ASPIRO: A Phase 1/2/3, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients
Phase: PHASE2
Conditions: X-Linked Myotubular Myopathy
Sponsor: Astellas Gene Therapies

 
Study Title: 
 ASPIRO: A Phase 1/2/3, Randomized, Open-Label, 
Ascending-Dose, Delayed-Treatment Concurrent 
Control Clinical Study to Evaluate the Safety and 
Efficacy of AT132, an AAV8-Delivered Gene Therapy in 
X-Linked Myotubular Myopathy (XLMTM) Patients 
Protocol Number: 
 ATX-MTM-002 
Investigational Product: 
 AT132 (resamirigene bilparvovec) 
Indication: 
 X-Linked Myotubular Myopathy 
Sponsor: 
 Astellas Gene Therapies, Inc.  
South San Francisco, CA 94080 
Development Phase: 
 1/2/3 
Responsible Medical 
Officer: 
 
 
EU CT Number: 
 2024-512637-32 
IND Number: 
 017367 
Protocol Version: 
 12.0 
Date: 
 17 May 2024  
Replaces Protocol 
Version: 
 11.0 (16 May 2023) 
 
  
Property of Astellas Gene Therapies, Inc. 
CONFIDENTIAL 
 
May not be divulged, published, or otherwise disclosed to others without  
prior written approval from Astellas Gene Therapies, Inc. 
 
This study will be conducted according to the principles of Good Clinical Practice as 
described in the US Code of Federal Regulations and the International Council for 
Harmonisation Guidelines, including the archiving of essential documents. 
PPD

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PROTOCOL SYNOPSIS 
TITLE OF STUDY: ASPIRO: A Phase 1/2/3, Randomized, Open-Label, Ascending-Dose, Delayed-
Treatment Concurrent Control Clinical Study to Evaluate the Safety and Efficacy of AT132, an AAV8-
Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients 
NAME OF TEST PRODUCT: AT132 (resamirigene bilparvovec) 
NAME OF ACTIVE INGREDIENT: rAAV8-Des-hMTM1 
PROTOCOL NUMBER: ATX-MTM-002 
STUDY SITES PLANNED: Approximately 8 sites worldwide 
PHASE OF DEVELOPMENT: Phase 1/2/3 
STUDY RATIONALE:  
Adeno-associated virus serotype 8 (AAV8)-mediated gene therapy offers the prospect of considerable 
long-term clinical benefit to X-linked myotubular myopathy (XLMTM) patients through persistent 
expression of the missing or damaged myotubularin protein following a single systemic therapeutic 
administration. Gene therapy is expected to provide persistent protein expression, corresponding long-
term clinical benefit, and the potential for substantial recovery of muscle function. Substantial functional 
recovery and prolongation of life in both the murine (knockout) and canine (missense mutation) models 
of XLMTM disease, employing the same AAV8 vector, support this therapeutic strategy. 
This Phase 1/2/3 study will evaluate safety and efficacy of AT132. The rarity of this disease (estimated 
incidence of 1 in 50,000 live male births) presents challenges to enrolling the study in a timely fashion. 
Enrollment of infants and young children into this first-in-human study exploring the safety of AT132 in 
XLMTM is justified for a number of reasons. Firstly, there are not enough adult or adolescent patients 
to enable a clinical study in the older population due to the rarity and early mortality of the disease. 
Death rates stay high throughout childhood and the majority of children do not survive into adolescence 
and adulthood. Therefore, there is a clear, unmet medical need in neonates and infants at high risk of 
death in the neonatal and infantile period. In addition, infants and younger children have fewer 
comorbidities, less accumulation of medical events (such as hypoxic damage and recurrent chest 
infections), and are not as debilitated as the few surviving patients with XLMTM, which increases the 
possibility of demonstrating clinical benefit. Furthermore, preexisting antibodies to adeno-associated 
viruses (AAVs), which could preclude administration of an AAV8 gene transfer therapy, are less 
prevalent in younger children compared with adults. 
OBJECTIVES:  
The objectives of the study are as follows: 
• To determine the therapeutic dose of AT132 
• To confirm the safety and efficacy of the therapeutic dose of AT132 
ENDPOINTS, SAFETY ASSESSMENTS, AND ESTIMANDS:  
Primary Efficacy Endpoint:  
• Change from baseline in hours of ventilation support at Week 24 
Key Secondary Efficacy Endpoint:  
• Percentage of subjects achieving functionally independent sitting for at least 30 seconds by 
Week 24 
Other Secondary Efficacy Endpoints: 
• Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who require 
invasive ventilation) at Week 24 

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• Change from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND) at Week 24  
• Change from baseline in maximal inspiratory pressure (MIP) at Week 24  
• Change from baseline in quantitative analysis of myotubularin expression in the muscle biopsy at 
Week 24  
• Change from baseline in quality of life assessments at Week 24 (ie, the Assessment of Caregiver 
Experience with Neuromuscular Disease [ACEND] and Pediatric Quality of Life Inventory 
[PedsQL]) 
• Number (%) of age-appropriate clinically relevant gross motor function milestones attained 
through Week 24 
• Percentage of subjects achieving full ventilator independence at Week 24 
• Survival  
Safety Endpoints:  
• Adverse events (AEs), serious AEs (SAEs), and findings from safety laboratory tests, 12-lead 
electrocardiogram (ECG), echocardiograms (ECHOs), vital signs, growth parameters, physical 
examinations, liver ultrasounds, antibody formation (anti-AAV8, anti-MTM1), viral shedding, 
annualized hospitalization rate, annualized respiratory and non-respiratory SAE rate, and length of 
stay per hospitalization 
Exploratory Endpoints: 
• Time to unassisted sitting for 30 seconds or more at Week 24 
• Change from baseline in the Motor Function Measure scale (MFM-32) at Week 24 
• Change from baseline in total raw score in the gross motor domain of the Bayley Scales of Infant 
and Toddler Development III (Bayley-III) at Week 24 
• Change from baseline in total raw score in the fine motor domain of the Bayley-III at Week 24 
• Change from baseline in the proportion of patients being able to feed without a gastrostomy or 
G-tube at Week 24 
• Change from baseline in the Communicative Development Inventories scores at Week 24 
• Change from baseline in the Parental Global Impression of Secretion Severity (PGIS-S) score at 
Week 24  
• Change in the Parental Global Impression of Secretion Improvement (PGIS-I) score at Week 24 
• Change from baseline in Clinical Global Impression of Severity (CGI-S) at Week 24 
• Change in the Clinical Global Impression of Improvement (CGI-I) score at Week 24 
Estimands: 
The estimand of the primary objective is defined by the following 5 attributes: 
• Treatment: Single dose of AT132 
• Population: Male subjects with ventilator-dependent XLMTM, as defined by the inclusion/exclusion 
criteria of the study 
• Endpoint: Change from baseline in hours per day of ventilation support at Week 24 
• Intercurrent events and their corresponding strategies: For study discontinuation due to death or 
due to lack of efficacy, a composite strategy will be adopted, where subjects with the intercurrent 
event before Week 24 having missing observation(s) after the intercurrent event will have those 
missing observations(s) imputed by unfavorable values 
• Population level summary: Mean change from baseline, by dose level 
NUMBER OF SUBJECTS PLANNED:  
Part 1: Approximately 16 subjects 

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Part 2: Approximately 10 subjects 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
INCLUSION CRITERIA: 
1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 
gene as assessed by a Sponsor-approved testing facility.* 
2. Subject is male.* 
3. Subject is aged less than 5 years old at dosing.* 
4. Subject requires mechanical ventilatory support: 
• Part 1: Subject requires some mechanical ventilatory support (eg, ranging from 24 hours per 
day full time mechanical ventilation, to noninvasive support such as continuous positive airway 
pressure [CPAP] or bilevel positive airway pressure [BiPAP] during sleeping hours). 
• Part 2: Subject requires invasive mechanical ventilatory support ranging from 20 to 24 hours 
per day at screening (confirmed by daytime polysomnographic study). 
5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a 
cuffed tracheostomy tube for some respiratory assessments.* 
6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cmH2O at screening.* 
7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when 
applicable).* 
8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study 
procedures.* 
9. UNIQUE to France: Subject’s weight is ≥ 4.8 kg. 
EXCLUSION CRITERIA: 
1. Subject is participating in an interventional study designed to treat XLMTM.* 
2. Subject born < 35 weeks gestation who is still not term as per corrected age. 
3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the age of 
18 months may be retested in cases where antibodies may have been maternally acquired and 
titers may decline in the first months of life).* 
4. Subject had recent surgery (< 3 months before Day 1) or has planned surgery that may confound 
data collection during the first 48 weeks of the study. 
5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the 
opinion of the Investigator.* 
6. Subject has a clinically significant underlying liver disease, defined as:  
• ≥ Grade 3 aspartate aminotransferase (AST) (> 5.0 x upper limit of normal [ULN]; Common 
Terminology Criteria for Adverse Events [CTCAE] v. 4.03)* 
• ≥ Grade 3 alanine aminotransferase (ALT) (> 5.0 x ULN; CTCAE v. 4.03)* 
• Hepatic peliosis or any other clinically significant structural abnormality detected by ultrasound* 
7. Subject is currently experiencing a clinically important respiratory infection or other active 
infection.* 
8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before 
Day 1.* 
9. Other than as required per protocol, subject has received immune-modulating agents within 
3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is 
allowed); use of other concomitant medications to manage chronic conditions must have been 
stable for at least 4 weeks before dosing.* 

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10. Subject has a contraindication to prednisolone.* 
11. Subject has a contraindication to study drug or ingredients.* 
12. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair 
surgery/procedure in the 12 months following Day 1 (Part 2 including any subjects enrolled under 
protocol v8 and beyond). 
13. Subject has contractures, scoliosis, or other medical condition that would limit the potential to 
achieve unassisted sitting, in the opinion of the Investigator (Part 2 including any subjects enrolled 
under protocol v8 and beyond).  
14. Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the 
Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond). 
15. Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia (< 10 g/dL 
hemoglobin).* 
16. Subject has a contraindication to ursodiol (ursodeoxycholic acid).* 
17. UNIQUE to France: Subject has a prior diagnosis or history of cardiac arrhythmias, myocarditis, or 
any other cardiac disease. 
18. UNIQUE to France: Subject has a contraindication to general anesthesia and to muscle biopsy 
procedures. 
* If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before 
receiving AT132. 
STUDY TREATMENT, DOSE, ROUTE, AND REGIMEN:  
Part 1: All study subjects will be administered a single dose of AT132 by intravenous (IV) infusion 
(control subjects will receive delayed treatment). The first dose level will be 1.0 × 1014 vg/kg, with 
planned subsequent dose levels of 3.0 × 1014 vg/kg and 5.0 × 1014 vg/kg. A maximum of 3 dose levels 
of AT132 will be evaluated in Part 1 of the study. Dose escalations or expansions will be based on 
evaluations of safety data and recommendations from the Data Monitoring Committee (DMC). As 
implemented in protocol v5, the DMC and Sponsor determined that 3.0 × 1014 vg/kg would be 
evaluated in Part 2 and escalation to the 5.0 × 1014 vg/kg dose level would not occur. 
Part 2 (prior to protocol v8): Subjects were randomized to receive a single dose of the optimal dose (as 
previously determined at the end of Part 1) of 3.0 × 1014 vg/kg AT132 by IV infusion or to receive 
delayed treatment following the Week 24 visit.  
As of protocol v9: Following the review of benefit/risk profiles of the 1.0 × 1014 and 3.0 × 1014 vg/kg 
dose levels, the Sponsor, in consultation with the DMC, determined that subjects not yet dosed were to 
be administered the lower dose level (ie, the therapeutic dose), which is 1.3 × 1014 vg/kg AT132 as 
determined by the 2nd generation vg titer assay (see Section 1.4.2).  
As of protocol v10 and beyond, no additional subjects will be dosed. 
DURATION OF STUDY:  
Approximately 10 years after AT132 administration; approximately 12 years for control subjects who 
are ultimately administered AT132 (at least 24 weeks to 3 years delayed treatment and an additional 
10 years after AT132 administration). 
REFERENCE THERAPY, DOSE, ROUTE, AND REGIMEN: None. 
STUDY DESIGN:  
This is a Phase 1/2/3, randomized, open-label, ascending-dose, delayed-treatment concurrent control 
clinical study to evaluate the safety and efficacy of AAV8-delivered gene therapy in XLMTM patients 
aged less than 5 years old. Subjects will receive a single dose of AT132 and be followed for safety and 
efficacy for 10 years, with the primary analysis occurring after all subjects have completed 24 weeks of 
posttreatment evaluation. 

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The study consists of 2 parts. Part 1 would establish the optimal dose of AT132. Part 2 would confirm 
the safety and efficacy of AT132 at the optimal dose level. The following describes how each part was 
designed and the changes as of protocol v8 and beyond. 
Part 1 (fully dosed as of protocol v8):  
A maximum of 3 dose levels of AT132 are planned for evaluation in Part 1 of this study (Figure 1). Four 
subjects will be enrolled in each dose level cohort, including 1 subject in each dose level cohort 
randomized to control with delayed administration of treatment. The first subject in each dose level 
cohort will be assigned to receive AT132 and will be treated as a sentinel subject. Subsequent subjects 
in that dose level cohort will be randomized (2:1) to treatment or control with delayed treatment if there 
are no safety concerns after at least 4 weeks of post-dose data from the sentinel subject is evaluated 
by the chair of the DMC. Dose escalation to the next dose level will be considered after evaluation of at 
least 4 weeks of data from all subjects dosed at the current dose level. Following the dose escalation 
portion of the study, an optimal dose will be determined in conjunction with the DMC, and control 
subjects will be treated at the optimal dose level. 
This study’s independent DMC will monitor subject safety and provide recommendations to the 
Sponsor regarding dose level determination, cohort expansion, and safety and study conduct matters. 
Subjects who are randomized to receive AT132 may be admitted to the study clinic 1 to 2 days prior to 
AT132 dosing for baseline procedures, including confirmation of baseline ventilator settings, and will 
stay in the study clinic for at least the first overnight post-dose. If medically appropriate, subjects may 
be discharged from the study clinic after completion of Day 2 assessments. 
Control subjects will generally have the same assessments as treated subjects but on a less frequent 
schedule to lessen the burden of study participation. It is anticipated that control subjects will 
participate for at least 24 weeks before an optimal dose is determined and the subject can be 
administered AT132. Following determination of the optimal dose, control subjects will undergo 
pretreatment baseline procedures to confirm that they remain eligible to receive treatment with AT132 
at the optimal dose. Once eligible, control subjects will be dosed with AT132, and will initiate the 
post-dose procedures. 
Treated subjects will be administered a course of concomitant prophylactic glucocorticoid (oral 
prednisolone) therapy commencing 1 day prior to AT132 dosing, and continuing for a period of 
approximately 8 weeks, then tapering from the original dose over an additional 8 weeks, per 
Investigator discretion, as a preventative measure for immune-mediated hepatic injury, which has been 
observed in gene therapy clinical studies with AAV. Tapering duration may be altered and/or 
supplemental administration of IV steroids (eg, methylprednisolone) or other immunosuppressive 
regimens may be considered in cases of potential malabsorption of oral medications. 
Subjects will be followed for a total of 10 years following AT132 administration, see Section 5.2. 
See Figure 1 for the individual study participation timeline (Parts 1 & 2) through Week 48. 
Part 2 (described herein as planned prior to protocol v8; partially dosed as of protocol v8):  
In Part 2, the optimal dose of AT132 will be evaluated in an expansion cohort of 10 subjects age 
matched randomized to a study drug or a delayed-treatment control group (1:1 allocation ratio). A pair 
of subjects in each group will be prospectively best-matched based on age (±6 months) before being 
randomized to 1 of the treatment arms (AT132 vs. delayed-treatment control). The administration of 
study drug and concomitant prophylactic glucocorticoids, and the assessment of safety will be the 
same as described in Part 1. Following collection of their Week 24 data, control subjects will be 
administered AT132 and followed according to the Schedule of Events. 
Part 2 as of protocol v8 and v9: 
Following the review of benefit/risk profiles of the 1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose levels, the 
Sponsor, in consultation with the DMC, determined that subjects not yet dosed were to be administered 
the lower dose level (ie, the therapeutic dose), which is 1.3 × 1014 vg/kg as determined by the 2nd 
generation vg titer assay (see Section 1.4.2). Dosing of the 3 enrolled delayed-treatment controls who 
have not yet been dosed will not be conducted as described above for Part 2, but will resume at 

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1.3 × 1014 vg/kg as long as each subject meets a subset of inclusion and exclusion criteria prior to 
dosing. If any of these control subjects is not eligible to be dosed, another eligible subject can be 
enrolled. Any new subject will not be considered a delayed-treatment control and therefore will not be 
required to wait 24 weeks before administration of study drug. Any new subject will be enrolled under 
all of the inclusion/exclusion criteria (including Exclusion Criteria 12-14 required for Part 2 subjects).  
In addition to prophylactic glucocorticoids, subjects will receive daily prophylactic ursodiol 
(ursodeoxycholic acid) beginning between Study Days -6 and -4. Subjects will be followed according to 
the Schedule of Events. 
As of protocol v10 and beyond: 
This study does not allow for enrollment or dosing of any future subjects. 
See Figure 2 for Overall Study Design. 
DATA MONITORING COMMITTEE:  
This study will utilize an independent DMC comprising at least 3 experts with relevant expertise who 
will monitor subject safety and key efficacy data and provide recommendations to the Sponsor 
regarding expansion of dose cohorts and dose escalation or decreases. The DMC may recommend 
accelerated dosing of control subjects if compelling efficacy results support such action.  
DMC review will occur, at minimum, at the following events: 
• A sentinel subject has been dosed and observed for at least 4 weeks in each of the cohorts (DMC 
chair review) 
• Consideration of a dose escalation after at least 3 subjects at a dose level have been dosed and 
observed for at least 4 weeks following AT132 administration (full DMC review) 
• Dose escalation has been stopped and participating subjects have 24 weeks of post-dose follow 
up, at which point it is anticipated that an optimal dose can be selected (full DMC review; 
applicable to Part 1 of study) 
• Consideration of expanding enrollment at a specific dose level (full DMC review) 
• Review of important medical events 
In addition, the DMC will perform ad hoc review if requested by the Sponsor, or if stopping criteria are 
met. Full details of the DMC will be provided in the ATX-MTM-002 DMC charter. 
DATA REVIEW COMMITTEES:  
There will be the following independent expert committee adjudicating endpoints and reviewing data in 
the study: 
Biopsy Review Committee  
• Responsible for the blinded adjudication of histopathology endpoints in muscle biopsies. 
STATISTICAL METHODS:  
The study is no longer able to address the stated objectives, hence the statistical analysis will provide 
descriptive summaries by treatment groups. Data will be summarized for the following 3 treatment 
groups: (i) subjects treated at 1.3 × 1014 vg/kg (low dose), (ii) subjects treated at 3.5 × 1014 vg/kg (high 
dose), and (iii) all subjects treated with AT132 (overall; not applicable to efficacy endpoints). As of 
protocol v9 and beyond: The 1.0 × 1014 vg/kg dose level based on a 1st generation titer method 
equates to 1.3 × 1014 vg/kg as determined by a 2nd generation vg titer assay (see Section 1.4.2); and 
3.0 × 1014 vg/kg dose level equates to 3.5 × 1014 vg/kg based on an analysis of the historical Study 
ATX-MTM-002 drug product lots using the 2nd generation vg titer assay. 
Number and percentage of subjects with treatment-emergent AEs (TEAEs) classified by system organ 
class (SOC) and preferred term (PT); by severity, causality, seriousness, and action taken with regard 
to study drug will be summarized. Number (%) of subjects with TEAEs leading to discontinuation of 
study will also be summarized. Clinical laboratory test results, vital signs, growth parameters, and ECG 

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findings will be summarized using descriptive statistics by time point. ECHO findings, liver ultrasounds, 
antibody formation (anti-AAV8, anti-MTM1), and viral shedding will be summarized. 
Graphical profiles of each subject will be created for key efficacy measurements. 
The primary efficacy endpoint (change from baseline in hours of ventilation support at Week 24) will be 
analyzed using a mixed effect model repeat measurement (MMRM) with baseline, treatment (low dose 
and high dose), time (Weeks 1, 4, 8, 12, 16, 24, 36 and 48) and treatment by time interactions as fixed 
effects and subject as random effect. The change from baseline in hours of ventilation support at 
Week 24 will be summarized by treatment group based on this model. The primary analysis will be 
conducted using the FAS.  
The key secondary efficacy endpoint (percentage of subjects achieving functionally independent sitting 
for at least 30 seconds by Week 24) will be summarized by treatment group (low dose and high dose) 
using the FAS. 
Other secondary or exploratory efficacy endpoints analyses of change from baseline, time to event and 
percentage variables will be summarized for low dose and high dose in a similar method to the 
analyses described above.  
Details of the analysis methods will be documented in the Statistical Analysis Plan (SAP). 
Analysis Population:  
• Full Analysis Set (FAS) is defined as all randomized and/or enrolled subjects who received AT132 
and had at least 1 postdose efficacy assessment. The FAS will be used for the primary analysis of 
the primary efficacy endpoint.  
• Safety Analysis Set (SAF) is defined as all randomized and/or enrolled subjects who received 
AT132. The SAF will be used for the analysis of the safety endpoints. 
Power Analysis: The following language was from protocol v9 that planned a formal analysis to 
compare 1.3 × 1014 vg/kg and delayed-treatment control, however given that the study will not be able 
to address the objectives, no such formal analysis will be conducted.  
A power analysis for the primary analysis of the primary endpoint was conducted at 80% power and 
0.05 level of alpha to estimate the required sample size based on Mean of 13.0 vs. 0.0 hours of 
reduction in ventilation need, with common SD of 6.0 by Week 24 using a t-test, resulting in at least 
N = 10 for a balanced 1:1 allocation between 1.0 × 1014 vg/kg AT132 (equates to 1.3 × 1014 vg/kg as 
determined by the 2nd generation vg titer assay) and delayed-treatment control. It is further assumed, 
that the same difference in means (SD), will provide at least 80% power using MMRM analysis 
proposed for the primary endpoint. However, it is possible that 1:1 allocation may not be feasible; 
1  control subject serving as control for multiple treated subjects, or multiple control subjects being a 
match for a single treated subject. Therefore, all qualified control subjects will be used in the analyses 
to ensure adequate power is available to detect the intended difference between treated and control 
subjects. 

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STUDY SCHEMA 
 
Figure 1: Summary of Individual Study Participation Timeline (Parts 1 & 2) 
 
 
Figure 2: Overall Study Design 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................. 2 
STUDY SCHEMA ....................................................................................................................... 9 
LIST OF ABBREVIATIONS/DEFINITION OF TERMS ............................................................... 15 
1 
INTRODUCTION ................................................................................................................. 19 
1.1 
Background ................................................................................................................ 19 
1.2 
Description of AT132 .................................................................................................. 21 
1.2.1 
Nonclinical Experience with AT132 ................................................................ 21 
1.2.2 
Clinical Data for AT132 .................................................................................. 23 
1.3 
Study Rationale .......................................................................................................... 23 
1.4 
Dose Selection Rationale ............................................................................................ 23 
1.4.1 
Starting Dose Selection Rationale ................................................................. 23 
1.4.2 
Current Dose Rationale ................................................................................. 24 
1.5 
Overall Risks and Benefits .......................................................................................... 26 
2 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 29 
2.1 
Estimands ................................................................................................................... 30 
3 
INVESTIGATIONAL PLAN .................................................................................................. 31 
3.1 
Overall Study Design and Plan ................................................................................... 31 
3.2 
Discussion of Study Design ........................................................................................ 33 
3.3 
Selection of Study Population ..................................................................................... 34 
3.3.1 
Inclusion Criteria ............................................................................................ 34 
3.3.2 
Exclusion Criteria ........................................................................................... 34 
3.3.3 
Number of Sites and Subjects ....................................................................... 35 
3.3.4 
Subject Identification ..................................................................................... 36 
3.3.5 
Replacement of Subjects ............................................................................... 36 
3.4 
Duration of Study Participation.................................................................................... 36 
3.5 
Removal of Subjects ................................................................................................... 36 
3.5.1 
Withdrawal of Subjects .................................................................................. 36 
3.5.2 
Withdrawal Follow-Up Procedures ................................................................. 37 

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3.6 
Termination of the Study ............................................................................................. 37 
3.7 
Start and End of Study Definitions .............................................................................. 37 
4 
STUDY TREATMENT ......................................................................................................... 38 
4.1 
Investigational Medicinal Product (IMP) ...................................................................... 38 
4.1.1 
Identity of IMP ............................................................................................... 38 
4.1.2 
Shipping and Handling of IMP ....................................................................... 38 
4.1.3 
IMP Accountability, Return, and Disposition .................................................. 38 
4.1.4 
Dosage and Administration of IMP................................................................. 39 
4.1.5 
Treatment Compliance .................................................................................. 39 
4.2 
Method of Assigning Subjects to Treatment Groups ................................................... 39 
4.3 
Blinding ....................................................................................................................... 39 
4.4 
Prophylaxis with Glucocorticoids ................................................................................. 39 
4.5 
Prophylaxis with Ursodiol ............................................................................................ 41 
4.6 
Monitoring for and Management of Cardiac, Liver, and Neuromuscular Related 
Safety Events ............................................................................................................. 41 
4.6.1 
Monitoring for and Management of Myocarditis ............................................. 41 
4.6.2 
Monitoring for and Management of Hepatobiliary Toxicity .............................. 43 
4.6.3 
Monitoring for and Management of Neuromuscular Abnormalities ................. 45 
4.7 
Prior and Concomitant Medications ............................................................................ 46 
4.8 
Excluded Therapies .................................................................................................... 47 
4.9 
Physical Therapy ........................................................................................................ 47 
5 
STUDY ASSESSMENTS AND SCHEDULE OF STUDY ASSESSMENTS ......................... 48 
5.1 
Study Assessments .................................................................................................... 48 
5.1.1 
Description of Study Assessments................................................................. 48 
5.2 
Schedule of Study Events ........................................................................................... 66 
5.3 
Schedule of Events for Screening ............................................................................... 67 
5.3.1 
Schedule of Events for Screening Visit .......................................................... 68 
5.4 
Schedule of Events for Subjects Treated with AT132: Biopsy – Week 8 ..................... 70 
5.5 
Schedule of Events for Subjects Treated with AT132: Week 9 – Month 60 ................. 75 

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5.6 
Schedule of Events for Subjects Treated with AT132: Month 72 (Year 6) – 
Month 120 (Year 10) (End of Study) ........................................................................... 80 
5.7 
Schedule of Events for Control Subjects: Control Baseline – Control Month 30 
(End of Study) ............................................................................................................ 82 
5.8 
Unscheduled Visits ..................................................................................................... 85 
5.9 
Assessments for Early Withdrawal from Study ............................................................ 85 
5.10 Assessments for Untreated Delayed-Treatment Control Subjects ............................... 85 
5.11 Amount of Blood (UNIQUE to France) ........................................................................ 85 
6 
ADVERSE EVENT MANAGEMENT .................................................................................... 86 
6.1 
Adverse Events .......................................................................................................... 86 
6.1.1 
Definition of Adverse Events .......................................................................... 86 
6.1.2 
Adverse Event Reporting and Collection Period ............................................ 86 
6.1.3 
Start of Adverse Event Collection Period ....................................................... 87 
6.2 
Serious Adverse Events.............................................................................................. 89 
6.2.1 
Definition of Serious Adverse Events ............................................................. 89 
6.2.2 
Serious Adverse Event Reporting Requirements ........................................... 89 
6.2.3 
Suspected Unexpected Serious Adverse Reaction ........................................ 91 
6.3 
Adverse Event and Serious Adverse Event Severity Grades and Relationship to 
Investigational Medicinal Product ............................................................................... 92 
6.3.1 
Assessment of Severity ................................................................................. 92 
6.3.2 
Assessment of Relationship........................................................................... 93 
6.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events................................................................ 94 
6.5 
AEs and Laboratory Results of Special Interest .......................................................... 95 
6.5.1 
Cardiac Enzyme Elevations ........................................................................... 95 
6.5.2 
Management of Potential Immune Responses .............................................. 95 
6.5.3 
Potential Cases of Drug-Induced Liver Injury ................................................. 95 
7 
STATISTICAL CONSIDERATIONS ..................................................................................... 98 
7.1 
Sample Size ............................................................................................................... 98 
7.2 
Analysis Populations ................................................................................................... 99 

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7.3 
Subject Disposition, Demographic Data, Baseline Characteristics, and Extent of 
Exposure .................................................................................................................... 99 
7.4 
Statistical Analysis ...................................................................................................... 99 
7.4.1 
Safety Analyses ............................................................................................. 99 
7.4.2 
Efficacy Analysis .......................................................................................... 100 
7.5 
Data Monitoring Committee ...................................................................................... 101 
7.6 
Study Safety Stopping Rules .................................................................................... 102 
7.7 
Data Review Committees ......................................................................................... 102 
8 
RESPONSIBILITIES AND ADMINISTRATIVE PROCEDURES ........................................ 103 
8.1 
Ethical Conduct of the Study ..................................................................................... 103 
8.2 
Investigator Responsibilities ..................................................................................... 103 
8.3 
Retention of Records ................................................................................................ 103 
8.4 
Institutional Review Board (IRB)/Ethics Committee (EC) Review and Approval ........ 104 
8.4.1 
Informed Consent ........................................................................................ 105 
8.4.2 
Subject Information and Confidentiality ........................................................ 105 
8.5 
Sponsor Responsibilities........................................................................................... 106 
8.5.1 
Protocol Modifications.................................................................................. 106 
8.5.2 
Study Discontinuation .................................................................................. 106 
8.5.3 
Study Reports .............................................................................................. 106 
8.5.4 
Study Monitoring and Auditing ..................................................................... 106 
8.5.5 
Data Monitoring Committee ......................................................................... 107 
8.6 
Joint Investigator/Sponsor Responsibilities ............................................................... 107 
8.6.1 
Case Report Forms ..................................................................................... 107 
8.6.2 
Payment Reporting ...................................................................................... 108 
8.6.3 
Financing and Insurance ............................................................................. 108 
9 
PUBLICATION AND USE OF INFORMATION .................................................................. 109 
10 REFERENCES .................................................................................................................. 110 
11 SIGNATURE PAGE – SPONSOR ..................................................................................... 116 
12 SIGNATURE PAGE – PRINCIPAL INVESTIGATOR ......................................................... 117 

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13 APPENDICES ................................................................................................................... 118 
PROTOCOL AMENDMENT SUMMARY OF CHANGES FOR PROTOCOL 
VERSION 12.0 .................................................................................................................. 134 
 
List of Tables 
Table 1: Required Parameters for Initiation of Ventilator Weaning ............................................ 54 
Table 2: Required Ventilator Discontinuation Parameters ......................................................... 55 
Table 3: Motor Developmental Milestones ................................................................................ 58 
Table 4: Adverse Event Severity Grading Scale (NCI-CTCAE) ................................................. 93 
Table 5: Assessment of Relatedness ........................................................................................ 93 
 
List of Figures 
Figure 1: Summary of Individual Study Participation Timeline (Parts 1 & 2) ................................ 9 
Figure 2: Overall Study Design ................................................................................................... 9 
Figure 3: Structure of the AT132 Vector Genome ..................................................................... 21 
 
List of Appendices 
Appendix 1: 
Laboratory Assessments ............................................................................. 119 
Appendix 2: 
Assessment of Tanner Stage for Boys ........................................................ 120 
Appendix 3: 
Secretions Management Assessment: PGIS-S and PGIS-I ......................... 121 
Appendix 4: 
Assessment of Time Off of Ventilator .......................................................... 122 
Appendix 5: 
Clinical Global Impression Scales: CGI-S and CGI-I ................................... 123 
Appendix 6: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) ................................................................................................ 125 
Appendix 7: 
Parental Swallowing Questionnaire ............................................................. 126 
Appendix 8: 
Parental Speech Development Questionnaire ............................................. 130 
Appendix 9: 
Genetics Testing ......................................................................................... 133 
 

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LIST OF ABBREVIATIONS/DEFINITION OF TERMS 
AAV 
adeno-associated virus 
AAV8 
adeno-associated virus serotype 8 
ACEND 
Assessment of Caregiver Experience with Neuromuscular Disease 
ADL 
activities of daily living 
AE 
adverse event 
AFO 
ankle-foot orthoses 
AHI 
Apnea-hypopnea index 
ALT 
alanine aminotransferase 
anti-AAV8 
anti-adeno-associated virus 8 
AST 
aspartate aminotransferase 
AT 
aminotransferases 
AT132 
rAAV8-Des-hMTM1 (resamirigene bilparvovec) 
Bayley-III 
Bayley Scales of Infant and Toddler Development III 
BID 
twice daily 
BiPAP 
bilevel positive airway pressure 
BLOD 
below the limit of detection 
BNP 
B-type natriuretic peptide 
CDI 
Communicative Development Inventories 
cDNA 
complementary DNA 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
cGMP 
current Good Manufacturing Practice 
CHOP INTEND 
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
CI 
Confidence intervals 
CK 
creatine kinase 
CNM 
centronuclear myopathy 
CO2 
carbon dioxide 
CPAP 
continuous positive airway pressure 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T cell 
DC 
discharge 

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DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
ELISpot 
enzyme-linked immunosorbent spot assay 
EMG 
electrophysiological assessments 
ENT 
ear, nose and throat 
ETCO2 
End tidal carbon dioxide 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
HBB2 
human β globin gene second intron 
HGB 
Hemoglobin 
HLA 
human leukocyte antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IL 
interleukin 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITR 
inverted terminal repeat 
ITT 
Intent to Treat 
IV 
intravenous 
Investigator 
Principal Investigator or Sub-Investigator 
KO 
knockout 
LAR 
legally authorized representative 
LFT 
liver function test 
MED 
minimal effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP 
maximal expiratory pressure 
MFM 
Motor Function Measure 
MFM-32 
Motor Function Measure-32 

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MIP 
maximal inspiratory pressure 
MITT 
Modified Intend to Treat 
MMRM 
Mixed Effect Model Repeat Measurement 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
MTM 
myotubular myopathy 
MTM1 
gene that codes for myotubularin (a mutation in the MTM1 gene results in 
myotubular myopathy) 
NAb 
neutralizing antibody 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs 
NHP 
nonhuman primate 
NIV 
noninvasive ventilation 
NMD 
neuromuscular disorders 
NOAEL 
no observed adverse effect level 
NREM 
non-rapid eye movement 
O2 
oxygen 
p.N155K 
mutation found in the canine model of XLMTM 
P0.1 
inspiratory occlusion pressure at 0.1 seconds 
pA 
polyadenylation 
PBMCs 
peripheral blood mononuclear cells 
PedsQL 
Pediatric Quality of Life Inventory 
PEEP 
positive end-expiratory pressure 
PGIS-I 
Parental Global Impression of Secretion Improvement 
PGIS-S 
Parental Global Impression of Secretion Severity 
PO2 
partial pressure of oxygen 
polyA 
polyadenylation 
PP 
Per Protocol 
PSG 
polysomnogram 
PT 
preferred term 
rAAV8 
recombinant adeno-associated viral vector, serotype 8 
rAAV8-Des-
hMTM1 
non-replicating recombinant adeno-associated viral vector, serotype 8, 
expressing the human MTM1 cDNA under the control of the muscle-specific 
human desmin gene promoter 
rATG 
rabbit anti-thymocyte globulin (eg, thymoglobulin) 
REM 
rapid eye movement 
RNA 
ribonucleic acid 
RR 
respiration rate 

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RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SMA 
spinal muscular atrophy 
SMA-I 
spinal muscular atrophy type I 
SMO 
supra-malleolar 
SOC 
system organ class 
SPO2 
oxygen saturation 
STIR 
short tau inversion recovery 
SUSAR 
suspected unexpected serious adverse reaction 
TAb 
total antibody 
TBL 
total bilirubin 
TCO2 
transcutaneous carbon dioxide 
TEAE 
treatment-emergent adverse event 
TID 
three times a day 
TMA 
thrombotic microangiopathy 
TNF-α 
tumor necrosis factor-alpha 
TST 
total sleep time 
ULN 
upper limit of normal 
USM 
urgent safety measure 
vg 
viral genomes 
vs 
versus 
XLMTM 
X-linked myotubular myopathy 
 

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1 INTRODUCTION 
1.1 
Background 
X-linked myotubular myopathy (XLMTM) is a rare, severe, congenital muscle disease and is one 
of the “centronuclear myopathies” (CNM). It has an estimated incidence of 1 in 50,000 live male 
births (Orphanet, 2009; Vandersmissen, 2018), although careful, large studies attempting 
complete ascertainment of incidence and prevalence have not been published (Das, 2011). The 
only identified cause of XLMTM is a mutation in the MTM1 gene; approximately 400 different 
mutations have been identified (Biancalana, 2012). The MTM1 gene encodes a protein called 
myotubularin, a highly conserved, dual-specific lipid phosphatase that is involved in the 
development, maturation, and maintenance of skeletal muscle cells. 
In normal fetal muscle, the nuclei are situated in a centrally placed chain; however, by birth, the 
majority of nuclei are located at the periphery of the skeletal muscle cell. Characteristic findings 
of XLMTM on muscle biopsy include myofiber hypotrophy, centrally nucleated myofibers, and 
mislocalization of organelles (Laporte, 2000; Lawlor, 2016; Pierson, 2005). 
In a study of 133 different mutations in 198 unrelated families, all males had disease 
manifestations resulting from too little functional protein or a nonfunctional protein, 88% of 
whom were considered to have high morbidity (Laporte, 2000). 
The majority of affected male infants with XLMTM are identified with a congenital myopathy in 
the perinatal period, although a definitive diagnosis of XLMTM may take several months 
depending on the clinical expertise available at the treating facility. There is often a prenatal 
history of weak or infrequent fetal movements (McEntagart, 2002) and polyhydramnios 
(Herman, 1999). In families without a known maternal carrier, diagnosis of XLMTM is generally 
based on clinical suspicion of a congenital myopathy shortly after birth, typically followed by a 
pathologic diagnosis from a muscle biopsy, and confirmation by subsequent genetic testing. 
Although myotubularin protein is ubiquitously expressed, the most apparent consequence of 
MTM1 mutations appears to be skeletal muscle pathology (Das, 2011). Genotype-phenotype 
correlations have occasionally been observed in XLMTM, but no definitive pattern exists. Apart 
from missense mutations, which manifest considerable phenotypic variation, most other 
mutations present with severe disease. Phenotypic variability has been observed in family 
members with the same mutation (Barth, 1998; Laporte, 2000) and in unrelated individuals with 
recurrent mutations (McEntagart, 2002). 
Males present at birth with severe hypotonia, weakness, and respiratory distress (ie, the 
newborns are profoundly hypotonic and need rapid intervention to assist breathing), and 
approximately 40% have been reported to die in the first year of life (Herman, 1999; 
McEntagart, 2002). McEntagart, et al., have reported a median survival of 29 months. Causes of 
death are primarily respiratory failure or related complications such as pneumonia/respiratory 
tract infection, ventilator-related accidents, or cardiorespiratory failure (Herman, 1999; 

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McEntagart, 2002; Wallgren-Pettersson, 1995). Rarely, deaths have been reported from 
liver-related complications (Herman, 1999). Profound delayed motor development is a result of 
global weakness, with only approximately half of surviving patients able to sit unassisted and 
most patients never reaching ambulatory status (Herman, 1999; McEntagart, 2002). Unlike most 
neuromuscular diseases, XLMTM patients have no evidence of cardiac muscle pathology. 
In a study of 120 XLMTM cases, 85% of patients required ventilation at birth, and 46% of 
patients died within 18 months (including a subset of patients who were not ventilated at birth) 
(McEntagart, 2002). Despite 24-hour ventilator support, 25% of patients died within the neonatal 
period, and only 14% of patients did not require full respiratory assistance (McEntagart, 2002). 
Of the proportion that survives, there is severe morbidity as well as compromised functional 
capability and quality of life. Despite normal or above-average intelligence, many patients have 
limited communication because of interference from ventilatory support aids (Herman, 1999). 
Additional common clinical features and comorbidities include ophthalmoplegia and 
cryptorchidism (both likely related to the underlying muscle abnormality), elongated facial 
features and distal extremities, and high palate. More rarely reported features include 
hypospadias resulting from a contiguous gene deletion (Tsai, 2005), pyloric stenosis often 
requiring surgical intervention, spherocytosis, and hydrocephalus (Herman, 1999). There has 
been an increased understanding of the prevalence of hepatobiliary disease in XLMTM patients. 
Hepatobiliary disease has been reported in 7 to 17% of XLMTM patients in medical chart 
reviews and natural history studies (Gangfuss, 2021; Annoussamy, 2019; Beggs, 2018; 
Amburgey, 2017; Herman, 1999) and can manifest as cholestasis, jaundice, cholelithiasis, 
pruritus, hepatomegaly, and elevated transaminases. Additionally, the recently published 
literature (Dowling, 2022) based on the data from Study ATX-MTM-009 (INCEPTUS, a 
prospective natural history study conducted by the Sponsor) suggested that hepatobiliary 
disease was identified as an under-recognized comorbidity, where 91% of subjects had histories 
of hepatic disease and/or prospectively experienced related adverse events (AEs) or laboratory 
or imaging abnormalities. The more recent case series and reports (Molera, 2022; D'Amico, 
2022; Neese, 2021) offered additional insight into key clinical characteristics of intrahepatic 
cholestasis and liver dysfunction in XLMTM patients. Presentation of liver dysfunction in XLMTM 
patients varies greatly among patients and within individual patients over time. 
The perinatal and respiratory findings of earlier studies, and the mortality and morbidity data, 
were confirmed in the dataset from the Sponsor’s retrospective chart review study (ATX-MTM-
001 [RECENSUS]) (Beggs, 2018). 
There is no known treatment or disease-modifying therapy for XLMTM, and patient 
management is mainly supportive, with a complicated multidisciplinary approach focused on 
trying to maximize functional abilities and minimize medical complications. 
The Sponsor has conducted 2 patient and family meetings to better understand the humanistic 
impact of XLMTM (XLMTM Patient Focus Group Summary, Audentes Therapeutics, Inc. internal 

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report). Families report that the psychological burden of living with XLMTM is substantial. 
Patients with XLMTM spend a significant proportion of time in the hospital, particularly during 
the first few years of life; in some cases, patients remain in a hospital for the entirety of this 
period. Children with XLMTM are particularly affected by respiratory infections, which frequently 
lead to hospitalization, pneumonia, and occasionally collapsed lungs. Suctioning secretions 
from the throat and airways is constantly required (up to every 5-10 minutes). In addition, 
children must receive regular (often daily) physical therapy. Parents of children with XLMTM are 
not able to communicate well with their children due to speech difficulties, which is an additional 
frustration. In addition, families of children with XLMTM report the disease has a significant 
impact on routine life and can be socially isolating for both the parents and children. Overall, 
XLMTM leads to a substantial impact on the clinical, humanistic (including quality of life, 
psychological aspects, and ability to undertake activities of daily life), and economic burden of 
disease for patients and their families. 
1.2 
Description of AT132 
The active substance is rAAV8-Des-hMTM1, a non-replicating recombinant adeno-associated 
virus serotype 8 (rAAV8), expressing the human MTM1 complementary DNA (cDNA). The 
rAAV8 lacks all of the viral protein coding sequences. In this vector, transgene expression is 
controlled by the human desmin promoter, and ribonucleic acid (RNA) processing is mediated 
by the human β globin gene second intron (HBB2) and polyadenylation (pA) signal. This MTM1 
expression cassette is flanked by the AAV2 inverted terminal repeats (ITRs). A schematic is 
shown in Figure 3. 
Figure 3: Structure of the AT132 Vector Genome 
 
hMTM1, human myotubularin cDNA; intron, engineered form of human β-globin 2nd intron; ITR, inverted terminal 
repeat; Pdesmin, human desmin promoter; polyA, human β-globin polyadenylation signals; SA, splice acceptor; 
SD, splice donor. 
 
For further information on AT132, refer to the current Investigator’s Brochure. 
1.2.1 
Nonclinical Experience with AT132 
1.2.1.1 
Nonclinical Pharmacodynamic Studies 
The efficacy of gene therapy for the correction of myotubularin deficiency was evaluated in 
2 animal models of XLMTM, the MTM1 knockout (KO) mouse in the 129/PAS background  
(Al-Qusairi, 2009; Buj-Bello, 2002) and the p.N155K missense mutational dog model  

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(Beggs, 2010). In preliminary proof-of-concept studies, conducted in the MTM1 KO mouse 
model, both the mouse-specific rAAV8-Des-mMTM1 and AT132 reversed the disease 
phenotype characteristic of XLMTM in a generally dose-dependent manner. Dose-dependent 
efficacy of AT132 was further corroborated in XLMTM dogs after administration of the 
canine-specific version of AT132 (rAAV8-Des-cMTM1), which resulted in increased survival and 
full correction of the MTM disease pathology and phenotype at 9 months following vector 
administration (≥ 2 × 1014 vg/kg) (Childers, 2014; Mack, 2017) and > 3 years following vector 
administration (~2 × 1014 vg/kg) (Elverman, 2016). 
In the pivotal minimal effective dose (MED) study in MTM1 KO mice, which evaluated AT132 
manufactured by the clinical process, doses of 1 to 2 × 1014 vg/kg demonstrated consistent 
improvement in the full spectrum of motor function and XLMTM disease-related pathology 
assessments performed at 8 weeks following vector administration. Based on these data, the 
MED for AT132 was defined as 1 × 1014 vg/kg. 
1.2.1.2 
Nonclinical Biodistribution Studies 
The biodistribution of AT132 delivered by IV injection was uniform in all tissues examined in a 
dose-dependent manner across species. Higher expression relative to skeletal muscle was 
observed in the cardiac tissue of mice and dogs, but not in nonhuman primates (NHPs). In 
NHPs, 8 × 1014 vg/kg AT132 resulted in vector distribution to skeletal muscles, heart, and brain, 
with the highest levels detected in the liver. Levels of messenger RNA (mRNA) and 
myotubularin protein expression were highest in the skeletal muscle, with slightly lower levels 
observed in the heart. Myotubularin protein levels in the liver were similar to those of control 
animals, supporting the specificity of the desmin promoter for expression in skeletal muscle. 
1.2.1.3 
Nonclinical Toxicology Studies 
The doses of AT132 and species-specific vectors administered in the nonclinical safety studies 
ranged from 2.5 × 1013 vg/kg (KO mice) to 8 × 1014 vg/kg (NHPs). The duration of exposure to 
AT132 and species-specific variants ranged from 5 days in MTM1 KO mice to > 3 years for 
p.N155K dogs, with safety assessments up to 9 months for dogs. 
In the pivotal good laboratory practice (GLP) toxicology study in NHPs, the no observed adverse 
effect level (NOAEL) was defined at 8 × 1014 vg/kg. No AT132-specific adverse toxicities were 
observed in either the KO mouse or canine disease models up to doses of 2 × 1014 vg/kg in 
mice and 5 × 1014 vg/kg in dogs. Both doses corrected the XLMTM phenotype in their respective 
models. Consistent with historic data, administration of AT132 to NHPs resulted in induction of 
the humoral immune response against the AAV8 capsid, whereas no antibodies were detected 
against the myotubularin protein. AT132 dosing did not induce detectable AT132-specific T cell 
immune responses in the NHP study. 
Asymptomatic cardiac lesions were observed in mice at necropsy, which were demonstrated to 
exhibit background cardiac lesions in the mouse strain. Although minimal to mild mononuclear 

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cell infiltration was observed in NHPs and dogs, no evidence of cardiac lesions was present. 
These data suggest there is minimal cardiac risk associated with AT132 treatment. 
1.2.2 
Clinical Data for AT132 
This is the first-in-human study of AT132. Interim results of the ATX-MTM-002 (ASPIRO) study 
are summarized in the Investigator’s Brochure. 
1.3 
Study Rationale 
AT132 is being developed by the Sponsor as a gene transfer therapy for the treatment of 
XLMTM and would represent the first gene transfer therapy for this disease. The aim is to 
develop a therapy that will achieve the following: 
• 
Improve survival 
• 
Improve skeletal muscle function 
• 
Improve diaphragmatic (and other respiratory muscle) function 
• 
Improve functional outcomes (eg, speech and communication, swallowing, secretion 
management, developmental progression) 
• 
Reduce the burden of disease for patients and caregivers and improve the Health-
Related Quality of life for children with XLMTM 
AAV8-mediated gene therapy offers the prospect of considerable long-term clinical benefit to 
XLMTM patients through persistent expression of the missing or damaged myotubularin protein 
following a single systemic therapeutic administration. Normal skeletal myofibers are long-lived, 
terminally differentiated, multinucleated cells in which transgene expression can be durable. 
Gene therapy is expected to provide persistent protein expression, corresponding long-term 
clinical benefit, and the potential for substantial recovery of muscle function (Beggs, 2018; 
Buj-Bello, 2008; Buj-Bello, 2002; Childers, 2015; Childers, 2014; Romero, 2010). Substantial 
functional recovery and prolongation of life in both the murine (KO) and canine (missense 
mutation) models of XLMTM disease, employing the same AAV8 vector, support this 
therapeutic strategy. 
This Phase 1/2/3 study will evaluate safety and efficacy of AT132 administered to male subjects 
with XLMTM aged < 5 years. 
1.4 
Dose Selection Rationale 
1.4.1 
Starting Dose Selection Rationale 
The proposed starting dose in Study ATX-MTM-002 was 1.0 × 1014 vg/kg, the second cohort 
3.0 × 1014 vg/kg, and the third dose cohort 5.0 × 1014 vg/kg. The starting dose and subsequent 
doses were selected based on the results from the nonclinical studies. 
In the pivotal MED study in MTM1 KO mice, which evaluated AT132 manufactured by the 
clinical process, doses of 1 to 2 × 1014 vg/kg demonstrated consistent improvement in the full 

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spectrum of motor function and XLMTM disease-related pathology assessments performed at 
8 weeks following vector administration. 
In the pivotal GLP toxicology study in NHPs, the NOAEL was defined at 8 × 1014 vg/kg. Based 
on the nonclinical studies, safety factors of up to 8-fold were identified over the clinical starting 
dose of 1.0 × 1014 vg/kg.  
1.4.2 
Current Dose Rationale 
The 1.0 × 1014 vg/kg dose level referred to herein was based on a 1st generation titer method 
and equates to 1.3 × 1014 vg/kg as determined by a 2nd generation viral genomes (vg) titer 
assay; and the 3.0 × 1014 vg/kg dose level equates to 3.5 × 1014 vg/kg based on an analysis of 
the historical Study ATX-MTM-002 drug product lots using the 2nd generation vg titer assay. The 
following rationale refers to the original nomenclature.  
The first dose cohort (1.0 × 1014 vg/kg) in Part 1 was originally comprised of 4 subjects 
(1 sentinel subject followed by 2 randomized to receive AT132 and 1 randomized to 
delayed-treatment control). After evaluation of the efficacy and safety data from the 3 subjects 
administered AT132 at 1.0 × 1014 vg/kg from Part 1, Cohort 1 and in conjunction with the study 
data monitoring committee (DMC), it was decided to enroll an additional 3 subjects at the 1.0 
× 1014 vg/kg dose (Cohort 1 expansion) to further evaluate the safety of this dose. After review 
of all 6 subjects administered AT132 in Cohort 1, in conjunction with the DMC, it was 
determined to be appropriate to escalate to the 3.0 × 1014 vg/kg dose cohort (Cohort 2). 
Following the administration of 3.0 × 1014 vg/kg AT132 to the initial 3 subjects, it was again 
agreed to evaluate the safety of this dose level in 3 to 5 additional subjects. 
As of Study ATX-MTM-002 protocol v5, the totality of safety, efficacy, and muscle biopsy data 
collected was assessed to determine the dose of AT132 to carry forward into Part 2 of Study 
ATX-MTM-002. A statistically significant difference was not observed between dose levels 
(1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg) in the respiratory and neuromuscular endpoints. At 
Week 24, myotubularin protein expression reached or exceeded normative levels in Cohort 2 
subjects who all were administered 3.0 × 1014 vg/kg AT132, and there was an indication of a 
faster rate of histopathological improvement at this dose. AT132 was well-tolerated with a 
manageable safety profile across both Cohort 1 and Cohort 2 in Part 1. However, in subjects 
treated with 3.0 × 1014 vg/kg, there was an indication of potential dose-related adverse events 
(AEs) (eg, transient decrease in platelet counts, and exacerbation of preexisting 
hyperbilirubinemia) that could increase in frequency and magnitude should dose escalation 
continue. Based on these data, the Sponsor, in conjunction with the DMC, agreed that it would 
not be in the best interest of patient safety to continue with dose escalation beyond the 
3.0 × 1014 vg/kg dose level; therefore, dose escalation to the planned 5.0 × 1014 vg/kg dose 
level (ie, Cohort 3) did not occur. The dose of AT132 selected to be carried forward into Part 2 
was 3.0 × 1014 vg/kg.  

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Following the occurrence of fatal serious AEs (SAEs) in Study ATX-MTM-002, the Sponsor, in 
consultation with the DMC and external experts, evaluated the data and reassessed the 
benefit/risk profiles of the 1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose levels. As of the data cutoff 
date of 08 July 2020, 5 subjects who received 3.0 × 1014 vg/kg AT132 developed AT132-related 
SAEs involving the hepatobiliary system. In 2 subjects, these SAEs resolved; in 3 subjects, fatal 
events occurred subsequent to severe cholestatic liver dysfunction. Within the 3.0 × 1014 vg/kg 
dose level cohort, 8 of 17 subjects (47.1%) experienced 26 SAEs considered related to AT132. 
In contrast, within the 6 subjects dosed at the 1.0 × 1014 vg/kg dose level, all of whom are 
≥ 2 years from AT132 administration, 1 (16.7%) subject experienced 4 AT132-related SAEs, all 
resolved, and none involved the hepatobiliary system. In addition to a favorable safety profile 
observed in the subjects treated with 1.0 × 1014 vg/kg, a clinically meaningful benefit continues 
to be observed in this group at last follow-up. In this group, which had a mean 20.5 hours 
(SE 2.02) of ventilation per day at baseline (n = 5 [83.3%] with invasive ventilation; n = 1 
[16.7%] with non-invasive ventilation), 5 out of 6 (83.3%) subjects were ventilatory independent 
at last follow-up (as of data cutoff date 08 July 2020). With respect to gross motor development, 
at baseline 5 of the 6 subjects did not perform any of the following major motor milestones: sit 
unassisted for 30 seconds, raise self to standing position, stand alone, or walk alone. At 
baseline, 1 subject did sit unassisted for 30 seconds but did not perform the remaining motor 
tasks. At last follow-up following AT132 administration at 1.0 × 1014 vg/kg, 5 out of 6 subjects 
performed all of these motor tasks, including walking alone. Regarding performance on the 
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), 
this 1.0 × 1014 vg/kg group demonstrated a baseline mean score of 37.7 (SE 2.42). At last 
follow-up, performance had improved to a mean score of 56.5 (3.97).  
As data from Study ATX-MTM-002 subjects treated at the 1.0 × 1014 vg/kg dose level 
demonstrate significant and clinically meaningful benefit, an overall benefit/risk analysis by the 
Sponsor, in consultation with the DMC, had determined the benefit/risk profile of the 
1.0 × 1014 vg/kg dose level to be favorable, and superior to the 3.0 × 1014 vg/kg dose level.  
Based on feedback from the US FDA, the Sponsor improved the assay for determination of vg 
titer of manufactured AT132 drug product lots. Following validation, the Sponsor used this 
2nd generation assay, with enhanced precision compared to the 1st generation methodology, to 
recharacterize the vg content of all previously administered drug product lots from 
Study ATX-MTM-002. This recharacterization analysis demonstrated that the 1.0 × 1014 vg/kg 
dose level based on the 1st generation titer method equates to 1.3 × 1014 vg/kg as determined 
by the 2nd generation vg titer assay. Of note, the 3.0 × 1014 vg/kg dose level equates to 
3.5 × 1014 vg/kg based on this historical analysis. 
As of protocol v9, subsequent subjects yet to be dosed were to be administered 1.3 × 1014 vg/kg 
AT132 as determined by the 2nd generation vg titer assay. 
Under protocol v10 and beyond, no additional subjects will be dosed. 

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1.5 
Overall Risks and Benefits 
Key study risks are listed below:  
• 
Subjects will have study procedure-related risks:  
- 
Blood collection: The risks of venous blood draws include discomfort at the site of 
puncture, possible bruising and swelling around the puncture site, rarely an infection; 
and, uncommonly, fainting, nausea, vomiting, and light-headedness from the 
procedure. 
- 
Muscle biopsy: The muscle biopsy has potential complications from the procedure 
that include infection at the biopsy site, bleeding and/or pain at the site of the biopsy, 
and psychological trauma from the scar at the site of the incision; in some cases, 
keloid formation can increase scarring.  
- 
Cardiac or muscle magnetic resonance imaging (MRI): The MRI scan is not 
associated with risks unless a subject has certain types of metal implants such as 
pacemakers.  
- 
Procedural sedation risk: Sedation risks in children with weak respiratory muscles 
varies with the medication used. Sedation risks will be explained to the family.  
Sedation for the imaging must be carefully administered in patients with XLMTM, 
since most anesthetic agents act directly on the muscle. Bulbar dysfunction, 
respiratory muscle weakness, gastroesophageal reflux, and scoliosis increase the 
risk of pneumonia. Children with respiratory and bulbar muscle weakness who are 
not ventilator dependent may require invasive or noninvasive ventilation after the 
procedure. The duration of increased ventilatory requirements would vary depending 
on the degree of respiratory muscle weakness. The potential side effects of specific 
medications administered for sedation (eg, vomiting, respiratory depression, 
laryngospasm, emergence reaction), and the likely duration of sedation will be 
discussed during informed consent for the procedure.  
- 
Prophylaxis (prednisolone, ursodiol): Subjects receive prophylactic prednisolone 
and ursodiol as part of the clinical study. Information regarding the risks associated 
with these medications can be found in the respective local prescribing information.  
• 
Overall risks associated with rAAV gene therapy administration include hepatotoxicity, 
cardiac events such as myocarditis, myositis, thrombocytopenia, thrombotic 
microangiopathy (TMA), and sensory ganglionopathy (Arjomandnejad, 2023; FDA, 2021; 
Lek, 2023; Shen, 2022; Whiteley, 2023).  
- 
Key identified risks associated with AT132 administration observed in Study ATX-
MTM-002 are listed below. Of the overall risks associated with rAAV gene therapy, 
thrombotic microangiopathy and sensory ganglionopathy have not been observed in 
ATX-MTM-002 study subjects. Long-term follow-up is important in understanding 
whether these AEs have long-term implications. Refer to the Investigator’s Brochure 
for further details.  
- 
Hepatobiliary events: Many XLMTM patients have liver dysfunction and 
cholestasis, which places them at increased risk for hepatobiliary dysfunction or even 
hepatic failure with rAAV administration. A prospective natural history study 
(Study ATX-MTM-009) reported that overall, 91% of subjects had histories of hepatic 

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disease and/or prospectively experienced related AEs or laboratory or imaging 
abnormalities (Dowling, 2022).   
◦ 
In Study ATX-MTM-002, SAEs due to hepatobiliary dysfunction occurred after 
AT132 administration and were characterized by hyperbilirubinemia, cholestatic 
liver dysfunction, transaminases elevations, ascites, and serum bile acid 
elevations. Fatal outcomes were observed in 4 subjects due to multifactorial 
causes including hepatobiliary failure: 1 subject who received the 1.0 × 1014 
vg/kg dose and 3 subjects who received the 3.0 × 1014 vg/kg dose. All 4 subjects 
showed increases in direct and total bilirubin values (> upper limit of normal 
[ULN]) beginning 1 to 4 weeks after AT132 administration (Shieh, 2023). Liver 
findings included intrahepatocellular and canalicular cholestasis, periportal and 
bile ductular reaction, secondary fibrosis, and notable lack of prominent liver 
parenchymal inflammatory cellular infiltrates (Shieh, 2020).  
- 
Myocardial events:  
◦ 
Acute cardiac risks: Acute myocardial events manifested as myocarditis and 
increases in troponins. In Study ATX-MTM-002, variable increases in troponin 
levels after AT132 administration were commonly observed. Two subjects 
experienced SAEs of myocarditis: 1 subject who received the 1.0 × 1014 vg/kg 
dose and 1 subject who received the 3.0 × 1014 vg/kg dose. Prolonged 
prednisolone administration plus addition of other immunosuppressive 
medications were used for treatment of myocarditis.  
◦ 
Chronic cardiac risks: Following prolonged immunosuppression for over 3 years, 
1 subject experienced an increase in cardiac troponin levels after withdrawal of 
immunosuppression. Abnormalities in cardiac function have not been observed in 
this subject. However, long term assessment is required to understand whether 
there could be more significant impact on cardiac function. 
- 
Muscle abnormalities: A skeletal muscle immune response to the rAAV capsid and 
to the transgene can occur after rAAV gene therapy administration.  
◦ 
Acute and subacute creatine kinase (CK) elevations: In Study ATX-MTM-002, 
variable increases in CK levels after AT132 administration were commonly 
observed, occurring soon after dosing. These CK levels generally returned to 
normal within the first year after AT132 administration.  
◦ 
Chronic CK elevations and inflammatory infiltrates in skeletal muscles: 
Assessment of muscle biopsies demonstrated treatment-associated inflammatory 
changes in muscle biopsy specimens of some subjects. No SAEs were reported 
in association to these findings. Improvements in neuromuscular function 
(respiratory and motor) have been maintained. Although the CK levels generally 
returned to normal within the first year after AT132 administration, chronic CK 
elevation over several years can occur.  
- 
Thrombocytopenia: Subjects may develop transient thrombocytopenia or 
decreases in platelet levels from baseline after AT132 administration. In Study ATX-
MTM-002, transient thrombocytopenia related to AT132 occurred within the first 2 
weeks of dosing (Shieh, 2023).  

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Key potential study benefits include the following: 
• 
Independent of efficacy, study subjects may receive better-coordinated and more 
comprehensive overall clinical care at centers of excellence. 
• 
AT132, even if only partially effective, could cause clinically important improvements in 
respiratory function and mobility and a lowered risk of disease-related comorbidities, 
leading to greater independence for the subject and caregivers. 
• 
Other patients may benefit from knowledge gained about XLMTM. 
 

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2 STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
The objectives of the study are as follows: 
• 
To determine the therapeutic dose of AT132 
• 
To confirm the safety and efficacy of the therapeutic dose of AT132 
The endpoints of the study are as follows: 
Primary Efficacy Endpoint:  
• 
Change from baseline in hours of ventilation support at Week 24 
Key Secondary Efficacy Endpoint:  
• 
Percentage of subjects achieving functionally independent sitting for at least 30 seconds 
at Week 24  
Other Secondary Efficacy Endpoints:  
• 
Time to reduction in required ventilator support to ≤ 16 hours a day (only in subjects who 
require invasive ventilation) at Week 24  
• 
Change from baseline in CHOP INTEND at Week 24  
• 
Change from baseline in maximal inspiratory pressure (MIP) at Week 24  
• 
Change from baseline in quantitative analysis of myotubularin expression in the muscle 
biopsy at Week 24  
• 
Change from baseline in quality of life assessments at Week 24 (ie, the Assessment of 
Caregiver Experience with Neuromuscular Disease (ACEND) and Pediatric Quality of 
Life Inventory (PedsQL) 
• 
Number (%) of age-appropriate clinically relevant gross motor function milestones 
attained through Week 24 
• 
Percentage of subjects achieving full ventilator independence at Week 24 
• 
Survival 
Safety Endpoints:  
• 
AEs, SAEs, and findings from safety laboratory tests, 12-lead electrocardiogram (ECG), 
echocardiograms (ECHOs), vital signs, growth parameters, physical examinations, liver 
ultrasounds, antibody formation (anti-AAV8, anti-MTM1), viral shedding, annualized 
hospitalization rate, annualized respiratory and non-respiratory SAE rate, and length of 
stay per hospitalization 
Exploratory Endpoints: 
• 
Time to unassisted sitting for 30 seconds or more at Week 24 
• 
Change from baseline in the Motor Function Measure-32 (MFM-32) at Week 24 
• 
Change from baseline in total raw score in the gross motor domain of the Bayley Scales 
of Infant and Toddler Development III (Bayley-III) at Week 24 

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• 
Change from baseline in total raw score in the fine motor domain of the Bayley-III at 
Week 24 
• 
Change from baseline in the proportion of patients being able to feed without a 
gastrostomy or G-tube at Week 24 
• 
Change from baseline in the Communicative Development Inventories scores at Week 
24 
• 
Change from baseline in the Parental Global Impression of Secretion Severity (PGIS-S) 
score at Week 24  
• 
Change in the Parental Global Impression of Secretion Improvement (PGIS-I) score at 
Week 24 
• 
Change from baseline in Clinical Global Impression of Severity (CGI-S) at Week 24 
• 
Change in the Clinical Global Impression of Improvement (CGI-I) score at Week 24 
2.1 
Estimands 
The estimand of the primary objective is defined by the following 5 attributes: 
• 
Treatment: Single dose of AT132 
• 
Population: Male subjects with ventilator-dependent XLMTM, as defined by the 
inclusion/exclusion criteria of the study 
• 
Endpoint: Change from baseline in hours per day of ventilation support at Week 24 
• 
Intercurrent events and their corresponding strategies: For study discontinuation due to 
death or due to lack of efficacy, a composite strategy will be adopted, where subjects 
with the intercurrent event before Week 24 having missing observation(s) after the 
intercurrent event will have those missing observations(s) imputed by unfavorable values 
• 
Population level summary: Mean change from baseline, by dose level 
 

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3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 1/2/3, randomized, open-label, ascending-dose, delayed-treatment concurrent 
control clinical study to evaluate the safety of AAV8-delivered gene therapy in XLMTM subjects 
aged less than 5 years old. Subjects will receive a single dose of AT132 and will be followed for 
safety and efficacy for 10 years, with the primary analysis occurring after all subjects have 
completed 24 weeks of posttreatment evaluation. 
The study consists of 2 parts. Part 1 would establish the optimal dose of AT132. Part 2 would 
confirm the safety and efficacy of AT132 at the optimal dose level. The following describes how 
each part was designed and the changes as of protocol v8 and beyond. 
Part 1 (fully dosed as of protocol v8): 
A maximum of 3 dose levels of AT132 are planned for evaluation in Part 1 of this study 
(Figure 1). Four subjects are planned to be enrolled in each dose level cohort, including 
1 subject in each dose level cohort randomized to control with delayed administration of AT132. 
The first subject in each dose level cohort will be assigned to receive AT132 and will be a 
sentinel subject. Subsequent subjects at that dose level will be randomized (2:1) to treatment or 
control with delayed treatment if there are no safety concerns after at least 4 weeks of 
post-dose data from the sentinel subject is evaluated by the chair of the DMC. Dose escalation 
to the next dose level will be considered after evaluation of at least 4 weeks of data from all 
subjects dosed at the current dose level. If the data warrants, additional subjects may be 
included at a single dose level prior to consideration of dose escalation. Following the dose 
escalation portion of the study, an optimal dose will be determined in conjunction with the DMC, 
and control subjects will be treated at this dose.  
This study’s independent DMC will monitor subject safety and provide recommendations to the 
Sponsor regarding dose level determination, cohort expansion, and safety and study conduct 
matters. 
Subjects who are randomized to receive AT132 may be admitted to the study clinic 1 to 2 days 
prior to AT132 dosing (Day -2 or Day -1) for baseline procedures, including confirmation of 
baseline ventilator settings, and will stay in the study clinic for at least the first overnight 
post-dose. If medically appropriate, subjects may be discharged from the study clinic after 
completion of Day 2 assessments.  
Control subjects will generally have the same assessments as treated subjects, but on a less 
frequent schedule to lessen the burden of study participation. It is anticipated that control 
subjects will participate for at least 24 weeks before an optimal dose is determined and the 
subject can be administered AT132. Following determination of the optimal dose, control 
subjects will undergo pre-treatment baseline procedures to confirm they remain eligible to 

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receive treatment with AT132 at the optimal dose. Once eligible, control subjects will be dosed 
with AT132, and will initiate the post-dose procedures. 
Treated subjects will be administered a course of concomitant prophylactic glucocorticoid (oral 
prednisolone) therapy commencing 1 day prior to AT132 dosing (Day -1), and continuing for a 
period of approximately 8 weeks, then tapering from the original dose over 8 weeks, per 
Investigator discretion (Section 4.4), as a preventative measure for immune-mediated hepatic 
injury, which has been observed in gene therapy clinical studies with AAV. Tapering duration 
may be altered and/or supplemental administration of IV steroids (eg, methylprednisolone) or 
other immunosuppressive regimens may be considered in cases of potential malabsorption of 
oral medications. 
Subjects will be followed for a total of 10 years following AT132 administration, see Section 5.2. 
See Figure 1 for the individual study participation timeline (Parts 1 & 2) through Week 48. 
Part 2 (described herein as planned prior to protocol v8; partially dosed as of 
protocol v8): 
In Part 2, the optimal dose of AT132 will be evaluated in an additional cohort of 10 subjects. 
These subjects will be prospectively paired based on age (±6 months) before being randomized 
to study drug or delayed-treatment control (1:1 allocation). The administration of study drug and 
concomitant prophylactic glucocorticoids, and the assessment of safety will be the same as that 
described in Part 1. Following collection of their Week 24 data, control subjects will be 
administered AT132 and followed according to the Schedule of Events. 
Part 2 as of protocol v8 and v9: 
Following the review of benefit/risk profiles of the 1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose 
levels, the Sponsor, in consultation with the DMC, determined that subjects not yet dosed were 
to be administered the lower dose level (ie, the therapeutic dose), which is 1.3 × 1014 vg/kg 
AT132 as determined by a 2nd generation vg titer assay (see Section 1.4.2). Dosing of the 3 
enrolled delayed-treatment controls who have not yet been dosed will not be conducted as 
described above for Part 2, but will resume at 1.3 × 1014 vg/kg as long as each subject meets a 
subset of inclusion and exclusion criteria prior to dosing. If any of these control subjects is not 
eligible to be dosed, another eligible subject can be enrolled. Any new subject will not be 
considered a delayed-treatment control and therefore will not be required to wait 24 weeks 
before administration of study drug. Any new subject will be enrolled under all of the 
inclusion/exclusion criteria (including Exclusion Criteria 12-14 required for Part 2 subjects). 
In addition to prophylactic glucocorticoids (Section 4.4), subjects will receive daily prophylactic 
ursodiol (ursodeoxycholic acid; Section 4.5) beginning between Study Days -6 and -4. Subjects 
will be followed according to the Schedule of Events (Sections 5.4 and 5.5). See Figure 2. 
As of protocol v10 and beyond: 
This study does not allow for enrollment or dosing of any future subjects. 

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3.2 
Discussion of Study Design 
Enrollment of infants and young children into this first-in-human study exploring the safety of 
AT132 in XLMTM is justified for several reasons: 
• 
There are not enough adult patients to enable a clinical study in the older population due 
to the rarity and early mortality of the disease. It has been established that death rates 
remain high throughout childhood and the majority of children do not survive into 
adolescence and adulthood. The risk of death by 18 months is 46%, with a median 
survival of 29 months (McEntagart, 2002). These data have recently been confirmed in 
the analyses of data from RECENSUS, where high mortality (44% overall) and 
substantial disease burden was demonstrated, particularly in patients ≤18 months of age 
at last follow-up, where mortality was 64%. 
• 
Children and infants represent the most relevant patient population for the evaluation of 
XLMTM. Again, due to the early mortality and severity of XLMTM, the majority of 
patients with XLMTM are children; therefore, this population is the most representative of 
subjects with XLMTM. Some patients with XLMTM do experience prolonged survival, 
although in these individuals the disease is often milder or the patients receive 
prolonged ventilation (Biancalana, 2003); therefore, the older population is not 
representative of infants and children, which display the more characteristically 
aggressive form of the disease. 
• 
If AT132 were to be investigated in the adult population first, there would be a delay in 
providing a potentially life-saving therapy to infants with XLMTM; this delay may not be 
considered ethically appropriate. To illustrate the fragility of the patient population, 
3 infant boys from INCEPTUS who were to be enrolled in ASPIRO died prior to 
enrollment in the study. The robust demonstration of efficacy of AT132 in mice and dogs 
strongly indicate that AT132 could have profound effects in patients with XLMTM and, 
therefore, enrollment of children could potentially save lives in this population. 
• 
Infants and younger children have fewer comorbidities, lower accumulation of medical 
events (such as hypoxic damage and recurrent chest infections), and are not as 
debilitated as the few surviving older children or adults with XLMTM, which increases the 
possibility of demonstrating clinical benefit. 
• 
Pre-existing neutralizing antibodies (NAbs) to AAV8 are less prevalent in younger 
children (Calcedo, 2011). Therefore, AAV8-mediated gene transfer therapy is likely to be 
most successful in the population of infants and young children. 
The compelling nonclinical data that have been generated to date offer the prospect of direct 
benefit to the subject. Coupled with the high infant mortality and absence of any treatment for 
this ultra-orphan disease, it is appropriate to enroll infants and young children into this study. 
Special attention will be paid to the Protection of Human Subjects (45 Code of Federal 
Regulations [CFR] Part 46), Subpart D, Additional Protections for Children Involved as Subjects 
in Research; 21 CFR Subpart D Part 50 (50.50-50.56), Additional Safeguards for Children in 
Clinical Investigations; International Council for Harmonisation (ICH) E6, Good Clinical Practice 
(GCP); and E11, Clinical Investigation of Medicinal Products in the Pediatric Population. 

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3.3 
Selection of Study Population 
3.3.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study. Subjects assigned to delayed-treatment control will be evaluated to confirm the subject 
still meets a subset (*) of the inclusion/exclusion criteria before receiving AT132. 
1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the 
MTM1 gene as assessed by a Sponsor-approved testing facility.* 
2. Subject is male.* 
3. Subject is aged less than 5 years old at dosing.* 
4. Subject requires mechanical ventilatory support: 
• 
Part 1: Subject requires some mechanical ventilatory support (eg, ranging from 24 hours 
per day fulltime mechanical ventilation, to noninvasive support such as continuous 
positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP] during 
sleeping hours). 
• 
Part 2: Subject requires invasive mechanical ventilatory support ranging from 
20 to 24 hours per day at screening (confirmed by daytime polysomnographic study). 
5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted 
with a cuffed tracheostomy tube for some respiratory assessments.*  
6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cmH2O at 
screening.* 
7. Signed informed consent by the parent(s) or legally authorized representative (LAR) (when 
applicable).* 
8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study 
procedures.* 
9. UNIQUE to France: Subject’s weight is ≥ 4.8 kg. 
3.3.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
1. Subject is participating in an interventional study designed to treat XLMTM.* 
2. Subject born < 35 weeks gestation who is still not term as per corrected age. 
3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the 
age of 18 months may be retested in cases where antibodies may have been maternally 
acquired and titers may decline in the first months of life).* 
4. Subject had recent surgery (< 3 months before Day 1) or has planned surgery that may 
confound data collection during the first 48 weeks of the study. 
5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in 
the opinion of the Investigator.* 

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6. Subject has a clinically significant underlying liver disease, defined as:  
• 
≥ Grade 3 aspartate aminotransferase (AST) (> 5.0 x ULN; Common Terminology 
Criteria for Adverse Events [CTCAE] v. 4.03)* 
• 
≥ Grade 3 alanine aminotransferase (ALT) (> 5.0 x ULN; CTCAE v. 4.03)* 
• 
Hepatic peliosis or any other clinically significant structural abnormality detected by 
ultrasound* 
7. Subject is currently experiencing a clinically important respiratory infection or other active 
infection.*  
8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months 
before Day 1.* 
9. Other than as required per protocol, subject has received immune-modulating agents within 
3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory 
conditions is allowed); use of other concomitant medications to manage chronic conditions 
must have been stable for at least 4 weeks before dosing.* 
10. Subject has a contraindication to prednisolone.* 
11. Subject has a contraindication to study drug or ingredients.* 
12. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis 
repair surgery/procedure, in the 12 months following Day 1 (Part 2 including any subjects 
enrolled under protocol v8 and beyond). 
13. Subject has contractures, scoliosis, or other medical condition that would limit the potential 
to achieve unassisted sitting, in the opinion of the Investigator (Part 2 including any subjects 
enrolled under protocol v8 and beyond).  
14. Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion 
of the Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond). 
15. Subject has a clinically important condition, including CTCAE v4.03 Grade ≥ 2 anemia 
(< 10 g/dL hemoglobin).* 
16. Subject has a contraindication to ursodiol (ursodeoxycholic acid).* 
17. UNIQUE to France: Subject has a prior diagnosis or history of cardiac arrhythmias, 
myocarditis, or any other cardiac disease. 
18. UNIQUE to France: Subject has a contraindication to general anesthesia and to muscle 
biopsy procedures. 
* If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132. 
 
3.3.3 
Number of Sites and Subjects 
Approximately 8 sites worldwide are anticipated to participate in this study. Approximately 
16 subjects in Part 1 and 10 subjects in Part 2 were planned to be enrolled under protocol 
amendments v5.0 through v9.0. Protocol v10 and beyond do not allow for enrollment of any 
future subjects.  

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3.3.4 
Subject Identification 
Each subject will be given a unique identifier. If a subject undergoes multiple screening 
attempts, the same unique identifier will be retained. 
3.3.5 
Replacement of Subjects 
Subjects who withdraw prior to Week 48 may be replaced. As of protocol v8, additional subjects 
may be enrolled if any of the 3 enrolled delayed-treatment control subjects who are yet to be 
dosed do not meet a subset of inclusion and exclusion criteria prior to dosing (see 
Sections 3.3.1 and 3.3.2, respectively). Any new subject enrolled will not be considered a 
delayed-treatment control and therefore will not be required to wait 24 weeks before 
administration of study drug. Any new subject will be enrolled under all of the inclusion/exclusion 
criteria (including Exclusion Criteria 12-14 required for Part 2 subjects). 
3.4 
Duration of Study Participation 
The expected study participation is approximately 10 years after AT132 administration; 
approximately 12 years for control subjects who are ultimately administered AT132 (at least 
24 weeks to 3 years delayed treatment and an additional 10 years after AT132 administration).  
3.5 
Removal of Subjects 
3.5.1 
Withdrawal of Subjects 
It is critical to the integrity of this study that subjects adhere to the visit schedule outlined in this 
protocol and to complete all scheduled procedures. As such, the Investigator and clinic staff 
should make every reasonable effort to convey the importance of remaining on the study to the 
subject or parent(s)/LAR(s). Any subject withdrawing from the study should be reported as soon 
as possible to the Sponsor’s Medical Monitor. 
Subjects may withdraw from further participation in the study at any time and for any reason. 
Efforts will be made to collect important data, if feasible, and if the subject agrees. 
Early withdrawal may occur for any of the following reasons: 
• 
Subject request or withdrawal of consent  
• 
AE 
• 
Protocol deviation (at the Sponsor’s discretion) 
• 
Investigator discretion 
• 
Study termination by the Sponsor 
• 
Lost to follow up 
In all cases, the reason(s) for study withdrawal will be recorded in the source document and on 
the appropriate electronic case report form (eCRF).  

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3.5.2 
Withdrawal Follow-Up Procedures 
The Investigator will make every reasonable effort to complete the protocol-specified follow-up 
procedures as specified in Section 5.9, including the follow up of any unresolved AEs as 
described in Section 6.1.3.2. See Section 5.10 for a description of assessments for 
delayed-treatment control subjects who are not eligible to be dosed. 
3.6 
Termination of the Study 
If the Investigator, Sponsor or its designee, Medical Monitor, or DMC (see Sections 7.5 and 7.6) 
becomes aware of conditions or events that suggest a possible hazard to subjects if the clinical 
study continues, then the clinical study may be terminated. The clinical study may also be 
terminated at the Sponsor’s discretion in the absence of such a finding, at any time and for any 
reason. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• 
The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled 
in the clinical study 
• 
Failure to enroll subjects at the required rate 
• 
A decision by the Sponsor to suspend the study, or to suspend or discontinue 
development of the study drug, for any reason 
3.7 
Start and End of Study Definitions 
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the date the first participant signs the informed 
consent form (ICF) and will be the study start date. 
End of study 
The end of the study is defined as the last visit or assessment shown in schedule of 
assessments (Section 5.6) for the last participant in the study. A participant is considered to 
have completed the study if the participant has completed all periods of the study including the 
last assessment shown in the schedule of assessments. 

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4 STUDY TREATMENT 
4.1 
Investigational Medicinal Product (IMP) 
4.1.1 
Identity of IMP 
AT132 (rAAV8-Des-hMTM1) is a genetically engineered AAV vector that expresses the human 
MTM1 cDNA under the control of the muscle-specific human desmin gene promoter. Viral 
particles are pseudotyped with AAV8 capsid, providing tropism for and transduction of muscle 
tissue (Wang, 2005). 
The IMP will be supplied as a sterile, liquid solution with the concentration noted on each of the 
single-use olefin polymer vials. 
The IMP packaging will comply with current Good Manufacturing Practice (cGMP), GCP, and 
local regulatory requirements and may include the following information: Sponsor identification, 
IMP name, lot number, volume, concentration, storage conditions, precautionary statements, 
study identification, subject ID, and use-by date. 
4.1.2 
Shipping and Handling of IMP 
The Sponsor will coordinate a shipment of the appropriate number of AT132-containing vials to 
the study site pharmacy for each subject. Details regarding this process will be outlined in the 
study Pharmacy Manual. 
At the study site, the IMP must be stored frozen at < −60C under restricted access. All IMP 
must be received, inventoried, stored, and dispensed with accountability through final 
disposition documented according to applicable state, federal, and local regulations; ICH 
guidelines; GCP; and study procedures.  
Institutional policy/site procedure for destruction must be reviewed and approved by the 
Sponsor or designee in order to destroy IMP on site. 
4.1.3 
IMP Accountability, Return, and Disposition 
The site is responsible for maintaining accurate records (including dates and quantities) of IMP 
administered to each subject and excess IMP vials. The site must retain all unopened and/or 
expired vials of AT132 in a secure location until a Sponsor designee has confirmed 
accountability data unless prohibited by site/institution policy. Details regarding the expected 
IMP accountability process are provided in the Pharmacy Manual. 
Upon documented accountability, sites with an approved destruction process may release 
product for destruction. A site that does not have an adequate destruction process will return 
unopened and/or expired IMP to the Sponsor or drug depot per the pharmacy manual 
instructions. 

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4.1.4 
Dosage and Administration of IMP 
All study subjects will be administered a single dose of AT132 by IV infusion (control subjects 
will receive delayed treatment) as specified in the study Pharmacy Manual. The starting and 
current dose rationales are described in Section 1.4.2.  
As of protocol v9, subjects not yet dosed were to receive 1.3 × 1014 vg/kg AT132 as determined 
by the 2nd generation vg titer assay (see Section 1.4.2). 
As of protocol v10 and beyond, no additional subjects will be dosed. 
4.1.5 
Treatment Compliance 
Study treatment will be administered by infusion to subjects at the study site by qualified 
personnel. Date, time, volume, and concentration of each dose must be recorded in the IMP 
preparation and IMP administration source documents. In the event that administration of study 
treatment is incomplete, the site should record the reason and any other pertinent information in 
the source document. 
4.2 
Method of Assigning Subjects to Treatment Groups 
Randomization codes will be preassigned for each subject before enrollment into the cohort. In 
Part 2, subjects will be matched with another subject close in age (±6 months) and will then be 
randomized to study treatment or delayed-treatment control. Subjects enrolled under protocol v8 
and beyond will be assigned to study treatment within Part 2. 
After confirmation of subject's eligibility by the Investigator, the Sponsor will provide to the 
Investigator the assigned dose or control designation for the subject number according to the 
randomization sequence and the order of subjects eligible for randomization. For subjects not 
assigned to the delayed-treatment control arm, the Sponsor will coordinate shipment of the 
appropriate number of AT132 vials to the study site pharmacy. Further details regarding this 
process will be outlined in the Pharmacy Manual. 
4.3 
Blinding 
This is an open-label study. The subjects, their caregivers, the site staff, the Sponsor and 
delegates will be unblinded to study treatment assignment. However, the Biopsy Review 
Committee will be blinded to study treatment assignment or study visit per Section 7.7.  
4.4 
Prophylaxis with Glucocorticoids 
Subjects will be administered a course of concomitant glucocorticoid therapy commencing 1 day 
prior to AT132 dosing, and continuing for a period of approximately 8 weeks, then tapering from 
the original dose over 8 weeks per Investigator discretion. This is intended to prevent any 
immune-mediated hepatic injury, which has been observed in subjects who have received 
systemic AAV gene therapy (discussed in Section 6.5.2). For subjects weighing < 60 kg, the 
dose will be 1 mg/kg prednisolone orally daily for 8 weeks, then tapered down for 8 weeks per 

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Investigator discretion. For subjects weighing ≥ 60 kg, the dose will be 60 mg prednisolone 
orally daily for 8 weeks, then tapered down for 8 weeks per Investigator discretion. Investigators 
should closely monitor all liver function (see Appendix 1) results throughout the study. 
Management of prophylactic prednisolone dosing in the setting of abnormal liver function test 
(LFT) results is discussed in Section 4.6.  
The suggested prednisolone tapering regimen for subjects weighing < 60 kg is: 
• 
Weeks 1 to 8:  
1.0 mg/kg/day 
• 
Weeks 8 to 9:  
0.75 mg/kg/day 
• 
Weeks 9 to 10: 
0.50 mg/kg/day 
• 
Weeks 10 to 11: 0.25 mg/kg/day 
• 
Weeks 11 to 12: 0.125 mg/kg/day 
• 
Weeks 13 to 14: 0.0625 mg/kg/day 
• 
Weeks 15 to 16: 0.03125 mg/kg/day 
• 
Week 16: 
Off 
The suggested prednisolone tapering regimen for subjects weighing ≥ 60 kg is: 
• 
Weeks 1 to 8: 
60 mg/day 
• 
Weeks 8 to 9: 
45 mg/day 
• 
Weeks 9 to 10: 
30 mg/day 
• 
Weeks 10 to 11: 15 mg/day 
• 
Weeks 11 to 12: 7.5 mg/day 
• 
Weeks 13 to 14: 3.75 mg/day 
• 
Weeks 15 to 16: 1.875 mg/day 
• 
Week 16: 
Off 
Tapering duration may be altered and/or supplemental administration of IV steroids 
(eg, methylprednisolone) or other immunosuppressive regimens may be considered in cases of 
potential malabsorption of oral medications. 
Side effects associated with oral prednisolone are well understood, and experience exists with 
use of steroids in pediatric populations; the most significant adverse effects (eg, growth 
suppression in children) usually occur after longer courses of treatment. Therefore, providing a 
modest dose [consistent with that used for a number of conditions, see the respective local 
prescribing information] of a short course of oral prednisolone is considered appropriate and an 
acceptable risk. UNIQUE to France: At the time of prescription there should be compliance, 
especially with contraindications, warnings, and precautions for use, with particular attention to 
drug interactions. Refer to the information available on the Public Drug Database, accessible 
through the Internet at: http://base-donnees-publique.medicaments.gouv.fr/. 

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Glucocorticoids will not be provided directly by the Sponsor but rather by a prescription from the 
Investigator (or another provider with notification and approval by the Investigator) and will be 
obtained from a local pharmacy. 
4.5 
Prophylaxis with Ursodiol 
As prophylaxis for possible cholestatic syndromes (see Section 6.5.3.3), subjects in this study 
will receive 20 mg/kg/day ursodiol (ursodeoxycholic acid) administered enterally, divided either 
twice daily (BID) or three times a day (TID) at the Investigator’s discretion. Subjects who are not 
already on ursodiol will begin treatment approximately 1 week before AT132 administration 
(see Schedule of Events in Section 5.4). Subjects who enter the study on ursodiol will continue 
treatment and will be adjusted to the protocol-specified dose regimen. Ursodiol treatment will 
continue to Week 12 and will be administered per the Investigator’s discretion thereafter 
(see Schedule of Events in Sections 5.4 and 5.5), which may be influenced by hepatic 
laboratory and clinical status.  
Appropriate care for an individual subject will be determined by the Investigator based on an 
assessment of the subject’s overall medical status. 
Ursodiol is generally well-tolerated and minimal side effects, most gastrointestinal in nature, 
have been described (see the respective local prescribing information). Therefore, a course of 
ursodiol as outlined in this protocol is considered appropriate and of acceptable risk. 
Ursodiol will not be provided directly by the Sponsor but rather by a prescription from the 
Investigator (or another provider with notification and approval by the Investigator) and will be 
obtained from a local pharmacy. 
4.6 
Monitoring for and Management of Cardiac, Liver, and Neuromuscular Related 
Safety Events 
4.6.1 
Monitoring for and Management of Myocarditis 
4.6.1.1 
Monitoring for Myocarditis  
Site Investigators are responsible for prompt review of all laboratory or procedural results. Due 
to the importance of accurate diagnosis and management of myocarditis for subject safety, sites 
must identify and establish a site pediatric cardiologist experienced in the treatment of 
myocarditis. The site pediatric cardiologist will assist the study site and any managing physician 
responsible for patient care with interpretation of abnormal cardiac test results and treatment. A 
high level of awareness and vigilance for potential myocarditis should be maintained in the 
setting of gene therapy clinical studies. 
The primary monitoring strategy for identifying potential myocarditis will be by clinical 
assessment and scheduled (surveillance) high-sensitivity Troponin T and/or Troponin I testing. 
Troponin elevations can be an early signal of myocarditis, a serious cardiac condition that is 
critical to promptly diagnose and treat. The frequency of assessments is outlined in the 

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Schedule of Events (Sections 5.4, 5.5, 5.6, and 5.7). Additional assessments may be performed 
at the discretion of the investigator and pediatric cardiologist as outlined in Section 4.6.1.3.  
4.6.1.2 
Clinical Role of the Site Pediatric Cardiologist 
The site pediatric cardiologist will serve as: 
• 
Cardiology resource for the study site and clinicians who manage subjects enrolled in 
the ASPIRO study 
• 
Primary reviewer of routine surveillance cardiac testing abnormalities identified by 
Investigators (Section 4.6.1.3) 
• 
Specialist relative to the diagnosis and management of myocarditis or suspected 
myocarditis 
As a member of the study site medical team, the site pediatric cardiologist will work together 
with the Investigator to assist with diagnosis, interpretation of cardiac testing, and treatment. In 
the case where the site pediatric cardiologist does not have direct access to the subject and no 
local cardiologist is available, the site pediatric cardiologist will provide guidance to the 
managing physician.  
4.6.1.3 
Diagnosis and Management of Myocarditis or Asymptomatic Troponin 
Elevations 
Clinical assessment, laboratory testing, and cardiac imaging can be used to detect myocarditis 
associated with AT132 administration. Documentation is required for data and discussions 
related to diagnosis and treatment. The Investigator for the study is responsible for all study-
related medical decisions. 
Routine Myocarditis Surveillance 
• 
Troponin I and/or Troponin T will be assessed at scheduled visits. Investigators will 
consult the site pediatric cardiologist when Troponin T and/or Troponin I are above the 
ULN for the laboratory reference range. All laboratory reference ranges are per the 
reporting of the local or central laboratory, as applicable. 
Additional Testing for Myocarditis Diagnosis and Management  
Test selection is performed at the discretion of the investigator in conjunction with consultation 
with the site pediatric cardiologist. Key testing that may assist in diagnosis and management of 
myocarditis includes but is not limited to:   
• 
Laboratory testing: A variety of laboratory testing can be useful in the diagnosis and 
management of myocarditis, including but not limited to complete blood count and 
differential, complete metabolic panel, troponin I and/or troponin T, N-terminal pro b-type 
natriuretic peptide, sedimentation rate, C-reactive protein, infectious assessments (eg, 
nasopharyngeal and rectal swabs, viral titers), CK with isoenzymes to identify elevations 
in the myocardial isoenzyme (CK-MB), and interferon gamma (IFN-γ) enzyme-linked 
immunosorbent spot assay (IFN-γ ELISpot) for MTM1 peptide pool and AAV8 peptide 
pool. Anti-MTM1 antibodies are optional.   

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• 
ECG 
• 
Transthoracic ECHO  
• 
Cardiac MRI 
• 
Cardiac catheterization with endomyocardial biopsy (in exceptional cases) 
4.6.2 
Monitoring for and Management of Hepatobiliary Toxicity 
Hepatobiliary toxicity has been reported with AAV gene therapy treatment (Chan, 2020) and in 
this study (ATX-MTM-002). In Study ATX-MTM-002, AT132-related SAEs involving the 
hepatobiliary system, including intrahepatic cholestasis, have occurred in subjects with XLMTM 
treated at the 1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose levels. Subjects will be administered 
glucocorticoid prophylaxis and ursodiol prophylaxis as outlined in Sections 4.4 and 4.5, 
respectively. Routine surveillance and evaluation of any signs or symptoms of hepatobiliary 
toxicity is an essential safety parameter. The primary monitoring strategy for identifying potential 
hepatobiliary toxicity will be through frequent, scheduled testing of the following LFTs: ALT, 
AST, gamma-glutamyltransferase (GGT), total bilirubin (TBL), and direct bilirubin. Additional 
monitoring will include scheduled liver ultrasound procedures and as of protocol v10 serum bile 
acid levels in order to better understand the long-term behavior of intrahepatic cholestasis in 
XLMTM subjects. The frequency of these assessments is outlined in the Schedule of Events 
(Sections 5.4, 5.5, and 5.6). 
Site Investigators are responsible for prompt review of all laboratory or procedural results 
related to potential hepatobiliary toxicity. To enhance the monitoring and management of 
potential hepatotoxicity, sites will identify a site hepatologist (preferably with expertise in 
pediatric cholestatic disease). The site hepatologist will assist the study site and any managing 
physician responsible for patient care with interpretation of abnormal hepatobiliary test results 
and treatment. A high level of awareness and vigilance for potential hepatobiliary toxicity should 
be maintained in the setting of gene therapy clinical studies. Details related to the monitoring, 
diagnosis, and treatment of hepatobiliary toxicity are described herein. Any laboratory tests 
and/or procedures performed for these safety events should be reported in the eCRF. 
4.6.2.1 
Clinical Role of the Site Hepatologist 
Given that AT132-related SAEs involving the hepatobiliary system, including severe intrahepatic 
cholestatic disease, have been observed in subjects with XLMTM administered AT132 at the 
1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose levels, the site hepatologist will serve as the: 
• 
Expert hepatology resource for the study site and clinicians who manage ASPIRO 
subjects  
• 
Primary specialist to assist in the diagnosis and management of hepatobiliary toxicity 
noted in subjects following treatment with AT132 
As a member of the study site medical team, the site hepatologist will work together with the 
Investigator to assist with interpretation of abnormal surveillance results, and if indicated, 

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additional diagnostic workup and treatment. In the case where the site hepatologist does not 
have direct access to the subject and no local hepatologist is available, the site hepatologist will 
provide guidance to the treating clinician to ensure subject safety. In all cases, the clinician that 
is providing direct patient care is ultimately responsible and the decision maker for the 
management and treatment of the subject. 
4.6.2.2 
Monitoring for Hepatobiliary Toxicity Risk 
A combination of hepatobiliary laboratory tests and procedures will be used to monitor for cases 
of potential toxicity after treatment with AT132. The following notification and consultative 
parameters are provided to assist Investigators, and/or other clinicians caring for ASPIRO 
subjects, to identify clinically significant abnormalities during routine hepatobiliary monitoring. All 
laboratory reference ranges are per the reporting of the local or central laboratory, as 
applicable. 
Routine Hepatobiliary Surveillance 
• 
Investigators will consult the site hepatologist for any of the following criteria:  
• 
GGT, AST, or ALT: ≥ 5 × ULN (or ≥ 3 × the Baseline Visit value if it was > ULN)  
• 
TBL or direct bilirubin: ≥ 3 × ULN (or ≥ 2 × the Baseline Visit value if it was > ULN)  
• 
Any abnormal liver ultrasound finding 
• 
Serum bile acid, total or fraction: ≥ 2 × ULN 
Abnormal Hepatobiliary Laboratory or Procedural Results not Associated with Routine 
Surveillance per the Protocol Schedule of Events 
• 
The approach for identifying potential hepatobiliary toxicity in this setting may be more 
complex (eg, the subject is hospitalized) 
• 
The Investigator should consult with the site hepatologist and notify the Medical Monitor 
to determine an appropriate follow-up plan based on the clinical circumstance 
Communication Guidelines 
• 
Details and discussions around the monitoring, diagnostic, and treatment 
(Section 4.6.2.3) activities of a subject that include the site hepatologist are required to 
be documented  
4.6.2.3 
Risk Management of Hepatobiliary Toxicity 
Management of subjects with hepatobiliary toxicity will depend on the interpretation of all 
available clinical data.  
• 
The site hepatologist must be actively involved in any case where the LFTs are higher 
than the values listed in the routine surveillance guidelines (Section 4.6.2.2). 
Management in this setting may be highly variable and may require additional diagnostic 
testing and/or alteration of the existing immunosuppressive regimen. 

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• 
In cases where the LFTs are rising but are within the values listed in the routine 
surveillance guidelines (Section 4.6.2.2) and the subject is on prophylactic 
glucocorticoids, prednisolone adjustments may be made at the discretion of the 
Investigator based on the stage of prophylaxis (steady dose or tapering). For cases 
refractory to prednisolone adjustment, consult the Medical Monitor. 
• 
In cases where the ALT or AST are rising but are within the values listed in the routine 
surveillance guidelines (Section 4.6.2.2) and the subject is not on prophylactic 
glucocorticoids, consultation with the Medical Monitor is recommended, and 
management may require additional diagnostic testing and/or treatment with 
immunosuppressive agents 
• 
In cases of clinically significant elevated LFTs and/or elevated CK that in the 
Investigator’s judgment may be related to T cell responses, repeat cytokine panel and 
IFN-γ ELISpot response testing is suggested 
• 
Following the Week 4 complement panel collection, in cases of clinically significant 
elevations in LFTs (and/or thrombocytopenia, acute renal insufficiency, or anemia), 
repeat complement panel testing is suggested  
4.6.3 
Monitoring for and Management of Neuromuscular Abnormalities 
4.6.3.1 
Monitoring for Neuromuscular Abnormalities 
Acute, subacute, and chronic CK elevations can occur after gene therapy administration. 
Muscle abnormalities vary and can include myositis, which can be asymptomatic or display 
muscle weakness. Neuromuscular abnormalities may manifest as bulbar, motor, and/or 
respiratory weakness.  
Site Investigators are responsible for prompt review of all laboratory or procedural results. Due 
to the importance of accurate diagnosis and management of neuromuscular dysfunction for 
subject safety, consultation with a pediatric pulmonologist is required for potential decline in 
respiratory function. The site pediatric pulmonologist will assist the study site and any managing 
physician responsible for patient care with interpretation of abnormal pulmonary test results and 
treatment. Due to risks associated with worsening bulbar function, a pediatric ear, nose and 
throat (ENT) specialist and/or speech-language pathologists will be consulted if worsening 
bulbar dysfunction is suspected. 
The primary monitoring strategy for identifying potential neuromuscular abnormalities will be by 
clinical assessment and scheduled (surveillance) of CK levels in blood. The frequency of these 
assessments is outlined in the Schedule of Events (Sections 5.4, 5.5, 5.6, and 5.7).  Additional 
assessments may be performed at the discretion of the investigator and pediatric 
neuromuscular specialist as outlined in Section 4.6.3.2. 
4.6.3.2 
Diagnosis and Management of Neuromuscular Abnormalities 
Clinical assessment, laboratory testing, and muscle imaging can be used to detect 
neuromuscular abnormalities associated with AT132 administration. Documentation is required 

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for data and discussions related to diagnosis and treatment. The Investigator for the study is 
responsible for all study-related medical decisions.  
Routine neuromuscular surveillance  
• 
Physical examination with detailed neurological evaluation and respiratory function 
assessment 
• 
CK will be measured at scheduled visits. If the CK is above the ULN for the laboratory 
reference range, the investigator will decide whether additional diagnostic evaluation is 
needed.  
Additional testing for diagnosis and management of neuromuscular abnormalities  
Test selection is performed at the discretion of the investigator in conjunction with consultation 
with the neuromuscular specialist as needed. Additional consultations with a pediatric ENT 
specialist, speech-language pathologist, pediatric pulmonologist, and a pediatric neuromuscular 
specialist may be needed. Key testing that may assist in diagnosis and management of 
neuromuscular abnormalities includes but is not limited to:    
• 
Laboratory testing: A variety of laboratory testing can be useful in the diagnosis and 
management of neuromuscular abnormalities, including but not limited to complete blood 
count and differential, complete metabolic panel, sedimentation rate, C-reactive protein, 
infectious assessments (eg, nasopharyngeal and rectal swabs, viral titers), CK , 
CK-isoenzymes for identification of elevations in the skeletal muscle isoenzyme 
(CK-MM) or CK-MB, and IFN-γ ELISpot for MTM1 peptide pool and AAV8 peptide pool. 
Anti-MTM1 antibodies are optional.  
• 
Electrophysiological assessment (electromyography [EMG]) 
• 
Skeletal muscle MRI with short tau inversion recovery (STIR) sequence  
• 
Diagnostic muscle biopsy 
4.7 
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by subjects for 3 months prior to the 
Screening Visit through the end of the study will be recorded on the concomitant medications 
eCRF. Receipt of SARS-CoV-2 vaccine products at any time prior to Screening Visit through the 
end of the study will be recorded on the concomitant medications eCRF. The Investigator may 
prescribe additional medications during the study, as long as the prescribed medication is not 
prohibited by the protocol as described in Section 4.8. In the event of an emergency, any 
needed medications may be prescribed without prior approval, but the Medical Monitor must be 
notified of the use of any excluded medications immediately thereafter. Any concomitant 
medications administered or discontinued during the study should be recorded on the eCRF. 
For guidance regarding the administration of vaccines, including timing considerations, to 
subjects on prolonged glucocorticoid regimens, refer to local country guidelines (eg, the Centers 
for Disease Control and Prevention [CDC] General Best Practice Guidelines for Immunization: 

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Best Practices Guidance of the Advisory Committee on Immunization Practices [ACIP]; Altered 
Immunocompetence [CDC, 2020]). 
4.8 
Excluded Therapies 
Investigational therapies, other than AT132, for XLMTM are not allowed during the first 
24 months after the subject receives AT132. The allowance of investigational therapies that are 
NOT related to XLMTM (eg, experimental vaccines or treatments for infectious diseases) will be 
determined on a case-by-case basis. Subjects should not be administered such investigational 
therapies without first obtaining approval from the Medical Monitor.  
The therapies listed below are excluded during the course of the study:  
• 
Pyridostigmine 
• 
Other than the prescribed oral prednisolone or the use of an immunosuppressive agent 
in response to a specific condition called out in the protocol, any immune-modifying 
medication is strongly discouraged during the course of the study (use of inhaled 
corticosteroids to manage chronic respiratory conditions is allowed) 
4.9 
Physical Therapy  
Physical therapists will continue to provide a consistent standard of care therapy for subjects in 
ASPIRO through Week 48. Following Week 48, if a subject has achieved new motor milestones, 
a physical therapist should alter their care to ensure a subject maintains these achieved 
milestones. 

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5 STUDY ASSESSMENTS AND SCHEDULE OF STUDY ASSESSMENTS 
5.1 
Study Assessments 
The Investigator is responsible for ensuring that all staff involved in the study are familiar and 
comply with the content of this section. The following describes the study procedures to be 
performed during the study. The Schedule of Events is provided in Section 5.2. For each 
subject, assessments should be conducted at approximately the same time of day at each visit, 
and in the same order, if possible. All study assessments will be recorded on the eCRF. 
In the event of unforeseen circumstances (eg, a global pandemic), Investigators are encouraged 
to engage with their governing Institutional Review Board (IRB)/Ethics Committee (EC) as early 
as possible when urgent or emergent changes to the protocol or informed consent are 
anticipated. Attempts should be made to conduct safety monitoring and other efficacy 
assessments even if on-site visits are not possible. Sites shall discuss any expected 
modifications to the protocol visit schedule or assessments with the Sponsor to protect study 
subjects and manage study conduct. 
The total volume of blood collected from each study subject is to be as small as possible, using 
pediatric tubes and the smallest volumes possible, while still allowing for validity of each test 
and protecting the safety of subjects. For a 1-year-old child, the 50th percentile average weight 
is 10.5 kg/23 lb, with a corresponding blood volume limit of 31.5 mL daily and 78.75 mL for an 
8-week period (Howie, 2011). Blood sample volumes for this study are approximately 2 to 
18 mL per visit, with a maximum of approximately 90 mL over an 8-week period. If the blood 
volumes at a visit exceed the maximum amount allowed, the study site should prioritize the 
assessments to be conducted and discuss with the Medical Monitor. 
UNIQUE to France: For a 1-year-old child, the 50th percentile average weight is 10.5 kg/23 lb, 
with a corresponding blood volume limit of 20 mL daily and 40 mL for a 4-week period (Howie, 
2011). Blood sample volumes for this study are 2.0 to 10 mL per visit, with a maximum of 
approximately 36.1 mL over a 4-week period. For visits where the amount of blood exceeds the 
limits stated above, the site should discuss with the Medical Monitor which samples should be 
prioritized. 
5.1.1 
Description of Study Assessments 
5.1.1.1 
Medical History 
All conditions and procedures occurring before the ICF is signed will be recorded as medical 
history. The name of the disease state (ie, XLMTM) does not need to be recorded as medical 
history. From the time of obtaining informed consent, all SAEs should be reported as such, if the 
Investigator believes they may have been caused by a protocol-required procedure. All other 
untoward medical occurrences observed during the screening period through Day -1, including 
exacerbation or changes in medical history, are to be captured on the medical history eCRF. 
The medical history at baseline should be updated to capture changes since the Screening 

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Visit. The Sponsor retains the right to request additional information regarding a medical history 
condition, if judged necessary. See Section 6 for details. 
5.1.1.2 
Procedures  
All procedures occurring after the ICF is signed but prior to dosing (Day -1) will be recorded as 
medical history. All procedures occurring after dosing will be recorded on the procedures eCRF.  
5.1.1.3 
Genetic Testing 
At screening, MTM1 genetic testing will be conducted to confirm a diagnosis of XLMTM for 
subjects without previous confirmation by a Sponsor-approved testing facility. 
Additionally, whole genome analysis may be conducted on leftover samples to further 
understand the molecular basis of XLMTM disease and interindividual heterogenicity in 
treatment response (see Appendix 9 Genetics for information regarding genetic research). 
5.1.1.4 
Human Leukocyte Antigen (HLA Testing) 
A laboratory test to identify the major HLA genes that the subject has inherited and their 
corresponding antigens that are present on the surface of their cells. The sample will only need 
to be collected 1 time during the study. The sample will be collected at the Week 12 visit, unless 
HLA type has been obtained in INCEPTUS. For subjects in Part 1 who have already passed the 
timepoint listed above, the HLA sample will be collected at the Week 48 visit or the Month 24 
visit, whichever occurs first. HLA typing will be used to study association of potential AEs in the 
ongoing and future potential gene therapy studies with particular HLA alleles.  
5.1.1.5 
Physical Examination 
A complete physical examination should include all body systems pertinent to the subject. 
Abbreviated physical examinations should focus on general appearance, cardiovascular, 
pulmonary, and abdominal examinations, as well as investigation of reported symptoms. Any 
clinically significant abnormalities observed should be recorded as medical history or AEs as 
described in Section 6. 
5.1.1.6 
Vital Signs 
Vital signs for this study include blood pressure, heart rate, respiration rate (RR), and 
temperature. Record whether the subject was on or off of ventilatory support when vital signs 
are taken. 
5.1.1.7 
Concomitant Medications 
All medications from the time of informed consent to when the subject withdraws or completes 
the study will be recorded on the concomitant medications eCRF. In this study, subjects will 
receive concomitant prophylactic glucocorticoid (see Section 4.4) and ursodiol (see 
Section 4.5). 

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5.1.1.8 
Standard Safety Laboratory Tests (Chemistry, Hematology, Coagulation, 
Urinalysis) 
Standard safety laboratory tests (chemistry, hematology, coagulation, urinalysis; as specified in 
Appendix 1) will be conducted using a combination of the central laboratory and local 
laboratories. It is recommended to use the central laboratory to analyze laboratory tests that are 
drawn prior to dosing, and after the Week 16 Visit and to use the local laboratory to analyze 
laboratory tests that are drawn at Baseline, Dosing, Days 1 and 2, and Weeks 1 through Week 
16. However, the local laboratory can be used for other visits if needed (for example, the local 
laboratory can accommodate the analysis with a smaller amount of blood) or if the local 
laboratory does not accommodate the appropriate analysis, the central laboratory may be used. 
Abnormal laboratory test results will be reported as described in Section 6. Laboratory samples 
may be collected by a trained home health nurse for protocol-required study visits and 
unscheduled visits, as needed. Samples collected by a home health nurse will be sent to the 
central laboratory for processing. 
In addition to standard safety laboratory tests, samples for troponin T and/or I, cytokine panels, 
and complement panels will be collected as per the Schedule of Events in Sections 5.3.1, 5.4, 
5.5, 5.6, and 5.7. Troponin T and/or troponin I will be monitored to assess cardiac safety. See 
Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and 
treatment of myocarditis; and the role of the site pediatric cardiologist. The cytokine profile of 
each subject will be established before dosing of study drug. Complement panel details are 
provided in Section 5.1.1.28. It is the Investigator’s responsibility to perform clinical laboratory 
assessments more frequently, if clinically indicated.  
Samples for laboratory tests will be collected as per Appendix 1 and the Schedule of Events in 
Sections 5.3.1, 5.4, 5.5, 5.6, and 5.7. Additional samples may be collected as clinically indicated 
per Section 6.5. Refer to study Laboratory Manual for additional sample handling details. 
5.1.1.9 
Liver Ultrasound 
Hepatic peliosis, an abnormality of the hepatic vasculature, which has the potential to cause a 
dramatic hemorrhage, is a rare but recognized complication of XLMTM. Serial ultrasound 
assessments will be used to assess change in size, shape, and structure of the liver, and will be 
evaluated in conjunction with serum LFTs. Refer to Section 4.6.2 for details related to the 
monitoring, diagnosis, and treatment of hepatobiliary toxicity and the role of the site 
hepatologist. 
5.1.1.10 
Cardiac Structure and Function (ECG, ECHO and Cardiac MRI) 
Unlike many neuromuscular diseases, individuals with XLMTM do not exhibit cardiac muscle 
disease. Mice treated with rAAV8-Des-MTM1 had asymptomatic cardiac lesions detected on 
necropsy (in the presence of gross over expression of myotubularin) (Section 1.2.1.3). It is 
unknown whether a risk exists for human subjects. Cardiac structure and function will be 

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routinely assessed using 12-lead ECG and ECHOs. Cardiac MRI may be performed at the 
discretion of the investigator in conjunction with consultation with the site pediatric cardiologist. 
If myocarditis is observed, cardiac catheterization and endomyocardial biopsy may be needed in 
exceptional cases.  
If troponin I and/or troponin T is elevated above the ULN of the laboratory reference range, test 
selection for diagnosis and management of myocarditis or asymptomatic troponin elevation is 
performed at the discretion of the investigator in conjunction with consultation with the site 
pediatric cardiologist. Key testing is discussed below. Refer to Section 4.6.1 for management of 
ECG, ECHO, and Cardiac MRI results and the role of the site pediatric cardiologist.  
• 
ECG: In patients with suspected myocarditis, the ECG can display a variety of non‑
specific abnormalities. Interpretation of ECG by the site pediatric cardiologist may be 
required due to the array of ECG changes that can occur with myocarditis.  
• 
Transthoracic ECHO: ECHO is a safe, widely available, and clinically extremely useful 
cardiac imaging tool, particularly for the initial assessment of myocarditis. The American 
College of Cardiology (ACC), American Heart Association (AHA), and European Society 
of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases 
recommend that all patients with clinically suspected myocarditis should undergo an 
ECHO at initial presentation (Adeboye, 2022). 
• 
Cardiac MRI: Cardiac MRI is considered the non-invasive reference standard for 
diagnosis of myocarditis in the absence of contraindications to MRI. Gadolinium may be 
used to assess for late gadolinium enhancement, a technique used for cardiac tissue 
characterization due to various types of myocardial injury and fibrosis. Cardiac MRI 
findings change depending on the phase of disease and timing of imaging. Myocardial 
edema is a characteristic early feature of acute myocarditis which typically improves 
over days to weeks and may not be detected if cardiac MRI is performed weeks to 
months after symptom onset. Diagnostic sensitivity is highest within 2 to 4 weeks of 
symptom onset; therefore, cardiac MRI should be performed quickly in patients with 
suspected myocarditis (Urzua Fresno, 2023). 
• 
Cardiac catheterization with endomyocardial biopsy in exceptional cases: Although the 
gold standard for diagnosis of myocarditis is endomyocardial biopsy, this procedure is 
usually not required for diagnosis and management. Considering this procedure’s 
invasiveness, low sensitivity when myocardial involvement is focal, and a complication 
rate ranging from 1% to 15%, the pediatric cardiologist may consider the clinical 
presentation to be of sufficient severity to necessitate the procedure, especially in 
uncommon clinical scenarios such as severe heart failure, cardiogenic shock, ventricular 
arrhythmias, and/or when there is significant diagnostic uncertainty, aiming to ensure the 
requirement of the procedure (Pilati, 2022).  
5.1.1.11 
Respiratory Function 
5.1.1.11.1 
Assessment of Ventilator Requirements with Polysomnogram 
Daytime polysomnograms (ie, respiratory physiology studies) will be performed at Screening 
and at Week 24 to assess the number of hours of ventilator support required. Daytime 
polysomnograms will also be performed at Week 48 only if the subject is still on ventilator at the 

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time of the visit. For example, if the subject has discontinued the ventilator at Week 40, the 
Week 48 daytime polysomnogram is not required. 
At Screening, ventilatory support will be provided for approximately 3 hours while observing the 
subject and subsequently the ventilatory support will be removed.  
At Week 24 and Week 48, ventilatory support will be provided for approximately 1 hour while 
observing the subject and subsequently the ventilatory support will be removed. Additionally, if a 
subject is already off ventilator for 1 hour or more, the 1-hour observation period will not be 
required. 
At Screening, Week 24, and Week 48 if any of the following criteria are met following the 
removal of ventilatory support, the polysomnogram will be stopped and the ventilator support 
will be reintroduced: 
• 
Oxygen saturation (SpO2) < 94% on room air for at least 20 seconds 
• 
Increased end tidal carbon dioxide (ETCO2) or transcutaneous carbon dioxide (TCO2) of 
10 mmHg or 1.33 kPA for at least 20 seconds 
• 
ETCO2 or TCO2 > 50 mmHg for at least 20 seconds 
• 
Increased respiratory rate by 25% over baseline value  
At Screening, if the subject does not reach criteria for the reintroduction of ventilation, they will 
remain off of the ventilator for a maximum of 4 hours. 
At Week 24 and Week 48 if the subject does not reach criteria for the reintroduction of 
ventilation, they will remain off of the ventilator for a minimum of 6 hours plus the amount of time 
off at Screening. For example, if at Screening, the subject was off the ventilator for 15 minutes, 
the daytime polysomnogram at Week 24 should be a minimum of 6 hours and 15 minutes off 
the ventilator. 
5.1.1.11.2 
Assessment of Time Off Ventilator  
5.1.1.11.2.1 
Daily Ventilator Dependence Diary 
For subjects in Part 1 who have not completed the Week 24 visit and for subjects in Part 2 
(including any subjects enrolled under protocol v5 and beyond), an electronic diary will be 
completed by the parent/LAR/caregiver to collect the type of ventilatory support and the amount 
of time the subject spent off of ventilatory support in a 24-hour period. The diary should be 
completed daily by the same parent/LAR/caregiver (whenever possible). Site staff should set up 
the electronic diary prior to distribution to the parent/LAR/caregiver and review the training with 
the parent/LAR/caregiver. The daily diary collection will begin after informed consent (or 
reconsent to protocol v5 or later for Part 1 subjects) and continue through Week 48. However, if 
after the Week 24 visit, ventilator support has been discontinued, the daily diary will no longer 
need to be completed. If ventilator support is resumed, the daily diary completion will resume 
through Week 48 or discontinuation of the ventilatory support, whichever occurs first. For 

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subjects in Part 1 who have already completed the Week 24 visit, a daily diary will not be 
completed. 
5.1.1.11.2.2 
Ventilator Dependence Questionnaire 
A questionnaire will be completed by the parent/LAR/caregiver to collect the type of ventilatory 
support and the amount of time the subject spent off of ventilatory support in a 24-hour period at 
clinic and contact visits (Appendix 4). 
For subjects in Part 1 who have already completed the Week 24 visit, the parent/LAR/caregiver 
will complete the ventilator dependence questionnaire at clinic and contact visits through 
Month 120. 
For subjects in Part 1 who have not completed the Week 24 visit and for subjects in Part 2 
(including any subjects enrolled under protocol v5 and beyond), the daily diary will be completed 
per Section 5.1.1.11.2.1. After the daily diary has been stopped or the subject has completed 
Week 48, the parent/LAR/caregiver will complete the ventilator dependence questionnaire at 
clinic and contact visits through Month 120.  
5.1.1.11.3 
Guidelines for Initiating Ventilator Weaning  
Weaning is the process of decreasing the amount of support that the subject receives from the 
mechanical ventilator, so that the subject assumes a greater proportion of the ventilatory effort. 
The objective is to assess the probability that mechanical ventilation can be successfully 
discontinued. 
Weaning from invasive or noninvasive ventilatory support will be conducted in collaboration with 
the Investigator, site pulmonologist, and the subject’s local pulmonologist, if applicable. The site 
pulmonologist and the local pulmonologist, if applicable, will review the results from the visit, 
assess the subject, and determine if the subject meets the criteria outlined in Table 1 to begin 
reduction of hours on the ventilator. Once the subject meets and maintains the criteria outlined 
in Table 1, the site pulmonologist and the local pulmonologist, if applicable, may change the 
ventilator settings and reduce the prescribed number of hours at their discretion. Refer to the 
ASPIRO: ATX-MTM-002 Ventilator Weaning and Discontinuation Manual for recommendations 
on ventilator weaning. The actual number of hours of ventilatory support a subject receives daily 
will be recorded via the electronic ventilator dependence diary or the Ventilator Dependence 
Questionnaire (Section 5.1.1.11.2.1).  

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Table 1: Required Parameters for Initiation of Ventilator Weaning  
Assessments 
Parameters 
Vital signs 
Normal for age 
Weight 
Normal for age 
Respiratory function tests 
Maximal inspiratory pressure (MIP) 
> 50 cmH2O 
Maximal expiratory pressure (MEP) 
> 40 cmH2O 
Positive end-expiratory pressure (PEEP) 
≤ 5 cmH2O 
Oxygen saturation (SpO2) 
> 94% 
Transcutaneous CO2 (TCO2) 
35-45 mmHg 
End tidal CO2 (ETCO2) 
35-45 mmHg 
Gas exchange markers 
Serum bicarbonate 
22-27 mEq/L 
Clinical judgement 
Consider week-to-week clinical improvements in motor 
milestones (rolling over, head control, sitting unassisted); 
vocalization; coughing; secretions, and neuromuscular 
function tests (CHOP INTEND) 
CHOP INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders 
 
The above parameters are to be assessed by site personnel during the normal routine site visits 
through Month 42. As of protocol v12, beginning at the Month 48 visit, some parameters (ie, 
MIP/MEP, ETCO2, TCO2) will no longer be collected per protocol and decision making related to 
initiation of ventilator weaning will occur by the site and local pulmonologists in collaboration 
with the Site Investigator, upon review of relevant clinical assessments and in consideration of 
standard practice in ventilator weaning in patients with neuromuscular disease.  
5.1.1.11.4 
Guidelines for Discontinuation of Ventilatory Support 
Discontinuation of mechanical ventilation can be attempted after the Week 12 visit, if 
appropriate. The site pulmonologist and the subject’s local pulmonologist, if applicable, will 
determine if the subject is ready to discontinue ventilatory support based on the parameters 
outlined in Table 1 and Table 2. 
At the Week 12 visit, the site pulmonologist and local pulmonologist, if applicable, should review 
the results from the previous assessments and determine if the subject continues to meet the 
criteria outlined in Table 1. If the subject meets the criteria in Table 1, the assessments in 
Table 2 should be conducted to assess readiness to discontinue ventilatory support. If the 
subject meets the criteria outlined in Table 2 and the pulmonologist and Investigator determine 
the subject is ready, the ventilator can be discontinued. The assessments in Table 2 should be 
conducted before discontinuing nighttime ventilation and should be repeated 3 to 4 weeks after 
discontinuation of nighttime ventilation. If the subject does not meet the criteria in either Table 1 

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and Table 2, the pulmonologist should continue to assess the subject at subsequent visits to 
determine readiness to discontinue ventilatory support. Details on assessment for 
discontinuation of ventilatory support and for decannulation will be provided in a separate 
procedure manual. 
It is advisable to wean tracheostomized subjects directly off ventilation to spontaneous 
respiration rather than to noninvasive ventilation (NIV) as an intermediate step because the 
masks required for NIV are not likely to be tolerated by infants and toddlers unaccustomed to 
masks.  
Table 2: Required Ventilator Discontinuation Parameters 
Assessments 
Parameters 
Gas exchange markers 
Sprinting (video record the 
assessment) 
• 
No distress  
• 
SpO2 > 94% 
• 
TCO2 ≤ 45 mmHg 
• 
No intercostal retraction, tachypnea, respiratory paradox, or 
phase delay 
Nocturnal Polysomnogram (PSG) (performed with trach open) 
Apnea-hypopnea index (AHI) 
< 5 (lower threshold for NMD than for obstructive processes) 
TCO2 
35-45 mmHg 
ETCO2 
• Consider % of sleep time with ETCO2 < 45 mmHg and 
<50 mmHg 
• Steady state capnometry in NREM and in REM sleep 
Oxygen saturation (SpO2) 
> 94% 
Respiration rate (RR) 
Within the age adjusted norms 
Sleep architecture 
Normal for age (Berry, 2012). The following parameters will be 
assessed: 
• Sleep efficiency (%) 
• Sleep latency (min) 
• REM latency (min) 
• Arousal index (N/hr) 
• Stage N1 (%TST) 
• Stage N2 (%TST) 
• Stage N3 (%TST) 
• Stage R (%TST) 
ETCO2 = End tidal carbon dioxide; min = minute(s); NMD = neuromuscular disorders; NREM = non-rapid eye 
movement; REM = rapid eye movement; TCO2 = transcutaneous carbon dioxide; TST = total sleep time 
 
The above parameters are to be assessed by site personnel during the normal routine site visits 
through Month 42. As of protocol v12, beginning at the Month 48 visit, some parameters (ie, 
MIP/MEP, ETCO2, TCO2) will no longer be collected per protocol and decision making related to 

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discontinuation of ventilator support will occur by the site and local pulmonologists in 
collaboration with the Site Investigator, upon review of relevant clinical assessments and in 
consideration of standard practice in ventilator discontinuation in patients with neuromuscular 
disease. 
5.1.1.11.5 
Assessment of Ventilator Parameters 
End tidal CO2, transcutaneous CO2, O2 saturation, and serum bicarbonate (from the local or 
central laboratory) will provide information about the effectiveness of ventilation. 
Assessment of ventilator parameters will include the baseline ventilator settings and changes in 
ventilator settings over time, end tidal CO2, transcutaneous CO2, respiratory rate, O2 saturation, 
and serum bicarbonate during clinic visits. During the contact calls, the site will ask the LAR if 
the subject is currently using ventilator support. 
Details on assessment of ventilator parameters will be provided in a separate procedure 
manual. The above parameters are to be assessed by site personnel during the normal routine 
site visits through Month 42. As of protocol v12, beginning at the Month 48 visit, the Assessment 
of Ventilator Parameters will no longer be collected per protocol and decision making related to 
collection and analysis of clinical ventilator and respiratory parameters will occur by the site and 
local pulmonologists in collaboration with the Site Investigator. 
5.1.1.11.5.1 
MIP, MEP, P0.1, and Tidal Volume 
Assessment of respiratory strength and endurance will include MIP, MEP, inspiratory occlusion 
pressure at 0.1 seconds (P0.1), and tidal volume. MIP and MEP will be obtained using a cuffed 
tracheostomy tube. Details on assessment of respiratory muscle strength and endurance will be 
provided in a separate procedure manual. 
MIP and MEP are noninvasively obtained estimates of respiratory muscle strength. Adult and 
pediatric reference values exist (Gaultier, 1983; Wilson, 1984) and this measure is becoming 
increasingly utilized in the neuromuscular disease setting (Smith, 2014). 
Inspiratory occlusion pressure at 0.1 seconds provides a measurement that represents a 
weighted sum of the effort of all respiratory muscles active at a given time (Whitelaw, 1993). 
This measure is not a separate procedure but rather is a calculated value from data collected 
during the assessment of MIP. 
If a subject has discontinued the use of the ventilator and has 2 assessments with the MIP at 
80 cmH2O, testing for MIP, MEP, and P0.1 will not be required for future visits. 
Respiratory strength and endurance assessments are to be performed by site personnel during 
the normal routine site visits through Month 42. As of protocol v12, beginning at the Month 48 
visit, respiratory strength and endurance assessments will no longer be collected per protocol 
and decision making related to collection and analysis of respiratory strength, endurance and 

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function assessments will occur by the site and local pulmonologists in collaboration with the 
Site Investigator. 
5.1.1.11.6 
Respiratory Infections and Annualized Respiratory Hospitalization Rate 
The incidence, severity, and duration of respiratory infections will be determined from AE 
reports. The annualized respiratory hospitalization rate will be calculated for all subjects. 
5.1.1.12 
Assessments of Neuromuscular Function 
Assessments of neuromuscular function will be video recorded and may be reviewed to confirm 
that assessment procedures are being conducted correctly, as well as for optional future review 
of subject performance. To fully assess disease manifestations, video recordings will not be 
deidentified (will show faces and limbs). The procedures for video recording assessments will 
be provided in a separate procedure manual. In all subjects, the assessments will include a set 
of key motor development milestones (Section 5.1.1.12.1), the CHOP INTEND 
(Section 5.1.1.12.3), and the motor domain of the Bayley-III (Section 5.1.1.12.2). The MFM-32 
will be used to assess children ≥ 2 years of age (Section 5.1.1.12.4).  
As of protocol v12, beginning at the Month 48 visit, only the Motor Developmental Milestones 
assessment will be performed. Decision making regarding collecting other assessments of 
neuromuscular function will occur by the Site Investigator, in collaboration with other 
neuromuscular specialists as indicated. 
5.1.1.12.1 
Motor Developmental Milestones 
The motor developmental milestones listed in Table 3 will be assessed and video recorded (on 
site or remotely) in all subjects according to the Schedule of Events. The motor developmental 
milestone assessments will be conducted separately from the Bayley-III scales and details on 
assessment of motor developmental milestones will be provided in a separate procedure 
manual. If a subject is unable to complete the motor developmental milestones of “Pulls to 
Stand”, “Stands with Assistance”, “Walks with Assistance”, “Stands Alone”, or “Walks Alone”, 
these may be evaluated with supra-malleolar or ankle-foot orthoses (SMO or AFOs). 

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Table 3: Motor Developmental Milestones 
a See motor milestone manual for full description of performance criteria 
 
5.1.1.12.2 
Bayley-III Scales (Gross and Fine Motor Domains) 
The motor domains of the Bayley-III are a standard series of measurements to assess the motor 
(fine and gross motor subscales) development of infants and toddlers. The motor domain of the 
Bayley-III will be conducted in all children. The Bayley-III is a tool that is used commonly in 
clinical practice to assess a child’s developmental progression. It has been used in many 
pediatric clinical studies to ensure that the children are attaining milestones at the requisite 
ages; and it has been used specifically in children with spinal muscular atrophy (SMA) (Mendell, 
2015) and infants with Duchenne muscular dystrophy (Connolly, 2013). Raw Bayley-III scores 
will be reported.  
5.1.1.12.3 
CHOP INTEND 
The CHOP INTEND is an assessment scale containing 16 questions, each of which is scored 
on a scale of 0 to 4. It was originally designed to quantify motor abilities in infants aged 1.4 to 
37.9 months, with spinal muscular atrophy type I (SMA-I) (Glanzman, 2010) and has been 
validated for XLMTM (Duong, 2021). It was designed such that the repertoire of motor skills and 
Development 
Milestone 
Reference 
Summary Description of 
Performance Criteriaa  
Head Control 
Bayley Gross Motor Subtest 
Item #9 
Child holds head erect for at least 15 seconds 
without support 
Rolls from Back 
to Sides 
Bayley Gross Motor Subtest 
Item #20 
Child turns from back to both right and left sides 
Sits Without 
Support 
WHO Multicentre Growth 
Reference Study 
Child sits alone without support for at least 
10 seconds 
Sits Without 
Support 
Bayley Gross Motor Subtest 
Item #26 
Child sits alone without support for at least 
30 seconds 
Stands with 
Assistance 
Bayley Gross Motor Subtest 
Item #33 
Child supports own weight for at least 2 seconds 
Crawls 
Bayley Gross Motor Subtest 
Item #34 
Child makes forward progress of at least 5 feet 
by crawling on hands and knees 
Pulls to stand 
Bayley Gross Motor Subtest 
Item #35 
Child raises self to standing position using chair 
or other convenient object for support 
Walks with 
Assistance 
Bayley Gross Motor Subtest 
Item #37 
Child walks by making coordinated, alternating 
stepping movements. He/she may hold on with 
1 or 2 hands for support. 
Stands Alone 
Bayley Gross Motor Subtest 
Item #40 
Child stands alone for at least 3 seconds after 
you release his or her hands. 
Walks Alone 
Bayley Gross Motor Subtest 
Item #42 
Child takes at least 3 steps without support, even 
if gait is stiff-legged and wobbly 

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movements associated with neuromuscular disorders could be quantified, without relying 
heavily on inherently challenging tasks such as prone positioning, long duration, or head control 
items. Face validity and inter-rater reliability has since been established in multiple 
neuromuscular diseases, including SMA-I, myotubular myopathy, infant botulism, nemaline 
myopathy, central core myopathy and XLMTM (Glanzman, 2011). 
If a subject has 2 assessments with a total score of 56, the CHOP INTEND will not be required 
for future visits. 
5.1.1.12.4 
Motor Function Measure 32 (MFM-32) 
The MFM-32 contains 32 tests of muscle strength, each measured on a scale of 0 to 3, for a 
total score of 96. The measures capture 3 dimensions of muscle tone: standing and transfers, 
axial and proximal motor function, and distal motor function. The MFM-32 has been validated in 
patients aged 6 to 62 years with Duchenne muscular dystrophy, Becker muscular dystrophy, 
limb-girdle muscular dystrophy, facio-scapulo-humeral dystrophy, myotonic dystrophy, 
congenital myopathy, congenital muscular dystrophy, SMA, and hereditary neuropathy (n = 303) 
(de Lattre, 2013). XLMTM shares key characteristics with these disorders including reduced 
fetal movements and polyhydramnios in the pregnant mother; and severe hypotonia, myopathy, 
respiratory distress and/or failure, and underdeveloped motor skills in the child (Sewry, 2012). 
The MFM-32 will be used to assess children ≥ 2 years of age. 
5.1.1.13 
Swallowing Assessments 
5.1.1.13.1 
Parental Swallowing Questionnaire 
The Parental Swallowing Questionnaire is a Sponsor-designed instrument designed to reflect a 
parents’ assessment of the child’s ability to swallow and will be used to document the child’s 
ability to feed without a gastrostomy or G-tube. The Parental Swallowing Questionnaire will be 
completed by a parent/LAR/caregiver based on their day-to-day observation of the child’s 
condition in the home environment. 
A 2-item questionnaire (Appendix 7) will evaluate elements of swallowing including the child’s 
ability to swallow liquids and foods. 
5.1.1.14 
Speech Assessments  
As of protocol v12, beginning at the Month 48 visit, speech assessments will no longer be 
performed per protocol. Decision making regarding collecting other clinical speech assessments 
will occur by the Site Investigator, in collaboration with other neuromuscular specialists as 
indicated. 
5.1.1.14.1 
Parental Speech Development Questionnaire 
The Parental Speech Development Questionnaire is a Sponsor-designed instrument designed 
to assess major speech developments. A series of probative questions will be asked to the 

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parent/LAR/caregiver (the same person every time, whenever possible) by the Investigator or 
delegate at study visits (Appendix 8).  
5.1.1.14.2 
Communicative Development Inventories  
The MacArthur Communicative Development Inventories (CDI) and their language adaptations, 
are parent-reported instruments for assessment of communicative skills in infants and toddlers 
(Fenson, 2000). The short-form versions of the English and Spanish CDIs have been validated. 
Adaptations in other languages of the MacArthur CDI will be used to assess communicative 
skills of children in other countries. 
Parents/LARs/caregivers (the same person every time, whenever possible) in ASPIRO will be 
asked to complete the inventory for subjects 8 months and older. Communicative Development 
Inventories will be used to assess change in baseline language development over time. 
5.1.1.15 
Secretions Management Assessments (PGIS-S and PGIS-I) 
Management of secretions is an important component of protecting the airway and lowering the 
risk of lung infections caused by aspiration. 
The PGIS-S and PGIS-I are 2 separate but related Sponsor-designed instruments designed to 
reflect parents’ assessment of the burden of care associated with the need to manage the 
secretions of a child with XLMTM. The scales assess both the severity of this aspect of the 
disease (PGIS-S) and change over time (PGIS-I). Related instruments are widely used and well 
validated as supportive endpoints (Busner, 2009). The PGIS (PGIS-I and PGIS-S) will be 
completed by a parent/LAR/caregiver based on their day-to-day observation of the child’s 
condition in the home environment. 
Parents/LAR/caregiver will report on the amount of suctioning and secretions management 
required over the previous week, using a scale of 1 to 7 to report impression of change from 
baseline and impression of current severity (Appendix 3). The same parent/LAR/caregiver 
should provide assessments throughout the study (whenever possible). During months that do 
not have a clinic visit, the parent/LAR/caregiver will be contacted by the study site. A minimum 
of 2 contact attempts will be made at each time point. 
5.1.1.16 
Clinical Global Impression Assessments (CGI-S and CGI-I) 
A global assessment by the Investigator or designee will be done to assess the severity of the 
subject’s disease utilizing a 7-point scale (CGI-S; Appendix 5). 
A global assessment by the Investigator or designee will be done to assess if there has been 
any improvement of the subject’s disease utilizing a 7-point scale (CGI-I; Appendix 5). The 
purpose of this assessment is to capture change in a subject’s clinical status compared with 
baseline severity. 

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For both assessments, the same person should assess a subject for the duration of the study 
(whenever possible). In addition to the numerical score, clinicians will be asked to draft a brief 
clinical narrative, to justify the score that is being given. 
5.1.1.17 
Burden of Disease 
5.1.1.17.1 
Assessment of Caregiver Experience with Neuromuscular Disease 
(ACEND) 
The ACEND was developed to measure impact on the lives of parents/LARs/caregivers caring 
for children with severe neuromuscular disorders (Matsumoto, 2011). Although currently 
validated for children aged 4 years and older, the ACEND was developed specifically for 
children with significant developmental disabilities. Several domains of the ACEND (time, 
finance, and emotion) are relevant to assessing the caregiver burden of the parents of children 
with XLMTM. 
5.1.1.17.2 
Pediatric Quality of Life Inventory (PedsQL)  
The PedsQL is a 23-item tool designed to measure health-related quality of life in healthy 
children and adolescents and those with acute and chronic health conditions. The PedsQL 
measures the core dimensions of health as delineated by the World Health Organization, as 
well as role (school) functioning. The PedsQL neuromuscular module was designed to measure 
health-related quality of life dimensions specific to children aged 2-18 years with neuromuscular 
disorders and has been validated in other neuromuscular disorders such as SMA (Iannaccone, 
2009). It will also be used for children < 2 years of age in this study. Subjects will continue to 
use the same version (from Baseline) of the questionnaire for the duration of the study even as 
the subject ages out of PedsQL version.  
5.1.1.18 
In-Depth Interviews of Caregivers and Subjects  
Parents/LARs/caregivers will be invited to participate in in-depth interviews to elicit the stories of 
families (parents/LARs/caregivers) related to the child’s illness, and their participation in the 
ASPIRO study. Participation in the interviews is optional and is not required to participate in the 
ASPIRO study. These interviews will explore and analyze parents/LARs/caregivers’ 
perspectives on, and experiences with, the impact of the treatment received (by the child) in the 
ASPIRO study. In in-depth interviews, a single respondent is probed by an experienced 
interviewer to uncover underlying motivations, beliefs, attitudes, and feelings on a topic (Harris, 
1996). Due to the rarity of the disease and the paucity of published literature describing the 
impact and burden of XLMTM, it is considered that these interviews will provide valuable 
information to help understand the disease. In addition, it is considered that detailed information 
regarding the involvement of XLMTM subjects in an interventional clinical study will facilitate the 
optimization of future clinical studies both in XLMTM and in other rare pediatric neuromuscular 
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These interviews will follow a generic qualitative design, with a critical qualitative component 
analyzing the narratives of parents in relation to their experiences, values, and perspectives on 
the child’s illness trajectory and participation in the ASPIRO study. An open-ended, narrative 
approach to data collection will be utilized. This approach is interpretive and involves 
storytelling. The interviews will take place in-person or over a video conference, and will be 
audio-recorded. The personnel conducting all the interviews will be scientists at St. Michael’s 
Hospital; all of whom are trained and experienced qualitative researchers, which is essential to 
manage interview dynamics, minimize social desirability bias, and ensure data quality. 
Parents/LARs/caregivers will be interviewed a maximum of 2 times in the study, ideally 
coinciding with the Baseline and Week 24 or Week 48 assessments. For subjects who have 
already passed the timepoints listed above, only 1 interview will be conducted at a subsequent 
visit. Subjects (aged 2 and older) may also be interviewed at the same timepoints to capture 
children’s stories through visual methods, including drawn images such as comics (Darnhofer, 
2018). 
5.1.1.19 
Anti-AAV8 Antibody Testing 
The timing of clearance of maternally acquired anti-adeno-associated virus 8 (anti-AAV8) 
antibodies in infants differs from individual to individual and has been described, but is not fully 
understood. In a study (Calcedo, 2011), approximately 18% of infants 0 to 2 months old tested 
positive for AAV8 NAbs with titers > 1:20. The prevalence of NAbs declined rapidly after birth, 
reaching a nadir at 7 to 11 months. The rate at which children develop anti-AAV8 antibodies in 
response to natural exposure to AAV8 is also incompletely understood. Because the presence 
of preexisting antibodies to AAV8 could affect the potential efficacy of AAV8 gene transfer 
therapy, information about binding, total antibodies (TAbs), and NAbs will be collected at 
Screening and following administration of AT132 per the Schedule of Events in Sections 5.3.1, 
5.4, 5.5, 5.6, and 5.7. An isotype-independent cell-based NAb assay will detect neutralizing 
factors specific to AAV8 (NAbs) (Calcedo, 2009). The TAbs to AAV8 will be measured using an 
enzyme-linked immunosorbent assay (ELISA)-based assay (Falese, 2017). 
5.1.1.20 
Anti-MTM1 Antibody Testing  
Anti-MTM1 is a specialty assay which will be used to measure binding human antibodies 
immunoglobulin G (IgG) against MTM1 protein. Titers of anti-MTM1 antibodies will be evaluated 
at Screening and following administration of AT132 per the Schedule of Events in 
Sections 5.3.1, 5.4, and 5.5. 

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5.1.1.21 
Interferon-γ (IFN-γ) ELISpot Assay 
Interferon-γ (IFN-γ) production is commonly used as an indicator of T cell immune reactivity. 
An ELISpot assay will measure IFN-γ producing T cells in subjects’ peripheral blood 
mononuclear cells (PBMCs) after challenge with a pool of AAV8 peptides or myotubularin 
peptides. Samples for testing will be collected per the Schedule of Events in Sections 5.4 and 
5.5. Additional samples will be collected as clinically indicated, as described in Section 4.6. 
5.1.1.21.1 
Flow Cytometry Assay 
A Flow Cytometry exploratory analysis will be performed to access the phenotype of T cells, 
B cells, Natural Killer cells, Monocytes, and Macrophages in the subject’s cryopreserved 
PBMCs, leftover from the IFN-γ ELISpot assay. This assay will be performed to assess the 
immune cells for available samples pre- and post-gene therapy administration. 
5.1.1.22 
Platelet Monitoring (not applicable for France) 
Samples for platelet monitoring will be collected at Baseline and following study drug 
administration at Day 2, Week 1, and Week 2. The samples will be analyzed for the following: 
• 
Complete blood count with differential (ensuring report of platelet counts and mean 
platelet volumes)  
• 
Peripheral blood smears (performed as part of the hematology panel) 
• 
Flow cytometry analysis of: 
- 
Activation surface antigens, degranulation and functional markers including: 
◦ 
CD62P (P-selectin) 
◦ 
Activated GP IIb/IIIa [αIIbβ3] with PAC-1 antibody 
◦ 
Phosphatidylserine 
- 
Platelet circulating antibodies 
- 
Reticulated platelets (platelet mRNA) 
5.1.1.23 
Growth and Developmental Parameters 
5.1.1.23.1 
Growth Parameters 
Growth will be assessed by measuring height, weight, and head circumference. 
5.1.1.23.2 
Bone Age (Wrist X-ray) (not applicable for Germany) 
X-ray of the left wrist in infants and children to ascertain bone age is a recognized method of 
assessing maturity and development of the skeleton. This is of particular relevance in XLMTM, 
because advanced bone age and a variety of skeletal abnormalities (although not well 
characterized) have been documented in some XLMTM patients (Herman, 1999). The radiation 
dose for this procedure is low (0.001 mSv per X-ray). Subjects in Germany will not have a wrist 
X-ray. 

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As of protocol v12, beginning at the Month 48 visit, bone age will no longer be collected per 
protocol. 
5.1.1.23.3 
Tanner Stage  
Tanner stage will be assessed to monitor for premature adrenarche, which has been 
documented in some XLMTM patients. Tanner staging criteria are provided in Appendix 2. 
As of protocol v12, beginning at the Month 48 visit, Tanner stage will no longer be collected per 
protocol. 
5.1.1.24 
Hospitalization Rate and Length of Stay 
The annualized hospitalization rate and length of stay per hospitalization will be determined for 
all subjects.  
5.1.1.25 
Survival  
Children with XLMTM have a high mortality rate (Section 1.1). Accordingly, survival will be 
assessed. Survival status should be assessed at each visit until the subject withdraws consent 
or completes the study. If the subject misses a visit or withdraws for a reason other than 
withdrawal of consent or death, the site should contact the parent(s)/LAR(s) to ascertain if the 
subject is alive. For subjects who withdraw from the study, the subject should be contacted 
every 6 months for 5 years after administration and every year for an additional 5 years (after 
the 5-year follow-up through 10-years follow-up) to assess for survival. If not alive, the cause 
and date of death should be requested and recorded. 
In the case of a subject’s death during participation in the study, an autopsy may be requested. 
5.1.1.26 
Muscle Biopsy (Quantitative Assessment of Tissue Changes) 
Muscle biopsies will be collected using a standard muscle open biopsy protocol. Preference of 
muscles to biopsy will be (1) left gastrocnemius; (2) right gastrocnemius; and (3) vastus lateralis 
(either side). A different muscle may be biopsied if imaging studies (eg, muscle MRI) suggest a 
higher probability of muscle tissue collection in another muscle group (eg, biceps brachii). 
Muscles that have been biopsied previously will not be re-biopsied during this study to avoid the 
potential for sampling of the old biopsy site. Biopsy sites will be taken from the target muscle at 
least 3 cm away from myotendinous insertion sites and sites of known prior muscle injections or 
electromyography needle sites. 
Muscle biopsies will be used to assess the efficacy and safety of AT132 by analyzing MTM1 
protein expression, vector copy number quantitation, RNA transcripts assessment, histological 
characterization and inflammatory markers. 
If a muscle biopsy is performed at the discretion of the investigator for diagnostic purposes, 
including but not limited to CK elevations and declining neuromuscular function 

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(Section 4.6.3.2), testing should be performed in accordance with standards of care for 
diagnostic muscle biopsy assessment. 
When possible after diagnostic muscle biopsy, muscle should be collected and sent to the 
central lab for the AT132-related assessments listed below: 
• 
MTM1 protein expression 
• 
Vector copy number quantitation 
• 
RNA transcript assessment 
• 
Histological characterization 
• 
Inflammatory markers 
Automatic muscle specimen segmentation techniques will be used to assess pathological 
features (eg, myofiber size, internally/centrally nucleated myofibers) using machine learning, 
computer vision techniques, and algorithms that have been developed to measure challenging 
skeletal muscle specimens (Liu, 2013; Liu, 2014; Liu, 2015) and further adapted for XLMTM 
tissue. Muscle specimens will be processed by the clinical study site and sent to a Sponsor 
designated central reader for review. Details will be provided in a separate procedure manual. 
If a subject had a diagnostic biopsy prior to study enrollment, it will not be eligible for use as the 
pre-treatment biopsy due to concerns about variable tissue handling procedures and 
age-related changes in pathology. 
5.1.1.27 
Viral Shedding 
Viral shedding will be assessed by quantitative polymerase chain reaction (PCR) on samples of 
saliva (swab), stool sample, and urine (diaper collection or urine bag). Collection of each sample 
type will begin on Day 1 and will continue until each sample type has 3 consecutive data points 
at or below the limit of detection (BLOD). For example, saliva collection will stop once 
3 consecutive saliva sample results are BLOD, but stool and urine collection will continue 
beyond that timepoint if they have not reached 3 consecutive BLOD results in each of those 
individual sample types. Sponsor will notify the site when collection can cease. 
5.1.1.28 
Complement Panel 
The complement system consists of a large number of plasma proteins, either soluble or 
membrane bound, that play an important role in the innate immune system. Activation of the 
complement system is tightly regulated to ensure a specific response against pathogen infection 
and to maintain homeostasis. Samples for complement panel testing will be collected per 
Appendix 1 and the Schedule of Events in Sections 5.3.1, 5.4, and 5.5. Additional samples will 
be collected as clinically indicated per Section 4.6.2. 

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5.1.1.29 
Serum Bile Acid Assay 
Serum bile acid levels are elevated in some cholestatic disorders. To better understand 
cholestatic tendency in XLMTM, serum bile acid levels will be measured. This assay will be 
performed once, any time prior to treatment with AT132, for subjects dosed in protocol v8 and 
beyond. As of protocol v10, the assay will also be performed following AT132 administration 
according to the Schedule of Events (see Sections 5.3.1, 5.4, 5.5, and 5.6). Serum bile acid 
levels will preferably be collected in the fasting state; however, the samples may be collected in 
the non-fasting state per the Investigator’s discretion. 
5.1.1.30 
Transient Elastography of the Liver by Ultrasound 
Transient elastography by ultrasound is a noninvasive, widely available technique to assess 
liver stiffness. Liver stiffness may be increased in cholestatic disorders, particularly if resulting 
fibrosis occurs. To better understand liver stiffness characteristics in baseline XLMTM, this 
exploratory procedure will be performed once, any time prior to treatment with AT132, for 
subjects dosed in protocol v8 and beyond (see Sections 5.3.1 and 5.4).  
5.1.1.31 
Muscle MRI with STIR Sequence 
The MRI STIR sequence is a type of MRI protocol that involves a short inversion time to nullify 
signals from tissues with short T1 relaxation times, highlighting areas with longer T1 values. It is 
useful for identifying edema, fluid, and inflammation in muscle. It is recommended that this 
imaging protocol be obtained in response to elevated CK to better understand the potential 
inflammatory changes that may occur after treatment with AT132. STIR sequences may be 
used to support identification of the cause for the neuromuscular abnormality, identify a muscle 
site for biopsy if needed, and monitor treatment response. In some circumstances, muscle MRI 
with STIR sequences may be performed when CK is elevated as part of the diagnostic 
assessment. This imaging is performed at the discretion of the investigator. 
5.1.1.32 
Electrophysiological Assessments (EMG) 
EMG may be performed to assess neuromuscular abnormalities. Nerve conduction studies can 
be performed if a neuropathic process is suspected.  
5.2 
Schedule of Study Events 
The assessments to be conducted for each subject enrolled in the study are presented in 
tabular form in Sections 5.3.1, 5.4, 5.5, 5.6, and 5.7. Additional information is provided above, in 
the study appendices, and study procedure manuals, as noted. 
For each subject and visit, assessments may be conducted over multiple days and should be 
performed at approximately the same time of day and in the same order, when possible, for 
each visit. Week 3, 5, 6, 7, 9, 10, 11, 13, 14, or 15 procedures can be performed at the study 
site clinic, or in the subject’s home by a trained home health nurse. Home health nurses may 
collect laboratory samples, perform a limited physical examination, vital signs, and review 

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concomitant medications and AEs upon request of the Investigator, as needed at any protocol 
scheduled visit or unscheduled visit. All subjects will undergo all assessments at the Screening 
Visit. Following randomization to treated or control arm, subjects will follow either the Treated or 
Control Subject Schedule of Events. Control subjects will use the Control Subjects Schedule of 
Events until they are assigned to receive AT132. 
Long-term follow-up visits and/or assessments after the 5-year (Month 60) visit can be done 
remotely per discretion of investigator in consultation with Medical Monitor. 
For subjects who end the study early, information related to post-dose safety assessments may 
continue to be collected via public data or Electronic Medical Record request per consent form 
until 10 years after AT132 dosing. Additional details can be found in the CRF Completion 
Guidelines. 
5.3 
Schedule of Events for Screening  
All subjects will undergo assessments at the Screening Visit. Eligibility of the control subjects 
will be confirmed before assignment to receive AT132. The assessments from a control visit 
may be used to assess eligibility. Following assignment to receive AT132, control subjects will 
follow the Treated Subject Schedule of Events, starting with the Biopsy Visit and Baseline Visit 
in Section 5.4. 
Informed consent must be obtained from the subject’s parent(s)/LAR(s) before initiation of any 
protocol-specified screening procedure. 
Subjects will be screened within 70 days before dosing to determine eligibility for participation in 
the study. Procedures and assessments may be done on different days. Procedures or 
assessments that have already been completed within 70 days prior to planned Day 1 as part of 
an Astellas Gene Therapies, Inc.-sponsored study do not need to be repeated and may be used 
as a Screening assessment for this study. Screening assessments that are not repeated at 
Day -1 will be considered baseline values. All results needed to evaluate study eligibility must 
be reviewed by prior to randomization. Eligibility should be re-confirmed by the Investigator prior 
to dosing (Day 1) by reviewing the Screening and Baseline results. In addition, 
delayed-treatment control subjects must meet a subset of the inclusion/exclusion criteria before 
receiving AT132, as indicated by an asterisk (*) in Sections 3.3.1 and 3.3.2. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
randomized to treatment or control and will return to the clinic on Day -2 or -1 for baseline 
assessments. Subjects must be randomized at least 6 days prior to planned Day 1 to allow 
adequate time for delivery of study drug to study site. 
Subjects moving from the delayed-treatment control period to the active treatment period should 
have screening procedures as noted above completed in order to confirm that the subject is still 
eligible for dosing. 

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From the time of obtaining informed consent through dosing of IMP, record all SAEs related to 
protocol-mandated procedures on the AE eCRF. All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history are 
to be captured on the medical history eCRF. See Section 6 for details. 
5.3.1 
Schedule of Events for Screening Visit 
Study Phase/Visit 
Screening a 
Study Day 
-70 to Day -7 
Visit Window (days) 
NA 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Randomization 
X 
Medical history 
X 
Complete physical examination b 
X 
Vital signs c 
X 
12-Lead ECG d 
X 
Growth parameters 
X 
Samples for: 
 
Genetic testing (central lab) e 
X 
Safety labs (hematology) (central lab) f,g 
X 
Safety labs (chemistry) (central lab) f g,h,i 
X 
Cytokine panel (central lab) f 
X 
Complement panel (central lab) f 
X 
Troponin T and/or I (central lab) i 
X 
Coagulation parameters (central lab) f,g 
X 
Anti-AAV8 NAb and TAb (central lab) 
X 
Anti-MTM1 antibody (central lab) 
X 
Urinalysis (central lab) f,g 
X 
Serum bile acid assay (fasting preferred; central lab) 
Once any time prior to dosing 
Liver ultrasound h 
X 
Transient elastography ultrasound of liver 
Once any time prior to dosing 
Begin electronic diary of ventilator dependence j 
X 
Assessment of ventilator parameters 
X 
Daytime polysomnogram 
X 
MIP, MEP, P0.1, tidal volume 
X 
Motor developmental milestone assessments k 
X 
AEs/concomitant medications 
X 
AEs = adverse events; anti-AAV8 = anti-adeno-associated virus 8; ECG = electrocardiogram; MTM1 = gene encoding 
the myotubularin protein; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; NA = not 
applicable; NAb = neutralizing antibody; P0.1 = inspiratory occlusion pressure at 0.1 seconds; TAb = total antibody.  
a Procedures and assessments may be done on different days. Procedures or assessments that have already been 
completed within 70 days prior to planned Day 1 as part of an Astellas Gene Therapies, Inc.-sponsored study do 
not need to be repeated and may be used as a Screening assessment for this study. All results needed to evaluate 
study eligibility must be reviewed by prior to randomization and prior to dosing. 
b Complete physical examination at screening. 

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c Record whether the subject was on or off of ventilatory support when vital signs are taken.  
d Particular attention should be paid to ECG abnormalities specific to myocarditis. Refer to Section 4.6.1 for 
management of ECG results and the role of the site pediatric cardiologist. 
e Genetic testing performed only for subjects without previous confirmation by a Sponsor-approved testing facility. 
f See Appendix 1 for list of laboratory assessments.  
g It is recommended to use the central laboratory to analyze laboratory tests that are drawn prior to dosing, and after 
the Week 16 Visit and to use the local laboratory to analyze laboratory tests that are drawn at Baseline, Dosing, 
Days 1, 2, and Weeks 1 through 16. However, the local laboratory can be used for other visits if needed (for 
example, the local laboratory can accommodate the analysis with a smaller amount of blood) or if the local 
laboratory does not accommodate the appropriate analysis, the central laboratory may be used. 
h See Section 4.6.2 for details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity and the 
role of the site hepatologist. 
i See Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and treatment of 
myocarditis; and the role of the site pediatric cardiologist.  
j Site staff should set up the electronic diary prior to distribution to the parent/LAR/caregiver and review the training 
with the parent/LAR/caregiver. The electronic diary should be given to the parent/LAR/caregiver following informed 
consent (or reconsent to protocol v5 or later for Part 1 subjects). The diary should be completed daily by the same 
parent/LAR/caregiver (when possible). 
k All physical therapy assessments should be videoed and performed according to the site manual. This assessment 
will be conducted for the evaluation of eligibility. 

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h See Appendix 1 for list of laboratory assessments. 
i It is recommended to use the central laboratory to analyze laboratory tests that are drawn prior to dosing, and after the Week 16 Visit and to use the local laboratory to 
analyze laboratory tests that are drawn at Baseline, Dosing, Days 1, 2, and Weeks 1 through 16. However, the local laboratory can be used for other visits if needed (for 
example, the local laboratory can accommodate the analysis with a smaller amount of blood) or if the local laboratory does not accommodate the appropriate analysis, 
the central laboratory may be used.  
j See Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and treatment of myocarditis; and the role of the site pediatric 
cardiologist. 
k See Section 4.6.2 for details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity and the role of the site hepatologist. 
l LFTs, CK (including CK isoenzymes), C-reactive protein, and serum bicarbonate only. 
m Cytokine panel: Following Week 4 cytokine panel collection, in cases of clinically important elevated bilirubin, elevated aminotransferases, elevated troponins, and/or 
elevated creatine phosphokinase that in the Investigator’s judgment may be related to T-cell responses, repeat cytokine panel testing is suggested. Appropriate care for 
an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical status. 
n Complement panel: Following Week 4 complement panel collection, in cases of clinically important elevated bilirubin, elevated aminotransferases, ascites, 
thrombocytopenia, acute renal insufficiency, and/or anemia that in the Investigator’s judgment may be related to complement activation, repeat complement panel testing 
is suggested. Appropriate care for an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical status. 
o Platelet monitoring: Peripheral blood smears should be performed as part of the hematology panel. Platelet monitoring consists of the following tests: Platelet Activation 
Assays (CD62P, Activated GP IIb/IIIa w/ PAC-1, and Phosphatidylserine), Reticulated Platelets, Platelet Circulating Antibodies. For EU sites ONLY: Reticulated platelets 
will be tested locally. Sample for platelet activation assays must be fixated locally prior to shipping. 
p IFN-γ ELISpot: Following AT132 administration, in cases of clinically important elevated bilirubin, elevated aminotransferases, elevated troponins, and/or elevated 
creatine phosphokinase that in the Investigator’s judgment may be related to T-cell responses, repeat IFN-γ ELISpot response testing is suggested. Appropriate care for 
an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical status. 
q Footnote was deleted. 
r For control subjects whose wrist X-ray was within the past 6 months, this does not need to be repeated at their second baseline assessment before treatment with 
AT132. Subjects in Germany will not have a wrist X-ray. 
s The diary should be completed daily by the same parent/LAR/caregiver (whenever possible); see Section 5.1.1.11.2.1. 
t If a subject has discontinued the use of the ventilator and has 2 assessments with the MIP at 80 cmH2O, testing for MIP, MEP, and P0.1 will not be required for future 
visits. 
u The site pulmonologist and local pulmonologist, if applicable, will review the results from the visit, assess the subject, determine if the subject meets the criteria outlined in 
Table 1 to begin reduction of hours on the ventilator, and determine if the subject meets the criteria outlined in Table 2 to discontinue the ventilator. 
v The severity of secretions and burden of secretions management will be assessed using the PGIS-S and PGIS-I (Appendix 3). The same parent/LAR/caregiver should 
report throughout the study (whenever possible).  
w At baseline, the PGIS-S is conducted for all subjects. At baseline, the PGIS-I is conducted only for control subjects who are attending their second baseline assessments 
before treatment with AT132 (whenever possible). 
x All physical therapy assessments should be videoed and performed according to the site manual. 
y If a subject has a total score of 56 for 2 consecutive assessments, the CHOP INTEND will not be required for future visits. 
z The PedsQL is to be performed for all subjects, regardless of age. Subjects < 2 years of age should be administered the version for 2- to 4-year-olds. 
aa See Appendix 5. At baseline, the CGI-S is conducted for all subjects. At baseline, the CGI-I is conducted only for control subjects who are attending their second baseline 
before treatment with AT132. 

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bb Parents/LARs/caregivers (the same person every time, whenever possible) in ASPIRO will be asked to complete forms for subjects 8 months and older.  
cc Subjects will be administered a course of glucocorticoid therapy commencing Day -1 and continuing for a period of 16 weeks as a preventative measure for 
immune-mediated hepatic injury. For subjects weighing < 60 kg, the dose will be 1 mg/kg prednisolone orally daily for 8 weeks, then tapered down for 8 weeks per 
Investigator discretion. For subjects weighing ≥ 60 kg, the dose will be 60 mg prednisolone orally daily for 8 weeks, then tapered down for 8 weeks per Investigator 
discretion.  
dd Ursodiol to be dosed at 20 mg/kg/day (divided either BID or TID at the Investigator’s discretion), beginning approximately 1 week (ie, between Days -6 and -4, at the 
Investigator’s discretion) before AT132 administration and continuing to Week 12.  
ee As of protocol v9: Subjects yet to be dosed will be administered 1.3 × 1014 vg/kg AT132 (see Section 1.4.2). 
ff Subject may be admitted to the study clinic on Day –2 or –1 for baseline procedures, including confirmation of baseline ventilator settings. If medically appropriate, 
subject may be discharged from the study clinic after completion of Day 2 assessments.  
gg Viral shedding will be assessed on samples of saliva (swab), stool, and urine (diaper collection or urine bag). Collection of each sample type will begin on Day 1 and will 
continue until each sample type has 3 consecutive data points at or below the limit of detection (BLOD) (see Section 5.1.1.27). Sponsor will notify site when collection can 
cease. Not conducted at Week 6.  
 

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a The diary should be completed daily by the same parent/LAR/caregiver (whenever possible); see Section 5.1.1.11.2.1. The daily diary collection will continue through 
Week 48. However, if after the Week 24 visit, ventilator support has been discontinued, the daily diary will no longer need to be completed. If ventilator support is 
resumed, the daily diary completion will resume through Week 48 or discontinuation of the ventilatory support, whichever occurs first. 
b For subjects in Part 1 who have already completed the Week 24 visit, the parent/LAR/caregiver will complete the ventilator dependence questionnaire at clinic and 
contact visits through Month 120. For subjects in Part 1 who have not completed the Week 24 visit and for subjects in Part 2, parent/LAR/caregivers will complete the 
daily diary (Section 5.1.1.11.2.1). After the daily diary has been stopped or after subject has completed Week 48, the parent/LAR/caregiver will complete the ventilator 
dependence questionnaire at clinic and contact visits through Month 120.  
c PGI-S, PGI-I, assessment of subject’s ventilator status, review of adverse events and concomitant medications should be assessed at each contact visit. 
d Complete physical examination at Week 24, Week 48, and Month 60 or Early Withdrawal. At all other timepoints, conduct an abbreviated physical examination based on 
the subject’s circumstances and in accordance with the Investigator’s clinical judgement.  
e Record whether the subject was on or off of ventilatory support when vital signs are taken. 
f ECHOs should include an assessment of pulmonary hypertension as well as structural and functional abnormalities. Particular attention should be paid to ECG and 
ECHO abnormalities specific to myocarditis. Refer to Section 4.6.1 for management of ECG and ECHO results and the role of the site pediatric cardiologist. 
g After the Week 48 visit, ECHO only needs to be performed annually thereafter (Month 24, Month 36, Month 48, Month 60). 
h See Appendix 1 for list of laboratory assessments.  
i It is recommended to use the central laboratory to analyze laboratory tests that are drawn prior to dosing, and after the Week 16 Visit and to use the local laboratory to 
analyze laboratory tests that are drawn at Baseline, Dosing, Days 1, 2, and Weeks 1 through 16. However, the local laboratory can be used for other visits if needed (for 
example, the local laboratory can accommodate the analysis with a smaller amount of blood) or if the local laboratory does not accommodate the appropriate analysis, 
the central laboratory may be used. 
j See Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and treatment of myocarditis; and the role of the site pediatric 
cardiologist. 
k See Section 4.6.2 for details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity and the role of the site hepatologist. 
l See Section 4.6.3 for details related to the monitoring, diagnosis, and treatment of neuromuscular abnormalities. 
m LFTs, CK (including CK isoenzymes), C-reactive protein, and serum bicarbonate only. 
n Cytokine panel (see Appendix 1): Following Week 4 cytokine panel collection, in cases of clinically important elevated bilirubin, elevated aminotransferases, elevated 
troponins, and/or elevated creatine phosphokinase that in the Investigator’s judgment may be related to T cell responses, repeat cytokine panel testing is suggested. 
Appropriate care for an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical status. 
o Complement panel (see Appendix 1): Following Week 4 complement panel collection, in cases of clinically important elevated bilirubin, elevated aminotransferases, 
ascites, thrombocytopenia, acute renal insufficiency, and/or anemia that in the Investigator’s judgment may be related to complement activation, repeat complement 
panel testing is suggested. Appropriate care for an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical 
status. 
p IFN-γ ELISpot: Following AT132 administration, in cases of clinically important elevated bilirubin, elevated aminotransferases, elevated troponins, and/or elevated 
creatine phosphokinase that in the Investigator’s judgment may be related to T-cell responses, repeat IFN-γ ELISpot response testing is suggested. Appropriate care for 
an individual subject will be determined by the Investigator based on an assessment of the subject’s overall medical status. 
q The sample will only need to be collected 1 time during the study. The sample will be collected at the Week 12 visit, unless HLA type has been obtained in INCEPTUS. 
For subjects in Part 1 who have already passed the timepoint listed above, the HLA sample will be collected at the Week 48 visit or the Month 24 visit, whichever occurs 
first. 
r If a subject has discontinued the use of the ventilator and has 2 assessments with the MIP at 80 cmH2O, testing for MIP, MEP, and P0.1 can be stopped. 

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s The site pulmonologist and local pulmonologist, if applicable, will review the results from the visit, assess the subject, determine if the subject meets the criteria outlined in 
Table 1 to begin reduction of hours on the ventilator, and determine if the subject meets the criteria outlined in Table 2 to discontinue the ventilator.  
t Daytime polysomnogram not required at Week 48 if subject has already been weaned off the ventilator. 
u The severity of secretions and burden of secretions management will be assessed using the PGIS-S and PGIS-I (Appendix 3). The same parent/LAR/caregiver should 
report throughout the study (whenever possible). 
v All physical therapy assessments should be videoed and performed according to the site manual. 
w If a subject has a total score of 56 for 2 consecutive assessments, the CHOP INTEND will not be required for future visits. 
x The PedsQL is to be performed for all subjects, regardless of age. Subjects < 2 years of age should be administered the version for 2- to 4-year-olds. 
y See Appendix 5.  
z In-depth interviews are optional and will be completed at either Week 24 or Week 48.  
aa Parents/LARs/caregivers (the same person every time, whenever possible) in ASPIRO will be asked to complete forms for subjects 8 months and older. 
bb Subjects will be administered a course of glucocorticoid therapy commencing Day -1 and continuing for a period of 16 weeks as a preventative measure for immune-
mediated hepatic injury. For subjects weighing < 60 kg, the dose will be 1 mg/kg prednisolone orally daily for 8 weeks, then tapered down for 8 weeks per Investigator 
discretion. For subjects weighing ≥ 60 kg, the dose will be 60 mg prednisolone orally daily for 8 weeks, then tapered down for 8 weeks per Investigator discretion.  
cc Ursodiol to be dosed at 20 mg/kg/day (divided either BID or TID at the Investigator’s discretion) to Week 12 and at the Investigator’s discretion thereafter.  
dd Viral shedding will be assessed on samples of saliva (swab), stool, and urine (diaper collection or urine bag). Collection of each sample type will begin on Day 1 and will 
continue until each sample type has 3 consecutive data points at or below the limit of detection (BLOD). Sponsor will notify site when collection can cease. Not conducted 
at Week 10 or 14. 
ee Subjects in Germany will not have a wrist X-ray. After the Week 48 visit, wrist X-ray only needs to be performed annually thereafter (Month 24, Month 36). As of protocol 
v12, the wrist X-ray assessment will no longer be collected at Month 48 visit onward.  
ff As of protocol v12, these assessments will no longer be collected at Month 48 visit onward. 

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5.6 
Schedule of Events for Subjects Treated with AT132: Month 72 (Year 6) – Month 120 (Year 10) (End of Study) 
Study Phase/Visit 
Month 72 
Month 84 
Month 96 
Month 108 
Month 120 
Study Day 
2190 
2555 
2920 
3285 
3650 
Visit Window (days)  
±60  
±60  
±60 
±60 
±60 
Physical Examination a 
X 
X 
X 
X 
X 
Ventilator Dependence Questionnaire b  
X 
X 
X 
X 
X 
Samples for:  
X 
X 
X 
X 
X 
Safety labs (hematology) (central lab) c,d  
X 
X 
X 
X 
X 
Safety labs (chemistry) (central lab) d,e,f,g 
Comprehensive metabolic profile 
ALT, AST, Total and direct bilirubin, GGT 
Serum bile acids, total (fasting preferred) 
PTT and PT/INR 
Troponin I and T 
CK 
Alpha fetoprotein 
X 
X 
X 
X 
X 
Liver ultrasound (local) f  
X 
X 
X 
X 
X 
Motor milestone assessments h 
X 
X 
X 
X 
X 
ACEND  
X 
X 
X 
X 
X 
Clinical global impression scales i 
X 
X 
X 
X 
X 
Swallowing questionnaire 
X 
X 
X 
X 
X 
Secretions management assessment j 
X 
X 
X 
X 
X 
AEs/concomitant medications  
X 
X 
X 
X 
X 
NOTE: Long-term follow-up visits and/or assessments after the 5-year (Month 60) visit can be done remotely per discretion of investigator in consultation with Medical 
Monitor. 
AEs = adverse events; ACEND = Assessment of Caregiver Experience with Neuromuscular Disease; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CK = creatine kinase; GGT = gamma-glutamyltransferase; INR = international normalized ratio; LAR = legally authorized representative; PGIS-I = Parental Global 
Impression of Secretion Improvement; PGIS-S = Parental Global Impression of Secretion Severity; PT = prothrombin time; PTT = partial thromboplastin time. 
a Complete physical examination with detailed neurological evaluation and respiratory function assessment will be conducted. It can be done remotely per discretion of 
investigator in consultation with Medical Monitor. When visit is done remotely, an abbreviated physical examination is acceptable. 
b After the daily diary has been stopped or after subject has completed Week 48, the parent/LAR/caregiver will complete the ventilator dependence questionnaire at clinic 
and contact visits through Year 10 (Month 120). 

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c See Appendix 1 for list of laboratory assessments. 
d The local laboratory can be used for visits, if needed (for example, the local laboratory can accommodate the analysis with a smaller amount of blood) or if the local 
laboratory does not accommodate the appropriate analysis, the central laboratory may be used. 
e See Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and treatment of myocarditis; and the role of the site pediatric 
cardiologist. 
f See Section 4.6.2 for details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity and the role of the site hepatologist. 
g See Section 4.6.3 for details related to the monitoring, diagnosis, and treatment of neuromuscular abnormalities. 
h All physical therapy assessments should be videoed and performed according to the site manual. 
i See Appendix 5.  
j The severity of secretions and burden of secretions management will be assessed using the PGIS-S and PGIS-I (Appendix 3). The same parent/LAR/caregiver should 
report throughout the study (whenever possible). 

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g It is recommended to use the central laboratory to analyze laboratory tests for delayed-treatment control visits. However, the local laboratory can be used if needed (for 
example, the local laboratory can accommodate the analysis with a smaller amount of blood) or if the local laboratory does not accommodate the appropriate analysis, 
the central laboratory may be used. 
h See Section 4.6.1 for details related to the evaluation of cardiac enzymes; monitoring, diagnosis, and treatment of myocarditis; and the role of the site pediatric 
cardiologist. 
i See Section 4.6.2 for details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity and the role of the site hepatologist. 
j Subjects in Germany will not have a wrist X-ray. 
k The diary should be completed daily by the same parent/LAR/caregiver (whenever possible); see Section 5.1.1.11.2.1. 
l The site pulmonologist and local pulmonologist, if applicable, will review the results from the visit, assess the subject, determine if the subject meets the criteria outlined in 
Table 1 to begin reduction of hours on the ventilator, and determine if the subject meets the criteria outlined in Table 2 to discontinue the ventilator.  
m The severity of secretions and burden of secretions management will be assessed using the PGIS-S and PGIS-I (Appendix 3). The same parent/LAR/caregiver should 
report throughout the study (whenever possible).  
n At baseline, the PGIS-S is conducted for all subjects.  
o All physical therapy assessments should be videoed and performed according to the site manual. 
p The PedsQL is to be performed for all subjects, regardless of age. Subjects < 2 years of age should be administered the version for 2- to 4-year-olds. 
q See Appendix 5. At baseline, only the CGI-S is conducted for all subjects.  
r Parents/LARs/caregivers (the same person every time, whenever possible) in ASPIRO will be asked to complete forms for subjects 8 months and older. 
 
 

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5.8 
Unscheduled Visits 
Additional assessments and optional assessments conducted as part of the study should be 
recorded on the unscheduled visit eCRFs.  
5.9 
Assessments for Early Withdrawal from Study 
If a subject chooses to withdraw from the study, every attempt should be made to perform the 
early withdrawal procedures as listed for Week 48 in Section 5.5 for treated subjects and for 
Control Week 48 in Section 5.7 for control subjects. Medical and public records and/or 
laboratory results should continue to be obtained once the subject has withdrawn consent for 
safety and scientific reporting. Additional details can be found in the CRF Completion 
Guidelines. 
5.10 
Assessments for Untreated Delayed-Treatment Control Subjects 
If a delayed-treatment control subject is not eligible to be dosed, and the subject agrees to 
remain on study, the subject will be followed up to Month 30 (from enrollment) as per the 
Schedule of Events in Section 5.7. 
5.11 
Amount of Blood (UNIQUE to France) 
Blood Samples for: 
Blood Volume 
per Visit 
Genetic testing (central lab)  
3 mL 
Safety labs (hematology) (central lab)  
0.5 mL 
Safety labs (hematology) (local lab)  
0.5 mL 
Safety labs (chemistry) (central lab), including cytokine panel and Troponin T and/or I 
2.5 mL 
Safety labs (chemistry) (local lab)  
2.0 mL 
Complement panel (central lab)  
3.2 mL 
Coagulation parameters (central lab)  
1.8 mL 
Anti-AAV8 NAb and TAb, and anti-MTM1 antibody (central lab)  
2.5 mL 
IFN-γ (PBMCs) (central lab)  
4.0 mL 
HLA typing (central lab)  
2.0 mL 
Serum bile acid assay (fasting preferred; central lab)  
1.0 mL 
Anti-AAV8 = anti-adeno-associated virus 8; anti-MTM1 = gene that codes for myotubularin (a mutation in the MTM1 
gene results in myotubular myopathy); HLA = human leukocyte antigen; IFN-γ = interferon-gamma; 
NAb = neutralizing antibody; PBMCs = peripheral blood mononuclear cells; TAb = total antibody.  

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6 ADVERSE EVENT MANAGEMENT 
6.1 
Adverse Events 
6.1.1 
Definition of Adverse Events 
According to the ICH 2EA guideline Definitions and Standards for Expedited Reporting and 
21 CFR 312.32, IND Safety Reporting, an AE is any untoward medical occurrence associated 
with the use of the IMP in a study subject whether or not considered drug-related. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally 
associated with the use of an IMP or study procedure, whether or not considered related to the 
IMP. This definition includes the following: 
• 
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of the IMP treatment administration or study procedure. 
• 
All AEs (regardless of relationship to IMP) should be recorded from the Baseline Visit 
(Day -2 to -1) through the end of the safety reporting period.  
• 
AEs occurring as a result of product withdrawal, abuse, overdose  
• 
A change in a laboratory test results (eg, hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements) if 
considered by the Investigator to be clinically significant or if it caused (or should have 
caused) the Investigator to initiate a non-protocol therapy or procedure (refer to 
Section 6.5 for further details regarding assessment of abnormal laboratories). This 
includes results that worsen from baseline. 
An AE does not include the following: 
• 
Elective surgery or procedures for pre-existing conditions that are stable and have not 
worsened (eg, hospitalization for elective surgery, social and/or convenience 
admissions). 
• 
Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the IMP administration that do not worsen; such events should be recorded in the 
medical history eCRF. 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is 
not an AE. It is considered to be pre-existing and should be documented on the medical 
history eCRF. 
The Investigator and any qualified designees are responsible for detecting, documenting and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to AT132 and other study treatments or procedures, 
or that caused the subject to discontinue the study. 
6.1.2 
Adverse Event Reporting and Collection Period 
The Investigator is responsible for monitoring the safety of subjects who have entered this study 
and for providing appropriate medical care.  

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The Investigator is responsible for evaluating all AEs, obtaining supporting documents, and for 
final review and confirmation of accuracy and completeness of event information and 
documentation. All SAEs will be reported on the eCRF and SAE worksheet. All AEs will be 
reported on the eCRF. 
If the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) grade of an 
SAE/AE changes, the event should be relisted on the eCRF, and SAE worksheet for SAEs, with 
the new NCI-CTCAE grade and new onset date. 
The exception is ongoing pre-dose events that continue post-dose and improve post-dose. Such 
events should not be re-listed. 
If the NCI-CTCAE grade of an SAE reduces, the details of the AE should be provided on the 
SAE worksheet for the medical assessor to be able to assess the course of the event. 
6.1.3 
Start of Adverse Event Collection Period 
If a subject experiences an AE after the informed consent document is signed, but before the 
Baseline/Control Baseline visit, the event will be considered medical history.  
If a control subject experiences an AE after the Control Baseline visit but before the Baseline 
visit prior to dosing, the event will be considered a Control AE. 
If the subject experiences an SAE after signing consent and before Baseline, it should only be 
reported as an SAE if the Investigator believes that the event may have been caused by a 
protocol-required procedure. 
6.1.3.1 
Ongoing Adverse Event Collection During the Study 
Before the Baseline visit, site personnel will note the occurrence and severity of each medical 
condition for the subject. During the study, site personnel will note any change in the severity of 
Baseline medical condition(s) and the occurrence and nature of any AEs. Whenever possible, 
an integrated diagnosis should be given for AE signs and symptoms of a common pathology. 
When recording AEs/SAEs, describe the event using commonly accepted medical terminology, 
if possible. 
The details of each event should be discussed with the subject. If the event is serious, it must 
be reported to the Sponsor or its designee within 24 hours of the Investigator/designee/site 
personnel learning of the event. 
6.1.3.2 
End of Adverse Event Collection Period 
AEs will be collected and reported until the subject completes the study or withdraws from the 
study. 
AEs and SAEs will be followed as clinically indicated until resolution or, if non-resolving, until 
considered stable or until the end of the AE collection period, whichever comes first. 

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The Sponsor retains the right to request additional information for any study subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and the event is considered to be reasonably 
related to the study drug or study participation, the Investigator must promptly notify the 
Sponsor. 
6.1.3.3 
Recording and Assessment of Seriousness, Severity, and Causality 
It is the responsibility of the Investigator to review all documentation (eg, hospital progress 
notes, laboratory reports, and diagnostics reports) related to the event. Assessment of AEs 
must include seriousness, severity, relationship to study drug, duration, and outcome. At the 
Screening Visit, site personnel will note the occurrence and severity of each medical condition 
for the subject and document in Medical History. During the study, site personnel will note any 
change in the severity of medical condition(s) and the occurrence and nature of any AEs. Use 
precise medical terminology when recording AEs or SAEs. Record only 1 diagnosis, sign, or 
symptom in the AE eCRF (eg, nausea and vomiting should not be recorded in the same entry, 
but as 2 separate entries). 
Whenever possible, a diagnosis should be recorded as the AE term rather than a series of 
terms relating to a diagnosis. If the diagnosis is unknown, record sign(s) and/or symptom(s). If a 
diagnosis subsequently becomes available, the diagnosis should be recorded, replacing the 
original entry(s) where appropriate. 
The details of each event should be discussed with the subject. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data 
to the Sponsor within 24 hours of it being available. 
The Sponsor retains the right to request additional information for any study subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. The Investigator will 
evaluate all AEs considered ongoing at the end of the study and document whether event has 
resolved, resolved with sequelae, or stabilized, with update to source and eCRF as appropriate. 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to 
the Sponsor in lieu of completion of the SAE worksheet. There may be instances when copies 
of medical records for certain cases are requested by the Sponsor. In this case, all subject 
identifiers, with the exception of the subject number, will be redacted on the copies of the 
medical records before submission to the Sponsor. 

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6.1.3.4 
Eliciting Adverse Events 
The site personnel will instruct the subject to report any changes in health or new symptoms 
they notice during the study. At each visit, AEs should be elicited with minimal connotations. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. For example: “Have 
you had any health problems since your last visit?” 
6.2 
Serious Adverse Events 
6.2.1 
Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence at any dose that results in the following: 
• 
Death 
• 
Life-threatening (The term “life-threatening” in the definition of “serious” refers to an 
event that, in the view of either the Investigator or Sponsor, places the subject at risk of 
death at the time of the event; it does not refer to an AE that hypothetically might have 
caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongs existing hospitalization 
• 
Elective surgery or procedures for preexisting conditions that are stable and have not 
worsened (eg, hospitalization for elective surgery, social and/or convenience 
admissions) are not considered SAEs; however, an event that prolongs this type of 
hospitalization would be considered an SAE 
• 
Persistent or significant disability/incapacity (The term disability means a substantial 
disruption of a person’s ability to conduct normal life functions). 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These important 
medical events should usually be considered medically significant, and therefore 
serious. Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization. Potential drug induced 
liver injury (DILI) should be considered a medically significant event.  
6.2.2 
Serious Adverse Event Reporting Requirements 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
drug under clinical investigation are met. The Investigator must complete and submit an SAE 
worksheet containing all information that is required by local and/or regional regulations to the 
Sponsor by fax or email immediately (within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified Investigator (as identified on 
delegation of authority log). Signature confirms accuracy and completeness of the SAE data, as 

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well as the Investigator causality assessment including the explanation for the causality 
assessment. 
Regardless of whether the SAE is deemed related to use of the IMP or study procedure, the 
data for the SAE must be reported with the appropriate information to the Sponsor or its 
designee within 24 hours of Investigator/designee/site personnel learning of the event. The 
Sponsor’s Medical Monitor or designee may be contacted at any time for immediate discussion 
regarding such an event.  
Please refer to the Study Management Plan for additional guidance regarding SAE reporting to 
the Sponsor. 
Sites must report all SAEs to their governing IRB/EC, as required by local regulations and 
guidelines. 
The Investigator is encouraged to discuss with the Medical Monitor any AEs for which the issue 
of seriousness is unclear or questioned. Contact information for the Medical Monitor can be 
found in the study contact list. 
All deaths, regardless of causality, occurring from the time the subject signs the ICF until the 
Month 60 Visit are to be reported as SAEs to the Sponsor or its designee within 24 hours of 
the Investigator, designee, and/or site personnel’s awareness of the event. For fatal or 
life-threatening events, copies of hospital case reports, autopsy reports, and other documents 
are also to be submitted by email or fax when requested and applicable. Any supportive SAE 
documentation (eg, hospital records, autopsy reports, progress notes) provided to the Sponsor 
or its designee should have all personal subject identification fully redacted in accordance with 
governing privacy regulations. 
Additional information may be requested by the Sponsor or its designee to ensure the timely 
completion of accurate safety reports. 
Any medications necessary for treatment of the SAE must be recorded onto the medication 
section of the subject’s eCRF and the event description of the SAE.  
6.2.2.1 
Follow-Up of Serious Adverse Events 
After the initial SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up. New follow-up data for SAEs must be 
reported within 24 hours of receipt. All SAEs will be followed as clinically indicated until 
resolution or, if non-resolving, until considered stable or until the end of the AE collection period 
(Section 6.1.2) whichever comes first.  
6.2.2.2 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets the criteria of a serious event. 
The resolution date is the date the event no longer meets the criteria of a serious event, the 

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date the symptoms resolve, or the event is deemed chronic. In cases of hospitalizations, the 
hospital admission date is considered the onset date. 
6.2.3 
Suspected Unexpected Serious Adverse Reaction 
6.2.3.1 
Definition of Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE for which there is a 
reasonable possibility that the drug caused the SAE and is considered unexpected per the 
current Reference Safety Information (RSI). For the purposes of expedited safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the AE. 
An AE is considered “unexpected” for regulatory reporting purposes if it is not listed in the 
current RSI within the Investigator’s Brochure or is not listed at the specificity or severity that 
has been observed. 
6.2.3.2 
Suspected Unexpected Serious Adverse Reaction Expedited Reporting 
Requirements 
The Sponsor or its designee will submit SUSARs to appropriate Regulatory Authorities 
(including Competent Authorities in all Member States concerned), IRBs/ECs, and Investigators 
as per local laws and regulations. Fatal and life-threatening SUSARs will be submitted no later 
than 7 calendar days of first knowledge of the event and follow-up information submitted within 
an additional 8 days. All other SUSARs will be submitted within 15 calendar days of first 
knowledge of the event. 
The Investigator will notify the IRBs/ECs of SUSARs in accordance with IRB/EC requirements 
and local laws and regulations. A copy of this notification must be provided to the Sponsor 
and/or its designee. 
6.2.3.3 
Urgent Safety Measures and Non-Suspected Unexpected Serious Adverse 
Reaction Reporting 
An urgent safety measure (USM) is an intervention that is not defined by the protocol and can 
be put in place with immediate effect without needing to gain prior approval by the Sponsor, 
relevant competent authorities, IRB/EC, where applicable, in order to protect subjects from any 
immediate hazard to their health and/or safety. Either the Investigator or the Sponsor can initiate 
a USM. The cause of a USM can be safety-, product-, or procedure-related.  
Investigators are required to report any USMs to the Sponsor or its designee within 24 hours. 
The Sponsor or its designee will inform the Regulatory Authorities, IRBs/ECs, and other 
Investigators of any events 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 reporting collection period for 

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urgent safety issues is the period from the signing of the ICF until the Year 10 Visit or the 
subject withdraws from the study. 
The Investigator will notify the IRB/ECs of USMs in accordance with IRB/EC requirements and 
local laws and regulations. A copy of this notification must be provided to the Sponsor and/or its 
designee. 
Non-SUSARs will be maintained by the Sponsor and provided in annual safety reports and/or 
other aggregate periodic summary reports to Regulatory Authorities and IRB/ECs as per local 
laws and regulations. 
6.3 
Adverse Event and Serious Adverse Event Severity Grades and Relationship to 
Investigational Medicinal Product 
6.3.1 
Assessment of Severity 
The seriousness of an AE should not be confused with its severity. Severity is a measure of 
intensity (eg, Grades 1 through 5 or mild, moderate, and severe), whereas seriousness is based 
on subject/event outcome as defined by the criteria in Section 6.2. The Investigator is 
responsible for assessing the severity of an AE according to the NCI CTCAE version 4.03 
(Appendix 6). 
It is important to distinguish between seriousness (AE versus SAE) and severity (Grades 1 to 5) 
of AEs. Seriousness, not severity, serves as a guide for defining regulatory reporting 
obligations. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered Grade 3 nausea, but not an SAE. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a 
Grade 1 stroke, but would be a SAE. 
Many common AEs are able to be graded according to NCI-CTCAE criteria. AEs that do not 
have a corresponding NCI-CTCAE term will be assessed according to the general guidelines for 
grading used in the NCI-CTCAE version 4.03 as shown in Table 4. 

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Table 4: Adverse Event Severity Grading Scale (NCI-CTCAE) 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) a 
3 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL b 
4 
Life threatening consequences; urgent intervention indicated 
5 
Death related to AE 
ADL = activities of daily living; AE = adverse event; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for AEs. 
a Instrumental ADL refer to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money. 
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, not bedridden. 
Source: Appendix 6. 
 
Any Grade 3 and 4 clinical laboratory result that represents an increase in severity from 
baseline will be reported as an AE if it is not associated with a diagnosis already reported on the 
eCRF. A Grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it is 
considered clinically significant by the Investigator. 
6.3.2 
Assessment of Relationship 
The Investigator is responsible for assessing whether the event was related to IMP based on 
the guidelines in Table 5. 
Table 5: Assessment of Relatedness 
Not related 
to IMP 
Another cause of the event is most plausible; and/or clinically plausible 
temporal sequence is inconsistent with the onset of the event and the IMP; 
and/or a causal relationship is considered biologically implausible. 
Possibly related 
to IMP 
An event that follows a reasonable temporal sequence with the IMP, but that 
could readily have been produced by a number of other factors. 
Related to IMP 
An event that follows a reasonable temporal sequence with the IMP, and the 
event could not be reasonably explained by the known characteristics of the 
subject’s clinical state. 
IMP = investigational medicinal product. 
 
For the purposes of reporting to regulatory agencies, AEs deemed as possibly or related to IMP 
will be considered related and those deemed not related will be considered unrelated. 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. While it is very important that the 

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Investigator always assesses causality for every event before the initial transmission of the SAE 
data to the Sponsor, the initial report should be submitted without delay (ie, within 24 hours of 
awareness). With limited or insufficient information about the event to make an informed 
medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered. In such instance, the 
Investigator is expected to obtain additional information regarding the event as soon as possible 
and to re-evaluate the causality upon receipt of additional information. The medically qualified 
Investigator may revise the assessment of causality in light of new information regarding the 
SAE and shall send an SAE follow-up report in the eCRF and follow-up SAE worksheet with the 
new information and updated causality assessment. 
6.4 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse 
Events or Serious Adverse Events 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents.  
Clinical significance of out-of-range laboratory findings is to be determined and documented by 
the Investigator or Sub-Investigator who is a qualified physician. Abnormal laboratory findings 
associated with the underlying disease are not considered clinically significant unless judged by 
the Investigator to be more severe than expected for the subject's condition. 
Laboratory abnormalities that are considered to be clinically significant by the Investigator must 
be recorded as AEs. Laboratory abnormalities (eg, clinical chemistry, hematology, coagulation 
parameters, and urinalysis) that require medical or surgical intervention must be recorded as an 
AE, as well as an SAE if the abnormality meets SAE criteria (defined in Section 6.2.1). In 
addition, laboratory or other abnormal assessments (eg, ECG, X-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 6.1.1 and 6.2.1, respectively. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), 
not the laboratory result (eg, decreased hemoglobin).  
The following laboratory abnormalities should be recorded as AEs regardless of whether 
considered to be clinically significant, unless the abnormality is considered to be part of an 
integrated diagnosis:  
• 
Troponin I or Troponin T values above the ULN (or a non-zero value if no ULN is 
reported) for which additional diagnostic workup and/or treatment is indicated per 
consultation with the site pediatric cardiologist (see Section 4.6.1) 
• 
Platelet values below the lower limit of normal, or below the subject’s baseline value if 
abnormal at baseline 
Please contact the Medical Monitor if there are questions regarding how to capture laboratory 
abnormalities.  

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6.5 
AEs and Laboratory Results of Special Interest 
See current AT132 Investigator’s Brochure for current RSI.  
6.5.1 
Cardiac Enzyme Elevations 
Troponin elevations have been observed in the ASPIRO study. Elevation of cardiac enzymes 
(including troponin levels) should be evaluated as described in Section 4.6.1.  
6.5.2 
Management of Potential Immune Responses 
Elevations of hepatic transaminases, CK, and troponin I, likely representing an immune 
response to the study treatment, have been reported in Study ATX-MTM-002 and are 
considered identified risks associated with AT132 administration. Refer to the Investigator’s 
Brochure for details. 
Guidelines for monitoring and management of such events are provided in Section 4.6. 
Appropriate care for an individual subject will be determined by the Investigator based on an 
assessment of the subject’s overall medical status. Corticosteroid treatment typically resolves 
the elevation of liver transaminases. However, when adverse events related to the immune 
response are of significant concern (eg, rAAV vector dose 1 × 1014 vg/kg and/or a transgene-
mediated immune response), immunomodulation may include medications such as rapamycin 
(sirolimus), mycophenolate mofetil, calcineurin inhibitors (eg, cyclosporine, tacrolimus), and 
rituximab (Prasad, 2022).  
6.5.3 
Potential Cases of Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT concurrent or with abnormal elevations in TBL that meet 
the criteria outlined below, in the absence of other causes of liver injury, are considered 
potential cases of drug-induced liver injury (eg, Hy’s Law) and are always to be considered 
clinically significant medical events and reported as SAEs. 
The 3 “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in serum aminotransferases (AT) elevations > 3 × ULN (“2 × ULN elevations are too 
common in treated and untreated subjects to be discriminating”).  
2. Cases of increased TBL (at least 2 × ULN) with concurrent AT elevations at least 3 × ULN 
and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated alkaline 
phosphatase) or Gilbert’s syndrome (Temple, 2006). 
3. No other reason can be found to explain the combination of increased AT and TBL, such as 
viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 
For studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the Investigator and study 
team. Subjects should be further evaluated for additional symptoms suggestive of hepatobiliary 
dysfunction.  

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6.5.3.1 
Definition of Liver Abnormalities 
For laboratory abnormalities (including liver) reported as AEs, severity grading assessment 
should follow the NCI-CTCAE (v4.03) Investigation system organ class. 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 5 × ULN for more than 2 weeks 
• 
ALT or AST > 3 × ULN and* TBL > 2 × ULN or international normalized ratio (INR) > 1.5 
(If INR testing is applicable/evaluated) 
• 
ALT or AST > 5 × ULN and* TBL > 2 × ULN 
• 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)  
* Samples taken simultaneously or within a maximum of 24 hours.  
The Investigator may determine that abnormal liver function results, other than those described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
6.5.3.2 
Liver Abnormality Follow-Up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination, and clinical laboratory tests. Subjects with confirmed abnormal liver function 
testing should be followed as described below.  
Confirmed moderately abnormal liver function tests should be repeated at least once per week, 
and then weekly or less if abnormalities stabilize and the subject is asymptomatic.  
Severe hepatic liver function abnormalities as defined above will be considered an 
important medical event and should be reported as an SAE. The Sponsor should be 
contacted and informed of all subjects for whom severe hepatic liver function abnormalities 
possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the Investigator is expected to: 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases are to be recorded as AEs. Illnesses and conditions such as 
hypotensive events and decompensated cardiac disease that may lead to secondary 
liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in obese 
hyperlipoproteinemic and/or diabetic subjects and may be associated with fluctuating AT 
levels. The Investigator should ensure that the medical history form captures any illness 
that predates study enrollment that may be relevant in assessing hepatic function.  
• 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 

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special diets. Medications, including dose, are to be entered in the eCRF. Information on 
alcohol, other substance use, and diet should be entered on the eCRF or an appropriate 
document. 
• 
Obtain a history of exposure to environmental chemical agents. 
• 
Based on the subject’s history, other testing may be appropriate including:  
- 
Acute viral hepatitis (A, B, C, D, E, or other infectious agents such as 
cytomegalovirus, Epstein-Barr virus)  
- 
Ultrasound or other imaging to assess biliary tract disease 
- 
Other relevant clinical laboratory tests including INR, total and direct bilirubin, 
albumin 
• 
Consider gastroenterology or hepatology consultations. 
• 
Submit results for any additional testing and possible etiology on the eCRF or an 
appropriate document. 
6.5.3.3 
Hyperbilirubinemia 
Investigations into the nature of liver dysfunction in patients with XLMTM before and after 
AT132 administration suggest intrahepatic cholestasis as a likely central feature. Ursodiol is an 
enterally administered hydrophilic bile acid that can decrease the hydrophobic bile acid content 
within bile (Poupon, 2012). As hydrophilic bile acids are generally non-toxic to hepatocytes, 
hydrophobic bile acids can be toxic to these same cells in direct contact, ursodiol has been used 
to treat severe cholestatic syndromes, such as progressive intrafamilial intrahepatic cholestasis 
(Balistreri, 1997; Strauss, 2006; Suskind, 2006) and intra-hepatic and extra-hepatic cholestatic 
diseases in childhood (Kriegermeier, 2020). Ursodiol has also been used for prophylaxis of 
hepatic veno-occlusive disease (Cheuk, 2015). Subjects in this study will begin treatment with 
prophylactic ursodiol prior to AT132 administration, as described in Section 4.5. 

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7 STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will provide a detailed description of the planned statistical 
analyses and data summaries. This section presents an overview of the planned analyses. Final 
analyses are not limited to the summaries described herein. If discrepancies exist between the 
text of the statistical analysis as planned in the protocol and the final SAP, the final SAP will 
define the planned analysis of record. Reasons for such discrepancies, will be described in the 
final study report. 
Data listings and summaries will be presented for all subjects and by dose levels. All continuous 
study assessments will be summarized using descriptive statistics (ie, n, mean, standard 
deviation, median, Q1, Q3, minimum, and maximum). All categorical study assessments will be 
summarized by time point, as applicable, using frequency counts and percentages. Details for 
the efficacy analyses will be provided below and in the SAP. 
As of protocol v9 and beyond: The 1.0 × 1014 vg/kg dose level based on a 1st generation titer 
method equates to 1.3 × 1014 vg/kg as determined by a 2nd generation vg titer assay (see 
Section 1.4.2); and the 3.0 × 1014 vg/kg dose level equates to 3.5 × 1014 vg/kg based on an 
analysis of the historical Study ATX-MTM-002 drug product lots using the 2nd generation vg titer 
assay. 
The study is no longer able to address the stated objectives, hence the statistical analysis will 
provide descriptive summaries by treatment groups. 
7.1 
Sample Size 
The following language was from protocol v9 that planned a formal analysis to compare 
1.3 × 1014 vg/kg and delayed-treatment control, however given that the study will not be able to 
address the objectives, no such formal analysis will be conducted. 
A power analysis for the primary analysis of the primary endpoint was conducted at 80% power 
and 0.05 level of alpha to estimate the required sample size based on Mean of 13.0 vs. 
0.0 hours of reduction in ventilation need, with common SD of 6.0 by Week 24 using a t-test, 
resulting in at least N = 10 for a balanced 1:1 allocation between 1.0 × 1014 vg/kg AT132 
(equates to 1.3 × 1014 vg/kg as determined by the 2nd generation vg titer assay) and delayed-
treatment control. It is further assumed, that the same difference in means (SD), will provide at 
least 80% power using a Mixed Effect Model Repeat Measurement (MMRM) analysis proposed 
for the primary endpoint. However, it is possible that 1:1 allocation may not be feasible; 1 control 
subject serving as control for multiple treated subjects, or multiple control subjects being a 
match for a single treated subject. Therefore, all qualified control subjects will be used in the 
analyses to ensure adequate power is available to detect the intended difference between 
treated and control subjects. 

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7.2 
Analysis Populations 
The following analysis sets for subjects treated with AT132 will be used: 
• 
Full Analysis Set (FAS) is defined as all randomized and/or enrolled subjects who 
received AT132 and had at least 1 postdose efficacy assessment. The FAS will be used 
for the primary analysis of the primary efficacy endpoint.  
• 
Safety Analysis Set (SAF) is defined as all randomized and/or enrolled subjects who 
received AT132. The SAF will be used for the analysis of the safety endpoints. 
In each analysis set, 3 treatment groups are defined by: (i) subjects treated at 1.3 × 1014 vg/kg 
(low dose), (ii) subjects treated at 3.5 × 1014 vg/kg (high dose), and (iii) all subjects treated with 
AT132 (overall; not applicable to efficacy endpoints).  
7.3 
Subject Disposition, Demographic Data, Baseline Characteristics, and Extent of 
Exposure 
The number and percentage of study subjects who complete and discontinue the study as well 
as reasons for early discontinuation will be presented by low dose, high dose, and overall for the 
SAF. 
Demographic and baseline measurements will be summarized by low dose, high dose, and 
overall on the FAS and SAF. Medical history will be summarized by low dose, high dose, and 
overall for the SAF. 
Exposure will be confirmed based on the report of dosing recorded in the eCRF, and will be 
presented in a listing. 
7.4 
Statistical Analysis 
7.4.1 
Safety Analyses 
The analysis of safety endpoints will be conducted by treatment group (low dose, high dose, 
and overall) for the SAF. 
7.4.1.1 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
Events will be identified as treatment-emergent (TEAE) and non-treatment-emergent 
(non-TEAE) on the basis of the date of onset relative to the date of AT132 dosing.  
Number and percentage of subjects with TEAEs classified by system organ class (SOC) and 
preferred term (PT); by severity, causality, seriousness, and action taken with regard to study 
drug will be summarized. Number (%) of subjects with TEAEs leading to discontinuation of 
study will also be summarized. Hospitalization will be summarized by frequency (%) and 
duration. TEAEs and/or hospitalizations may be annualized.  

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7.4.1.2 
Laboratory and Other Safety Evaluations 
For clinical safety laboratory test results, vital signs, and ECG parameters, the numeric values 
and corresponding changes from baseline will be summarized using descriptive statistics by 
parameter and time point. 
Incidence of laboratory abnormalities that increase at least 1 toxicity grade from baseline at any 
time postbaseline will be summarized. If baseline data are missing, then any graded abnormality 
(ie, at least a Grade 1) will be considered. 
ECHO findings, liver ultrasounds, antibody formation (anti-AAV8, anti-MTM1), and viral 
shedding will be summarized. 
Change in special liver laboratory parameters of interest (eg, bilirubin, AST, ALT, and CK) will 
be summarized.  
7.4.2 
Efficacy Analysis 
7.4.2.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in hours of ventilation support at 
Week 24. The hours of ventilation support will be based on diary data from subjects for whom 
diary data was collected at baseline (those administered AT132 under protocol v5 and beyond, 
including all subjects in Part 2), and by assessment of time off ventilator questionnaire for all 
other subjects (those administered AT132 under protocol v4 and prior). Weekly scores will be 
the average of ventilation hours needed for at least 5 out of the 7 days. Missing values will be 
ignored if number of ventilation hours are available for at least 5 days, otherwise they will be 
imputed by the worst score of the week. 
7.4.2.1.1 
Primary Analysis 
The primary efficacy endpoint will be analyzed using a MMRM with baseline, treatment (low 
dose or high dose), time (Weeks 1, 4, 12, 16, 24, 36, and 48), and treatment by time interaction 
as fixed effects and subject as random effect. The change from baseline in hours of ventilation 
support at Week 24 will be summarized by treatment group based on this model. The primary 
analysis will be conducted using the FAS. 
7.4.2.1.2 
Secondary Analysis 
Based on the MMRM described in Section 7.4.2.1.1, the change from baseline in hours of 
ventilation support at Week 1, 4, 12, 16, 36, and 48 will be summarized by treatment group. 
7.4.2.2 
Analysis of Secondary Efficacy Endpoints 
7.4.2.2.1 
Key Secondary Efficacy Endpoints 
The analysis of key secondary efficacy endpoints will be conducted using the FAS. 

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The number and percentage of subjects achieving functionally independent sitting for at least 
30 seconds by Week 24 will be summarized by low dose and high dose. 
7.4.2.2.2 
Other Secondary Efficacy Endpoints 
The analysis of other secondary efficacy endpoints will be conducted using the FAS.  
Time to reduction in required daily ventilator support to ≤ 16 hours by Week 24, time to 
reduction of at least 6 hours in daily ventilator support by Week 24, and time to death will be 
summarized for low dose and high dose. Kaplan-Meier plots along with median (95% CI) time 
from the study start date to event will be provided.  
The CHOP INTEND, MIP, ACEND, and PedsQL, as well as their changes from baseline, will be 
summarized descriptively over time, and the changes from baseline will be analyzed using the 
MMRM in a similar method to that used for the primary analysis of the primary efficacy endpoint. 
The number and percentage of subjects attaining age-appropriate clinically relevant gross motor 
function milestones through Week 24, and subjects achieving full ventilator independence at 
Week 24, will be summarized for low dose and high dose. 
7.4.2.3 
Analysis of Exploratory Efficacy Endpoints 
The analysis of exploratory efficacy endpoints will be conducted using the FAS.  
Exploratory efficacy variables will be summarized descriptively over time for low dose and high 
dose. 
Growth parameters will be evaluated graphically and compared to standard World Health 
Organization or National Institutes of Health normal curves, where possible. 
7.5 
Data Monitoring Committee 
This study will utilize an independent DMC comprising at least 3 experts with relevant expertise 
who will monitor subject safety and efficacy and provide recommendations to the Sponsor 
regarding expansion of dose cohorts and dose escalation or decreases. The DMC may 
recommend accelerated dosing of control subjects if compelling efficacy results support such 
action. 
DMC review will occur, at minimum, at the following events: 
• 
A sentinel subject has been dosed and observed for at least 4 weeks in each of the 
cohorts (DMC chair review) 
• 
Consideration of a dose escalation after at least 3 subjects at a dose level have been 
dosed and observed for at least 4 weeks following AT132 administration (full DMC 
review) 
• 
Dose escalation has been stopped and participating subjects have 24 weeks of post-
dose follow up, at which point it is anticipated that an optimal dose can be selected (full 
DMC review; applicable to Part 1 of study) 

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• 
Consideration of expanding enrollment at a specific dose level (full DMC review) 
• 
Review of important medical events 
In addition, the DMC will perform an ad hoc review, if requested by the Sponsor, or if stopping 
criteria listed in Section 7.6 are met. 
The DMC’s specific activities will be defined by a mutually agreed ATX-MTM-002 charter, which 
will define the DMC’s membership, conduct, and meeting schedule. 
While the DMC will be asked to advise the Sponsor regarding future conduct of the study, 
including possible early study termination due to treatment-related AEs, the Sponsor retains 
final decision-making authority on all aspects of the study. 
7.6 
Study Safety Stopping Rules 
Dosing of additional subjects will be paused and the DMC will conduct a review if any of the 
following stopping criteria are reached: 
• 
One Grade ≥ 4 AE or the occurrence of the same treatment-related Grade ≥ 3 AE on 2 
or more occasions 
• 
Any Grade ≥ 3 neuromuscular AE in a treated subject considered possibly related or 
related to AT132, as assessed by the Investigators 
• 
Any Grade ≥ 3 cardiac AE in a treated subject considered possibly related or related to 
AT132, as assessed by the Investigators 
• 
Any Grade ≥ 3 hepatobiliary AE in a treated subject considered possibly related or 
related to AT132, as assessed by the Investigators 
The DMC may advise that the study should be terminated or that clinical protocol should be 
revised to mitigate the risk to subjects. Such revisions may include changes to the enrollment 
criteria, changes in the monitoring plan, and/or changes to the informed consent form. 
If dosing of additional subjects is paused, all remaining protocol specified study visits, safety 
assessments, and end-of-study procedures should be completed in subjects who have already 
been dosed. If any Study Safety Stopping Rules are met while the study is already paused or on 
hold, these will be reported to the DMC since such criteria may change management of a 
previously treated subject. 
7.7 
Data Review Committees 
In addition to the DMC described in Section 7.5, the following independent expert committee will 
adjudicate endpoints and review data: 
• 
Biopsy Review Committee: Responsible for the blinded adjudication of histopathology 
endpoints in muscle biopsies. 

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8 RESPONSIBILITIES AND ADMINISTRATIVE PROCEDURES 
The Sponsor aims to conduct its studies according to the highest scientific standards. The 
following sections articulate standards to which sites are held accountable, as well as matters of 
compliance to document adherence to such standards. 
8.1 
Ethical Conduct of the Study 
It is expected that Investigators understand and comply with the letter and spirit of this protocol. 
This includes and is not limited to establishing and meeting enrollment commitments, including 
only eligible subjects in the study, adhering to diagnostic and other procedures as specified in 
the study, and assuring appropriate compliance with study medication. 
This study will be conducted in accordance with the following: 
• 
United States (US) CFR sections that address clinical research studies 
• 
European Union (EU) Directive 2001/20/EC and EU Clinical Trial Regulation 536/2014 
• 
Other National and Local regulations, as applicable 
• 
International Council for Harmonisation (ICH) E6 
• 
The ethical principles established by the Declaration of Helsinki 
• 
All human clinical research and data privacy regulations in the countries where the study 
is to be conducted 
8.2 
Investigator Responsibilities 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and that all persons involved in the 
conduct of the study are informed about the protocol, study procedures and any study related 
duties. The Investigator is responsible for assuring that study site staff are properly trained and 
credentialed to perform any delegated tasks. 
Prior to beginning the study, the Investigator at each site must provide to the Sponsor or 
designee a fully executed Form FDA 1572 (or equivalent form) and Financial Disclosure Form. 
Financial Disclosure Forms must be completed for all Sub-Investigators listed on the Form 
FDA 1572 (or equivalent form) who will be directly involved in the evaluation of research 
subjects in this study. 
8.3 
Retention of Records 
The Investigator must retain all study records required by the Sponsor and by the applicable 
regulations in a secure and safe facility. The Investigator must consult a Sponsor representative 
before disposal of any study records, and must notify the Sponsor of any change in the location, 
disposition, or custody of study files. The Investigator and/or institution must take measures to 
prevent accidental or premature destruction of essential documents, that is, documents that 
individually and collectively permit evaluation of the conduct of a study and the quality of data 

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produced, including paper copies of study records (eg, subject charts) as well as any original 
source documents that are electronic, as required by applicable regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the US or an ICH region or (2) at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. The Investigator and/or institution 
should retain subject identifiers for at least 25 years after completion or discontinuation of the 
study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution, or private practice but not less than 25 years. These 
documents should be retained per the applicable regulatory requirements in the country/local 
region in which the study is being conducted or by a Sponsor agreement. The Sponsor must be 
notified and will assist with retention should an Investigator and/or institution be unable to 
continue maintenance of subject files for the full 25 years. It is the responsibility of the Sponsor 
to inform the Investigator and/or institution when these documents no longer need to be 
retained. 
8.4 
Institutional Review Board (IRB)/Ethics Committee (EC) Review and Approval 
Prior to initiating the study, the Investigator will obtain written confirmation that the IRB/EC is 
properly constituted and compliant with ICH Guidelines and GCP requirements, applicable laws 
and local regulations. A copy of the confirmation from the IRB/EC will be provided to the 
Sponsor, or designee. The Investigator (or Sponsor as appropriate according to local 
regulations) will submit this protocol, ICF (including compensation procedures), and any 
accompanying material to be provided to the subject (such as subject information sheets or 
descriptions of the study used to obtain informed consent) to an IRB/EC. The Investigator will 
not begin any study subject activities until approval from the IRB/EC has been documented and 
provided as a letter to the Investigator. 
Before implementation, the Investigator will submit to and receive documented unconditional 
approval from the IRB/EC for any modifications made to the protocol or any accompanying 
material to be provided to the subject after initial IRB/EC approval, with the exception of those 
necessary to reduce immediate risk to study subjects. The approval document should refer to 
the study by protocol title, Sponsor, and study number (if possible), identify the documents 
reviewed, and include the date of the review and approval. 
Other Investigator responsibilities include the following: 
• 
Submit to the appropriate committees and to the Sponsor or its designee for review any 
advertisements that will be used to recruit subjects 
• 
During the conduct of the study, submit progress reports to the appropriate committees, 
if required, and request re-review of the study at least once a year 
• 
Report, in writing, to the appropriate committees any SAEs that occur during the study or 
SAEs reported in other studies using study treatment, per local regulations 

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• 
Inform the appropriate committees of any changes in the protocol and obtain 
documented approval of the changes 
• 
Provide the appropriate committees with any other information it requests before or 
during the conduct of the study 
• 
Maintain a file of study-related information, including all correspondence with the 
committees 
• 
Provide the appropriate committees with a final report on the study within a time period 
consistent with local requirements 
8.4.1 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 and 21 CFR 50 (Subpart B 
[50.20-50.27], and 50.55, if applicable) and other applicable local regulations, will be obtained 
by the Investigator or a person delegated by the Investigator. Due to the pediatric nature of the 
disorder, the study will be in compliance with 21 CFR 50 Subpart D. The site will prepare the 
ICF and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/EC. Both the Sponsor and the IRB/EC must approve the documents before they are 
implemented. A copy of the approved ICF and, if applicable, a copy of the approved subject 
information sheet must be received by the Sponsor prior to enrollment of subjects. 
The Investigator or designee is responsible for obtaining written informed consent from each 
subject or parent/LAR after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The site 
must use the most current IRB-/EC-approved ICF for documenting written informed consent. 
Each ICF will be appropriately signed and dated by the subject or parent/LAR and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/EC or 
local requirements. 
A subject younger than 18 years (or defined as a minor, depending on the region) will provide 
assent if required by IRB/EC or local requirements. 
8.4.2 
Subject Information and Confidentiality 
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only a unique identifier (as allowed by local 
law), and an identification code will be recorded on any form or biological sample submitted to 
the Sponsor, IRB/EC, or laboratory. Laboratory specimens must be labeled in such a way as to 
protect subject identity while allowing the results to be recorded to the proper subject. 
NOTE: The Investigator must keep a screening log showing codes, names, and addresses for 
all subjects screened and for all subjects enrolled in the study. Subject data will be processed in 
accordance with all applicable regulations. 
The Investigator agrees that all information received from the Sponsor, including but not limited 
to this protocol, eCRF, and any other study information, remain the sole and exclusive property 

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of the Sponsor during the conduct of the study and thereafter. This 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 the Sponsor. The Investigator 
further agrees to take all reasonable precautions to prevent the disclosure by any employee or 
agent of the study site to any third party or otherwise into the public domain. 
8.5 
Sponsor Responsibilities 
8.5.1 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may 
be made only by the Sponsor. If there are any substantial changes to the study protocol, these 
changes will be documented in a study protocol amendment and, where required, in a new 
version of the study protocol. The amendment should be approved by the IRB/EC and the 
appropriate regulatory authority(ies) before implementation, as appropriate. Local requirements 
should be followed for amended protocols. If a protocol amendment requires a change to the 
ICF, the IRB/EC must approve the revised ICF before the revised form is used. 
8.5.2 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, the 
Sponsor and the Investigators will arrange discontinuation procedures and notify the appropriate 
IRBs/ECs. In terminating the study, the Sponsor and the Investigators will assure that adequate 
consideration is given to the protection of the subjects’ interests. 
8.5.3 
Study Reports 
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) by the 
Sponsor, as appropriate. The Sponsor will ensure that the report meets the standards set out in 
the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an 
abbreviated report may be prepared in certain cases. 
8.5.4 
Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according to 
GCP and standard operating procedures for compliance with applicable government 
regulations. The Investigator agrees to allow these monitors direct access to the clinical 
supplies and storage areas and to the clinical files, including original medical records of the 
study subjects, and, if requested, agrees to assist the monitors. The Investigator and staff are 
responsible for being present or available for consultation during routinely scheduled site visits 
conducted by the Sponsor or its designees. 
Members of the Sponsor or designee may conduct an audit of a clinical site, IRB, or EC at any 
time before, during, or after completion of the study. The Investigator will be informed if an audit 
is to take place and advised as to the scope of the audit. Representatives of the FDA or other 
regulatory agencies may also conduct an audit of the study. If informed of such an inspection, 

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the Investigator should notify the Sponsor immediately. The Investigator will ensure that auditors 
have access to clinical supplies, study site facilities, original source documentation, and all 
study files. 
8.5.5 
Data Monitoring Committee 
A DMC consisting of at least 3 independent medical experts will review data for subject safety 
and provide recommendations for study conduct to the Sponsor (Section 7.5). 
8.6 
Joint Investigator/Sponsor Responsibilities 
8.6.1 
Case Report Forms 
eCRFs will be provided by the Sponsor to the Investigator for each subject. eCRFs must be 
completed using a validated web-based application. Study site personnel, central reviewer, or 
designee will be trained to enter the clinical data onto the eCRFs from source documentation 
using the web-based application. Unless explicitly allowed in the eCRF instructions, blank data 
fields are not acceptable. 
The Investigator must review and electronically sign the eCRF casebook completed by the site 
to verify its accuracy. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the initial response and then selecting or entering the updated 
response. In compliance with US 21 CFR Part 11, the web-based eCRF system will require the 
personnel making the correction to enter a reason for changing the value. The documented 
audit trail will include the reason for the change, the original value, the new value, the time of 
the correction, and the identity of the operator. 
Study data entered into the eCRFs must be verifiable to source data, which necessitates access 
to all original recordings, laboratory reports, and subject records. In addition, all source data 
should be attributable (signed and dated). The Investigator must, therefore, agree to allow direct 
access to all source data. Subjects (or legally authorized representative) must also allow access 
to their medical records. Subjects will be informed of the necessity for such access and will 
confirm their agreement with this when providing informed consent. If an Investigator or 
institution refuses to allow access to subject records because of confidentiality, arrangements 
must be made to allow an “interview” style of data verification. 
A Sponsor clinical research associate (CRA) (or designee) will compare eCRFs with original 
source documents at the study site and evaluate eCRFs for completeness and accuracy before 
designating them as “source data verified.” If an error is discovered at any time or a clarification 
is needed, the CRA (or designee) will create an electronic query on the associated field. Study 
site personnel will then answer the query by either correcting the data or responding to the 
query. The CRA will then review the response and determine either to close the query or 
re-query the site if the response does not fully address the question. This process is repeated 
until all open queries have been answered and closed.  

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8.6.2 
Payment Reporting 
The Investigator and Sub-Investigators are required to disclose any financial arrangement 
during the study and for 1 year after study completion, whereby the outcome of the study could 
be influenced by the value of the compensation for conducting the study, or other payments the 
Investigator received from the Sponsor. The following information is collected: any significant 
payments from the Sponsor or subsidiaries such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation or honoraria; any 
proprietary interest in investigational product; any significant equity interest in the Sponsor or 
subsidiaries (Investigator, spouse, or dependent children) as defined in 21 CFR 54 2(b). 
8.6.3 
Financing and Insurance 
Financing and insurance for this clinical study will be addressed in appropriate study 
documents, in the Clinical Trial Agreement between the Sponsor and the Investigator and/or 
institution, or in the clinical study insurance policy(ies). 
 

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9 PUBLICATION AND USE OF INFORMATION 
The Sponsor recognizes the importance of communicating medical study data and, therefore, 
encourages publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on data from this study will be described in the Clinical Trial Agreement 
between the Sponsor and the Investigator and/or institution. Consideration for authorship of all 
publications will be based on compliance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals (“ICMJE 
Recommendations”) of the International Committee of Medical Journal Editors 
(http://www.icmje.org/recommendations/), Good Publication Practices (GPP), and the Sponsor’s 
internal publication and authorship policies. 

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11 SIGNATURE PAGE – Sponsor 
Accepted for the Sponsor: 
Required sponsor signatures as required by ICH GCP 4.5.1 are located in the first attachment. 
Attachment 1 
Electronic Sponsor Signatures 
 

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12 SIGNATURE PAGE – Principal Investigator 
Accepted for the Principal Investigator: 
I have read the protocol and agree to conduct this study as described herein. I confirm that I will 
comply with all obligations as detailed in all applicable regulations and guidelines. I will ensure 
that the subject(s) and parent(s)/legal guardian(s) are informed of important information that 
becomes available during the conduct of this study.  
 
 
 
 
Principal Investigator signature 
 
Date 
 
 
 
 
Printed name 
 
 
 
 

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13 APPENDICES 
Appendix 1: 
Laboratory Assessments 
Appendix 2: 
Assessment of Tanner Stage for Boys 
Appendix 3: 
Secretions Management Assessment: PGIS-S and PGIS-I 
Appendix 4: 
Assessment of Time Off of Ventilator 
Appendix 5: 
Clinical Global Impression Scales: CGI-S and CGI-I 
Appendix 6: 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) 
Appendix 7: 
Parental Swallowing Questionnaire 
Appendix 8: 
Parental Speech Development Questionnaire 
Appendix 9: 
Genetics Testing 

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Appendix 1: Laboratory Assessments 
The following laboratory parameters will be measured by the central or local laboratory per the 
timing specified in the Schedule of Events (Sections 5.3.1, 5.4, 5.5, 5.6, and 5.7): 
Hematology 
Serum Chemistry 
Urinalysis 
White blood cells 
Red blood cells 
Hemoglobin (HGB) 
Hematocrit 
Platelet count 
Absolute neutrophil 
Absolute lymphocytes 
Absolute monocytes 
Absolute eosinophils 
Absolute basophils 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Mean corpuscular volume 
Mean corpuscular HGB 
Mean corpuscular HGB 
concentration 
Red cell distribution width 
Mean platelet volume 
Additional Hematology for 
Platelet Monitoring*  
Platelet Activation Assays 
- CD62P 
- Activated GP IIb/IIIa w/PAC-1 
- Phosphatidylserine 
Reticulated Platelets 
Platelet Circulating Antibodies  
Liver Function Tests 
• Albumin, serum 
• Alkaline phosphatase, serum 
• Alanine transaminase, serum 
• Aspartate transaminase 
• Bilirubin direct 
• Bilirubin, total 
• Gamma-glutamyl transferase  
Bicarbonate  
Calcium, serum 
Chloride, serum 
Creatine kinase 
- CK-MM 
- CK-BB 
- CK-MB 
C reactive protein 
Creatinine, serum  
Glucose, serum 
Lactate dehydrogenase 
Phosphorus, serum 
Potassium, serum 
Protein, total serum 
Sodium, serum 
Urate (Uric Acid), serum 
Urea nitrogen (BUN), serum 
Alpha fetoprotein 
Additional Serum Chemistry 
Troponin T and/or troponin I 
Complement Panel 
- Complement C3 
- Complement C4 
- Complement CH50 
- Soluble Complement C5b-9 
Cytokine Panel 
- IL-1b, IL-2, IL-6, IL-8, IL-10, 
IL-15, IFN-y, and TNF-α 
Serum Bile Acids 
Color 
Appearance 
Urine pH 
Urine specific gravity 
Leukocyte esterase urine 
Nitrite urine 
Urine protein semiquant random 
Urine glucose 
Urine ketones (acetone) random 
Urine urobilinogen random 
Urine blood 
Urine bile 
 
 
Coagulation Parameters 
Prothrombin time (PT) 
Activated partial thromboplastin 
time (PTT) 
International normalized ratio (INR) 
*Not applicable for France. 

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Appendix 2: Assessment of Tanner Stage for Boys 
Stage 
Genital Development 
Pubic Hair Growth 
1 
Prepubertal; no change in size or proportion of testes, 
scrotum, and penis from early childhood 
Prepubertal; no pubic hair 
2 
Enlargement of scrotum and testes; reddening and 
change in texture in skin of scrotum; little or no penis 
enlargement 
Sparse growth of hair at base of 
penis 
3 
Increase first in length then width of penis; growth of 
testes and scrotum 
Darkening, coarsening and 
curling, increase in amount 
4 
Enlargement of penis with growth in breadth and 
development of glands; further growth of testes and 
scrotum, darkening of scrotal skin 
Hair resembles adult type, but 
not spread to medial thighs 
5 
Adult size and shape genitalia 
Adult type and quantity, spread 
to medial thighs 
Source: Tanner, 1962 
 

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Appendix 3: Secretions Management Assessment: PGIS-S and PGIS-I 
Parental Global Impression of Secretion Severity (PGIS-S) 
Taking into consideration the experience and understanding you have of your child; in terms of 
secretion management (ie, volume and thickness of secretions, and how often you need to 
suction your child) – how affected has your child been over the past 7 days? 
1 – not affected 
2 – borderline affected 
3 – mildly affected 
4 – moderately affected 
5 – markedly affected 
6 – severely affected 
7 – among the worst he has ever been 
 
Parental Global Impression of Secretion Improvement (PGIS-I) 
In comparison to the baseline assessment (ie, the start of the study), and specifically with 
regard to management of secretions (ie, volume, thickness, frequency of suctioning), how has 
he changed? 
1 – very much improved 
2 – much improved 
3 – minimally improved 
4 – no change 
5 – minimally worse 
6 – much worse 
7 – very much worse 
 
Name of parent/LAR/caregiver providing information: _________________________________ 
Date of completion: ___________________________ 

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Appendix 4: Assessment of Time Off of Ventilator 
                       Site No.             Subject ID 
 
Subject No:   1 ___ ___   -  9 ___ ___ ___ 
Date of Assessment (DD/Mon/YYYY): 
 
 ___ ___/___ ___ ___/20 ___ ___ 
Ventilator Dependence Questionnaire 
 
1. Over the past 24 hours, 
what type of ventilation 
has your child used? 
☐ BiPAP/CPAP 
☐ Invasive 
☐ None (do not complete question 2) 
2. Over the past 24 hours, 
total number of minutes 
or hours the child has 
spent off of ventilator 
support? 
 
___ ___ # of hours  
 
OR 
 
___ ___ ___ ___ # of minutes 
 
Name of parent/LAR/caregiver providing information: __________________________________ 
Date of completion: ___________________________ 
 

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Appendix 5: Clinical Global Impression Scales: CGI-S and CGI-I 
The Clinical Global Impression – Severity scale (CGI-S) 
Rate the severity of the patient's illness at the time of assessment, relative to the clinician's past 
experience with patients who have the same diagnosis. Considering total clinical experience, a 
patient is assessed on severity of illness at the time of rating. 
 
 
□ Not assessed 
 
 
□ 1 = Normal, shows no signs of illness 
 
 
□ 2 = Borderline ill 
 
 
□ 3 = Slightly ill 
 
 
□ 4 = Moderately ill 
 
 
□ 5 = Markedly ill 
 
 
□ 6 = Severely ill 
 
 
□ 7 = Among the most extremely ill of patients 
 
Please provide rationale for score provided. 
 
 
 
 
 
 

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The Clinical Global Impression – Improvement scale (CGI-I) 
Assess how much the patient's illness has improved or worsened relative to baseline (Study 
Day 1) 
 
 
□ Not assessed 
 
 
□ 1 = Very much improved 
 
 
□ 2 = Much improved 
 
 
□ 3 = Minimally improved 
 
 
□ 4 = No change 
 
 
□ 5 = Minimally worse 
 
 
□ 6 = Much worse 
 
 
□ 7 = Very much worse 
 
Please provide rationale for score provided. 
 
 
 
 
 
 
 
 
 

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Appendix 6: National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) 
Adverse events will be graded according to CTCAE v4.03. 
The NCI CTCAE criteria are available at the following web location (accessed 22 February 
2017): http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 

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Appendix 7: Parental Swallowing Questionnaire 
1.  Since the last visit how often do you use the following with your child (check one box for 
each line) 
a. 
Tube Feeding 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
b. 
Bottle Feeding 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
c. 
Spoon from caregiver 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
d.  
Fingers (self) 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
e.  
Utensils (self) 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
f.  
No spill cup 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 

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g.  
Straw 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
h.  
Open cup 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
 
2.  Since the last visit, how often does your child consume drinks or food of the following 
consistency? 
a. 
Thin  
Description 
• 
Flows like water 
• 
Fast flow 
• 
Can drink through any type of 
teat/nipple, cup or straw as appropriate 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
b. 
Slightly Thick 
Description 
• 
Thicker than water 
• 
 Requires a little more effort to drink 
than thin liquids 
• 
Flows through a straw, syringe, 
teat/nipple 
• 
Similar to the thickness of commercially 
available ‘Anti-regurgitation’ (AR) infant 
formula 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
c. 
Mildly Thick 
Description 
• 
Flows off a spoon 
• 
Sippable, pours quickly from a spoon, 
but slower than thin drinks 
• 
 Effort is required to drink this thickness 
through standard straw 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 

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d.  
Moderately Thick/Liquidized 
Description 
• 
Will not hold its shape on a spoon 
• 
Sippable, pours slowly off a spoon 
• 
Difficult to suck through a standard or 
wide straw 
• 
Cannot be piped, layered or moulded 
• 
Cannot be eaten with a fork because it 
drops through the prongs 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
e.  
Extremely Thick/Pureed 
 
Description 
• 
Holds shape on spoon 
• 
Flows very slowly under gravity 
• 
Does not require chewing 
• 
Could be piped, layered or moulded 
• 
No lumps 
• 
Falls off spoon in a single spoonful 
when tilted and continues to hold a 
shape on a plate 
• 
Cannot be sucked through a straw 
• 
Not sticky 
• 
Liquid does not separate from solid 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
f.  
Minced and Moist 
Description 
• 
Very small pieces of moist food 
• 
Holds shape on spoon 
• 
Falls off spoon if the spoon is tilted or 
turned sideways or shaken slightly 
• 
Not sticky 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
g.  
Soft 
Description 
• 
Food can be mashed with fork 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 

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h.  
Regular 
Description 
• 
Food too hard to be mashed with fork 
• 
Can be eaten with a fork 
☐ Never 
☐ Almost Never 
☐ Sometimes 
☐ Often 
☐ Almost Always 
☐ Always 
 
Name of parent/LAR/caregiver providing information: _________________________________ 
Date of completion: ___________________________ 
 

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Appendix 8: Parental Speech Development Questionnaire 
1. 
Does your child speak? 
☐ Yes, off of ventilator 
☐ Yes, only with a speaking 
valve 
☐ No  
2. 
Does your child cry audibly? 
☐ Yes  ☐ No  
3. 
Does your child giggle or laugh audibly? 
☐ Yes  ☐ No 
4. 
Does your child produce coos or gurgles? 
☐ Yes  ☐ No 
5.  
Does your child produce the following sounds? 
 
a. 
da 
☐ Yes  ☐ No 
b. 
ba 
☐ Yes  ☐ No 
c. 
ga 
☐ Yes  ☐ No 
d. 
ma 
☐ Yes  ☐ No 
e. 
pa 
☐ Yes  ☐ No 
6.  
Does your child produce the following sounds in a 
sequence? 
 
a. 
dada 
☐ Yes  ☐ No 
b. 
baba 
☐ Yes  ☐ No 
c. 
gaga 
☐ Yes  ☐ No 
d. 
mama 
☐ Yes  ☐ No 

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e. 
papa 
☐ Yes  ☐ No 
7. 
Does your child jabber loudly? 
☐ Yes  ☐ No 
8. 
Does your child try to imitate your speech? 
☐ Yes  ☐ No 
9. 
Does your child produce animal sounds from the 
following animals? 
 
a. 
cat 
☐ Yes  ☐ No 
b. 
dog 
☐ Yes  ☐ No 
c. 
bird 
☐ Yes  ☐ No 
d. 
pig 
☐ Yes  ☐ No 
e. 
horse 
☐ Yes  ☐ No 
f. 
duck 
☐ Yes  ☐ No 
10. 
Does your child use mama or dada to call for that 
specific parent? 
☐ Yes  ☐ No 
11. 
When your child sees an animal (i.e. dog, cat, bird) 
do they say the animal name consistently? 
☐ Yes  ☐ No 
12. 
Does your child use specific words to label 
everyday objects (i.e. juice, cookie, blanket, etc.)? 
☐ Yes  ☐ No 
13. 
Can your child produce their own name? 
☐ Yes  ☐ No 
14. 
Can the following people understand what your 
child is saying? 
 
a. 
mother 
☐ Yes  ☐ No 
b. 
father 
☐ Yes  ☐ No 

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c. 
sibling 
☐ Yes  ☐ No 
d. 
grandparent 
☐ Yes  ☐ No 
e. 
stranger 
☐ Yes  ☐ No 
15. 
Can your child alert you in another room? 
☐ Yes  ☐ No 
 
Name of parent/LAR/caregiver providing information: __________________________________ 
Date of completion: ___________________________ 

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Appendix 9: Genetics Testing 
Use/Analysis of DNA 
• 
Genetic variation may impact a subject’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting subjects. 
• 
DNA samples will be used for research related to gene therapy or XLMTM and 
related diseases. They may also be used to develop tests/assays, including 
diagnostic tests related to gene therapy and XLMTM disease. Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of the entire 
genome as appropriate. 
• 
The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to the gene therapy or study interventions of this class to 
understand the study disease or related conditions. 
• 
The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary or may be published in medical or scientific journals 
and conferences. 
• 
The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on AT132 is ongoing but no longer than 
15 years after the final study results have been reported and then destroyed, or other 
period as per local requirements. 
 

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PROTOCOL AMENDMENT 
SUMMARY OF CHANGES FOR PROTOCOL VERSION 12.0 
Study Title: 
ASPIRO: A Phase 1/2/3, Randomized, Open-Label, 
Ascending-Dose, Delayed-Treatment Concurrent Control 
Clinical Study to Evaluate the Safety and Efficacy of 
AT132, an AAV8-Delivered Gene Therapy in X-Linked 
Myotubular Myopathy (XLMTM) Patients 
Protocol Number: 
ATX-MTM-002 
Protocol Versions and Dates: 
1.0 (Global) 
22 February 2017 
 
2.0 (Global) 
14 June 2017 
 
3.0 (Global) 
25 January 2018 
 
4.0 (Global) 
21 November 2018 
 
5.0 (Global) 
01 May 2019 
 
6.0 (Global) 
08 October 2019 
 
7.0 (Global) 
07 April 2020 
 
8.0 (Global) 
16 November 2020 
 
9.0 (Global) 
15 January 2021 
 
10.0 (Global) 
03 February 2022 
 
11.0 (Global) 
16 May 2023 
 
12.0 (Global)  
17 May 2024 
 
Amendment 12 [Substantial] 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union and 
EU Clinical Trial Regulation. 
Overall Rationale for Amendment 
The main purpose of this protocol amendment was to 1) update the overall risks and benefits 
based on the latest risk evaluations and available information, 2) update and reorganize the 
monitoring and management plan for safety events as well as potential immune responses, 3) 
update study assessments for safety events and 4) streamline efficacy assessments in the long-
term follow-up period.  

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Summary of Changes 
Substantial Changes 
Deleted text is denoted with strikethrough font and added text is underlined. When needed, “…” indicates a skipped sentence or paragraph. 
Location(s) 
Description of Change 
Rationale for 
Change 
Justification for 
Substantial 
Designation 
Section 1.5 
1.5  Overall Risks and Benefits 
Key risks of the study include the following: 
• Subjects participating in this study will have study procedure related risks, including invasive 
assessments and muscle biopsies. 
• Subjects participating in this study will receive prophylactic prednisolone and ursodiol. Information 
regarding the risks associated with these medications can be found in the respective USPIs 
(Prednisolone USPI, 2013; Ursodiol USPI, 2013). 
• The important identified risks associated with AT132 that have been observed during the clinical 
development program include: 
- Hepatobiliary events (hyperbilirubinemia, cholestatic liver dysfunction, transaminases increase 
and elevated serum bile acids levels): In Study ATX-MTM-002, SAEs representing significant 
hepatobiliary dysfunction have been observed in 4 subjects (1 at the 1.0 × 1014 vg/kg dose; 3 at 
the 3.0 × 1014 vg/kg dose), and led to fatal outcomes. Each of the 4 subjects had a history of 
hyperbilirubinemia prior to treatment. 
- Myocardial events (myocarditis and troponin increased): In Study ATX MTM 002, 2 subjects (1 
at the 1.0 × 1014 vg/kg dose; 1 at the 3.0 × 1014 vg/kg dose) presented with SAEs of myocarditis. 
In both cases, neither subject was hemodynamically unstable, and echocardiograms and 
magnetic resonance imaging (MRIs) showed normal biventricular systolic function, with no wall 
motion abnormalities. Both events of myocarditis responded to administration of IV steroids and 
both events were considered recovered without sequelae. 
• Subclinical inflammatory hepatitis, manifest by elevations in hepatic transaminases have occurred in 
the setting of AAV gene therapies in clinical development; for example, in Hemophilia B (factor IX 
deficiency), Hemophilia A (factor VIII deficiency), and spinal muscular atrophy (SMA). This 
inflammatory hepatitis has been responsive to treatment with prednisolone (Mendell, 2015; 
Nathwani, 2014; Nathwani, 2011; Pasi, 2016; Spark Therapeutics, 2016). 
• As with all biological agents, severe inflammatory responses at the systemic or organ level may 
result from unpredicted reactivity to AT132 or to cells transduced by AT132. 
• Subjects may develop thrombocytopenia after receiving AT132, due to platelet and/or complement 
activation. Events of thrombocytopenia in Study ATX MTM 002 have been consistently mild to 
moderate in severity, and self-limiting or responsive to additional steroid treatment. 
To reflect the latest 
risk evaluation and 
available information 
 
 
New safety findings 
which are likely to 
impact the risk/benefit 
assessment 

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Location(s) 
Description of Change 
Rationale for 
Change 
Justification for 
Substantial 
Designation 
• Subjects may develop an antibody response to the AAV capsid and/or the myotubularin protein after 
administration of AT132. 
• An effective dose for AT132 is not known for humans. AT132, if only partly effective, may expose 
existing comorbidities, worsen existing comorbidities (eg, uneven muscle response causing a 
worsening of scoliosis or ophthalmoplegia), or result in new comorbidities (eg, bone fractures 
resulting from increased capacity for mobility, or as yet unknown disease manifestations occurring in 
children who live longer). 
Key study risks are listed below:  
• Subjects will have study procedure-related risks:  
- Blood collection: The risks of venous blood draws include discomfort at the site of puncture, 
possible bruising and swelling around the puncture site, rarely an infection; and, uncommonly, 
fainting, nausea, vomiting, and light-headedness from the procedure. 
- Muscle biopsy: The muscle biopsy has potential complications from the procedure that include 
infection at the biopsy site, bleeding and/or pain at the site of the biopsy, and psychological 
trauma from the scar at the site of the incision; in some cases, keloid formation can increase 
scarring.  
- Cardiac or muscle magnetic resonance imaging (MRI): The MRI scan is not associated with 
risks unless a subject has certain types of metal implants such as pacemakers.  
- Procedural sedation risk: Sedation risks in children with weak respiratory muscles varies with 
the medication used. Sedation risks will be explained to the family.  Sedation for the imaging 
must be carefully administered in patients with XLMTM, since most anesthetic agents act directly 
on the muscle. Bulbar dysfunction, respiratory muscle weakness, gastroesophageal reflux, and 
scoliosis increase the risk of pneumonia. Children with respiratory and bulbar muscle weakness 
who are not ventilator dependent may require invasive or noninvasive ventilation after the 
procedure. The duration of increased ventilatory requirements would vary depending on the 
degree of respiratory muscle weakness. The potential side effects of specific medications 
administered for sedation (eg, vomiting, respiratory depression, laryngospasm, emergence 
reaction), and the likely duration of sedation will be discussed during informed consent for the 
procedure.  
- Prophylaxis (prednisolone, ursodiol): Subjects receive prophylactic prednisolone and ursodiol 
as part of the clinical study. Information regarding the risks associated with these medications 
can be found in the respective local prescribing information.  
• Overall risks associated with rAAV gene therapy administration include hepatotoxicity, cardiac 
events such as myocarditis, myositis, thrombocytopenia, thrombotic microangiopathy (TMA), and 
sensory ganglionopathy (Arjomandnejad, 2023; FDA, 2021; Lek, 2023; Shen, 2022; Whiteley, 
2023).  

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Location(s) 
Description of Change 
Rationale for 
Change 
Justification for 
Substantial 
Designation 
- Key identified risks associated with AT132 administration observed in Study ATX-MTM-002 are 
listed below. Of the overall risks associated with rAAV gene therapy, thrombotic microangiopathy 
and sensory ganglionopathy have not been observed in ATX-MTM-002 study subjects. Long-
term follow-up is important in understanding whether these AEs have long-term implications. 
Refer to the Investigator’s Brochure for further details.  
- Hepatobiliary events: Many XLMTM patients have liver dysfunction and cholestasis, which 
places them at increased risk for hepatobiliary dysfunction or even hepatic failure with rAAV 
administration. A prospective natural history study (Study ATX-MTM-009) reported that overall, 
91% of subjects had histories of hepatic disease and/or prospectively experienced related AEs 
or laboratory or imaging abnormalities (Dowling, 2022).   
◦ 
In Study ATX-MTM-002, SAEs due to hepatobiliary dysfunction occurred after AT132 
administration and were characterized by hyperbilirubinemia, cholestatic liver dysfunction, 
transaminases elevations, ascites, and serum bile acid elevations. Fatal outcomes were 
observed in 4 subjects due to multifactorial causes including hepatobiliary failure: 1 subject 
who received the 1.0 × 1014 vg/kg dose and 3 subjects who received the 3.0 × 1014 vg/kg 
dose. All 4 subjects showed increases in direct and total bilirubin values (> upper limit of 
normal [ULN]) beginning 1 to 4 weeks after AT132 administration (Shieh, 2023). Liver 
findings included intrahepatocellular and canalicular cholestasis, periportal and bile ductular 
reaction, secondary fibrosis, and notable lack of prominent liver parenchymal inflammatory 
cellular infiltrates (Shieh, 2020).  
- Myocardial events:  
◦ 
Acute cardiac risks: Acute myocardial events manifested as myocarditis and increases in 
troponins. In Study ATX-MTM-002, variable increases in troponin levels after AT132 
administration were commonly observed. Two subjects experienced SAEs of myocarditis: 1 
subject who received the 1.0 × 1014 vg/kg dose and 1 subject who received the 3.0 × 1014 
vg/kg dose. Prolonged prednisolone administration plus addition of other immunosuppressive 
medications were used for treatment of myocarditis.  
◦ 
Chronic cardiac risks: Following prolonged immunosuppression for over 3 years, 1 subject 
experienced an increase in cardiac troponin levels after withdrawal of immunosuppression. 
Abnormalities in cardiac function have not been observed in this subject. However, long term 
assessment is required to understand whether there could be more significant impact on 
cardiac function. 
- Muscle abnormalities: A skeletal muscle immune response to the rAAV capsid and to the 
transgene can occur after rAAV gene therapy administration.  
◦ 
Acute and subacute creatine kinase (CK) elevations: In Study ATX-MTM-002, variable 
increases in CK levels after AT132 administration were commonly observed, occurring soon 

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Rationale for 
Change 
Justification for 
Substantial 
Designation 
after dosing. These CK levels generally returned to normal within the first year after AT132 
administration.  
◦ 
Chronic CK elevations and inflammatory infiltrates in skeletal muscles: Assessment of muscle 
biopsies demonstrated treatment-associated inflammatory changes in muscle biopsy 
specimens of some subjects. No SAEs were reported in association to these findings. 
Improvements in neuromuscular function (respiratory and motor) have been maintained. 
Although the CK levels generally returned to normal within the first year after AT132 
administration, chronic CK elevation over several years can occur.  
- Thrombocytopenia: Subjects may develop transient thrombocytopenia or decreases in platelet 
levels from baseline after AT132 administration. In Study ATX-MTM-002, transient 
thrombocytopenia related to AT132 occurred within the first 2 weeks of dosing (Shieh, 2023).  
Key potential study benefits include the following: 
• Independent of efficacy, study subjects may receive better-coordinated and more comprehensive 
overall clinical care at centers of excellence. 
• AT132, even if only partially effective, could cause clinically important improvements in respiratory 
function and mobility and a lowered risk of disease -related comorbidities, leading to greater 
independence for the subject and caregivers. 
• Other patients may benefit from knowledge gained about XLMTM. 
Subjects randomized to the control delayed treatment arm are not considered to have additional risk 
from receiving treatment at a later date, because AT132 has not yet been shown to be an effective 
treatment for XLMTM. 
Section 4.6 
and Section 
4.6.1 
4.6.  Monitoring for and Management of Cardiac, and Liver, and Neuromuscular Related Safety 
Events 
4.6.1  Monitoring for and Management of Myocarditis 
4.6.1.1 Monitoring for Myocarditis 
Troponin elevations have been observed in the ASPIRO study. Troponin elevations can be an early 
signal of myocarditis, a serious cardiac condition that is critical to promptly diagnose and treat. The 
clinical presentation of myocarditis is variable. Affected patients can present with a broad clinical 
spectrum of signs and symptoms ranging from subclinical disease to cardiogenic shock, arrhythmias, 
and sudden death. A high level of awareness and vigilance for potential myocarditis should be 
maintained in the setting of gene therapy clinical studies.  
The primary monitoring strategy for identifying potential myocarditis will be through frequent, scheduled 
(surveillance) testing of high sensitivity Troponin T and/or I parameters. Additional monitoring that may 
identify potential myocarditis will include scheduled CK (with isoenzymes) laboratory testing as well as 
scheduled procedures such as electrocardiogram (ECG) and echocardiogram (ECHO). The frequency 
of these assessments is outlined in the Schedule of Events (Sections 5.4, 5.5, 5.6, and 5.7).  
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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Description of Change 
Rationale for 
Change 
Justification for 
Substantial 
Designation 
Site Investigators are responsible for prompt review of all laboratory or procedural results related to 
cardiac monitoring. Interpretation of abnormal test results is complex as it relates to identifying signals 
for potential myocarditis. Given that this interpretation is critical to subject safety, sites will identify and 
establish a site pediatric cardiologist preferably with expertise/experience in the diagnosis and 
treatment of myocarditis. The site pediatric cardiologist will assist the study site, as well as other 
clinicians who manage study subjects (eg, if the subject lives remote from the site), with interpretation 
of abnormal cardiac test results indicative of potential myocarditis. Details related to the monitoring, 
diagnosis, and treatment of myocarditis are described herein. 
Site Investigators are responsible for prompt review of all laboratory or procedural results. Due to the 
importance of accurate diagnosis and management of myocarditis for subject safety, sites must identify 
and establish a site pediatric cardiologist experienced in the treatment of myocarditis. The site pediatric 
cardiologist will assist the study site and any managing physician responsible for patient care with 
interpretation of abnormal cardiac test results and treatment. A high level of awareness and vigilance 
for potential myocarditis should be maintained in the setting of gene therapy clinical studies. 
The primary monitoring strategy for identifying potential myocarditis will be by clinical assessment and 
scheduled (surveillance) high-sensitivity Troponin T and/or Troponin I testing. Troponin elevations can 
be an early signal of myocarditis, a serious cardiac condition that is critical to promptly diagnose and 
treat. The frequency of assessments is outlined in the Schedule of Events (Sections 5.4, 5.5, 5.6, and 
5.7). Additional assessments may be performed at the discretion of the investigator and pediatric 
cardiologist as outlined in Section 4.6.1.3. 
Section 
4.6.1.1 
4.6.1.12 Clinical Role of the Site Pediatric Cardiologist 
The site pediatric cardiologist will serve as the: 
… 
As a member of the study site medical team, the site pediatric cardiologist will work together with the 
Investigator to assist with diagnosis, of abnormal surveillance results, and if indicated, additional 
diagnostic workup interpretation of cardiac testing, and treatment. In the case where the site pediatric 
cardiologist does not have direct access to the subject and no local cardiologist is available, the site 
pediatric cardiologist will provide guidance to the managing physician treating clinician to ensure 
subject safety. In all cases, the clinician that is providing direct patient care is ultimately responsible 
and the decision maker for the management and treatment of the subject. 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 
Section 
4.6.1.2 
4.6.1.2 Monitoring for Potential Myocarditis 
A combination of cardiac laboratory tests and cardiac procedures will be used to monitor for cases of 
potential myocarditis after treatment with AT132. The following notification and consultative parameters 
are provided to assist Investigators, and/or other clinicians caring for ASPIRO subjects, to identify 
clinically significant abnormalities during routine cardiac monitoring. All laboratory reference ranges are 
per the reporting of the local or central laboratory, as applicable. 
Routine Troponin Surveillance 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
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• Investigators will consult the site pediatric cardiologist for any Troponin T or I value that meets either 
of the following criteria:  
 
Above the ULN if a reference range is reported  
 
Any non zero value if no ULN is reported or if the result indicates that the upper limit reflects 
myocardial ischemia (thus not informative for myocarditis monitoring); if this is not clear, the 
Investigator will contact the site pediatric cardiologist to discuss the case 
Other Routine Cardiac Surveillance 
• Investigators will consult the site pediatric cardiologist in the following scenarios:  
 
For any clinically significant abnormal ECHO or ECG 
 
For any elevated routine CK MB that is considered clinically significant by the Investigator 
Abnormal Cardiac Laboratory or Procedural Results not Associated with Routine Cardiac Surveillance 
per the Protocol Schedule of Events 
• The approach for identifying potential myocarditis in this setting may be more complex (eg, the 
subject is hospitalized)  
• The Investigator should consult with the site pediatric cardiologist and notify the Medical Monitor to 
determine an appropriate follow-up plan based on the clinical circumstance 
Communication Guidelines 
• Details and discussions around the monitoring, diagnostic (Section 4.6.1.3), and treatment activities 
(Section 4.6.1.4) of a subject that include the site pediatric cardiologist are required to be 
documented  
4.6.1.3 Diagnosis and Management of Myocarditis or Asymptomatic Troponin Elevations 
Clinical assessment, laboratory testing, and cardiac imaging can be used to detect myocarditis 
associated with AT132 administration. Documentation is required for data and discussions related to 
diagnosis and treatment. The Investigator for the study is responsible for all study-related medical 
decisions. 
Routine Myocarditis Surveillance 
• Troponin I and/or Troponin T will be assessed at scheduled visits. Investigators will consult the site 
pediatric cardiologist when Troponin T and/or Troponin I are above the ULN for the laboratory 
reference range. All laboratory reference ranges are per the reporting of the local or central 
laboratory, as applicable. 
Additional Testing for Myocarditis Diagnosis and Management  
Test selection is performed at the discretion of the investigator in conjunction with consultation with the 
site pediatric cardiologist. Key testing that may assist in diagnosis and management of myocarditis 
includes but is not limited to: 
• Laboratory testing: A variety of laboratory testing can be useful in the diagnosis and management of 
myocarditis, including but not limited to complete blood count and differential, complete metabolic 

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panel, troponin I and/or troponin T, N-terminal pro b-type natriuretic peptide, sedimentation rate, C-
reactive protein, infectious assessments (eg, nasopharyngeal and rectal swabs, viral titers), CK with 
isoenzymes to identify elevations in the myocardial isoenzyme (CK-MB), and  interferon gamma 
(IFN-γ) enzyme-linked immunosorbent spot assay (IFN-γ ELISpot) for MTM1 peptide pool and AAV8 
peptide pool. Anti-MTM1 antibodies are optional.   
• ECG 
• Transthoracic ECHO  
• Cardiac MRI 
• Cardiac catheterization with endomyocardial biopsy (in exceptional cases) 
Section 
4.6.1.4 
4.6.1.4  Classification and Management of Suspected Myocarditis 
Classification and management of subjects in the setting of confirmed myocarditis, or where a high 
probability of myocarditis is suspected, will depend on the interpretation of all available clinical data by 
the treating physician in consultation with the site pediatric cardiologist. Table 1 outlines high level DMC 
treatment recommendations on the basis of severity. Initiation or alteration of immunosuppressive 
treatments (including prophylactic prednisolone) as a result of myocarditis will be implemented by the 
treating clinician in consultation with the site pediatric cardiologist (and the Investigator and the Medical 
Monitor, when appropriate).  
In the unlikely event a subject presents with or develops severe myocarditis (as described in Table 1), 
transfer to a tertiary referral hospital is warranted for institutions without advanced heart failure surgical 
and medical management capabilities, including expertise in myocarditis management. 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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Table 1: DMC Recommendations for Management of Myocarditis Events 
Severity 
Criteria 
Management 
Mild 
Symptoms of chest pain; elevation of heart rate 
above expected by 20 bpm or less; ST segment 
changes on surface ECG; elevations of troponin; 
atrial or ventricular ectopy including single beats or 
couplets; or any combination of these findings, in the 
absence of any findings suggesting more serious 
forms of myocarditis. Clinical impression must 
support diagnosis of myocarditis as likely etiology of 
findings. 
Methylprednisolone IV 
10 mg/kg/day for 5 days. 
Continue with prednisolone PO 
1-2 mg/kg until resolution of 
myocarditis symptoms/signs. 
Moderate 
Elevation of heart rate by more than 20 bpm above 
expected; evidence of hypotension requiring support 
with either volume infusion or a single inotropic agent; 
atrial or ventricular tachycardia that is 
hemodynamically tolerated and self terminating; 
mildly or moderately reduced ejection fraction of left 
ventricle as measured by any imaging technique; new 
onset pericardial effusion other than trivial in size; or 
any combination of these findings, in the absence of 
any findings suggesting more serious forms of 
myocarditis. Clinical impression must support 
diagnosis of myocarditis as likely etiology of findings. 
Methylprednisolone IV 
10 mg/kg/day for 5 days, plus 
tacrolimus at an initial starting dose 
of 0.1 mg/kg/day PO, divided BID. 
Target trough level: 10 12 ng/mL 
until resolution of myocarditis 
symptoms/signs. 
Severe 
Hemodynamic instability requiring treatment with 
multiple infusions of volume or more than a single 
inotropic agent; severely reduced ejection fraction of 
left ventricle as measured by any imaging technique; 
atrial or ventricular tachycardia requiring either 
pharmacologic management or cardioversion; end
organ injury due to circulatory insufficiency or any 
combination of these findings. Clinical impression 
must support diagnosis of myocarditis as likely 
etiology of findings. 
Methylprednisolone IV 
10 mg/kg/day and rATG (eg, 
thymoglobulin) 1.5 mg/kg/dose, for 
3 doses as needed to a maximum 
of 5 doses as deemed clinically 
appropriate. 
Monitor the absolute CD3 count 
during this process and aim to 
reduce the count to < 20 cells/L. 
BID = twice daily; bpm = beats per minute; DMC = Data Monitoring Committee; ECG = electrocardiogram; 
IV = intravenous; PO = per os (by mouth). 
 
 
Section 4.6.2 
4.6.2  Monitoring for and Management of Hepatobiliary Toxicity 
Hepatobiliary toxicity has been reported with AAV gene therapy treatment (Chan, 2020) and in this 
study (ASPIRO ATX-MTM-002). In ASPIRO Study ATX-MTM-002, AT132-related SAEs involving the 
hepatobiliary system, including intrahepatic cholestasis, have occurred in subjects with XLMTM treated 
at the 1.0 × 1014 vg/kg and 3.0 × 1014 vg/kg dose levels. Subjects will be administered glucocorticoid 
To update the 
monitoring and 
management plan 
for safety events 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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prophylaxis and ursodiol prophylaxis as outlined in Sections 4.4 and 4.5, respectively. Routine 
surveillance and evaluation of any signs or symptoms of hepatobiliary toxicity is an essential safety 
parameter. The primary monitoring strategy for identifying potential hepatobiliary toxicity will be through 
frequent, scheduled testing of the following LFTs: ALT, AST, gamma-glutamyltransferase (GGT), total 
bilirubin (TBL), and direct bilirubin. Additional monitoring will include scheduled liver ultrasound 
procedures and as of protocol v10 serum bile acid levels in order to better understand the long-term 
behavior of intrahepatic cholestasis in XLMTM subjects. The frequency of these assessments is 
outlined in the Schedule of Events (Sections 5.4, 5.5, and 5.6). 
Site Investigators are responsible for prompt review of all laboratory or procedural results related to 
potential hepatobiliary toxicity. To enhance the monitoring and management of potential hepatotoxicity, 
sites will identify a site hepatologist (preferably with expertise in pediatric cholestatic disease). The site 
hepatologist will assist the study site and any managing physician responsible for patient care with 
interpretation of abnormal hepatobiliary test results and treatment. A high level of awareness and 
vigilance for potential hepatobiliary toxicity should be maintained in the setting of gene therapy clinical 
studies. Details related to the monitoring, diagnosis, and treatment of hepatobiliary toxicity are 
described herein. Any laboratory tests and/or procedures performed for these safety events should be 
reported in the eCRF. 
based on the latest 
safety information 
Section 
4.6.2.3 
4.6.2.3  Risk management of Hepatobiliary Toxicity 
… 
• Nasobiliary drainage (NBD) will be initiated in any subject who demonstrates total or direct bilirubin 
levels  5 × ULN (or  3 × the Baseline value if it was > ULN) within the first 16 weeks following 
AT132 administration, unless clinical contraindications are present. Beyond Week 16, strong 
consideration to NBD placement should be given to any subject who develops these laboratory 
abnormalities. If well tolerated, consider maintaining NBD through normalization of total and direct 
bilirubin levels (or return to Baseline Visit values), though duration will be determined on a case by
case basis. Investigators and site hepatologists should consult the Medical Monitor when deciding 
on NBD placement and duration. Associated clinical and laboratory monitoring (including for 
pancreatitis which has been reported with NBD) will be determined on a case by case basis, but 
should include periodic monitoring of biochemical markers of pancreatitis (such as serum lipase and 
amylase levels) as well as hepatic laboratory parameters to assess response to NBD. See 
Section 5.1.1.30 for additional details regarding NBD. 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 
Section 
4.6.3.1 
4.6.3  Monitoring for and Management of Neuromuscular Abnormalities 
4.6.3.1 Monitoring for Neuromuscular Abnormalities 
Acute, subacute, and chronic CK elevations can occur after gene therapy administration. Muscle 
abnormalities vary and can include myositis, which can be asymptomatic or display muscle weakness. 
Neuromuscular abnormalities may manifest as bulbar, motor, and/or respiratory weakness.  
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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Site Investigators are responsible for prompt review of all laboratory or procedural results. Due to the 
importance of accurate diagnosis and management of neuromuscular dysfunction for subject safety, 
consultation with a pediatric pulmonologist is required for potential decline in respiratory function. The 
site pediatric pulmonologist will assist the study site and any managing physician responsible for 
patient care with interpretation of abnormal pulmonary test results and treatment. Due to risks 
associated with worsening bulbar function, a pediatric ear, nose and throat (ENT) specialist and/or 
speech-language pathologists will be consulted if worsening bulbar dysfunction is suspected. 
The primary monitoring strategy for Identifying potential neuromuscular abnormalities will be by clinical 
assessment and scheduled (surveillance) of CK levels in blood. The frequency of these assessments is 
outlined in the Schedule of Events (Sections 5.4, 5.5, 5.6, and 5.7). Additional assessments may be 
performed at the discretion of the investigator and pediatric neuromuscular specialist as outlined in 
Section 4.6.3.2. 
Section 
4.6.3.2 
4.6.3.2 Diagnosis and Management of Neuromuscular Abnormalities 
Clinical assessment, laboratory testing, and muscle imaging can be used to detect neuromuscular 
abnormalities associated with AT132 administration. Documentation is required for data and 
discussions related to diagnosis and treatment. The Investigator for the study is responsible for all 
study-related medical decisions.  
Routine neuromuscular surveillance  
• Physical examination with detailed neurological evaluation and respiratory function assessment 
• CK will be measured at scheduled visits. If the CK is above the ULN for the laboratory reference 
range, the investigator will decide whether additional diagnostic evaluation is needed.  
Additional testing for diagnosis and management of neuromuscular abnormalities  
Test selection is performed at the discretion of the investigator in conjunction with consultation with the 
neuromuscular specialist as needed. Additional consultations with a pediatric ENT specialist, speech-
language pathologist, pediatric pulmonologist, and a pediatric neuromuscular specialist may be 
needed. Key testing that may assist in diagnosis and management of neuromuscular abnormalities 
includes but is not limited to:    
• Laboratory testing: A variety of laboratory testing can be useful in the diagnosis and management of 
neuromuscular abnormalities, including but not limited to complete blood count and differential, 
complete metabolic panel, sedimentation rate, C-reactive protein, infectious assessments (eg, 
nasopharyngeal and rectal swabs, viral titers), CK , CK-isoenzymes for identification of elevations in 
the skeletal muscle isoenzyme (CK-MM) or CK-MB, and IFN-γ ELISpot for MTM1 peptide pool and 
AAV8 peptide pool. Anti-MTM1 antibodies are optional.  
• Electrophysiological assessment (electromyography [EMG]) 
• Skeletal muscle MRI with short tau inversion recovery (STIR) sequence  
• Diagnostic muscle biopsy 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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Section 
5.1.1.10 
5.1.1.10 Cardiac Structure and Function (ECG, and ECHO and Cardiac MRI) 
Unlike mostmany neuromuscular diseases, individuals with XLMTM subjects have no evidence of do 
not exhibit cardiac muscle disease. Mice treated with rAAV8-Des-MTM1 had asymptomatic cardiac 
lesions detected on necropsy (in the presence of gross over expression of myotubularin) (Section 
1.2.1.3). It is unknown whether a risk exists for human subjects. Cardiac structure and function will be 
routinely assessed using 12 lead ECG and ECHOs. The ECHOs should include an assessment of 
pulmonary hypertension as well as structural and functional abnormalities. Particular attention should 
be paid to ECG and ECHO abnormalities specific to myocarditis. Refer to Section 4.6.1 for 
management of ECG and ECHO results and the role of the site pediatric cardiologist. Cardiac MRI may 
be performed at the discretion of the investigator in conjunction with consultation with the site pediatric 
cardiologist. If myocarditis is observed, cardiac catheterization and endomyocardial biopsy may be 
needed in exceptional cases. 
If troponin I and/or troponin T is elevated above the ULN of the laboratory reference range, test 
selection for diagnosis and management of myocarditis or asymptomatic troponin elevation is 
performed at the discretion of the investigator in conjunction with consultation with the site pediatric 
cardiologist. Key testing is discussed below. Refer to Section 4.6.1 for management of ECG, ECHO, 
and Cardiac MRI results and the role of the site pediatric cardiologist.  
• ECG: In patients with suspected myocarditis, the ECG can display a variety of non‑specific 
abnormalities. Interpretation of ECG by the site pediatric cardiologist may be required due to the 
array of ECG changes that can occur with myocarditis.  
• Transthoracic ECHO: ECHO is a safe, widely available, and clinically extremely useful cardiac 
imaging tool, particularly for the initial assessment of myocarditis. The American College of 
Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) 
Working Group on Myocardial and Pericardial Diseases recommend that all patients with clinically 
suspected myocarditis should undergo an ECHO at initial presentation (Adeboye, 2022). 
• Cardiac MRI: Cardiac MRI is considered the non-invasive reference standard for diagnosis of 
myocarditis in the absence of contraindications to MRI. Gadolinium may be used to assess for late 
gadolinium enhancement, a technique used for cardiac tissue characterization due to various types 
of myocardial injury and fibrosis. Cardiac MRI findings change depending on the phase of disease 
and timing of imaging. Myocardial edema is a characteristic early feature of acute myocarditis which 
typically improves over days to weeks and may not be detected if cardiac MRI is performed weeks 
to months after symptom onset. Diagnostic sensitivity is highest within 2 to 4 weeks of symptom 
onset; therefore, cardiac MRI should be performed quickly in patients with suspected myocarditis 
(Urzua Fresno, 2023). 
• Cardiac catheterization with endomyocardial biopsy in exceptional cases: Although the gold 
standard for diagnosis of myocarditis is endomyocardial biopsy, this procedure is usually not 
required for diagnosis and management. Considering this procedure’s invasiveness, low sensitivity 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 

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when myocardial involvement is focal, and a complication rate ranging from 1% to 15%, the 
pediatric cardiologist may consider that the clinical presentation to be of sufficient severity to 
necessitate the procedure, especially in uncommon clinical scenarios such as severe heart failure, 
cardiogenic shock, ventricular arrhythmias, and/or when there is significant diagnostic uncertainty, 
aiming to ensure the requirement of the procedure (Pilati, 2022). 
Section 
5.1.1.11.3 
… The actual number of hours of ventilatory support a subject receives daily will be recorded via the 
electronic ventilator dependence diary or the Ventilator Dependence Questionnaire (Section 
5.1.1.11.2.1). 
… 
Table 21: Required Parameters for Initiation of Ventilator Weaning 
… 
The above parameters are to be assessed by site personnel during the normal routine site visits. 
through Month 42. As of protocol v12, beginning at the Month 48 visit, some parameters (ie, MIP/MEP, 
ETCO2, TCO2) will no longer be collected per protocol and decision making related to initiation of 
ventilator weaning will occur by the site and local pulmonologists in collaboration with the Site 
Investigator, upon review of relevant clinical assessments and in consideration of standard practice in 
ventilator weaning in patients with neuromuscular disease. 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.11.4 
Table 32: Required Ventilator Discontinuation Parameters 
… 
The above parameters are to be assessed by site personnel during the normal routine site visits 
through Month 42. As of protocol v12, beginning at the Month 48 visit, some parameters (ie, MIP/MEP, 
ETCO2, TCO2) will no longer be collected per protocol and decision making related to discontinuation of 
ventilator support will occur by the site and local pulmonologists in collaboration with the Site 
Investigator, upon review of relevant clinical assessments and in consideration of standard practice in 
ventilator discontinuation in patients with neuromuscular disease. 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.11.5 
… Details on assessment of ventilator parameters will be provided in a separate procedure manual. 
The above parameters are to be assessed by site personnel during the normal routine site visits 
through Month 42. As of protocol v12, beginning at the Month 48 visit, the Assessment of Ventilator 
Parameters will no longer be collected per protocol and decision making related to collection and 
analysis of clinical ventilator and respiratory parameters will occur by the site and local pulmonologists 
in collaboration with the Site Investigator. 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.11.5.1 
If a subject has discontinued the use of the ventilator and has 2 assessments with the MIP at 80 
cmH2O, testing for MIP, MEP, and P0.1 will not be required for future visits.  
Respiratory strength and endurance assessments are to be performed by site personnel during the 
normal routine site visits through Month 42. As of protocol v12, beginning at the Month 48 visit, 
respiratory strength and endurance assessments will no longer be collected per protocol and decision 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 

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making related to collection and analysis of respiratory strength, endurance and function assessments 
will occur by the site and local pulmonologists in collaboration with the Site Investigator. 
Section 
5.1.1.12 
… The MFM-32 will be used to assess children ≥ 2 years of age (Section 5.1.1.12.4).  
As of protocol v12, beginning at the Month 48 visit, only the Motor Developmental Milestones 
assessment will be performed. Decision making regarding collecting other assessments of 
neuromuscular function will occur by the Site Investigator, in collaboration with other neuromuscular 
specialists as indicated. 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.14 
5.1.1.14 Speech Assessments  
As of protocol v12, beginning at the Month 48 visit, speech assessments will no longer be performed 
per protocol. Decision making regarding collecting other clinical speech assessments will occur by the 
Site Investigator, in collaboration with other neuromuscular specialists as indicated. 
To streamline the 
efficacy assessment 
in the long-term 
follow-up period 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.23.2 
5.1.1.23.2 Bone Age (Wrist X-ray) (not applicable for Germany) 
X-ray of the left wrist in infants and children to ascertain bone age is a recognized method of assessing 
maturity and development of the skeleton. This is of particular relevance in XLMTM, because advanced 
bone age and a variety of skeletal abnormalities (although not well characterized) have been 
documented in some XLMTM patients (Herman, 1999). The radiation dose for this procedure is low 
(0.001 mSv per X-ray). Subjects in Germany will not have a wrist X-ray.  
As of protocol v12, beginning at the Month 48 visit, bone age will no longer be collected per protocol. 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1. 23.3 
5.1.1.23.3 Tanner Stage  
Tanner stage will be assessed to monitor for premature adrenarche, which has been documented in 
some XLMTM patients. Tanner staging criteria are provided in Appendix 2.  
As of protocol v12, beginning at the Month 48 visit, Tanner stage will no longer be collected per 
protocol. 
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change in study 
design which reduces 
required study 
assessments 
Section 
5.1.1.26 
Muscle biopsies will be used to assess the efficacy and safety of AT132 by analyzing MTM1 protein 
expression, vector copy number quantitation, RNA transcripts assessment, histological characterization 
and histology data. Muscle biopsies may also be used to assess safety measures such as the 
presence of inflammatory markers. 
If a muscle biopsy is performed at the discretion of the investigator for diagnostic purposes, including 
but not limited to CK elevations and declining neuromuscular function (Section 4.6.3.2), testing should 
be performed in accordance with standards of care for diagnostic muscle biopsy assessment. 
When possible after diagnostic muscle biopsy, muscle should be collected and sent to the central lab 
for the AT132-related assessments listed below: 
• MTM1 protein expression 
• Vector copy number quantitation 
• RNA transcript assessment 
To add a 
recommended 
assessment/testing 
for safety events 
based on the latest 
safety information 
Change of medical 
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a significant impact 
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ee Subjects in Germany will not have a wrist X-ray. After the Week 48 visit, wrist X-ray only needs to be performed 
annually thereafter (Month 24, Month 36). As of protocol v12, the wrist X-ray assessment will no longer be 
collected at Month 48 visit onward.  
ff As of protocol v12, these assessments will no longer be collected at Month 48 visit onward. 
Section 5.6 
5.6 
Schedule of Events for Subjects Treated with AT132: Month 72 (Year 6) – Month 120 
(Year 10) (End of Study) 
Study Phase/Visit 
Month 
72 
Month 
84 
Month 
96 
Month 
108 
Month 
120 
… 
… 
… 
… 
… 
… 
Physical Examination a 
X 
X 
X 
X 
X 
Ventilator Dependence Questionnaire ab  
… 
… 
… 
… 
… 
Samples for:  
… 
… 
… 
… 
… 
Safety labs (hematology) (central lab) b,c,d  
… 
… 
… 
… 
… 
Safety labs (chemistry) (central lab) b,c,d,e,f,g 
… 
… 
… 
… 
… 
Comprehensive metabolic profile 
… 
… 
… 
… 
… 
ALT, AST, Total and direct bilirubin, GGT 
 
 
 
 
 
Serum bile acids, total (fasting preferred) 
 
 
 
 
 
PTT and PT/INR 
 
 
 
 
 
Troponin I and T 
 
 
 
 
 
CK 
 
 
 
 
 
Alpha fetoprotein 
 
 
 
 
 
Liver ultrasound (local) ef  
X 
X 
X 
X 
X 
Motor milestone assessments fh 
X 
X 
X 
X 
X 
ACEND  
X 
X 
X 
X 
X 
Clinical global impression scales i 
X 
X 
X 
X 
X 
Swallowing questionnaire 
X 
X 
X 
X 
X 
Secretions management assessment j 
X 
X 
X 
X 
X 
…; CK = creatine kinase; … 
a Complete physical examination with detailed neurological evaluation and respiratory function assessment will be 
conducted. It can be done remotely per discretion of investigator in consultation with Medical Monitor. When visit 
is done remotely, an abbreviated physical examination is acceptable. 
g See Section 4.6.3 for details related to the monitoring, diagnosis, and treatment of neuromuscular abnormalities. 
i 
See Appendix 5. 
j 
The severity of secretions and burden of secretions management will be assessed using the PGIS-S and PGIS-I 
(Appendix 3). The same parent/LAR/caregiver should report throughout the study (whenever possible). 
To update the study 
assessments 
accordingly with 
changes to the 
management plan 
for safety events  
 
To capture 
necessary efficacy 
data in the long-term 
follow-up period 
(Years 6 and 10) 
 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 
 
Change in study 
design which reduces 
required study 
assessments 

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Section 6.5.2 
6.5.2  Management of Potential Immune Responses 
There are potential immune responses that may be considered when administering a gene transfer 
agent. The 2 broad categories are a cell mediated (T cell) response and a humoral (B cell) response.  
B cell responses for a gene therapy vector, such as AT132, might include the development of 
antibodies to the AAV capsid and/or to the resulting protein (myotubularin). Samples will be taken 
during the course of the study to monitor for both neutralizing and binding antibodies to AAV8 capsid 
protein and myotubularin protein.  
If a humoral response to capsid occurs, it would likely not impact the subject unless a poststudy 
situation develops whereby consideration is being given to re dose the subject with AT132 (perhaps 
due to declining efficacy over time, after an initial positive response to treatment). It may be difficult to 
re dose a subject in the context of high levels of circulating AAV8 antibodies.  
Transient, asymptomatic elevations in hepatic transaminases, likely due to T cell mediated 
inflammatory responses, were reported in a study of subjects with hemophilia B (factor IX deficiency) 
infused with a single dose of a gene transfer product using the AAV8 vector (Nathwani, 2014; 
Nathwani, 2011). An asymptomatic, transient increase in the mean ALT level to 86 IU/L (range, 36 202) 
occurred between Weeks 7 and Week 10 in 4 of the 6 subjects treated at the highest dose but resolved 
over a median of 5 days (range, 2 35) after a short course of glucocorticoid therapy (oral prednisolone). 
Such transient, asymptomatic, increases in liver transaminases have been noted in AAV hemophilia A 
(factor VIII deficiency) studies  
(Pasi, 2016) and in the AAV9 studies of SMA (Mendell, 2017). Use of prophylactic glucocorticoids is 
intended to prevent any immune mediated hepatic injury, which has been observed in subjects who 
have received systemic AAV gene therapy (Section 4.4).  
Elevations of hepatic transaminases, CK, and troponin I, likely representing an immune response to the 
study treatment, have been reported in the ASPIRO study Study ATX-MTM-002 and are considered 
identified risks associated with AT132 administration. Refer to the Investigator’s Brochure for details. 
Guidelines for monitoring and management of such events are provided in Section 4.6. Appropriate 
care for an individual subject will be determined by the Investigator based on an assessment of the 
subject’s overall medical status. Corticosteroid treatment typically resolves the elevation of liver 
transaminases. However, when adverse events related to the immune response are of significant 
concern (eg, rAAV vector dose 1 x 1014 vg/kg and/or a transgene-mediated immune response), 
immunomodulation may include medications such as rapamycin (sirolimus), mycophenolate mofetil, 
calcineurin inhibitors (eg, cyclosporine, tacrolimus), and rituximab (Prasad, 2022).  
To update the 
monitoring and 
management plan 
for safety events 
based on the latest 
safety information 
Change of medical 
monitoring procedure 
which is likely to have 
a significant impact 
on the safety 
 
 

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Nonsubstantial Changes 
In addition to the changes detailed in this list below, other non-substantive changes, including change of the Sponsor name and logo, 
change of “Audentes” to “Sponsor”, correction of typographical errors, grammar, abbreviations, and formatting were made, but are not 
delineated here. Deleted text is denoted with strikethrough font and added text is underlined. When needed, “…” indicates a skipped 
sentence or paragraph. 
Location(s) 
Description of Change 
Brief Rationale 
COVER 
PAGE 
Sponsor:   Audentes Therapeutics, Inc., an Astellas Company 
San Francisco, CA 94108 
Astellas Gene Therapies, Inc. 
South San Francisco, CA 94080 
EudraU CT Number:  2017 000876 27 2024-512637-32 
Administrative change  
COVER 
PAGE 
Investigational Product: AT132 (resamirigene bilparvovec) 
Administrative change 
PROTOCOL
SYNOPSIS 
NAME OF TEST PRODUCT: AT132 (resamirigene bilparvovec) 
Administrative change 
PROTOCOL
SYNOPSIS 
STUDY RATIONALE: 
…. Following a single systemic therapeutic administration. In the absence of progressive pathology in 
XLMTM, Gene therapy is … 
Administrative change for accuracy 
PROTOCOL
SYNOPSIS 
and Section 2 
and Section 
7.4.2.2.2 
ENDPOINTS, SAFETY ASSESSMENTS, AND ESTIMANDS:  
Safety Endpoints:  
• Adverse events (AEs), serious AEs (SAEs), and findings from safety laboratory tests, 12 lead 
electrocardiogram (ECG), echocardiograms (ECHOs), vital signs, growth parameters, physical 
examinations, liver ultrasounds, antibody formation (anti AAV8, anti MTM1), viral shedding, 
annualized hospitalization rate, annualized respiratory and non respiratory SAE rate, and length of 
stay per hospitalization 
Key Secondary Efficacy Endpoint:  
… 
Other Secondary Efficacy Endpoints:  
… 
Safety Endpoints:  
• Adverse events (AEs), serious AEs (SAEs), and findings from safety laboratory tests, 12-lead 
electrocardiogram (ECG), echocardiograms (ECHOs), vital signs, growth parameters, physical 
examinations, liver ultrasounds, antibody formation (anti-AAV8, anti-MTM1), viral shedding, 
annualized hospitalization rate, annualized respiratory and non-respiratory SAE rate, and length of 
stay per hospitalization 
Administrative change for clarity 
 

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Location(s) 
Description of Change 
Brief Rationale 
PROTOCOL
SYNOPSIS 
and Section 2  
and Section 
7.4.2.2.2 
ENDPOINTS, SAFETY ASSESSMENTS, AND ESTIMANDS:  
… 
Other Secondary Efficacy Endpoints:  
… 
• Percentage of subjects achieving full ventilator independence in the absence of acute illness and 
perioperatively at Week 24 
• Survival 
… 
 
Exploratory Endpoints: 
… 
In depth interviews to assess the experiences and perspectives of caregivers and children with XLMTM  
To update the endpoints based on nature and 
limitations of the collected data 
PROTOCOL
SYNOPSIS 
STUDY DESIGN:  
… 
The study consists of 2 parts. Part 1 would establish the optimal dose of AT132. Part 2 would confirm 
the safety and efficacy of AT132 at the optimal dose level. The following describes how each part was 
designed and the changes as of protocol v8 and beyond. 
Administrative change for consistency 
PROTOCOL
SYNOPSIS 
See Figure 1 for the individual study participation timeline (Parts 1 & 2) through Week 48. 
Summary of Individual Study Participation Timeline (Parts 1 & 2)  
Part 2 (described herein as planned prior to protocol v8; partially dosed as of protocol v8):  
… 
Administrative change to remove an extra 
heading 

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Location(s) 
Description of Change 
Brief Rationale 
LIST OF 
ABBREVI-
ATIONS/ 
DEFINITION 
OF TERMS 
 
ACTIVE 
abilities captured through interactive video evaluation 
AD 
Analytical Development 
ADL 
activities of daily living 
CMH 
Cochran Mantel Haenszel 
ELIsSpot 
enzyme-linked immunosorbent spot assay 
EMG 
electrophysiological assessments 
ENT 
ear, nose and throat 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
NBD 
nasobiliary drainage 
SAF 
safety analysis set 
SD 
summarized by N, Mean 
STIR 
short tau inversion recovery 
TMA 
thrombotic microangiopathy 
US 
United States 
 
Administrative change  
Section 1.1 
1.1  Background 
… 
Additionally, the recently published literature (Dowling, 2022) based on the data from Study ATX-MTM-
009 (INCEPTUS, a prospective natural history study conducted by the Sponsor) suggested that 
hepatobiliary disease was identified as an under-recognized comorbidity, where 91% of subjects had 
histories of hepatic disease and/or prospectively experienced related adverse events (AEs) or 
laboratory or imaging abnormalities. 
… 
The more recent case series and reports (Molera, 2022; D'Amico, 20221; Neese, 2021) offered 
additional insight into key clinical characteristics of intrahepatic cholestasis and liver dysfunction in 
XLMTM patients. 
Administrative change 
Section 1.3 
1.2  Study Rationale 
… 
In the absence of progressive pathology in XLMTM, gGene therapy is expected to provide persistent 
protein expression, corresponding long-term clinical benefit, and the potential for substantial recovery 
of muscle function 
Administrative change for accuracy 

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Location(s) 
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Brief Rationale 
Section 3.7 
3.7  Start and End of Study Definitions 
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the date the first participant signs the informed consent form (ICF) and will 
be the study start date. 
End of study 
The end of the study is defined as the last visit or assessment shown in schedule of assessments 
(Section 5.6) for the last participant in the study. A participant is considered to have completed the 
study if the participant has completed all periods of the study including the last assessment shown in 
the schedule of assessments. 
To clarify the definition of start and end dates 
(no change to the definition itself)  
Section 4.4 
4.4  Prophylaxis with Glucocorticoids 
… 
Therefore, providing a modest dose [consistent with that used for a number of conditions, see USPI 
(Prednisolone USPI, 2013) the respective local prescribing information] of a short course of oral 
prednisolone is considered appropriate and an acceptable risk. 
Administrative change 
Section 4.5 
4.4  Prophylaxis with Ursodiol 
… 
Ursodiol is generally well-tolerated and minimal side effects, most gastrointestinal in nature, have been 
described (Ursodiol USPI, 2013 see the respective local prescribing information). 
Administrative change 
Section 
5.1.1.11.2.2  
5.1.1.11.2.2 Ventilator Dependence Questionnaire 
… 
For subjects in Part 1 who have already completed the Week 24 visit, the parent/LAR/caregiver will 
complete the ventilator dependence questionnaire at clinic and contact visits through Month 60120. 
For subjects in Part 1 who have not completed the Week 24 visit and for subjects in Part 2 (including 
any subjects enrolled under protocol v5 and beyond), the daily diary will be completed per Section 
5.1.1.11.2.1. After the daily diary has been stopped or the subject has completed Week 48, the 
parent/LAR/caregiver will complete the ventilator dependence questionnaire at clinic and contact visits 
through Month 60120. 
Administrative changes for correction 
Section 
5.1.1.21 
5.1.1.21 Interferon-γ (IFN-γ) ELISpot Assay 
Interferon-γ (IFN-γ) production is commonly used as an indicator of T cell immune reactivity. An 
ELISpot assay will assess the measure IFN-γ response of producing T cells in subjects’ peripheral 
blood mononuclear cells (PBMCs) when challenged after challenge with a pool of AAV8 peptides and 
or myotubularin peptides. Samples for testing will be collected per the Schedule of Events in Sections 
5.4 and 5.5. Additional samples will be collected as clinically indicated, as described in Section 4.6.2.3. 
Administrative change for clarity 
Section 5.8 
5.8  Unscheduled Visits 
Additional assessments and optional assessments conducted as part of the study should be recorded 
on the unscheduled visit eCRFs. 
Administrative change for clarity 

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Location(s) 
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Brief Rationale 
Section 
6.2.3.3 
6.2.3.3 Urgent Safety Measures and Non-Suspected Unexpected Serious Adverse Reaction 
Reporting 
… The reporting collection period for urgent safety issues is the period from the signing of the ICF until 
the Year 10 Visit or the subject withdraws from the study. 
Administrative change for clarity 
Section 6.5.3 
6.5.3  Potential Cases of Drug-Induced Liver Injury 
… 
Any subject enrolled in a study reveals an increase of AT to > 3 × ULN (to > 5 × ULN in subjects with 
liver metastases) or TBL > 2 × ULN should undergo detailed testing for liver enzymes (including at least 
alkaline phosphatase, ALT, AST and TBL). Testing should be repeated within 72 hours of notification of 
the test results. For studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the Investigator and study team. 
Subjects should be asked if they have any further evaluated for additional symptoms suggestive of 
hepatobiliary dysfunction. 
To align with the current procedure for liver 
enzyme testing 
Section 
7.4.2.2.2 
7.4.2.2.2 Other Secondary Efficacy Endpoints 
… 
The number and percentage of subjects attaining age-appropriate clinically relevant gross motor 
function milestones through Week 24, and subjects achieving full ventilator independence in the 
absence of acute illness and perioperatively at Week 24, will be summarized for low dose and high 
dose. 
Administrative change 
Section 8.1 
8.1  Ethical Conduct of the Study 
… 
This study will be conducted in accordance with the following: 
• United States (US) CFR sections that address clinical research studies 
• European Union (EU) Directive 2001/20/EC and EU Clinical Trial Regulation 536/2014its updates 
Administrative changes to reflect the 
regulation changes 
Section 10 
10  REFERENCES 
Adeboye A, Alkhatib D, Butt A, et al. A review of the role of imaging modalities in the evaluation of viral 
myocarditis with a special focus on COVID-19-related myocarditis. Diagnostics (Basel). 
2022;12(2):549. 
Appleby VJ, Hutchinson JM and Davies MH. Safety and efficacy of long term nasobiliary drainage to 
treat intractable pruritus in cholestatic liver disease. Frontline Gastroenterol. 2015;6(4):252 4. 
Arjomandnejad M, Dasgupta I, Flotte TR, et al. Immunogenicity of recombinant adeno-associated virus 
(AAV) vectors for gene transfer. BioDrugs. 2023;37(3):311-29. 
D’Amico A, Longo A, Fattori F, et al. Correction to: Hepatobiliary disease in xlmtmXLMTM: Aa common 
comorbidity with potential impact on treatment strategies (with correction). Orphanet J Rare Dis. 
20212022;17(1):18. Erratum for: Orphanet J Rare Dis. 2021;16(1):425. 
FDA. Toxicity Risks of Adeno-associated Virus (AAV) Vectors for Gene Therapy (GT). FDA Cellular, 
Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting #70. 2021. Available from: 
https://www.fda.gov/media/151969/download. 
Administrative changes to reflect more recent 
citations. 

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Brief Rationale 
Hegade VS, Krawczyk M, Kremer AE, et al. The safety and efficacy of nasobiliary drainage in the 
treatment of refractory cholestatic pruritus: A multicentre european study. Aliment Pharmacol Ther. 
2016;43(2):294 302. 
Jannone G, Stephenne X, Scheers I, et al. Nasobiliary drainage prior to surgical biliary diversion in 
progressive familial intrahepatic cholestasis type ii. Eur J Pediatr. 2020;179(10):1547 52. 
Lek A, Atas E, Hesterlee SE, et al. Meeting Report: 2022 Muscular Dystrophy Association summit on 
'safety and challenges in gene transfer therapy’. J Neuromuscul Dis. 2023;10:327-36. 
Mendell JR, Al Zaidy S, Shell R, et al. Single dose gene replacement therapy for spinal muscular 
atrophy. N Engl J Med. 2017;377(18):1713 22. 
Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor ix gene therapy 
in hemophilia b. N Engl J Med. 2014;371(21):1994 2004. 
Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus associated virus vector mediated gene 
transfer in hemophilia b. N Engl J Med. 2011;365(25):2357 65. 
Pasi J, Wong W, Rangarajan S, et al. Interim results of an open label, phase 1/2 study of bmn 270, an 
aav5-fviii gene transfer in severe hemophilia a. Haemophilia. 2016(22 (Suppl. 4)):151. 
Pilati M, Rebonato M, Formigari R, et al. Endomyocardial biopsy in pediatric myocarditis and dilated 
cardiomyopathy: a tool in search for a role. J Cardiovasc Dev Dis. 2022;9(1):24.  
Prasad S, Dimmock DP, Greenberg B, et al. Immune responses and immunosuppressive strategies for 
adeno-associated virus-based gene therapy for treatment of central nervous system disorders: current 
knowledge and approaches. Hum Gene Ther. 2022;33(23-24):1228-45. 
Prednisolone USPI. Pediapred (prednisolone sodium phosphate) oral solution [united states package 
insert]. Manasquan, NJ: Royal Pharmaceuticals; 2013. 
Shen W, Liu S and Ou L. rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-
analysis. Front Immunol. 2022;13:1001263. 
Shieh PB, Bönnemann CG, Müller-Felber W, et al. Re:“Moving forward after two deaths in a 
genetherapy trial of myotubular myopathy” by Wilson and Flotte. Hum Gene Ther. 2020;31:787. 
Shieh PB, Kuntz NL, Dowling JJ, et al. Safety and efficacy of gene replacement therapy for X-linked 
myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. Lancet Neurol. 2023 
Dec;22(12):1125-39. 
Spark Therapeutics. Spark therapeutics and pfizer present updated preliminary data from hemophilia b 
phase 1/2 trial suggesting consistent and sustained levels of factor ix activity at annual ash meeting 
[press release]. 2016 
Stapelbroek JM, van Erpecum KJ, Klomp LWJ, et al. Nasobiliary drainage induces long lasting 
remission in benign recurrent intrahepatic cholestasis. Hepatology. 2006;43(1):51 3. 
Sun B, Yu D, Chen J, Tang Y and Wu H. Endoscopic biliary drainage management for children with 
serious cholangitis caused by congenital biliary dilatation. Pediatr Surg Int. 2018;34(8):897 901. 
Ursodiol USPI. Ursodiol (ursodeoxycholic acid) [united states prescribing information]. Bridgewater, NJ: 
Aptalis Pharma US, Inc.; 2013. 

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Brief Rationale 
Urzua Fresno C, Sanchez Tijmes F, Shaw KE, et al. Cardiac imaging in myocarditis: current evidence 
and future directions. Can Assoc Radiol J. 2023 Feb;74(1):147-59. 
Whiteley LO. An Overview of nonclinical and clinical liver toxicity associated with AAV gene therapy. 
Toxicol Pathol. 2023:1926233231201408. 
Zellos A, Lykopoulou L, Polydorou A, et al. Nasobiliary drainage in an episode of intrahepatic 
cholestasis in a child with mild abcb11 disease. J Pediatr Gastroenterol Nutr. 2012;55(1):88 90. 
Section 11 
I confirm that Audentes Therapeutics, Inc. will comply with all obligations as detailed in all applicable 
regulations and guidelines. I will ensure that the Investigators and subjects/parents/legal guardians are 
informed of important information that becomes available during the conduct of this study. 
 
 
 
 
  
Date 
 
 
 
 
 
 
Date 
 
 
Required sponsor signatures as required by ICH GCP 4.5.1 are located in the first attachment. 
Attachment 1 
Electronic Sponsor Signatures 
Administrative change 
 
 
PPD
PPD
PPD
PPD