFR) ≤ 29 mL/min 
(Levey et al., 2005). 
5. Any prior history of hepatocellular carcinoma or presence of liver adenoma > 5 cm at the 
longest diameter or > 3 cm and ≤ 5 cm in size that has an annual growth rate of ≥ 0.5 cm 
per year  
6. Current or history of malignancies in the 3 years prior to the Screening Visit (ISV for 
RD) 
7. Hospitalizations related to GSD III disease between the Screening (ISV for RD) and 
Baseline Visit 
8. Known history of human immunodeficiency virus infection  
9. Presence or history of any hypersensitivity reactions requiring medical evaluation and 
management (including injection/IRRs, such as lymphadenopathy) to UX053, its 
excipients, or any drug products that contain polysorbate or polyethyleneglycol (PEG). 
This may include vaccines that contain PEG or polysorbate  
10. Significant cardiac disease, including heart failure with New York Heart Association 
(NYHA) Function Capacity III or IV or Objective Assessment C or D, unstable angina, 
or ejection fraction (EF) < 35%, or uncontrolled arrhythmia or resistant hypertension 
(Carey et al., 2018). Mild cardiomyopathy and left ventricular hypertrophy (LVH) are 
allowed  
11. Presence or history of any co-morbid condition or abnormal labs that, in the view of the 
Investigator, places the subject’s safety at risk; places the subject at high risk of poor 
treatment compliance or not completing the study; or would significantly affect the 
interpretation of study results 
12. Poorly controlled diabetes, defined as the presence of any of the following:  
a. Hemoglobin A1C > 8% (Qaseem et al., 2018) 
b. History of diabetic nephropathy, neuropathy, or retinopathy 
c. History of diabetic ketoacidosis during the past year 
13. Poorly controlled hypothyroidism, based on the judgement of the Investigator or 
Ultragenyx, whichever is most conservative 
14. History of chronic coagulopathy, thrombophilia, or disorder of complement activation 
15. Use of concomitant medications that alter prothrombin time/international normalized 
ratio (PT/INR), including warfarin and direct oral anticoagulants (eg, rivaroxaban, 
apixaban, and edoxaban). Patients who receive medications that affect platelet function, 
such as aspirin or clopidogrel, are allowed unless they have comorbidities that in the 
judgment of the Investigator place them at undue risk to participate in the study. 


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16. Current treatment with long-term immunosuppressive medications. This includes subjects 
with autoimmune conditions managed with immunosuppressive medications and solid 
organ transplant recipients. 
17. Active tuberculosis requiring treatment in the past 3 years 
18. Symptomatic coronavirus disease 2019 (COVID-19) infection 
19. History of active alcohol and/or drug abuse that in the Investigator’s assessment would 
impair the subject’s ability to comply with the protocol 
20. Receipt of only 1 of 2 planned doses of a coronavirus disease 2019 (COVID-19) vaccine. 
Subjects who have not received a COVID-19 vaccine, and those who have completed 
COVID-19 vaccination are eligible.  
21. Planned surgery, including dental surgeries, during the study 
22. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time 
during the study 
23. Females of childbearing potential with hepatocellular adenoma who are unwilling to use 
nonhormonal contraception 
24. Use of any IP or investigational medical device within 30 days or for IP within 
5 half-lives, whichever is longer, prior to screening (or rescreening, as applicable), or 
requirement for any investigational agent prior to completion of all scheduled study 
assessments 
25. For subjects rescreening into OL-RD cohorts, any of the following after treatment with 
UX053 in a SAD cohort: 
a. New or worsening symptoms of liver disease (including new or worsening 
hepatomegaly) along with any increase in transaminase levels 
b. Receipt of any blood product administration (eg, packed red blood cells, platelet, 
fresh frozen plasma [FFP]) for management of consumptive coagulopathy  
c. An ALT level that is ≥ 8x ULN and > 2x the subject’s baseline value in the absence 
of an alternative explanation 
Duration of Subject Participation: 
SAD Cohorts 
Screening is approximately 2 weeks. After screening and dosing, subjects will be monitored for 
90 days after dosing. 
OL-RD Cohorts 
Subjects who have completed participation in a SAD cohort, consisting of screening and a 
90-day Follow-up Period, may enter an OL-RD cohort. These subjects are rescreened for 
participation in the OL-RD cohorts, which is expected to occur over the course of approximately 
3 weeks prior to redosing; eligibility for additional dosing in the OL-RD cohorts can be 
combined with assessments at the SAD Day 90 Visit. After rescreening, subjects will receive a 
total of 4 additional doses of UX053, with doses administered Q4W, and will be monitored for 
36 weeks (Week 48 Visit) after their last dose of UX053.  


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DB-RD Cohorts 
Screening is approximately 8 to 12 weeks. Due to the staggered nature of the cohorts, subjects 
may remain in nutrition stabilization during screening for ≥ 6 weeks. After screening, subjects 
will receive a total of 5 doses of UX053, with doses administered Q2W, and will be monitored 
for 40 weeks (Week 48 Visit) after the last dose of study drug.  
Assessments: 
Assessments are described in Section 10, and associated timing for each assessment is provided 
in Table 4, Table 5, and Table 6 for SAD, OL-RD, and DB-RD cohorts, respectively. 


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Table 4: 
Schedule of Events for the Single Ascending Dose Cohorts 
 
 
BL 
Follow-up Period 
EOS I (D90)b/ 
ETc 
Day (D) / Week (W) 
Screeninga 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Drug Administration 
 
X 
 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
General & GSD III-specific medical history 
X 
 
 
 
 
 
 
 
 
COVID-19 testing 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical examd 
X 
Xe 
X 
 
 
 
 
 
X 
Vital signs 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
Xe 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
X 
Xe 
 
 
 
 
 
X 
X 
ATX95 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
AGL mRNA 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
Anti-drug antibodies  
 
Xe 
 
 
 
X 
 
X 
X 
Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
Hemoglobin A1C 
X 
 
 
 
 
 
 
 
 
Serum CH50, AH50, sC5b-9, & IL-6 
 
Xh 
X 
 
 
X 
 
 
 
Plasma fibrinogen & d-dimer 
 
Xh 
X 
 
 
X 
 
 
 
Hematology 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Chemistryi 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Urinalysisj 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Serum CRP 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
Liver  
 
 
 
 
 
 
 
 
 
Liver MRIk 
X 
 
 
 
 
 
 
 
 
Liver MRSk 
X 
 
 
 
 
 
 
 
 
FibroScan or ultrasound elastography 
X 
 
 
 
 
 
 
 
 
PT/INRi 
X 
Xe 
X 
 
X 
 
 
 
X 
Serum HDL & LDLl 
X 
Xe 
 
 
 
 
 
 
 


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BL 
Follow-up Period 
EOS I (D90)b/ 
ETc 
Day (D) / Week (W) 
Screeninga 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
Cardiac 
 
 
 
 
 
 
 
 
 
Serum CK-M/B 
X 
Xe 
 
 
 
 
 
 
 
Plasma BNP 
X 
Xe 
 
 
 
 
 
 
 
Serum troponin I 
X 
Xe 
 
 
 
 
 
 
 
ECG 
X 
Xe 
X 
 
 
 
 
 
X 
Skeletal Muscle & Strength 
 
 
 
 
 
 
 
 
 
Serum CK 
X 
Xe 
 
 
 
 
 
 
 
HHD 
X 
Xe 
 
 
 
 
 
 
 
Clinician- & Patient-reported Outcomes 
 
 
 
 
 
 
 
 
 
PROMIS questionnaires & SF-36v2 
 
Xe 
 
 
 
 
 
 
 
GNEM-FAS expanded version  
 
Xe 
 
 
 
 
 
 
 
Nutrition diary 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Exploratory Assessments  
 
 
 
 
 
 
 
 
 
Serum ketones 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Serum biotinidase 
X 
Xe 
 
 
 
 
 
 
 
CGMn  
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Xn 
Urine Glc4j 
X 
Xe 
 
 
X 
 
 
 
X 
AGL variant analysis  
X 
 
 
 
 
 
 
 
 
WBC, RBC, Serum & Plasma for Future Useo 
 
Xe 
 
 
X 
 
 
X 
X 
Footnotes continue on the following page. 
a Screening assessments can be done over the course of multiple days. There must be a minimum of 10 days between any assessments that are measured at both 
the Screening and the BL Visit.  
b At the Day 90 Visit, marking completion of the Follow-up Period, subjects can be rescreened for entry into the OL-RD cohorts. Subjects must sign informed 
consent to enter into OL-RD cohorts prior to rescreening. Only EOS I Day 90 Visit assessments are included in the table above; please refer to Table 5 for 
assessments that should be performed for rescreening for OL-RD. If rescreening for OL-RD occurs in conjunction with the SAD EOS I Day 90 visit, 
assessments in common should not be duplicated.  
c In the event a subject has an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will 
occur within the 4 weeks following the subject’s last treatment. 
d Complete physical exam is required at the Screening, BL, and EOS I/ET Visits. Targeted physical exams may be performed at the D1 Visit. 
e Assessments to be performed prior to dosing. The following assessments can be collected within a week prior to dosing, as long as there is a minimum of 10 
days between assessments that are repeated at the Screening Visit and the Baseline Visit: HHD, PROMIS questionnaires, SF-36v2, and GNEM-FAS 
expanded version. 
f Refer to Table 7 for the timing of vital sign assessments during dosing.  


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g Refer to Table 8 for details of PK sampling. Please note that sample collections are marked for D1, D4, D7, D14, D21, and D28 in this table (Table 4) 
corresponding to a sample collection 1, 4, 7, 14, 21, and 28 days after infusion of UX053 on D0 as outlined in the final rows of the first column in Table 8.  
h Sample to be collected pre-dose and at the end of the infusion. Post-infusion blood samples should be collected in the opposite arm of the infusion to avoid 
dilution.  
i Close monitoring is required for subjects who develop elevations in ALT > 3x ULN and > 2x their baseline value, or elevation in ALT > 3x ULN with INR > 
1.5. This includes repeating liver enzymes and INR within 48 hours and consideration of additional diagnostic tests such as liver ultrasound (Section 10.1.5).  
j All efforts should be made for urine collections to be consistently taken from the first morning void.  
k If feasible, glycoNOE imaging of the liver, may be collected at the time of the liver MRI. Liver MRS are only required at sites with 
capability. Scanning for liver MRS can be conducted immediately following the liver MRI. 
l A 3- to 4-hour fasting period is preferred, but not required, prior to blood collection for serum HDL and LDL. All efforts should be made to obtain samples for 
HDL and LDL consistently for a given subject.  
m The nutrition diary recordings should be recorded at least 3 consecutive days per week through Screening and for the 3 consecutive days in the week leading up 
to each subsequent visit.  
n The subject will receive CGM and HHG devices and will be trained on proper use at the Screening Visit. The CGM device is intended to be worn continuously 
from the Screening Visit to the EOS I D90/ET Visit. If the CGM device alarm notifies a subject that their blood sugar is abnormally high or low or the subject 
suspects their blood sugar is abnormally high or low, the subject will need to check their blood sugar with a HHG device that will be provided by Ultragenyx 
during screening. When CGM data is being collected, all subjects will connect their CGM and HHG devices to a study-provided laptop weekly and upload 
CGM and HHG data. At remote visits, in conjunction with assessments performed by a home health nurse, the site will contact subjects by telephone or 
videoconference to confirm the CGM device is properly in use and data was uploaded; answer any questions regarding or help troubleshoot (if necessary) 
CGM device use; and review CGM data, HHG data (when applicable), and nutrition diary entries; outside of scheduled visits, these telephone calls will occur 
as needed. At in-clinic visits, a conversation between the site and the subject should occur to ensure CGM compliance and troubleshoot if needed. 
o Serum and plasma samples will be collected for future biomarker assessments yet to be determined.  
Note: White columns indicate in-clinic visits (Screening, BL D0, D1, and EOS I D90/ET). Gray columns indicate visits conducted at home by a home health 
nurse in conjunction with a phone call as needed (D4, D7, D14, D21, and D28). 
Note: Laboratory assessments included in chemistry, hematology, and urinalysis are provided in Appendix 3.  
AGL, amylo-α-1,6-glucosidase 4-alpha-glucanotransferase; AH50, alternative complement activity; ALT, alanine aminotransferase; BL, baseline; BNP, B-Type 
Natriuretic Peptide; CGM, continuous glucose monitor; CH50, classical pathway complement activity; CK, creatinine kinase; CK-M/B, CK-muscle/brain; 
COVID-19, coronavirus disease 2019; CRP, C-reactive protein; D, day; ECG, electrocardiogram; EOS, end of study; ET, early termination; Glc4, glucose 
tetrasaccharide; glycoNOE, glycogen nuclear overhauser enhancement; GNEM-FAS, GNE Myopathy Functional Activities Scale; GSD, glycogen storage 
disease; HHD, handheld dynamometry; HHG, handheld glucometer; HDL, high density lipoprotein; IL-6, interleukin-6; LDL, low density lipoprotein; MRI, 
magnetic resonance imaging; MRS, magnetic resonance spectroscopy; OL, open-label; PROMIS, Patient-Reported Outcomes Measurement Information 
System; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic; PT/INR, prothrombin time/international normalized ratio; RBC, red blood cell; 
RD, repeat dose; sC5b-9, soluble Complement 5b-9; SF-36v2, Short Form Health Survey 36 Version 2; ULN, upper limit of normal; WBC, white blood cell.  
 


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Table 5: 
Schedule of Events for Open-label Repeat Dose Cohorts  
Week (W) 
Rescreeninga 
Treatment Period 
Follow-up Period 
EOS 
II 
(W48)/ 
ETb 
ISVa 
NOVa STVa BL/ 
W0 W1 W2 W4 W5 W8 W9 W12 W13 W14 W16 W24 W36 
Visit Window Relative to BL/Week 0 
- 
- 
- 
- 
± 1 
day 
± 2 days 
± 3 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nutrition optimization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nutrition stabilization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Administration 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examc 
 
 
 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
X 
 
 
X 
Vital signs 
X 
 
 
Xe 
X 
X 
Xe 
X 
Xe 
X 
Xe 
X 
X 
X 
X 
X 
X 
Weight 
 
 
 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
X 
 
 
X 
Adverse events 
X 
X 
X 
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 
X 
X 
X 
Pregnancy 
Xd 
 
 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
X 
X 
X 
X 
ATX95 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
AGL mRNA 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
Anti-drug antibodies  
 
 
 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
X 
X 
 
X 
Hemoglobin A1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum CH50, AH50, sC5b-9, & IL-6 
 
 
 
Xg 
X 
X 
Xg 
X 
Xg 
X 
Xg 
X 
 
 
 
 
 
Plasma fibrinogen & d-dimer 
 
 
 
Xg 
X 
X 
Xg 
X 
Xg 
X 
Xg 
X 
 
 
 
 
 
Hematology  
X 
Xh 
X 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Chemistryi 
X 
Xh 
X 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Urinalysisj 
X 
Xh 
X 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Serum CRP 
 
 
 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Liver  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver MRIk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Liver MRSk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
FibroScan or ultrasound elastographyk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
PT/INRi 
X 
 
X 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Serum HDL & LDLl 
X 
Xh 
X 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
X 
X 
X 
X 


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Week (W) 
Rescreeninga 
Treatment Period 
Follow-up Period 
EOS 
II 
(W48)/ 
ETb 
ISVa 
NOVa STVa BL/ 
W0 W1 W2 W4 W5 W8 W9 W12 W13 W14 W16 W24 W36 
Visit Window Relative to BL/Week 0 
- 
- 
- 
- 
± 1 
day 
± 2 days 
± 3 days 
Cardiac 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CK-M/B 
 
 
X 
Xd 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Plasma BNP 
 
Xh 
X 
Xd 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Serum troponin I 
 
 
X 
Xd 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
ECG 
X 
 
 
Xd 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Skeletal & Muscle Strength 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CK 
X 
Xh 
 
Xd 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
HHD 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Clinician- & Patient-reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS questionnaires & SF-36v2 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
GNEM-FAS expanded version  
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Nutrition diary 
Xm 
 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Exploratory Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFC and associated labsn 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
Capillary ketoneso 
X 
 
 
Xd 
 
 
Xd  
Xd  
Xd 
 
 
Xo 
 
 
X 
CGMp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Urine Glc4j 
X 
 
 
Xd 
X 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
WBC, RBC, Serum & Plasma for Future Useq 
X 
 
 
Xd 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
Footnotes continue on the following page. 
a Subjects must sign informed consent for OL-RD cohorts prior to rescreening procedures. Rescreening for OL-RD can be completed at the SAD EOS 1 Day 90 
Visit (Table 4); in this situation, the assessments in common should not be duplicated. The ISV includes 3 consecutive days of nutrition diary collection. A 
dietician will review these 3 days of data and all nutrition data from the subject’s prior participation in a SAD cohort to determine if the subject’s diet meets 
nutritional guidelines and has been stable. If no nutritional changes are needed, subjects can proceed to OL-RD STV as soon as ISV assessments are 
completed. If nutrition changes are needed, NOVs occur as needed during the following week (approximately 2 weeks after the ISV). After 1 week of 
nutrition optimization, the subject proceeds to the STV (occurring approximately 2 weeks before the subject’s OL-RD Baseline/Week 0 Visit) and thereafter 
maintains a stable diet as defined by the nutritional guidelines for GSD III. If a subject is unable to achieve an optimized diet within 2 weeks of the ISV, they 
are still eligible to proceed to the STV; the reason for inability to achieve an optimized diet should be documented and a stable diet should be maintained 
throughout the rest of the study. Figure 2 provides guidance on which screening visits are required for a given subject. All Rescreening Visits can be done 
remotely, with the exception of completion of imaging assessments (liver MRI, liver MRS, Fibroscan or ultrasound elastography) which must be completed 
in person at anytime during rescreening.  


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b In the event a subject has an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will 
occur within the 4 weeks following the subject’s last treatment. 
c Complete physical exam is required at rescreening (SAD EOS I Day 90 Visit), W0, and EOS II W48/ET. Targeted physical exams may be performed at W4, 
W8, W12, and W16. 
d Assessments to be performed prior to dosing on the same day as dosing visits or on the day before dosing for visits that include a CFC (ie, W16). When 
applicable, the following assessments can be collected within a week prior to dosing: HHD, PROMIS questionnaires, SF-36v2, and GNEM-FAS expanded 
version. 
e Refer to Table 7 for the timing of vital sign assessments during dosing.  
f Refer to Table 8 for details of PK sampling. Please note that sample collections are marked for W1, W2, W4, W12, W13, W14, and W16 in this table (Table 5) 
corresponding to a sample collection 7, 14, and 28 days after infusion of UX053 on W0 and/or W12 as outlined in the final rows of the first column in 
Table 8; a 28-day post infusion collection is only collected for the W12 assessment for the OL-RD cohorts. PK samples are also collected 24-hours post 
infusion for OL-RD cohorts as noted in Table 8. 
g Sample to be collected predose and at the end of the infusion. Postinfusion blood samples should be collected in the opposite arm of the infusion to avoid 
dilution. 
h Optional safety assessments to be performed (and repeated as necessary) at the discretion of the Investigator if nutrition changes are made during screening. 
i Close monitoring is required for subjects who develop elevations in ALT > 3x ULN and > 2x their baseline value, or elevation in ALT > 3x ULN with INR > 
1.5. This includes repeating liver enzymes and INR within 48 hours and consideration of additional diagnostic tests such as liver ultrasound (Section 10.1.5). 
j All efforts should be made for urine collections to be consistently taken from the first morning void. 
k All imaging assessments (liver MRI, liver MRS, and Fibroscan or ultrasound elastography) can be conducted in person at any time during rescreening or within 
1 week prior to the corresponding postbaseline visit. Liver MRS are only required at sites with capability. Scanning for liver MRS can be conducted 
immediately following the liver MRI. If feasible, glycoNOE imaging of the liver, may be collected at the time of the liver MRI. 
l A 3- to 4-hour fasting period is preferred, but not required, prior to blood collection for serum HDL and LDL. All efforts should be made to obtain samples for 
HDL and LDL consistently for a given subject.  
m Nutrition diary recordings should be recorded at least 3 consecutive days per week through rescreening and for the 3 consecutive days in the week leading up to 
each subsequent visit. Qualified Investigator site staff should review nutrition diary data at each visit.  
n CFC is an optional assessment. Please see Section 10.5.1 for a description of the CFC. Cortisol must be measured between 6 and 9 am on the morning of the 
CFC. The CFC begins after completion of a meal (breakfast for daytime fast or dinner for overnight fast) or associated cornstarch consumption (as 
applicable). A venous blood sample for measurement of glucose, cortisol, glucagon, insulin, C-peptide, and β-hydroxybutyrate will be collected at the 
beginning (ie, immediately after completion of the meal or the evening cornstarch, as applicable), at end of the CFC, and 30 minutes after the end of the CFC. 
During the CFC, venous blood samples for STAT analysis of glucose will be collected through an indwelling catheter every 60 minutes (± 5 minutes) until 
the glucose level decreases to ≤ 70 mg/dL (≤ 3.9 mmol/L). Thereafter, venous blood glucose is measured approximately every 30 minutes (± 5 minutes) until 
the end of the CFC. The CFC will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 mmol/L), when the subject experiences signs and 
symptoms of hypoglycemia, or the fast reaches 12 hours (daytime fast) or 15 hours (overnight fast) without hypoglycemia, whichever occurs first. 
o Assessment for capillary ketones does not need to be repeated for visits that include the CFC (ie, W16 Visit). 
p The CGM is intended to be worn continuously from the ISV to the W24 Visit. The CGM will be worn again for the week prior to the W36 and EOS II W48/ET 
Visits. If the ISV coincides with the SAD EOS I Day 90 Visit, then the CGM device will be worn continuously through screening in the SAD cohort to Week 
24 in the RD cohort. If the CGM device alarm notifies a subject that their blood sugar is abnormally high or low or the subject suspects their blood sugar is 
abnormally high or low, the subject will need to check their blood sugar with a HHG that will be provided by Ultragenyx during screening. When CGM data 
is being collected, all subjects will connect their CGM and HHG devices to a study-provided laptop weekly and upload CGM and HHG data on a weekly 
basis. At remote visits, in conjunction with assessments performed by a home health nurse, the site will contact subjects by telephone or videoconference to 


Protocol 
 
 
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Confidential 
confirm the CGM device is properly in use and data was uploaded; answer any questions regarding or help troubleshoot (if necessary) CGM device use; and 
review CGM data, HHG data (when applicable), and nutrition diary entries; outside of scheduled visits, these telephone calls will occur as needed. At 
in-clinic visits, a conversation between the site and the subject should occur to ensure CGM compliance and troubleshoot if needed. 
q RBC, WBC, serum and plasma samples will be collected for future biomarker assessments yet to be determined.  
Note: White columns indicate in-clinic visits (ISV, STV, BL/W0, W4, W8, W12, W16, and EOS II W48/ET). Gray columns indicate visits conducted at home 
(NOV, W1, W2, W5, W9, W13, W14, W24, and W36).  
Note: Laboratory assessments included in chemistry, hematology, and urinalysis are provided in Appendix 3.  
AGL, amylo-α-1,6-glucosidase 4-alpha-glucanotransferase; AH50, alternative complement activity; ALT, alanine aminotransferase; BL, baseline; BNP, B-Type 
Natriuretic Peptide; CFC, controlled fasting challenge; CGM, continuous glucose monitor; CH50, classical pathway complement activity; CK, creatinine 
kinase; CK-M/B, CK-muscle/brain; CRP, C-reactive protein; ECG, electrocardiogram; EOS, end of study; ET, early termination; Glc4, glucose 
tetrasaccharide; GNEM-FAS, GNE Myopathy Functional Activities Scale; HDL, high density lipoprotein; HHD, handheld dynamometry; HHG, handheld 
glucometer; IL-6, interleukin-6; LDL, low density lipoprotein; ISV, Initial Screening Visit; MRI, magnetic resonance imaging; MRS, magnetic resonance 
spectroscopy; NOV, Nutrition Optimization Visit; OL, open label; PROMIS, Patient-Reported Outcomes Measurement Information System; PK, 
pharmacokinetic; PT/INR, prothrombin time/international normalized ratio; RBC, red blood cell; RD, repeat dose; SAD, single ascending dose; sC5b-9, 
soluble Complement 5b-9; SF-36v2, Short Form Health Survey 36 Version 2; STV, Stabilization Visit; ULN, upper limit of normal; W, Week; WBC, white 
blood cell. 
 


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Table 6: 
Schedule of Events for Randomized, Double-blind, Placebo-controlled Repeat Dose Cohorts 
Week (W) 
Screening 
Treatment Period 
Follow-up Period 
EOS 
III 
(W48)/ 
ETb 
ISVa NOVa STVa BL/ 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 W10 W12 W24 W36 
Visit Window Relative to Baseline  
- 
- 
- 
- 
± 1 
day 
± 2 days 
± 3 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nutrition optimization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nutrition stabilization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Administration 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General & GSD III-specific medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examc 
X 
 
X 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
 
 
X 
Vital signs 
X 
 
X 
Xe 
X 
Xe 
X 
Xe 
X 
Xe 
X 
Xe 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
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 
X 
X 
X 
X 
Pregnancy 
X 
 
X 
Xd 
 
 
 
Xd 
 
 
 
Xd 
 
X 
 
X 
X 
X 
ATX95 
 
 
 
Xf 
Xf 
Xf 
 
 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
AGL mRNA 
 
 
 
Xf 
Xf 
Xf 
 
 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
 
 
Anti-drug antibodies  
 
 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
X 
 
X 
Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum CH50, AH50, sC5b-9, & IL-6 
 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
X 
X 
 
 
 
 
Plasma fibrinogen & d-dimer 
 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
X 
X 
 
 
 
 
Hematology  
X 
Xh 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Chemistryi 
X 
Xh 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Urinalysisj 
X 
Xh 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Serum CRP 
 
 
 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 


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Week (W) 
Screening 
Treatment Period 
Follow-up Period 
EOS 
III 
(W48)/ 
ETb 
ISVa NOVa STVa BL/ 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 W10 W12 W24 W36 
Visit Window Relative to Baseline  
- 
- 
- 
- 
± 1 
day 
± 2 days 
± 3 days 
Liver  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver MRIk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Liver MRSk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
FibroScan or ultrasound elastographyk 
Xk 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PT/INRi 
X 
 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
Serum HDL & LDLl 
X 
Xh 
X 
Xd 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Cardiac 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CK-M/B 
 
 
X 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Plasma BNP 
 
Xh 
X 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum troponin I 
 
 
X 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
 
 
Xd 
 
 
 
 
 
 
 
Xd 
 
 
 
 
 
X 
Skeletal & Muscle Strength 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum CK 
X 
Xh 
X 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
HHD 
 
 
X 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Clinician- & Patient-reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS questionnaires & SF-36v2 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
GNEM-FAS expanded version  
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Nutrition diary 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Exploratory Assessments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFC and associated labsn 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
 
Capillary ketoneso 
X 
 
Xo 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xd 
 
Xo 
 
 
 
X 
CGMp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Glc4j 
 
 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
AGL variant analysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC, RBC, Serum & Plasma for Future Useq 
 
 
 
Xd 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Footnotes continue on the following page. 
a The ISV includes a review of the subject’s diet. Within the first 2 weeks after the ISV, the Investigator will review nutrition diary data to determine if nutrition 
optimization is needed. If nutrition optimization is not needed, the STV occurs in clinic approximately 2 weeks after the ISV, and the Baseline/Week 0 Visit 
occurs approximately 6 weeks after the STV. If nutrition changes are needed, a 2- to 4-week period of nutrition optimization will be performed. The first 


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NOV occurs as a phone visit approximately 2 weeks after the ISV; during nutrition optimization, NOVs can occur weekly or more frequently as needed. 
When the Investigator determines that the subject has achieved nutritional optimization the STV is performed. Figure 3 provides a schematic of screening for 
DB-RD cohorts.  
b In the event a subject has an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will 
occur within the 4 weeks following the subject’s last treatment. 
c Complete physical exam is required at ISV, BL/W0, W2, and EOS III W48/ET. Targeted physical exams may be performed at STV, W4, W6, W8, and W10. 
d Assessments to be performed prior to dosing on the same day as dosing visits or on the day before dosing for visits that include a CFC (ie, W10). When 
applicable, the following assessments can be collected within a week prior to dosing: HHD, PROMIS questionnaires, SF-36v2, and GNEM-FAS expanded 
version. 
e Refer to Table 7 for the timing of vital sign assessments during dosing.  
f Refer to Table 8 for details of PK sampling. Please note that sample collections are marked for W1, W2, W9, W10, and W12 in this table (Table 6) 
corresponding to a sample collection 7, 14, and 28 days after infusion of UX053 on W0 and/or W8 as outlined in the final rows of the first column in Table 8; 
a 28-day post infusion collection is only collected for the W8 assessment for DB-RD cohorts. PK samples are also collected 24-hours post infusion as noted 
in Table 8. 
g Sample to be collected pre-dose and at the end of the infusion. Post-infusion blood samples should be collected in the opposite arm of the infusion to avoid 
dilution. 
h Optional safety assessments to be performed (and repeated as necessary) at the discretion of the Investigator if nutrition changes are made during screening. 
i Close monitoring is required for subjects who develop elevations in ALT > 3x ULN and > 2x their baseline value, or elevation in ALT > 3x ULN with 
INR > 1.5. This includes repeating liver enzymes and INR within 48 hours and consideration of additional diagnostic tests such as liver ultrasound 
(Section 10.1.5). 
j All efforts should be made for urine collections to be consistently taken from the first morning void. 
k All imaging assessments (liver MRI, liver MRS, and Fibroscan or ultrasound elastography) can be conducted at any time during screening or within 1 week 
prior to the corresponding visit. Liver MRS are only required at sites with capability. Scanning for liver MRS can be conducted immediately following the 
liver MRI. If feasible, glycoNOE imaging of the liver, may be collected at the time of the liver MRI.  
l A 3- to 4-hour fasting period is preferred, but not required, prior to blood collection for serum HDL and LDL. All efforts should be made to obtain samples for 
HDL and LDL consistently for a given subject.  
m Nutrition diary recordings should be recorded at least 3 consecutive days per week through Screening and for the 3 consecutive days in the week leading up to 
each subsequent visit. Qualified Investigator site staff should review nutrition diary data at each visit.  
n CFC is an optional assessment. Please see Section 10.5.1 for a description of the CFC. Cortisol must be measured between 6 and 9 am on the morning of the 
CFC. The CFC begins after completion of a meal (breakfast for daytime fast or dinner for overnight fast) or associated cornstarch consumption (as 
applicable). A venous blood sample for measurement of glucose, cortisol, glucagon, insulin, C-peptide, and β-hydroxybutyrate will be collected at the 
beginning (ie, immediately after completion of the meal or the evening cornstarch, as applicable), at end of the CFC, and 30 minutes after the end of the CFC. 
During the CFC, venous blood samples for STAT analysis of glucose will be collected through an indwelling catheter every 60 minutes (± 5 minutes) until 
the glucose level decreases to ≤ 70 mg/dL (≤ 3.9 mmol/L). Thereafter, venous blood glucose is measured approximately every 30 minutes (± 5 minutes) until 
the end of the CFC. The CFC will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 mmol/L), when the subject experiences signs and 
symptoms of hypoglycemia, or the fast reaches 12 hours (daytime fast) or 15 hours (overnight fast) without hypoglycemia, whichever occurs first. 
o Assessment for capillary ketones does not need to be repeated for visits that include the CFC (ie, W10 Visit). 
p The subject will receive a CGM and HHG device and will be trained on proper use at the ISV. The CGM is intended to be worn continuously from ISV to the 
W24 Visit. The CGM will be worn again for the week prior to the W36 and EOS III W48/ET Visits. If the CGM device alarm notifies a subject that their 
blood sugar is abnormally high or low or the subject suspects their blood sugar is abnormally high or low, the subject will need to check their blood sugar 


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with a HHG that will be provided by Ultragenyx at ISV. When CGM data is being collected, all subjects will connect their CGM and HHG devices to a 
study-provided laptop weekly and upload CGM and HHG data. At remote visits, in conjunction with assessments performed by a home health nurse, the site 
will contact subjects by telephone or videoconference to confirm the CGM device is properly in use and data was uploaded; answer any questions regarding 
or help troubleshoot (if necessary) CGM device use; and review CGM data, HHG data (when applicable), and nutrition diary entries; outside of scheduled 
visits, these telephone calls will occur as needed. At in-clinic visits, a conversation between the site and the subject should occur to ensure CGM compliance 
and troubleshoot if needed. 
q RBC, WBC, serum and plasma samples will be collected for future biomarker assessments yet to be determined.  
Note: White columns indicate in-clinic visits (ISV, STV, BL/W0, W2, W4, W6, W8, W10, and EOS III W48/ET). Gray columns indicate visits conducted at 
home (NOV, W1, W3, W5, W7, W9, W12, W24, and W36). A telephone call is required if NOVs occur, but not for W1 and W9. A visit from a home health 
nurse is required for W1, W3, W5, W7, W9, W12, W24, and W36, but may not be necessary for NOVs. 
Note: Laboratory assessments included in chemistry, hematology, and urinalysis are provided in Appendix 3.  
AGL, amylo-α-1,6-glucosidase 4-alpha-glucanotransferase; AH50, alternative complement activity; ALT, alanine aminotransferase; BL, baseline; BNP, B-Type 
Natriuretic Peptide; CFC, controlled fasting challenge; CGM, continuous glucose monitor; CH50, classical pathway complement activity; CK, creatinine 
kinase; CK-M/B, CK-muscle/brain; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; DB, double-blind; ECG, electrocardiogram; EOS, end of 
study; ET, early termination; Glc4, glucose tetrasaccharide; glycoNOE, glycogen nuclear overhauser enhancement; GNEM-FAS, GNE Myopathy Functional 
Activities Scale; GSD, glycogen storage disease; HDL, high density lipoprotein; HHD, handheld dynamometry; HHG, handheld glucometer; IL-6, 
interleukin-6; ISV, Initial Screening Visit; LDL, low density lipoprotein; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NOV, 
Nutrition Optimization Visit; PROMIS, Patient-Reported Outcomes Measurement Information System; PK, pharmacokinetic; PT/INR, prothrombin 
time/international normalized ratio; RBC, red blood cell; RD, repeat dose; sC5b-9, soluble Complement 5b-9; SF-36v2, Short Form Health Survey 36 
Version 2; STV, Stabilization Visit; ULN, upper limit of normal; W, Week; WBC, white blood cell.  
 
 


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Table 7: 
Schedule of Vital Sign Assessments at Infusion Visits 
Pre-Infusion 
Within 30 min prior to initiating the infusion 
X 
After initiation of infusiona 
15 min (± 5 min) 
X 
30 min (± 5 min) 
X 
45 min (± 5 min) 
X 
1 hr (± 10 min) 
X 
2 hr (± 10 min) 
X 
3 hr (± 10 min) 
X 
4 hr (± 10 min) 
X 
5 hr (± 5 min) 
X 
6 hr (± 5 min) 
X 
7 hr (± 10 min) 
X 
8 hr (± 10 min) 
X 
9 hr (± 10 min) 
X 
10 hr (± 10 min) 
X 
16 hr (+/- 1hr) 
X 
24 hr (+/- 2hr) 
X 
Dischargeb 
X 
a All post-infusion time points refer to time from the beginning of the infusion.  
b The discharge vital signs assessment is not required and can be used to record any vital signs taken just prior to 
discharge.  
Note: This schedule applies to every infusion of study drug, regardless of cohort (SAD, DB-RD, or OL-RD)  
hr, hour; min, minute; OL, open-label; DB-RD, randomized, double-blind, placebo-controlled; RD, Repeat Dose; 
SAD, Single Ascending Dose.  
 
 


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Table 8: 
Schedule of PK Assessments during and following Study Drug Infusion 
Study Cohort 
SAD Cohorts 
RD Cohorts 
Sample Type 
Blood 
Plasma 
Blood 
Plasma 
Blood 
Plasma 
Analyte 
AGL mRNA 
ATX95 
AGL mRNA 
ATX95 
AGL mRNA 
ATX95 
Infusion 
Day 0 Infusion 
DB-RD and OL-RD 
Week 0 Infusion 
DB-RD Week 8 Infusion 
&OL-RD Week 12 Infusion 
Pre-infusion 
 
 
 
 
Within 1 hr prior to 
initiating infusion 
X 
X 
X 
X 
X 
X 
After initiation of infusion 
 
1 hr (± 10 min)a 
X 
X 
X 
X 
X 
X 
3 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
4 hr (± 10 min)b 
X 
X 
X 
X 
X 
X 
4.5 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
5 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
6 hr (± 20 min) 
X 
X 
X 
X 
X 
X 
8 hr (± 30 min) 
X 
X 
X 
X 
X 
X 
10 hr (± 30 min) 
X 
X 
X 
X 
X 
X 
24 hr (± 2 hr); Day 1 
X 
X 
X 
X 
X 
X 
96 hr (± 24 hr); Day 4 
X 
X 
 
 
 
 
168 hr (± 24 hr); Day 7 
X 
X 
X 
X 
X 
X 
336 hr (± 48 hr); Day 14 
X 
X 
Xc 
Xc 
X 
X 
504 hr (± 48 hr); Day 21 
X 
X 
 
 
 
 
672 hr (± 48 hr); Day 28  
X 
X 
Xd 
Xd 
X 
X 
a The 1-hour sample during infusion is to be collected prior to the infusion rate change (refer to Pharmacy Manual 
for additional details regarding the infusion rate).  
b The 4-hour sample is to be collected at the end of the infusion.  
c Subjects in the DB-RD cohorts receive study drug at the (Week 2) Day 14 Visit, and therefore, their sample is to be 
collected predosing. While subjects in the OL-RD cohorts do not receive study drug at the Week 2 (Day 14) 
Visit, their sample should still be collected within the specified time window.  
d Sample is to be collected pre-dosing at the Week 4 (Day 28) Visit for the OL-RD cohorts only.  
Note: 0 hr is the start of the drug infusion.  
Note: If the total infusion time is extended beyond 4 hours, a blood sample should be collected at the new EOI time. 
If the new EOI time overlaps with a prespecified time point, sampling should continue at the next scheduled time 
point. 
AGL, amylo-α-1,6-glucosidase 4-alpha-glucanotransferase; EOI, end of infusion; hr, hour; min, minute; PK, 
pharmacokinetic; DB, Randomized Double-Blind Placebo-Controlled; RD, Repeat Dose; OL, Open-Label; SAD, 
Single Ascending Dose. 
 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS .................................................................................................................14 
3. 
TABLE OF CONTENTS ...........................................................................................43 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................48 
5. 
INTRODUCTION ......................................................................................................52 
5.1. 
Overview of Glycogen Storage Disease III ................................................................52 
5.2. 
Overview of UX053 Development .............................................................................53 
5.3. 
Rationale for UX053 in Glycogen Storage Disease III ..............................................54 
5.4. 
Potential Risks and Benefits .......................................................................................56 
5.4.1. 
Potential Risks for UX053 ..........................................................................................56 
5.4.1.1. 
Potential Risks Identified from Nonclinical Studies ..................................................56 
5.4.1.2. 
Potential Risks Identified from Relevant LNP-formulated Oligonucleotide 
Therapies .....................................................................................................................57 
5.4.2. 
Potential Risks of Premedication ................................................................................58 
5.4.3. 
Potential Risks for Study Participation .......................................................................59 
5.4.4. 
Potential Benefits ........................................................................................................59 
5.5. 
Risk Minimization ......................................................................................................59 
6. 
OBJECTIVES AND ENDPOINTS ............................................................................62 
7. 
INVESTIGATIONAL PLAN .....................................................................................63 
7.1. 
Study Design ...............................................................................................................63 
7.1.1. 
Number of Sites ..........................................................................................................67 
7.1.2. 
Number of Subjects ....................................................................................................67 
7.1.3. 
Rationale for Study Design .........................................................................................68 
7.1.4. 
Dose Rationale ............................................................................................................69 
7.1.5. 
Changes to the Protocol Due to Coronavirus Disease 2019 (COVID-19) .................70 
7.2. 
Duration ......................................................................................................................70 
7.2.1. 
Duration of Subject Participation ...............................................................................70 
7.2.2. 
End of Study Definition ..............................................................................................70 
8. 
POPULATION ...........................................................................................................71 
8.1. 
Inclusion Criteria ........................................................................................................71 
8.2. 
Exclusion Criteria .......................................................................................................72 
8.3. 
Subject Discontinuation and Stopping Rule Criteria ..................................................74 


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8.3.1. 
Discontinuation of Intervention, Subject, or Study ....................................................74 
8.3.2. 
Subject-level Redosing and Stopping Criteria ............................................................74 
8.3.3. 
Study Stopping Criteria ..............................................................................................75 
8.3.4. 
Subject Replacement ..................................................................................................76 
8.4. 
Informed Consent .......................................................................................................77 
8.5. 
Screening Requirements .............................................................................................77 
9. 
INTERVENTION(S) ..................................................................................................78 
9.1. 
UX053 .........................................................................................................................79 
9.1.1. 
Premedications ............................................................................................................79 
9.1.2. 
Preparation and Administration ..................................................................................79 
9.1.3. 
Clinical Observation and Supportive Care .................................................................80 
9.1.4. 
Guidance on Communication and Seeking Immediate Medical Attention ................80 
9.1.5. 
Dose Modification ......................................................................................................81 
9.1.6. 
Coronavirus Disease 2019 (COVID-19) Vaccination ................................................81 
9.2. 
Reference Therapy ......................................................................................................81 
9.2.1. 
Preparation and Administration ..................................................................................82 
9.3. 
Nutrition Management ................................................................................................82 
9.4. 
Prior and Concomitant Therapy ..................................................................................82 
9.5. 
Rescue Medications ....................................................................................................82 
9.6. 
Restricted or Prohibited Medications, Devices, and Procedures ................................83 
9.7. 
Treatment Compliance ................................................................................................83 
9.8. 
Treatment Assignment and Blinding ..........................................................................84 
9.8.1. 
Treatment Assignment ................................................................................................84 
9.8.2. 
Blinding ......................................................................................................................84 
10. 
ASSESSMENTS.........................................................................................................85 
10.1. 
Safety Assessments .....................................................................................................85 
10.1.1. 
Coronavirus Disease 2019 (COVID-19) Testing .......................................................85 
10.1.2. 
Vital Signs ..................................................................................................................85 
10.1.3. 
Electrocardiogram .......................................................................................................85 
10.1.4. 
Physical Examinations ................................................................................................85 
10.1.5. 
Safety Laboratory Tests ..............................................................................................86 
10.1.6. 
Anti-drug Antibodies ..................................................................................................86 
10.1.7. 
Pregnancy Testing ......................................................................................................86 


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10.1.8. 
Concomitant Medications ...........................................................................................87 
10.2. 
Pharmacokinetic Assessments ....................................................................................87 
10.3. 
General Assessments ..................................................................................................87 
10.3.1. 
General Medical History and GSD III-specific Medical History ...............................87 
10.3.2. 
Demographics .............................................................................................................88 
10.3.3. 
Anthropometric Assessments .....................................................................................88 
10.4. 
Efficacy Assessments .................................................................................................88 
10.4.1. 
Liver Assessments ......................................................................................................88 
10.4.1.1. 
Liver Magnetic Resonance Imaging ...........................................................................88 
10.4.1.2. 
Liver Magnetic Resonance Spectroscopy ...................................................................88 
10.4.1.3. 
FibroScan or Liver Ultrasound Elastography .............................................................88 
10.4.1.4. 
Prothrombin Time/International Normalized Ratio ....................................................89 
10.4.1.5. 
High Density Lipoprotein and Low Density Lipoprotein ...........................................89 
10.4.2. 
Cardiac Assessments ..................................................................................................89 
10.4.2.1. 
Creatinine Kinase – Muscle Brain, B-Type Natriuretic Peptide, and 
Troponin I ...................................................................................................................89 
10.4.3. 
Skeletal Muscle, Strength, and Physical Functioning Assessments ...........................89 
10.4.3.1. 
Creatinine Kinase ........................................................................................................89 
10.4.3.2. 
Handheld Dynamometry .............................................................................................90 
10.4.4. 
Clinician- and Patient-reported Outcomes ..................................................................90 
10.4.4.1. 
Patient-Reported Outcomes Measurement Information System ................................90 
10.4.4.2. 
36-item Short-Form Health Survey ............................................................................90 
10.4.4.3. 
GNE Myopathy Functional Activities Scale Expanded Version ................................91 
10.4.4.4. 
Nutrition Diary ............................................................................................................91 
10.5. 
Pharmacodynamic and Biomarker Assessments ........................................................91 
10.5.1. 
Controlled Fasting Challenge .....................................................................................91 
10.5.2. 
Ketones .......................................................................................................................93 
10.5.3. 
Continuous Glucose Monitoring.................................................................................93 
10.5.4. 
Hemoglobin A1C ........................................................................................................94 
10.5.5. 
Glucose Tetrasaccharide .............................................................................................94 
10.5.6. 
AGL Gene Sequencing ................................................................................................94 
10.5.7. 
Exploratory Future Use of Blood ...............................................................................94 
10.6. 
Appropriateness of Measurements .............................................................................95 


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11. 
STATISTICAL CONSIDERATIONS .......................................................................96 
11.1. 
Sample Size Determination ........................................................................................96 
11.2. 
Analysis Sets ...............................................................................................................96 
11.3. 
Planned Methods of Analysis .....................................................................................96 
11.3.1. 
General Principles .......................................................................................................96 
11.4. 
Safety Analyses ..........................................................................................................97 
11.5. 
Pharmacokinetic Analyses ..........................................................................................97 
11.6. 
Anti-drug Antibody Analyses .....................................................................................97 
11.7. 
Efficacy Analyses .......................................................................................................98 
11.8. 
Nutrition Diary ............................................................................................................98 
11.9. 
Exploratory Analyses ..................................................................................................98 
11.10. 
Planned Subgroup Analyses .......................................................................................98 
11.11. 
Planned Analyses ........................................................................................................98 
11.12. 
Data Monitoring Committee .......................................................................................98 
12. 
REFERENCES .........................................................................................................100 
13. 
APPENDICES ..........................................................................................................105 
APPENDIX 1. SAFETY DEFINITIONS AND ASSESSMENTS ...........................................106 
APPENDIX 2. ADVERSE EVENT COLLECTION: ELICITING, RECORDING, 
AND REPORTING ..................................................................................................111 
APPENDIX 3. LABORATORY ASSESSMENTS ..................................................................116 
APPENDIX 4. CONTRACEPTION GUIDANCE ...................................................................117 
APPENDIX 5. ETHICS AND CONDUCT ..............................................................................119 
APPENDIX 6. PROTOCOL AMENDMENT HISTORY ........................................................124 
STATEMENT OF COMPLIANCE .............................................................................................138 
 
LIST OF TABLES 
Table 1: 
Primary and Secondary Endpoints..............................................................................14 
Table 2: 
Nutrition Guidelines for Adults with GSD III ............................................................16 
Table 3: 
Study Investigational Product, Premedication, and Rescue Medication ....................24 
Table 4: 
Schedule of Events for the Single Ascending Dose Cohorts ......................................30 
Table 5: 
Schedule of Events for Open-label Repeat Dose Cohorts ..........................................33 
Table 6: 
Schedule of Events for Randomized, Double-blind, Placebo-controlled 
Repeat Dose Cohorts ..................................................................................................37 


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Table 7: 
Schedule of Vital Sign Assessments at Infusion Visits ..............................................41 
Table 8: 
Schedule of PK Assessments during and following Study Drug Infusion .................42 
Table 9: 
Study Objectives and Endpoints .................................................................................62 
Table 10: Action in the Event of an Infusion-Related Reaction .................................................75 
Table 11: Clinical Criteria for Diagnosing Anaphylaxis ............................................................76 
Table 12: Study Investigational Product, Premedication, and Rescue Medication ....................78 
Table 13: American Society for Transplantation and Cellular Therapy Consensus 
Grading for Cytokine Release Syndrome .................................................................108 
Table 14: Collection Period & Reporting Timeframe: Adverse Event & Other Safety 
Information Reporting ..............................................................................................111 
Table 15: Safety Contact Information .......................................................................................112 
Table 16: Protocol Amendment History ...................................................................................124 
Table 17: Summary of Protocol Amendment Changes ............................................................124 
 
LIST OF FIGURES 
Figure 1: 
UX053-CL101 Study Design .....................................................................................15 
Figure 2: 
Rescreening Schematic for OL-RD Cohorts ..............................................................18 
Figure 3: 
Screening Schematic for the DB-RD Cohorts ............................................................20 
Figure 4: 
Schematic Representation of UX053 Mechanism of Action ......................................55 
 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition or Explanation 
ADA 
anti-drug antibody 
AE 
adverse event 
AGL 
amylo-Į-1,6-glucosidase 4-alpha-glucanotransferase 
AH50 
alternative complement activity 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoE 
apolipoprotein E 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUC 
area under the concentration-time curve 
AUCinf 
AUC from time 0 to infinity 
AUClast 
AUC from time 0 to the last measurable concentration 
AUCtau 
AUC from time 0 to end of dosing period 
BNP 
B-type natriuretic peptide 
BL 
Baseline 
BUN 
blood urea nitrogen 
CBC/diff 
complete blood count with differential 
CFC 
controlled fasting challenge 
CGM 
continuous glucose monitor 
CH50 
classical pathway complement activity 
CK 
creatinine kinase 
CK-M/B 
CK – muscle/brain  
CL 
Clearance 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRP 
C-reactive protein 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP2B6 
cytochrome P450 2B6 
DB 
double blind 
DMC 
Data Monitoring Committee 
 
 
CCI


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Abbreviation 
Definition or Explanation 
DPIA 
Data Privacy Impact Assessment 
 
 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EF 
ejection fraction 
EOS 
end of study 
ET 
early termination 
EU 
European Union  
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FFP 
fresh frozen plasma  
FIH 
first-in-human  
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDE 
glycogen debranching enzyme 
GDPR 
General Data Protection Regulation  
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
Glc4 
glucose tetrasaccharide 
glycoNOE 
glycogen nuclear overhauser enhancement 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
GMP 
Good Manufacturing Practices  
GSD 
glycogen storage disease 
HDL 
high density lipoprotein 
HED 
human equivalent dose 
HEENT 
head, eyes, ears, nose, and throat 
HHD 
handheld dynamometry  
HHG 
Handheld glucometer 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IL-6 
Interleukin-6 
IND 
Investigational New Drug (application) 
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Abbreviation 
Definition or Explanation 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRT 
interactive response technology  
ISV 
Initial Screening Visit 
IV 
intravenous  
 
 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LDL-R 
low density lipoprotein-receptor  
LNP 
lipid nanoparticle  
LVH 
left ventricular hypertrophy  
MCH 
mean corpuscular hemoglobin  
MCHC 
MCH concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MRI 
magnetic resonance imaging 
MRS 
magnetic resonance spectroscopy  
MTD 
maximum tolerated dose 
NIAID FAAN 
National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network 
NOAEL 
no-observed adverse effect level 
NOV 
Nutrition Optimization Visit 
NYHA 
New York Heart Association  
OL 
open label 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic(s) 
 
 
PK 
pharmacokinetic(s) 
PP 
Per Protocol 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
prothrombin time 
Q2W 
every 2 weeks 
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Abbreviation 
Definition or Explanation 
Q4W 
every 4 weeks 
RAUC 
accumulation ratio (calculated as AUC after repeat dose / AUC after a single dose) 
RBC 
red blood cells 
RD 
repeat dose 
RT-PCR 
real time – polymerase chain reaction  
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sC5b-9 
soluble Complement 5b-9 
SF-36v2 
Short Form Health Survey 36 version 2 
SOC 
System Organ Class  
STV 
Stabilization Visit 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half life 
TEAE 
treatment-emergent adverse event 
Tlast 
time of last measurable concentration 
Tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at a steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
 
Definition of Terms  
Investigational Product (IP) is defined as, “A pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical study, 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 term “study drug” may also be used in place of “investigational product” in the protocol. 


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5. 
INTRODUCTION 
UX053 is an mRNA-based biologic that is being developed for the treatment of Glycogen 
Storage Disease (GSD) III. The purpose of this first-in-human (FIH) trial is to investigate the 
safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of UX053 in 
adults with GSD III.  
5.1. 
Overview of Glycogen Storage Disease III 
Glycogen Storage Diseases represent a group of metabolic disorders in which there is a 
deficiency in the function of enzymes required to metabolize glycogen, including synthesis, 
degradation or regulation of glycogen (Wolfsdorf and Weinstein, 2003). Glycogen is the stored 
form of glucose, with glycogen formation occurring with carbohydrate loading and glycogen 
degradation (glycogenolysis) to glucose occurring to provide immediate energy and maintain 
blood glucose levels. GSD III is a rare, autosomal recessive, metabolic disease, characterized by 
a broad spectrum of clinical manifestations affecting primarily the liver, cardiac muscle, and 
skeletal muscle (Kishnani et al., 2010). Other names for GSD III include limit dextrinosis 
disease, Cori disease, and Forbes disease.  
GSD III is caused by mutations in the AGL (amylo-alpha-1,6-glucosidase 4-alpha-
glucanotransferase) gene, encoding for the glycogen debranching enzyme (GDE) (Sentner et al., 
2013). GDE is required for complete enzymatic processing of the branch chain linkage in 
glycogen, a key step in the degradation of glycogen to glucose. AGL mutations lead to 
accumulation of partially metabolized glycogen (limit dextrins) in tissues and a specific 
incompletely degraded limit dextrin, glucose tetrasaccharide (Glcα1-6Glcα1-4Glcα1-4Glc 
[Glc4]), in the urine (Halaby et al., 2019). Limit dextrin accumulation results in hepatic 
dysfunction, including hypoglycemia, hepatomegaly, and cirrhosis; skeletal myopathy; 
cardiomyopathy; and growth impairment (Kishnani et al., 2010).  
GSD III is a heterogeneous disorder with variable phenotype depending on the site and 
functional implication of AGL mutation. In turn, clinical characteristics vary depending on the 
relative extent of liver or muscle involvement, with most patients experiencing consequences of 
both liver and muscle involvement (Sentner et al., 2016). Patients with GSD III generally present 
by the age of 1.5 years (Sentner et al., 2016; Van Hoof and Hers, 1967), with hepatomegaly the 
most common presenting clinical sign. Other hallmarks of the disease include ketotic 
hypoglycemia with fasting, hyperlipidemia, growth retardation, elevated liver transaminases, and 
elevated creatine kinase. Some individuals also develop osteoporosis or osteopenia over time 
(Derks and Smit, 2015). Hepatomegaly may appear to improve with age with a reduced relative 
glucose requirement; however, it is increasingly recognized that progressive liver cirrhosis and 
hepatic failure can occur, with some patients developing hepatic adenoma, hepatocellular 
carcinoma, or end-stage liver cirrhosis (Kishnani et al., 2010). Skeletal and cardiac muscle 
involvement also varies widely, with reports of asymptomatic cardiomyopathy, symptomatic 
cardiomyopathy leading to death, ventricular hypertrophy, sudden death due to cardiac 
arrhythmia, and slowly progressing myopathy with distal, proximal or generalized myopathy.  
Four subtypes of GSD III have been described: IIIa, IIIb, IIIc, and IIId. Types IIIa and IIIb are 
the most common, comprising 85% and 15% of the total incidence, respectively. Types IIIc and 
IIId are extremely rare, with a combined incidence less than 1% of the GSD III population 


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(Kishnani et al., 2010). The incidence of GSD III is approximately 1:100,000 in the United 
States (US), with higher incidences in some populations including the North African Jewish 
population (~1:5,400) and in the Inuit population in Nunavik, Canada (~1:2,500) (Rousseau-
Nepton et al., 2015; Endo et al., 2006; Parvari et al., 1997; Moses et al., 1973).  
Currently, there is no approved treatment for GSD III, and symptoms are managed with nutrition 
intervention, including small, frequent feedings and cornstarch to avoid hypoglycemia in 
children, a high protein diet, low complex carbohydrates, avoidance of fasting, and avoidance of 
simple sugars (Kishnani et al., 2010). Current nutrition management is focused on prevention of 
hypoglycemia and maintenance of glucose levels. Case reports indicate that a strict ketogenic 
regimen may reduce hypertrophic cardiomyopathy (Valayannopoulos et al., 2011; Dagli et al., 
2009). No specific management approach has been shown to address the progressive and 
debilitating muscle impairment experienced by patients with GSD III. The current treatment 
approach of nutrition management is supportive, but incomplete, and highlights a need for a 
targeted therapy that replaces the missing or defective enzyme. 
5.2. 
Overview of UX053 Development 
A brief overview of existing information on UX053 is provided below; a comprehensive review 
of available data, including the structural components of UX053, detailed summaries of the 
nonclinical studies of UX053, and the potential risks and expected benefits of UX053, is 
contained in the Investigator’s Brochure (IB). Information regarding the storage, handling, and 
administration of UX053 are provided in Section 9.1.  
UX053 consists of an mRNA encoding full-length, human GDE encapsulated in a lipid 
nanoparticle (LNP), supplied in a sterile solution. 
 
.  
Intravenous (IV) administration of UX053 demonstrated improvement in GSD III disease 
manifestations in Agl -/- mice and a dog model of GSD IIIa, both of which recapitulate features 
of human GSD III. Improvement of disease in these models was demonstrated by sustained 
reductions in glycogen content in the liver that correlated with increases in GDE protein. 
Glycogen reduction in skeletal muscles has been observed in GSD IIIa dogs treated with UX053, 
but only at a very low incidence and with minimal effect. It is hypothesized that a longer 
duration treatment will be necessary to show benefit in the muscle. 
The PK characteristics of UX053, determined by measuring both AGL mRNA and ATX95, were 
evaluated in Sprague-Dawley rats and cynomolgus monkeys. Limited PK was also assessed in 
GSD IIIa and Beagle dogs. In all species, following a single 1-hour IV infusion of UX053, both 
AGL mRNA and ATX95 displayed a biphasic PK profile which can be generally characterized 
by a rapid distribution phase within the 
 after the start of infusion and a slower 
terminal elimination phase with a longer half-life thereafter (T1/2 in monkey: mRNA 
 
hours; ATX95 
 hours). Dose-dependent increases in AGL mRNA and ATX95 
exposure were observed from 
 mg/kg and 
 mg/kg in rat and monkeys, 
respectively.
.  
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Toxicology studies in rats and cynomolgus monkeys indicated dose-dependent effects related to 
hepatic injury, coagulopathy, fibrinolysis, and complement activation, which are consistent with 
effects that have been reported for other siRNA or mRNA LNP therapies (Levin, 2019; Sabnis et 
al., 2018; Sedic et al., 2018; Henry et al., 2016).  
This protocol is a FIH study; to date, no clinical investigations of UX053 have been conducted. 
5.3. 
Rationale for UX053 in Glycogen Storage Disease III  
The current treatment approach for GSD III is through nutrition management, including small, 
frequent feedings and cornstarch to avoid hypoglycemia in children, a high protein diet, low 
complex carbohydrates, avoidance of fasting, and avoidance of simple sugars (Kishnani et al., 
2010). The nutrition management approach demonstrates a limited clinical benefit and does not 
directly address the underlying pathophysiology of GSD III.  
UX053, consisting of an mRNA encoding full-length human GDE encapsulated in an LNP, was 
designed as a targeted therapy for GSD III. The LNP serves as a delivery system that limits 
systemic degradation of GDE-encoding mRNA and facilitates its uptake into target cells, 
predominantly via ApoE receptors (Akinc et al., 2010). In addition, the LNP components 
promote endosomal escape of the mRNA into the cytoplasm, a necessary step for translation into 
GDE (Figure 4). The mRNA is codon optimized for expression in human cells, thereby 
addressing GDE deficiency, the underlying pathophysiology of GSD III. In nonclinical species, 
UX053-derived GDE is active in the cytoplasm of target cells, where it facilitates glycogen 
breakdown. GDE expression in target cells is transient because the encoding mRNA is degraded 
over time by endogenous cellular mechanisms. As briefly described in Section 5.2, UX053 
demonstrated improvement in GSD III disease manifestations in nonclinical models. Restoration 
of GDE activity in patients with GSD III is expected to slow or halt disease progression by 
restoring glucose homeostasis and reducing liver and muscle injury. Hepatomegaly due to 
glycogen overload is expected to reverse.  
The mRNA-LNP modality was selected for the treatment of GSD III because the LNP facilitates 
targeted distribution of full-length GDE-encoding mRNA to the liver, and may also facilitate 
uptake into skeletal and cardiac muscles, thereby enabling sufficient expression of GDE in key 
target tissues. The transient nature of both mRNA and UX053-derived GDE necessitates periodic 
repeat dosing of UX053, presenting an opportunity to adjust the dose as needed to attain optimal 
safety and clinical outcomes. Of note, the size of the human AGL mRNA (5023 nucleotides) 
precludes gene delivery using a viral vector-DNA–based modality (Wu et al., 2010), and 
traditional enzyme replacement is not feasible with GDE given that it functions in cellular 
cytoplasm (Solomon and Muro, 2017).


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Figure 4: 
Schematic Representation of UX053 Mechanism of Action 
 
 
During glycogenolysis, the glycogen phosphorylase enzyme cleaves the peripheral glucosyl residues until 4 residues remain before the D-1,6 branch point. The 
terminal 3 residues are then transferred to another branch by the transferase component of GDE. The glucosidase component of GDE then cleaves the D-1,6 
branch point. When the debranching enzyme is deficient, only the peripheral glucosyl residues can be cleaved and an abnormal glycogen, called limit dextrin, 
accumulates (Dagli et al., 2009).  
ApoE, Apolipoprotein E; GDE, glycogen debranching enzyme; LDL-R, low density lipo-protein receptor; LNP, lipid nanoparticle; CCI


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5.4. 
Potential Risks and Benefits 
Considering measures to minimize risk to subjects in this study, the potential risks associated 
with UX053 are justified by the anticipated benefits that may be afforded to subjects. 
5.4.1. 
Potential Risks for UX053 
This FIH study was designed to mitigate the known risks associated with siRNA or mRNA LNP 
therapies and potential risks identified in nonclinical toxicology studies with UX053. Potential 
risks for UX053 were identified by reviewing data from nonclinical toxicology studies with 
UX053 and pharmacological class effects from clinical studies with relevant LNP-formulated 
oligonucleotide therapies, including mRNA-LNP therapies. The potential risks of treatment with 
UX053 include: 
x Hypersensitivity 
x Hepatotoxicity  
x Consumptive coagulopathy  
Hypersensitivity may include infusion-related reactions (IRRs), immune system activation, as 
well as the development of anti-drug antibodies (ADA) to human GDE, 
, or both. Example symptoms 
related to immune system activation may include, but are not limited to, increased complement 
activity and cytokine release, elevated body temperature, neutrophilia, and tachycardia.  
Hepatotoxicity may be evident by increases in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT).  
Consumptive coagulopathy may be evident as prolonged PT/INR, decreased fibrinogen, or 
unusual bleeding or bruising.  
For details on how the FIH study was designed to mitigate the potential risks of UX053, refer to 
Section 5.5.  
5.4.1.1. 
Potential Risks Identified from Nonclinical Studies 
A review of nonclinical studies with UX053 informed the identification of the following 
potential risks for UX053: hypersensitivity, hepatotoxicity, and consumptive coagulopathy.  
Summaries of nonclinical studies with UX053 are provided in the IB. Across species (mouse, rat, 
dog, and monkey), the key potential risks identified in nonclinical studies were hypersensitivity, 
consumptive coagulopathy, and hepatotoxicity. The potential risks are likely triggered in part by 
immune system activation including, complement activation and cytokine release. Clinical signs 
of complement activation can include fever, tachycardia, hypotension, body aches, nausea and 
vomiting, rash, and edema.  
ADAs to human GDE and 
 developed in rats, dogs, and monkeys after repeat 
administration of UX053. Increasing titers over time coincided with a progressively higher 
magnitude induction of cytokines and complement activation at later doses in dogs and monkeys 
(cytokines and complement not measured in rats). The presence of 
 ADAs did 
not have an impact on UX053 mRNA and ATX95 exposure in these studies.  
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Hepatotoxicity was identified by increases in transaminases and corresponding changes in 
histopathology. At lower doses, rises in transaminases were transient and reversible. Importantly, 
these changes are clinically monitorable.  
In the nonclinical toxicology studies in rat and cynomolgus monkey, toxicity was observed at 
doses of 
 higher than the highest potential dose assigned in this FIH study on a 
mg/kg basis. Dogs, which have been reported as a model with hypersensitivity to nanoparticle 
formulations (Szebeni et al., 2018; Szebeni et al., 2007), had symptoms of toxicity at 
 mg/kg 
UX053, which is higher than the highest potential dose in this FIH study (option to dose up to 
mg/kg). The heightened sensitivity to such reactions in dogs may translate to similar types of 
findings in patients who experience hypersensitivity (eg, IRRs), and hypersensitivity has been 
identified as an important potential risk and will be carefully monitored. Toxicology findings 
from UX053 nonclinical studies across species were consistent with findings for other siRNA or 
mRNA LNP therapies (Levin, 2019; Sabnis et al., 2018; Sedic et al., 2018; Henry et al., 2016). 
5.4.1.2. 
Potential Risks Identified from Relevant LNP-formulated Oligonucleotide 
Therapies 
A review of clinical studies with similar LNP-formulated oligonucleotide therapies informed the 
identification hypersensitivity and immune system activation as potential risks for UX053. 
Potential class effects were identified by review of data from similar molecules in clinical 
development and data from clinical studies of patisiran (ALN-TTR02, ONPATTRO), an siRNA 
LNP treatment approved by the US Food and Drug Administration (FDA) in 2018 for the 
treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults 
(ONPATTRO). IRRs were observed in patients treated with patisiran in clinical trials. IRR 
symptoms included, but were not limited to: arthralgia or pain (including back, neck, or 
musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal 
pain, dyspnea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, 
increased heart rate or palpitations, hypotension, hypertension, and facial edema.  
It is anticipated that administration of UX053 may induce antibody responses to human GDE and 
 Anti-human GDE antibodies may develop once the full-length human GDE is 
translated from UX053 mRNA in patients with GSD III. 
antibodies may 
develop as a direct response to the 
 present in the LNP, 
 
 as UX053 (ONPATTRO). 
 
 ADA will be 
measured as described in Section 10.1.6.  
Available safety data for the following mRNA LNP therapeutics were also reviewed to identify 
potential pharmacological class effects: 
 (mRNA for OTC deficiency); mRNA-1273 
(mRNA-based vaccine for SARs-CoV-2); and H10N8 and H7N9 (mRNA-based vaccines against 
influenza). As previously noted, 
 
  
After completion of the 3 dose-escalation cohorts with 
 up to 0.3 mg/kg in a Phase 1 
study in healthy volunteers, all adverse events (AEs) were mild to moderate and no serious 
adverse events (SAEs) occurred (Arcturus Therapeutics, 2020).  
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Although the structure of the LNP is similar to UX053, mRNA-1273 is administered 
intramuscularly and only 2 doses are provided (Jackson et al., 2020). In the Phase 1 study, AEs 
reported in more than half of the 45 subjects following treatment with mRNA-1273 included 
fatigue, chills, headache, myalgia, and pain at the injection site. One subject in the Phase 1 study 
experienced Grade 3 (severe) incidents of syncope and lightheadedness on the day of the second 
vaccination; these events were considered related to treatment and resolved the following day. 
Adverse events were more common after the second vaccination. No pattern of concern emerged 
among safety laboratory values. Preliminary analysis of the Phase 3 study was consistent with 
findings from the Phase 1 study (Moderna Therapeutics, 2020). Grade 3 (severe) AEs occurring 
in > 2% of subjects (> 30,000 subjects included in the analysis) were injection site pain, fatigue, 
myalgia, arthralgia, headache, pain, and erythema/redness at the injection site. 
In a Phase 1 trial with H10N8 and H7N9, LNP-based mRNA vaccines against influenza, AEs 
included injection site pain and swelling, erythema, headache, fatigue, myalgia, arthralgia, 
nausea, and fever (Feldman et al., 2019). 
A similar spectrum of AEs has been reported for other relevant IV LNP-based nucleic acid 
therapies in clinical trials: ALN-TTR01 (siRNA also evaluated for treatment of hereditary 
transthyretin mediated amyloidosis) (Coelho et al., 2013), ALN-PCS02 (siRNA for 
hypercholesterolemia) (Fitzgerald et al., 2014), ARB-1467 (siRNA targeting hepatitis B virus) 
(Streinu-Cercel et al., 2017), and BMS-986263 (siRNA for HSP47 to treat liver and pulmonary 
fibrosis) (Sakamoto et al., 2018; Soule et al., 2018). The most common safety finding among 
these agents was infusion reactions which were in some cases reported to be mitigated by 
slowing the infusion rate. Headache, flushing, edema, and flu-like symptoms were commonly 
reported AEs in some of these studies. 
5.4.2. 
Potential Risks of Premedication  
The premedication regimen for this study is based on the premedication regimen established for 
the approved siRNA LNP therapy, patisiran (ONPATTRO). Premedications recommended for 
patisiran are IV corticosteroids (dexamethasone 10 mg, or equivalent), acetaminophen, IV H1 
blocker (eg, diphenhydramine 50 mg or equivalent), and an IV H2 blocker (eg, ranitidine 50 mg 
or equivalent). IV diphenhydramine is associated with drowsiness, dizziness, constipation, upset 
stomach, blurred vision, and dry mouth, possibly due to anticholinergic effects. Instead of IV 
diphenhydramine, premedication for UX053 includes a more selective oral antihistamine, 
cetirizine 10 mg, or equivalent, which is less sedating. Premedication for UX053 also includes an 
oral H2 blocker (famotidine 20 mg or equivalent). The safety profiles of oral 
acetaminophen/paracetamol, cetirizine, and famotidine have been well characterized. These 
formulations are available without a prescription in all participating countries. At the discretion 
of the Investigator, with input from Ultragenyx and the Data Monitoring Committee (DMC), and 
based on the emerging safety profile of UX053, additional premedications and rescue 
medications may be used to reduce the risk and severity of immune reactions, including IRR, in 
repeat dose (RD) cohorts. Premedication and rescue medication selection will be based on the 
nature of the reactions being observed and the risks of such medications in patients with GSD III. 
To minimize potentially unnecessary chronic exposure to corticosteroids, dexamethasone will be 
used as a rescue agent for subjects who develop a hypersensitivity reaction ≥ Grade 2 in severity 
suspected to be due to immune activation (Section 8.3.2 and Section 9.1.1), and should be 


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considered as a premedication for subsequent infusions for that subject after discussion with the 
Medical Monitor.  If a subject develops an infusion-related reaction that meets diagnostic criteria 
for anaphylaxis (Section 8.3.3), epinephrine should be administered as initial rescue medication. 
5.4.3. 
Potential Risks for Study Participation 
Physical injury associated with study assessments and procedures is also a potential risk. 
This includes discomfort, bleeding, bruising from phlebotomy and local skin irritation from the 
continuous glucose monitor (CGM) or electrocardiogram (ECG) electrodes. There is also the 
potential risk of injury during muscle strength tests.  
5.4.4. 
Potential Benefits  
Nonclinical studies suggest that treatment with UX053 may improve clinical manifestations of 
GSD III, including increases in functional GDE levels and reductions in glycogen content in the 
liver. A more detailed summary of the potential benefits observed in nonclinical studies of 
UX053 are provided in the IB. Subjects with GSD III participating in this FIH study may 
experience a transient, but meaningful, benefit from even a single dose of UX053. Nonclinical 
studies suggest that treatment with UX053 may reduce hepatomegaly, hypoglycemia, and liver 
damage. Secondary beneficial effects may include improvements in glucose metabolic 
availability during exercise, which may have indirect benefits on muscle injury and function. 
Due to the short half-life of the mRNA, such benefits are likely to be lost after discontinuation of 
UX053 treatment. To maximize potential benefit to study subjects, those who complete the SAD 
90-day follow-up may be rescreened to enter open-label (OL)-RD cohorts, in which they will 
receive 4 additional doses of UX053 at monthly intervals. Assuming the clinical development of 
UX053 continues, subjects who participate in this FIH study will also be eligible for additional 
treatment within  a long-term open-label extension study.  
Currently, there is no approved treatment for GSD III, and symptoms are managed with diet. 
Subjects may benefit from participation in this study by receiving enhanced disease management 
from clinicians with expertise treating GSD III. Subjects in the OL-RD and double-blind 
(DB)-RD cohorts, including those randomized to placebo may benefit from nutrition 
optimization during screening and dietary monitoring throughout the study (Section 7.1). 
Subjects may also directly benefit by having previously undetected disease manifestations 
identified during the study assessments.  
Participation in this study will help to provide a better understanding of the disease-specific 
features of GSD III and support the development of therapies for GSD III, including UX053.  
5.5. 
Risk Minimization 
Several components of this FIH study are designed to mitigate the potential risks of study 
participation, including implementation of a DMC, 72-hour intervals between dosing of 
individual subjects within a given SAD cohort, a cautious dose escalation scheme, slow drug 
infusion rate, prespecified premedications, availability of rescue medications, continuous 
cardiorespiratory monitoring during infusions, and 24-hour observation post infusion to monitor 
for post infusion effects.  
Dose escalation will occur only after safety data reviews by the DMC. The DMC consists of a 
panel of independent medical and scientific experts (Section 7.1 and Section 11.12). Standard 


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safety laboratory tests are collected immediately prior to dosing (all cohorts) and again 
approximately 24 hours after dosing and at Day 4 (SAD cohorts) and Day 7 (both SAD and RD 
cohorts) (Section 10.1.5). In addition, characterization of complement activation through 
classical and alternative pathways, cytokine release, fibrinogen, and d-dimer will be assessed 
predose and at the end of each infusion. Potential risks of UX053 treatment identified from 
available nonclinical data with UX053 and known risks associated with siRNA or mRNA LNP 
therapies (Section 5.4.1) will be monitored throughout participation in the SAD and RD cohorts. 
Subjects will be monitored in an inpatient or observational unit for 24 hours after the end of each 
infusion.  
The starting dose of UX053, 0.05 mg/kg, is approximately 
 below the human equivalent 
dose (HED) for the no-observed adverse effect level (NOAEL) for repeat dosing in dogs, 
approximately 
 below the HED for the NOAEL for repeat dosing in rats, and 
approximately 
 below the HED for the NOAEL for repeat dosing in cynomolgus 
monkeys using 
 scaling to calculate HED. The relative dose increase 
becomes smaller with each subsequent cohort: after a 
 dose increase from Cohorts 1S to 2S 
to 3S, there is a 
 dose increase between cohorts 3S and 4S. For RD cohorts, sequential 
doses may be reduced for individual subjects or for entire cohorts based on emerging safety 
findings.  
Subjects in SAD cohorts will be dosed at least 72 hours apart in each cohort, minimizing 
exposure to subjects if an early safety signal occurs. At least 2 weeks of safety data from at least 
2 subjects in each SAD cohort will be reviewed prior to making a decision to proceed with the 
next cohort. Either at least 6 weeks of safety data from at least 4 subjects in a DB-RD cohort or 
12 weeks of safety data from at least 3 subjects in an OL-RD cohort (whichever is available first) 
will be reviewed prior to making a decision to proceed with repeat dosing at the next dose level. 
The intervals between subjects and cohorts dosing were determined based on nonclinical studies, 
which showed that single-dose toxicities generally occurred soon after dosing, and that 
repeat-dose toxicities were observed after 
 
A detailed summary of nonclinical findings with UX053 is provided in the IB.  
Study drug will be administered as an infusion over the course of at least 4 hours, with a slower 
rate of infusion for the first hour to minimize the risk of hypersensitivity or anaphylactoid-type 
reactions. The infusion rate may be slowed to minimize the risk of IRRs in individual subjects. 
Subjects will receive premedication at least 1 hour prior to infusion.  
 If a subject develops an infusion-related reaction that meets diagnostic criteria for anaphylaxis 
(Section 8.3.3), epinephrine should be administered as initial rescue medication. For all other 
K\SHUVHQVLWLYLW\UHDFWLRQV*UDGHLQVHYHULW\VXVSHFWHGWREHGXHWRLPPXQHDFWLYDtion, 
dexamethasone should be the initial rescue medication (Section 9.5). The Medical Monitor must 
be notified if any rescue medication is used. If dexamethasone (or equivalent) is used as a rescue 
medication, premedication with dexamethasone (or equivalent) should be considered for that 
subject’s subsequent infusions after discussion with the Medical Monitor.  
A similar premedication regimen that includes dexamethasone is used for patisiran, a siRNA 
LNP treatment approved by the FDA in 2018 for the treatment of polyneuropathy of hereditary 
transthyretin-mediated amyloidosis in adults (ONPATTRO).  
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Testing for ADA to both human GDE and 
 will be performed, and titers will be 
obtained. ADA testing will be performed at appropriate frequencies (schedule provided in 
Table 4, Table 5, and Table 6), based on FDA guidance (FDA, 2019b; FDA, 2014). Back-up 
serum samples will be banked and stored frozen for future use if further characterization of the 
immune response is required.  
To minimize risk of coronavirus disease 2019 (COVID-19) exposure, subjects will be 
encouraged to observe social distancing, wear face masks/coverings, and avoid social gatherings 
during the conduct of the clinical trial and site visits, as long as country and local health 
authorities recommend. Subjects should follow local public health guidance and Institutional 
Review Board (IRB) recommendations. Guidance on potential changes to the protocol due to 
COVID-19 is in Section 7.1.5. Guidance on COVID-19 vaccination is in Section 9.1.6. 
Subjects will be continually monitored by trained site personnel during study procedures, 
including laboratory collection and handheld dynamometry (HHD), to ensure safety and 
minimize risk of injury.  
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6. 
OBJECTIVES AND ENDPOINTS 
Table 9: 
Study Objectives and Endpoints  
OBJECTIVES 
ENDPOINTS 
Primary  
 
Evaluate the safety of UX053 in adults with GSD III 
The incidence and severity of TEAEs, serious TEAEs, 
and related TEAEs in the SAD and RD cohorts 
Secondary  
 
Characterize the PK of UX053 in adults with GSD III 
PK parameters of AGL mRNA and ATX95, which may 
include Tmax, Cmax, AUClast, AUCinf, AUCtau (RD cohorts 
only), RAUC (RD cohorts only), Tlast, T1/2, CL, Vss  
AGL, amylo-Į-1,6-glucosidase 4-alpha-glucanotransferase; AUC, area under the concentration-time curve; AUCinf, 
AUC from time 0 to infinity; AUClast, AUC from time 0 to the last measurable concentration; AUCtau, AUC from 
time 0 to end of dosing period; CL, clearance; Cmax, maximum observed concentration; PK, pharmacokinetics; 
RAUC, accumulation ratio (calculated as AUC after repeat dose / AUC after a single dose); RD, Repeat Dose; 
SAD, Single Ascending Dose; T1/2, half life; TEAE, treatment-emergent adverse events; Tlast, time of last 
measurable concentration; Tmax, time of maximum observed concentration; Vss, volume of distribution at a 
steady state. 
Tertiary
 
and exploratory objectives 
 
 and their corresponding endpoints are provided in the Statistical Analysis 
Plan (SAP).  
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Study Design 
UX053-CL101 is a phase 1/2 FIH study to evaluate the safety, tolerability, and PK of SAD and 
RD of UX053 in patients with GSD III (Figure 1). The SAD cohorts will be OL. There will be 
2 types of RD cohorts: 1) OL-RD and 2) randomized, DB, and placebo-controlled RD (referred 
to as DB-RD). Treatment-naïve subjects enter the SAD and DB-RD cohorts. Subjects in the SAD 
cohorts who complete the 90-day Follow-up Period can enter OL-RD cohorts. Details for each of 
these cohorts are described below.  
Single Ascending Dose Cohorts 
The SAD cohorts evaluate safety and PK of single doses of UX053 in treatment-naïve subjects. 
All subjects in the SAD cohorts will undergo a Screening Visit prior to their Baseline Visit. 
There are 3 planned SAD cohorts, each consisting of at least 2 subjects, all of whom will receive 
open-label UX053 (Figure 1). The planned dose escalation will proceed from 0.05 mg/kg in 
Cohort 1S, to 0.10 mg/kg in Cohort 2S, and to 0.20 mg/kg in Cohort 3S. An independent DMC 
will review at least 2 weeks of safety data for at least 2 subjects within a SAD cohort and the 
cumulative data from all subjects in prior dosing cohorts (when applicable) before deciding to 
proceed with the next SAD cohort.  
Each subject in the SAD cohorts will be followed for a follow-up of 90 days after dosing. At the 
SAD Day 90 Visit, marking completion of the follow-up, subjects can be rescreened for entry 
into the OL-RD cohorts described below.  
Open-Label Repeat Dosing Cohorts (Extension for SAD Cohorts) 
The OL-RD cohorts serve as a short-term extension for subjects who participated in a SAD 
cohort. The OL-RD cohorts evaluate the safety and PK of 4 additional OL doses of UX053 in 
subjects who received a single dose of UX053 in a SAD cohort and completed the 90-day 
Follow-up Period. Subjects from the SAD cohorts are rescreened for participation in the OL-RD 
cohorts; eligibility for additional dosing in the OL-RD cohorts can be combined with 
assessments at the SAD Day 90 Visit.  
During rescreening, a nutrition assessment will be completed at an Initial Screening Visit (ISV) 
to determine if the subject’s diet meets the nutritional guidelines for adults with GSD III based 
on expert recommendations (Table 2). OL-RD subjects will proceed through rescreening as 
shown in Figure 2 based on whether they meet these nutritional guidelines. 
The first day of the ISV (which may coincide with the SAD Day 90 Visit) is followed by 
3 consecutive days of nutrition diary collection. If a subject’s diet during participation in a SAD 
cohort meets nutritional guidelines, and continues to do so at the ISV, the subject can proceed 
directly to the OL-RD Nutrition Stabilization Visit (STV) as soon as the ISV assessments are 
completed. 
If the subject’s diet does not meet nutritional guidelines, a Nutrition Optimization Visit (NOV) is 
performed. At this visit, nutritional counseling is provided to the subject on dietary changes 
needed to comply with GSD III-specific nutrition guidelines (Table 2). Nutrition diary and 
continuous glucose monitor (CGM) data will be reviewed by the Investigator and safety 


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laboratory tests may be obtained at the discretion of the Investigator. After 1 week of nutrition 
optimization (approximately 2 weeks after the ISV), the subject proceeds to the STV (occurring 
approximately 2 weeks before the subject’s OL-RD Baseline/Week 0 Visit) and thereafter 
maintains a stable diet as defined by the nutritional guidelines for GSD III (Table 2) for the 
remainder of the study. If an OL-RD subject is unable to achieve an optimized diet, they are still 
eligible to proceed to the STV. The reason for the inability to achieve an optimized diet should 
be documented and the subject should make no substantial nutrition changes for the remainder of 
the study. 
For selected sites and subjects, the OL-RD STV includes an optional controlled fasting challenge 
(CFC). Prior to the CFC, a morning cortisol is obtained between 6 and 9 am. The CFC is 
conducted during the subject’s stay in the hospital, usually overnight, but can be conducted 
during the day. For the same sites and subjects, another optional CFC occurs at the Week 16 
Visit; only subjects who completed the optional CFC at STV complete the CFC at Week 16. 
Additional details regarding the CFC are in Section 10.5.1.  
 
Beginning with the OL-RD Baseline/Week 0 Visit, subjects in the OL-RD cohorts will receive 
4 additional OL doses of UX053 Q4W at the same or lower dose than they received in the SAD 
cohorts, based on ongoing assessment of safety data.  
Randomized, Double-Blind, and Placebo Controlled Cohorts 
The DB-RD cohorts will evaluate the safety and PK of 5 doses of UX053 or placebo in 
treatment-naïve subjects. All DB-RD subjects will participate in a Screening Period 
(approximately 8 to 12 weeks) (Figure 3), in which subjects will be screened for study eligibility 
and assessed for the need to optimize their diet based on nutrition guidelines for adults with GSD 
III based on expert recommendations (Table 2). Within the first 2 weeks after the ISV, the 
Investigator will review nutrition diary data to determine if nutrition optimization is needed. If 
nutrition optimization is not needed, the STV occurs in clinic approximately 2 weeks after the 
ISV, and the Baseline/Week 0 Visit occurs approximately 4 weeks after the STV, to demonstrate 
6 weeks of nutrition stability. 
If nutrition changes are needed, a 2- to 4-week period of nutrition optimization will be performed 
to comply with GSD III-specific nutrition guidelines (Table 2). In this situation, the first NOV 
occurs as a phone visit approximately 2 weeks after the ISV. During nutrition optimization, NOV 
phone visits occur weekly or more frequently as needed; nutrition diary and CGM data are 
reviewed; and safety laboratory tests may be obtained at the discretion of the Investigator. 
Nutritional counseling is provided to the subject. When the Investigator determines that the 
subject has achieved nutritional optimization the STV is performed. 
The Baseline/Week 0 Visit occurs as least 6 weeks after the STV. Due to the staggered nature of 
the cohorts (described below), a subject may be in nutrition stabilization for longer than 6 weeks 
before their Baseline Visit; in such instances, the total duration of the Screening Period may 
exceed 12 weeks. Nutrition guidance and monitoring for this study was established with 
available health authority guidance, and greater detail is available in the Study Reference 
Manual. 
After the STV, no substantial nutrition changes should be made through the remainder of the 
study, notwithstanding temporary changes due to illness. 


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For selected sites and subjects, the DB-RD STV includes an optional controlled fasting challenge 
(CFC). Prior to the CFC, a morning cortisol is obtained between 6 and 9 am. The CFC is 
conducted during the subject’s stay in the hospital, usually overnight, but can be conducted 
during the day. For the same sites and subjects, another optional CFC occurs at the Week 10 
Visit; only subjects who completed the optional CFC at STV complete the CFC at Week 10. 
Additional details regarding the CFC are in Section 10.5.1.  
In DB-RD cohorts, treatment-naive subjects will be randomized 3:1 to UX053 or placebo in 
ascending dose cohorts (4 subjects per cohort) (Figure 1). DB-RD subjects will receive study 
drug Q2W; a total of 5 doses of study drug are planned. The planned dose levels  are 0.05 mg/kg 
in cohort DB-1R, 0.10 mg/kg in cohort DB-2R, and 0.20 mg/kg in cohort DB-3R.  
Initiation of RD Cohorts (Both OL-RD and DB-RD) 
Initiation of RD cohorts is as follows:  
• Initiation of Cohort DB-1R and OL-1R will be guided by DMC review of at least 
2 weeks of safety data from at least 2 Cohort 2S subjects and any available  data from 
all subjects in prior and ongoing cohorts.  
• Initiation of Cohort OL-2R and DB-2R will be guided by DMC review of either 1) at 
least 6 weeks of safety data from at least 4 subjects within Cohort DB-1R  or 2) at 
least 12 weeks of safety data from at least 3 subjects within Cohort OL-1R 
(whichever is available first). In both of these scenarios, all available data from all 
subjects in prior and ongoing cohorts will also be reviewed.  
• Initiation of Cohort OL-3R and Cohort DB-3R will be guided by DMC review of 
either 1) at least 6 weeks of safety data from at least 4 subjects within Cohort DB-2R 
or 2) at least 12 weeks of safety data from at least 3 subjects within Cohort OL-2R 
(whichever is available first). In both of these scenarios, all available data from all 
subjects in prior and ongoing cohorts will also be reviewed.  
Cohort- and Subject-level Dose Selection and Modification for All Cohorts (SAD, OL-RD, and 
DB-RD)  
At any time Ultragenyx may decide not to initiate a planned dose cohort. Dose levels for each 
cohort may be altered depending on safety, PK, and/or PD findings from prior cohorts. If needed 
to evaluate safety and dose-response relationships, additional cohorts may be added to test doses 
up to 0.30 mg/kg or additional subjects may be added to a cohort at the discretion of Ultragenyx 
to further characterize safety, PK, and PD effects, with input from the DMC. In every case, the 
safety of a single dose will be evaluated prior to repeat doses at the same dose level.  
If a subject in an RD cohort develops a treatment-emergent adverse event (TEAE)/serious TEAE 
≥ Grade 3 that is considered by the Investigator to be related to study drug or an intolerable 
TEAE, subject-level dose reductions are allowed in consultation with the Medical Monitor. 
Ultragenyx will notify the DMC immediately if any subject experiences an event that satisfies 
subject-level stopping criteria (Section 8.3.2) or study-level stopping criteria (Section 8.3.3).  
Glucose and Nutrition Data Collection by Study Subjects 
At the Screening Visit for the SAD cohorts and ISV for the DB-RD cohorts, all subjects will 
receive CGM and handheld glucometer (HHG) devices and will be trained on the proper use of 


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these devices. Subjects will also be trained on completion of the nutrition diary During 
screening. Subjects entering the OL-RD cohorts do not need to be retrained if compliance was 
acceptable during participation in the SAD cohorts. When CGM data is being collected, all 
subjects will connect their CGM and HHG devices to a study-provided laptop weekly and upload 
CGM and HHG data. At remote visits, in conjunction with assessments performed by a home 
health nurse, the site will contact subjects by telephone or videoconference to confirm the CGM 
device is properly in use and data was uploaded; answer any questions regarding or help 
troubleshoot (if necessary) CGM device use; and review CGM data, HHG data (when 
applicable), and nutrition diary entries; outside of scheduled visits, these telephone calls will 
occur as needed. At in-clinic visits, a conversation between the site and the subject should occur 
to ensure CGM compliance and troubleshoot if needed.  
Drug Administration, Dose Interval, and Blinding 
UX053 will be administered as an intravenous (IV) infusion over the course of at least 4 hours, 
with a slower rate of infusion for the first hour to minimize the risk of hypersensitivity or 
anaphylactoid-type reactions (refer to the Pharmacy Manual for additional infusion details) 
(Table 3 and Section 9). The infusion rate may be slowed to minimize the risk of IRRs in 
individual subjects. 
Premedication and Rescue Medication  
All subjects, including those treated with placebo, will receive premedication at least 1 hour prior 
to the infusion, consisting of oral paracetamol/acetaminophen (500 mg) or ibuprofen (400 to 
800 mg), an H2 blocker (eg, famotidine 20 mg or equivalent dose of another H2 blocker), and an 
H1 blocker (eg, cetirizine 10 mg or equivalent dose of another H1 blocker). For the 
premedication, paracetamol/acetaminophen is preferred over ibuprofen.  
At the discretion of the Investigator, with input from Ultragenyx and the DMC, and based on the 
emerging safety profile of UX053, additional premedications and rescue medications may be 
used to reduce the risk and severity of immune reactions in RD cohorts. Premedication and 
rescue medication selection will be based on the nature of the reactions being observed and the 
risks of such medications in patients with GSD III.  
If a subject develops an IRR that meets diagnostic criteria for anaphylaxis (Section 8.3.3), 
epinephrine should be administered as initial rescue medication. For all other hypersensitivity 
reactions ≥ Grade 2 in severity suspected to be due to immune activation, dexamethasone should 
be the initial rescue medication.  The Medical Monitor must be notified if any rescue medication 
is used.  
If dexamethasone (or equivalent) is used as a rescue medication, premedication with 
dexamethasone (or equivalent) should be considered for that subject’s subsequent infusions after 
discussion with the Medical Monitor. 
Section 8.3.2 provides subject-level redosing criteria, stopping criteria, and additional 
instructions on how to proceed in the event of an IRR. 
Subjects will have cardiorespiratory monitoring throughout the infusions and will stay overnight 
for visits in which they receive study drug and be observed in an inpatient or observational unit 
for 24 hours after the end of each infusion. Prior to discharge, all the following criteria must be 
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● All scheduled study assessments have been completed. 
● No evidence of vital sign instability or clinical instability in the opinion of the 
investigator. 
● Any signs or symptoms of potential IRRs are resolving or resolved. 
Guidance on signs and symptoms that subjects should be vigilant for upon discharge and how to 
proceed in the event that these signs and symptoms manifest are provided in Section 9.1.4. 
In each SAD cohort, subjects will be dosed sequentially with review of safety laboratory data 
from the 24-hour time point prior to dosing of the next subject. Within SAD cohorts, dosing of 
individual subjects will occur at a minimum interval of 72 hours. For example, the second 
subject in a cohort receives their first dose after a minimum of 72 hours after the first subject in 
the same cohort received their first dose. Subjects within a given RD cohort can be dosed 
simultaneously. After the first dose, DB-RD subjects maintain a Q2W dosing regimen and 
OL-RD subjects maintain a Q4W dosing regimen.  
Subjects may receive COVD-19 vaccines during participation in the study. To facilitate 
discrimination of UX053 IRRs and adverse effects of vaccine administration, vaccines should 
not be administered within 48 hours after the most recent administration of UX053 and until 
safety labs obtained have been reviewed and the subject has been assessed for any possible 
hypersensitivity reaction to the most recent dose of UX053 (Section 9.1.6). 
For the DB-RD cohort, the subjects, Investigators, and site staff will be blinded to the treatment. 
Due to the difference in the opacity of UX053 and placebo, an unblinded pharmacist will prepare 
the investigational product (IP) and an unblinded nurse will prepare the infusion before masking 
the infusion syringe and tubing with colored covers.  
The full schedules of events for the SAD, OL-RD and DB-RD, cohorts are listed in Table 4, 
Table 5, and Table 6, respectively. Additional details regarding the timing of assessments before, 
during, and following treatment infusion are provided in Table 7 for vital signs and Table 8 for 
PK samples.  
Although they are eligible, it is expected that few patients with GSD IIIb, IIIc, or IIId will enroll. 
Subjects with GSD IIIb/c/d will participate in all assessments, including muscle imaging and 
function tests, and will be included in all safety analyses. Sensitivity analyses for cardiac and 
skeletal muscle endpoints may exclude patients with GSD IIIb/c/d as described in the SAP.  
Future protocol amendments may occur to include pediatric subjects with GSD III or the addition 
of an open-label extension for all subjects after an interim review of safety, PK, and PD data. 
7.1.1. 
Number of Sites  
Approximately 10 sites globally will participate.  
7.1.2. 
Number of Subjects  
Approximately 18 adult subjects are planned to be enrolled. Additional subjects may be enrolled 
to further characterize safety. 


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7.1.3. 
Rationale for Study Design 
The purpose of this study is to determine the safety, PK, PD, and preliminary efficacy of UX053 
in adults with GSD III. The nutrition optimization and stabilization according to nutrition 
guidelines specific to GSD III aim to minimize confounding of safety and PD/efficacy data by 
dietary interventions. The duration of the nutrition optimization and stabilization period for the 
OL-RD cohorts is shorter than the same period for the DB-RD cohorts because nutrition data is 
collected and reviewed for OL-RD subjects during participation in the SAD cohorts. Screening 
includes assessments of the disease state and potential biomarkers that will inform the design of 
subsequent studies. 
The wide range of screening assessments are designed to improve understanding of measurable 
pathology in adults with GSD III. Continued evaluation of these assessments in the RD cohorts 
will help to determine the preliminary efficacy of UX053. Post-treatment assessments for some 
procedures (eg, liver magnetic resonance imaging [MRI], liver magnetic resonance spectroscopy 
[MRS], and Fibroscan or liver ultrasound) are not performed during the SAD Period to minimize 
burden on sites and subjects.  
The DB-RD cohorts are double-blind to prevent conscious or unconscious bias in safety and 
efficacy data collection. The SAD cohorts are open label, as RD better reflects dosing in a 
real-world setting and provides a more relevant safety profile; therefore, blinding to avoid bias is 
more critical for DB-RD cohorts. In an effort to further understand the safety, PK, and optimal 
dosing regimen of UX053, subjects in the SAD cohorts can enroll in OL-RD cohorts; these 
OL-RD cohorts allow for the investigation of a Q4W dosing regimen in previously exposed 
subjects.  
Subject-level dose-reductions are designed to minimize risk to subjects and determine the 
optimal dose for subsequent cohorts and future studies. After data from Cohort 1S are reviewed, 
and with each subsequent data review, the ensuing cohort dose levels may be modified. After 
establishing safety in Cohort 2S, the RD cohorts will characterize the safety of RD of UX053. 
To minimize reporting bias for safety and PD/efficacy assessments, placebo was chosen as the 
appropriate control for the DB-RD cohorts. Data from this FIH study will provide the basis for 
the initial safety profile of UX053. Enrolled subjects are expected to have signs and symptoms of 
GSD III, AEs related to the GSD III, and numerous laboratory abnormalities. Blinded treatment 
allocation reduces bias in reporting of AEs; the placebo control is helpful to determine whether 
UX053 exacerbates the underlying disease, or whether the events represent disease progression. 
Minimizing bias in the safety and PD data from this study is critical to inform the clinical 
development of UX053. An unbiased assessment of PD endpoints will allow for the 
identification and prioritization of clinically relevant endpoints in subsequent phases of clinical 
development. 
There are no approved treatments for GSD III. All study participants will receive standard of 
care in addition to placebo or UX053. In fact, standard of care nutrition management guidelines 
have been incorporated into the protocol to ensure that standard of care will be followed 
(Section 7.1). The use of a placebo control will not impact standard of care. Once chronic 
toxicity data are available, a future protocol amendment is planned to allow all subjects, 
including those previously treated with placebo, to receive long-term open-label treatment with 
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7.1.4. 
Dose Rationale 
The planned doses of UX053 (0.05, 0.10, and 0.20 mg/kg) aim to establish a safe dose of UX053 
in adults with GSD III, as well as provide a preliminary PK and PD profile of UX053. These 
doses were chosen based on single-dose and repeat-dose pharmacology studies in mouse and dog 
models of GSD III, and RD toxicology and toxicokinetic studies in rats, cynomolgus monkeys, 
and Beagle dogs. The NOAEL in repeat-dose studies with 5 total doses of UX053 administered 
Q2W was 
mg/kg in dogs, 
 mg/kg in rats, and 
mg/kg in monkeys. The maximum 
tolerated dose (MTD) was 
mg/kg in rats and 
 mg/kg in monkeys. The MTD in dogs is not 
known since higher doses were not evaluated with Q2W administration. The MTD in dogs with 
weekly dosing of UX053 is 
 mg/kg, but this short interval between doses is believed to 
promote an accumulation of toxicity that does not occur with Q2W dosing. Hence, the MTD in 
dogs may be greater than 
 mg/kg when UX053 is administered Q2W, but remains 
undetermined.
 
 Taken together, these PK and drug metabolism properties of the drug 
support 1:1 weight-based scaling from nonclinical species to humans, which is an approach 
endorsed by a cross-industry consortium of experts in oligonucleotide therapies, the 
Oligonucleotide Safety Working Group (Kornbrust, 2019; Marlowe et al., 2017). The FIH 
starting dose of 0.05 mg/kg is 
 less than the NOAEL in the most sensitive nonclinical 
species, the dog. The highest potential FIH dose of 0.30 mg/kg is 
 less than the dog 
NOAEL. Additional details regarding the use of weight-based scaling versus body-surface area 
scaling, as well as summaries of nonclinical studies with UX053 are available in the IB.  
Sequential dosing with an interval of 72 hours between subjects’ first dose within a cohort and a 
2-week minimum review of data between cohorts was chosen to allow enough time to detect any 
potential TEAEs, including potential immune responses. In nonclinical studies, toxicities 
generally occurred soon after dosing and promptly resolved. The DB-RD cohorts will aim to 
achieve a steady state with Q2W dosing. The OL-RD cohorts will aim to evaluate a Q4W dosing 
regimen. Subjects will receive premedication prior to the treatment infusion to prevent 
hypersensitivity reactions, in line with previously established programs evaluating RNA 
therapeutics. 
Subjects will receive premedication at least 1 hour prior to infusion. Study drug will be 
administered as an IV infusion over at least 4 hours, with a slower rate of infusion for the first 
hour to minimize the risk of anaphylactoid-type or hypersensitivity reactions (which may include 
IRRs). If a subject develops an IRR that meets diagnostic criteria for anaphylaxis (Section 8.3.3) 
epinephrine should be administered  as initial rescue medication. For all other hypersensitivity 
reactions. *UDGHLQVHYHULW\VXVSHFWHGWRbe due to immune activation, dexamethasone should 
be the initial rescue medication (Section 9.5). The Medical Monitor must be notified if any 
rescue medication is used. If dexamethasone (or equivalent) is used as a rescue medication, 
premedication with dexamethasone (or equivalent) should be considered for that subject’s 
subsequent infusions after discussion with the Medical Monitor. Section 8.3.2 provides 
subject-level redosing criteria, stopping criteria, and additional instructions on how to proceed in 
the event of an IRR. A similar premedication regimen that includes dexamethasone has proven 
effective for patisiran, a siRNA LNP treatment approved by the FDA in 2018 for the treatment of 
polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (ONPATTRO). 
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7.1.5. 
Changes to the Protocol Due to Coronavirus Disease 2019 (COVID-19) 
Changes to the protocol or Investigational Plan to minimize or eliminate immediate hazards or to 
protect the life and well-being of research subjects and/or study staff may be implemented 
without IRB/IEC approval or before filing an amendment to the competent authority but are 
required to be reported afterward. Investigators should contact Ultragenyx or Designee to 
determine an appropriate course of action, which may include but is not limited to remote visits, 
home health visits, and out of window visits or assessments. Any changes to the protocol or 
investigational plan must be documented. The Investigator will work with Ultragenyx or 
Designee and IRB/IEC to prioritize reporting of protocol deviations that impact safety of trial 
subjects. 
7.2. 
Duration 
7.2.1. 
Duration of Subject Participation 
SAD Cohorts 
Screening is approximately 2 weeks. After screening and dosing, subjects will be monitored for 
90 days after dosing. 
OL-RD Cohorts 
Subjects who have completed participation in a SAD cohort, consisting of screening and a 
90-day Follow-up Period, may enter an OL-RD cohort. These subjects are rescreened for 
participation in the OL-RD cohorts, which is expected to occur over the course of approximately 
3 weeks prior to redosing; eligibility for additional dosing in the OL-RD cohorts can be 
combined with assessments at the SAD Day 90 Visit. After rescreening, subjects will receive a 
total of 4 additional doses of UX053, with doses administered Q4W, and will be monitored for 
36 weeks (Week 48 Visit) after their last dose of UX053.  
DB-RD Cohorts 
Screening is approximately 8 to 12 weeks. Due to the staggered nature of the cohorts, subjects 
may remain in nutrition stabilization during screening for ≥ 6 weeks. After screening, subjects 
will receive a total of 5 doses of UX053, with doses administered Q2W, and will be monitored 
for 40 weeks (Week 48 Visit) after the last dose of study drug. 
7.2.2. 
End of Study Definition 
The end of the study is defined as the date of the last protocol-specified visit (including safety 
follow-up telephone calls in the event of early termination [ET]) for the last subject in the study.  


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8. 
POPULATION 
Prospective protocol deviations for recruitment and eligibility criteria (ie, protocol waivers or 
exemptions) are not permitted. 
8.1. 
Inclusion Criteria 
Each subject must meet the inclusion criteria listed below at screening (ISV for DB-RD cohorts) 
or rescreening (OL-RD cohorts) and baseline (Day 0 for SAD cohorts or Week 0 in all RD 
cohorts), as applicable, to be enrolled in the study: 
1. Confirmed diagnosis of GSD III (all subtypes) based on pathogenic mutations in the AGL 
gene on both alleles or GDE deficiency based on biopsy of liver, muscle, or fibroblasts  
2. History of any of the following:  
a. Severe hypoglycemia, defined as neuroglycopenia (eg, altered mental status, seizure, 
dizziness, slurred speech, blurry vision, abnormal behavior, perioral paresthesia,  
requiring intervention by a caregiver) or blood glucose < 54 mg/dL (3 mmol/L) 
within the last year 
b. ≥ 2 incidents of symptomatic hypoglycemia (defined as blood glucose < 70 mg/dL 
[3.9 mmol/L] if measured at the time of symptoms) within the last year, despite 
nutrition management 
c. Ongoing liver injury, defined as alanine aminotransferase (ALT) > 2.5x the upper 
limit of normal (ULN) within the last year 
3. For treatment-naïve subjects (SAD and DB-RD cohorts), ALT ≤ 5x the upper limit of 
normal (ULN) during the 3 months prior to the Baseline Visit.  
4. Males or females ≥ 18 years of age  
5. For subjects enrolling into DB-RD cohorts, willing and able to demonstrate nutrition 
stability based on nutrition guidelines for adults with GSD III (Table 2)  
6. Willing and able to provide access to medical records surrounding medical treatment that 
occurred prior to enrollment and during the study  
7. Willing and able to provide written informed consent, or in the case of adult subjects with 
cognitive limitation, provide written assent (if required) and written informed consent by 
a legally authorized representative after the nature of the study has been explained and 
prior to any test procedures or assessments  
8. Females of childbearing potential must have a negative pregnancy test at screening 
(and rescreening, as applicable) and be willing to have additional pregnancy tests during 
the study. Subjects of child-bearing potential or males who are sexually active with 
partners of child-bearing potential must consent to use a highly effective contraceptive 
method, as described in Appendix 4, from the Period following the signing of the 
informed consent through 30 days after last dose of study drug 
9. For subjects rescreening into OL-RD cohorts after treatment with UX053 in a SAD 
cohort, subjects must meet the following criteria: 


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a. If a significant rise in ALT occurs after the prior dose, ALT should show a decreasing 
trend toward the subject’s baseline value 
b. Total bilirubin is within normal limits  
c. Platelets are within normal limits 
d. International normalized ratio (INR) is within normal limits 
8.2. 
Exclusion Criteria 
Each subject must not meet the exclusion criteria listed below at screening (ISV for DB-RD 
cohorts) and baseline (Day 0 for SAD cohorts or Week 0 in all RD cohorts), as applicable, to be 
enrolled in the study: 
1. History of liver transplant, including hepatocyte cell therapy/transplant, or active listing 
for liver transplant  
2. History of cirrhosis, or presence of any of the following: 
a. Total bilirubin ≥ 1.3 mg/dL and INR ≥ 1.3 
b. Evidence of portal hypertension, including, but not limited to the following symptoms 
splenomegaly, ascites, thrombocytopenia, esophageal varices, or history of hepatic 
encephalopathy 
c. Model for End Stage Liver Disease (MELD) score > 12 
3. Current Hepatitis B or C infection or history of chronic Hepatitis B or C infection 
4. Severe renal impairment defined as a glomerular filtration rate (GFR) ≤ 29 mL/min 
(Levey et al., 2005). 
5. Any prior history of hepatocellular carcinoma or presence of liver adenoma > 5 cm at the 
longest diameter or > 3 cm and ≤ 5 cm in size that has an annual growth rate of ≥ 0.5 cm 
per year  
6. Current or history of malignancies in the 3 years prior to the Screening Visit (ISV for 
RD) 
7. Hospitalizations related to GSD III disease between the Screening (ISV for RD) and 
Baseline Visit 
8. Known history of human immunodeficiency virus infection  
9. Presence or history of any hypersensitivity reactions requiring medical evaluation and 
management (including injection/IRRs, such as lymphadenopathy) to UX053, its 
excipients, or any drug products that contain polysorbate or PEG. This may include 
vaccines that contain PEG or polysorbate  
10. Significant cardiac disease, including heart failure with New York Heart Association 
(NYHA) Function Capacity III or IV or Objective Assessment C or D, unstable angina, 
or ejection fraction (EF) < 35%, or uncontrolled arrhythmia or resistant hypertension 
(Carey et al., 2018). Mild cardiomyopathy and left ventricular hypertrophy (LVH) are 
allowed  
11. Presence or history of any co-morbid condition or abnormal labs that, in the view of the 
Investigator, places the subject’s safety at risk; places the subject at high risk of poor 


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treatment compliance or not completing the study; or would significantly affect the 
interpretation of study results 
12. Poorly controlled diabetes, defined as the presence of any of the following:  
a. Hemoglobin A1C > 8% (Qaseem et al., 2018) 
b. History of diabetic nephropathy, neuropathy, or retinopathy 
c. History of diabetic ketoacidosis during the past year 
13. Poorly controlled hypothyroidism, based on the judgement of the Investigator or 
Ultragenyx, whichever is most conservative 
14. History of chronic coagulopathy, thrombophilia, or disorder of complement activation 
15. Use of concomitant medications that alter prothrombin time/international normalized 
ratio (PT/INR), including warfarin and direct oral anticoagulants (eg, rivaroxaban, 
apixaban, and edoxaban). Patients who receive medications that affect platelet function, 
such as aspirin or clopidogrel, are allowed unless they have comorbidities that in the 
judgment of the Investigator place them at undue risk to participate in the study. 
16. Current treatment with long-term immunosuppressive medications. This includes subjects 
with autoimmune conditions managed with immunosuppressive medications and solid 
organ transplant recipients. 
17. Active tuberculosis requiring treatment in the past 3 years 
18. Symptomatic COVID-19 infection 
19. History of active alcohol and/or drug abuse that in the Investigator’s assessment would 
impair the subject’s ability to comply with the protocol 
20. Receipt of only 1 of 2 planned doses of a COVID-19 vaccine. Subjects who have not 
received a COVID-19 vaccine, and those who have completed COVID-19 vaccination 
are eligible.  
21. Planned surgery, including dental surgeries, during the study 
22. Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time 
during the study 
23. Females of childbearing potential with hepatocellular adenoma who are unwilling to use 
nonhormonal contraception 
24. Use of any IP or investigational medical device within 30 days or for IP within 
5 half-lives, whichever is longer, prior to screening (or rescreening, as applicable), or 
requirement for any investigational agent prior to completion of all scheduled study 
assessments 
25. For subjects rescreening into OL-RD cohorts, any of the following after treatment with 
UX053 in a SAD cohort: 
a. New or worsening symptoms of liver disease (including new or worsening 
hepatomegaly) along with any increase in transaminase levels 
b. Receipt of any blood product administration (eg, packed red blood cells, platelet, 
FFP) for management of consumptive coagulopathy  


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c. An ALT level that is ≥ 8x ULN and > 2x the subject’s baseline value in the absence 
of an alternative explanation 
8.3. 
Subject Discontinuation and Stopping Rule Criteria 
8.3.1. 
Discontinuation of Intervention, Subject, or Study  
Subjects have the right to discontinue study drug or withdraw from the study at any time for 
any reason. Subjects will only be removed from the study due to withdrawal of consent. 
The Investigator and Ultragenyx also have the right to discontinue a subject’s treatment to 
protect subject’s safety (Section 8.3.2), but subjects will remain in the study for safety 
monitoring purposes, unless continued participation in the study poses a risk to the subject due to 
a concurrent medical condition or illness. Ultragenyx must be notified of all subject withdrawals 
as soon as possible. Ultragenyx also reserves the right to discontinue participation of an 
Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects who are discontinued from study drug treatment because of safety concerns are 
encouraged to remain in the study and to continue to complete study assessments to the extent 
possible. If a subject discontinues from the study prematurely, reasonable efforts should be made 
to perform the ET Visit procedures within 4 weeks of discontinuation. In the event a subject has 
an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, 
a safety follow-up phone call will occur within the 4 weeks following the subject’s last 
treatment. 
If a subject is withdrawn from treatment due to safety reasons or if a subject has an ongoing SAE 
at the end of participation, the subject should be followed until the event resolves, the subject’s 
condition has stabilized, or until a pre-defined outcome is reached. 
8.3.2. 
Subject-level Redosing and Stopping Criteria  
At any time after the first dose of study drug, if a marked increase in transaminases (ie, > 2x the 
subject’s baseline value and 3x ULN) is observed, liver enzymes, bilirubin, and INR should be 
obtained again within 48 to 72 hours. Study drug should not be re-administered unless the 
following criteria are met: 
• If a significant rise in ALT occurs after the prior dose, ALT should show a decreasing 
trend toward the subject’s baseline value 
• Total bilirubin is within normal limits  
• Platelets are within normal limits 
• INR is within normal limits 
Additionally, subjects who meet any of the following criteria will not be redosed:  
• Subjects who develop new or worsening symptoms of liver disease (including new or 
worsening hepatomegaly) along with any increase in transaminase levels 
• Subjects who require any blood product administration (eg, packed red blood cells, 
platelet, fresh frozen plasma) for management of consumptive coagulopathy  


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• Subjects who develop an ALT level that is ≥ 8x ULN and > 2x the subject’s baseline 
value in the absence of an alternative explanation 
If a subject develops an IRR that meets diagnostic criteria for anaphylaxis (Table 11), 
epinephrine should be administered as initial rescue medication. For all other hypersensitivity 
reactions ≥ Grade 2 in severity suspected to be due to immune activation,  dexamethasone should 
be the initial rescue medication. The Medical Monitor must be notified if any rescue medication 
is used.  
If dexamethasone (or equivalent) is used as a rescue medication, premedication with 
dexamethasone (or equivalent) should be considered for that subject’s subsequent infusions after 
discussion with the Medical Monitor.  
In the event of an IRR, action outlined in Table 10 should be implemented based on the level of 
severity. Ultragenyx will confer with the DMC whenever subject- or study-level stopping criteria 
are potentially met.  
Table 10: 
Action in the Event of an Infusion-Related Reaction 
IRR CTCAE Severity 
Action 
Grade 1 (Mild)  
The infusion may be slowed or interrupted temporarily and resumed at the 
original speed 
Grade 2 (Moderate) 
 
The infusion should be interrupted. The post-infusion complement and cytokine 
labs should be obtained within 1 hour of the start of the reaction. The subject 
should be closely monitored, and supportive care should be provided. 
Dexamethasone 10 mg IV (or equivalent) should be administered. Additional 
treatment, including a complement inhibitor (such as eculizumab) may be 
considered. The infusion may be restarted at half the rate after symptomatic 
treatment and resolution of the reaction. If the subject has IRR following 
resumption at the lower rate, stop the infusion. 
Grade ≥ 3 (Severe, Life-
threatening, Death) 
 
The infusion should immediately be terminated. The post-infusion complement 
and cytokine labs will be obtained within 1 hour of the start of the reaction. The 
subject should be closely monitored, and supportive care should be provided. 
Dexamethasone 10 mg IV (or equivalent) should be administered. Additional 
treatment, including a complement inhibitor (such as eculizumab) may be 
considered. The subject will not be redosed.  
CTCAE, Common Terminology Criteria for Adverse Events; IRR, infusion-related reaction; IV, intravenous.  
8.3.3. 
Study Stopping Criteria  
Study enrollment and any further administration of study drug for subjects already enrolled, will 
be paused and the DMC and regulatory authorities will be notified if, at any time during the 
study, any of the criteria listed below occur after UX053 administration:  
• Death of a subject 
• Any serious TEAE with a severity ≥ Grade 3 that is assessed as related to study drug 
or study procedures by the Investigator or Ultragenyx 
• Any TEAE with a severity ≥ Grade 3 affecting the cardiopulmonary, renal, or 
neurological systems, regardless of relationship to study drug, pending a DMC safety 
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• Anaphylaxis, as defined by the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID FAAN) criteria (Table 11), 
pending a DMC safety review 
• Increases in ALT or AST > 2x from Baseline and > 3x the ULN, accompanied by 
total bilirubin > 2x ULN or INR > 1.5, without findings of cholestasis (defined as 
serum ALP activity < 2x ULN) and in the absence of a plausible alternate explanation 
• Increases in serum concentrations of ALT or AST > 2x from Baseline and > 3x ULN 
with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia (> 5% of total leukocytes) 
• 3 subjects develop platelet counts < 50,000 per mm3 (or thrombocytopenia ≥ Grade 3 
in severity)  
• 3 subjects develop INR > 1.5 (or INR increase ≥ Grade 2 in severity) 
In addition to the above criteria, the DMC may at any time recommend dose reduction or 
discontinuation of dosing for an individual subject or for all subjects (Section 9.1.5). Regulatory 
authorities will be notified immediately if the study stopping criteria are met and study 
enrollment or dosing is halted.  
Table 11: 
Clinical Criteria for Diagnosing Anaphylaxis  
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. 
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes 
to several hours): 
a. 
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. 
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. 
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s 
baseline 
PEF, Peak expiratory flow; BP, blood pressure.  
a Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than 
(70 mm Hg 1 [2 3 age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. 
Source: (Sampson et al., 2006) 
8.3.4. 
Subject Replacement 
Subjects will be replaced at Ultragenyx’s discretion only if they have not received study drug. 
Subjects will not be replaced if they have received any study drug. 


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8.4. 
Informed Consent  
Informed consent must be obtained from the patient before performing any study-related 
procedures.  
In the event that a subject is rescreened (Section 8.5), a new informed consent form (ICF) must 
be signed.  
8.5. 
Screening Requirements 
All screening evaluations specified in Table 4, Table 5, and Table 6 must be completed and 
reviewed to confirm eligibility. The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
At the Screening Visit for SAD cohorts and ISV for DB-RD cohorts, informed consent will be 
obtained, and general medical information (ie, demographics, general medical history, and GSD 
III specific medical history), a complete physical exam, vital signs, anthropometrics, 
concomitant medications, and dietary information will be collected. Subjects will also be 
screened for hepatitis B and C. Several laboratory assessments, as outlined in Table 4, Table 5, 
and Table 6, will be collected during screening.  
Subjects in the SAD cohorts who complete the 90-day Follow-up Period can elect to enter 
OL-RD cohorts. These subjects will complete an abbreviated rescreening for participation in the 
OL-RD cohorts, occurring over the course of at least 3 weeks prior to redosing; eligibility for 
additional dosing in the OL-RD cohorts (ie, rescreening) can be combined with assessments at 
the SAD Day 90 Visit. Informed consent for participation in the OL-RD cohorts must be signed 
prior to rescreening. 
Rescreening for subjects who previously failed screening is permissible on a case-by-case basis. 
Each case should be discussed with the Medical Monitor. If a subject is rescreened for the 
DB-RD cohorts, the subject will still be required to complete up to 6 weeks of nutrition 
stabilization during screening. Subjects who undergo rescreening for DB-RD cohorts may not 
need to repeat the imaging assessments. 


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9. 
INTERVENTION(S) 
An overview of all interventions, including the IP, premedications, and rescue medications are provided in Table 12.  
Table 12: 
Study Investigational Product, Premedication, and Rescue Medication 
Interventiona 
 
UX053 
Placebo 
Paracetamol/ 
acetaminophen or 
ibuprofenb 
H1 blocker; 
cetirizine or 
equivalent 
H2 blocker; 
famotidine or 
equivalent 
Dexamethasone or 
equivalentc 
Dose 
Formulation 
Ampule 
Ampule 
Tablet 
Tablet 
Tablet 
Ampule  
Unit Dose 
Strength(s) / 
Dosage Level(s) 
0.05, 0.10, and 0.20, 
mg/kg single dose 
during in SAD 
cohorts and Q2W or 
Q4W in RD cohortsd  
- 
500 mg 
(paracetamol 
/acetaminophen); 
400-800 mg 
(ibuprofen) 
10 mg for cetirizine 
20 mg for 
famotidine 
10 mg for IV 
dexamethasone 
Route of 
Administration 
IV infusion 
IV infusion 
Oral 
Oral 
Oral 
IV infusion 
Use 
Experimental 
Placebo 
Premedicatione 
Premedicatione 
Premedicatione 
Rescue medication, 
or premedication for 
subsequent infusions 
if used as rescue 
medication 
previously 
a Regardless of assigned treatment (UX053 or placebo), all subjects in DB-RD cohorts will also be asked to maintain a diet based on expert recommendations for 
adults with GSD III throughout the study (Table 2). 
b Paracetamol/acetaminophen is preferred over ibuprofen.  
c Dexamethasone should be the first-in-line rescue medication; alternative or additional rescue medications are allowed, if necessary, at the discretion of the 
Investigator. The Medical Monitor must be notified if any rescue medication is used. 
d Additional cohort(s) at dose levels between 0.05 mg/kg to 0.30 mg/kg may also be included pending review of safety data. 
e Premedications will be administered to all subjects, including subjects receiving placebo. At the discretion of the Investigator, with input from Ultragenyx and 
the DMC, and based on the emerging safety profile of UX053, additional premedications and rescue medications may be used to reduce the risk and severity 
of immune reactions in RD cohorts. Premedication and rescue medication selection will be based on the nature of the reactions being observed and the risks 
of such medications in patients with GSD III. 
DB, double-blind; DMC, Data Monitoring Committee; GSD, Glycogen Storage Disease; IV, intravenous; Q2W, every 2 weeks; Q4W, every 4 weeks; RD, 
Repeat Dose; SAD, Single Ascending Dose. 


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9.1. 
UX053 
UX053 consists of an mRNA encoding full-length, human GDE encapsulated in an LNP. 
 
Both UX053 and placebo will be diluted prior administration such that the 
concentration of components, including sucrose, is identical. The final concentration (for both 
UX053 and placebo) will be 
 
 Additional information on physical and chemical properties of UX053 are provided in 
the IB.  
UX053 is supplied in a frozen sterile solution in a vial. UX053 should be stored in a freezer, set 
to maintain 
° C, protected from light. UX053 is manufactured, packaged and labelled 
according to current Good Manufacturing Practices (GMP).  
9.1.1. 
Premedications  
The study site will supply premedications that will be obtained locally. Subjects will receive 
premedication at least 1 hour prior to the infusion, consisting of oral paracetamol/acetaminophen 
(500 mg) or ibuprofen (400 to 800 mg), an H2 blocker (eg, famotidine 20 mg or equivalent dose 
of another H2 blocker), and an H1 blocker (eg, cetirizine 10 mg or equivalent dose of another H1 
blocker). For the premedication, paracetamol/acetaminophen is preferred over ibuprofen. At the 
discretion of the Investigator, with input from Ultragenyx and the DMC, and based on the 
emerging safety profile of UX053, additional premedications and rescue medications may be 
used to reduce the risk and severity of immune reactions in RD cohorts. Premedication and 
rescue medication selection will be based on the nature of the reactions being observed and the 
risks of such medications in patients with GSD III. If a subject develops an IRR that meets 
diagnostic criteria for anaphylaxis (Section 8.3.3), should be administered as initial rescue 
medication. For all other hypersensitivity reactions *UDGHLQVHYHULW\VXVSHFWHGWREHGXHWR
immune activation, dexamethasone should be the initial rescue medication (Section 9.5). 
The Medical Monitor must be notified if any rescue medication is used. If dexamethasone 
(or equivalent) is used as a rescue medication, premedication with dexamethasone (or 
equivalent) should be considered for that subject’s subsequent infusions after discussion with the 
Medical Monitor. Section 8.3.2 provides subject-level redosing criteria, stopping criteria, and 
additional instructions on how to proceed in the event of an IRR. 
9.1.2. 
Preparation and Administration 
For detailed preparation and administration information, refer to the Pharmacy Manual. Prior to 
each infusion, the amount of study drug will be determined based on subject weight (in kg). 
The volume of study drug calculated to deliver the correct dose will be withdrawn from the vial. 
Study drug will be diluted and transferred to an infusion bag as a final dose. Undiluted UX053 
must never be infused. 
Study drug is administered as an IV infusion over the course of at least 4 hours, with a slower 
rate of infusion for the first hour to minimize the risk of hypersensitivity or anaphylactoid-type 
reactions. The infusion rate schedule may be slowed to minimize the risk of IRRs in individual 
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subjects. Study drug is administered once in the SAD cohorts and either Q2W or Q4W in the RD 
cohorts. 
9.1.3. 
Clinical Observation and Supportive Care 
Subjects will stay overnight onsite on for all dosing visits for safety and PK assessments. If a 
subject develops an IRR that meets diagnostic criteria for anaphylaxis (Section 8.3.3), 
epinephrine should be administered as initial rescue medication. For all other hypersensitivity 
reactions ≥ Grade 2 in severity suspected to be due to immune activation, dexamethasone should 
be the initial rescue medication; alternative or additional rescue medications are allowed, if 
necessary, at the discretion of the Investigator. The Medical Monitor must be notified if any 
rescue medication is used. If dexamethasone (or equivalent) is used as a rescue medication, 
premedication with dexamethasone (or equivalent) should be considered for that subject’s 
subsequent infusions after discussion with the Medical Monitor. Section 8.3.2 provides 
subject-level redosing criteria, stopping criteria, and additional instructions on how to proceed in 
the event of an IRR. Table 7 and Table 8 show the schedule for vital signs and PK assessments, 
respectively, occurring before, during, and after study drug infusion.  
9.1.4. 
Guidance on Communication and Seeking Immediate Medical Attention 
Subjects should inform their primary care provider of their participation in the UX053-CL101 
clinical trial. Communication between the subject’s primary care provider and study 
Investigators is strongly encouraged, and study Investigators should share visit summaries and 
hospital discharge summaries with the subject’s primary care provider. Subjects should contact 
their primary care provider for routine care outside the management of GSD III.  
At any time during the study, subjects should contact the Investigator if they notice any changes 
in their health or any other symptoms that cause the subject distress. Based on the clinical 
assessment and judgement of the study Investigator, the subject may be referred to their primary 
care physician, to seek treatment in an emergency room, or to contact local emergency services. 
At any time during the study, subjects should seek immediate medical attention and notify the 
Investigator if they develop any of the following signs or symptoms: 
• Signs of a severe hypersensitivity reaction, such as generalized urticaria, angioedema, 
respiratory distress, or anaphylaxis 
• Jaundice 
• Unusual bleeding or bruising 
• Altered mental status, seizure, syncope, dizziness, or presyncope 
• Severe chest or abdominal pain 
• Blood sugar below 54 mg/dL (3 mmol/L) accompanied by symptoms of 
neuroglycopenia (dizziness, weakness, drowsiness, confusion, or altered mental 
status) 


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9.1.5. 
Dose Modification  
If a subject develops a TEAE/serious TEAE *UDGHWKDWLVFRQVLGHUHGE\WKH,QYHVWLJDWRUWR
be related to study drug or an intolerable TEAE in the RD cohorts, subject-level dose reductions 
are allowed in consultation with the Medical Monitor, as outlined in the guidance provided in the 
Pharmacy Manual. At any time, the DMC may recommend discontinuation of dosing for an 
individual subject or for all subjects. At any time, Ultragenyx may modify or discontinue dosing 
for an individual subject or for all subjects.  
Dose levels for each cohort, in either the SAD or RD cohorts, may be reduced and/or higher dose 
cohorts may not be initiated, depending on safety and PD findings from prior cohorts, as 
determined by Ultragenyx (with input from the DMC for the RD cohorts). 
9.1.6. 
Coronavirus Disease 2019 (COVID-19) Vaccination  
Both UX053 and the mRNA-LNP vaccines for SARS-CoV-2 contain some of the same 
excipients, which are the LNP structural lipid components, namely 
 Currently available mRNA-LNP COVID-19 vaccines 
also contain either the same 
 or a similar 
 as UX053. 
Patients who have experienced a severe hypersensitivity reaction in response to an mRNA-LNP 
vaccine are excluded from this study due to potential cross-reactivity of antibodies to UX053, 
such as 
 antibodies (Section 8.2).  
While COVID-19 vaccination is allowed during study participation, COVID-19 vaccines should 
not be administered within 48 hours after the most recent administration of UX053 and until 
safety labs obtained have been reviewed and the subject has been assessed for any possible 
hypersensitivity reaction to the most recent dose of UX053. The timing of COVID-19 
vaccination doses will be captured in the case report form (CRF), as these would inform the 
interpretation of AEs. 
If a subject has an immediate or severe hypersensitivity reaction to UX053, consultation with an 
allergist/immunologist is recommended prior to administration of an COVID-19 vaccine due to 
potential antibody cross-reactivity 
 (Banerji et al., 2020). It is not known 
whether treatment with UX053 increases the likelihood of developing a severe hypersensitivity 
reaction to an mRNA-LNP vaccine. For additional information on potential interventions in the 
event of toxicity, please refer to the IB.  
9.2. 
Reference Therapy 
A placebo consisting of the UX053 formulation buffer (without UX053) will be supplied as a 
sterile solution in a vial. Placebo should be stored in a refrigerator, set to 2 to 8° C, protected 
from light. The placebo consists of the same components as the formulation buffer for UX053. 
Placebo is manufactured, packaged and labelled according to current GMPs. Both placebo and 
UX053 will be diluted prior to administration such that the concentration of components, 
including sucrose, is identical. The final concentration (for both placebo and UX053) will be 
 
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9.2.1. 
Preparation and Administration 
Preparation, administration, observation, and supportive care procedures for placebo are similar 
to those described for UX053 (Section 9.1.2). For detailed preparation and administration 
information, refer to the Pharmacy Manual.  
9.3. 
Nutrition Management  
Subjects in the OL-RD cohorts will be assessed to determine if their diet meets nutritional 
guidelines based on expert recommendations for adults with GSD III (Table 2). Once optimized, 
subjects in the OL-RD cohort are required to demonstrate nutrition stability for 2 weeks prior to 
their Baseline/Week 0 Visit (Section 7.1). Subjects are instructed not to make any substantial 
changes to their diet throughout the remainder of the study. If an OL-RD subject is unable to 
achieve an optimized diet, they are still eligible to proceed to the OL-RD Baseline/Week 0 Visit. 
The reason for the inability to achieve an optimized diet should be documented and the subject 
must agree not to make any substantial changes to their diet throughout the remainder of the 
study.  
Regardless of assigned treatment (UX053 or Placebo), subjects in the DB-RD cohorts will be 
assessed to determine if the subject’s diet meets nutritional guidelines based on expert 
recommendations for adults with GSD III (Table 2). Once the diet is optimized, subjects are 
required to demonstrate maintenance of this diet for at least 6 weeks prior to their DB-RD 
Baseline Visit/Week 0 Visit (Section 7.1). Subjects should not make any substantial changes to 
their diet throughout the remainder of the study.  
Nutrition guidance and monitoring for this study was established with available health authority 
guidance, and greater detail is available in the Study Reference Manual. 
9.4. 
Prior and Concomitant Therapy 
Subjects may receive concomitant medications as required, with the exception of those identified 
in Section 9.6 as prohibited.  
The study site should indicate to laboratories if the subject is using any high dose biotin 
supplements (found in multivitamins, biotin supplements, and some supplements to promote 
hair, skin, and nail growth) to potential risk of assay interference (eg, troponin) (Section 10.1.5) 
(FDA, 2019a). 
9.5. 
Rescue Medications 
The study site will supply rescue medication that will be obtained locally. Dexamethasone (or 
equivalent) may be used as a rescue medication for hypersensitivity reactions (which may 
include IRRs) as determined by the Investigator. Alternative or additional rescue medications are 
allowed, if necessary, at the discretion of the Investigator. Premedication and rescue medication 
selection will be based on the nature of the reactions being observed and the risks of such 
medications in patients with GSD III.  
• Dexamethasone should generally be the initial rescue medication for infusion-related 
reactions. However, if diagnostic criteria for anaphylaxis are met (Table 11), epinephrine 
should be provided immediately. 


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• In the event of severe consumptive coagulopathy, treatment with blood products such as 
fresh frozen plasma (FFP)/cryoprecipitate and/or platelets may be considered.  
• If profound complement activation is suspected, a complement inhibitor such as 
eculizumab may be considered. 
For additional guidance, please refer to the Investigator Brochure. 
The Medical Monitor must be notified if any rescue medication is used. If dexamethasone (or 
equivalent) is used as a rescue medication, premedication with dexamethasone (or equivalent) 
should be considered for that subject’s subsequent infusions after discussion with the Medical 
Monitor. 
The use of rescue medications is allowable at any time during the study. 
Section 8.3.2 provides subject-level redosing criteria, stopping criteria, and additional 
instructions on how to proceed in the event of an IRR. 
9.6. 
Restricted or Prohibited Medications, Devices, and Procedures 
The following are specifically prohibited during study participation, as noted in the exclusion 
criteria (Section 8.2):  
• Use of any IP or investigational medical device within 30 days or for IP within 
5 half-lives, whichever is longer, prior to screening (or rescreening, as applicable), or 
requirement for any investigational agent prior to completion of all scheduled study 
assessments 
• Planned surgery, including dental surgeries, during the study 
If a subject is on a drug that is metabolized primarily by cytochrome P450 2B6 (CYP2B6), 
caution is advised as UX053 may result in decreased CYP2B6 activity and altered exposure of 
the drug. Additional details regarding this potential interaction and nonclinical studies with 
UX053 are available in the IB. 
9.7. 
Treatment Compliance 
Study drug will be administered at the study site via a single IV infusion by qualified personnel. 
The dose, start time, stop time, and volume of infusion will be recorded in the subject’s CRF. 
Nutrition management and compliance in the RD cohorts will be monitored by reviewing 
subjects’ nutrition diary data at time points specified in Table 5 and Table 6 and comparing this 
information with nutrition guidelines for adults with GSD III (Table 2). Nutrition guidance and 
monitoring for this study was established with available health authority guidance, and greater 
detail is available in the Study Reference Manual. 


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9.8. 
Treatment Assignment and Blinding 
9.8.1. 
Treatment Assignment 
In the SAD and OL-RD cohorts, all subjects receive open-label UX053. Subjects in the DB-RD 
cohorts are randomized 3:1 to UX053 and Placebo, using an interactive response technology 
(IRT) system. Subjects in the OL-RD cohorts receive open-label UX053.  
Each subject will be assigned a unique identification number.  
9.8.2. 
Blinding 
Blind conditions will be established so that Ultragenyx, the subject, and site personnel will not 
know the identity of a subject’s treatment in the DB-RD cohorts. Randomization using an IRT 
system will ensure subjects in the DB-RD cohorts are blind to treatment. Due to the difference in 
opacities of the UX053 and the placebo, an unblinded pharmacist will prepare the study drug and 
an unblinded nurse will prepare the infusion before masking the infusion syringe and tubing with 
colored covers. Prespecified employees from Ultragenyx who do not have any contact with the 
investigative sites may also be unblinded as specified in the Blinding Plan.  
All imaging assessments will be sent to central readers for evaluation. Readers will be blinded to 
the subject’s treatment.  
Treatment assignment for an individual subject should be unblinded by the Investigator only in 
an emergency, and only if when knowledge of the treatment assignment is urgently needed for 
the clinical management or welfare of the subject. Unblinding at the study site for any other 
reason will be considered a protocol deviation.  
The Investigator is strongly encouraged to contact Ultragenyx before unblinding any subject’s 
treatment assignment, but priority should be given to the safety of the subject. 


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10. 
ASSESSMENTS 
Assessments and associated timing are provided in Table 4, Table 5, and Table 6 for SAD , 
OL-RD, and DB-RD cohorts, respectively. Protocol waivers or exemptions are not allowed. 
10.1. 
Safety Assessments 
Safety will be evaluated by the incidence and severity of TEAEs and by changes from study 
baseline to scheduled time points in vital signs, weight, physical examination, clinical laboratory 
evaluations, and ECGs. In addition, safety will be evaluated by the development of ADA to 
 and GDE, concomitant medications, and monitoring pregnancies (or pregnancy 
of partner, if occurs or applicable). ADA will be assessed before the first dose of study drug and 
throughout the study.  
Safety definitions and instructions for assessing severity and causality are presented in 
Appendix 1.  
Refer to Appendix 2 for instructions regarding AE collection, including collection period 
timeframes and timelines for AEs, SAEs, pregnancies, other safety information, and any urgent 
safety measures taken to protect the safety or welfare of subjects. 
10.1.1. 
Coronavirus Disease 2019 (COVID-19) Testing 
COVID-19 testing by real time – polymerase chain reaction (RT-PCR) will be performed at time 
points specified in Table 4 and Table 6. 
10.1.2. 
Vital Signs 
Vital signs to be measured include seated systolic blood pressure and diastolic blood pressure, 
heart rate, respiration rate, temperature, and oxygen saturation. Vital signs are assessed at study 
visits specified provided in Table 4, Table 5, and Table 6. The schedule of vital sign assessments 
during dosing visits is provided in Table 7. Any new, clinically significant vital sign 
abnormalities should be captured as AEs. 
10.1.3. 
Electrocardiogram  
Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the 
heart rate and measures RR, PR, QRS, QT, and QTc intervals. ECGs are performed at time 
points specified in Table 4, Table 5, and Table 6. While conduction intervals provided by the 
ECG machine may be used, final interpretation of ECGs, including any rhythm abnormalities, 
must be performed by a qualified local physician. Any new, clinically significant findings 
identified by ECG interpretation should be captured as AEs. 
10.1.4. 
Physical Examinations 
Complete and targeted physical exams are performed at time points specified in Table 4, Table 5, 
and Table 6. For visits in which subjects are receiving study drug, physical exams should occur 
prior to dosing.  
A complete physical examination will include, at a minimum, assessments of the dermatologic; 
head, eyes, ears, nose, and throat (HEENT); respiratory; cardiovascular; gastrointestinal; 
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endocrine and metabolic; blood and lymphatic; musculoskeletal, psychiatric, and neurologic 
(including mental status, cranial nerves, motor system, reflexes, coordination and gait, and 
sensory system) systems.  
A targeted physical examination will include, at a minimum, assessments of the respiratory, 
cardiovascular, and gastrointestinal systems. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Any new, clinically significant findings from physical examinations should be captured as AEs. 
10.1.5. 
Safety Laboratory Tests 
Blood and urine samples will be collected for safety laboratory tests as specified in Table 4, 
Table 5, and Table 6. Fasting is not required. For visits in which subjects are receiving study 
drug, laboratory samples will be collected prior to dosing. All efforts should be made for urine 
collections to be from the first morning void. Samples will be processed by a central lab to 
ensure consistency across study sites. 
In addition to chemistry, hematology, and urinalysis, additional assessments to monitor safety 
include activation of the complement pathway, coagulation factors, and interleukin-6. As noted 
in Table 4, Table 5, and Table 6, samples for complement pathway, coagulation factors, and 
interleukin-6 are collected pre- and post-infusion. Post-infusion blood samples should be 
collected in the opposite arm of the infusion to avoid laboratory artefacts. The full list of safety 
laboratory evaluations to be performed in this study are listed in Appendix 3. All laboratory 
samples listed in Appendix 3 will be processed by a central laboratory, except urine pregnancy. 
The study site should indicate to laboratories if the subject is taking high dose biotin supplements 
(found in multivitamins, biotin supplements, and some supplements to promote hair, skin, and 
nail growth) to potential risk of assay interference (eg, troponin) (FDA, 2019a). 
The Investigator (and/or Medical Monitor) may at his/her discretion perform additional 
laboratory tests for subject safety if a subject experiences an SAE or other AE that may warrant 
further follow up.  
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enzymes and INR within 48 hours and consideration of additional diagnostic tests such as liver 
ultrasound.  
10.1.6. 
Anti-drug Antibodies 
Blood will be collected to measure serum 
 antibody level and anti-GDE 
antibody level using validated electrochemiluminescent methods at time points specified in 
Table 4, Table 5, and Table 6. For visits in which subjects are receiving study drug, blood will be 
collected prior to dosing.  
10.1.7. 
Pregnancy Testing  
Female subjects of childbearing potential will have urine pregnancy tests at visits indicated in 
Table 4, Table 5, and Table 6. For visits in which subjects are receiving study drug, results of 
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urine pregnancy testing should be reviewed prior to dosing. Females not of childbearing potential 
are not required to undergo pregnancy testing. Refer to Appendix 4 for contraception guidance.  
Female subjects with a positive pregnancy test at the Screening Visit (ISV for DB-RD) will not 
be enrolled in the study.  
Additional pregnancy tests will be performed at any visit in which pregnancy is in question. 
A serum pregnancy test will be performed in the event of a positive or equivocal urine pregnancy 
test result or can be performed if pregnancy test by urine is not feasible. 
Refer to Appendix 2 for pregnancy reporting requirements.  
10.1.8. 
Concomitant Medications 
Medications (investigational, prescription, over the counter, vaccines, and herbal supplements) 
and nutrition supplements taken during screening will be reviewed and recorded at all screening 
visits (ISV through STV). Use of any concomitant medications during the study should be 
recorded on the CRF. All concomitant medications will be coded according to the World Health 
Organization (WHO) Drug Dictionary. 
Site personnel should record date the medication was taken, the name of the medication, 
medication dosage, formulation, route of administration and the reason the medication was 
taken. 
10.2. 
Pharmacokinetic Assessments  
Serial blood and plasma samples will be collected to analyze for the concentrations of AGL 
mRNA and ATX95 at visits specified in Table 4, Table 5, and Table 6. AGL mRNA will be 
analyzed using a 
. ATX95 will 
be analyzed using a 
 
The schedule for PK assessments during dosing visits is provided in 
Table 8.  
Pharmacokinetic parameters will be derived by non-compartmental analysis. PK parameters to 
be estimated may include, but not limited to, the following: time of maximum observed 
concentration (Tmax), maximum concentration (Cmax), area under the concentration-time curve 
from time 0 to the last measurable concentration (AUClast), AUC from time 0 to infinity 
(AUCinf), AUC from time 0 to end of dosing period (AUCtau), accumulation ratio (calculated as 
AUC after repeat dose / AUC after a single dose; RAUC), time of last measurable concentration 
(Tlast), half-life (T1/2), clearance (CL), and volume of distribution at steady state (Vss). 
Residual PK samples may be used for exploratory analysis to identify metabolites. 
10.3. 
General Assessments 
10.3.1. 
General Medical History and GSD III-specific Medical History 
General medical history and GSD III-specific medical history will be collected during screening 
for the SAD and DB-RD cohorts (Table 4 and Table 6). General medical information includes 
subject demographics and a history of major medical illnesses, diagnoses, and surgeries. The 
GSD III-specific medical history will collect information on GSD III diagnostic history; current 
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and past disease management; GSD III-specific symptoms, conditions, and progression; and 
resource utilization, including physical/occupational therapy. 
10.3.2. 
Demographics 
Demographic information will be collected during screening for the SAD and DB-RD cohorts 
(Table 4 and Table 6). 
10.3.3. 
Anthropometric Assessments  
Height will be measured during screening for the SAD and DB-RD cohorts (Table 4 and 
Table 6). Weight will be assessed for all cohorts at time points specified in Table 4, Table 5, and 
Table 6. For visits in which subjects are receiving study drug, weight will be measured prior to 
dosing and used to calculate dose (Section 9.1.2). Additional details regarding anthropometric 
assessments are available in the Study Reference Manual.  
10.4. 
Efficacy Assessments 
10.4.1. 
Liver Assessments 
10.4.1.1. Liver Magnetic Resonance Imaging  
The volume of the liver will be determined using MRI and compared with normal values for age 
and sex. The liver MRI will also be analyzed to determine hepatic fat fraction. MRIs will be 
conducted at the study site; however, all results will be transmitted to a central radiologist for 
interpretation to ensure consistent assessment across study sites. Additional details regarding 
imaging sequences to be performed and instructions for transmitting MRI results are provided in 
the Imaging Manual. 
Liver MRI will be performed at time points specified in Table 4, Table 5, and Table 6.  
If feasible, glycogen nuclear overhauser enhancement (glycoNOE) imaging (Zhou et al., 2020) 
of the liver, may be collected at the time of the liver MRI. 
10.4.1.2. Liver Magnetic Resonance Spectroscopy  
When locally available, MRS will be used to quantitate glycogen in the liver. Scanning for liver 
MRS can be conducted immediately following the liver MRI, as both the MRI and MRS are 
conducted in an MRI machine. MRS will be conducted at the study site; however, all results will 
be transmitted to a central radiologist for interpretation and to ensure consistent assessments 
across study sites. Additional details regarding imaging sequences to be performed and 
instructions for transmitting MRS results are provided in the Imaging Manual. 
Liver MRS will be performed at time points specified in Table 4, Table 5, and Table 6.  
10.4.1.3. FibroScan or Liver Ultrasound Elastography 
Transient elastography or the FibroScan System (Echosen; Paris, France) is a non-invasive, 
ultrasound-based technique to assess stiffness of soft tissue or, in the case of the liver, fibrosis 
and cirrhosis (Patel and Wilder, 2014; Castera et al., 2008). The technique allows for the 
measurement of velocity (m/s) of an elastic shear wave to provide a liver stiffness measurement 


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expressed in kilopascals (kPa), which correlates with fibrosis stage. Steatosis is measured using a 
controlled attenuation parameter score. In the event that FibroScan equipment is not available, 
liver ultrasound elastography will be performed.  
FibroScan or liver ultrasound elastography will be performed at time points specified in Table 4, 
Table 5, and Table 6. FibroScan or liver ultrasound elastography will be conducted at the study 
site, and results will be sent to a central reader to ensure consistent assessments across study 
sites. 
10.4.1.4. Prothrombin Time/International Normalized Ratio  
Blood will be collected for the measurement of prothrombin time (PT) and to calculate PT/INR 
to aid in the assessment of liver health at time points specified in Table 4, Table 5, and Table 6. 
For visits in which subjects are receiving study drug, laboratory samples will be collected prior 
to dosing. Samples will be processed by a central lab to ensure consistency across study sites. 
10.4.1.5. High Density Lipoprotein and Low Density Lipoprotein  
Blood with be collected to measure serum high density lipoprotein (HDL) and low density 
lipoprotein (LDL) to aid in the assessment of liver health at time points specified in Table 4, 
Table 5, and Table 6. A 3- to 4-hour fasting period is preferred, but not required, prior to blood 
collection for serum HDL and LDL. All efforts should be made to obtain samples for HDL and 
LDL consistently for a given subject. For visits in which subjects are receiving study drug, 
laboratory samples will be collected prior to dosing. Samples will be processed by a central lab 
to ensure consistency across study sites. 
10.4.2. 
Cardiac Assessments 
Details regarding ECG are provided in Section 10.1.3. 
10.4.2.1. Creatinine Kinase – Muscle Brain, B-Type Natriuretic Peptide, and Troponin I 
Blood will be collected to measure serum creatinine kinase – muscle brain (CK-M/B), B-type 
natriuretic peptide (BNP), and Troponin I to aid in the assessment of cardiac health at time points 
specified in Table 4, Table 5, and Table 6. For visits in which subjects are receiving study drug, 
laboratory samples will be collected prior to dosing. Samples will be processed by a central lab 
to ensure consistency across study sites. 
The study site should indicate to laboratories if the subject is taking high dose biotin supplements 
(found in multivitamins, biotin supplements, and some supplements to promote hair, skin, and 
nail growth) to potential risk of assay interference (eg, troponin) (FDA, 2019a). 
10.4.3. 
Skeletal Muscle, Strength, and Physical Functioning Assessments  
10.4.3.1. Creatinine Kinase  
Blood with be collected to measure serum creatinine kinase (CK) to aid in the assessment of 
muscle health at time points specified in Table 4, Table 5, and Table 6. For visits in which 
subjects are receiving study drug, laboratory samples will be collected prior to dosing. Samples 
will be processed by a central lab to ensure consistency across study sites. 


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10.4.3.2.  Handheld Dynamometry  
HHD will be used to assess muscle strength of the following muscle groups: key pinch, grip, 
elbow flexors, elbow extensors, hip adductors, hip abductors, knee flexors, and knee extensors. 
As functional ability/disability can vary from patient to patient, the subject only has to complete 
assessments for the muscle groups for which the clinician administering dynamometry considers 
safe.  
Ultragenyx will conduct formal training with the clinicians administering dynamometry (licensed 
physical therapist, unless approved by Ultragenyx) to standardize technique and minimize 
variability. Training must be completed successfully prior to testing any subject for the study. 
The maximum voluntary isometric contraction against a dynamometer will be used to measure 
muscle strength. Specialized dynamometers for the measurement of limb, grip, and key pinch 
strength will be used. 
All measurements will be taken bilaterally. The total force (in kg) will be recorded at the time of 
test administration. The percent predicted values will be calculated after the testing using 
published normative data (Peters et al., 2011; Bohannon, 1997; NIMS, 1996). 
HHD will be performed at specified time points in Table 4, Table 5, and Table 6. HHD should be 
conducted within a week prior to dosing visits. Additional details regarding HHD are available in 
the Clinical Evaluator Manual. 
10.4.4. 
Clinician- and Patient-reported Outcomes  
10.4.4.1. Patient-Reported Outcomes Measurement Information System 
The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed by 
the National Institutes of Health and uses domain-specific measures to assess patient well-being 
(NIH, 2015; Broderick et al., 2013). The domain-specific approach is based on the idea that 
health attributes, such as pain and physical function are not unique to a specific disease. 
PROMIS Fatigue, Pain Interference, Physical Function, and Global Heath scales will be 
administered.  
The PROMIS questionnaires will be completed at time points specified in Table 4, Table 5, and 
Table 6. The PROMIS questionnaires should be completed within a week prior to dosing visits. 
Additional details regarding the PROMIS questionnaires are available in the Clinical Evaluator 
Manual. 
10.4.4.2. 36-item Short-Form Health Survey 
The 36-item Short-Form Health Survey version 2 (SF-36v2) health survey captures practical, 
reliable, and valid information about functional health and well-being from the subject’s 
perspective. The SF-36v2 is a 36-item, self-reported questionnaire designed to assess 
health-related quality of life in healthy and ill individuals. Specifically, the SF-36v2 assesses 
physical and mental health based on 8 scaled scores that are the weighted sums of the questions 
in their section: vitality, physical functioning, bodily pain, general health perceptions, physical 
role functioning, emotional role functioning, social role functioning, and mental health. Each 
scale is directly transformed into a 0 to 100 scale on the assumption that each question carries 


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equal weight. Lower scores indicate more disability, and higher scores indicate less disability, ie, 
a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no 
disability. 
The SF-36v2 will be completed at time points specified in Table 4, Table 5, and Table 6. The 
SF-36v2 should be completed within a week prior to dosing visits. Additional details regarding 
the SF-36v2 are available in the Clinical Evaluator Manual. 
10.4.4.3. GNE Myopathy Functional Activities Scale Expanded Version 
The GNE Myopathy Functional Activities Scale (GNEM-FAS; also referred to as HIBM-FAS in 
some studies) was designed to assess the functional impact of changes in muscle strength in 
GNE myopathy and similar diseases (Mayhew et al., 2017; Skrinar et al., 2013). The scale 
consists of 3 domains: mobility, upper extremity, and self-care; scores for each domain and a 
total score will be obtained. 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 original GNEM-FAS was developed for ambulatory patients with GNE 
myopathy but has since been modified to include additional items to accommodate weaker 
patients. This modified version is referred to as the GNEM-FAS expanded version and will be 
used in this study. The scale will be administered by a clinician trained by Ultragenyx (licensed 
physical therapist, unless approved by Ultragenyx). Training must be completed successfully 
prior to assessing any subject for the study. The clinicians’ role is a combination of observing 
subjects conducting activities and asking subjects questions to assess performance of these 
activities.  
The GNEM-FAS expanded version will be assessed at time points specified in Table 4, Table 5, 
and Table 6. The GNEM-FAS expanded version should be completed within a week prior to 
dosing visits. Additional details regarding the GNEM-FAS expanded version are available in the 
Clinical Evaluator Manual. 
10.4.4.4. Nutrition Diary 
Subjects will be asked to maintain a record of daily diet using a diary at time points specified in 
Table 4, Table 5, and Table 6. For all cohorts, the nutrition diary recordings should be recorded 
at least 3 consecutive days per week through screening or rescreening, as applicable, and for the 
3 consecutive days in the week leading up to each subsequent visit. Qualified Investigator site 
staff should review nutrition diary data at each visit. Additional details regarding the nutrition 
diary are available in the Study Reference Manual. 
10.5. 
Pharmacodynamic and Biomarker Assessments 
10.5.1. 
Controlled Fasting Challenge  
In RD cohorts, the subject’s ability to maintain symptom-free euglycemia during an optional 
CFC at select sites for select subjects will be assessed at the STV and Week 16 (OL-RD Cohorts) 
or Week 10 (DB-RD Cohorts) Visits; only subjects who completed the optional CFC at STV 
complete the CFC at Week 16 or 10. The CFC can be conducted at the hospital during the day or 
an overnight stay, but the time of day should be consistent within subjects between the STV and 
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before might be needed. With either a daytime or overnight CFC, it is critical that appropriate 
personnel are present to monitor the subject during the CFC and to provide rescue treatment if 
needed. Special attention should be provided during nursing shift changes. 
Before the CFC is conducted, morning cortisol is collected between 6 and 9 am and analyzed by 
the central lab. This collection can occur on the morning of the CFC or, for the STV CFC, 
anytime between the ISV and STV. For subjects with suspected hypothalamic-pituitary axis 
(HPA) dysfunction (eg, those with a history of prolonged steroid treatment), morning cortisol 
should be reviewed by the Investigator and discussed with the Medical Monitor before deciding 
if it is safe to conduct the CFC. In this scenario, the morning cortisol sample should be collected 
at least a week prior to the CFC, providing sufficient time to review the lab results.  
Before the CFC begins, a venous catheter is placed for serial blood sampling and to allow for 
provision of a rescue glucose infusion if needed. A venous blood sample for measurement of 
glucose, cortisol, glucagon, insulin, C-peptide, and β-hydroxybutyrate will be collected at the 
beginning (ie, immediately after the provided meal or cornstarch, as applicable, described 
below), at end of the CFC, and 30 minutes after the end of the CFC. These samples will be sent 
to a central lab, except glucose which will be analyzed by the local lab.  
During the CFC, venous blood samples for STAT analysis of glucose will be collected through 
an indwelling catheter every 60 minutes (± 5 minutes) until the venous glucose level decreases to 
≤ 70 mg/dL (≤ 3.9 mmol/L). Thereafter, venous blood glucose is measured approximately every 
30 minutes (± 5 minutes) until the end of the CFC. Venous blood glucose taken during the CFC 
will be analyzed locally and available within 30 minutes to ensure subject safety. Capillary 
glucose and ketone measurements using an HHG and ketone meter will also be performed during 
the CFC at the same time as venous blood glucose or more frequently as needed.  
The CFC will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 mmol/L), 
when the subject experiences signs and symptoms of hypoglycemia, or the fast reaches 
12 (daytime) or 15 (overnight) hours without hypoglycemia, whichever occurs first. During the 
CFC, subjects may drink water, but cannot ingest any other food or drink. The start and end 
times of the CFC will be recorded in EDC. 
Data from the HHG will be uploaded via the study provided laptop. Data from venous blood 
glucose and capillary ketones taken during the CFC will be entered into the EDC. Subjects 
should continue to wear their CGM device throughout the fasting challenge. Readings from the 
CGM device during the CFC may alert the site to a potentially low glucose value that would 
require confirmation by capillary and venous blood glucose. 
At the end of the CFC, the subject’s hypoglycemia should be treated per the institution’s 
standard procedure, which may include providing the subject with a meal, cornstarch, or 
IV glucose, if medically indicated.  
Daytime CFC 
If the CFC is conducted during the day, the study site will provide breakfast for the subject. 
The breakfast meal will be personalized for each subject and will include a target carbohydrate 
range that should be as close as possible to the subject’s usual breakfast meal based on their 
current nutrition prescription; for the Week 16 (OL-RD Cohorts) or 10 (DB-RD Cohorts) CFC, 
the breakfast meal will be identical to the breakfast consumed for the STV CFC. Subjects will be 


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instructed to consume the entire breakfast meal and minimize activity after they finish eating 
breakfast until the end of the CFC. Breakfast meal stop time and its full nutrient composition will 
be recorded by the subject in the nutrition diary with the assistance of the study dietitian as 
needed. If a subject is taking a morning dose of cornstarch or protein supplement with breakfast, 
they will be given their usual morning dose at the usual time but no more than 4 hours after 
breakfast. The amount of cornstarch and protein to administer at the Week 16 or 10 CFC should 
be the same as what the subject received at their STV CFC. The time and amount will also be 
recorded by the subject in the nutrition diary with the assistance of the study dietitian as needed. 
The CFC starts when the subject finishes breakfast and the associated cornstarch and/or protein 
dose, as applicable. 
Overnight CFC 
If the CFC is conducted overnight, the study site will provide dinner for the subject. The dinner 
meal will be personalized for each subject and will include a target carbohydrate range that 
should be as close as possible to the subject’s usual dinner meal based on current nutrition 
prescription. for the Week 16 (OL-RD Cohorts) or 10 (DB-RD Cohorts) CFC, the dinner meal 
will be identical to that of the STV CFC. Subjects will be instructed to consume the entire dinner 
meal and minimize activity after they finish eating dinner until the end of the CFC. Dinner meal 
stop time and its full nutrient composition will be recorded by the subject in the nutrition diary 
with the assistance of the study dietician as needed. If a subject is taking cornstarch or protein 
supplement, they will be given their usual oral dose at the usual time but no more than 4 hours 
after dinner. The amount of cornstarch and/or protein to administer at the Week 16 or 10 CFC 
should be the same as what the subject received at their STV CFC. The time and amount will 
also be recorded by the subject in the nutrition diary with the assistance of the study dietician as 
needed. If a subject does not a receive cornstarch or protein supplement before going to bed, the 
CFC starts when the subject finishes dinner. The CFC starts when the subject finishes dinner and 
the associated cornstarch and/or protein dose, as applicable. 
10.5.2. 
Ketones  
In addition to urine ketones assessed in urinalysis (Section 10.1.5 and Appendix 3), blood (serum 
for SAD cohorts and capillary for RD cohorts) will be analyzedto evaluate the PD effect of 
UX053 on ketosis at specified time points in Table 4, Table 5, and Table 6. For visits in which 
subjects are receiving study drug, blood or capillary measurements will be collected prior to 
dosing. 
10.5.3. 
 Continuous Glucose Monitoring  
At the Screening Visit for the SAD cohort and ISV for the DB-RD cohort, each subject will 
receive a CGM and HHG device and be trained on how to use the device. For SAD cohorts, the 
CGM device will be worn from the Screening Visit until the End of Study (EOS) I D90/ET Visit 
(Table 4). For OL-RD cohorts, the continual glucose monitor will be worn from the OL-RD 
rescreening ISV to the Week 24 Visit, and for the week prior to the Week 36 and EOS II 
W48/ET Visits (Table 5). For DB-RD cohorts, the CGM will be worn for from ISV to the 
Week 24 Visit, and for the week prior to the Week 36 and EOS III W48/ET Visits (Table 6).  
If the CGM device alarm notifies a subject that their blood sugar is abnormally high or low or the 
subject suspects their blood sugar is abnormally high or low, the subject will need to check their 


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blood sugar with a HHG that will be provided by Ultragenyx during screening (or rescreening, as 
applicable). If action is taken to rectify abnormal blood glucose levels, the event should be 
recorded as an AE (Appendix 1 and Appendix 2).  
When CGM data is being collected, all subjects will connect their CGM and HHG devices to a 
study-provided laptop weekly and upload CGM and HHG data. At remote visits, in conjunction 
with assessments performed by a home health nurse, the site will contact subjects by telephone 
or videoconference to confirm the CGM device is properly in use and data was uploaded; answer 
any questions regarding or help troubleshoot (if necessary) CGM device use; and review CGM 
data, HHG data (when applicable), and nutrition diary entries; outside of scheduled visits, these 
telephone calls will occur as needed. At in-clinic visits, a conversation between the site and the 
subject should occur to ensure CGM compliance and troubleshoot if needed. 
Additional details regarding the CGM device are available in the Study Reference Manual. 
10.5.4. 
Hemoglobin A1C 
Hemoglobin A1C integrates average blood glucose over a 3-month period and can be used to 
monitor more chronic changes in blood glucose. Blood will be collected to measure hemoglobin 
A1C at specified time points in Table 4, Table 5, and Table 6. Samples will be processed by a 
central lab to ensure consistency across study sites. 
10.5.5. 
Glucose Tetrasaccharide 
Glc4 is a limit dextrin of the glucose polymer amylopectin and is elevated in GSD III (Halaby et 
al., 2019).  
Urine will be collected for assessment of Glc4 to evaluate a biomarker of disease activity in GSD 
III at specified time points in Table 4, Table 5, and Table 6. All efforts should be made for urine 
collection to be consistently taken from the first morning void. 
 
10.5.6. 
AGL Gene Sequencing  
Blood will be collected for AGL mutation analysis for all qualified subjects, even if the subject or 
a family member has a confirmed AGL mutation, at time points in Table 4 and Table 6. For each 
subject, both alleles of the AGL gene will be analyzed by a central laboratory for known 
pathogenic or likely pathogenic mutations. Results will be used for research purposes to better 
understand the genotype-phenotype relationships in affected individuals with GSD III. 
10.5.7. 
Exploratory Future Use of Blood 
Blood will be collected and processed into serum, plasma, white blood cells, and red blood cells 
for optional, non-protocol-required additional future research at time points in Table 4, Table 5, 
and Table 6. These additional samples will be used to assess novel emerging biomarkers of GSD 
III and/or UX053 and the relationship to GSD III presentation or prognosis. For visits in which 
subjects are receiving study drug, blood will be collected prior to dosing. 


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10.6. 
Appropriateness of Measurements 
This is a FIH study designed to assess the safety, PK, PD, and preliminary efficacy of UX053 in 
patients with GSD III. The safety parameters to be evaluated in this study include standard 
assessments such as recording of medical history, AEs, SAEs, physical examination, vital signs, 
serum chemistry, concomitant medications, and other clinical and laboratory procedures.  
The efficacy endpoints to be evaluated in this study examine liver health, cardiac health, muscle 
health, strength, and patient- and clinician-reported outcomes. Exploratory assessments include 
potential biomarkers of disease activity that can be used to monitor PD effects of UX053. 
These efficacy and exploratory assessments are standard measures used to identify, assess, and 
monitor the signs and symptoms of GSD III. Where possible, timing of assessments has been 
coordinated with standard safety laboratory tests to minimize risk of discomfort and avoid 
unnecessary duplication of testing. Nutrition diaries will also be used to characterize disease 
management and monitor care throughout the study. 


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11. 
STATISTICAL CONSIDERATIONS  
A full description of the analysis details will be provided in the SAP. 
11.1. 
Sample Size Determination 
The sample size for this study is based on practical considerations and is consistent with a FIH 
study in a rare disease population. The study plans to enroll approximately 18 subjects (assuming 
Cohorts 1-3S and DB-1-3R are initiated), with a minimum of 6 subjects in the SAD cohorts and 
12 subjects in the DB-RD cohorts, with the option to enroll additional subjects in any cohort to 
further characterize safety or PD findings. With at least 6 subjects receiving UX053 in the SAD 
cohorts, there is an 74% chance of detecting a more common AE given the TEAE has a true 
incidence of 20%. If at least 18 subjects receive UX053 in both SAD and RD cohorts, there is an 
85% chance of detecting a TEAE with true incidence of 10%. 
Subjects will be replaced at Ultragenyx’s discretion only if they have not received study drug. 
Subjects will not be replaced if they have received any study drug.  
11.2. 
Analysis Sets  
The Safety Analysis Set will include all enrolled subjects, defined as subjects deemed eligible for 
treatment at D0 in the SAD cohorts, and those randomized in the DB-RD cohorts, and those who 
continue into OL-RD from SAD cohorts. A Per Protocol (PP) Analysis Set, consisting of 
subjects who complete the study without major protocol deviations that could compromise PD or 
efficacy assessments may be analyzed as described in the SAP. The PK Analysis Set is a subset 
of subjects in the Safety Analysis Set who have at least 1 evaluable IP concentration. The PK 
Analysis Set will be used for the analysis of PK endpoints. 
11.3. 
Planned Methods of Analysis 
This section is a summary of the planned statistical analyses of the most important endpoints. 
11.3.1. 
General Principles 
A general description of the statistical methods to be used to analyze the study endpoints is 
outlined below. The analyses planned in this protocol will be expanded in the SAP to include 
detailed description of the analyses.  
Descriptive statistics will be provided for selected demographics, safety, PK, and PD data. 
After review, data for subjects receiving placebo may be combined across all cohorts to form a 
pooled placebo group. If a sufficient number of subjects with different disease subtypes are 
enrolled, subgroup summaries by disease subtype will be provided. Continuous variables will be 
summarized by number of subjects and mean, SD and/or SE, median, minimum, and maximum 
values. Categorical variables will be summarized by number and percentage of subjects. Data 
will be summarized with descriptive statistics for the Screening Period for the DB-RD cohorts. 
COVID-19 contingency measures and trial subjects affected by COVID-19 will be listed. 
Although they are eligible, it is expected that few patients with GSD IIIb, IIIc, or IIId will enroll. 
Subjects with GSD IIIb/c/d will participate in all assessments, including muscle imaging and 


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function tests, and will be included in all safety analyses. Sensitivity analyses for cardiac and 
skeletal muscle endpoints may exclude patients with GSD IIIb/c/d as described in the SAP.  
11.4. 
Safety Analyses 
Safety variables including all AEs, SAEs, TEAEs, serious TEAEs, related TEAEs, safety 
laboratory assessments (full list available in Appendix 3), vital signs, weight, physical 
examination, clinical laboratory evaluations, and ECGs will be summarized for all subjects 
throughout the study and by treatment and cohort. Incidence and severity of IRRs and 
hypersensitivity reactions will also be summarized for all subjects throughout the study and by 
treatment and cohort. All AEs occurring from the onset of the study treatment infusion, and 
within 4 hours following the end of the infusion, regardless of the Investigator’s assessment of 
whether or not the event was related to study drug administration will be considered an IRR. 
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0. The frequency and severity of all TEAEs, SAEs, and clinically relevant laboratory 
and ECG abnormalities will be reported by System Organ Class (SOC), by preferred term, and 
by relationship to study drug. All AEs reported with onset after the first dose of study drug (ie, 
TEAEs) will be included in the analysis. All SAEs will also be reported by relationship to study 
drug as reported by Investigator, seriousness, and outcome. For all AEs, SAEs, and 
treatment-related AEs, SAEs, the percentage of subjects who experienced at least 1 occurrence 
of the given event will be summarized for all subjects in the SAD cohorts and by treatment and 
cohort for the RD cohorts. Data summaries, listings, and narratives will be provided for subjects 
who died, discontinued treatment or withdrew from study due to an AE, or experienced SAEs, 
and any study procedure-related AEs. 
Clinical laboratory data will be summarized by the type of laboratory test and by changes from 
baseline. Reference ranges and abnormal results (specified in the SAP) will be used in the 
summary of laboratory and ECG data. The frequency and percentage of subjects who experience 
abnormal clinical laboratory results (ie, outside of reference ranges) and/or clinically significant 
abnormalities (as determined by the Investigator) will be presented for each clinical laboratory 
measurement, including for Hy’s Law analysis (ALT, AST, total and direct bilirubin, ALP). 
Shift tables may be provided for changes from baseline in selected chemistry and hematology 
laboratory parameters. Listings of abnormal vital signs and physical findings will be provided. 
The SAP will provide additional details on the planned safety analyses. Several safety laboratory 
tests will also be examined for efficacy (Section 11.7).  
11.5. 
Pharmacokinetic Analyses 
PK parameters will be derived by non-compartmental analysis. PK parameters to be estimated 
may include, but not limited to, the following: Tmax, Cmax, AUClast, AUCinf, AUCtau, RAUC, Tlast, 
T1/2, CL, and Vss. PK parameters will be descriptively summarized by dose levels and time in 
SAD and RD, respectively. The SAP will provide additional details on PK analyses. 
11.6. 
Anti-drug Antibody Analyses 
The incidence and titer for ADA to 
 and GDE will be evaluated and 
summarized for each subject at time points specified in Table 4, Table 5, and Table 6. Samples 
may be stored for further assessment to evaluate the presence of neutralizing antibodies.  
CCI


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11.7. 
Efficacy Analyses  
Efficacy parameters will be summarized at screening (or rescreening, as applicable) and baseline 
(or both), and at each observed time point that the assessment is collected thereafter, as specified 
in Table 4, Table 5, and Table 6; change from screening (or rescreening, as applicable) or 
baseline (or both) will also be summarized where applicable. Several laboratory tests examined 
for safety will also be considered for efficacy (Section 11.4). Additional details regarding tertiary 
and exploratory endpoint analysis are available in the SAP.  
11.8. 
Nutrition Diary  
Data from the nutrition diary will be summarized with descriptive statistics. Additional details 
regarding analysis of the nutrition diaries are available in the SAP.  
11.9. 
Exploratory Analyses 
Details regarding exploratory analyses are available in the SAP.  
11.10. 
Planned Subgroup Analyses 
If a sufficient number of subjects with different disease subtypes are enrolled, subgroup 
summaries by disease subtype will be provided. Additional details regarding potential subgroup 
analysis are available in the SAP.  
11.11. 
Planned Analyses 
Analyses are planned for each data review described in the study design (Section 7.1). For the 
SAD cohorts, Ultragenyx will review at least 2 weeks of safety data for all subjects within a 
cohort before deciding to proceed with the next SAD cohort. For the RD cohorts, an unblinded 
DMC will review either at least 6 weeks of safety from at least 4 subjects in a DB-RD cohort or 
12 weeks of safety data from at least 3 subjects in an OL-RD cohort (whichever is available first) 
before providing a recommendation for proceeding with repeat dosing at the next dose level. All 
available data from prior cohorts will also be reviewed when considering proceeding with new 
cohorts. 
11.12. 
Data Monitoring Committee  
An independent DMC will be constituted with experts in metabolic liver disease, GSD III, and/or 
immune activation and will act in an advisory capacity to Ultragenyx. Additionally, at least 1 of 
the DMC members will have expertise concerning statistical methods used in the design and 
analysis of clinical trials.  
The DMC will meet and review study data at the frequency defined and in accordance with the 
scope and objectives set forth in the DMC Charter. The DMC may provide advice to Ultragenyx 
regarding the safety of subjects, the ethics of the study and the continuing scientific validity of 
the study. The DMC may also make recommendations to Ultragenyx concerning continuation, 
termination or other modifications of the study based on their review of data. Further details 
regarding the DMC can be found in the DMC charter, which will be available prior to the 
administration of IP. 


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Ultragenyx will review the DMC recommendations and determine necessary actions that will be 
communicated accordingly to all stakeholders, eg, Regulatory Authorities, IRBs/IECs, and 
Investigators.  


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12. 
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13. 
APPENDICES 


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APPENDIX 1. SAFETY DEFINITIONS AND ASSESSMENTS 
Adverse Event (AE)  
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. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a 
pre-existing condition is considered an AE. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urine) or other safety 
assessments (eg, vital sign measurements), including those that worsen from screening/baseline 
that are felt to be clinically significant in the medical and scientific judgment of the Investigator 
are to be recorded as AEs. 
Treatment-emergent AE (TEAE) 
A TEAE is defined as any AE not present prior to the initiation of the drug treatment or any AE 
already present that worsens in either intensity or frequency following exposure to the drug 
treatment. 
Serious Adverse Event (SAE) 
An SAE is an AE that meets any of the following criteria in the view of either the Investigator or 
Ultragenyx:  
• Death 
• Life-threatening 
− A life-threatening AE is an event that places the patient or subject at immediate 
risk of death. It does not include events that if it had occurred in a more serious 
or severe form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal. 
• Inpatient hospitalization or prolongation of existing hospitalization 
− Hospitalization is defined by Ultragenyx as a full admission to hospital for a 
period of 24 hours or longer for diagnosis and treatment. This includes 
prolongation of an existing inpatient hospitalization. Examples of visits to a 
hospital facility that do not meet the serious criteria for hospitalization include: 
• Emergency room visits (that do not result in a full hospital admission)  
• Preplanned or elective procedures prior to study enrollment (eg, outpatient 
surgery)  
• Protocol procedures  


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− Hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or 
outpatient setting. When in doubt as to whether 'hospitalization' occurred or was 
necessary, the AE should be considered serious.  
− AEs requiring hospitalization should be considered SAEs. Hospitalization 
planned prior to study enrollment (eg, for elective surgery or routine clinical 
procedures) that are not the result of AE (eg, elective surgery for a pre-existing 
condition that has not worsened) need not be considered AEs or SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as 
an AE, either 'serious' or 'non-serious' according to seriousness criteria described 
above. 
• Disability/Incapacity 
− An AE is disabling or incapacitating if it results in substantial and/or permanent 
disruption of the subject’s ability to carry out normal life functions. 
• Congenital anomaly/birth defect not present at screening 
• 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 criteria listed in the 
definition. Examples of such events are: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm 
− Blood dyscrasias that do not result in inpatient hospitalization 
− Development of drug dependency or drug abuse  
− Emergency room visits requiring medical intervention related to the study or 
study procedures, where subjects, due to hospital capacity, could not be admitted 
(eg, due to coronavirus 2019 [COVID-19]) 
Participation-emergent Adverse Events 
These events may be related to study participation or biological specimen collection and will be 
reported by the Investigator and noted as such in the case report form (CRF) as related to study 
intervention. 
Overdose  
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. All cases of overdose (with or without associated AEs) will be 
documented in the CRF.  
Assessment of Severity  
The severity or intensity of an AE refers to the extent to which an AE affects the patient’s daily 
activities. The severity of all AEs will be graded using the Common Terminology Criteria for 


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Adverse Events (CTCAE) version 5.0, published on November 27, 2017, unless the AE is 
Cytokine Release Syndrome (CRS), in which case the AE will be graded by the American 
Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS (Lee et 
al., 2019). 
 
Table 13: 
American Society for Transplantation and Cellular Therapy Consensus 
Grading for Cytokine Release Syndrome  
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
 
with 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow 
nasal cannulac, 
facemask, 
nonrebreather mask, 
or Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
a Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
Note: Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
BiPAP, bilevel positive airway pressure; CPAP, Continuous positive airway pressure; CRS, cytokine release 
syndrome; CTCAE, Common Terminology Criteria for Adverse Events. 
Source: (Lee et al., 2019). 
 
If an AE cannot be graded using the CTCAE criteria, it should be graded using the following 
definitions:  
• Mild (Grade 1): Subject has awareness of signs or symptoms, but easily tolerated and 
are 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 
subject 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 subject’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 


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• Life-threatening (Grade 4): Events that place the subject at immediate risk of death or 
are disabling. 
• Death (Grade 5): Events that result in death. 
Note: 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 and is usually associated with events that pose 
a threat to a subject's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
Assessment of Causality 
The Investigator will make a causality assessment about the relationship of each AE to study 
drug. Treatment-related conditions must be distinguished from disease-related conditions. 
The Investigator should determine the causality (relation to the study drug) based on his/her 
clinical experience and on the information given in the Investigator’s Brochure. The causal 
relationship of all AEs to the study drug will be judged as either related (which includes 
possibly, probably or definitely related) or not related (which includes unlikely or doubtfully 
related). 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline:  
• A related causal relationship means that there is at least a reasonable possibility that the 
event is caused by the study drug or the research procedures. There may be a reasonable 
possibility of a causal relationship between study drug/Investigational Product (IP) and 
the AE when: 
o The event follows a reasonable temporal sequence post IP administration 
o The event is known to be or could be a response to the IP, based upon pre-clinical 
or clinical data with the product or similar products 
o The event could not be explained by the subject's primary disease including 
progression/expression of the disease state, other concurrent or underlying illness, 
and/or prior/concomitant therapies 
o Positive dechallenge: the event resolves or improves after discontinuation of IP 
(when this information is available) 
o Positive rechallenge: the event reappears or worsens when dosing with IP is 
resumed after an interruption (when this information is available)  
• Not related means there is unlikely to be a reasonable possibility of a causal relationship 
between the event and study drug/IP or the research procedures, and/or that there is a 
clear causal relationship between other conditions and the AE. There is not likely to be a 
reasonable possibility of a causal relationship between study drug/IP and the AE when:  


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o The event does not follow a reasonable temporal sequence post IP administration 
o There are no data with the IP or similar products, suggesting the event occurs or 
may occur with the IP 
o There is a more likely alternative etiology, such as subject’s underlying primary 
disease including disease progression or expression, other concurrent or 
underlying illness, or prior/concomitant therapies 
o Negative de-challenge: the event does not improve after discontinuation of IP 
(when this information is available) 
o Negative re-challenge: the event does not worsen after interruption of IP when 
dosing is resumed after an interruption (when this information is available) 
Note: The Investigator’s assessment of causality for individual AEs is part of the study 
documentation process and will be recorded in the patient’s medical record, CRF, and SAE form, 
if applicable. AEs recorded without the Investigator’s assessment of the relationship to study 
drug will be followed up until causality is assigned. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) means a SAE that occurs in a 
clinical trial subject, which is assessed by the Investigator or Ultragenyx as being serious and 
unexpected based on Reference Study Information (eg, Investigators Brochure [IB]), and as 
having a reasonable possibility of a causal relationship with the study drug/IP. 
Urgent Safety Measure means any measure taken to protect the subjects of a clinical trial 
against an immediate hazard to their health or safety. 
 


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APPENDIX 2. ADVERSE EVENT COLLECTION: ELICITING, RECORDING, AND REPORTING 
Table 14: 
Collection Period & Reporting Timeframe: Adverse Event & Other Safety Information Reporting 
Event Type 
Screening Period (including nutrition 
optimization and standardization), SAD 
cohorts, RD cohorts 
Reporting Timeframe 
Report to 
SAE 
Start: From the time the subject signs the ICF 
End: 28 days following the final dose of study 
drug or the EOS I (SAD cohorts) and EOS II or 
EOS III (RD cohorts) final study visit, 
whichever occurs later 
Suspected related SAEs can be reported at any 
time following the EOS I/II visit 
Report all SAEs within 24 hours of site 
Investigator, designee or site personnel’s 
knowledge of the event. 
Electronic Data Capture (primary) 
 
Ultragenyx 
(back-up if Electronic Data Capture is 
down or not available) 
email: ultragenyx@primevigilance.com 
Fax:1 (415) 930-4033 
AE  
Start: From the time the subject signs the ICF 
End: 28 days following the final dose of study 
drug or the EOS I (SAD cohorts) and EOS II or 
EOS III (RD cohorts) final study visit, 
whichever occurs later 
Report all non-serious AEs within a target 
of 3 business days of site Investigator, 
designee or site personnel’s knowledge of 
the event. 
Electronic Data Capture 
Pregnancy 
(includes Partner 
pregnancy) 
Start: From the time the subject signs the ICF 
End: 28 days following the final dose of study 
drug or the EOS I (SAD cohorts) and EOS II or 
EOS III (RD cohorts) final study visit, 
whichever occurs later 
Report all pregnancies within 24 hours of 
site Investigator, designee or site 
personnel’s knowledge of the event. 
 
Request consent to follow partner 
pregnancy (if applicable). 
 
Follow pregnancy until outcome is known 
(live birth, stillbirth, spontaneous 
abortion, elective termination, etc.). 
Ultragenyx email: 
ultragenyx@primevigilance.com 
Fax:1 (415) 930-4033 
AE, adverse event; EOS, end of study; ICF, informed consent form; RD, Repeat Dose; SAD, Single Ascending Dose; SAE, serious adverse event.


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Table 15: 
Safety Contact Information 
Global Drug Safety & Pharmacovigilance  
SAE and Pregnancy Reporting 
Medical Monitor 
Fax: 1 (415) 930-4033 
email: ultragenyx@primevigilance.com 
 
60 Leveroni Ct. 
Novato, CA 94949 
 
 
 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting adverse events (AEs) at all 
patient evaluation time points should be adopted. Examples of non-directive questions include:  
“Since the last visit, has the patient experienced any health problems?”  
“Have there been any new or changed health problems since you were last here?” 
Recording AEs and SAEs 
All AEs (ie, any new condition or worsening in severity or frequency of a preexisting condition) 
experienced by the patient within the protocol defined timeframes must be promptly documented 
on the case report form (CRF) and serious adverse event (SAE) form if applicable. This includes 
any AEs or SAEs considered associated with study protocol required procedures. For clinically 
significant worsening of a preexisting condition from Baseline the changes will be documented 
as AEs on the CRF. Clinical significance is defined as any variation in signs, symptoms, or 
testing that has medical relevance and may result in an alteration in medical care. The 
Investigator will continue to monitor the patient until the assessment returns to Baseline or until 
the Investigator determines that follow-up is no longer medically necessary. 
The Investigator is responsible for evaluating all AEs, obtaining supporting documents, and 
ensuring documentation of the events is adequate. Details of the AEs must include severity, 
seriousness, relationship to study drug, duration (dates of onset and resolution), and outcome.  
In addition, the Investigator should report any AE or SAE they are made aware of that occurs 
after the end of the study and that is believed to have a reasonable possibility of being associated 
with study drug.  
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF and SAE form (if applicable) rather than 
individual signs and symptoms. Whenever medically appropriate, the Investigator should group 
signs or symptoms that constitute a single diagnosis into a unifying event term. For example, 
record “liver failure” rather than jaundice, asterixis, and elevated transaminases, or record “upper 
respiratory tract infection” rather than cough, rhinitis, and sneezing. However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE on the CRF and SAE 
form (if applicable). If a diagnosis is subsequently established, it should be reported as follow-up 
information by revising the CRF and SAE form (if applicable). Vague, nonspecific AE terms 
PPD
PPD


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such as “erythema,” “rash,” or “lump on head” should be avoided and more specific information 
should be provided, such as “erythematous macule on right leg,” “allergic dermatitis,” or “scalp 
cyst.” 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as the AE on the CRF and, if also 
serious, on the SAE form. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on the CRF. 
For example, if a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
recorded separately on the CRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient evaluation 
time points. Such events should only be recorded once in the CRF unless their severity increases. 
If a persistent AE becomes more severe, it should be recorded again on the CRF.  
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded individually on the CRF. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities in the opinion of the Investigator are to be 
recorded as AEs on the CRF and SAE form (if applicable). For example, abnormalities that 
require study drug dose modification, discontinuation of study treatment, more frequent 
follow-up assessments, or further diagnostic investigation may be considered clinically 
significant by the Investigator. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 × upper limit of normal (ULN) associated with cholecystitis), only 
the diagnosis (eg, cholecystitis) needs to be recorded on the CRF and the SAE form (if 
applicable). 
If the laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs on the CRF and SAE form (if applicable), unless their 
severity, seriousness, or etiology changes. 
Reporting Serious Adverse Events  
Any AE that meets SAE criteria must be reported to Ultragenyx or its designee within 24 hours 
of the site Investigator, designee or site personnel’s knowledge of the event. Regardless of 
causality, all SAEs must be reported during the time period. All SAEs must also be recorded in 
the patient’s source documentation and on the CRF. Copies of discharge summaries, consultant 
reports, and any other relevant documents should be provided with the SAE report when 
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If follow-up is obtained or requested by Ultragenyx and/or Medical Monitor, the additional 
information should be sent within 24 hours of knowledge.  
Refer to Safety Contact Information for SAE reporting (Appendix 2). 
Reporting of Pregnancy in Subject or Partner  
For protocols requiring pregnancy reporting, any reported pregnancy of a subject or a subject’s 
partner that occurs during participation in the study will be monitored for the full duration of the 
study 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 in a subject or subject’s partner, complications of the pregnancy and the outcomes of 
pregnancy should be reported to the Ultragenyx or designee within 24 hours of site Investigator, 
designee or site personnel’s knowledge of the event.  
Pregnancies will be reported by completing and submitting Pregnancy Notification Form to 
Ultragenyx or designee.  
Pregnancy outcomes will be reported by completing and submitting Pregnancy Outcome Form to 
Ultragenyx or designee.  
The following pregnancy outcomes should always be classified as serious and reported to 
Ultragenyx or designee within 24 hours by completing and submitting the SAE and Pregnancy 
Outcome Form: 
• Spontaneous abortion/Miscarriage  
• Therapeutic abortion  
• Ectopic pregnancy  
• Fetal death/Still birth  
• Molar pregnancy  
• Birth defect/Congenital anomaly 
Reporting Suspected Unexpected Serious Adverse Reactions 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSARs) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs), and Investigators as per local laws and regulations. Fatal and life-threatening 
SUSARs will be submitted no later than seven calendar days of first knowledge of the event and 
follow-up information submitted within an additional eight days. All other SUSARs will be 
submitted within 15 calendar days of first knowledge of the event.  
The Investigator will notify the IRBs/IECs of SUSAR, in accordance with IRB/IEC requirements 
and local laws and regulations.  
Non-SUSARs will be maintained in the Ultragenyx global safety database and provided in 
annual safety reports and/or other aggregate periodic summary reports to Regulatory Authorities 
and IRBs/IECs per local laws and regulations. 


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Reporting Urgent Safety Measures 
Investigators are required to report any urgent safety measures taken to protect the safety or 
welfare of subject to Ultragenyx or its designee within 24 hours. Ultragenyx or its designee will 
inform the Regulatory Authorities, IRBs/IECs, and other investigators of any events (eg, change 
to the safety profile of Investigational Product (IP), major safety findings) that may occur during 
the clinical study that do not fall within the definition of a SUSAR but may affect the safety of 
subjects participating in the clinical study, as required, in accordance with applicable laws and 
regulations.  
The Investigator will notify the IRBs/IECs of urgent safety measures, in accordance with 
IRB/IEC 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 global safety database and provided in 
annual safety reports and/or other aggregate periodic summary reports to Regulatory Authorities 
and IRBs/IECs per local laws and regulations. 
 


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APPENDIX 3. LABORATORY ASSESSMENTS 
Chemistry 
Hematology 
Urinalysis 
Additional Labs  
Alanine aminotransferase (ALT) 
Hematocrit 
Appearance 
Blood Collection:  
Alkaline phosphatase (ALP)  
Hemoglobin 
Color 
Alternative complement activity (AH50) 
Amylase 
Mean corpuscular hemoglobin (MCH) pH 
B-type natriuretic peptide (BNP) 
Aspartate aminotransferase (AST) 
MCH concentration (MCHC) 
Specific gravity 
Classical pathway complement activity (CH50) 
Bicarbonate 
Mean corpuscular volume (MCV) 
Bilirubin 
C-reactive protein (CRP) 
Bilirubin (direct and total) 
Platelet count 
Creatinine 
Creatinine kinase (CK)  
Blood urea nitrogen (BUN) 
Red blood cell (RBC) count 
Glucose 
Creatinine kinase-muscle/brain (CK-M/B) 
Calcium 
Reticulocyte count 
Hemoglobin 
D-dimer 
Chloride 
White blood cell (WBC) count 
Ketones  
Fibrinogen 
Cholesterol (total) 
WBC differential 
Nitrite 
Hemoglobin A1C  
Creatinine 
Basophil count (absolute and %) 
Protein 
High density lipoprotein (HDL)  
Gamma-glutamyl transferase (GGT) 
Eosinophil count (absolute and %) 
Urobilinogen 
Interleukin-6 (IL-6)  
Glucose 
Lymphocyte count (absolute and %) 
Pregnancy (if applicable) 
Ketones 
Lactate dehydrogenase (LDH) 
Monocyte count (absolute and %) 
 
Low density lipoprotein (LDL)  
Lipase 
Neutrophil count (absolute and %) 
 
Prothrombin time/international normalized ratio 
(PT/INR) 
Magnesium 
Complete blood count with differential 
(CBC/diff) 
 
Troponin I 
Phosphorus 
 
 
Soluble complement 5b-9 (sC5b-9) 
Potassium 
 
 
Urine Collection:  
Protein (albumin and total) 
 
 
Glucose tetrasaccharide (Glc4) 
Sodium 
 
 
 
Triglycerides 
 
 
 
Note: table does not include blood collection for PK (ATX95, AGL mRNA), anti-drug antibodies, AGL variant analysis, and serum and plasma for future use; 
these assessments are measured as specified in Table 4, Table 5, Table 6, and Table 8. 


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APPENDIX 4. CONTRACEPTION GUIDANCE 
The guidance below applies for development products with potential or unknown reproductive 
toxicity (for products in clinical trials, where pre-clinical data are indicative of risk or have not 
yet been completed). 
Female subjects of childbearing potential who are heterosexually active must consent to use a 
highly effective method of contraception as listed below to prevent pregnancy over the time 
period required for product levels to decrease to a concentration that is no longer considered 
relevant for human teratogenicity/fetotoxicity. This time period is generally determined by the 
pharmacokinetic properties of the study product and non-clinical reproductive toxicity data and 
is defined in the protocol or product Investigator Brochure (IB).  
Highly effective contraceptive methods are those with a failure rate of less than 1% per year 
when used consistently and correctly.  
Female subjects of childbearing potential are defined as having reached menarche prior to or 
during the study. Females not of childbearing potential include those who have not experienced 
menarche, are postmenopausal (defined as having no menses for at least 12 months without an 
alternative medical cause) or are permanently sterile due to having total hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy.  
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient and multiple measurements are 
needed.  
Male subjects who are heterosexually active with female partners of childbearing potential must 
consent to use one of the highly effective methods of contraception listed below to prevent 
pregnancy over the period defined in the protocol or product Investigator Brochure. The time 
period required is generally determined by the pharmacokinetic properties of the study product 
and non-clinical reproductive toxicity data. 
Highly effective methods of contraception (CTFG, 2014) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (eg, oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(eg, oral, injectable, implantable) 
• Intrauterine device or intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Male sterilization, also called vasectomy  
• Sexual abstinence is defined as refraining from heterosexual intercourse during the 
entire study period associated with risk of the Investigational Product (IP), other 
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− The reliability of sexual abstinence should be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the subject.  
− Abstinence is only considered a highly effective method of contraception if 
practiced consistently for the entire period of exposure to IP or other study 
treatments. 
− Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
methods are not acceptable methods of contraception. 
Notes: Barrier methods (such as a condom used with or without a spermicide or a diaphragm or 
cervical cap used with a spermicide) used alone are NOT highly effective contraception methods. 
Additional Requirement if IP is an advanced therapy medicinal product (eg, gene therapy), a 
condom with spermicide is also required to be used by all sexually active males in the study in 
order to prevent potential transmission of the vector via seminal fluid. 


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APPENDIX 5. ETHICS AND CONDUCT 
This protocol is written in accordance with the principles established by the 18th World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human 
Subjects and subsequent amendments and clarifications adopted by the General Assemblies 
(World Medical Association, 2013). 
Ultragenyx and Investigator will ensure the study described in this protocol is conducted in 
compliance with those principles and International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and 
applicable local law, eg, Food and Drug Administration (FDA) regulations, European Union 
(EU) regulations, and any other local ethical and regulatory requirements (“Applicable Study 
Conduct Obligations”). Should a conflict arise, Ultragenyx and Investigator will follow 
whichever Applicable Study Conduct Obligations affords the greater protection to the subject(s). 
Institutional Review Board or Independent Ethics Committee and Competent Health 
Authority 
The Institutional Review Boards/Independent Ethics Committees (IRB/IEC) must be a properly 
constituted board or committee operating in accordance with Applicable Study Conduct 
Obligations and should safeguard the rights, safety, and well-being of all study subjects. Before 
screening any subject, the IRB/IEC, and as applicable Competent Health Authority, must review 
and approve this protocol and if applicable, the associated assents and informed consent forms 
(ICFs), agreed to by the study site (ie, Institution) and by Ultragenyx. Further, IRB/IEC and 
Competent Health Authority approval of any protocol amendments must be received before any 
of the changes outlined in the amendments are put into effect, unless there is a need to protect 
subject safety. In that case and with prior IRB/IEC approval/favorable opinion, the Investigator 
may deviate from the protocol to eliminate an immediate hazard(s) to study subjects and will 
immediately notify the chair of the IRB/IEC and Ultragenyx of the amendment. 
If Investigational product (IP) is provided under the protocol, IP will not be shipped to the study 
site until Ultragenyx or its designee has received a copy of the letter or certificate of 
approval/favorable opinion from the IRB/IEC, all Ultragenyx-required documents, and, where 
required, the Competent Health Authority authorization/approval of the protocol. If IP is not 
provided under the protocol, this paragraph and the section on IP accountability do not apply. 
Before releasing advertisements or solicitations to the public for subject enrollment in the study, 
such advertisements or public solicitations must be submitted to Ultragenyx or its designee for 
review and approval. After receiving Ultragenyx approval for the advertisements or public 
solicitations, the Investigator must submit them to his/her IRB/IEC for review and approval 
before using them. 
Subject Information and Consent 
The contents of the ICF and any assents for minors, as well as the method of obtaining and 
documenting informed consent must comply with Applicable Study Conduct Obligations. 
Ultragenyx or its designee will provide the Investigator written informed consent(s), which 
includes assents for minors. Any revisions to the ICF must be reviewed and approved by 
Ultragenyx before submission to the IRB/IEC for its approval. The study site agrees not to begin 
enrolling subjects until the IRB/IEC approval is complete. 


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Adequate consent for access to, use of, and/or processing of coded personal health information 
and other personally identifiable information will be obtained in accordance with the applicable 
laws, such as US Health Insurance Portability and Accountability Act regulations, state data 
privacy laws, the EU General Data Protection Regulation (GDPR), or other applicable national 
or local data usage and protection laws. 
In accordance with applicable local laws and with the subject’s express and optional consent, any 
remaining biological samples taken for the purposes of the study, as well as any voluntary 
samples, may be used by Ultragenyx for additional research and development in accordance with 
the subject’s express consent. Any such consent will be optional and not a requirement to study 
participation. 
Before conducting any study procedures, the Investigator must obtain written informed consent 
for or from each potential subject. Part of obtaining that written informed consent requires the 
Investigator to fully explain to each potential subject the methods, objectives, requirements, and 
potential risks of the study and to answer any inquiries. Further, the Investigator must explain to 
each potential subject that the subject is completely free to refuse to enter the study or to 
withdraw from the study at any time without either decision impacting his/her care. The 
Investigator or a qualified designee must 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. 
Pediatric subjects or adult subjects with cognitive limitations will provide written assent 
(if possible) and a legally authorized representative (parent or legal guardian) must provide 
written informed consent for such subjects. If, over the course of the study, a pediatric subject 
becomes old enough for a subsequent assent or reaches the legal age of majority, he/she must 
sign the then-age-appropriate assent or consent as the case may be. 
Subjects will be given a copy of the signed ICF and/or assent and will be provided any new 
information during the course of the study that might affect their continued participation in the 
study. If the protocol is amended and the ICF is revised, each subject will be required to provide 
written informed consent again using the revised ICF. The signed ICF or assent will remain in 
each subject's study file and must be available to the study monitor(s) at all times. 
Data Protection, Anonymization, and Security 
Any study data transferred to Ultragenyx will be coded and will not contain names or any other 
information that would make the subject identifiable. 
Study information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Ultragenyx.  
The subject must be informed of his/her rights under applicable data protection laws regarding 
how his/her personal information is being treated. Additionally, the subject must be informed, 
and where possible, be provided with the details and references, that certain persons or entities 
may have access to his/her medical records for various, legitimate reasons and purposes, 
including Ultragenyx’s auditors or other authorized personnel appointed by Ultragenyx may 
examine his/her medical records, appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.  


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The subject must also be provided with the applicable contact information for Ultragenyx, site, 
and/or the country’s/regional’s Data Protection Authority in order to inquire about their rights, 
raise concerns, or issue complaints regarding the treatment of his/her personal information by 
Ultragenyx. 
Ultragenyx complies with applicable data protection laws and treats personal information in 
accordance with standard security measures. Ultragenyx has implemented policies and 
procedures to prevent security issues, including data breaches, and avoid/minimize any negative 
consequences. All computerized systems to be used during the study have been selected 
following a strict process that encompassed a System Level Risk Assessment, including system 
identification, GxP, GDPR, Sarbanes and Oxley Act, and 21 CFR Part 11 applicability. As far 
GDPR compliance is concerned, a Data Classification Assessment which includes the Data 
Privacy Impact Assessment (DPIA) was also conducted on all systems, and their results are 
memorialized in DPIA assessments stored in the Ultragenyx Document Management System. 
Ultragenyx imposes the same principles to all vendors supporting the study, which translates into 
(i) selecting such vendors and their systems against equally stringent security protocols and 
standards; (ii) ensuring that they comply with applicable data protection laws, and (iii) agreeing 
to specific data protection terms that include, among others, a data breach response plan and an 
obligation to collaborate with Ultragenyx in such circumstances timely. These measures exist so 
Ultragenyx can mitigate any security occurrence and meet their obligations under applicable data 
protection laws. Therefore, in case of a data breach, Article 33 GDPR will be followed. 
Additionally, in order to maintain/restore a GxP-compliant environment, an audit will be 
conducted, and the necessary remedial actions implemented in a timely fashion (including, but 
not limited to, termination of any relevant third party from the research) to guarantee the 
integrity of the concerned data and avoid any future repetition. 
Protocol Deviations 
A protocol deviation is any instance of protocol noncompliance, either at study entry or during 
the study conduct. A major protocol deviation is defined by Ultragenyx as a having a significant 
impact on a clinical study data and subject rights, safety, or welfare. All other protocol deviations 
are considered minor protocol deviations. 
Ultragenyx does not issue protocol deviation waivers. The Investigator must inform Ultragenyx 
of all protocol deviations in a timely manner; provided, however, that Ultragenyx be informed of 
all major Protocol deviations immediately of becoming aware of such deviations. 
Future Use of Stored Study Samples 
With the subject’s written consent, Ultragenyx will use remaining protocol-driven samples 
and/or will collect optional, non-protocol-required biologic samples to be used for additional 
future research. These samples will be de-identified and may be stored for up to 20 years from 
the end of the study, or shorter as required by local law. 
Investigators and Study Administrative Structure 
Prior to the Investigator beginning performance of the study, Ultragenyx must be in receipt of all 
essential documents, including, among others, a signed Form FDA 1572 or equivalent signed by 
the Investigator and any sub-investigators, and an appropriate Financial Disclosure Form from 
each. 


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A Coordinating Investigator will be identified for multicenter studies. The Coordinating 
Investigator will be selected on the basis of active participation in the study, thorough knowledge 
of the therapeutic area being studied, and the ability to interpret data. The Coordinating 
Investigator will read and sign the Clinical Study Report. 
Investigational Product Accountability  
The Investigator must be thoroughly familiar with the appropriate administration and potential 
risks of administration of the IP, as described in this protocol and the Investigator Brochure (IB), 
prior to initiation of the study. 
IP delivered to the study site and/or Investigator must be stored in a secure limited access 
location at controlled temperature as described in the IB and product packaging. Any such 
location must be available for inspection by the study monitor or auditors for inspection at any 
time during the study. If subjects take IP offsite, they will be given instructions on the proper 
storage of IP when initially dispensed and reminded of storage requirements at all subsequent 
visits. 
An IP accountability record must be maintained for all IP received, dispensed, returned, 
destroyed, and/or lost during the study. This record must be kept current and made available to 
the study monitor or auditors for inspection. At the completion of the study, all unused IP must 
be returned to Ultragenyx and/or its designee, unless other instructions have been provided for 
final disposition of the IP. 
Data Handling and Record Keeping 
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. Data 
must be recorded on Case Report Forms (CRFs), electronic or otherwise, in accordance with the 
Clinical Trial Agreement executed between Ultragenyx and the study site and/or Investigator. 
Recorded data is subject to Ultragenyx verification. All information recorded on CRFs must be 
consistent with the subject's source documentation. For electronic CRFs, a validated Electronic 
Data Capture (EDC) system will be used for entry of the data. 
Data entry and data corrections will be made only by Ultragenyx-authorized users and will be 
captured in an electronic audit trail. 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 Ultragenyx or its 
designee direct access to all source documents. 
Data Quality Assurance 
Monitoring and auditing procedures will be implemented to ensure compliance with Applicable 
Study Conduct Obligations. Ultragenyx's designated representative (ie, the site monitor) will 
contact the Investigator and conduct regular visits to the study site. The site monitor will also be 
responsible for confirming adherence to the study protocol, inspecting CRFs and source 
documents, and ensuring the integrity of the data. Instances of missing or uninterpretable data 
will be resolved in coordination with the Investigator. 


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The site monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The site monitor will 
maintain contact through frequent direct communications with the study site by e-mail, 
telephone, facsimile, and/or mail. The Investigator and all other personnel supporting the study 
(ie, Project Personnel) must agree to cooperate fully with the site monitor and will work in good 
faith with the site monitor to resolve all questions raised and all identified issues. 
Record Retention 
For study monitoring, audit, or inspection, the IRB/IEC and Ultragenyx or its designees have the 
right to access all CRFs, source documents, and other study documentation. The Investigator or 
study site will retain such documents from the start of the study to at least 25 years after the close 
of the study, guarantee access to these documents and cooperate with and support such audits 
and inspections. 
Publication Policy 
The Investigator and/or study site must submit any publication or presentation about the study to 
Ultragenyx prior to making it public in accordance with the process in the Clinical Trial 
Agreement executed between Ultragenyx and the study site and/or Investigator. 
Registration of Study and Disclosure of Results 
Ultragenyx will register the study and post results regardless of outcome on a publicly accessible 
website in accordance with the applicable laws and regulations. 
Budgeting and Insurance 
The budget and insurance for this clinical study will be addressed in the Clinical Trial 
Agreement between Ultragenyx and the study site and/or Investigator executed between 
Ultragenyx and the study site and/or Investigator.


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APPENDIX 6. PROTOCOL AMENDMENT HISTORY 
Table 16: 
Protocol Amendment History 
Document 
Date of Issue 
Overall Rationale for the Amendment 
Amendment 2.3 
03 January 2022 
To clarify the timing of assessments, use of premedications, and procedures for glucose monitoring 
Amendment 2.1 
01 October 2021 
This protocol amendment was submitted to FDA on 19 October 2021 and withdrawn on 
01 December 2021. Changes included in this withdrawn protocol amendment are not reflected in 
Table 17. 
Amendment 1 
24 March 2021 
 To clarify and align with recommendations from regulatory authorities 
Original Protocol 
20 January 2021 
 Not applicable 
Table 17: 
Summary of Protocol Amendment Changes 
Amendment 2.3 / 03 January 2022 / Substantial 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Event Table 6 
The liver MRI, MRS, and Fibroscan/ultrasound elastrography 
occurring during screening was moved from the Stablization 
Visit (STV) to the Initial Screening Visit (ISV). 
Hepatic imaging will help determine if subjects meet 
eligibility criteria, such as exclusion based on the 
presence of cirrhosis.  
Schedule of Event Table 6, 
Section 5.4.2 Potential Risks 
for Premedications, Section 7.1 
Study Design, Section 9 
Interventions, and Section 9.1.1 
Premedications  
At the discretion of the Investigator, with input from Ultragenyx 
and the Data Monitoring Committee (DMC), and based on the 
emerging safety profile of UX053, additional premedications 
and rescue medications may be used to reduce the risk and 
severity of immune reactions in Repeat Dose (RD) cohorts. 
Premedication and rescue medication selection will be based on 
the nature of the reactions being observed and the risks of such 
medications in patients with GSD III. 
Acetaminophen, ibuprofen, cetirizine, famotidine, and 
dexamethasone may not be sufficient to prevent 
immune-mediated reactions to UX053. If 
infusion-related reactions are observed, other 
medications may be used to minimize risk to study 
subjects.  


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Amendment 2.3 / 03 January 2022 / Substantial  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 4 and 
Table 6  
A row was added to both Schedule of Events tables to indicate 
that all visits after Day 7 in the SAD Period and Week 1 in the 
RD Period may occur within a window of ± 2 days. In line with 
this change, in Table 8, the window of ± 24 hours for Day 14, 
21, and 28 for pharmacokinetic sampling is now ± 48 hours. If 
all assessments for a given visit occur within the visit window, it 
will not constitute a protocol deviation. Some assessments may 
occur within a week prior to dosing (footnote c of Table 4 and 
footnote d in Table 6). 
A visit window was established to reduce patient 
burden.  
Schedule of Events Table 4 and 
Table 6, Section 7.1, and 
Section 10.5.3 Continuous 
Glucose Monitoring  
The following text was added: “At the Screening Visit for the 
SAD cohort and ISV for the RD cohort, all subjects will receive 
continuous glucose monitoring (CGM) and handheld 
dynamometry (HHG) devices and will be trained on the proper 
use of these devices. Subjects will also be trained on completion 
of the nutrition diary. When CGM data is being collected, all 
subjects will connect their CGM and HHG devices to a 
study-provided laptop weekly and upload CGM and HHG data. 
At remote visits, in conjunction with assessments performed by 
a Home Health nurse, the site will contact subjects by telephone 
or videoconference to confirm the CGM device is properly in 
use and data was uploaded; answer any questions regarding or 
help troubleshoot (if necessary) CGM device use; and review 
CGM data, HHG data (when applicable), and nutrition diary 
entries; these telephone calls will occur as needed for the SAD 
Period between Day 28 and Day 90/EOS I Visits and for the RD 
Period between the Week 12 and 24 Visit. At in-clinic visits, a 
conversation between the site and the subject should occur to 
ensure CGM compliance and troubleshoot if needed.” Related to 
this addition, the following text was removed from the schedule 
of events tables “The site should record the handheld 
glucometer data in the CRF at the next site visit.” 
The site no longer needs to record HHG data in the Case 
Report Form (CRF), as subjects are asked to upload 
both CGM and HHG data on a weekly basis when CGM 
is being collected. This additional text also clarifies how 
CGM and HHG data will be collected.  
Schedule of Events Table 4 and 
Table 6, and Section 10.5.5 
Limit Dextrins 
Hexose tetrasaccharide (Hex4) nomenclature is changed to 
glucose tetrasaccharide (Glc4), which is a more specific 
description of this analyte.  
Hexose tetrasaccharide (Hex4) includes glucose 
tetrasaccharide and maltotetraose, but only glucose 
tetrasaccharide will be measured.  


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Amendment 2.3 / 03 January 2022 / Substantial 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 4 and 
Table 6, and Appendix 3 
Laboratory Assessments  
Appendix 3 was updated to include all laboratory assessments 
instead of only safety laboratory assessments. Related to this 
change, creatine kinase was removed from the chemistry panel 
in Appendix 3, as it is already collected under Skeletal Muscle 
& Strength Assessments, noted in Table 4 and Table 6.  
To further clarify all labs being measured, and to clarify 
that creatine kinase is not measured twice for a given 
visit.  
Schedule of Events Table 4 
A footnote was added to the SAD Period Schedule of Events 
Table 4 to indicate that a complete physical exam is required at 
the Screening, Baseline, and End of Study/Early Termination 
Visits. A targeted physical exam may be performed at the Day 1 
Visit.  
To clarify requirements for physical exams. 
Schedule of Events Table 4 
The Patient-Reported Outcomes Measurement Information 
System (PROMIS) questionnaires, Short Form Health Survey 
36 Version 2 (SF-36v2), and GNE Myopathy Functional 
Activities Scale (GNEM-FAS) were removed from the 
Screening Visit during the SAD Period.  
During the SAD Period, the PROMIS questionnaires, 
SF-36v2, and GNEM-FAS do not need to be assessed at 
the Screening Visit, as they are assessed at the Baseline 
Visit, which occurs shortly after the Screening Visit.  
Schedule of Events Table 4 and 
Table 6 
Serum B-type natriuretic peptide (BNP) was updated to plasma 
BNP.  
Plasma will be used for the assessment of BNP. 
Section 10.4.1.1 Liver 
Magnetic Resonance 
Spectroscopy and Section 0 
Calf Magnetic Resonance 
Spectroscopy  
Magnetic resonance spectroscopy (MRS) is no longer limited to 
13C MRS.  
Imaging methodology was expanded based on site 
feasibility. Broadening the methodology will increase 
the number of sites capable and therefore provide more 
meaningful imaging results.  
Schedule of Events Table 4 and 
Table 6; Section 0 GDE 
Enzyme Activity  
Peripheral blood mononuclear cell (PBMC) collection for the 
assessment of glycogen debranching enzyme (GDE) enzyme 
activity will no longer be collected.  
Nonclinical studies revealed that this assessment will 
not reliably predict GDE activity, and is therefore no 
longer necessary.  
Schedule of Events Table 4 and 
Table 6;Section 0 Exploratory 
Future Use Blood Cell Pellet, 
Serum, and Plasma Collection 
Blood cell pellets for future use will now be collected instead of 
whole blood samples for limit dextrins. Reflecting this change, 
“whole blood limit dextrins” was removed from the “whole 
blood limit dextrins & plasma Glc4” row; and a new row for 
“blood cell pellet for future use” was added. Though there is no 
change to the sample collection schedule, the analysis of the 
blood samples has changed.    
Nonclinical studies revealed that UX053 treatment is 
unlikely to impact glycogen content in circulating blood 
cells. Instead, blood cell pellets will be used to measure 
GDE production in a more sensitive manner.  


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Amendment 2.3 / 03 January 2022 / Substantial  
Section # and Name 
Description of Change 
Brief Rationale 
Amendment 1 / 24 March 2021 / Substantial 
Section # Name 
Description of Change 
Brief Rationale 
 Title Page 
The D and EudraCT number was added. 
 
This information was not available for the finalization of 
the original protocol.  
 Title Page 
The contact information for the Medical Monitor was updated to 
include a telephone number in addition to an email address. The 
address was removed. 
 
A telephone number and email address is the more 
appropriate method of contact.  
Schedule of Events Table 4 and 
Table 6, Section 7.1 Study 
Design, Section 9.7 Treatment 
Compliance, Section 10.4.4.4 
Nutrition Diary, and 
Section 11.8 Nutrition Diary 
The term “diet diary” was changed to “nutrition diary” 
throughout the protocol. 
 
The name of the assessment was changed to more 
accurately reflect the data being captured.  
Schedule of Events Table 4 and 
Table 6, Section 10.1.5 Safety 
Laboratory Tests, and 
Section 10.1.5 Safety 
Laboratory Tests 
The footnote referring to urine collections was updated to clarify 
that all efforts should be made for urine collections to be 
consistently taken from the first morning void. Relevant text 
was also updated in Section 10.1.5 Safety Laboratory Tests and 
Section 10.5.5 Limit Dextrins, Including Hexose 
Tetrasaccharide. 
To clarify  
Schedule of Events Table 6 
Vital signs was added as an assessment at the home health 
Week 1 visit during the RD Period. 
 
Vital signs assessment at this visit was accidentally 
omitted from the original protocol. 


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Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Events Table 6  
Additional home health visits at Weeks 3, 5, and 7 in the Repeat 
Dose (RD) Period were added to the RD Schedule of Events 
Table 6 and relevant footnotes. Assessments at these home 
health visits include: vital signs, adverse events (AEs), 
concomitant medications, hematology, chemistry, urinalysis, 
serum C-reactive protein (CRP), nutrition diary, and continuous 
glucose monitoring. 
To ensure subject safety per recommendation from 
regulatory authorities 
Schedule of Events Table 6  
Sample collection for anti-drug antibody (ADA) analysis was 
added at Weeks 2 and 6 in the RD Period. With this update, 
ADA collection occurs at Baseline and Weeks 2, 4, 6, 8, 10, 24, 
and 48 (End of Study Visit).  
Updated per recommendation from regulatory 
authorities 
Schedule of Events Table 6 
Footnote K and the corresponding assessments in the Schedule 
of Events Table 6 were updated to indicate that All imaging 
assessments (liver MRI, liver MRS, Fibroscan or ultrasound 
elastography, and calf MRS) can be conducted within 1 week 
prior to the corresponding visit. 
To minimize subject burden by having the option to 
spread assessments across multiple days 
Schedule of Vital Sign 
Assessments Table 7  
An optional vital sign assessment was added at the time of 
discharge.  
Subjects are monitored in the clinic for 24 hours from 
the end of study drug infusion. This addition of this 
optional vital sign assessment will capture any vital 
signs assessed just prior to discharge.  
Section 5.5 Risk Minimization 
and Section 7.1 Study Design  
The Single Ascending Dose (SAD) cohort data review was 
updated from an internal review to a review by the independent 
Data Monitoring Committee (DMC). Additional text was added 
to clarify that all cumulative data from prior cohorts, when 
applicable, will be reviewed in addition to data from within a 
cohort before subsequent dosing cohorts may begin.  
Updated per recommendation by regulatory authorities  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.5 Risk Minimization, 
Section 7.1 Study Design, and 
Section 7.1.5 Dose Rationale 
The interval between dosing of individual subjects within a 
given SAD cohort was updated from a minimum of 48 hours to 
a minimum of 72 hours.  
• 
Updated to ensure review of post-
treatment laboratory assessments from 
each subject prior to proceeding with the 
next subject 
Schedule of Events Table 4 and 
Table 6 and Section 10.1.1 
Coronavirus Disease 2019 
(COVID-19) Testing 
Coronavirus 2019 (COVID-19) testing by real time – 
polymerase chain reaction (RT-PCR) was added to the Initial 
Screening Visit. 
Updated per recommendation by regulatory authorities 
Schedule of Events Table 4 and 
Table 6 and Section 10.5.4 
Hemoglobin A1C 
Hemoglobin A1C was added to the Initial Screening Visit for 
both the SAD and RD Periods, as well as the Week 12 and 
Week 48/End of Study (EOS) Visit for the RD Period. 
To ensure subject safety per recommendation by 
regulatory authorities 
Section 7.1 Study Design 
Criteria for discharge 24 hours after the end of study drug 
administration were added.  
To ensure subject safety per recommendation by 
regulatory authorities 
Section 7.1 Study Design 
The following statement “Mean weekly protein intake < 20% of 
total calorie intake and mean weekly carbohydrate intake ≥ 60% 
of total calorie intake for subjects will be considered protocol 
deviations” was amended to include “notwithstanding 
temporary changes to diet due to illness.”  
To accommodate subjects who may experience a minor 
viral illness that impacts food intake for a few days 
Schedule of Events Table 6 and 
Section 7.1 Study Design 
Additional text was added to clarify the process in which a 
subject moves through the screening visits (Initial Screening 
Visit, Nutrition Optimization Visits [if needed], and 
Stabilization Visit) in the RD Period. Related text in the 
footnotes of the Schedule of Events Table 6 was also updated 
for clarity.  
To clarify the sequence of events for the screening visits 
in the RD Period 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 Study Design and 
Section 9.1.4 Guidance on 
Communication and Seeking 
Immediate Medical Attention 
Section 9.1.4 Guidance on Communication and Seeking 
Immediate Medical Attention was added. This section provides 
guidance on the encouraged communication between subject, 
primary care provider, and Investigator. This section also 
provides guidance to be provided to subjects on signs and 
symptoms to be vigilant for and how to proceed in the event that 
these signs and symptoms manifest. This section is referenced in 
Section 7.1.  
To ensure subject safety per recommendation from 
regulatory authorities 
Section 5.5 Risk Minimization, 
Section 7.1 Study Design, 
Section 9.1.6 Coronavirus 
Disease 2019 (COVID-19) 
Vaccination, and Section 0 
Exclusion Criteria 
Section 9.1.6 Coronavirus Disease 2019 (COVID-19) 
Vaccination was added to clarify the ability and timing for 
subjects to receive a COVID-19 vaccine. COVID-19 
vaccination is allowed during study participation. COVID-19 
vaccination should not be administered within 48 hours after the 
most recent administration of UX053 and until safety labs 
obtained have been reviewed and the subject has been assessed 
for any possible hypersensitivity reaction to the most recent 
dose of UX053. Consultation with an allergist/immunologist is 
recommended prior to a COVID-19 vaccination if a subject has 
an immediate or severe hypersensitivity reaction to UX053 
(Banerji et al., 2020). A reference to this additional text was 
added to Section 7.1 Study Design.  
Related to this added section, the following exclusion criterion 
was added: “Receipt of only 1 of 2 planned doses of a 
coronavirus disease 2019 (COVID-19) vaccine. Subjects who 
have not received a COVID-19 vaccine, and those who have 
completed COVID-19 vaccination are eligible.”  
Also related to this section, measures taken to minimize risk of 
COVID-19 exposure were added to Section 5.5 Risk 
Minimization.  
Subjects who develop an immediate or severe 
hypersensitivity reaction to UX053 are at risk for having 
a similar reaction to an mRNA based COVID-19 
vaccine due to the similarity of the LNP formulations. 
Based on nonclinical studies, hypersensitivity reactions 
to UX053 are expected to occur within minutes to hours 
following drug administration. Therefore, subject safety 
should be assessed prior to receipt of a COVID-19 
vaccine to ensure subject safety.  
AEs are more likely to occur after the second dose of 
mRNA-based COVID-19 vaccines. Preventing 
enrollment of subjects who have not completed a 
planned second dose of a COVID-19 vaccination 
ensures subject safety. Subjects who have received only 
1 of a planned 2-shot vaccination series should complete 
the vaccination series prior to screening. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4.2 Potential Risks 
for Premedication, Section 7.1 
Study Design, Section 7.1.5 
Dose Rationale, Section 8.3.1 
Discontinuation of 
Intervention, Subject, or Study, 
Section 8.3.2 Subject-level 
Redosing and Stopping 
Criteria, Section 9.1.1 
Premedications, Section 9.1.3 
Clinical Observation and 
Supportive Care, and 
Section 9.5 Rescue Medications 
Section 8.3.2 Subject-level Redosing and Stopping Criteria was 
added; a reference to this section was added in various sections 
of the protocol, as relevant. The following information was 
provided: requirements for redosing study drug, criteria that 
exclude subjects from redosing (eg, developing new or 
worsening symptoms of liver disease, receipt of blood products 
for treatment of consumptive coagulopathy, and specific 
elevations in ALT levels), and action required in the event that 
an IAR occurs, as specified by Common Terminology Criteria 
for Adverse Events (CTCAE) severity. 
Additionally, text in Section 7.1 Study Design was updated to 
reflect that Ultragenyx will notify the DMC immediately if any 
subject experiences an event that satisfies subject-level or 
study-level stopping criteria.  
To ensure subject safety per recommendation from 
regulatory authorities  
Section 7.1 Study Design, 
Section 7.1.4 Dose Rationale, 
Section 8.3.2 Subject-level 
Redosing and Stopping 
Criteria, Section 9.1.1 
Premedications, and 
Section 9.1.3 Clinical 
Observation and Supportive 
Care 
If dexamethasone (or equivalent) is used as a rescue medication, 
premedication with dexamethasone (or equivalent) should be 
considered for all subjects’ subsequent infusions. Previous text 
indicated that dexamethasone (or equivalent) should be 
considered as a premedication only for subjects who required 
dexamethasone (or equivalent) as a rescue medication.  
To ensure subject safety per recommendation from 
regulatory authorities 
Section 7.1.3 Rationale for 
Study Design 
Text was added to expand upon the rationale for the use of a 
placebo control arm.  
Updated per recommendation from regulatory 
authorities 
Section 8.1 Inclusion Criteria 
An additional inclusion criterion was added to ensure enrolled 
subjects have clinically significant disease manifestations that 
are likely to be improved by UX053 treatment.  
Updated per recommendation from regulatory 
authorities  
Section 8.1 Inclusion Criteria 
The following inclusion criterion was added “ALT ≤ 5x ULN 
during the 3 months prior to the Baseline Visit.” 
Updated to facilitate review of potential drug-induced 
liver injury (DILI) signals  


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Brief Rationale 
Section 8.2 Exclusion Criteria  
 
 
 
 
x 
 
 
 
 
 
 
 
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Severe renal 
impairment defined as a defined as a glomerular filtration rate 
*)5P/PLQ(Levey et al., 2005).” 
Subjects with severe renal impairment may be more 
vulnerable to fluid shifts that could occur in the setting 
of a hypersensitivity reaction 
Section 8.2 Exclusion Criteria  
Resistant hypertension was added to the exclusion criterion for 
cardiac diseases: “Significant cardiac disease, including heart 
failure with New York Heart Association (NYHA) Function 
Capacity III or IV or Objective Assessment C or D, unstable 
angina, or ejection fraction (EF) < 35%, or uncontrolled 
arrhythmia or resistant hypertension (Carey et al., 2018). 
Asymptomatic cardiomyopathy and left ventricular hypertrophy 
(LVH) are allowed.” 
Patients with persistent hypertension are at high risk for 
adverse cardiovascular events, despite multiple 
medications; such patients could affect interpretation of 
safety data 
Section 8.2 Exclusion Criteria  
Poorly controlled diabetes and its definitions were added to the 
exclusion criteria 
To ensure subject safety and data interpretability 
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Poorly controlled 
hypothyroidism, based on the judgement of the Investigator or 
Ultragenyx, whichever is most conservative” 
To ensure subject safety and data interpretability 
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “History of 
chronic coagulopathy, thrombophilia, or disorder of 
complement activation” 
To ensure subject safety and safety data interpretability 
CCI
CCI


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Use of 
concomitant medications that alter PT/INR, including warfarin 
and direct oral anticoagulants (eg, rivaroxaban, apixaban, and 
edoxaban). Patients who receive medications that affect platelet 
function, such as aspirin or clopidogrel, are allowed unless they 
have comorbidities that in the judgment of the Investigator place 
them at undue risk to participate in the study.” 
To ensure subject safety and interpretation of potential 
DILI signals  
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Current treatment 
with long-term immunosuppressive medications. This includes 
subjects with autoimmune conditions managed with 
immunosuppressive medications and solid organ transplant 
recipients” 
To ensure subject safety per recommendation from 
regulatory authorities  
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Active 
tuberculosis requiring treatment in the past 3 years” 
To ensure subject safety per recommendation from 
regulatory authorities  
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Symptomatic 
COVID-19 infection” 
To ensure subject safety per recommendation from 
regulatory authorities  
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “History of active 
alcohol and/or drug abuse that in the Investigator’s assessment 
would impair the subject’s ability to comply with the protocol” 
To ensure subject safety per recommendation from 
regulatory authorities  
Section 8.2 Exclusion Criteria  
The following exclusion criterion was added: “Females of 
childbearing potential with hepatocellular adenoma who are 
unwilling to use nonhormonal contraception.” 
To ensure subject safety per recommendations from 
regulatory authorities  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.1 Discontinuation 
of Intervention, Subject, or 
Study  
Ultragenyx will no longer reserve the right to discontinue 
subjects or the study for administrative reasons. Subjects will 
only be removed from the study due to withdrawal of consent. 
Dosing may be discontinued to protect subject’s safety, but 
subjects will remain in the study for safety monitoring purposes, 
unless continued participation in the study poses a risk to the 
subject due to a concurrent medical condition or illness.  
Updated per recommendation from regulatory 
authorities 
Section 8.3.1 Discontinuation 
of Intervention, Subject, or 
Study 
The following text, which is already included as a footnote in 
the Schedule of Events Tables (Table 4 and Table 6), was added 
to Section 8.3.1 Discontinuation of Intervention, Subject, or 
Study: “In the event a subject has an early termination (ET), all 
efforts will be made to monitor the subject through the end of 
the study. At minimum, a safety follow-up phone call will occur 
within the 4 weeks following the subject’s last treatment.” 
To ensure subject safety per recommendation from 
regulatory authorities 
Section 8.3.3 Study Stopping 
Criteria 
The following study stopping criterion was added: 
“Anaphylaxis, as defined by the National Institute of Allergy 
and Infectious Diseases/Food Allergy and Anaphylaxis Network 
(NIAID FAAN) criteria (Table 11), pending a DMC safety 
review”  
To ensure subject safety per recommendation from 
regulatory authorities  
Section 8.3.3 Study Stopping 
Criteria 
The following study stopping criterion was added: “Any 
treatment-emergent adverse event (TEAE) with a severity ≥ 
Grade 3 (CTCAE version 5.0) affecting the cardiopulmonary, 
renal, or neurological systems, regardless of relationship to 
study drug, pending a DMC safety review” 
To ensure subject safety per recommendation from 
regulatory authorities 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.3 Study Stopping 
Criteria 
The following study stopping criterion was modified from 
“Increases in serum concentrations of alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) > 2x from Baseline 
and > 3x the upper limit of normal (ULN), accompanied by 
increases in serum concentrations of total bilirubin > 2x ULN or 
international normalized ratio > 1.5, without any other 
underlying cause that may account for such changes” to 
“Increases in ALT or AST > 2x from Baseline and > 3x the 
ULN, accompanied by total bilirubin > 2x ULN or INR > 1.5, 
without findings of cholestasis (defined as serum ALP activity 
< 2x ULN) and in the absence of a plausible alternate 
explanation.” 
To ensure subject safety per recommendation from 
regulatory authorities 
Section 8.3.3 Study Stopping 
Criteria 
The following study stopping criterion was added: “3 subjects 
develop platelet counts < 50,000 per mm3 (or thrombocytopenia 
≥ Grade 3 in severity)” 
To ensure subject safety per recommendation from 
regulatory authorities 
Section 8.3.3 Study Stopping 
Criteria 
The following study stopping criterion was added: “3 subjects 
develop INR > 1.5 (or INR increase ≥ Grade 2 in severity)” 
To ensure subject safety per recommendation from 
regulatory authorities 
Section 8.3.3 Study Stopping 
Criteria 
The following text was added: “Regulatory authorities will be 
notified immediately if the study stopping criteria are met and 
study enrollment or dosing is halted.” 
Updated per recommendation from regulatory 
authorities 
Section 8.3.4 Subject 
Replacement and Section 11.1 
Sample Size Determination 
Text was added to indicate that subjects will not be replaced if 
they have received any study drug.  
Updated per recommendation from regulatory 
authorities 
Section 9.3 Nutrition 
Management and Section 9.7 
Treatment Compliance  
All instances of “Nutrition Guide” were changed to “Study 
Reference Manual.” 
Nutritional guidance will be available in the Study 
Reference Manual.  
Section 10.1.2 Vital Signs 
Oxygen saturation was added to the list of vital sign 
assessments.  
To ensure subject safety 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.3 
Electrocardiogram  
RR was added to the list of measurements calculated for the 
electrocardiogram assessement.  
To ensure subject safety 
Section 0  
In addition to glycogen content, muscle fat fraction in the calf 
will also be assessed during the calf 13C Magnetic Resonance 
Spectroscopy (MRS) assessment.  
Fatty degeneration of muscle should also be assessed, as 
it can affect the 13C MRS signal for glycogen 
quantitation in muscle.  
Section 10.5.6 AGL Gene 
Sequencing 
Text was added to clarify that blood collected for AGL mutation 
analysis will be analyzed by a central laboratory.  
To clarify the method of analysis  
Appendix 1 Safety Definitions 
and Assessments 
Text was added to define a TEAE.  
Updated per recommendation from regulatory 
authorities 
Appendix 1 Safety Definitions  
Previously, the severity of all AEs were to be graded using the 
Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0, published on November 27, 2017. Text was added 
to reflect that the AE Cytokine Release Syndrome (CRS) will be 
graded by the American Society for Transplantation and 
Cellular Therapy (ASTCT) Consensus Grading for CRS (Lee et 
al., 2019). The grading scale is provided in Table 13. 
Updated per recommendation from regulatory 
authorities  
Appendix 2 Adverse Event 
Collection: Eliciting, 
Recording, and Reporting  
The end of the safety reporting period was updated to 28 days 
following the final dose of study drug or the EOS I (SAD 
Period) and EOS II (RD Period) final study visit, whichever 
occurs later. Additionally, suspected related SAEs can be 
reported at any time following the EOS I/II visit. 
To ensure subject safety  
Appendix 3 Safety Laboratory 
Assessments 
Magnesium and bicarbonate were added to the list of 
assessments included in the standard chemistry panel.  
Magnesium and bicarbonate were accidentally omitted 
from the standard chemistry panel in the original 
protocol.  


Protocol 
 
UX053-CL101 
137 
Confidential 
Amendment 2.3 / 03 January 2022 / Substantial  
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 4 Contraception 
Guidance  
The text “plus 90 days for a full sperm cycle” was removed 
from the following statement: “The time period required is 
generally determined by the pharmacokinetic properties of the 
study product and non-clinical reproductive toxicity data, plus 
90 days for a full sperm cycle.” 
Guidance regarding the time period for contraception 
use in males to prevent pregnancy is 1 month after the 
last dose of UX053, as discussed in the Informed 
Consent Form 


Protocol 
 
UX053-CL101 
138 
Confidential 
STATEMENT OF COMPLIANCE 
Protocol Title: A Phase 1/2 First-in-human, Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Single Ascending Doses and Repeat Doses of UX053 in Patients with GSD 
III  
Protocol Number: UX053-CL101 
Amendment Number and Date: Amendment 3.1 (US-specific) 14 July 2022 
INVESTIGATOR SIGNATURE: 
I have read the Protocol and agree to conduct the study as detailed in this protocol and in 
compliance with the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable 
regulatory requirements and guidelines.  
 
 
 
 
Investigator Signature 
 
Date 
 
Printed Name: _______________________________________________________________ 
 
SPONSOR SIGNATURE: 
As the Sponsor representative, I confirm that Ultragenyx Pharmaceutical Inc will comply with all 
Sponsor obligations as detailed in this protocol and in compliance with the Declaration of 
Helsinki, Good Clinical Practices (GCP), and all applicable regulation requirements and 
guidelines. I will ensure that the Investigator is informed of all relevant information that becomes 
available during the conduct of this study.  
 
 
 
 
  
 
Ultragenyx Pharmaceutical Inc.  
 
Date 
 
PPD

SAP_001.pdf: 
UX053-CL101  
Statistical Analysis Plan  
13 April 2023, Version 1.0 
 
 
Proprietary and Confidential 
Page 1 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Title 
A Phase 1/2 First-in-human, 2-part Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of 
Single Ascending Doses (Part 1: Open-label) and 
Repeat Doses (Part 2: Randomized, Double-blind, 
Placebo-controlled) of UX053 in Patients with GSDIII 
Protocol: 
UX053-CL101 
Investigational Product: UX053 
 
Phase: 
1/2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
 
Date: 
13 April 2023  
Version Number: 
1.0 
 
 
 
 
 
PPD


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TABLE OF CONTENTS 
1 INTRODUCTION ...............................................................................................................9 
2 STUDY OBJECTIVE(S) .....................................................................................................9 
2.1 Primary Objective(s) ...................................................................................................9 
2.2 Secondary Objective(s) ...............................................................................................9 
2.3 Tertiary Objectives ......................................................................................................9 
2.4 Exploratory Objectives .............................................................................................10 
3 STUDY DESIGN...............................................................................................................10 
3.1 Study Population .......................................................................................................14 
3.2 Dosage and Administration .......................................................................................14 
3.3 Blinding and Randomization Methods .....................................................................14 
3.4 Stratification Factors .................................................................................................15 
3.5 Sample Size Considerations ......................................................................................15 
3.6 Data Monitoring Committee .....................................................................................15 
3.7 Planned Analyses ......................................................................................................16 
4 STUDY ENDPOINTS AND COVARIATES ...................................................................16 
4.1 Primary Endpoint(s) ..................................................................................................16 
4.2 Secondary Endpoint(s) ..............................................................................................16 
4.3 Tertiary Endpoints.....................................................................................................16 
 
Safety Tertiary Endpoints ............................................................................16 
4.3.2.   PD/Efficacy Tertiary Endpoints ...................................................................17 
4.4 Exploratory Endpoints ..............................................................................................18 
4.5 Potential Covariate(s) ................................................................................................18 
4.6 Subgroups..................................................................................................................18 
5 DEFINITIONS ...................................................................................................................18 
5.1 Baseline .....................................................................................................................18 


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5.2 Duration of exposure .................................................................................................18 
5.3 Study Day and Study Period .....................................................................................19 
5.4 Age ............................................................................................................................19 
5.5 
 .......................................................................................................19 
5.6 
 ...........................................20 
5.7 
 .................................................................................................20 
5.8 
 ...............................................................................21 
5.9 
 ............22 
5.10 
 .........................................22 
5.11 
) ..................................24 
6 ANALYSIS POPULATIONS ...........................................................................................25 
6.1 Safety Analysis Set ...................................................................................................25 
6.2 Per Protocol Analysis Set ..........................................................................................25 
6.3 Pharmacokinetics Analysis Set .................................................................................25 
7 STATISTICAL METHODS OF ANALYSES ..................................................................25 
7.1 General Principles .....................................................................................................25 
7.2 Subject Accountability ..............................................................................................26 
7.3 Protocol Deviations ...................................................................................................26 
7.4 Extent of Exposure ....................................................................................................26 
7.5 Demographic and Baseline Characteristics...............................................................26 
7.6 Prior and Concomitant Medication ...........................................................................26 
7.7 Analysis of Primary Endpoints .................................................................................27 
7.8 Analysis of Secondary Endpoints .............................................................................28 
7.9 Analysis of Tertiary Endpoints .................................................................................28 
 
Nutrition Diary data .....................................................................................29 
7.10 Analysis of Exploratory Endpoints ...........................................................................29 
7.11 Analysis of Other Endpoints .....................................................................................30 


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 Vital Signs ...................................................................................................30 
 Electrocardiogram .......................................................................................30 
 Urine Pregnancy Test ..................................................................................30 
8 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................30 
9 REFERENCES ..................................................................................................................31 
10 APPENDICES ...................................................................................................................32 
10.1 Handling of Missing and Incomplete Data ...............................................................32 
 Missing Medical History Related Dates ......................................................32 
 Missing Birth Dates .....................................................................................32 
 Missing Date Imputation for Adverse Events and Concomitant 
Medications .................................................................................................32 
 Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................33 
 
 .........33 
 Missing Data for Other Efficacy Endpoints ................................................36 
 Visit Time Windows ...................................................................................36 
10.2 Endpoints Derivation Details ....................................................................................37 
 
 ...........................................................................................37 
10.2.1.1 
 ...............................................................................37 
10.2.1.2 
 ...............................................................................37 
10.2.1.3 
 
 ......................................................................................38 
10.2.1.4 
....................................................................................38 
10.2.1.5 
 ..........39 
10.3 Schedule of Evaluations: ...........................................................................................41 
10.4 Visit Window Example .............................................................................................47 
 
 
 


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ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AGL 
amylo-α-1,6-glucosidase 4-alpha-glucanotransferase 
AH50 
alternative complement activity 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf 
AUC from time 0 to infinity 
AUClast 
AUC from time 0 to the last measurable concentration 
AUCtau 
AUC from time 0 to end of dosing period 
BNP 
B-type natriuretic peptide 
BL 
Baseline 
BUN 
blood urea nitrogen 
CAP 
controlled attenuation parameter 
CBC/diff 
complete blood count with differential 
CH50 
classical pathway complement activity 
CK 
creatinine kinase 
CK-M/B 
CK – muscle/brain  
CL 
clearance 
Cmax 
maximum observed concentration 
COVID-19 
corona virus disease 2019 
CRF 
case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP2B6 
cytochrome P450 2B6 
DMC 
Data Monitoring Committee 
 
 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EF 
ejection fraction 
EOS 
end of study 


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ET 
early termination 
EU 
European Union  
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FIH 
first-in-human  
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDE 
glycogen debranching enzyme 
GGT 
gamma-glutamyl transpeptidase 
Glc4 
glucose tetrasaccharide 
GNEM-FAS 
GNE Myopathy Functional Activities Scale 
GMP 
Good Manufacturing Practices  
GSD 
glycogen storage disease 
HDL 
high density lipoprotein 
HED 
human equivalent dose 
HEENT 
head, eyes, ears, nose, and throat 
Hex4 
hexose tetrasaccharide 
HHD 
handheld dynamometry  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IAR 
infusion-associated reaction 
IL-6 
Interleukin-6 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IP 
investigational product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRT 
interactive response technology  
ISV 
Initial Screening Visit 
ITT 
Intention to Treat 
IV 
intravenous  
 
 


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LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LDL-R 
low density lipoprotein-receptor  
LEC 
lower extremity composite 
LFTs 
liver function tests 
LNP 
lipid nanoparticle  
LV 
left ventricular 
LVH 
left ventricular hypertrophy  
LVM 
left ventricular mass 
LSM 
liver stiffness measurement 
MCH 
mean corpuscular hemoglobin  
MCHC 
MCH concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MRI 
magnetic resonance imaging  
MRS 
magnetic resonance spectroscopy  
MTD 
maximum tolerated dose 
NOAEL 
no-observed adverse effect level 
NOV 
Nutrition Optimization Visit 
NYHA 
New York Heart Association  
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic(s) 
 
 
PK 
pharmacokinetic(s) 
PP 
Per Protocol 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
preferred term 
PT/INR 
prothrombin time/international normalized ratio 
Q2W 
every 2 weeks 
RAUC 
accumulation ratio (calculated as AUC after repeat dose / AUC after a single 
dose) 
RD 
repeat dose 
SAD 
single ascending dose 


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SAE 
serious adverse event 
SAP 
statistical analysis plan 
sC5b-9 
soluble Complement 5b-9 
SF 
shortening fraction  
SF-36v2 
Short Form Health Survey 36 version 2 
SOC 
System Organ Class  
STV 
Stabilization Visit 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half life 
TEAE 
treatment-emergent adverse event 
Tlast 
time of last measurable concentration 
Tmax 
time of maximum observed concentration 
UEC 
upper extremity composite 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at a steady state 
WBC 
white blood cell 
WHO 
World Health Organization 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the UX053-CL101 Protocol dated 3 January 2022. 
Changes from these guidelines must be substantiated by sound statistical reasoning and 
documented in the clinical study report (CSR). 
Should there be a difference between the SAP and the protocol with respect to data analysis, 
the SAP will take precedence over the protocol. 
2 STUDY OBJECTIVE(S) 
2.1 
Primary Objective(s) 
The primary objective of the study is to evaluate the safety of UX053 in adults with 
Glycogen Storage Disease (GSD) III. 
2.2 
Secondary Objective(s) 
The secondary objective of the study is to characterize the PK of UX053 in adults with GSD 
III. 
2.3 
Tertiary Objectives 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.4 
Exploratory Objectives 
 
 
3 STUDY DESIGN 
UX053-CL101 is a phase 1/2 FIH, 2-part study to evaluate the safety, tolerability, and PK of 
a single ascending dose (SAD; part 1) and repeat doses (RD; part 2) of UX053 in patients 
with GSD III (Figure 1). SAD and RD of UX053 are tested in separate cohorts. The SAD 
cohorts will be open-label, while the RD dose cohorts will be randomized, double-blind, and 
placebo-controlled. 
Part 1: Single Ascending Dose Period 
All subjects in the SAD Period will undergo a Screening Visit prior to their Baseline Visit. 
The SAD Period will consist of 4 cohorts, each consisting of 2-3 subjects, all of whom will 
receive open-label UX053 (Figure 1). The planned dose escalation will proceed from 0.05 
mg/kg in cohort 1S, to 0.10 mg/kg in cohort 2S, to 0.20 mg/kg in cohort 3S, and to 0.30 
mg/kg in cohort 4S. During the SAD Period, the independent Data Monitoring Committee 
(DMC) will review at least 2 weeks of safety data for all subjects within a cohort and the 
cumulative data from all subjects in prior dosing cohorts (when applicable) before deciding 
to proceed with the next SAD cohort. Dose levels for each cohort, in either the SAD or RD 
Period (described below), may be reduced depending on safety findings from prior cohorts. 
Each subject in the SAD Period of the study will be followed for 90 days after dosing. 
Additional subjects may be added to SAD cohorts at the discretion of Ultragenyx to further 
characterize safety and PD effects.  
Part 2: Repeat Dose Period 
All subjects in the RD Period will participate in a Screening Period (approximately 8 to 
12 weeks), in which subjects will be screened for study eligibility and assessed for the need 
to optimize their diet based on nutrition guidelines for adults with GSD III based on expert 
recommendations (Table 1). Within the first 2 weeks after the Initial Screening Visit (ISV), 
the Investigator will review nutrition diary data to determine if nutrition optimization is 
needed. To facilitate progression through the screening period, subjects should be scheduled 
for a phone visit to occur 2 weeks after the ISV. If nutrition optimization is not needed, 
subjects will be informed at the 2-week follow-up ISV phone call that they can proceed to the 
Nutrition Stabilization Visit (STV). 
If nutrition changes are needed, a 2 to 4 week period of nutrition optimization, including 
Nutrition Optimization Visits (NOV), will be performed to comply with GSD III-specific 
nutrition guidelines based on expert recommendations (Table 1). If nutrition optimization is 
needed, the 2-week follow-up ISV phone call becomes an NOV. During nutrition 
optimization, NOV phone visits may occur weekly or more frequently, nutrition diary and 
continual glucose monitoring (CGM) data may be reviewed, and safety laboratory tests may 
be obtained at the discretion of the Investigator. During NOVs, advice is provided to the 
subject on what dietary changes should be made and when safety labs, if any, will be 


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obtained. During nutrition optimization, the Investigator will review nutrition diaries and any 
available labs, ideally on a weekly basis, and determine when the subject has achieved 
nutritional compliance per protocol. When nutritional compliance per protocol is achieved, 
the site will call the subject to schedule the STV. 
After nutrition changes are made (if necessary), all subjects will proceed to a nutrition STV 
that will occur at least 6 weeks prior to the Baseline Visit. No substantial nutrition changes 
should be made after the STV for the remainder of the study. Due to the staggered nature of 
the cohorts (described below), a subject may be in nutrition stabilization for longer than 6 
weeks before their Baseline Visit; in such instances, the total duration of the Screening 
Period may exceed 12 weeks. Nutrition guidance and monitoring for this study was 
established with available health authority guidance, and greater detail is available in the 
Study Reference Manual. 
Table 1: 
Nutrition Guidelines for Adults with GSD III 
High protein intake with a target of ≥ 25% of total calories  
Low complex carbohydrates intake with a target of < 50% of total calories 
Minimal intake of simple sugars 
Avoidance of fasting 
Consideration of high-protein bedtime snack or a high-protein formula for overnight enteral feeding 
Based on expert guidelines (Kishnani et al., 2010) 
Mean weekly protein intake < 20% of total calorie intake and mean weekly carbohydrate 
intake ≥ 60% of total calorie intake for subjects will be considered protocol deviations, 
notwithstanding temporary changes to diet due to illness. The classification of such 
deviations will be determined by the magnitude, frequency, and duration of excursions 
beyond the specified guidelines. 
In the RD Period, treatment-naive subjects will be randomized 3:1 to UX053 or placebo in 
ascending dose cohorts (4 subjects per cohort). Subjects enrolled in RD cohorts will receive 
study drug every 2 weeks (Q2W); a total of 5 doses of study drug are planned (Figure 1). 
Planned dose levels will be the same as for the SAD cohorts: 0.05 mg/kg in cohort 1R, 
0.10 mg/kg in cohort 2R, 0.20 mg/kg in cohort 3R, and 0.30 mg/kg in cohort 4R. Dose 
escalation will be guided by DMC review of at least 6 weeks of safety data and any available 
PD and preliminary efficacy data from all subjects within a cohort and the cumulative data 
from all subjects in prior cohorts before proceeding with subsequent cohorts. At any time 
Ultragenyx may decide to stop dose escalation (ie, not initiate a planned dose cohort) or test 
intermediate dose levels. If safety data for all planned dose cohorts up to 0.30 mg/kg RD are 
acceptable and there is limited evidence of efficacy or PD effects through Week 12 from the 
0.30 mg/kg RD cohort (4R), a 5th RD cohort receiving 0.45 mg/kg (cohort 5R not shown in 
Figure 1) may be added. Given the accumulation of safety data at this stage, no SAD cohort 
with 0.45 mg/kg is planned prior to the potential RD cohort 5R.   


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Cohort 1R may begin after review of safety data from cohort 2S. During the RD Period, an 
unblinded DMC will review at least 6 weeks of safety data from cohort 1R and all available 
data from prior cohorts before providing a recommendation for proceeding with cohort 2R. 
The same review and recommendation process will be used to determine the initiation for 
each of the remaining RD cohorts.  
If a subject develops a treatment-emergent adverse event (TEAE)/serious TEAE ≥ Grade 3 
that is considered by the Investigator to be related to study drug or an intolerable TEAE 
during the RD Period, subject-level dose reductions are allowed in consultation with the 
Medical Monitor, as outlined in the guidance provided in the Pharmacy Manual. 
Additionally, dose levels for each cohort may be reduced or higher dose cohorts may not be 
initiated, depending on safety and PD findings from prior cohorts. Ultragenyx will notify the 
DMC immediately if any subject experiences an event that satisfies subject-level stopping 
criteria or study-level stopping criteria. Additional subjects in blocks of 4 may be added to 
RD cohorts at the discretion of Ultragenyx to further characterize safety and PD effects, with 
input from the DMC.  
 
 


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Figure 1: 
UX053-CL101 Study Design 
 
Note: Additional subjects may be included in any cohort at the discretion of Ultragenyx. Dose levels for each 
cohort, in either the SAD or RD Period, may be reduced depending on safety findings from prior cohorts. 
Additional cohort(s) at dose levels between 0.10 mg/kg to 0.45 mg/kg may also be included pending review 
of safety data.  
Q2W, every 2 weeks; RD, Repeat Dose; SAD, Single Ascending Dose.  


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3.1 
Study Population 
Approximately 26-30 subjects will be enrolled in this study. The study will be conducted in 
adult subjects with a confirmed diagnosis of GSD III (ages ≥ 18 years). Subjects who are in 
participating in the RD Period are required to maintain a stable diet consistent with the 
nutrition guidelines based on expert recommendations after Nutrition Optimization during 
screening through the remainder of the study. Another key entry criteria is the exclusion of 
subjects with a history of liver transplant, history or cirrhosis, current hepatitis B or C 
infection or history of chronic hepatitis B or C infection, history of hepatocellular carcinoma. 
Additional entry criteria are outlined in the protocol.  
3.2 
Dosage and Administration 
UX053 will be administered as an intravenous (IV) infusion over the course of at least 4 
hours, with a slower rate of infusion for the first hour to minimize the risk of hypersensitivity 
or anaphylactoid-type reactions (refer to the Pharmacy Manual for additional infusion 
details). All subjects, including those treated with placebo, will receive premedication at least 
1 hour prior to the infusion, consisting of oral paracetamol/acetaminophen (500 mg) or 
ibuprofen (400 to 800 mg), an H2 blocker (eg, famotidine 20 mg or equivalent dose of 
another H2 blocker), and an H1 blocker (eg, cetirizine 10 mg or equivalent dose of another 
H1 blocker). For the premedication, paracetamol/acetaminophen is preferred over ibuprofen. 
At the discretion of the Investigator, with input from Ultragenyx and the DMC, and based on 
the emerging safety profile of UX053, additional premedications and rescue medications may 
be used to reduce the risk and severity of immune reactions in RD cohorts.  
In each cohort, subjects will be dosed sequentially with a minimum of 72 hours in between 
dosing for each subject’s first dose. For example, the second subject in a cohort receives their 
first dose after a minimum of 72 hours after the first subject in the same cohort received their 
first dose. For subjects in the RD period, after sequential dosing for the first dose, subjects 
maintain a Q2W dosing regimen. 
3.3 
Blinding and Randomization Methods 
In the SAD Period of the study, all subjects receive open-label UX053. In the RD Period of 
the study, subjects are randomized 3:1 to UX053 and Placebo, using an interactive response 
technology (IRT) system. The RD Period of the study is double-blind. Each subject will be 
assigned a unique identification number. 
Blind conditions will be established so that Ultragenyx, the subject, and site personnel will 
not know the identity of a subject’s treatment during the RD Period of the study. The only 
unblinded Ultragenyx members, who will be involved, as needed, in the preparation of the 
unblinded DMC outputs, are the Independent Statistician, Independent Statistical 
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Randomization using an IRT system will ensure subjects in the RD Period of the study are 
blind to treatment. Due to the difference in opacities of the UX053 and the placebo, an 
unblinded pharmacist will prepare the study drug and an unblinded nurse will prepare the 
infusion before masking the infusion syringe and tubing with colored covers. Prespecified 
employees from Ultragenyx who do not have any contact with the investigative sites may 
also be unblinded as specified in the Blinding Plan.  
All imaging assessments will be sent to central readers for evaluation. Readers will be 
blinded to the subject’s treatment.  
Treatment assignment for an individual subject should be unblinded by the Investigator only 
in an emergency, and only if when knowledge of the treatment assignment is urgently needed 
for the clinical management or welfare of the subject. Unblinding at the study site for any 
other reason will be considered a protocol deviation.  
The Investigator is strongly encouraged to contact Ultragenyx before unblinding any 
subject’s treatment assignment, but priority should be given to the safety of the subject. 
3.4 
Stratification Factors 
Not Applicable. 
3.5 
Sample Size Considerations 
The sample size for this study is based on practical considerations and is consistent with a 
FIH study in a rare disease population. Approximately 26 to 30 subjects will enroll in this 
study, with a minimum of 10 subjects in the SAD period, 16 subjects in the RD period, and 
with the option to enroll additional subjects in any cohort to further characterize safety or PD 
findings. With at least 10 subjects receiving UX053 in the SAD Period, there is an 89% 
chance of detecting a more common AE given the TEAE has a true incidence of 20%. If at 
least 22 subjects receive UX053 in both SAD and RD Periods, there is a 90% chance of 
detecting a TEAE with true incidence of 10%. 
Subjects will be replaced at Ultragenyx’s discretion only if they have not received study 
drug. Subjects will not be replaced if they have received any study drug.  
3.6 
Data Monitoring Committee 
An independent DMC will be constituted with experts in metabolic liver disease, GSD III, 
and/or immune activation and will act in an advisory capacity to Ultragenyx. Additionally, at 
least one of the DMC members will have expertise concerning statistical methods used in the 
design and analysis of clinical trials.  
The DMC will meet and review study data at the frequency defined and in accordance with 
the scope and objectives set forth in the DMC Charter. The DMC may provide advice to 
Ultragenyx regarding the safety of subjects, the ethics of the study and the continuing 
scientific validity of the study. The DMC may also make recommendations to Ultragenyx 
concerning continuation, termination or other modifications of the study based on their 


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review of data. Further details regarding the DMC can be found in the DMC charter, which 
will be available prior to the administration of investigational product (IP). 
Ultragenyx will review the DMC recommendations and determine necessary actions that will 
be communicated accordingly to all stakeholders, eg, Regulatory Authorities, IRBs/IECs, and 
Investigators. 
3.7 
Planned Analyses 
Analyses are planned for each data review described in the study design (Section 3). During 
the SAD Period, an unblinded DMC will review at least 2 weeks of safety data for all 
subjects within a cohort before deciding to proceed with the next SAD cohort. During the RD 
Period, the unblinded DMC will review at least 6 weeks of safety from cohort 1R and all 
available data from prior cohorts before providing a recommendation for proceeding with 
cohort 2R. The same review and recommendation process will be used to determine the 
initiation for each of the remaining RD cohorts. 
4 STUDY ENDPOINTS AND COVARIATES  
The full schedule of assessments is shown in Appendix 12.4.  
4.1 
Primary Endpoint(s) 
• The incidence and severity of TEAEs, serious TEAEs, and related TEAEs. 
4.2 
Secondary Endpoint(s) 
• PK parameters of AGL mRNA and ATX95, including Tmax, Cmax, AUClast, AUCinf, 
Tlast, T1/2, CL, Vss. 
4.3 
Tertiary Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 


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•  
4.3.2.   PD/Efficacy Tertiary Endpoints 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
CCI
CCI


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4.4 
Exploratory Endpoints 
 
 
 
 
4.5 
Potential Covariate(s) 
Not Applicable. 
4.6 
Subgroups 
If a sufficient number of subjects with different disease subtypes (IIIa, IIIb, IIIc, and IIId) are 
enrolled, subgroup summaries by disease subtype may be provided at the discretion of 
Ultragenyx. 
5 DEFINITIONS 
5.1 
Baseline 
Baseline is defined as the last non-missing assessments prior to or on the date of initiation of 
the first dose of investigational product.  
For nutrition diary data, baseline is defined as the average of all complete days (all values 
between screening and prior to dosing in SAD and between Stabilization Visit and prior to 
Dosing in RD). For CGM data, baseline is defined as the average of all daily measurements 
collected prior to the day of the first dose of IP administration. 
5.2 
Duration of exposure  
Duration of exposure in days is defined as the last dose of investigational product – first dose 
of investigational product + 14 days. 
CCI
CCI


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5.3 
Study Day and Study Period 
If the visit date is on or after the first dose of IP administration:  
• Study day = visit date – date of the first dose of IP administration + 1.  
If the visit date is prior to the first dose of IP administration:  
• Study day = visit date – date of the first dose of IP administration.  
There are three analysis periods in this study: Screening (data collected before the first IP 
dose), Treatment (from first IP dose up to two weeks after the last IP dose) and Follow-up 
Period (from two weeks after the last IP dose up to the last measurement in the study). 
5.4 
Age 
Unless specified, the age will be derived based on the informed consent date: Age = (Inform 
Consent Date – Birth Date +1)/365.25. The age will be rounded down to the nearest years, 
keeping 1 decimal place.  
If birth date is missing, the birth date will be imputed to calculate age (See Section 7.3 for the 
algorithm to impute birth date). 
5.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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5.6 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
5.7 
 
 
 
 
 
 
 
 
 
5.8 
 
 
 
 
 
  
 
 
 


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5.9 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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5.10 
 
 
 
 
 
 
 
 
 
 
 
5.11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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5.12 
 
 
 
 
 
 
 
 
 
 
 


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6 ANALYSIS POPULATIONS 
6.1 
Safety Analysis Set 
Safety analysis set will include all enrolled subjects who received any volume of UX053. 
The primary analysis will be performed on the Safety Analysis Set.  
6.2 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will exclude subjects from Safety Analysis Set with 
major protocol deviations that may impact PD or efficacy analysis. Reasons for exclusion 
will be documented for each subject. If deemed appropriate, a sensitivity analysis will be 
performed on the PP Analysis Set. 
6.3 
Pharmacokinetics Analysis Set 
The Pharmacokinetics (PK) Analysis Set is the subset of subjects in the Safety analysis set 
who have at least 1 evaluable IP concentration. The PK analysis set will be used for the 
analysis of the PK endpoints. 
7 STATISTICAL METHODS OF ANALYSES 
7.1 
General Principles 
Descriptive statistics will be provided for selected demographics, safety, PK, and PD data. If 
a sufficient number of subjects with different disease subtypes are enrolled, subgroup 
summaries by disease subtype may be provided at the discretion of Ultragenyx. Continuous 
variables will be summarized by number of subjects and mean, SD and/or SE, median, 
minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of subjects. Data will be summarized with descriptive statistics for the Screening 
Period. 
The subject-level and cohort-level graphs of endpoints measurements over time will 
highlight the three periods of the study: Screening (data collected before the first IP dose), 
Treatment (from first IP dose up to two weeks after the IP dose) and Follow-up Period (from 
two weeks after the IP dose up to the last measurement in the study). 
Although they are eligible, it is expected that few patients with GSD IIIb, IIIc, or IIId will 
enroll. Subjects with GSD IIIb/c/d will participate in all assessments, including muscle 
imaging and function tests, and will be included in all safety analyses. Sensitivity analyses 
for cardiac and skeletal muscle endpoints that exclude patients with GSD IIIb/c/d may be 
conducted.  
The analysis will be presented by cohort and total group (Table 3). All raw data obtained 
from the CRFs will be included in data listings.  


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Table 2 Analysis Groups in the SAD Period 
Cohort 1 
Cohort 2 
Total 
 
7.2 
Subject Accountability 
The number and percentage of subjects in study populations will be summarized for each 
period. Subject disposition table will also include the number of subjects screened, and 
enrolled. No formal statistical comparisons will be performed. 
Screen-failure subjects (ie, subjects screened but not enrolled) and the associated reasons for 
failure to enroll will be tabulated overall for the Screened Population. The reasons for 
premature discontinuation from study as recorded on electronic case report forms (eCRFs) 
will be summarized. 
7.3 
Protocol Deviations 
Major and Minor Protocol deviations will be separately summarized by analysis group in 
each period. Both major and minor protocol deviations will be listed. 
At the discretion of the Ultragenyx, major protocol violations may result in the removal of a 
subject’s data from the PP Analysis Set. Ultragenyx will be responsible for producing the 
final protocol violation file; this file will include a description of the protocol violation, and 
clearly identify whether this violation warrants exclusion from the PP Analysis Set.  
7.4 
Extent of Exposure 
The cumulative dose administered and duration of exposure will be summarized overall and 
by cohort. 
7.5 
Demographic and Baseline Characteristics 
Demographic parameters (age, age group, race, ethnicity, sex, weight, height, and body mass 
index) and other baseline characteristics will be summarized descriptively by period and 
cohort. 
7.6 
Prior and Concomitant Medication 
Prior medications are defined as medications with start date and end date before the first dose 
of IP. 
Concomitant medications are defined as medications with end date on or after the first dose 
of IP or ongoing. 
 


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Both prior and concomitant medications will be coded by drug name and therapeutic class 
using World Health Organization (WHO) Drug Dictionary, version B3 September 2020. If a 
subject took a specific medication multiple times or took multiple medications within a 
specific therapeutic class, that subject will be counted only once for the coded drug name or 
therapeutic class. 
Prior and Concomitant medication will be presented by analysis group in each period. 
7.7 
 Analysis of Primary Endpoints 
The primary analysis endpoint is the incidence and severity of TEAEs, serious TEAEs, and 
related TEAEs in the SAD and RD Periods. The primary analyses will be based on Safety 
Analysis Set and displayed by analysis group in each period. 
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA version 23.1 or above). 
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurred on or after the first dose of investigational product and was not present 
prior to the first dose, or it was present at the first dose but increased in severity or frequency. 
TEAE will be separately reported in SAD and RD Period. 
Subject incidence of TEAEs and percentages will be tabulated as the following: 
• TEAEs by analysis group in each period, SOC and PT (preferred term) (sorted by 
descending frequency in the pooled UX053 group by SOC and PT) 
• Related TEAEs by analysis group in each period, SOC and PT (sorted by descending 
frequency by SOC and PT)  
• Serious TEAEs by analysis group in each period, SOC and PT (sorted by descending 
frequency by SOC and PT) 
• Serious Related TEAEs by analysis group in each period, SOC and PT (sorted by 
descending frequency by SOC and PT). 
• TEAE by greatest severity, SOC and PT 
• Deaths by analysis group in each period, SOC and PT (sorted by descending 
frequency by SOC and PT). 
• TEAEs leading to discontinuation of study by analysis group in each period, SOC and 
PT (sorted by descending frequency by SOC and PT). 
Detailed listings for all AEs, serious TEAEs, AEs leading to the discontinuation of study, 
AEs leading to the discontinuation of treatment, and death will also be generated.  


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The severity of all AEs will be based on Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, published on November 27, 2017, unless the AE is Cytokine Release 
Syndrome (CRS), in which case the AE will be graded by the American Society for 
Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS (Lee et al. 2019). If 
an AE cannot be graded based on CTCAE, the investigator will assign a severity based on 1 
= mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = Death. 
7.8 
Analysis of Secondary Endpoints 
The secondary analysis endpoints are the PK parameters of AGL mRNA and ATX95, 
including Tmax, Cmax, AUClast, AUCinf, AUCtau (RD Period only), RAUC (RD Period only), 
Tlast, T1/2, CL, Vss (SAD Period only). The secondary analyses will be analyzed for the PK 
Analysis Set and PP Analysis Set, if applicable. 
Descriptive statistics will be summarized by number of subjects and arithmetic mean, SD, 
CV%, geometric mean, geometric SD, geometric CV%, median, minimum and maximum 
values for these PK parameters by analysis group in each applicable period, excluding total 
group in RD period. For Tmax, only median, minimum and maximum values will be 
presented.  
7.9 
Analysis of Tertiary Endpoints 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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•  
  
 
Nutrition Diary data 
Nutrition diary data such as daily caloric intake (total kcalories), daily protein intake (grams 
and % of total caloric intake), daily total carbohydrate intake (grams and % of total caloric 
intake), daily non-cornstarch carbohydrate intake (grams and % of total caloric intake), daily 
cornstarch intake (grams, grams/kg and % of total caloric intake), daily fat intake (grams % 
of total caloric intake), and daily sugar intake (grams) will be listed by cohort and visit. 
Weekly descriptive summaries for all the nutrition diary components will be provided.  
At least 3 complete days out of 7 will be necessary for the calculation of mean weekly 
intakes. For each week, if more than 4 days are either missing or not checked as complete, 
the nutrition diary data is considered missing for that week.  
The following sensitivity analysis may be considered:  
• 
Exclude data from days marked complete and with total caloric intake less than 500 
kcals and 
• Include data from days not marked as complete and with total caloric intake within 
one standard deviation of the average of days completed.   
 
All data, regardless of completeness status, will be included in the listings. 
 
7.10 
Analysis of Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
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7.11 
Analysis of Other Endpoints 
 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressures, heart rate, 
respiration rate, temperature (C) and weight) and changes from baseline values at each visit 
and at the end of study will be presented by analysis group in each period. Individual subject 
listing and individual plots over time of vital signs parameters during dosing and separately 
over time for all visits will be provided. 
 
Electrocardiogram 
Descriptive statistics for the absolute measurements and changes from baseline for selected 
ECG parameters will be reported. These include the following intervals: QT, QT corrected 
for heart rate, the time elapsed from the onset of atrial depolarization to the onset of 
ventricular depolarization (PR), and time elapsed for depolarization of the ventricles (QRS).  
The frequency of subjects with a maximum increase from baseline in the QTc interval will be 
summarized according to the following categories: > 30 ms and > 60 ms. In addition, the 
frequency of subjects with QTc post dose values according to the following categories: > 450 
ms, > 480 ms and > 500 ms, will be summarized. 
The normality or abnormality of the ECG tracing will be summarized using shift tables of 
numbers of subjects who have a normal/abnormal ECG tracing at each scheduled time of 
assessment.  
A listing of all ECG parameters including the overall assessment will also be created. 
 
Urine Pregnancy Test 
Urine pregnancy test results will be listed. 
8 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Due to administrative reasons, the study terminated after enrollment of 4 subjects in Cohort 
1S and 4 subjects in Cohort 2S. As such, only analyses specific to SAD cohorts 1S and 2S 
will be provided. 
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9 REFERENCES 
Bohannon, RW. 1997. "Reference values for extremity muscle strength obtained by hand-
held dynamometry from adults aged 20 to 79 years." Arch Phys Med Rehabil 78 
(1):26-32. 
Bonder, A and Afdhal, N. 2014 "Utilization of FibroScan in Clinical Practice". Curr 
Gastroenterol Rep 16:372 
Broderick, JE, DeWitt, EM, Rothrock, N, Crane, PK, and Forrest, CB. 2013. "Advances in 
Patient-Reported Outcomes: The NIH PROMIS Measures." EGEMS (Wash DC) 1 
(1):1015. 
Friedrich-Rust, M, Ong, MF, Martens, S, Sarrazin, C, Bojunga, J, Zeuzem, S and Herrmann, 
E. 2008. "Performance of Transient Elastgraphy for the Staging of Liver Fibrosis: A 
Meta-Analysis" Gastroenterology 134:960-974 
Mathiowetz, V,  et.all. 1985. “Grip & Pinch Strength: Normative Data for Adults”. Archives 
of Physical Medicine and  Rehabilitation 66(2): 69-72. 
Mayhew, J, Bonner, N, Arbuckle, R, Turnbull, A, Bowden, A, and Skrinar, A. 2017. 
"Development and preliminary evidence of the psychometric properties of the GNE 
myopathy functional activity scale." J Comp Eff Res 7 (4):381-395. 
NIH. 2015. PROMIS  2015 [cited January 2015]. Available from 
http://www.nihpromis.org/default.aspx#6. 
NIMS. 1996. "Muscular weakness assessment: use of normal isometric strength data. The 
National Isometric Muscle Strength (NIMS) Database Consortium." Arch Phys Med 
Rehabil 77 (12):1251-5. 
Peters, MJ, van Nes, SI, Vanhoutte, EK, Bakkers, M, van Doorn, PA, Merkies, IS, Faber, 
CG, and PeriNom, SSg. 2011. "Revised normative values for grip strength with the 
Jamar dynamometer." J Peripher Nerv Syst 16 (1):47-50. 
Skrinar, AM, Argov, Z, Caraco, Y, Kolodny, E, Lau, H, Pestronk, A, Shieh, P, Bronstein, F, 
Esposito, A, and Feinsod-Meiri, Y. 2013. "P. 3.1 GNE myopathy functional activity 
scale (GNEM-FAS): Development of a disease-specific instrument for measuring 
function and independence." Neuromuscul Disord 23 (9):755. 
Tsochatzis, EA, Gurusamy, KS, Ntaoula, S, Cholongitas, E, Davidson, BR and Burroughs, 
AK. 2011 Elastography for the diagnosis of severity of fibrosis in chonic liver 
disease: A meta-analysis of diagnostoc accuracy". Journal of Hepatology 54: 650-659  
Visser, J, Mans, E, de Visser, M, van den Berg-Vos, RM, Franssen, H, de Jong, JM, van den 
Berg, LH, Wokke, JH, and de Haan, RJ. 2003. "Comparison of maximal voluntary 


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isometric contraction and hand-held dynamometry in measuring muscle strength of 
patients with progressive lower motor neuron syndrome." Neuromuscul Disord 13 
(9):744-50. 
 
10  APPENDICES 
10.1 Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through the data quality review plan for this study. Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
study database lock or snapshot. 
Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
 
Missing Medical History Related Dates  
• If only day is missing, impute 1. 
• If month is missing, impute January 1st. 
• If year is missing, then no imputation will be done; the date will be missing.  
• If the imputed start date is earlier than the birth date, then the birth date will be used. 
• If the imputed end date is earlier than the start date, the start date will be used. 
 
Missing Birth Dates 
To impute missing birth date, the following rules will be applied: 
• If day is missing, impute 15. 
• If month is missing, impute June. 
• If year is missing, then no imputation will be done; the date will be missing.  
If the imputed date is later than any study visit date/observed adverse event start date/ 
observed concomitant medication start date, then earliest available visit date/adverse event 
start date/ concomitant medication start date will be used without changing observed 
information. 
 
Missing Date Imputation for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications. Note that the imputed values outlined here may not 
always provide the most conservative date.  


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Missing Start Dates 
• If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this study, then impute the month and day of the first dose date in this study. 
o Otherwise, assign ‘January’  
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 
Missing Stop Dates (for AEs not ongoing) 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value, and the event will be considered ongoing. If the AE has been recorded 
as resolved/recovered, all efforts should be made to obtain the date from the 
Investigator. 
If the resulting end date is after the date of study completion / discontinuation/ data 
cutoff, set the imputed end date as close to the date of study completion / discontinuation/ 
data cutoff as possible without overwritten existing information 
If the year is missing for the start date, and stop date (observed or imputed) is on or after the 
first dose or event is ongoing. The start date will be imputed as the first dose date. 
 
Missing Causal Relationship to Investigational Product for Adverse Events 
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of double-blind investigational product, a causality of “related” 
will be assigned. The imputed values for causal relationship to investigational product will be 
used for the incidence summary; the values will be shown as missing in the data listings. 
 
  
 
 


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Table 3 
 
  
  
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
  
 
  
 
 
 
 
 
 
 
 
  


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• 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  


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Missing Data for Other Efficacy Endpoints 
When a change from baseline is assessed, missing data will not be imputed and only subjects 
with a baseline and at least 1 post-baseline measurement will be included in the analysis.  
For the weekly nutrition diary data, at least 3 complete days out of 7 will be necessary for the 
calculation of mean weekly intakes. For each week, if more than 4 days are either missing or 
not checked as complete, the nutrition diary data is considered missing for that week. 
 
 
 
 
Visit Time Windows 
For an unscheduled visit that occurred after the first dose date of IP, the unscheduled visit 
will be mapped into the closest post-baseline study scheduled visit for the assessment based 
on the study day of the unscheduled visit, and the target study day of the scheduled visit of 
the assessment in the protocol. If the unscheduled visit has equal distance to the 2 study 
scheduled visits, it will be mapped to the later visit.  
The unscheduled visit will be only mapped to study visit within each period during it occurs.  
When there is more than 1 measurement mapped to the same scheduled visit (including the 
original measurement taken from the scheduled visit), the measurement taken on the 
scheduled visit will be used if it is not missing, otherwise the visit closest to the target day 
will be used. If more than 1 visit has equal distance to the target day, then the later visit will 
be used. If more than 1 measurement is collected on the same day, the time or sequence 


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number will be used to select the latest record. For listings and shift tables, all data points 
will be included. 
Early termination visit will follow the same rule for unscheduled visit as described above. 
10.2 
Endpoints Derivation Details 
 
 
 
 
 
 
 
 
10.2.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.2.1.3 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
10.2.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.2.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.3 
Schedule of Evaluations:  
Table 4: Schedule of Events for the Single Ascending Dose Period 
 
Screeninga 
Treatment Period 
EOS I (D90)/ 
ETb 
 
BL 
Single Ascending Dose Period 
Day (D) / Week (W) 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
D42 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
Drug Administration 
 
X 
 
 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
General & GSD III-specific medical history 
X 
 
 
 
 
 
 
 
 
 
COVID-19 testing 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Physical examc 
X 
Xd 
X 
 
 
 
 
 
 
X 
Vital signs 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xd 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
X 
Xd 
 
 
 
 
 
X 
X 
X 


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Screeninga 
Treatment Period 
EOS I (D90)/ 
ETb 
 
BL 
Single Ascending Dose Period 
Day (D) / Week (W) 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
D42 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
ATX95 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
 
AGL mRNA 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
 
Anti-drug antibodies  
 
Xd 
 
 
 
X 
 
X 
 
X 
Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
Hemoglobin A1C 
X 
 
 
 
 
 
 
 
 
 
Serum CH50, AH50, sC5b-9, & IL-6 
 
Xg 
X 
 
 
X 
 
 
 
 
Plasma fibrinogen & d-dimer 
 
Xg 
X 
 
 
X 
 
 
 
 
Hematology 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistryh 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisi 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Serum CRP 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Liver  
 
 
 
 
 
 
 
 
 
 
Liver MRI 
X 
 
 
 
 
 
 
 
 
 
Liver MRSj 
X 
 
 
 
 
 
 
 
 
 
FibroScan or ultrasound elastography 
X 
 
 
 
 
 
 
 
 
 
PT/INRg 
X 
Xd 
X 
 
X 
 
 
 
 
X 
Serum HDL & LDLk 
X 
Xd 
 
 
 
 
 
 
 
 
Cardiac 
 
 
 
 
 
 
 
 
 
 
Serum CK-M/B 
X 
Xd 
 
 
 
 
 
 
 
 


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Screeninga 
Treatment Period 
EOS I (D90)/ 
ETb 
 
BL 
Single Ascending Dose Period 
Day (D) / Week (W) 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
D42 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
Plasma BNP 
X 
Xd 
 
 
 
 
 
 
 
 
Serum troponin I 
X 
Xd 
 
 
 
 
 
 
 
 
ECG 
X 
Xd 
X 
 
 
 
 
 
 
X 
Skeletal Muscle & Strength 
 
 
 
 
 
 
 
 
 
 
Serum CK 
X 
Xc 
 
 
 
 
 
 
 
 
Serum myoglobin  
X 
Xd 
 
 
 
 
 
 
 
 
Calf MRSj 
X 
 
 
 
 
 
 
 
 
 
HHD 
X 
Xd 
 
 
 
 
 
 
 
 
Clinician- & Patient-reported Outcomes 
 
 
 
 
 
 
 
 
 
 
PROMIS questionnaires & SF-36v2 
 
Xd 
 
 
 
 
 
 
 
 
GNEM-FAS expanded version  
 
Xd 
 
 
 
 
 
 
 
 
Nutrition diary 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Exploratory Assessments  
 
 
 
 
 
 
 
 
 
 
Serum ketones 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Urine beta hydroxybutyratei 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Serum biotinidase 
X 
Xd 
 
 
 
 
 
 
 
 


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Screeninga 
Treatment Period 
EOS I (D90)/ 
ETb 
 
BL 
Single Ascending Dose Period 
Day (D) / Week (W) 
D0 
D1 
D4 
D7 
D14 
D21 
D28 
D42 
Visit Window Relative to Baseline 
- 
- 
- 
± 1 day 
± 2 days 
CGMm  
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
X 
Plasma Glc4 
X 
Xd 
 
 
 
 
 
 
 
 
Urine Glc4i 
X 
Xd 
 
 
X 
 
 
 
 
X 
Whole blood RNA expression 
X 
 
 
 
 
 
 
 
 
 
AGL variant analysis  
X 
 
 
 
 
 
 
 
 
 
Blood Cell Pellet for Future Use 
X 
Xd 
 
 
 
 
 
 
 
 
Serum & Plasma for Future Usen 
 
Xd 
 
 
X 
 
 
X 
 
X 
Footnotes continue on the following page.  
a Screening assessments can be done over the course of multiple days. There must be 10 to 14 days between any assessments that are measured at both the 
Screening Visit and the BL Visit.  
b In the event a subject has an ET, all efforts will be made to monitor the subject through the end of the study. At minimum, a safety follow-up phone call will 
occur within the 4 weeks following the subject’s last treatment.  
c Complete physical exam is required at the Screening, BL, and EOS I/ET Visits. Targeted physical exams may be performed at the D1 Visit. 
d Assessments to be performed prior to dosing. The following assessments can be collected within a week prior to dosing, as long as there is 10 to 14 days 
between assessments that are repeated at the Screening Visit and the Baseline Visit: HHD, PROMIS questionnaires, SF-36v2, and GNEM-FAS expanded 
version.  
e Refer to Table 6 for the timing of vital sign assessments during dosing.  
f Refer to Table 7 for details of PK sampling. Please note that sample collections are marked for D1, D4, D7, D14, D21, and D28 in this table (Table 4) 
corresponding to a sample collection 1, 4, 7, 14, 21, and 28 days after infusion of UX053 on D0 as outlined in the final rows of the first column in Table 7.  
g Sample to be collected pre-dose and at the end of the infusion. Post-infusion blood samples should be collected in the opposite arm of the infusion to avoid 
dilution.  
h Close monitoring is required for subjects who develop elevations in ALT > 3x ULN and > 2x their baseline value, or elevation in ALT > 3x ULN with INR > 
1.5. This includes repeating liver enzymes and INR within 48 hours and consideration of additional diagnostic tests such as liver ultrasound (Section 10.1.5).  
i All efforts should be made for urine collections to be consistently taken from the first morning void.  
j Liver and calf MRS are only required at sites with capability. Scanning for liver and calf MRS can be conducted immediately following the liver MRI.  
k A 3 to 4 hour fasting period is preferred, but not required, prior to blood collection for serum HDL and LDL. All efforts should be made to obtain samples for 
HDL and LDL consistently for a given subject.  
l The nutrition diary recordings should be recorded daily from the Screening Visit through the EOS I D90/ET Visit.  


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m The subject will receive CGM and HHG devices and will be trained on proper use at the Screening Visit. The CGM device will be worn continuously from the 
Screening Visit to the EOS I D90/ET Visit. If the CGM device alarm notifies a subject that their blood sugar is abnormally high or low or the subject suspects 
their blood sugar is abnormally high or low, the subject will need to check their blood sugar with a HHG device that will be provided by Ultragenyx at the 
Screening Visit (ISV for RD). When CGM data is being collected, all subjects will connect their CGM and HHG devices to a study-provided laptop weekly and 
upload CGM and HHG data. At remote visits, in conjunction with assessments performed by a home health nurse, the site will contact subjects by telephone or 
videoconference to confirm the CGM device is properly in use and data was uploaded; answer any questions regarding or help troubleshoot (if necessary) CGM 
device use; and review CGM data, HHG data (when applicable), and nutrition diary entries; these telephone calls will occur as needed for the SAD Period 
between Day 28 and Day 90/EOS I Visits. At in-clinic visits, a conversation between the site and the subject should occur to ensure CGM compliance and 
troubleshoot if needed.  
n Serum and plasma samples will be collected for future biomarker assessments yet to be determined.  
Note: White columns indicate in-clinic visits (Screening, BL D0, D1, and EOS I D90/ET). Gray columns indicate visits conducted at home by a home health 
nurse in conjunction with a phone call as needed (D4, D7, D14, D21, D28, and D42).  
Note: Laboratory assessments included in chemistry, hematology, and urinalysis are provided in Appendix 3.  
AGL, amylo-α-1,6-glucosidase 4-alpha-glucanotransferase; AH50, alternative complement activity; BL, baseline; BNP, B-Type Natriuretic Peptide; CGM, 
continuous glucose monitor; CH50, classical pathway complement activity; CK, creatinine kinase; CK-M/B, CK-muscle/brain; COVID-19, coronavirus disease 
2019; CRP, C-reactive protein; D, day; ECG, electrocardiogram; EOS, end of study; ET, early termination; GDE, glycogen debranching enzyme; Glc4, glucose 
tetrasaccharide; GSD, glycogen storage disease; GNEM-FAS, GNE Myopathy Functional Activities Scale; HHD, handheld dynamometry; HHG, handheld 
glucometer; HDL, high density lipoprotein;IL-6, interleukin-6; LDL, low density lipoprotein; MRI, magnetic resonance imaging; MRS, magnetic resonance 
spectroscopy; PROMIS, Patient-Reported Outcomes Measurement Information System; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic; 
PT/INR, prothrombin time/international normalized ratio; sC5b-9, soluble Complement 5b-9; SF-36v2, Short Form Health Survey 36 Version 2.


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Table 6: Schedule of Vital Sign Assessments 
Study Period 
SAD Period 
RD Period 
Time 
Day 0 
Week 0 
Week 2 
Week 4 
Week 6 
Week 8 
Pre-Infusion 
 
 
 
 
 
 
Within 30 min of 
initiating the infusion 
X 
X 
X 
X 
X 
X 
During infusion (4 hr infusion) 
 
15 min (± 5 min) 
X 
X 
X 
X 
X 
X 
30 min (± 5 min) 
X 
X 
X 
X 
X 
X 
45 min (± 5 min) 
X 
X 
X 
X 
X 
X 
1 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
2 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
3 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
4 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
Post-infusion (24 hr monitoring)a 
 
 
 
 
 
5 hr (± 5 min) 
X 
X 
X 
X 
X 
X 
6 hr (± 5 min) 
X 
X 
X 
X 
X 
X 
7 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
8 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
9 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
10 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
16 hr (+/- 1hr) 
X 
X 
X 
X 
X 
X 
24 hr (+/- 2hr) 
X 
X 
X 
X 
X 
X 
hr, hour; min, minute; RD, Repeat Dose; SAD, Single Ascending Dose.  
a All post-infusion time points refer to time from the beginning of the infusion. 
Table 7: Schedule of PK Assessments during and following Treatment Infusion 
Study Period 
SAD Period 
RD Period 
Sample Type 
Blood 
Plasma 
Blood 
Plasma 
Blood 
Plasma 
Analyte 
AGL 
mRNA 
ATX95 
AGL 
mRNA 
ATX95 
AGL 
mRNA 
ATX95 
Infusion 
Day 0 Infusion 
Week 0 Infusion 
Week 8 Infusion 
Pre-infusion 
 
 
 
 
Within 1 hr prior to 
initiating infusion 
X 
X 
X 
X 
X 
X 


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During infusion (4 hr infusion) 
 
1 hr (± 10 min)a 
X 
X 
X 
X 
X 
X 
3 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
Post-infusion 
4 hr (± 10 min)b 
X 
X 
X 
X 
X 
X 
4.5 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
5 hr (± 10 min) 
X 
X 
X 
X 
X 
X 
6 hr (± 20 min) 
X 
X 
X 
X 
X 
X 
8 hr (± 30 min) 
X 
X 
X 
X 
X 
X 
10 hr (± 30 min) 
X 
X 
X 
X 
X 
X 
24 hr (± 2 hr); Day 1 
X 
X 
X 
X 
X 
X 
96 hr (± 24 hr); Day 4 
X 
X 
 
 
 
 
168 hr (± 24 hr); Day 7 
X 
X 
X 
X 
X 
X 
336 hr (± 24 hr); Day 14 
X 
X 
Xc 
Xc 
X 
X 
504 hr (± 24 hr); Day 21 
X 
X 
 
 
 
 
672 hr (± 24 hr); Day 28  
X 
X 
 
 
X 
X 
 
10.4 
Visit Window Example 
SAD period: 
Visit 
Scheduled Visit Day 
Window 
Baseline  
Day 0 
< =1 
Day 1 
Day 1 
[2] 
Day 4 
Day 4 
[3, 5] 
Day 7 
Day 7 
[6, 10] 
Day 14 
Day 14 
[11, 17] 
Day 21 
Day 21 
[18, 24] 
Day 28 
Day 28 
[25, 34] 
Day 42 
Day 42 
>=35