Clinical trial NCT03729362
Conditions: Pompe Disease (Late-onset)
Keywords: Pompe rhGAA
Sponsor: Amicus Therapeutics
Start date: 2018-12-04; Completion date: 2021-01-15
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3 double-blind randomized study to study the efficacy and safety of intravenous ATB200 Co-administered with oral AT2221 in adult subjects with Late Onset Pompe Disease compared with Alglucosidase Alfa/placebo.

Detailed description:
This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult subjects with late-onset Pompe disease (LOPD) who have received enzyme replacement therapy with alglucosidase alfa (ie, ERT-experienced) or who have never received ERT (ie, ERT naïve) compared with alglucosidase alfa/placebo.

The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 30 day safety follow-up period. Subjects who complete this study will have the option to participate in an open label extension study to receive ATB200/AT2221 under a separate protocol.

Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during the screening period; treatment with alglucosidase alfa will then be replaced by study drug (ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption (ie, every 2 weeks).

Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical laboratory tests) for initial safety monitoring will be performed at these visits for the first 6 weeks of the study. Study visits that include efficacy, safety, and other assessments will be scheduled approximately every 3 months and may occur over 2 days, provided all study assessments and procedures (with the exception of pharmacokinetic \[PK\] sample collection) are performed before administration of study drug.

Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function (6MWT), motor function tests (Gait, Stair, Gowers' maneuver, and Chair \[GSGC\] test and Timed Up and Go \[TUG\] test), muscle strength (manual muscle testing and quantitative muscle testing), and pulmonary function tests (forced vital capacity \[FVC\], slow vital capacity \[SVC\], maximal inspiratory pressure \[MIP\], maximal expiratory pressure \[MEP\], and sniff nasal inspiratory pressure \[SNIP\]). Patient reported outcomes (Rasch-built Pompe-specific Activity \[R PAct\] Scale, EuroQol 5 Dimensions 5 Levels Instrument \[EQ-5D-5L\], Patient-Reported Outcomes Measurement Information System \[PROMIS®\] instruments for physical function, fatigue, dyspnea, and upper extremity, and Subject's Global Impression of Change). The Physician's Global Impression of Change will also be performed.

Pharmacodynamic assessments include measurement of biomarkers of muscle injury (creatine kinase \[CK\]) and disease substrate (urinary hexose tetrasaccharide \[Hex4\]). Blood samples will be collected for determination of total GAA protein levels and AT2221 concentrations in plasma for a population PK analysis. Safety assessments include monitoring of adverse events (AEs), including infusion associated reactions (IARs), clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs, physical examinations including weight, electrocardiograms (ECGs), and immunogenicity. Concomitant medications and nondrug therapies will also be recorded.

Arms: arm 1: Participants received cipaglucosidase alfa co-administered with miglustat every 2 weeks (Q2W). arm 2: Participants received alglucosidase alfa co-administered with placebo Q2W.
Interventions: intervention 1: Cipaglucosidase Alfa intervention 2: Miglustat intervention 3: Alglucosidase Alfa intervention 4: Placebo
Intervention descriptions: intervention 1: Participants received an intravenous (IV) infusion dose over a 4-hour duration every 2 weeks (Q2W). intervention 2: Participants received weight-based doses 1 hour prior to cipaglucosidase alfa infusion Q2W. intervention 3: Participants received an IV infusion dose over a 4-hour duration Q2W. intervention 4: Miglustat matching placebo was administered orally 1 hour prior to alglucosidase alfa infusion Q2W.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 3 Double-blind Randomized Study to 
Assess the Efficacy and Safety of Intravenous 
ATB200 Co-administered With Oral AT2221 in 
Adult Subjects With Late-Onset Pompe Disease 
Compared With Alglucosidase Alfa/Placebo  
 
 
NCT Number: 
NCT03729362 
 
 
Document Date: 
Amendment 3: 14 August 2020 
 
 
 
 
 


1.
TITLE PAGE
CLINICAL STUDY PROTOCOL 
A PHASE 3 DOUBLE-BLIND RANDOMIZED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF INTRAVENOUS 
ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT 
SUBJECTS WITH LATE-ONSET POMPE DISEASE 
COMPARED WITH ALGLUCOSIDASE ALFA/PLACEBO  
Protocol Number: ATB200-03 
Original Protocol: 19 March 2018 
Amendment 1: 21 September 2018 
Amendment 2: 25 January 2019 
Amendment 3: 14 August 2020 
EudraCT Number: 2018-000755-40 
US IND Number: 127,387 
Compounds: ATB200 and AT2221 
Sponsor 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ  
08512, USA 
Phone: +1-609-662-2000 
The information in this document is the property of Amicus Therapeutics, Inc. (Amicus) and is 
strictly confidential. Neither the document nor the information contained herein may be 
reproduced or disclosed outside of Amicus without the prior written consent of the company. 


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Protocol ATB200-03 Amendment 3 
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Table 1: 
Serious Adverse Event Contact Information 
Role 
Contact Information 
Reporting of serious adverse events 
Safety FAX number: +1-866-693-2307 
Email address: 
blindedsafetyreporting@amicusrx.com 


Amicus Therapeutics, Inc. 
Protocol A TB200-03 Amendment 3 
2.
DECLARATIONS OF SPONSOR AND INVESTIGATOR
2.1. 
Declaration of Sponsor
This clinical study protocol is subject to critical review and has been approved by Amicus 
Therapeutics, Inc. 
The information it contains is consistent with the following: 
•
the current benefit-risk evaluation of ATB200 (recombinant human acid
a-glucosidase) co-administered with AT2221 (N-butyl-deoxynojirimycin)
•
the safety information of alglucosidase alfa
•
the moral, ethical, and scientific principles governing clinical research, as set out in
the current version of Declaration of Helsinki and the principles of Good Clinical
Practice (GCP) described in the United States (US) Code of Federal Regulations
(CFR) Parts 50, 54, 56, and 312 and in the International Council on Harmonisation
(ICH) GCP E6 guidelines
The investigator will be supplied with details of any significant or new findings related to 
treatment with ATB200 co-administered with AT2221. 
Signature: 
2.2. 
Declaration of Investigator 
Amicus Therapeutics, Inc. 
I confirm that I have read this clinical study protocol. I understand it, and I will work according 
to the moral, ethical, and scientific principles governing clinical research, as set out in the 
Declaration of Helsinki and the principles of GCP described in the US CFR Parts 50, 54, 56, and 
312 and in the ICH GCP E6 guidelines. I will also work in accordance with applicable local 
requirements. 
Date: 
Signature: 
Printed Name: 
Page 3 of 102
Amicus


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3.
PROTOCOL SYNOPSIS
Name of Sponsor/Company: 
Amicus Therapeutics, Inc. (Amicus) 
Name of Investigational Products: ATB200 and AT2221 
Name of Active Ingredients:  
ATB200: Recombinant human acid α-glucosidase (rhGAA) 
AT2221: N-butyl-deoxynojirimycin 
ATB200/AT2221: ATB200 co-administered with AT2221 
Title of Study: A Phase 3 Double-blind Randomized Study to Assess the Efficacy and Safety of 
Intravenous ATB200 Co-administered With Oral AT2221 in Adult Subjects With Late-Onset Pompe 
Disease Compared With Alglucosidase Alfa/Placebo  
Study Sites: Up to approximately 90 sites globally 
Phase of Development: 3 
Objectives: 
Primary 
•
To assess the efficacy of ATB200/AT2221 co-administration on ambulatory function, as
measured by the 6-Minute Walk Test (6MWT), compared with alglucosidase alfa/placebo
Secondary 
•
To assess the efficacy of ATB200/AT2221 co-administration on pulmonary function, as
measured by sitting forced vital capacity (FVC) (% predicted), compared with
alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on muscle strength,
compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on health-related
patient-reported outcomes, compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on motor function, compared
with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on overall clinical
impression as assessed by both physician and subject, compared with alglucosidase
alfa/placebo
•
To assess the safety, tolerability, and immunogenicity of ATB200/AT2221
co-administration compared with alglucosidase alfa/placebo
•
To assess the effect of ATB200/AT2221 co-administration on biomarkers of muscle injury
and disease substrate compared with alglucosidase alfa/placebo


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Protocol ATB200-03 Amendment 3 
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•
To characterize the population pharmacokinetics of ATB200 and alglucosidase alfa in
enzyme replacement therapy (ERT)-experienced subjects using plasma total acid
α-glucosidase (GAA) protein level by signature peptide assay and plasma AT2221
concentration
•
To characterize the pharmacokinetics of ATB200, alglucosidase alfa, and AT2221 in
ERT-naïve subjects using noncompartmental analysis
•
To explore the exposure-response relationship for ATB200/AT2221 and alglucosidase
alfa/placebo co-administration
Methodology: 
This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult 
subjects with late-onset Pompe disease (LOPD) who have received enzyme replacement therapy with 
alglucosidase alfa (ie, ERT-experienced) or who have never received ERT (ie, ERT-naïve) compared 
with alglucosidase alfa/placebo. As this study was initially designed to assess the effects of 
ATB200/AT2221 in ERT-experienced subjects who continued to receive alglucosidase alfa in 
Study POM-003, subjects from that study who meet the eligibility criteria for this study will make up 
part of the ERT-experienced study population. 
The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 30-day 
safety follow-up period. Subjects who missed visits due to SARS-CoV-2 (COVID-19) related 
quarantines, travel restrictions, and risk of infection may be enrolled longer than 12 months in the 
study. Subjects who complete this study will have the option to participate in an open-label extension 
study to receive ATB200/AT2221 under a separate protocol. 
Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during the 
screening period; treatment with alglucosidase alfa will then be replaced by study drug 
(ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption (ie, every 
2 weeks). The Screening Visit will occur over 2 or more days to allow for repeated 6MWT and 
pulmonary function test assessments. The repeated tests for 6MWT or for pulmonary function (FVC, 
slow vital capacity [SVC], maximal inspiratory pressure [MIP], maximal expiratory pressure [MEP], 
and sniff nasal inspiratory pressure [SNIP]) should not be done on the same day. No other assessments 
should be performed on the day that the 6MWT and pulmonary function tests are repeated. Eligible 
subjects will be randomly assigned in a 2:1 ratio to receive ATB200/AT2221 or alglucosidase 
alfa/placebo and stratified by ERT status (ERT-experienced, ERT-naïve) and baseline 6-minute walk 
distance (6MWD) (75 to < 150 meters, 150 to < 400 meters, ≥ 400 meters).  
Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical 
laboratory tests) for initial safety monitoring will be performed at these visits for the first 6 weeks of 
the study. Study visits that include efficacy, safety, and other assessments will be scheduled 
approximately every 3 months and may occur over 2 or more days, provided all study assessments and 
procedures (with the exception of pharmacokinetic [PK] sample collection) are performed before 
administration of study drug. During the conduct of the study, the COVID-19 pandemic emerged and 
impeded the conduct of site visits and laboratory testing due to quarantines, travel restrictions, and risk 
of infection. With the intention of maintaining regular infusions, home infusions will be allowed 
wherever possible for subjects who may be eligible. If infusions were missed near the scheduled 
assessments on Week 26, 38, or 52, it should be communicated with Amicus on a case-by-case basis to 
determine whether catch-up infusions are needed and how many catch-up infusions are needed prior to 
the study assessments. If 5 or more consecutive infusions are missed due to any circumstance, 
including COVID-19, the subject must be discontinued from this protocol. Any subjects discontinued 
due to COVID-19 may be eligible for ATB200-07 with Amicus approval. 


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Protocol ATB200-03 Amendment 3 
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Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function (6MWT), 
motor function tests (Gait, Stair, Gower, and Chair maneuver [GSGC] test and Timed Up and Go 
[TUG] test), muscle strength (manual muscle testing and quantitative muscle testing), and pulmonary 
function tests (FVC, SVC, MIP, MEP, and SNIP). Patient-reported outcomes (Rasch-built Pompe-
specific Activity [R-PAct] Scale, EuroQol 5 Dimensions-5 Levels Instrument [EQ-5D-5L], Patient-
Reported Outcomes Measurement Information System [PROMIS®] instruments for physical function, 
fatigue, dyspnea, and upper extremity, and Subject’s Global Impression of Change). The Physician’s 
Global Impression of Change will also be performed.  
Pharmacodynamic assessments include measurement of biomarkers of muscle injury (creatine kinase 
[CK]) and disease substrate (urinary hexose tetrasaccharide [Hex4]). Sparse blood samples will be 
collected for determination of total GAA protein levels and AT2221 concentrations in plasma for a 
population PK analysis in ERT-experienced subjects. Serial blood sampling for characterization of the 
PK profile of total GAA protein and AT2221 will be done in ERT-naïve subjects. GAA activity may 
be evaluated during the terminal phase in all subjects (ie, ERT-experienced and ERT-naïve subjects). 
Safety assessments include monitoring of adverse events (AEs), including infusion-associated 
reactions (IARs), clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs, physical 
examinations including weight, electrocardiograms (ECGs), and immunogenicity. Concomitant 
medications and nondrug therapies will also be recorded. 
Number of Subjects (Planned): 
The planned sample size is approximately 110 subjects, with a total of 100 subjects (including at least 
30 ERT-naïve subjects) expected to complete the study. 
Diagnosis and Main Criteria for Inclusion: 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be eligible to 
participate in the study. 
Inclusion Criteria 
1.
Subject must provide signed informed consent prior to any study-related procedures being
performed.
2.
Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
3.
Female subjects of childbearing potential and male subjects must agree to use medically
accepted methods of contraception during the study and for 90 days after the last dose of study
drug.
4.
Subject must have a diagnosis of LOPD based on documentation of one of the following:
a.
deficiency of GAA enzyme
b.
GAA genotyping
5.
Subject is classified as one of the following with respect to ERT status:
a.
ERT-experienced, defined as currently receiving standard of care ERT (alglucosidase alfa)
at the recommended dose and regimen (ie, 20 mg/kg dose every 2 weeks) for ≥ 24 months
−
Specific to Australia, ERT-experienced, defined as currently receiving standard of care
ERT (alglucosidase alfa) at the recommended dose and regimen, at a dose of 20 mg/kg
based on lean or ideal body weight every 2 weeks
b.
ERT-naïve, defined as never having received investigational or commercially available
ERT


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6.
Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National Health and
Nutrition Examination Survey III) at screening.
7.
Subject performs two 6MWTs at screening that are valid, as determined by the clinical
evaluator, and that meet all of the following criteria:
a.
both screening values of 6MWD are ≥ 75 meters
b.
both screening values of 6MWD are ≤ 90% of the predicted value for healthy adults
c.
the lower value of 6MWD is within 20% of the higher value of 6MWD
Exclusion Criteria 
1.
Subject has received any investigational therapy or pharmacological treatment for Pompe
disease, other than alglucosidase alfa, within 30 days or 5 half-lives of the therapy or
treatment, whichever is longer, before Day 1 or is anticipated to do so during the study.
2.
Subject has received gene therapy for Pompe disease.
3.
Subject is taking any of the following prohibited medications within 30 days before Day 1:
•
miglitol (eg, Glyset)
•
miglustat (eg, Zavesca)
•
acarbose (eg, Precose or Glucobay)
•
voglibose (eg, Volix, Vocarb, or Volibo)
Note: None of these medications have a half-life that, when multiplied by 5, is longer than 
30 days. 
4.
Subject requires the use of invasive or noninvasive ventilation support for > 6 hours per day
while awake.
5.
Subject has a hypersensitivity to any of the excipients in ATB200, alglucosidase alfa, or
AT2221.
6.
Subject has a medical condition or any other extenuating circumstance that may, in the opinion
of the investigator or medical monitor, pose an undue safety risk to the subject or may
compromise his/her ability to comply with or adversely impact protocol requirements. This
includes clinical depression (as diagnosed by a psychiatrist or other mental health professional)
with uncontrolled or poorly controlled symptoms.
7.
Subject, if female, is pregnant or breastfeeding at screening.
8.
Subject, whether male or female, is planning to conceive a child during the study.
9.
Subject refuses to undergo genetic testing.
Investigational Product, Dosage, and Mode of Administration: 
ATB200/AT2221 will be administered as a combination treatment regimen, consisting of AT2221 
260 mg (4 × 65-mg oral capsules) for subjects weighing ≥ 50 kg and 195 mg (3 × 65-mg oral capsules) 
for subjects weighing ≥ 40 kg to < 50 kg, followed approximately 1 hour later by ATB200 20 mg/kg 
(reconstituted lyophilized drug product for intravenous [IV] infusion, 105 mg/vial). The 
ATB200/AT2221 combination regimen will be administered every 2 weeks.  
Note: Subjects are required to fast at least 2 hours before and 2 hours after administration of AT2221. 


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Duration of Treatment: 
The duration of treatment is 52 weeks. Subjects who complete this study will have the option to 
participate in an open-label extension study to receive ATB200/AT2221 under a separate protocol. 
Reference Therapy, Dosage, and Mode of Administration: 
Alglucosidase alfa/placebo will be administered as a combination treatment regimen, consisting of 
4 placebo oral capsules for subjects weighing ≥ 50 kg and 3 placebo oral capsules for subjects 
weighing ≥ 40 kg to < 50 kg, followed approximately 1 hour later by alglucosidase alfa 20 mg/kg 
(reconstituted lyophilized drug product for IV infusion, 50 mg/vial). The alglucosidase alfa/placebo 
combination regimen will be administered every 2 weeks. 
Note: Subjects are required to fast at least 2 hours before and 2 hours after administration of placebo. 
Criteria for Evaluation:  
The primary efficacy endpoint is the change from baseline to Week 52 in 6MWD. 
Key secondary efficacy endpoints are as follows: 
•
change from baseline to Week 52 in sitting FVC (% predicted)
•
change from baseline to Week 52 in the manual muscle test score for the lower extremities
•
change from baseline to Week 52 in the total score for the PROMIS – physical function
•
change from baseline to Week 52 in the total score for the PROMIS – fatigue
•
change from baseline to Week 52 in GSGC total score
•
change from baseline to Week 26 in 6MWD
Other secondary efficacy endpoints are as follows: 
•
change from baseline to Week 52 in the following variables related to motor function:
−
time to complete the 10-meter walk (ie, assessment of gait) of the GSGC test
−
time to complete the 4-stair climb of the GSGC test
−
time to complete the Gower’s maneuver of the GSGC test
−
time to arise from a chair as part of the GSGC test
−
time to complete the TUG test
•
change from baseline to Week 52 in the following variables related to muscle strength:
−
manual muscle test score for the upper extremities
−
manual muscle test total score
−
quantitative muscle test value (kg) for the upper extremities
−
quantitative muscle test value (kg) for the lower extremities
−
quantitative muscle test total value (kg)
•
change from baseline to Week 52 in the following variables from patient-reported outcome
measures:
−
total score for the PROMIS – dyspnea


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−
total score for the PROMIS – upper extremity
−
R-PAct Scale total score
−
EQ-5D-5L health status
•
actual value of the subject’s functional status (improving, stable, or declining) pertaining
to the effects of study drug in the following areas of life at Week 52, as measured by the
Subject’s Global Impression of Change
−
overall physical wellbeing
−
effort of breathing
−
muscle strength
−
muscle function
−
ability to move around
−
activities of daily living
−
energy level
−
level of muscular pain
•
actual value of the subject’s functional status (improving, stable, or declining) at Week 52,
as measured by the Physician’s Global Impression of Change
•
change from baseline to Week 52 in the following measures of pulmonary function, as
follows:
−
sitting SVC (% predicted)
−
MIP (cmH2O)
−
MIP (% predicted)
−
MEP (cmH2O)
−
MEP (% predicted)
−
SNIP (cmH2O)
Pharmacodynamic endpoints are as follows: 
•
change from baseline to Week 52 in serum CK level
•
change from baseline to Week 52 in urinary Hex4 level
Pharmacokinetic endpoints from a population PK analysis of total GAA protein level and AT2221 
concentration will be provided in a separate modeling and simulation plan. 
The safety profile of ATB200/AT2221 will be characterized using incidence of treatment-emergent 
adverse events (TEAEs), serious adverse events (SAEs), and AEs leading to discontinuation of study 
drug, frequency and severity of immediate and late IARs, and any abnormalities noted in other safety 
assessments. The impact of immunogenicity to ATB200 and alglucosidase alfa on safety and efficacy 
will also be described. 
Statistical Methods: 
Randomization 


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The following 2 factors have been identified as design stratification variables: 
1.
baseline 6MWD (75 to < 150 meters, 150 to < 400 meters, ≥ 400 meters)
2.
ERT status (ERT-experienced, ERT-naïve)
These 2 factors form 6 factorial combinations (ie, levels, strata).
A centralized block randomization procedure will be used to balance the above risk factors, 1) to 
reduce bias and increase the precision of statistical inference, and 2) to allow various planned and 
unplanned subset analyses. The block randomization scheme will be performed for each of the 6 strata. 
The randomization ratio is 2:1 ATB200/AT2221 to alglucosidase alfa/placebo, fixed. 
Sample Size Calculation 
A 2-group t-test with a 2-sided significance level of 0.05 and a 2:1 randomization scheme (66 subjects 
in the ATB200/AT2221 group and 33 subjects in the alglucosidase alfa/placebo group, for a total 
sample size of 99 subjects) will have approximately 90% power to detect a standardized effect size of 
0.7 between the 2 groups in a superiority test. This calculation was performed using Nquery 8©®. 
Assuming a 10% dropout rate, the sample size will be approximately 110 subjects. 
Efficacy Analyses 
The primary efficacy endpoint (ie, change from baseline to Week 52 in 6MWD) will be analyzed using 
a parametric analysis of covariance (ANCOVA) model to compare between the new treatment and the 
control. This model would typically adjust for baseline 6MWD (as a continuous covariate), and the 
2 factors used to stratify randomization: ERT status (ERT-naïve vs. ERT-experienced) and baseline 
6MWD (75 to < 150 meters, 150 to < 400 meters, ≥ 400 meters). However, the baseline 6MWD cannot 
be used in the model twice (both as a continuous and a categorical variable) due to the expected high 
point-biserial correlation between them. Thus, the 6MWD continuous variable will remain in the 
model but the categorical 6MWD will be removed. The ANCOVA model then has terms for treatment, 
baseline 6MWD (continuous), and ERT status (categorical).  
Additionally, potential treatment-by-covariate interactions (ie, TREATMENT-by-ERT-STATUS and 
TREATMENT-by-BASELINE 6MWD continuous) will be examined. If an interaction term is 
statistically significant (eg, p < 0.10, 2-sided), and there is logical biological interpretation, then the 
interaction term can potentially be added in the final ANCOVA model that will be used for the primary 
endpoint analysis. The data would then be analyzed based on the ANCOVA model, and all the relevant 
estimates (eg, LS means for each treatment group, LS means difference, 95% confidence intervals 
[CIs] for the LS mean difference, and p-value for comparing between the 2 treatment groups) would be 
provided. 
To support the interpretation of clinical benefit, a composite subject-level response will be defined 
based on the totality of the treatment outcome data. Subjects will be classified by an ordinal response 
variable consisting of significant improvement, moderate improvement, or minor/no improvement 
based on treatment outcomes.  
Key secondary endpoints will be analyzed according the hierarchical order as specified in the protocol, 
using stepwise closed testing procedure to control the type I error rate. Key secondary and other 
secondary endpoints will be analyzed separately with a similar method used for the primary endpoint 
analysis. 
Safety Analyses 
Safety data will be summarized using counts and percentages for categorical data and descriptive 
statistics (mean, standard deviation, median, minimum, maximum) for continuous data. 


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4.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
1.
TITLE PAGE ................................................................................................................1 
2.
DECLARATIONS OF SPONSOR AND INVESTIGATOR .......................................3 
2.1. 
Declaration of Sponsor .................................................................................................3 
2.2. 
Declaration of Investigator ...........................................................................................3 
3.
PROTOCOL SYNOPSIS .............................................................................................4 
4.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
5.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................17 
6.
INTRODUCTION ......................................................................................................20 
6.1. 
Pompe Disease ............................................................................................................20 
6.2. 
ATB200/AT2221 ........................................................................................................22 
6.2.1. 
Pharmacokinetics of AT2221 .....................................................................................22 
6.2.2. 
Use of AT2221 as a Small Molecule Enzyme Stabilizer ...........................................23 
6.2.2.1. 
Effect of Miglustat on Plasma α-Glucosidase Activity of Alglucosidase Alfa ..........23 
6.2.2.2. 
Characterization of Plasma Miglustat With Alglucosidase Alfa in Subjects 
With Pompe Disease ...................................................................................................24 
6.3. 
Interim Data From Ongoing Study ATB200-02 .........................................................24 
6.3.1. 
Pharmacodynamics .....................................................................................................24 
6.3.2. 
Functional Outcomes ..................................................................................................26 
6.3.3. 
Pulmonary Function ....................................................................................................27 
6.3.4. 
Pharmacokinetics ........................................................................................................27 
6.3.5. 
Safety ..........................................................................................................................28 
6.4. 
Human Dosing Rationale ............................................................................................28 
6.4.1. 
Dose Selection for Co-administered ATB200/AT2221 .............................................28 
6.4.1.1. 
Dose Selection for ATB200 ........................................................................................29 
6.4.1.2. 
Dose Selection for AT2221 ........................................................................................30 
6.4.2. 
Pharmacokinetics of Co-administered ATB200/AT2221 ..........................................31 
6.4.3. 
Total GAA Protein Using Signature Peptide(s) T09/T50 ...........................................34 
6.5. 
Primary Endpoint Rationale .......................................................................................37 
6.6. 
Summary of Known Potential Risks and Benefits .....................................................38 
7.
STUDY OBJECTIVES ..............................................................................................39 
7.1. 
Primary Objective .......................................................................................................39 


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7.2. 
Secondary Objectives .................................................................................................39 
8.
INVESTIGATIONAL PLAN .....................................................................................40 
8.1. 
Study Design ...............................................................................................................40 
8.2. 
Duration of Study .......................................................................................................41 
8.3. 
Criteria for Termination of the Study .........................................................................42 
8.4. 
Definition of the End of Study ....................................................................................42 
8.5. 
Discussion of Study Design, Including Choice of Control Groups ............................42 
9.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...................................43 
9.1. 
Number of Subjects ....................................................................................................43 
9.2. 
Eligibility Criteria .......................................................................................................43 
9.2.1. 
Inclusion Criteria ........................................................................................................43 
9.2.2. 
Exclusion Criteria .......................................................................................................44 
9.3. 
Withdrawal Criteria ....................................................................................................44 
9.4. 
Subjects of Reproductive Potential .............................................................................45 
10.
TREATMENT OF SUBJECTS ..................................................................................47 
11.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................48 
11.1. 
Study Drug ..................................................................................................................48 
11.2. 
Study Drug Packaging and Labeling ..........................................................................49 
11.3. 
Study Drug Storage .....................................................................................................49 
11.4. 
Study Drug Preparation ..............................................................................................50 
11.5. 
Administration ............................................................................................................50 
11.5.1. 
ATB200/Alglucosidase Alfa ......................................................................................50 
11.5.2. 
AT2221/Placebo .........................................................................................................50 
11.6. 
Randomization and Blinding ......................................................................................51 
11.6.1. 
Randomization ............................................................................................................51 
11.6.2. 
Blinding ......................................................................................................................51 
11.6.3. 
Unblinding of Treatment Assignment ........................................................................51 
11.7. 
Study Drug Accountability .........................................................................................51 
11.8. 
Study Drug Handling and Disposal ............................................................................52 
11.9. 
Prohibited Medications ...............................................................................................52 
12.
STUDY PARAMETERS AND PROCEDURES .......................................................53 
12.1. 
Schedule of Assessments ............................................................................................53 
12.2. 
Additional Details on Study Visits .............................................................................59 


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12.2.1. 
Screening/Baseline .....................................................................................................59 
12.2.2. 
Day 1 ...........................................................................................................................59 
12.2.3. 
Infusion Visits and Home Infusion Visits ..................................................................60 
12.2.4. 
Post-baseline Assessment Visits .................................................................................61 
12.2.5. 
Unscheduled Visits .....................................................................................................61 
12.2.6. 
Week 52/Early Termination (End of Study) ...............................................................62 
12.2.7. 
Follow-up Period ........................................................................................................62 
12.3. 
Description of Study Assessments ..............................................................................62 
12.3.1. 
Demographic Data Collection ....................................................................................62 
12.3.2. 
Medical History ..........................................................................................................62 
12.3.3. 
Prior/Current Medications ..........................................................................................63 
12.3.4. 
Retrospective Data Collection ....................................................................................63 
12.3.5. 
Physical Examination .................................................................................................63 
12.3.6. 
Body Weight and Height ............................................................................................63 
12.3.7. 
Vital Signs ..................................................................................................................63 
12.3.8. 
Adverse Events ...........................................................................................................64 
12.3.9. 
Patient-reported Outcomes .........................................................................................64 
12.3.10. 
Physician’s Global Impression of Change ..................................................................64 
12.3.11. 
Electrocardiogram .......................................................................................................65 
12.3.12. 
Clinical Laboratory Tests ...........................................................................................65 
12.3.12.1. Chemistry, Hematology, and Urinalysis .....................................................................65 
12.3.12.2. Pregnancy Tests ..........................................................................................................66 
12.3.13. 
Immunogenicity Assessments ....................................................................................66 
12.3.14. 
Biological Specimens .................................................................................................67 
12.3.15. 
Blood Samples for Pharmacokinetic Analysis ...........................................................67 
12.3.15.1. Population Pharmacokinetic Analysis ........................................................................67 
12.3.15.2. Pharmacokinetic Subanalysis (ERT-naïve Subjects Only) .........................................67 
12.3.16. 
Creatine Kinase and Urinary Hexose Tetrasaccharide ...............................................68 
12.3.17. 
Gene for Encoding Acid α-Glucosidase Genotyping .................................................68 
12.3.18. 
Pulmonary Function Tests ..........................................................................................68 
12.3.19. 
Motor Function Tests ..................................................................................................68 
12.3.20. 
6-Minute Walk Test ....................................................................................................69
12.3.21. 
Muscle Strength Testing .............................................................................................69 


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13.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................71 
13.1. 
Definitions ..................................................................................................................71 
13.1.1. 
Adverse Events ...........................................................................................................71 
13.1.2. 
Serious Adverse Events ..............................................................................................72 
13.1.3. 
Infusion-associated Reactions ....................................................................................73 
13.1.4. 
Relationship to Study Drug ........................................................................................77 
13.1.5. 
Assessment of Severity ...............................................................................................77 
13.2. 
Reporting of Adverse Events ......................................................................................78 
13.3. 
Reporting Requirements for Serious Adverse Events ................................................78 
13.3.1. 
Additional Reporting Requirements for Suspected Unexpected Serious 
Adverse Reaction ........................................................................................................79 
13.3.2. 
Overdose/Under Dose .................................................................................................79 
13.3.3. 
Missed Dose ................................................................................................................80 
13.4. 
Reporting of Pregnancy ..............................................................................................80 
13.5. 
Data Monitoring Committee .......................................................................................81 
14.
DATA MANAGEMENT ...........................................................................................82 
15.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .............................83 
15.1. 
Endpoints ....................................................................................................................83 
15.1.1. 
Primary Efficacy Endpoint .........................................................................................83 
15.1.2. 
Secondary Efficacy Endpoints ....................................................................................83 
15.1.3. 
Pharmacodynamic Endpoints .....................................................................................84 
15.1.4. 
Pharmacokinetic Endpoints ........................................................................................84 
15.1.4.1. 
Population Pharmacokinetic Analysis (ERT-Experienced Subjects) .........................84 
15.1.4.2. 
Pharmacokinetic Subanalysis (ERT-naïve Subjects) ..................................................85 
15.1.5. 
Safety Endpoints .........................................................................................................86 
15.2. 
Sample Size Considerations .......................................................................................86 
15.3. 
Data Analysis Considerations .....................................................................................86 
15.3.1. 
Analysis Populations ..................................................................................................86 
15.3.2. 
Statistical Methods ......................................................................................................87 
15.3.2.1. 
Randomization ............................................................................................................87 
15.3.2.2. 
Missing Data Handling ...............................................................................................87 
15.3.2.3. 
Efficacy Analyses .......................................................................................................87 
15.3.2.4. 
Pharmacokinetic Analyses ..........................................................................................89 


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15.3.2.5. 
Safety Analyses ..........................................................................................................90 
15.3.2.6. 
Immunogenicity Analyses ..........................................................................................90 
16.
STUDY CONDUCT CONSIDERATIONS ...............................................................91 
16.1. 
Posting of Information on Publicly Available Clinical Trial Registers ......................91 
16.2. 
Regulatory and Ethical Considerations ......................................................................91 
16.2.1. 
Ethical Conduct of the Study ......................................................................................91 
16.2.2. 
Independent Ethics Committees/Institutional Review Boards Approval and 
Study Compliance .......................................................................................................91 
16.2.3. 
Ongoing Information for Independent Ethics Committees/Institutional 
Review Boards ............................................................................................................91 
16.2.4. 
Subject Information and Informed Consent ...............................................................92 
16.3. 
Quality Control (Study Monitoring) ...........................................................................92 
16.3.1. 
Quality Assurance .......................................................................................................93 
16.3.2. 
Confidentiality ............................................................................................................93 
16.3.3. 
Protocol Amendments and Deviations .......................................................................93 
16.3.4. 
Delegation of Investigator Duties ...............................................................................94 
16.3.5. 
Study and Site Closure ................................................................................................94 
16.4. 
Legal and Financial Aspects .......................................................................................95 
16.4.1. 
Liability and Insurance ...............................................................................................95 
16.4.2. 
Financial Disclosure ...................................................................................................95 
16.5. 
Records Retention .......................................................................................................95 
16.6. 
Use of Study Findings ................................................................................................96 
17.
REFERENCES ...........................................................................................................97 
APPENDIX 1. SAMPSON CRITERIA FOR ANAPHYLAXIS ...............................................99 
APPENDIX 2. POTENTIALLY CLINICALLY SIGNIFICANT GUIDELINES ...................100 


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LIST OF TABLES 
Table 1: 
Serious Adverse Event Contact Information ................................................................2 
Table 2: 
Change in 6-minute Walk Test Distance in Meters in Cohorts 1 and 3 
Through Month 18 ......................................................................................................27 
Table 3: 
Change in Percentage Predicted Sitting FVC (%) in Cohorts 1 and 3 Subjects 
Through Month 18 ......................................................................................................27 
Table 4: 
Pharmacokinetic Summary of Single Ascending Doses of ATB200 in Cohort 
1 Subjects with Late-onset Pompe Disease ................................................................32 
Table 5: 
Summary of PK Parameters for ATB200/AT2221 Co-administration vs 
ATB200 Alone in Cohort 1 Subjects ..........................................................................33 
Table 6: 
Statistical Comparisons by ANOVA Between Cohort 1 Single Dose vs 
Multiple Dose and Between Cohort 1 and Cohort 3 ...................................................35 
Table 7: 
ATB200-02 PK Summary from Preliminary Plasma AT2221 Concentrations 
Sampled From Cohort 1 and Cohort 3 Subjects with Late-onset Pompe 
Disease ........................................................................................................................37 
Table 8: 
Treatment Assignment ................................................................................................47 
Table 9: 
Investigational Products ..............................................................................................48 
Table 10: Schedule of Assessments ............................................................................................54 
Table 11: Serum Chemistry Parameters .....................................................................................65 
Table 12: Hematology Parameters ..............................................................................................66 
Table 13: Urinalysis Parameters .................................................................................................66 
Table 14: Guidelines for Management of Immediate Infusion-associated Reactions ................74 
LIST OF FIGURES 
Figure 1: 
Mean Percentage Change from Baseline in Creatine Kinase Through 
Month 18: All Cohorts ................................................................................................25 
Figure 2: 
Mean Percentage Change from Baseline in Urinary Hexose Tetrasaccharide 
Through Month 18: All Cohorts .................................................................................26 
Figure 3: 
Distributions of AUC by Weight for 260 mg AT2221 versus 195 mg 
AT2221 .......................................................................................................................29 
Figure 4: 
Mean (STDEV) Total GAA Protein Concentration-time Profiles for Cohort 
1 (Stages 1 and 2) and Cohort 3 (Stage 3) ..................................................................34 
Figure 5: 
Plasma Total GAA Protein Concentration Comparisons Between 
Co-administration Treatments vs ATB200 Alone at 12 and 24 Hours 
Post-dose (1-sided t-tests) for Cohort 1 ......................................................................35 
Figure 6: 
Study Design Schematic .............................................................................................40 


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5.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or Specialist 
Term 
Definition of Term 
6MWD 
6-minute walk distance
6MWT 
6-Minute Walk Test
Ab(s) 
antibody(ies) 
AE 
adverse event 
ATB200 
recombinant human acid α-glucosidase (rhGAA) 
AT2221 
N-butyl-deoxynojirimycin
ATB200/AT2221 
ATB200 co-administered with AT2221 
AUC 
area under the plasma concentration-time curve 
AUC0-t 
area under the plasma drug concentration-time curve from 0 time 
(predose) to the time of last quantifiable concentration (t), calculated 
with the linear up/log-down trapezoidal method 
AUC0-∞ 
the area under the plasma drug concentration-time curve from 0 time 
(predose) extrapolated to infinite time will be calculated as follows: 
AUC0-∞ = AUC0-t + Ct/+λz 
where Ct is the last observed quantifiable concentration 
AUCtmax-24h 
partial area under the plasma drug concentration-time curve from the 
time of maximum concentration (tmax) to 24 hours post initiation of 
ATB200 infusion 
BLQ 
below the limit of quantification 
CLT 
total plasma clearance of drug after intravenous administration, 
calculated as dose/AUC0-∞ 
CLT/F 
total plasma clearance from an oral administration, calculated as 
dose/AUC0-∞ 
CK 
creatine kinase 
Cmax 
maximum observed concentration obtained directly from the 
concentration profile 
COVID-19 
SARS-CoV-2 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EQ-5D-5L 
EuroQol 5 Dimensions-5 Levels Instrument 
ERT 
enzyme replacement therapy 


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Abbreviation or Specialist 
Term 
Definition of Term 
FVC 
forced vital capacity 
Gaa 
gene encoding acid α-glucosidase (mouse protein) 
GAA 
human acid α-glucosidase 
GAA 
gene encoding human acid α-glucosidase 
GCP 
Good Clinical Practice 
GSGC 
Gait, Stair, Gower, and Chair maneuver 
Hex4 
hexose tetrasaccharide 
IAR 
infusion-associated reaction 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
IND 
Investigational New Drug 
IOPD 
infantile-onset Pompe disease 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
Kel or λz 
the apparent terminal phase elimination rate constant will be 
estimated by linear regression of logarithmically transformed 
concentration versus time data; only those data points which are 
judged to describe the terminal log-linear decline will be used in the 
regression 
Ki 
dissociation constant 
LOPD 
late-onset Pompe disease 
MEP 
maximal expiratory pressure 
MIP 
maximal inspiratory pressure 
mITT 
modified intent-to-treat 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
R-PAct
Rasch-built Pompe-specific Activity 
rhGAA 
recombinant human acid α-glucosidase 


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Abbreviation or Specialist 
Term 
Definition of Term 
REB 
research ethics board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SNIP 
sniff nasal inspiratory pressure 
SUSAR 
suspected unexpected serious adverse reaction 
SVC 
slow vital capacity 
t½ 
terminal elimination half-life 
t½α 
the alpha-phase terminal half-life, calculated as ln(2)/λz from the first 
3 or more quantifiable concentrations after Cmax; estimated for 
plasma total GAA protein concentration only 
t½β 
the beta-phase terminal elimination half-life, calculated as ln(2)/λz 
from the last 3 or more quantifiable concentrations from the beta 
phase of elimination 
tmax 
observed time to reach Cmax; time of the first occurrence of the 
maximum observed concentration obtained directly from the 
concentration profile 
TUG 
Timed Up and Go 
US(A) 
United States (of America) 
Vz/F 
volume of distribution based on the terminal elimination phase from 
an oral administration, calculated as dose/(AUC0-∞ • λz) 


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6.
INTRODUCTION
6.1. 
Pompe Disease
Pompe disease (Online Mendelian Inheritance in Man #232300, also known as acid maltase 
deficiency or glycogen storage disease type II) is an autosomal recessive genetic disorder caused 
by mutations in the gene encoding human acid α-glucosidase (GAA). These mutations may result 
in complete absence or partial loss of endogenous human acid α-glucosidase (GAA) activity, 
which is responsible for the breakdown of lysosomal glycogen. The enzyme deficiency results in 
accumulation of intracellular glycogen leading to progressive disruption of cellular function, 
particularly in heart, skeletal muscles, and diaphragm. The age at onset of clinical 
manifestations, rate of progression, and severity, including degree of organ and/or muscular 
(skeletal, respiratory, and cardiac) involvement, largely depends on the severity of the mutations 
and consequently on the residual enzyme activity (Hirschhorn and Reuser 2001; Raben et al 
2002). Lower enzyme activity is generally associated with a more severe clinical course of the 
disease (Kishnani et al 2006).  
Pompe disease may be categorized into 2 classes: infantile-onset Pompe disease (IOPD; classic 
and nonclassic) and late-onset Pompe disease (LOPD) (Leslie and Bailey 2017).  
Late-onset Pompe disease can present at any age greater than 12 months and does not present 
with clinically apparent cardiac involvement (Leslie and Bailey 2017). Late-onset Pompe disease 
is often referred to as juvenile-onset Pompe disease when occurring in the pediatric 
subpopulation of the LOPD category. Late-onset Pompe disease has a slower rate of progression 
compared with IOPD, with most patients experiencing progressive limb-girdle weakness and 
respiratory failure due to involvement of muscles in the proximal lower and upper limbs, 
paraspinal muscles, and diaphragm. Clinical manifestations include difficulty walking, climbing 
stairs, and progressive limitations of motor activities of daily living with progression to a need 
for ambulatory support followed by wheel chair dependence (Hirschhorn and Reuser 2001). 
Clinical manifestations of the disease are compounded by respiratory involvement, initially as 
sleep-disordered breathing and orthopnea (shortness of breath in supine position). The 
progressive nature of Pompe disease generally results in the use of invasive mechanically 
assisted ventilation. Biochemical abnormalities include increased level of serum creatine kinase 
(CK), a biomarker of muscle injury, and urinary hexose tetrasaccharide (Hex4), a biomarker of 
disease substrate. Life expectancy for patients with LOPD can range from early childhood to late 
adulthood, depending on the age of onset, rate of disease progression, the extent of respiratory 
muscle involvement, and the presence of co-morbidities (Hagemans et al 2004).  
Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA), 
alglucosidase alfa, became available for all patients in Europe and the United States (US) in 
2006. While alglucosidase alfa provides initial benefit to many patients, the magnitude and 
duration of therapeutic response with continuing therapy vary among individual patients 
(van der Ploeg et al 2010; Schoser et al 2017). The current ERT, at best, may offer improvement 
in measures of muscle function, strength and respiratory function for a finite duration followed 
by slow decline in these parameters (Toscano and Schoser 2013; Wyatt et al 2012). 
In 2012, a systematic review of all studies performed in subjects with LOPD was performed by 
Toscano and Schoser 2013. This review included data on 368 subjects with LOPD from 


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published studies, including 27 juvenile subjects (age range: 2 to17 years old) and 251 adult 
subjects who received alglucosidase alfa for at least 2 preceding years. Results indicated that 
> 30% of subjects do not show an initial improvement during treatment with alglucosidase alfa
and continue to experience deterioration of muscular and respiratory functions despite treatment.
In the group of subjects who initially respond to alglucosidase alfa treatment, several additional 
longer-term studies show that improvements usually last for only approximately 2 years. 
Thereafter, subjects generally plateau before beginning to progressively decline.  
In 2012, the United Kingdom Health Technology Assessment program, as part of the National 
Institute for Health Research (Wyatt et al 2012), issued recommendations drawn from review of 
longitudinal data for 81 patients with Pompe disease (including infantile- and late-onset forms 
[children and adults]) who received the current approved ERT standard of care, alglucosidase 
alfa. Key markers of Pompe disease progression (forced vital capacity [FVC], ventilation 
dependency, mobility, 6-Minute Walk Test [6MWT], muscle strength, and body mass index) 
were assessed and modeled with time of treatment on alglucosidase alfa therapy. Results of this 
assessment indicated that improvements in FVC, 6-minute walk distance (6MWD), and muscle 
strength by patients with LOPD occur for the first 2 years after commencing ERT with 
alglucosidase alfa, and decline occurs with continuing treatment beyond this timeframe. 
Additionally, a 3-year study in 38 subjects with LOPD receiving alglucosidase alfa showed that 
the subjects demonstrated an improvement in motor function in the first year of treatment, which 
remained generally stable in the second year and began to decline in the third year (Regnery et al 
2012).  
Furthermore, a recent report providing a 10-year follow-up on the Phase 3 Lumizyme® 
(Genzyme Corporation) (LOTS) study showed that after experiencing some improvement in 
motor and pulmonary function during the first couple of years of treatment, subjects began to 
slowly decline with ongoing treatment (van der Ploeg et al 2017). In this study, from years 3 to 6 
on therapy, there was an average decline of approximately 10% in percent predicted 6MWD, 
with approximately 80% of subjects experiencing a decline. 
The most serious tolerability issue with alglucosidase alfa is the occurrence of 
infusion-associated reactions (IARs), which, in some instances can include life-threatening 
anaphylaxis or other severe allergic responses (Myozyme® Summary of Product Characteristics, 
December 2018). Management of these events include dose reduction, reduced infusion rates and 
prolonged infusion times, and dose interruption or discontinuation. Premedication with 
antihistamines and steroids (prior to infusion) is also regularly used to prevent and reduce the 
occurrence and severity of IARs and hypersensitivities related to alglucosidase alfa infusion. 
Despite these measures, patients with Pompe disease may still experience IARs, and some 
cannot tolerate regular infusions of the currently approved ERT. 
In 2017, a systematic review of the literature was undertaken by the European Pompe 
Consortium, a network of experts from 11 European countries in the field of Pompe disease 
(van der Ploeg et al 2017). Based on the data obtained from 1 clinical study and 43 observational 
studies, covering a total of 586 individual adult subjects, evidence of an effect of ERT at group 
level was assessed by the consortium. The current European Pompe Consortium consensus is to 
discontinue ERT therapy upon the occurrence of severe IARs or the progressive clinical 
worsening of disease symptoms, as well as occurrence of high-neutralizing antibody (Ab) titers, 
which effectively inactivate the existing ERT treatment. The European Pompe Consortium 


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consensus recommendation also included consideration for re-initiation of ERT treatment if 
disease progression and clinical worsening recur after ERT has been stopped.  
Co-administration of ATB200 (rhGAA) with AT2221 (miglustat; N-butyl deoxynojirimycin) 
(ATB200/AT2221) is designed to address these limitations of alglucosidase alfa and meet this 
unmet medical need. 
6.2. 
ATB200/AT2221 
ATB200/AT2221 is a novel first-in-class combination product approach for the treatment of 
adult and pediatric patients with LOPD. ATB200/AT2221 is being developed as a combination 
product for which (1) ATB200 is the main active substance (enzyme) that is engineered for 
optimal targeting to lysosomes, the site of glycogen catabolism in affected tissues and 
(2) AT2221 is a co-administered small molecule enzyme stabilizer that stabilizes ATB200 from
denaturation in systemic circulation, which enhances the delivery of the active component
ATB200 to lysosomes.
ATB200: ATB200 is a next-generation rhGAA enzyme. ATB200 differs structurally from 
currently approved rhGAA (alglucosidase alfa) enzyme. Based on the published literature, 
ATB200 matches the sequence for human alpha glucosidase but has important differences on its 
posttranslational glycan structures that enable more rapid cellular uptake and lysosomal targeting 
of the enzyme. ATB200 is a new biological entity and is currently being evaluated in clinical 
trials. 
AT2221: AT2221 is an iminosugar that functions as a small molecule enzyme stabilizer of 
ATB200. Because ATB200 is a recombinant lysosomal enzyme, it is most stable at lysosomal 
acidic pH and thus is susceptible to denaturation and enzyme inactivation at neutral blood pH 
when administered intravenously (IV). AT2221 binds to ATB200 and protects ATB200 from 
denaturation in blood. This interaction of AT2221 with ATB200 results in stabilization of the 
ATB200 enzyme in the blood and enhancement of the pharmacokinetics of the ATB200 leading 
to a more efficient percentage of active enzyme being delivered to key disease-relevant tissue 
(ie, muscles). 
6.2.1. 
Pharmacokinetics of AT2221  
AT2221 capsules contain the same active ingredient, N-butyl deoxynojirimycin, as in Zavesca® 
(Actelion Pharmaceuticals US Inc.) and Yargesa® (Edenbridge Pharmaceuticals, LLC) which is 
approved for the treatment of adults with type I Gaucher disease (in the US and European Union) 
and for treatment of adults and pediatrics with Niemann Pick-C disease (in European Union). As 
of 2017, Yargesa is approved as a generic miglustat product for the treatment of adults with type 
I Gaucher disease. The pharmacokinetics of miglustat have been well characterized in subjects 
with Gaucher disease. In this study, AT2221 acts as a small molecule enzyme stabilizer that 
stabilizes ATB200 and enhances its activity. AT2221 is administered at a lesser frequency 
(1 dose every 2 weeks) in contrast to dosing with miglustat for Gaucher disease (3 times daily) 
(see Section 11.5 for dosing for this study). 
Absorption: After a 100-mg oral dose of miglustat, the observed time to reach maximum plasma 
concentration (tmax) of miglustat ranged from 2.0 to 2.5 hours in subjects with Gaucher disease. 
Plasma concentrations show a bi-exponential decline, characterized by a short distribution phase 


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and a longer elimination phase. The effective terminal elimination half-life (t½) of miglustat is 
approximately 6.0 to 7.0 hours, which predicts that steady-state will be achieved by 1.5 to 
2.0 days following the start of 3 times daily dosing. 
Miglustat, dosed at 50 and 100 mg 3 times daily in subjects with Gaucher disease, exhibits 
dose-proportional pharmacokinetics. The pharmacokinetics of miglustat was not altered after 
repeated dosing 3 times daily for up to 12 months. In healthy subjects, co-administration of 
Zavesca® with food results in a decrease in the rate of absorption of miglustat (maximum 
observed concentration [Cmax] in plasma was decreased by 36% and tmax was delayed for 2 hours) 
but had no statistically significant effect on the extent of absorption of miglustat (area under the 
plasma concentration-time curve [AUC] was decreased by 14%). The mean oral bioavailability 
of a 100-mg miglustat capsule is about 97% relative to an oral solution administered under 
fasting conditions. The pharmacokinetics of miglustat was similar between adult subjects with 
type I Gaucher disease and healthy subjects after a single dose administration of miglustat 
100 mg (Zavesca Labeling-Package Insert 2014). The absolute bioavailability of miglustat was 
approximately 80% (Wraith and Imrie 2009). 
Distribution: Miglustat does not bind to plasma proteins. Mean apparent volume of distribution 
of miglustat is 83 to 105 L in Gaucher patients. At steady state, the concentration of miglustat in 
cerebrospinal fluid of 6 subjects without Gaucher disease was 31.4% to 67.2% of that in plasma, 
indicating that miglustat crosses the blood-brain barrier (Zavesca Labeling-Package Insert 2014). 
Metabolism and Excretion: The major route of excretion of miglustat is via kidney. Following 
administration of a single dose of 100 mg 14C-miglustat to healthy subjects, 83% of the 
radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the 
administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite 
in urine was miglustat glucuronide accounting for 5% of the dose. The t½ of radioactivity in 
plasma was 150 hours, suggesting the presence of 1 or more metabolites with a prolonged 
half-life. The metabolite accounting for this observation has not been identified but may 
accumulate and reach concentrations exceeding those of miglustat at steady state. Miglustat did 
not inhibit or induce substrates of cytochrome P450 enzymes (Zavesca Labeling-Package Insert 
2014). 
6.2.2. 
Use of AT2221 as a Small Molecule Enzyme Stabilizer 
N-butyl deoxynojirimycin, the active ingredient in AT2221, is a small molecule acting as a small
molecule enzyme stabilizer and has been shown to bind and stabilize GAA to improve its
pharmacological properties. Two clinical studies (see Section 6.2.2.1 and Section 6.2.2.2)
evaluating the co-administration of miglustat with the current approved ERT (alglucosidase alfa)
in Pompe disease have been reported in the literature (Parenti et al 2015; Doerfler et al 2014).
6.2.2.1. 
Effect of Miglustat on Plasma α-Glucosidase Activity of Alglucosidase Alfa 
In a clinical study conducted in 13 subjects with Pompe disease (3 subjects with IOPD and 
10 subjects with LOPD) at 4 treatment sites in Italy, 20 to 40 mg/kg alglucosidase alfa was 
administered alone and then co-administered with 4 doses of 80 mg/m2 miglustat every 2 weeks. 
Compared with alglucosidase alfa alone, the results of the study showed a mean of 6.8-fold 
increase in GAA activity exposure (measured in terms of AUC) following co-administration 
(Parenti et al 2015). 


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6.2.2.2. 
Characterization of Plasma Miglustat With Alglucosidase Alfa in Subjects With 
Pompe Disease 
A study conducted at the University of Florida evaluated the pharmacokinetics of plasma 
miglustat when co-administered with IV infusion of alglucosidase alfa to subjects with Pompe 
disease. Preliminary plasma miglustat pharmacokinetic (PK) data following oral administrations 
of 100 mg and 200 mg miglustat on the day of alglucosidase alfa infusion are available. Plasma 
miglustat exposures were approximately dose proportional. Maximum observed concentration
values following administration of 100 and 200 mg miglustat were 1120 and 2450 ng/mL, 
respectively, and area under the plasma drug concentration-time curve from time 0 (predose) to 
the time of last quantifiable concentration (t) (AUC0-t) values were 8587 and 16092 ng•h/mL, 
respectively. Miglustat reached peak concentrations at approximately 3 hours after single-dose 
administration, and the t½ ranged from 4.5 to 6.0 hours. Volume of distribution ranged from 78 to 
94 L (Doerfler et al 2014).  
6.3. 
Interim Data From Ongoing Study ATB200-02 
A clinical development program is being conducted by Amicus Therapeutics, Inc. (Amicus) that 
evaluates ATB200/AT2221 co-administration for treatment of LOPD. A Phase 1/2 (ATB200-02, 
NCT-02675465) open-label, fixed-sequence, ascending-dose clinical study is ongoing to assess 
safety, tolerability, pharmacokinetics, pharmacodynamics, and interim efficacy of IV infusion of 
ATB200 with AT2221 in adult subjects with Pompe disease (subjects with LOPD). The 
ATB200-02 study is ongoing in the US, Germany, United Kingdom, the Netherlands, New 
Zealand, and Australia. As of August 2018, results from an interim analysis (n = 21) of data from 
subjects in Cohorts 1 through 3 are available through Month 18. 
Subjects treated with ATB200/AT2221 for up to 18 months showed improvements in 6MWD 
and other measures of motor function, stability or increases in FVC, and durable reductions in 
biomarkers of muscle damage and disease substrate. 
6.3.1. 
Pharmacodynamics 
All cohorts demonstrated persistent improvement in biomarkers of muscle damage (CK) 
(Figure 1) and disease substrate (urinary Hex4) (Figure 2) for up to 18 months. 


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Figure 1: 
Mean Percentage Change from Baseline in Creatine Kinase Through 
Month 18: All Cohorts 
Notes: Cohort 1 includes ERT-experienced (2 to 6 years) subjects; Cohort 2 includes ERT-experienced (≥ 2 years) 
subjects; Cohort 3 includes ERT-naïve subjects. Reported through interim data analysis (maximum 18 months); 
missing values either unable to be analyzed or not yet analyzed. 
Source: Interim Analysis 6 (data cutoff of August 2018), Figure 14.2.1.4  


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Figure 2: 
Mean Percentage Change from Baseline in Urinary Hexose Tetrasaccharide 
Through Month 18: All Cohorts 
Notes: Cohort 1 includes ERT-experienced (2 to 6 years) subjects; Cohort 2 includes ERT-experienced (≥ 2 years) 
subjects; Cohort 3 includes ERT-naïve subjects. Reported through interim data analysis (maximum 18 months); 
missing values either unable to be analyzed or not yet analyzed. 
Source: Interim Analysis 6 (data cutoff of August 2018), Figure 14.2.1.5  
6.3.2. 
Functional Outcomes 
A primary measure of motor function in Pompe disease subjects, 6MWD, improved in both 
ERT-naïve and ERT-experienced subjects with continued benefit observed through Month 18 
(Table 2). 
•
For ERT-naïve subjects from Cohort 3 (n=5), mean increases in 6MWD were
observed at all time points through Month 18 (42 m at Month 6, 64 m at Month 9,
63 m at Month 12, and 49 m at Month 18).
•
For ERT-experienced subjects in Cohort 1, mean increases in 6MWD were observed
at all time points through Month 18 (24 m at Month 6 [n = 10], 25 m at Month 9
[n = 10], 42 m at Month 12 [n = 10], and 52 m at Month 18 [n = 9]).


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Table 2: 
Change in 6-minute Walk Test Distance in Meters in Cohorts 1 and 3 
Through Month 18 
Mean (SD) 
Mean (SD) Change from Baseline 
Cohort 
Baseline 
Month 6 
Month 9 
Month 12 
Month 18 
1a 
ERT-experienced (2 to 6 years) 
(n = 10) 
397.2 
(96.8) 
(n = 10) 
+23.9
(52.2)
(n = 10) 
+24.5
(40.8)
(n = 10) 
+42.2
(46.5)
(n = 9) 
+51.7
(45.9)
3 
ERT-naïve 
(n = 5) 
399.5 
(83.5) 
(n = 5) 
+41.8
(29.4)
(n = 5) 
+63.5
(23.1)
(n = 5) 
+63.1
(29.1)
(n = 5) 
+49.0
(28.3)
Abbreviations: ERT = enzyme replacement therapy; n = number of patients; SD = standard deviation 
a For the purposes of assigning nominal time points to data from Cohort 1, the 6-week duration of Stage 1 (single 
ascending doses of ATB200) and the 12-week duration of Stage 2 (multiple ascending doses of miglustat [130 mg 
for 6 weeks, followed by 260 mg for 6 weeks]) were included. Therefore, the Month 6, 9, 12, and 18 time points 
reflect cumulative data to Stage 3 Month 3, Stage 3 Month 6, Stage 3 Month 9, and Stage 3 Month 15, respectively. 
Source: Interim Analysis 6 (data cutoff date of August 2018), Table 14.2.1.3  
There was a trend toward improvement in Gait, Stair, Gower, and Chair maneuver (GSGC) total 
score across the first 18 months with Cohort 1 showing improvement at Months 12 and 18 and 
Cohort 3 showing improvement at Months 6, 9, 12, and 18.  
6.3.3. 
Pulmonary Function 
Forced vital capacity was improved in ERT-naïve subjects and was generally stable in 
ERT-experienced subjects (Table 3). 
Table 3: 
Change in Percentage Predicted Sitting FVC (%) in Cohorts 1 and 3 Subjects 
Through Month 18 
Mean (SD) 
Mean (SD) Change from Baseline 
Cohort 
Baseline 
Month 6 
Month 9 
Month 12 
Month 18 
1a 
ERT-experienced (2 to 6 years) 
(n = 9) 
52.6 
(14.7) 
(n = 9) 
–1.3
(4.1)
(n = 9) 
–1.7
(3.9)
(n = 9) 
–3.3
(6.1)
(n = 8) 
–4.0
(7.0)
3 
ERT-naïve 
(n = 5) 
53.4 
(20.3) 
(n = 5) 
+4.2
(5.6)
(n = 5) 
+6.2
(5.3)
(n = 5) 
+4.4
(8.7)
(n = 5) 
+6.8
(2.5)
Abbreviations: FVC = forced vital capacity; ERT = enzyme replacement therapy; n = number of patients; 
SD = standard deviation 
a For the purposes of assigning nominal time points to data from Cohort 1, the 6-week duration of Stage 1 (single 
ascending doses of ATB200) and the 12-week duration of Stage 2 (multiple ascending doses of miglustat [130 mg 
for 6 weeks, followed by 260 mg for 6 weeks]) were included. Therefore, the Month 6, 9, 12, and 18 time points 
reflect cumulative data to Stage 3 Month 3, Stage 3 Month 6, Stage 3 Month 9, and Stage 3 Month 15, respectively. 
Source: Interim Analysis 6 (data cutoff date of 03 August 2018), Table 14.2.1.1  
6.3.4. 
Pharmacokinetics 
The clinical PK profile of ATB200/AT2221 combination therapy has been consistent with 
previously reported nonclinical data; see Section 6.4.2 for a summary of pharmacokinetics and 
the Investigator’s Brochure for additional details. 


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6.3.5. 
Safety 
Safety and tolerability data in all 21 subjects reflect 18 months of treatment (data cutoff date of 
August 2018), with 1 subject having received ATB200/AT2221 for over 28 months. Adverse 
events (AEs) have been generally mild to moderate and transient. ATB200/AT2221 has resulted 
in a low rate of IARs following more than 900 infusions (8 events of IARs in 6 subjects).  
6.4. 
Human Dosing Rationale 
In clinical study ATB200-02, ATB200/AT2221, at a co-administered dose of 20 mg/kg 
ATB200 + 260 mg AT2221 every 2 weeks, was safe and efficacious in subjects with LOPD. 
Furthermore, the PK disposition of ATB200 alone in plasma confirmed the human exposure 
predicted by translational modeling. Addition of AT2221, at doses of 130 mg and 260 mg, 
prolonged distribution phase plasma t½ of total GAA protein by 20% and 40%, respectively, and 
increased partial AUCtmax-24h by 25% to 46%, respectively, thus confirming the mechanism of 
action of AT2221 as a small molecule enzyme stabilizer that stabilizes exogenously administered 
ATB200 (data on file). 
6.4.1. 
Dose Selection for Co-administered ATB200/AT2221 
Dose selection of 20 mg/kg ATB200 + 260 mg AT2221 for Study ATB200-03 to assess the 
safety and efficacy of ATB200/AT2221 co-administration in LOPD subjects, has been based on 
a body of evidence that includes clinical pharmacokinetics/ pharmacodynamics, efficacy, and 
safety data from Phase 1/2 Study ATB200-02, nonclinical PK/pharmacodynamics (PD) data 
from studies conducted in the murine gene encoding acid α-glucosidase (mouse protein) (ie, 
Gaa) knockout model, and in vitro data demonstrating the stabilizing effects of AT2221 on the 
ATB200 enzyme. Based on the mouse model, AT2221 at a dose of 260 mg provided maximal 
duration of binding and stabilization in plasma for up to 18 hours, with minimal duration of 
inhibition for up to only 4 hours in tissues [Modeling and Simulations to Support Dosing of 
ATB200 and AT2221 for a First-In-Human Study in Patients with Late-Onset Pompe Disease, 
AMIC-PCS-102. Sep 2015]. 
For patients who weigh ≥ 40 kg to < 50 kg, AT2221 dose modification is necessary. Patients in 
this body weight category will receive 195 mg AT2221 (3 × 65-mg capsules). 
Exposure-matching modeling and simulations for body weights of ≥ 40 kg to < 50 kg for the 
195 mg dose were similar to body weights of 70 kg at the 260 mg dose (Figure 3). 


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Figure 3: 
Distributions of AUC by Weight for 260 mg AT2221 versus 195 mg AT2221 
Notes: N represents number of simulated subjects. Black solid and dashed lines are the median and 95% prediction 
interval for a typical 70-kg subject. 
Source: Data on file 
Patients who have a baseline body weight of < 50 kg, but gain weight during the study and reach 
a weight of 55 kg, will have the dose of AT2221 increased to 260 mg (4 × 65-mg capsules). If 
their body weight subsequently decreases and returns to a level below 50 kg, then the AT2221 
dose would be reduced to 195 mg (3 × 65-mg capsules).  
6.4.1.1. 
Dose Selection for ATB200 
Dose selection for ATB200 (20 mg/kg) is based on providing a comparable total protein dose for 
ATB200 as labelled for alglucosidase alfa. The labelled total protein dose is determined by the 
spectrophotometric analysis (ultraviolet absorbance 280 nm, A280). The specific activity 
(GAA enzyme activity/mg protein/hour) as determined by Amicus for alglucosidase alfa 
(129,171 nmol/mg/hr), compared to the specific activity for ATB200 (127,712 to 
133,523 nmol/mg/hr) are essentially the same. Although similarity in total protein and specific 
activity is demonstrated, a lower administered dose of ATB200 (approximately 7% to 8%) is 
expected simply based on methodological differences (A280 extinction coefficient) used for the 
2 products. Overall lower exposures of ATB200 in humans as compared to alglucosidase alfa are 
also expected based on the advantages of the improved ATB200 targeting effects of the 
ATB200. 
A similar ATB200 clinical dose (20 mg/kg) as compared to alglucosidase alfa is selected so as to 
maintain exposures at/or below established exposures as demonstrated alglucosidase alfa, yet to 
demonstrate superior clinical benefits of ATB200/AT2221 co-administration, including benefits 


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associated with improved lysosomal targeting due to optimal glycan structure and 
phosphorylation (ATB200) and enzyme stabilization in blood (AT2221). ATB200 is the primary 
active agent with an enzymatic mechanism of action specifically to reduce intramuscular 
glycogen, the primary lysosomal storage material in LOPD. ATB200 differs structurally from the 
currently approved rhGAA (alglucosidase alfa) based on both its amino acid sequence and 
post-translational glycan structures and phosphorylation. One of the key distinguishing features 
of ATB200 from alglucosidase alfa is substantially more (~95%) of the initial ATB200 dose can 
bind CI-MPR whereas only ~27% of alglucosidase alfa binds receptor at equivalent enzyme 
concentrations. The substantially higher binding of ATB200 to the CI-MPR receptor is due to the 
greater bis-M6P content of ATB200 compared to alglucosidase alfa, which has 10X higher 
affinity to bind to the receptor compared to M6P. As a result, ATB200 is internalized into the 
disease-relevant muscles at a much greater magnitude than alglucosidase alfa and therefore is 
more potent. In vitro studies have demonstrated this by improved uptake of ATB200 into muscle 
cells as well as by substantially greater glycogen reduction with 20 mg/kg ATB200 compared to 
20 mg/kg alglucosidase alfa. In addition, in vivo studies have indicated that the co-administration 
of AT2221 with ATB200 shows even greater trends in glycogen reduction compared to ATB200 
alone as well as alglucosidase alfa. Therefore, a 20 mg/kg dose of ATB200 with AT2221 is 
expected to provide improved uptake into muscle tissue than even higher doses at 40 mg/kg of 
alglucosidase alfa. 
Pharmacokinetics of ATB200 and ATB200 co-administered with AT2221 is well-characterized, 
as part of Stages 1 and 2 of Cohort 1 of the ATB200-02 clinical study. Safety and tolerability 
data in 20 subjects reflect greater than 20 months of treatment and greater than 550 infusions. As 
of the most recent data-cut, AEs have been generally mild and transient. No clinically significant 
risks have been identified that would preclude the use of ATB200 co-administered with AT2221 
in the LOPD subjects. Based on confirmatory evidence of the pharmacokinetics for 
ATB200/AT2221 in the ATB200-02 study, as well as evidence of safety and functional benefit 
on 6MWD to LOPD subjects in this study, an ATB200 clinical dose of 20 mg/kg is planned for 
evaluation in the current study. 
6.4.1.2. 
Dose Selection for AT2221 
Dose selection for AT2221 is based on nonclinical (in vitro and in vivo), clinical (ATB200-02) 
data, and population PK modeling. These data confirm that the selected doses (260 mg for 
subjects ≥ 50 kg and 195 mg for subjects ≥ 40 kg to < 50 kg) acts as a small molecule enzyme 
stabilizer when co-administered with ATB200.  
As a small molecule enzyme stabilizer, AT2221 demonstrates specific and reversible interaction 
with the ATB200 enzyme. Due to the specific binding characteristics of AT2221 with the 
ATB200 enzyme at neutral (pH 7, blood) and acidic pH (pH 4 to 5, lysosome), an administered 
dose of 260 mg in humans result in exposures producing effective interaction (and stabilizing 
effects) with ATB200 in blood and dissociation from ATB200 in the lysosome. 
The dissociation constant (Ki value) represents the binding affinity of AT2221 towards the 
ATB200 enzyme. Nonclinical in vitro studies have confirmed Ki values of 0.18 μM at 
pH 5.2 and 0.21 μM at pH 7.4 for AT2221 with ATB200. Based on the Ki values for the 
AT2221, blood exposures of AT2221 at concentrations > 0.21 μM (pH 7.4, blood) result in 


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effective interaction with ATB200 and AT2221 concentrations < 0.18 μM (pH 5.2) result in 
effective dissociation of AT2221 from the ATB200 enzyme. 
AT2221 exposures in blood and muscle tissue were subsequently confirmed in nonclinical 
in vivo studies. These studies confirmed that an orally administered AT2221 dose (10 mg/kg) in 
mice produced concentrations required for effective interaction with ATB200 in the blood 
(plasma > 30 μM). Nonclinical in vivo studies also confirmed that a 10 mg/kg-dose of AT2221 
(at 24 hours post-administration) produced concentrations in targeted muscle tissue (muscle 
~ 0.013 μM) greater than 10-fold lower than required for effective dissociation from ATB200 in 
the lysosomal microenvironment. Higher doses of AT2221 (> 10 mg/kg) resulted in 
improvements in exposures of ATB200 (limited additional increase of ATB200 exposure). 
Nonclinical in vitro studies (thermostabilization of ATB200 enzyme and stabilization of 
ATB200 in blood) also confirm the stabilizing properties of AT2221 as a small molecule enzyme 
stabilizer of ATB200 at these determined clinically relevant concentrations. 
The efficacy and safety of the ATB200 20 mg/kg AT2221 260 mg co-administration regimen in 
adults has also been subsequently confirmed in the clinical study ATB200-02. 
6.4.2. 
Pharmacokinetics of Co-administered ATB200/AT2221 
The PK portion of first-in-human clinical study ATB200-02 is complete. A summary of the PK 
data from 11 ERT-experienced (Cohort 1) adult subjects with LOPD is presented in Table 4 and 
Table 5. 


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Table 4: 
Pharmacokinetic Summary of Single Ascending Doses of ATB200 in Cohort 1 Subjects with Late-onset 
Pompe Disease 
Total GAA Protein Signature Peptide T09 PK Summary 
Treatment Group 
N 
Cmaxa 
(μg/mL) 
tmaxb 
(h) 
AUC0-ta
(μg•h/mL) 
AUCtmax-24ha
(μg•h/mL) 
AUC0-∞a 
(μg•h/mL) 
Fa,c
Ratio 
ALPHA t½d 
(h) 
CLTd 
(L/h) 
5 mg/kg 
10 
58.4 (19.1) 
4.0 (3.0-4.0) 
208 (17.4) 
108 (25.1) 
211 (17.2) 
- 
1.1 (10.2) 
2.15 (16.9) 
10 mg/kg 
11 
135 (18.3) 
4.0 (3.5-4.0) 
534 (24.4) 
287 (25.6) 
538 (24.4) 
2.63 (9.4) 
1.3 (10.6) 
1.65 (22.4) 
20 mg/kg 
11 
325 (13.5) 
4.0 (3.5-4.0) 
1414 (17.1) 
844 (20.8) 
1418 (16.9) 
6.89 (7.4) 
1.5 (8.5) 
1.26 (18.4) 
AUC = area under the plasma concentration-time curve; AUC0-t = area under the plasma concentration-time curve from time zero to the last quantifiable concentration; 
AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; AUCtmax-24h = area under the plasma concentration-time curve from observed time to reach 
Cmax to 24 hours; CLT = total plasma clearance of drug after intravenous administration; Cmax = maximum observed concentration; CV% = coefficient of variation; F = fraction 
bioavailable expressed as an AUC ratio; GAA = human acid α-glucosidase; max = maximum; min = minimum; PK = pharmacokinetic; t½ = terminal elimination half-life; 
tmax = observed time to reach Cmax. 
a Geometric mean (CV%). 
b Median (min-max). 
c Area under the plasma concentration-time curve ratios for 20 mg/kg and 10 mg/kg are relative to 5 mg/kg.  
d Arithmetic mean (CV%). 


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Table 5: 
Summary of PK Parameters for ATB200/AT2221 Co-administration vs ATB200 Alone in Cohort 1 Subjects 
Total GAA Protein Signature Peptide T09 PK Summary 
Treatment Group 
N 
Cmaxa 
(μg/mL 
tmaxb 
(h) 
AUC0-ta
(μg•h/mL) 
AUCtmax-24ha
(μg•h/mL) 
AUC0-∞a 
(μg•h/mL) 
Fa,c 
Ratio 
ALPHA t½d 
(h) 
CLTd 
(L/h) 
20 mg/kg 
11 
325 (13.5) 
4.0 (3.5-4.0) 
1414 (17.1) 
844 (20.8) 
1418 (16.9) 
- 
1.5 (8.5) 
1.26 (18.4) 
20 mg/kg ATB200 + 130 mg 
AT2221 single dose 
11 
329 (14.3) 
4.0 (3.5-4.0) 
1634 (17.2) 
1057 (19.6) 
1643 (16.9) 
1.16 (6.7) 
1.8 (9.7) 
1.09 (18.8) 
20 mg/kg ATB200 + 130 mg 
AT2221 multiple doses 
11 
335 (15.4) 
4.0 (3.5-5.0) 
1654 (20.8) 
1062 (23.8) 
1662 (20.5) 
1.17 (7.7) 
1.8 (21.8) 
1.08 (20.5) 
20 mg/kg ATB200 + 260 mg 
AT2221 single dose 
10 
339 (12.9) 
4.0 (3.5-4.0) 
1780 (17.7) 
1198 (18.2) 
1789 (17.6) 
1.29 (7.0) 
2.1 (19.5) 
0.99 (21.8) 
20 mg/kg ATB200 + 260 mg 
AT2221 multiple doses 
11 
345 (18.5) 
4.0 (3.5-4.0) 
1815 (21.4) 
1203 (24.2) 
1821 (21.5) 
1.28 (9.4) 
2.1 (16.1) 
0.99 (22.7) 
AUC = area under the plasma concentration-time curve; AUC0-t = area under the plasma concentration-time curve from time zero to the last quantifiable concentration; 
AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; AUCtmax-24h = area under the plasma concentration-time curve from observed time to reach 
Cmax to 24 hours; CLT = total plasma clearance of drug after intravenous administration; Cmax = maximum observed concentration; CV% = coefficient of variation; F = fraction 
bioavailable expressed as an AUC ratio; GAA = human acid α-glucosidase; max = maximum; min = minimum; PK = pharmacokinetic; t½ = terminal elimination half-life;  
tmax = observed time to reach Cmax. 
a Geometric mean (CV%). 
b Median (min-max). 
c Area under the plasma concentration-time curve ratios for 20 mg/kg + AT221 are relative to 20 mg/kg alone. 
d Arithmetic mean (CV%). 


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6.4.3. 
Total GAA Protein Using Signature Peptide(s) T09/T50 
Total GAA protein in plasma was measured by signature peptides T09 (primary) and T50. 
Generally, the pharmacokinetics of signature peptide T50 was similar to T09, and therefore 
confirmed the results of the assay. Mean (standard deviation) plasma total GAA activity by 
signature peptide T09 concentration-time profiles for Cohorts 1 and 3 are presented in Figure 4. 
As shown for Cohort 1 in Figure 5, dose-related increases in plasma total GAA protein are 
observed during Stage 1 for ATB200 alone. Further increases, particularly during the distribution 
elimination phase, are observed during Stage 2 with co-administration of low-dose and high-dose 
AT2221 following both single and multiple dose administrations. Cohort 3 demonstrates a 
similar total GAA protein profile to Cohort 1. 
Figure 4: 
Mean (STDEV) Total GAA Protein Concentration-time Profiles for Cohort 1 
(Stages 1 and 2) and Cohort 3 (Stage 3) 
0
4
8
1 2
1 6
2 0
2 4
0 .1
1
1 0
1 0 0
1 0 0 0
M e a n  (S T D E V ) T o ta l G A A  P ro te in  C o n c -tim e  P ro file s
C o h o rt 1 : S in g le  D o s e
T im e  (h r)
T o ta l G A A  P ro te in  S ig n a tu re
P e p tid e  T 0 9  C o n c  (u g /m L )
5  m g /k g  A T B 2 0 0
1 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0  +  1 3 0  m g  A T 2 2 2 1  S D
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1  S D
C o h o rt 1
0
4
8
1 2
1 6
2 0
2 4
0 .1
1
1 0
1 0 0
1 0 0 0
M e a n  (S T D E V ) T o ta l G A A  P ro te in  C o n c -tim e  P ro file s
C o h o rt 1 : M u ltip le  D o s e
T im e  (h r)
T o ta l G A A  P ro te in  S ig n a tu re
P e p tid e  T 0 9  C o n c  (u g /m L )
5  m g /k g  A T B 2 0 0
1 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0  +  1 3 0  m g  A T 2 2 2 1  M D
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1  M D
C o h o rt 1
0
4
8
1 2
1 6
2 0
2 4
0 .1
1
1 0
1 0 0
1 0 0 0
M e a n  (S T D E V ) T o ta l G A A  P ro te in  C o n c -tim e  P ro file s
C o h o rt 1  v s . 3 : S in g le  D o s e
T im e  (h r)
T o ta l G A A  P ro te in  S ig n a tu re
P e p tid e  T 0 9  C o n c  (u g /m L )
2 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1
S D  C o h o rt 1
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1
S D  C o h o rt 3
0
4
8
1 2
1 6
2 0
2 4
0 .1
1
1 0
1 0 0
1 0 0 0
M e a n  (S T D E V ) T o ta l G A A  P ro te in  C o n c -tim e  P ro file s
C o h o rt 1  v s  3 : M u ltip le  D o s e
T im e  (h r)
T o ta l G A A  P ro te in  S ig n a tu re
P e p tid e  T 0 9  C o n c  (u g /m L )
2 0  m g /k g  A T B 2 0 0
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1  M D
C o h o rt 1
2 0  m g /k g  A T B 2 0 0  +  2 6 0  m g  A T 2 2 2 1  M D
C o h o rt 3
Abbreviations: ATB200 = recombinant human acid α-glucosidase; AT2221 = N-butyl deoxynojirimycin; 
GAA = human acid α-glucosidase; hr = hour; MD = multiple dose; SD = single dose; STDEV = standard deviation 
Source: Amicus data on file 
In Cohort 1 (ERT-experienced LOPD subjects), total GAA protein by signature peptide T09 
exposures (Cmax and AUC) demonstrated greater than dose-proportional increases during Stage 1 
(single ascending doses of 5, 10, and 20 mg/kg ATB200), as shown in column “F” in the table. 
Co-administration with 130 mg AT2221 resulted in a 16% to 17% increase in total GAA protein 
mean AUC. Co-administration with 260 mg AT2221 increased total GAA protein AUCs by 28% 
to 29%. These increases were mainly observed during the early, distribution terminal phase, as 
shown by observed increases in the alpha half-life. The increased distribution phase area can be 
more clearly observed in the partial AUCs from tmax to 24-hours post-dose. These increases 
suggest stabilization of ATB200 by the small molecule enzyme stabilizer, AT2221, while in 
blood. Clearance of plasma total GAA protein decreased with dose escalation with further 
decreases observed when co administered with AT2221, again suggesting better stabilization of 
ATB200 while in circulation. Further evidence of stabilization can be observed in Figure 4 and 


Amicus Therapeutics, Inc. 
Protocol ATB200-03 Amendment 3 
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Figure 5. During terminal phase time points, 12 hours and 24 hours, statistically significant 
increases in total GAA protein are observed following co-administration with low-dose and high-
dose AT2221 relative to 20 mg/kg ATB200 alone. At 12 hours post dose, the differences were 
highly significant (p < 0.01 or p < 0.001) for high-dose AT2221 co-administration. 
Figure 5: 
Plasma Total GAA Protein Concentration Comparisons Between 
Co-administration Treatments vs ATB200 Alone at 12 and 24 Hours 
Post-dose (1-sided t-tests) for Cohort 1 
2 0  m g /k g
2 0  m g /k g  +  1 3 0  m g  S D
2 0  m g /k g  +  1 3 0  m g  M D
2 0  m g /k g  +  2 6 0  m g  S D
2 0  m g /k g  +  2 6 0  m g  M D
0
1 0
2 0
3 0
A T B 2 0 0 -0 2  IA 4  T o ta l G A A  P ro te in
C o m p a ris o n s  to  2 0  m g /k g  A lo n e  a t 1 2 h  P o s t D o s e
P la s m a  T o ta l G A A  P ro te in
(µ g /m L )
*
***
***
**
** p < 0 .0 1
*** p < 0 .0 0 1
* p < 0 .0 5
2 0  m g /k g
2 0  m g /k g  +  1 3 0  m g  S D
2 0  m g /k g  +  1 3 0  m g  M D
2 0  m g /k g  +  2 6 0  m g  S D
2 0  m g /k g  +  2 6 0  m g  M D
0 .0
0 .5
1 .0
1 .5
2 .0
A T B 2 0 0 -0 2  IA 4  T o ta l G A A  P ro te in
C o m p a ris o n s  to  2 0  m g /k g  A lo n e  a t 2 4 h  P o s t D o s e
P la s m a  T o ta l G A A  P ro te in
(µ g /m L )
n s
*
**
*
* p < 0 .0 5
** p < 0 .0 1
n s = n o t sig n ific a n t
Abbreviations: ATB200 = recombinant human acid α-glucosidase; h = hour; IA = interim analysis; GAA = human 
acid α-glucosidase; MD = multiple dose; SD = single dose 
Source: Amicus data on file 
Generally, the pharmacokinetics of 20 mg/kg ATB200 based on plasma total GAA protein was 
similar between single and multiple doses when co-administered with 130 mg AT2221, and 
between single and multiple doses when co-administered with 260 mg AT2221. 
The plasma total GAA protein PK profile of Cohort 3 (ERT-naïve subjects with LOPD) was 
generally similar to Cohort 1 and not statistically different as shown in Table 6, where all 
comparisons are contained with the 90% to 125% confidence intervals. 
Table 6: 
Statistical Comparisons by ANOVA Between Cohort 1 Single Dose vs 
Multiple Dose and Between Cohort 1 and Cohort 3 
ANOVA for Total GAA Protein by Signature Peptide T09 AUC (μg·h/mL) 
Reference 
Test 
AUC 
Ratio 
90% Lower-bound 
CI 
90% Upper-bound 
CI 
% Ref 
Cohort 1 Single 
Dose  
Cohort 1 Multiple 
Dose 
98.0 
94.9 
101.2 
Cohort 1 Single 
Dose 
Cohort 3 Single 
Dose 
100.1 
82.3 
121.8 


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Table 6: 
Statistical Comparisons by ANOVA Between Cohort 1 Single Dose vs 
Multiple Dose and Between Cohort 1 and Cohort 3 (Continued) 
ANOVA for Total GAA Protein by Signature Peptide T09 AUC (μg·h/mL) 
Reference 
Test 
AUC 
Ratio 
90% Lower-bound 
CI 
90% Upper-bound 
CI 
% Ref 
Cohort 1 Multiple 
Dose 
Cohort 3 Multiple 
Dose 
97.5 
80.2 
118.6 
Abbreviations: ANOVA = analysis of variance; AUC = area under the plasma concentration-time curve; 
GAA = human acid α-glucosidase; CI = confidence interval 
Source: Data on file 
A PK summary of plasma AT2221 is presented in Table 7. Plasma AT2221 exposures (Cmax and 
AUC) are approximately dose proportional. The rate of absorption (tmax) values support dosing 
with AT2221 1 hour before the start of ATB200 infusion, so that peak AT2221 concentrations 
are attained midway into infusion. Termination elimination half-life was consistent at 
approximately 5 to 6 hours, as was plasma clearance (approximately 10 L/h) and terminal 
volume of distribution (77 to 106 L). Generally, the PK profile of dose-normalized AT2221 is 
similar to marketed formulations of miglustat.  
Overall, the preliminary exposures of ATB200 and AT2221 subjects with LOPD are well within 
the limits of the established safety margins. 


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Table 7: 
ATB200-02 PK Summary from Preliminary Plasma AT2221 Concentrations 
Sampled From Cohort 1 and Cohort 3 Subjects with Late-onset Pompe 
Disease 
AT2221 PK Summary 
Treatment Group (N) 
Cohort 
Cmaxa 
tmaxb 
AUC0-ta 
AUC0-∞a 
Frel 
t½c 
CL/Fc 
Vz/Fc 
(ng/mL) 
(h) 
(ng•h/mL) (ng•h/mL) Ratio 
(h) 
(L/h) 
(L) 
20 mg/kg ATB200 + 130 mg 
AT2221 SD (11) 
1 
1527 
(26.0) 
3.5 
(1.5 – 5.0) 
11870 
(24.2) 
12721 
(24.7) 
- 
6.1 
(18.9) 
10.5 
(22.1) 
92.1 
(32.0) 
20 mg/kg ATB200 + 130 mg 
AT2221 MD (11) 
1 
1505 
(23.9) 
3.0 
(1.5 – 4.0) 
11968 
(24.5) 
12913 
(25.6) 
- 
6.5 
(29.3) 
10.3 
(21.3) 
97.3 
(39.3) 
20 mg/kg ATB200 + 260 mg 
AT2221 SD (10) 
1 
2665 
(31.8) 
4.0 
(2.0 – 5.0) 
22928 
(33.0) 
24803 
(33.3) 
1.98 
(24.8) 
6.7 
(17.1) 
10.9 
(26.6) 
106 
(33.1) 
20 mg/kg ATB200 + 260 mg 
AT2221 MD (11) 
1 
3089 
(28.8) 
3.0 
(1.0 – 4.0) 
23565 
(29.8) 
25029 
(30.4) 
1.94 
(14.9) 
6.0 
(18.4) 
10.7 
(25.5) 
94.4 
(35.8) 
20 mg/kg ATB200 + 260 mg 
AT2221 SD (5) 
3 
3559 
(25.8) 
2.0 
(1.5 – 3.0) 
25747 
(13.2) 
26936 
(12.3) 
NA 
5.5 
(19.2) 
9.71 
(12.7) 
77.3 
(25.4) 
20 mg/kg ATB200 + 260 mg 
AT2221 MD (5) 
3 
3083 
(34.0) 
2.5 
(2.0 – 3.0) 
25306 
(17.8) 
26591 
(15.5) 
NA 
5.7 
(19.4) 
9.87 
(14.6) 
81.8 
(29.5) 
Abbreviations: ATB200 = recombinant human acid α-glucosidase; AT2221 = N-butyl deoxynojirimycin; AUC0-∞ = area under 
the plasma concentration-time curve from time zero to infinity; AUC0-t = area under the plasma concentration-time curve from 
time zero to the last quantifiable concentration; CL/F = apparent total plasma clearance; Cmax = maximum observed 
concentration; CV = coefficient of variation; Frel = relative bioavailability; t½ = terminal elimination half-life; Max = maximum; 
Min = minimum; N = number of subjects; NA = not applicable; tmax = observed time to reach Cmax; Vz/F = apparent volume of 
distribution. 
a Geometric mean (CV%) 
b Median (Min – Max) 
c Arithmetic mean (CV%) 
Source: Data on file 
6.5. 
Primary Endpoint Rationale 
The primary efficacy variable in this study is the 6MWD as measured by the 6MWT. This 
measure has been used in registration studies in Pompe, and it is part of the Clinical Outcome 
Assessment Compendium (December 2015). The 6MWD was also used in the approval of 
alglucosidase alfa.  
In LOPD, the disease course varies substantially among patients with respect to age at onset and 
rate of decline of muscular and respiratory function. Furthermore, there is no clear pattern in the 
sequence of clinical deterioration of respiratory and skeletal muscles (Hagemans et al 2005). 
The 6MWT evaluates the global and integrated responses of all the systems involved during 
ambulatory function, including the pulmonary and cardiovascular systems, systemic circulation, 
neuromuscular units, and muscle metabolism (ATS 2002). Thus, the 6MWT is a more holistic 
assessment than other measures, such as the Timed Up and Go (TUG) or FVC. 
The improvement in the endurance test (6MWT) is a reflection of overall improvement in the 
subject’s muscular and pulmonary functions. Based on predicted values for 6MWD in healthy 
adults (Enright, Sherrill 1998) and adults with pathology (Bohannon, Crouch 2017), a minimum 
of 20 meters is considered a clinically important difference. Therefore, Study ATB200-03 will 
use 6MWD as measured by the 6MWT for its primary endpoint. 


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6.6. 
Summary of Known Potential Risks and Benefits 
A summary of the known and potential risks and benefits are provided in a separate document, 
Benefit Risk Profile Document. 


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7.
STUDY OBJECTIVES
7.1. 
Primary Objective
•
To assess the efficacy of ATB200/AT2221 co-administration on ambulatory function,
as measured by the 6MWT, compared with alglucosidase alfa/placebo
7.2. 
Secondary Objectives
•
To assess the efficacy of ATB200/AT2221 co-administration on pulmonary function,
as measured by sitting FVC (% predicted) compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on muscle strength,
compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on health-related
patient-reported outcomes, compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on motor function,
compared with alglucosidase alfa/placebo
•
To assess the efficacy of ATB200/AT2221 co-administration on overall clinical
impression as assessed by both physician and subject, compared with alglucosidase
alfa/placebo
•
To assess the safety, tolerability, and immunogenicity of ATB200/AT2221
co-administration compared with alglucosidase alfa/placebo
•
To assess the effect of ATB200/AT2221 co-administration on biomarkers of muscle
injury and disease substrate compared with alglucosidase alfa/placebo
•
To characterize the population pharmacokinetics of ATB200 and alglucosidase alfa in
ERT-experienced subjects using plasma total GAA protein level by signature peptide
assay and plasma AT2221 concentration
•
To characterize the pharmacokinetics of ATB200, alglucosidase alfa, and AT2221 in
ERT-naïve subjects using noncompartmental analysis
•
To explore the exposure-response relationship for ATB200/AT2221 and
alglucosidase alfa/placebo co-administration


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8.
INVESTIGATIONAL PLAN
8.1. 
Study Design
This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult 
subjects with LOPD who have received ERT with alglucosidase alfa (ie, ERT-experienced) or 
who have never received ERT (ie, ERT-naïve) compared with alglucosidase alfa/placebo. As this 
study was initially designed to assess the effects of ATB200/AT2221 in ERT-experienced 
subjects who continued to receive alglucosidase alfa in Study POM-003, subjects from that study 
who meet the eligibility criteria for this study will make up part of the ERT-experienced study 
population. 
Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during 
the screening period; treatment with alglucosidase alfa will then be replaced by study drug 
(ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption 
(ie, every 2 weeks). The Screening Visits will occur over 2 or more days to allow for repeated 
6MWT and pulmonary function test assessments. The repeated tests for 6MWT or for pulmonary 
function (FVC, slow vital capacity [SVC], maximal inspiratory pressure [MIP], maximal 
expiratory pressure [MEP], and sniff nasal inspiratory pressure [SNIP]) should not be done on 
the same day. No other assessments should be performed on the day that the 6MWT and 
pulmonary function tests are repeated. Eligible subjects will be randomly assigned in a 2:1 ratio 
to receive ATB200/AT2221 or alglucosidase alfa/placebo and stratified by ERT status (ERT-
experienced, ERT-naïve) and baseline 6MWD (75 to < 150 meters, 150 to < 400 meters, ≥ 400 
meters) (Figure 6). 
Figure 6: 
Study Design Schematic 
Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical 
laboratory tests) for monitoring of initial safety will be performed at these visits for the first 
6 weeks of the study. Subjects may be eligible for administration of study drug at their home 
after participating in the study for 6 months. During the conduct of the study, the SARS-CoV-2 
(COVID-19) pandemic emerged and impeded the conduct of site visits and laboratory testing 
due to quarantines, travel restrictions, and risk of infection. With the intention of maintaining 


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regular infusions, home infusions will be allowed wherever possible for subjects who may be 
eligible (see Section 12.2.3). Study visits that include efficacy, safety, and other assessments will 
be scheduled approximately every 3 months and may occur over 2 or more days, provided all 
study assessments and procedures (with the exception of pharmacokinetic [PK] sample 
collection) are performed before administration of study drug. If a visit was missed due to 
COVID-19 related quarantines, travel restrictions, and risk of infection, it should be recorded as 
such in the Interactive Voice/Web Response System and electronic data capture (EDC) system. 
A reason for the missed visit should be entered into the EDC as COVID-19 related. The relevant 
institutional review boards (IRBs), independent ethics committees (IECs), and research ethics 
boards (REBs) should be notified of any deviations from the protocol. If infusions were missed 
near the scheduled assessments on Week 26, 38 or 52, it should be communicated with Amicus 
on a case-by-case basis to determine whether catch-up infusions are needed and how many 
catch-up infusions are needed prior to the study assessments. If 5 or more consecutive infusions 
are missed due to any circumstance, including COVID-19, the subject must be discontinued from 
this protocol. Any subjects discontinued due to COVID-19 may be eligible for ATB200-07 with 
Amicus approval. 
Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function 
(6MWT), motor function tests (GSGC test and TUG test), muscle strength (manual muscle 
testing and quantitative muscle testing), and pulmonary function tests (FVC, SVC, MIP, MEP, 
and SNIP). Patient-reported outcomes (Rasch-built Pompe-specific Activity [R-PAct] Scale, 
EuroQol 5 Dimensions-5 Levels Instrument [EQ-5D-5L], Patient-Reported Outcomes 
Measurement Information System [PROMIS®] instruments for physical function, fatigue, 
dyspnea, and upper extremity, and Subject’s Global Impression of Change). The Physician’s 
Global Impression of Change will also be performed.  
Pharmacodynamic assessments include measurement of biomarkers of muscle injury (CK) and 
disease substrate (urinary Hex4). Blood samples will be collected for determination of total GAA 
protein levels and AT2221 concentrations in plasma for a population PK analysis. Safety 
assessments include monitoring of AEs, including IARs, clinical laboratory tests (chemistry, 
hematology, and urinalysis), vital signs, physical examinations including weight, 
electrocardiograms (ECGs), and immunogenicity. Concomitant medications and nondrug 
therapies will also be recorded. 
8.2. 
Duration of Study 
The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 
30-day safety follow-up period. Subjects who missed visits due to COVID-19 related
quarantines, travel restrictions, and risk of infection may be enrolled longer than 12 months in
the study. In addition, subjects who discontinue study drug for any reason will be followed for up
to 12 months for monitoring of immunogenicity; these results will be reported separately.
Subjects who complete this study will have the option to participate in an open-label extension 
study to receive ATB200/AT2221 under a separate protocol. 


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8.3. 
Criteria for Termination of the Study 
The study may be terminated by the sponsor for any of the following reasons: 
•
evidence suggesting that safety risks associated with ATB200/AT2221 treatment
outweigh the potential benefits or at the recommendation of the Data Monitoring
Committee (DMC) (Section 13.5)
•
lack of efficacy
•
inability to enroll the targeted number of subjects
8.4. 
Definition of the End of Study
End of study is defined as the date of the last subject’s last visit. The final analysis will be 
performed when all subjects have completed the study or have been withdrawn from the study. 
8.5. 
Discussion of Study Design, Including Choice of Control Groups 
This is a double-blind, active/placebo-controlled, randomized study. 
The study design includes randomization to a control, alglucosidase alfa/placebo, in order to 
provide adequate blinding of the study population and to address potential bias. This is a 
standard design for a registration study. 


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9.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
9.1. 
Number of Subjects
The planned sample size is approximately 110 subjects at up to approximately 90 sites globally. 
A total of 100 subjects (including at least 30 ERT-naïve subjects) are expected to complete the 
study. 
9.2. 
Eligibility Criteria 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be eligible to 
participate in the study. 
9.2.1. 
Inclusion Criteria 
1. Subject must provide signed informed consent prior to any study-related procedures
being performed.
2. Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
3. Female subjects of childbearing potential and male subjects must agree to use medically
accepted methods of contraception during the study and for 90 days after the last dose of
study drug.
4. Subject must have a diagnosis of LOPD based on documentation of one of the following:
a.
deficiency of GAA enzyme
b. GAA genotyping
5. Subject is classified as one of the following with respect to ERT status:
a.
ERT-experienced, defined as currently receiving standard of care ERT (alglucosidase
alfa) at the recommended dose and regimen (ie, 20 mg/kg dose every 2 weeks) for
≥ 24 months
−
Specific to Australia, ERT-experienced, defined as currently receiving standard of
care ERT (alglucosidase alfa) at the recommended dose and regimen, at a dose of
20 mg/kg based on lean or ideal body weight every 2 weeks
b. ERT-naïve, defined as never having received investigational or commercially
available ERT
6. Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National
Health and Nutrition Examination Survey III) at screening.
7. Subject performs two 6MWTs at screening that are valid, as determined by the clinical
evaluator, and that meet all of the following criteria:
a.
both screening values of 6MWD are ≥ 75 meters
b. both screening values of 6MWD are ≤ 90% of the predicted value for healthy adults
c.
the lower value of 6MWD is within 20% of the higher value of 6MWD


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9.2.2. 
Exclusion Criteria 
1. Subject has received any investigational therapy or pharmacological treatment for Pompe
disease, other than alglucosidase alfa, within 30 days or 5 half-lives of the therapy or
treatment, whichever is longer, before Day 1 or is anticipated to do so during the study.
2. Subject has received gene therapy for Pompe disease.
3. Subject is taking any of the following prohibited medications within 30 days before
Day 1:
•
miglitol (eg, Glyset)
•
miglustat (eg, Zavesca)
•
acarbose (eg, Precose or Glucobay)
•
voglibose (eg, Volix, Vocarb, or Volibo)
Note: None of these medications have a half-life that, when multiplied by 5, is longer 
than 30 days. 
4. Subject requires the use of invasive or noninvasive ventilation support for > 6 hours per
day while awake.
5. Subject has a hypersensitivity to any of the excipients in ATB200, alglucosidase alfa, or
AT2221.
6. Subject has a medical condition or any other extenuating circumstance that may, in the
opinion of the investigator or medical monitor, pose an undue safety risk to the subject or
may compromise his/her ability to comply with or adversely impact protocol
requirements. This includes clinical depression (as diagnosed by a psychiatrist or other
mental health professional) with uncontrolled or poorly controlled symptoms.
7. Subject, if female, is pregnant or breastfeeding at screening.
8. Subject, whether male or female, is planning to conceive a child during the study.
9. Subject refuses to undergo genetic testing.
9.3. 
Withdrawal Criteria 
Subjects may withdraw or be withdrawn from the study for any reason, including, but not limited 
to, the following:  
•
at their own request
•
if, in the investigator’s opinion, continuation in the study would be detrimental to the
subject’s well-being
•
persistent noncompliance with study requirements, such as failure to comply with the
study visit schedule, in the judgment of the investigator and/or medical monitor
•
persistent noncompliance with study drug or failure to return to the study site for
infusion visits, in the judgment of the investigator and/or medical monitor
•
missed 5 consecutive infusions at any time during the study


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•
inability to contact subject (ie, subject is lost to follow-up)
•
pregnancy (female subjects)
•
planning to conceive a child (male or female subjects)
•
sponsor decision to terminate the study
In all cases, the reason for withdrawal and the date of withdrawal must be recorded in the 
electronic case report form (eCRF) and in the subject’s medical records.  
Subjects who withdraw will be requested to complete the Early Termination Visit. The 
investigator will make every effort to contact withdrawing subjects and schedule the early 
termination assessments. Upon study completion or subject discontinuation, subjects who are 
confirmed positive for anti-rhGAA antibodies (Abs) will complete follow-up immunological 
testing for up to 12 months (see Section 12.2.7). 
9.4. 
Subjects of Reproductive Potential 
Subjects must be willing to apply highly effective contraception during the study and through the 
duration as defined below and for 90 days after the final dose of study treatment. 
The allowed methods of contraception described in the following text are only effective when 
used consistently, correctly, and in accordance with the product label. The investigator is 
responsible for ensuring subjects understand how to properly use these methods of contraception. 
A highly effective birth control is defined as one that results in a low failure rate (ie, < 1% per 
year) when used consistently and correctly. 
Female subjects of child-bearing potential are defined as all women physiologically capable of 
becoming pregnant, ie, fertile, following menarche unless permanently sterile. Highly effective 
methods of contraception include the following: 
•
total abstinence, when this is in line with the preferred and usual lifestyle of the
subject
•
combined (estrogen- and progestogen-containing) hormonal contraception associated
with inhibition of ovulation: oral, intravaginal, transdermal
•
progestogen-only hormonal contraception associated with inhibition of ovulation:
oral, injectable, implantable
•
intrauterine device
•
intrauterine hormone-releasing system
•
bilateral tubal occlusion
•
vasectomized partner
Note: Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with a 
serum FSH level > 40 mIU/mL and estradiol < 20 pg/mL, or have had surgical bilateral 


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oophorectomy, only when the reproductive status of the woman has been confirmed by follow-
up hormone level assessment and she is considered not of child-bearing potential. 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Male subjects and their partners must use highly effective methods of contraception (ie, condom 
in male subjects and highly effective contraception, as listed previously in this section, in their 
female partners) for the entire duration of the study and continue to use contraception and refrain 
from fathering a child for 90 days following the study treatment. 
In the event of pregnancy in a female subject, study drug must be discontinued. Pregnancies 
occurring during study participation (female subject or a female partner of a male subject) must 
be reported to Amicus and followed as described in Section 13.4. 


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10.
TREATMENT OF SUBJECTS
Subjects will be randomized with a randomization ratio of at least 2:1 to receive either 
ATB200/AT2221 or alglucosidase alfa/placebo according to the treatment assignment in Table 8. 
Table 8: 
Treatment Assignment 
Treatment Assignment 
Treatment 
Regimen 
ATB200/AT2221 
AT2221a 
Subjects ≥ 50 kg: 260 mg (4 × 65-mg oral 
capsules) 1 hour prior to ATB200 infusion 
every 2 weeks  
Subjects ≥ 40 kg to < 50 kg: 195 mg 
(3 × 65-mg oral capsules) 1 hour prior to 
ATB200 infusion every 2 weeks  
ATB200 
20 mg/kg IV infusion over a 4-hour duration 
every 2 weeks 
Alglucosidase alfa/placebo 
Placebo 
Subjects ≥ 50 kg: Placebo (4 oral capsules) 
1 hour prior to alglucosidase alfa infusion 
every 2 weeks 
Subjects ≥ 40 kg to < 50 kg: Placebo (3 oral 
capsules) 1 hour prior to alglucosidase alfa 
infusion every 2 weeks 
Alglucosidase alfa 
20 mg/kg IV infusion over a 4-hour duration 
every 2 weeks 
Abbreviations: IV = intravenous  
a Note: Subjects are required to fast at least 2 hours before and 2 hours after administration of AT2221 or placebo. 


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11.
STUDY DRUG MATERIALS AND MANAGEMENT
11.1. 
Study Drug
Study drug is defined in this protocol as ATB200, AT2221, alglucosidase alfa, placebo, or a 
combination of these. Investigational product refers only to ATB200, AT2221, or a combination 
of these.  
The study drug will be administered every 2 weeks at the study site in a blinded fashion. After 
6 months in the study without any IARs, subjects may be eligible for administration of study 
drug at their home (see Section 12.2.3). In countries or at sites where the administration of 
alglucosidase alfa is reserved for hospital use, however, all study drug will be administered in a 
hospital setting.   
ATB200 (rhGAA) functions as ERT. AT2221 (N-butyl-deoxynojirimycin) is an iminosugar that 
functions as a selective small molecule enzyme stabilizer of rhGAA.  
Table 9 provides details on the investigational products. 
Table 9: 
Investigational Products 
Product name 
ATB200 
AT2221 
Dosage form 
Lyophilized powder for IV infusion 
Hard gelatin capsule 
Unit dose 
15 mg/mL 
65 mg 
Route of administration 
IV infusion 
Oral 
Physical description 
Sterile, nonpyrogenic, white to 
off-white lyophilized cake or powder 
supplied in single-use, clear 20-mL 
(cc) glass vials
White, size 2, hard gelatin 
capsules supplied in 40-cc HDPE 
bottles 
Excipients 
sodium citrate dihydrate, 
citric acid monohydrate,  
mannitol,  
polysorbate-80 
Microcrystalline cellulose, 
pregelatinized starch,  
Emprove® sucralose powder, 
magnesium stearate,  
colloidal silicon dioxide 
Manufacturer 
WuXi Biologics Co., Ltd 
108 Meiliang Rd 
Mashan, Binhu District, 
WuXi, China 
Alcami 
1726 N 23rd St 
Wilmington, NC 
28405, USA 
Abbreviations: HDPE = high density polyethylene; IV = intravenous; USA = United States of America 
Alglucosidase alfa (Myozyme/Lumizyme) functions as ERT. Its dosage form is lyophilized 
powder for IV infusion, and its unit dose is 5 mg/mL. It is a sterile, nonpyrogenic, white to 
off-white lyophilized cake or powder supplied in single-use, clear 20-mL (cc) glass vials. 
Excipients include mannitol, polysorbate-80, sodium phosphate dibasic heptahydrate, and 
sodium phosphate monobasic monohydrate. Alglucosidase alfa is manufactured by Genzyme 
Corporation (Cambridge, MA). Placebo oral capsules match AT2221 in appearance, contain the 
same excipients as AT2221, and are manufactured by Alcami (Wilmington, NC). 


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11.2. 
Study Drug Packaging and Labeling 
AT2221 (65 mg capsule) and associated placebo will be supplied by Amicus as hard gelatin 
capsules in high density polyethylene bottles and will be administered orally. 
ATB200 (105 mg/vial) will be supplied by Amicus as a lyophilized powder in glass vials and 
will be administered by IV infusion upon reconstitution with sterile water for injection and 
followed by dilution with 0.9% sodium chloride for injection prior to administration. Sterile 
water for injection and 0.9% sodium chloride for injection will be supplied by the study sites. 
Alglucosidase alfa (50 mg/vial) will be supplied by Amicus as a lyophilized powder in glass 
vials and will be administered by IV infusion upon reconstitution with sterile water for injection 
and followed by dilution with 0.9% sodium chloride for injection prior to administration. Sterile 
water for injection and 0.9% sodium chloride for injection will be supplied by the study sites.  
Each container will be labeled in conformance to regulatory requirements and, where applicable, 
local laws. All labels will be printed with the following information at a minimum: study 
identifier, identity of drug and dosage, sponsor name and contact details (and/or details of a local 
designee contact), dosing instructions, storage information, and other applicable local law 
statements. All labels will comply with legal requirements of each country. 
11.3. 
Study Drug Storage 
Sites will be instructed to store AT2221 65-mg oral capsules according to the conditions 
identified on the labels of each study drug, at room temperature (15°C to 25°C or 59°F to 77°F), 
with excursions permitted to (40°C or 104°F) in a secure area, free from environmental 
extremes, and with restricted access.  
Sites will be instructed to store ATB200 lyophilized powder vials according to the conditions 
identified on the study drug label, at cold temperature (2°C to 8°C or 36°F to 46°F), with short 
excursions permitted to (25°C or 77°F) in a secure area, free from environmental extremes, and 
with restricted access. 
Temperature logs must be maintained for the duration of the study. The temperature of the 
refrigerator where the ATB200 and alglucosidase alfa products are stored and the temperature of 
the storage room (or cabinet) where the AT2221 and placebo are stored must be recorded for 
each working day of the week the pharmacy personnel (or designated study personnel) is 
available. Temperature is required to be recorded using a standard min-max thermometer that has 
calibration records available (details usually contained within the device leaflet) and is 
maintained according to institutions standard maintenance policy. 
The study drugs are to be stored only at the site(s) listed on Form FDA 1572 or Statement of 
Foreign Investigator form for non-US sites. Study drug is to be dispensed only to subjects who 
have provided written informed consent, have met all entry criteria, and are randomized using 
the interactive response technology (IRT). 
Alglucosidase alfa will be stored in the same manner as described for ATB200. Placebo will be 
stored in the same manner as described for AT2221. 
Because the vial sizes and appearance of ATB200 and alglucosidase alfa differ, vials should be 
kept inside of cartons (which appear identical between both product types) if possible while 


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being stored to avoid the potential of partial unblinding and should only be removed by an 
unblinded pharmacist at the time of reconstitution in an area with restricted access for unblinded 
staff. If it is not possible to keep the vials in the carton due to space limitations at a particular 
site, vials must be stored in a secure location in which only the unblinded pharmacist has access. 
Cartons containing ATB200/alglucosidase alfa should only be handled by unblinded staff 
because they may have slight differences in weight. Details of the storage conditions can be 
found in the pharmacy manual. 
11.4. 
Study Drug Preparation 
Instructions for preparation for oral product and infusion and the volume and rate of infusions 
will be provided in the pharmacy manual. 
Only unblinded qualified personnel will handle and/or prepare the study drugs to maintain the 
integrity of the double-blind design of the study.  
11.5. 
Administration 
11.5.1. 
ATB200/Alglucosidase Alfa 
The dose of ATB200/alglucosidase alfa is 20 mg/kg body weight. Dose will be calculated based 
on actual body weight, even if a subject’s previous dose was based on lean body weight. The 
value for body weight will be obtained at the previous protocol-specified visit for obtaining 
weight. 
ATB200/alglucosidase alfa does not contain any preservatives. Vials are single-use only. 
Reconstituted vials should be retained at the site until the monitor checks accountability. 
ATB200/alglucosidase alfa is to be administered every 2 weeks as an approximate 4-hour IV 
infusion. Changes in the duration of ATB200/alglucosidase alfa infusion due to safety or 
tolerability issues will be documented. The total volume of infusion is determined by the 
subject’s body weight. Instructions for preparation for infusion and the volume and rate of 
infusions will be provided in the pharmacy manual. Reconstitution of ATB200/alglucosidase alfa 
should be performed by unblinded qualified study personnel (eg, pharmacist or pharmacy 
technician or nurse under physician supervision). Intravenous administration of 
ATB200/alglucosidase alfa should be performed by qualified study personnel. Subjects should 
be carefully monitored during and after the first 3 infusions (Section 12.2.3). Any delegation of 
this responsibility must follow Section 16.3.4. Rate and duration of infusion must be constant for 
each infusion. Changes in the rate and/or duration of infusion due to safety or tolerability issues 
will be documented. 
The protocol-specified administration of alglucosidase alfa is consistent with the Lumizyme 
Prescribing Information (August 2014) and the Myozyme Summary of Product Characteristics 
(December 2018). 
11.5.2. 
AT2221/Placebo  
The dose of AT2221 is 260 mg (4 capsules at the 65-mg strength) for subjects weighing ≥ 50 kg 
and 195 mg (3 capsules at the 65-mg strength) for subjects weighing ≥ 40 kg to < 50 kg. 
The dose of placebo is 3 or 4 placebo capsules of the same size as AT2221, that is, size 2.  


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AT2221/placebo is administered orally, approximately 1 hour before ATB200/alglucosidase alfa 
infusion according to their treatment arm. Subjects will take 3 or 4 capsules of AT2221/placebo, 
depending on their body weight. Subjects should fast for at least 2 hours before and 2 hours after 
administration of AT2221/placebo. Fasting is defined as nothing by mouth except for water; this 
includes prescription or over-the-counter medications, vitamins, or herbal supplements other than 
premedications for administration of ATB200. Subjects should arrive at the clinic at least 1 hour 
prior to the start of the ATB200/alglucosidase alfa infusion to receive AT2221/placebo. 
11.6. 
Randomization and Blinding 
11.6.1. 
Randomization 
The randomization code used in this study was generated and will be maintained by an external 
resource not involved with the conduct of the study. 
11.6.2. 
Blinding 
The following methods are used to maintain the blind of the investigator and site personnel, 
sponsor, and/or subject:  
•
use of IRT to randomly assign subjects to study drug and to calculate dose of study
drug
•
an unblinded pharmacist to handle and prepare the study drug
•
an unblinded monitor to perform study drug accountability at the site
•
an unblinded medical monitor to review select laboratory results that could
potentially unblind a subject’s treatment assignment
•
black or dark covering over ATB200 and alglucosidase alfa reconstituted solution to
be used during infusion
•
a matching placebo for AT2221 to be used with alglucosidase alfa
11.6.3. 
Unblinding of Treatment Assignment 
The medical care of subjects includes medical decisions, such as whether to start or stop 
treatment or institute alternative treatment, if required. In emergency situations, the investigator 
may need to unblind a subject’s treatment assignment immediately using IRT (see the IRT 
manual) or as quickly as possible if he/she finds it is in the best interest of the subject. If IRT is 
unavailable or inaccessible at the time of an emergency unblinding, investigators are to contact 
IRT Technical Support, as described in the pharmacy manual. A subject’s treatment assignment 
should be unblinded only if knowledge of the study drug administered will affect the treatment 
options available to that subject. It is the responsibility of the investigator to promptly document 
and explain any premature unblinding of treatment assignment to the Sponsor. 
11.7. 
Study Drug Accountability 
In accordance with local regulatory requirements, the investigator, designated site personnel, or 
head of the medical institution (where applicable) must document the amount of study drug 
dispensed and/or administered to study subjects, and the amount received from and returned to 


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Amicus (or designee), where applicable. Product accountability records must be maintained 
throughout the course of the study. 
11.8. 
Study Drug Handling and Disposal 
Because vials of ATB200 and alglucosidase alfa are distinguishable, the unblinded pharmacist or 
appropriately assigned unblinded designee will inventory and acknowledge receipt of all 
shipments of the study drugs. The investigator must keep an accurate record/log of the quantities 
of study drug dispensed and administered to each subject. The unblinded monitor will 
periodically check the supplies of study drugs held at the site to verify accountability of all study 
drugs used and to verify the drug accountability logs are completed and maintained in the 
investigator study file. The monitor will return all original containers of study drugs, whether 
empty or containing used or unused study drugs, to Amicus or their designee for destruction. 
Sites may not destroy study drugs on site unless Amicus has provided prior written approval. 
11.9. 
Prohibited Medications 
Use of the following medications is prohibited during this study: 
•
miglitol (eg, Glyset)
•
non-study miglustat (eg, Zavesca)
•
Myozyme or Lumizyme after treatment with ATB200/AT2221 has begun
•
acarbose (eg, Precose or Glucobay)
•
voglibose (eg, Volix, Vocarb, or Volibo)
•
any investigational/experimental drug
Subjects who are taking β2-receptor agonists or non-selective β-blockers (eg, propranolol, 
nadalol, carvedilol) before Day 1 must maintain a stable dose for the duration of the study. 


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12.
STUDY PARAMETERS AND PROCEDURES
12.1. 
Schedule of Assessments
The Schedule of Assessments displays each study assessment and procedure along with the 
scheduled time of occurrence (Table 10). All study assessments should be conducted by the 
investigator and/or a suitably qualified designee. Information will be recorded in the source 
documents and, where appropriate, the eCRF. 
If assessments are not able to be completed in 2 days, an additional day may be scheduled. Once 
established, every effort should be made to maintain the order of procedures, approximately at 
the same time of day, at each study visit throughout the study, regardless of the number of days 
that are used for the visit. 


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Table 10: 
Schedule of Assessments 
Screening/Baseline 
(Day –30 to Day –1)a 
Treatment 
Follow-up 
Study visit 
Screening
1b 
Screening 
2 
Day 
1 
Infusion visits 
(every 2 weeks 
through Week 52)c 
Weeks 
2, 4, 6 
Week 
12 
Week 
26, 38 
Week 52/ 
ETd 
≥ 30 days 
after last 
dose 
Visit window (days) 
— 
— 
— 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Administrative 
Informed consent 
X 
Randomization 
>Day –10
Assign subject number 
X 
Demographics 
X 
Eligibility criteria 
X 
X 
Schedule next visit 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment 
Medical history 
X 
Retrospective data collection 
See Section 12.3.4. 
Prior/concomitant medications and 
nondrug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE 
X 
X 
Brief physical examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weighte 
X 
X 
X 
X 
X 
Height 
X 
AEs/SAEs, including IARs 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 10: 
Schedule of Assessments (Continued) 
Screening/Baseline 
(Day –30 to Day –1)a 
Treatment 
Follow-up 
Study visit 
Screening
1b 
Screening 
2 
Day 
1 
Infusion visits 
(every 2 weeks 
through Week 52)c 
Weeks 
2, 4, 6 
Week 
12 
Week 
26, 38 
Week 52/ 
ETd 
≥ 30 days 
after last 
dose 
Visit window (days) 
— 
— 
— 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Subject/physician-reported outcomesf 
R-PAct Scale
X 
X 
X 
X 
PROMIS instruments for physical 
function, fatigue, dyspnea, upper 
extremity 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
Physician’s Global Impression of 
Change 
X 
X 
X 
Subject’s Global Impression of 
Change 
X 
X 
X 
Laboratory assessments 
12-Lead ECG
X 
X 
X 
X 
X 
Serum chemistry, hematology 
X 
X 
X 
X 
X 
X 
Anti-rhGAA Abs (total, 
cross-reactive, and neutralizing) 
X 
Xg 
X 
X 
X 
Xh 
X 
IgE 
X 
See Section 12.3.13. 
Urine pregnancy test (FOCBPs 
only)i 
X 
X 
X 
X 
X 
X 
X 
Urinary Hex4 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 


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Table 10: 
Schedule of Assessments (Continued) 
Screening/Baseline 
(Day –30 to Day –1)a 
Treatment 
Follow-up 
Study visit 
Screening
1b 
Screening 
2 
Day 
1 
Infusion visits 
(every 2 weeks 
through Week 52)c 
Weeks 
2, 4, 6 
Week 
12 
Week 
26, 38 
Week 52/ 
ETd 
≥ 30 days 
after last 
dose 
Visit window (days) 
— 
— 
— 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
PK blood sampling in 
ERT-experienced subjects 
(total GAA protein, AT2221) 
Xj 
Xj 
PK blood sampling in ERT-naive 
subjects 
(total GAA protein, AT2221) 
Xk 
Xk 
GAA genotyping 
X 
Pulmonary function tests 
MIP, MEP, SNIP 
X 
X 
X 
X 
X 
FVC, SVC (sitting, supine) 
X 
X 
X 
X 
X 
Motor function assessmentsl 
TUG 
X 
X 
X 
X 
GSGC (10 m walk, 4-Stair climb, 
Gowers’ maneuver, chair) 
X 
X 
X 
X 
6MWT 
Xm 
Xm 
X 
X 
X 


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Table 10: 
Schedule of Assessments (Continued) 
Screening/Baseline 
(Day –30 to Day –1)a 
Treatment 
Follow-up 
Study visit 
Screening
1b 
Screening 
2 
Day 
1 
Infusion visits 
(every 2 weeks 
through Week 52)c 
Weeks 
2, 4, 6 
Week 
12 
Week 
26, 38 
Week 52/ 
ETd 
≥ 30 days 
after last 
dose 
Visit window (days) 
— 
— 
— 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Muscle strength 
Manual muscle strength (MRC) 
X 
X 
X 
X 
Quantitative muscle strength 
(hand-held dynamometer) 
X 
X 
X 
X 
Study drug administration 
AT2221/placebo 
Every 2 weeks 1 hour before infusion of ATB200/alglucosidase alfa 
ATB200/alglucosidase alfa 
Every 2 weeks 
Abbreviations: 6MWT = 6-Minute Walk Test; Abs = antibodies; AE = adverse event; COVID-19 = SARS-CoV-2; ECG = electrocardiogram; EQ-5D-5L = 
EuroQol 5 Levels-5 Dimensions Instrument; ERT = enzyme replacement therapy; FOCBPs = females of childbearing potential; FVC = forced vital capacity; 
GAA = human acid α-glucosidase; GAA = gene encoding human acid α-glucosidase; GSGC = Gait, climbing stairs, Gower’s maneuver, arising from a Chair; 
Hex4 = hexose tetrasaccharide; IAR = infusion-associated reaction; IgE = immunoglobulin E; IRT = interactive response technology; MEP = maximal expiratory 
pressure; MIP = maximal inspiratory pressure; MRC = Medical Research Council; PE = physical examination; PK = pharmacokinetic; PROMIS = Patient-
Reported Outcomes Measurement Information System; rhGAA = recombinant human acid α-glucosidase; R-PAct = Rasch-built Pompe-specific Activity; 
SAE = serious adverse event; SNIP = sniff nasal inspiratory pressure; SVC = slow vital capacity; TUG = Timed Up and Go 
a Baseline efficacy assessments will be performed during screening, and baseline safety assessments will be performed on Day 1. 
b For ERT-experienced subjects, Screening Visits will be scheduled on approximately Day -30 and/or Day -15, to be 1 to 4 days before the subject’s next 
alglucosidase alfa infusion. For ERT-naïve subjects, the Screening Visit may be scheduled any time before Day -10. 
c During the conduct of the study, the COVID-19 pandemic emerged and impeded the conduct of site visits and laboratory testing due to quarantines, travel 
restrictions, and risk of infection. With the intention of maintaining regular infusions, home infusions will be allowed wherever possible for subjects who may 
be eligible. 
d The 6MWT will be performed twice at the Week 52/Early Termination Visit, once on each day of the 2-day visit. Due to COVID-19, the Week 52 visit may be 
limited to a 1-day visit. 
e Weight will be entered into IRT at quarterly visits for calculation of dose. 
f Subjects are to complete patient-reported outcome questionnaires before any other study assessment, if the questionnaires are available in that subject’s 
language. 


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g Blood samples to test for presence of rhGAA Abs will be collected at the first 3 infusion visits after Day 1 (ie, approximately Days 14, 28, and 42). 
h Subjects who are confirmed to have a positive result for anti-rhGAA Abs at the 30-day safety follow-up visit will continue to have follow-up immunological 
testing as long as they have a positive result for up to 12 months or until they begin treatment with another ERT or investigational therapy (ie, at 6 months and 
12 months) after the last dose of study drug.  
i If the urine pregnancy test has a positive result, study drug will not be administered and a confirmatory serum pregnancy test will be performed. 
j On Day 1 and Week 52, sparse blood samples will be collected for PK analysis in ERT-experienced subjects at the time points specified in Section 12.3.15.1. 
k Serial PK blood sampling in ERT-naïve subjects may be performed on Day 1 in coordination with the first infusion of study drug, or at the infusion visits for 
the second or third infusions of study drug. Sparse PK blood sampling in ERT-naïve subjects will be performed at Week 52 at the time points specified in 
Section 12.3.15.1.  
l Consenting subjects at sites where videotaping is feasible will have motor function tests videotaped at the Screening Visit and the Week 52/Early Termination
Visit, and the 6MWT may be videotaped at every visit.
m If a subject fails inclusion criterion #7 (see Section 9.2.1), then the 2 screening 6MWTs may be repeated within approximately 2 weeks if, in the opinion of the 
investigator, the subject is considered likely to meet this criterion on a second attempt. If either screening 6MWD is ≥ 90% of the predicted value for healthy 
adults, that subject will not be permitted to repeat the 6MWTs or rescreen at a later date and will be considered a screen failure.


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12.2. 
Additional Details on Study Visits 
12.2.1. 
Screening/Baseline 
For ERT-experienced subjects, the Screening Visits will be scheduled on approximately Day -30 
and/or Day -15, 1 to 4 days before the subject’s next alglucosidase alfa infusion. For ERT-naïve 
subjects, the Screening Visit may be scheduled any time before Day -10. The Screening Visit 
will occur over 2 or more days to allow for repeated 6MWT and pulmonary function test 
assessments. The repeated tests for 6MWT or for pulmonary function (FVC, SVC, MIP, and 
MEP, and SNIP) should not be done on the same day. No other assessments should be performed 
on the day that the 6MWT and pulmonary function tests are repeated. 
The informed consent form (ICF) must be signed before any study procedures are performed. 
Subjects will then be registered using IRT.  
Subjects who meet eligibility criteria at screening will be randomly assigned to study drug using 
IRT at least 10 days prior to the first scheduled infusion on Day 1 to allow sufficient lead time 
for the first drug shipment. All subsequent shipments will be sent automatically through IRT. 
Refer and comply with detailed guidelines in the IRT manual. The subject does not have to be 
present for randomization.  
Baseline efficacy assessments will be performed during screening. The average of the 
2 screening 6MWDs will be the baseline 6MWD value. For FVC, the higher of the 2 screening 
values will be the baseline value, and baseline values for all other pulmonary function tests 
(SVC, MIP, MEP, and SNIP) will be those obtained at the same visit during which the higher 
value for FVC was obtained. 
Subjects who fail to qualify for the study may be rescreened up to 2 times in consultation with 
the Amicus medical monitor, with the following exception regarding inclusion criterion #7 
(see Section 9.2.1). 
If a subject fails inclusion criterion #7, then the 2 screening 6MWTs may be repeated within 
approximately 2 weeks from the initial screening visit if, in the opinion of the investigator, the 
subject is considered likely to meet this criterion on a second attempt. If either screening 6MWD 
is ≥ 90% of the predicted value for healthy adults (calculated automatically using IRT [Enright, 
Sherill 1998]), that subject will not be permitted to repeat the 6MWTs or rescreen at a later date.  
Subjects who sign an ICF but fail to qualify for the study will be considered screen failures. The 
reason for not being started on study drug will be entered into the electronic data capture system. 
The demographic information, informed consent, and Inclusion/Exclusion pages must be 
completed for subjects who are considered screen failures. Subjects who are rescreened after 
1 month must re-sign the ICF and re-perform all screening assessments. For those subjects who 
had already undergone the confirmatory GAA genotyping as part of the previous screening 
procedures, no repeat GAA genotyping is required. Instead, the results of GAA genotyping can 
be used to determine subject's eligibility during the rescreening process. 
12.2.2. 
Day 1 
Day 1 is the first day of study drug administration. All study assessments will be performed 
predose and results from this visit will serve as baseline for safety assessments.  


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12.2.3. 
Infusion Visits and Home Infusion Visits 
Infusion visits will be scheduled every 2 weeks for administration of study drug. Changes in the 
protocol-prescribed duration of study drug infusion due to safety or tolerability issues will be 
documented in the eCRF. In addition to the assessments noted in Table 10, each site should 
follow their facility guidelines for performing infusions to monitor vital signs or other safety 
procedures that may be in place. 
At visits through Week 6, additional safety assessments (eg, clinical laboratory tests) will be 
performed for monitoring of initial safety. In addition, subjects will be monitored for 3 hours 
after the end of the first 3 infusions (ie, Day 1 and Weeks 2 and 4) by study personnel who are 
trained in diagnosing and treating acute hypersensitivity reactions and who have immediate 
access to medication and equipment to treat such reactions. Any additional monitoring according 
to standards at individual sites should also be performed. Any signs or symptoms noted during or 
after the infusion should be reported as an AE. All assessments will be performed before infusion 
of study drug. No efficacy assessments will be performed at these visits. 
If consistent with local laws and regulations, subjects may be considered eligible for 
administration of ATB200/AT2221 at their home. Eligible subjects may request participation in 
the Home Infusion Program with requests granted on a case-by-case basis following discussion 
between the Amicus medical monitor and investigator with prior approvals from 
IRBs/IECs/REBs and regulatory authorities. Home infusions of ATB200 will be performed by a 
trained home infusion nurse provided by an Amicus designated home infusion service provider. 
All subjects participating in the Home Infusion Program will be required to complete all 
functional assessments at the protocol-specified site visits. 
Subjects who participate in the Home Infusion Program must meet all of the following inclusion 
criteria and none of the following exclusion criteria. 
Inclusion Criteria: 
•
Resides in a country where it is permissible to administer alglucosidase alfa outside
of a hospital setting
•
Meets the following requirements regarding feasibility of the home site for ERT
infusion:
−
Availability of sufficient space to prepare and administer ATB200 infusion
−
Availability of utilities and equipment required for storage of study drug upon
receipt
−
Accessibility for delivery of study drug and associated supplies
−
Accessibility of trained home infusion nurse for preparation/administration
−
Preparation of ATB200 lyophilized drug product for reconstitution or
alglucosidase alfa by an unblinded, qualified individual while maintaining the
blind of the subject
−
Infusion of large volume parenteral product
−
Disposal of waste and discarding of used medical supplies


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•
Amicus/designee deems the home site to be appropriate for home infusion following
home assessment
•
Investigator agrees to collaborate with the home infusion agency/home infusion nurse
with respect to providing advice and support as needed by the home infusion nurse
Exclusion Criteria: 
•
Subject experiences a moderate or severe IAR, or a mild IAR that is not controlled
with medication after receiving study drug during this study, or with a history of a
recurrent severe or life-threatening IAR including anaphylaxis at any time.
During the conduct of the study, the COVID-19 pandemic emerged and impeded the conduct of 
site visits and laboratory testing due to quarantines, travel restrictions, and risk of infection. With 
the intention of maintaining regular infusions, home infusions will be allowed wherever possible 
for subjects who may be eligible. For subjects who may be eligible for home infusions, the 
approval to receive home infusions is contingent upon all the following conditions being 
satisfied: 
•
Approval by the Amicus clinical and safety group upon review of the subject’s
medical history and overall AEs reported during the study
•
Investigator agreeing to provide additional oversight and support to home care nurses
either in person or via telemedicine (eg. video chat) and to closely monitor safety for
the first few infusions
These contingency measures are planned to be followed until resolution of COVID-19 related 
issues specific to the individual subject. 
12.2.4. 
Post-baseline Assessment Visits 
Assessments may occur over 2 or more days for each post-baseline visit, provided all 
assessments (with the exception of PK sampling) are performed before administration of study 
drug.  
If a subject is ill or injured at a scheduled visit, functional assessments (ie, 6MWT, motor 
function tests, muscle strength tests, and pulmonary function tests) may be deferred to an 
unscheduled visit when the subject’s condition has improved, in consultation with the medical 
monitor.  
During the conduct of the study, the COVID-19 pandemic emerged and impeded the conduct of 
site visits and laboratory testing due to quarantines, travel restrictions, and risk of infection. If 
infusions were missed close to the scheduled assessments on Week 26 or 38, it should be 
communicated with Amicus on a case-by-case basis to determine whether catch-up infusions are 
needed and how many catch-up infusions are needed prior to the study assessments. 
12.2.5. 
Unscheduled Visits 
Unscheduled visits may be conducted at any time at the investigator’s discretion for medical 
reasons (eg, evaluation of AEs, repeat laboratory tests for safety, other safety assessments). 


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12.2.6. 
Week 52/Early Termination (End of Study) 
Subjects who complete 52 weeks of study drug administration, who discontinue study drug, or 
who are withdrawn from the study will be asked to return for the Week 52/Early Termination 
Visit.  
The 6MWT will be performed twice at the Week 52/Early Termination Visit, once on each day 
of the 2-day visit. Due to COVID-19, the Week 52 visit may be limited to a 1-day visit. The 
average of these 2 values for 6MWD will be the Week 52 value for analysis purposes. If either of 
the two 6MWTs is invalid, as determined by the clinical evaluator, then that test will be repeated. 
The subject will not complete the study until the subject has 2 valid 6MWD values or has 
exceeded 4 attempts. During the conduct of the study, the COVID-19 pandemic emerged and 
impeded the conduct of site visits and laboratory testing due to quarantines, travel restrictions, 
and risk of infection. If infusions were missed close to the scheduled assessments on Week 52, it 
should be communicated with Amicus on a case-by-case basis to determine whether catch-up 
infusions are needed and how many catch-up infusions are needed prior to the study assessments. 
12.2.7. 
Follow-up Period 
A 30-day safety follow-up visit for monitoring of any AEs that were ongoing at end of study and 
collection of a blood sample for anti-rhGAA Abs will be scheduled only for subjects who do not 
continue treatment with ATB200/AT2221 in Study ATB200-07.  
Subjects who are confirmed to have a positive result for anti-rhGAA Abs at the 30-day safety 
follow-up visit will continue to have follow-up immunological testing as long as they have a 
positive result for up to 12 months (ie, at 6 months and 12 months) after the last dose of study 
drug. 
12.3. 
Description of Study Assessments 
All assessments will occur according to the Schedule of Assessments displayed in Table 10. 
Any study procedures that involve supine positions may be deferred if the subject is unable to 
complete them in a supine position. 
Significant findings for vital signs, physical examinations, clinical laboratory tests, or ECGs that 
were not present prior to start of treatment and meet the definition of an AE must be recorded on 
the AE eCRF page. 
12.3.1. 
Demographic Data Collection 
Demographic data to be collected include date of birth/age, sex, and race. 
12.3.2. 
Medical History 
Comprehensive medical history, including a history of falls will be collected. Details are to be 
recorded for any past IARs (including intensity, start date, stop date, and outcome), medication 
use to manage symptoms (including dosage, frequency of administration, start date, and stop 
date), and any laboratory tests that were obtained as part of the assessment of IARs. An IAR is 
defined in Section 13.1.3. 


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Pompe disease history will include onset of symptoms, date of diagnosis, and start of ERT, if 
applicable. 
12.3.3. 
Prior/Current Medications 
Subjects will be asked to report any medications (including, to the extent possible, dosage, 
frequency, start dates, and stop dates) that they are currently taking and have taken for 
approximately the past 2 years. All prescription and nonprescription medications will be 
recorded. In addition, any nondrug therapies (including physiotherapy and occupational therapy) 
that a subject is undergoing are to be recorded. Details regarding use of ambulatory aids such as 
a cane or walker as well as respiratory support such as continuous positive airway pressure or 
bi-level positive airway pressure should also be recorded. 
Medications/procedures will be reviewed at each study visit in order to capture any changes that 
occurred during the study period. 
Concomitant medications and nondrug therapies (eg, procedures, surgery, physical therapy, or 
assistive devices) specifically associated with an AE or IAR should be entered into the 
corresponding eCRFs. 
12.3.4. 
Retrospective Data Collection 
Historical results for 6MWT, MMT, and FVC, as available, obtained in the past 5 years will be 
recorded.  
12.3.5. 
Physical Examination 
Complete physical examinations will include assessment of head, ears, eyes, nose, throat 
(HEENT), respiratory, cardiovascular, lymphatic, gastrointestinal, and neurologic systems. 
Brief examinations will be targeted towards any abnormal findings noted at the previous visit 
and/or review of ongoing AEs.  
All body systems with no abnormal findings must be noted so in the source documents. 
12.3.6. 
Body Weight and Height 
Body weight will be entered into IRT each time it is measured at protocol-specified visits for 
measuring body weight. Calibration or standardization of the scale should be performed on a 
monthly basis or according to scale specifications. 
Height (at screening only) will also be measured. 
12.3.7. 
Vital Signs 
Vital signs include blood pressure (systolic and diastolic), respiration rate, heart rate, and 
temperature. Blood pressure measurements should be obtained using the same arm. 
Measurements will be taken with the subject in sitting position after having rested for a 5-minute 
period. The same position should be used at all visits. 


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12.3.8. 
Adverse Events 
Reporting of AEs begins after written informed consent is provided, including study-related 
events that occur as a direct result of a study procedure (eg, if a subject falls during a functional 
assessment) and IARs. As required by their institutions, investigators will be responsible for 
reporting AE information to their IRB, IEC, or REB (see Section 13). If the start date of an AE is 
prior to enrollment in this study, it should be captured as medical history. 
12.3.9. 
Patient-reported Outcomes 
Patient-reported outcomes include R-PAct scale, the EQ-5D-5L, and PROMIS instruments for 
physical function, fatigue, dyspnea, and upper extremity, as available.  
The R-PAct scale is an 18-item questionnaire to measure limitations in activities and restriction 
in social participation. Possible responses to questions are as follows: unable to perform, able to 
perform, but with difficulty, and able to perform without difficulty. A raw score ranging from 
0 to 36 points is generated.  
The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems and extreme problems. Subjects are asked to indicate their health 
state by ticking the box next to the most appropriate statement in each of the 5 dimensions. The 
subject’s self-rated health is also recorded on a vertical visual analogue scale, where the 
endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can 
imagine’. 
Short forms for the PROMIS instruments for physical function (20 items) and upper extremity 
(7 items) measure signs and symptoms using general questions without a temporal reference. 
Short forms for the PROMIS instruments for fatigue (8 items) and dyspnea severity (10 items) 
measure signs and symptoms over the past 7 days. A 5-point scale is used for each instrument 
(though responses may vary within or among instruments), and a total score is generated for each 
instrument.  
The Subject’s Global Impression of Change is designed to record the subjects’ impression of 
their functional status since starting study drug using a 7-point scale ranging from “very much 
worse” to “very much improved”. The administrator of the Subject’s Global Impression of 
Change will read the questions to the subject and record the answers. 
Subjects are to complete patient-reported outcome questionnaires before any other study 
assessment, if the questionnaires are available in that subject’s language. Separate detailed 
instructions will be provided in the study functional assessment manual. 
12.3.10. 
Physician’s Global Impression of Change 
The Physician’s Global Impression of Change is designed to record the physician’s assessment 
of the subject’s status, taking into account the subject’s signs and symptoms and other 
neuromuscular symptoms, and signs relative to their status at screening. 


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12.3.11. 
Electrocardiogram 
A standard 12-lead ECG will be performed after subjects have rested for approximately 
5 minutes prior to the start of the ECG recording. Subjects will be in the supine position 
throughout the ECG evaluation. A central ECG vendor will be used. 
12.3.12. 
Clinical Laboratory Tests 
12.3.12.1. Chemistry, Hematology, and Urinalysis 
Clinical laboratory tests for safety monitoring include serum chemistry (Table 11), hematology 
(Table 12), and urinalysis (Table 13). Clinical laboratory tests will be performed prior to 
administration of study drug. The collection, processing, and shipment of all biological samples 
will be fully described in the study laboratory manual.  
The investigator (or his/her designee) will review each laboratory report from the central 
laboratory and assess any out-of-range laboratory results as “not clinically significant” or 
“clinically significant” (see Appendix 2). Any results that are considered clinically significant 
should be confirmed in a repeat test at the investigator’s discretion. The investigator should 
consider repeat testing of persistent clinically significant results until the analyte returns to 
normal or until an etiology is determined. The investigator (or his/her designee) will sign and 
date all laboratory reports. Results for CK, ALT, and AST will be blinded to investigators and 
reviewed by an unblinded medical monitor. 
Table 11: 
Serum Chemistry Parameters 
ALT 
Creatinine 
Alkaline phosphatase 
GGT 
AST 
Glucose 
Albumin 
LDH 
Bilirubin, total 
Magnesium 
BUN 
Phosphorous 
Calcium, total 
Potassium 
Carbon dioxide, total (bicarbonate) 
Protein, total 
Chloride 
Sodium 
CK 
Uric acid 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CK = creatine kinase; GGT = gamma-glutamyltransferase; LDH = lactate dehydrogenase 


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Table 12: 
Hematology Parameters 
Platelet count 
Automated white blood cell differential: 
Red blood cell count 
Neutrophils 
White blood cell count (absolute) 
Lymphocytes 
Hematocrit 
Monocytes 
Hemoglobin 
Eosinophils 
Basophils 
Table 13: 
Urinalysis Parameters 
Color 
Ketones 
Appearance 
Blood 
Specific gravity 
White blood cells 
pH 
Nitrite 
Protein 
Bilirubin 
Glucose 
Microscopy of sediment 
12.3.12.2. Pregnancy Tests 
All female subjects of childbearing potential will have a urine pregnancy test performed at 
infusion visits. If the urine pregnancy test has a positive result, study drug will not be 
administered and a confirmatory serum pregnancy test will be performed. Any pregnancy that 
occurs during the study period must be reported, and that subject must be withdrawn from the 
study (see Section 13.4). 
12.3.13. 
Immunogenicity Assessments 
Blood samples for measurement of anti-rhGAA Abs (total, cross-reactive, and neutralizing) will 
be collected predose along with the clinical safety laboratory samples.  
Neutralizing Ab assays may include the following: 
•
inhibition of rhGAA-mediated hydrolysis of 4-MU-α-glucoside
•
inhibition of rhGAA-mediated hydrolysis of glycogen
•
inhibition of rhGAA binding to CI-MPR
In addition to the time points noted in Table 10, blood samples to test for the presence of rhGAA 
Abs will be collected at the first 3 infusion visits after Day 1 (ie, approximately Weeks 2, 4, and 
6). Subjects who are confirmed to have a positive result for anti-rhGAA Abs at the 30-day safety 
follow-up visit will continue to have follow-up immunological testing as long as they have a 
positive result for up to 12 months or until they begin treatment with another ERT or 
investigational therapy (to be confirmed) (ie, at 6 months and 12 months) after the last dose of 
study drug.  


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If a subject experiences anaphylaxis or a moderate to severe IAR (in the opinion of the 
investigator) as outlined in Section 13.1.3, 3 blood draws will be required for measurement of 
immunoglobulin E (IgE) levels. The first blood draw should be obtained 6 to 8 hours after onset 
of the infusion reaction, the second blood draw at 24 hours for measurement, and the third 
immediately before the next administration of study drug. Because IgE results could potentially 
reveal a subject’s treatment assignment, these results will not be included on laboratory test 
reports. 
Total GAA protein concentration will also be measured from the same blood sample since assay 
sensitivity for both anti-rhGAA Abs and IgE can be affected by GAA protein levels. 
An unblinded medical monitor not involved in the operational aspects of the study will manage 
review of all immunogenicity results. 
12.3.14. 
Biological Specimens 
Any biological specimens remaining at the end of the study may be used for future exploratory 
assays to improve the understanding of Pompe disease and its management. The retention of 
samples is optional; subjects will have the option to agree or refuse to have their samples 
retained. The retained samples will not be used for any future genetic testing. 
These activities are in line with the European Union General Data Protection Regulation (GDPR) 
and any other local applicable regulations. 
12.3.15. 
Blood Samples for Pharmacokinetic Analysis 
12.3.15.1. Population Pharmacokinetic Analysis 
At the visits outlined in Table 10, ERT-experienced subjects will have sparse blood samples 
collected just prior to initiation of ATB200/alglucosidase alfa infusion (time 0) and at 1, 4, 6, 12, 
and 24 hours after the start of ATB200 infusion for plasma total GAA protein signature peptide 
T09 and plasma AT2221 determinations. Collection of the 12-hour sample will be optional.  
For sparse blood sampling, the predose (Time 0) PK blood sample should be collected within 
30 minutes before the start of ATB200 infusion. The 1-, 4-, 6-, 12-, and 24-hour PK blood 
samples should be collected within a ± 30-minute window. 
Vital signs may be measured after each PK blood sample for monitoring of safety, as per local 
clinical guidelines, but results will not be recorded in the eCRF. 
12.3.15.2. Pharmacokinetic Subanalysis (ERT-naïve Subjects Only) 
A PK subanalysis will be conducted in ERT-naïve subjects. Serial blood samples will be 
collected just prior to initiation of ATB200/alglucosidase alfa infusion (time 0) and at 1, 2, 3, 
3.5, 4, 4.5, 6, 8, 10, and 24 hours after the start of ATB200 infusion for plasma total GAA 
protein signature peptide T09 and plasma AT2221 determinations. Collection of a 12-hour 
sample will be optional.  
For serial blood sampling on Day 1, the predose (Time 0) PK blood sample should be collected 
within 30 minutes before the start of ATB200 infusion. The 1-, 2-, 6-, 8-, 10-, and 12-hour PK 
blood samples should be collected within a ± 15-minute window. The 3-, 3.5-, 4-, and 4.5-hour 


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PK blood samples should be collected within a ± 5-minute window. The Day 2, 24-hour PK 
blood sample should be collected within a ± 30-minute window. 
At Week 52, ERT-naïve subjects will also have sparse blood samples taken at same the time 
points listed for ERT-experienced subjects (Section 12.3.15.1). 
Vital signs may be measured after each PK blood sample for monitoring of safety, as per local 
clinical guidelines, but results will not be recorded in the eCRF. 
12.3.16. 
Creatine Kinase and Urinary Hexose Tetrasaccharide 
Creatine kinase is a type of enzyme found within muscles. Injury to the membrane surrounding 
muscle cells allows CK to leak into the bloodstream; therefore, increased levels of CK can be 
indicative of muscle injury. Creatine kinase levels will be measured as part of the serum 
chemistry panel.  
Levels of urinary Hex4, a biomarker of disease substrate, will be measured. The assay 
specifically targets one hexose tetrasaccharide, the glucose tetrasaccharide Glc4, which is a 
biomarker of glycogen storage. Glc4 is separated from other hexose tetrasaccharides in urine by 
ultra performance liquid chromatography and quantified by stable isotope dilution. The reported 
Hex4 value is actually a measure of Glc4. Concentrations of Glc4 are compared with 
age-matched control ranges. 
12.3.17. 
Gene for Encoding Acid α-Glucosidase Genotyping 
Regardless of whether previous documentation is provided for a subject’s diagnosis of Pompe 
disease for eligibility purposes (see Section 9.2.1), a blood sample will be collected at the 
Screening Visit to determine or confirm the subject’s GAA genotype that may be associated with 
Pompe disease. Subjects who do not have historic documentation of diagnosis (either deficiency 
of GAA enzyme or GAA genotyping) at the time of screening will need to wait for the results of 
screening genotyping to be randomized. Subjects who have historic documentation can be 
randomized prior to receiving the results of screening genotyping. If confirmation of diagnosis is 
not obtained, then the subject must be withdrawn from the study. No DNA or gene sequencing 
not related to Pompe disease will be performed.  
12.3.18. 
Pulmonary Function Tests 
Pulmonary function tests to be performed include FVC (sitting and supine), SVC (sitting and 
supine), MIP, MEP, and SNIP. These tests should be performed in the same position and in the 
same order at each study visit. If possible, the tests should be administered by the same person at 
each visit. The identity and qualification of the test administrator will be recorded. Training will 
be provided for site personnel. 
Pulmonary function tests must be performed as detailed in a separate manual. A central vendor 
for pulmonary function tests will be used for this study. 
12.3.19. 
Motor Function Tests  
Motor function tests to be performed include the TUG test and GSGC test. 
The GSGC consists of a 10-meter walk for evaluation of gait, a 4-stair climb, Gower’s 
maneuver, and arising from a chair. Results of the GSGC include the time required to complete 


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the individual tests, individual scores for each of the tests (1 to 7 points for each of gait, 4-stair 
climb, and Gower’s maneuver and 1 to 6 points for arising from a chair), and a total score. The 
total score ranges from a minimum of 4 points (normal performance) to a maximum of 27 points 
(worst score).  
For the TUG test, the time it takes for the subject to rise from a chair, walk 3 meters, turn around, 
walk back to the chair, and sit down will be recorded.  
These assessments should be performed without an assistive device (eg, cane, walker). If during 
screening or at any time during the study, it is unsafe for a subject to perform an assessment 
without an assistive device, that test should not be performed and a comment should be entered 
on the source document indicating why the assessment was not completed. 
The motor function tests will be performed in the same order at each study visit. If possible, the 
tests should be administered by the same person at each visit. The identity and qualification of 
the test administrator will be recorded. Training will be provided for site personnel by a central 
vendor. 
Videotaping of motor function tests may be conducted at the Screening Visit and the 
Week 52/Early Termination Visit for consenting subjects at sites where this is feasible. 
Separate detailed instructions for these tests will be provided in the study functional assessment 
manual. 
12.3.20. 
6-Minute Walk Test 
The 6MWT is an assessment of ambulatory function that involves the skeletal muscle, 
pulmonary, and cardiac systems as well as motor function.  
The objective of the 6MWT is to walk (not run or jog) as far as possible for 6 minutes. The timed 
walk test should be performed with walking shoes on a flat surface. Subjects may use an 
assistive device (eg, cane, walker, rollator) to perform the 6MWT. If they do so at the 
Screening Visit, they must use the same assistive device at all subsequent visits.  
The tests should be administered by the same person, as much as possible, at each visit. The 
identity and qualification of the test administrator will be recorded. Training will be provided for 
site personnel by a central vendor. 
The clinical evaluator will make an assessment of validity (ie, valid or invalid), according to 
detailed criteria in the study functional assessment manual. Videotaping of the 6MWT may be 
conducted at all visits for consenting subjects at sites where this is feasible. The assessment of 
validity by clinical evaluator will be used for determining eligibility at screening.  
Separate detailed instructions for this test will be provided in the study functional assessment 
manual. 
12.3.21. 
Muscle Strength Testing 
Muscle groups tested include shoulder abductors, shoulder adductors, elbow extensors, elbow 
flexors, hip flexors, hip abductors, hip adductors (hand-held dynamometer only), knee extensors, 
and knee flexors.  


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Manual muscle strength will be assessed by neurological (physical exam) assessment using the 
Medical Research Council scale (0 to 5 points, with 5 indicating normal function). The same 
rater and method must be utilized as much as possible throughout the subject’s participation in 
the study.  
Quantitative muscle strength will also be measured using a hand-held dynamometer and 
measured in kg of pressure. If possible, the tests should be administered by the same person at 
each visit. The identity and qualification of the test administrator will be recorded. Training will 
be provided for site personnel. 
Separate detailed instructions for these tests will be provided in the study functional assessment 
manual. 


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13.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
13.1. 
Definitions
13.1.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, biologic (at any dose), or medical device, which 
does not necessarily have a causal relationship with the treatment. Therefore, an AE can be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
medical product, whether or not considered related to the medical product. 
According to this protocol, expected or anticipated evolution of the disease under treatment will 
be evaluated as part of the disease symptom assessment. Changes in Pompe disease symptoms 
must be reviewed by the investigator or a medically qualified subinvestigator and recorded as 
“clinically significant” or “not clinically significant” in subjects’ source records (see 
Appendix 2). Expected or anticipated changes in the clinical condition may not qualify as AEs. 
However, if there is a clinically relevant worsening of a sign or symptom of the disease under 
treatment and the outcome fulfills the definition of an AE, it must be reported as directed in the 
protocol. 
Any AE that begins after the first dose of study drug will be considered a treatment-emergent 
AE. 
Subjects experiencing AEs should be followed up until their health has returned to baseline 
status or stabilized. 
AEs include the following: 
•
the onset of new signs, symptoms, conditions, and illnesses
•
exacerbation of pre-existing conditions or illnesses
•
abnormal laboratory findings deemed clinically significant by the investigator
•
physical examination changes deemed clinically significant by the investigator
•
abnormal medical evaluation findings (eg, ECG) that are not documented at the
Screening Visit and/or, in the investigator’s opinion, represent a clinically significant
change in the subject’s health during study participation
−
Screening medical evaluation findings (eg, ECG) that were not previously
provided as medical history and that can be determined as starting prior to the
Screening Visit are not considered AEs and will be recorded as medical history.


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13.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that: 
•
Results in death
•
Is life-threatening
−
An AE, in the view of either the investigator or Amicus, that places the subject at
immediate risk of death. It does not include an AE that, had it occurred in a more
serious form, might have caused death.
•
Requires inpatient hospitalization or prolongs existing hospitalization
−
Hospitalization signifies that the subject has been admitted, regardless of duration,
for observation and/or treatment that would not have been appropriate in a
physician’s office or outpatient setting.
−
Hospitalizations for elective or preplanned treatment of a pre-existing condition
do not have to be reported as SAEs, provided that
−
the condition is documented in the subject’s medical history and has not
worsened since the ICF was first signed, and
−
the planned procedure is documented in the subject’s eCRF at the
Screening Visit
Note: Outpatient procedures performed in a hospital do not qualify as an SAE.
−
Emergency room/department or outpatient treatments that do not result in
admission do not have to be reported as an SAE, unless another SAE criterion is
met.
−
Events assessed and treated in these circumstances should be captured as AEs.
−
Hospitalizations solely based on logistics (eg, subject is admitted due to limited
hospital accessibility for what would otherwise be an outpatient procedure) do not
have to be reported as SAEs.
−
These hospitalizations should be clearly defined as such in the subject’s
source record.
•
Results in persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions, as decided by the investigator
•
Is a congenital anomaly/birth defect
An important medical event that may not result in one of the abovementioned serious outcomes 
may be considered an SAE when, based on appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the serious outcomes. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or development of drug dependency or drug abuse. 


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For all subjects, AEs and SAEs will be reported from time of informed consent signing, until 
30 days after the last dose of study drug. 
13.1.3. 
Infusion-associated Reactions 
An IAR is a disorder characterized by 1 or more adverse reaction(s) to the infusion of 
pharmacological or biological substances. These reactions are classified into 2 major subtypes, 
immediate and late, according to the time interval between the infusion and the onset of an 
infusion-related AE. 
The reactions are divided into 5 severity grades as follows: 
1. Mild (requires observation only); for example, transient flushing or rash
2. Moderate (minimal, usually oral, intervention suffices); for example,
urticaria/myalgia/drug fever
3. Severe (vital organ involved yet not in a life-threatening manner; usually requires
parenteral medication); for example, bronchospasm/angioedema/hypotension
4. Life threatening (multisystem involvement of vital organs, urgent and critical care
required); for example, systemic anaphylactic reaction
5. Death
Immediate-type IARs commonly involve 1 or more of the following systems: skin (urticaria and 
erythema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues 
(wheezing, bronchospasm), and gastrointestinal tract (diarrhea, vomiting). 
Late-type reactions first manifest more than 24 hours postinfusion, usually 1 to 3 days 
postinfusion. The most common symptoms of late-type infusion reactions are pruritic skin 
eruptions, fever, malaise, and polyarthralgia. 
Any symptom or sign occurring during or within 2 hours of completion of the infusion should be 
reported as an immediate-IAR and deemed drug-related AE, unless an alternative obvious 
explanation exists, eg, mechanical fall. Any symptom or sign occurring between 2 and 24 hours 
will be recorded as an IAR if it fits within the description of an IAR in the investigator’s opinion. 
It would be reported as immediate-type IAR and deemed a drug-related AE. 
Any symptom or sign occurring between 24 and 96 hours after completion of the infusion that, in 
the investigator’s opinion, fits the clinical description of a symptom or sign associated with an 
IAR should be reported as a late-type IAR and deemed a drug-related AE. 
A symptom or sign that occurs 24 hours or later and in the investigator’s opinion is possibly, 
probably, or likely an IAR should be reported as such and deemed drug-related AE. 
Note: The list of IAR symptoms provided in Table 14 is not comprehensive. It is meant to serve 
as a guideline to the investigators to report and manage IAR as AE. Table 14 also provides a 
guideline for management of IARs and anaphylaxis (see also Appendix 1). It is at the 
investigator’s discretion to follow the guidelines or implement treatment protocol that their 
center is accustomed to following. 


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In the event that a subject experiences an IAR, the subject should be premedicated for 
subsequent infusions with antihistamines, steroids, and/or acetaminophen. The premedications 
should be continued for all remaining infusions.  
Table 14: 
Guidelines for Management of Immediate Infusion-associated Reactions 
Severity 
Symptoms (such as, 
but not restricted to) 
Management Guidelines 
Mild reaction 
Flushing 
Nausea  
Mild headache 
Tachycardia (pulse 
< 100 bpm) 
Abdominal pain 
REDUCE INFUSION RATE BY 50% 
Contact investigator. 
Give oral antihistamine/acetaminophen/paracetamol and/or 
IV antihistamine. 
Prepare emergency equipment for any subsequent study 
drug escalation. 
Subject must be observed at site or medical facility for 
2-4 hours after resolution of the symptoms.
Record all details of times, concomitant medications and 
nondrug therapies, and infusion rates. 
Draw IgE and total GAA sample 6 to 8 and 24 hours after 
the start of the infusion reaction (2 samples). 
IF SYMPTOMS PERSIST: 
STOP THE INFUSION 
After 30 minutes, if subject has improved, increase to 
previous infusion rate on direction of investigator/designee. 
If subject has not improved after 60 minutes, consult with 
investigator as to whether additional medications should be 
administered. 
If subject reacts for second time after return to the prior 
infusion rate, reduce rate by 50% and contact 
investigator/designee. 
IF IN DOUBT, STOP INFUSION 


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Table 14: 
Guidelines for Management of Immediate Infusion-associated Reactions 
(Continued) 
Severity 
Symptoms (such as, 
but not restricted to) 
Management Guidelines 
Moderate 
reaction 
Localized itchiness, 
and/or raised 
Urticarial rash (hives) 
Severe headache 
Fever or shivering 
Tachycardia (pulse 
> 100 bpm)
Tachypnea
Flushing
Nausea
Irritability
Headache
Vomiting
Diarrhea
Abdominal cramps
Myalgia
** STOP INFUSION ** 
Immediately contact investigator. 
Administer high-flow oxygen if respiratory 
symptoms/distress. 
Give IM or IV antihistamines (eg, promethazine 25 to 
50 mg). 
Give IV fluid bolus if warranted. 
Give IV steroids (hydrocortisone 100 mg) on direction of 
PI/designee. 
Continue management as directed by the PI/designee. 
If deemed appropriate by PI/investigator, resume study drug 
infusion at reduced rate and prepare emergency equipment. 
If deemed appropriate by PI/investigator, infusion can be 
suspended and reinitiated 48 hours later with 
premedications and at the infusion rate that was last 
tolerated. 
Observe subject for a minimum of 6 hours after resolution 
of the event. 
Record all details. Report AE, if applicable. 
Draw IgE and total GAA sample 6 to 8 and 24 hours after 
the start of the infusion reaction and immediately before the 
next administration of study drug (3 samples). 


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Table 14: 
Guidelines for Management of Immediate Infusion-associated Reactions 
(Continued) 
Severity 
Symptoms (such as, 
but not restricted to) 
Management Guidelines 
Severe 
reaction, 
anaphylaxis, 
or 
anaphylactoid 
reactions 
Chest pain 
Generalized urticarial/ 
angioedema 
Symptomatic 
hypotension(subject 
feeling faint, paleness) 
Hoarseness of 
voice/laryngeal edema 
Bronchospasm 
** STOP INFUSION ** 
Activate emergency response and immediately contact 
investigator. 
For chest pain and symptomatic hypotension, initiate 
emergency procedures. 
Administer high-flow oxygen or intubate and mechanically 
ventilate as appropriate. 
Give IM adrenaline 300 mcg EpiPen into thigh (avoid 
buttock). If no response, repeat dose in 5 minutes. Prepare 
infusion of adrenaline 3 mg/50 mL NS (60 µg/mL), if 
needed. 
Give IV fluids 10- to 20-mL/kg fluid bolus on direction of 
PI/designee. 
Give IV antihistamines (promethazine 25 to 50 mg in 
10 mL WFI over 2 to 3 minutes). 
Give IV steroids (hydrocortisone 100- to 500-mg bolus IV 
injection; dilute in 10 mL NS for doses between 100 and 
500 mg) and infuse over 2 minutes. 
Give nebulized beta-2 agonists with high-flow oxygen on 
direction of PI/designee. 
Administer other treatments and/or transfer patient to 
hospital/ ICU as recommended by investigator/ designee. 
Observe subject for a minimum of 24 hours after resolution 
of the event. 
If deemed appropriate by PI/investigator, study drug 
infusion can be re-initiated 7 to 14 days with premedications 
and at the 4-hour duration. 
Draw IgE and total GAA sample 6 to 8 and 24 hours after 
the start of the infusion reaction and immediately before the 
next administration of study drug (3 samples). 
Record all details. Report AE, if applicable. 
Abbreviations: GAA = human acid α-glucosidase; IgE = immunoglobulin E; IM = intramuscular; IV = intravenous; 
NS = normal saline; PI = Principal Investigator; SAE = serious adverse event; WFI = water for injection  
Sources: Vogel 2010; Sampson et al 2006 


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13.1.4. 
Relationship to Study Drug 
The investigator or a qualified sub-investigator will review each event and assess its relationship 
to ERT based on available information according to the following guidelines: 
•
Definite: A reaction that follows a distinct temporal relationship from administration
of the study drug, that follows a known reaction to the agent or chemical group of the
study drug, and that cannot be explained by the subject’s clinical state or other
factors. By definition, IARs (immediate or late type) are considered definite (see
Section 13.1.3).
•
Probable: A reaction that follows a reasonable temporal sequence from administration
of the study drug, that follows a known or expected response pattern to the suspected
study drug, and that could not be reasonably explained by the known characteristics
of that subject/subject’s clinical state.
•
Possible: A reaction that follows a reasonable temporal sequence from administration
of the study drug and that follows a known or expected response pattern to the
suspected study drug, but that could readily have been produced by a number of other
factors.
•
Unlikely: A reaction that does not follow a reasonable temporal sequence from
administration of the study drug. However, causality from the study drug cannot be
ruled out.
•
Unrelated: A reaction for which sufficient data exist to indicate that the etiology is
unrelated to the study drug.
For the purpose of reporting SAEs to regulatory authorities and IRBs/IECs/REBs, any AE 
assessed by the investigator as definitely, probably, or possibly related to study drug will be 
considered “related” to study drug (ie, associated with the use of the study drug). Any AE 
assessed as unlikely or unrelated will be considered “not related” to study drug (ie, not associated 
with the use of study drug). 
13.1.5. 
Assessment of Severity 
The following definitions for rating severity will be used: 
•
Grade 1/Mild: Awareness of sign, symptom or event, but the AE is easily tolerated
and does not interfere with daily activity, intervention not indicated.
•
Grade 2/Moderate: Enough discomfort to cause interference with usual activities and
may warrant intervention, but the subject is still able to function.
•
Grade 3/Severe: Medically significant but not immediately life-threatening, unable to
do usual activities or significantly affects clinical status and requires medical
intervention.
•
Grade 4/Life-threatening: Life-threatening consequences; urgent intervention
indicated 
•
Grade 5/Fatal: Death related to AE


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When the determination of AE severity rests on medical judgment, the determination of severity 
must be made with the appropriate involvement of the investigator or a qualified 
sub-investigator. 
13.2. 
Reporting of Adverse Events 
Information regarding AEs is to be obtained by questioning or examining the subject. 
Adverse events will be recorded in the eCRF and subject’s source record beginning from the 
time written consent is provided until 30 days after the last treatment visit. 
A single diagnosis should be entered when known. If a clear diagnosis cannot be determined at 
the time of the eCRF and subject’s source record entries, each sign and symptom must be 
recorded individually, until a final diagnosis is established. Pompe-related conditions, signs, 
symptoms, etc, that are present in the subject’s medical history at the Screening Visit should only 
be reported as AEs if they worsen (ie, increase in severity) from the Screening Visit. 
For each AE reported, the date and time the event started and ended, action taken, outcome 
(resolved, resolved with sequelae, ongoing, or fatal), and severity must be noted. 
All subjects who have AEs, whether or not considered associated with the use of study drug, 
must be monitored to determine the outcome. The clinical course of the AE will be followed up 
according to accepted standards of medical practice, even after the end of the period of 
observation, until a satisfactory explanation is found or the investigator considers it medically 
justifiable to terminate follow-up. Should the AE result in death, a full pathologist’s report 
should be supplied, if possible. For all AEs that require or result in subject discontinuation from 
the study, relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate, until final resolution or stabilization of the event(s). 
If the investigator considers it necessary to report a nonserious AE in a study subject more than 
30 days after the last visit, he or she should contact Amicus to determine how the AE should be 
documented and reported. 
13.3. 
Reporting Requirements for Serious Adverse Events 
If an AE is serious (as defined in Section 13.1.2), the investigator must submit an SAE report 
form at the time the SAE is identified. All SAEs must be immediately reported by the 
investigator to Amicus or Amicus’ representative, but no later than 24 hours after any study site 
personnel is aware of the event. Serious adverse event report forms must be faxed to the 
designated safety fax number (+1-866-693-2307) or sent to the designated email address 
(blindedsafetyreporting@amicusrx.com). All supporting documentation available at the time of 
reporting, with all subject identifiers redacted in accordance with local requirements, must be 
included in the fax along with the SAE report form. 
The initial report must be completed as soon as possible. All known details of the SAE and an 
assessment of the causal relationship between the event and study drug, or study procedure 
should be included in the initial report. All information not available at the time of the initial 
report (eg, event end date, discharge summary, or results of diagnostic procedures/evaluations 
related to the event) must be provided in a follow-up report. Follow-up information must be 
reported using the designated fax number within 24 hours of receipt at study sites. 


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Every attempt should be made to describe events in terms of a diagnosis. If a clear diagnosis has 
been made, individual signs and symptoms should not be recorded unless they represent atypical 
or extreme manifestations of the diagnosis, in which case they should be reported as separate 
events. If a clear diagnosis cannot be established, each sign and symptom must be recorded 
individually. 
Study endpoints that meet SAE criteria (as per Section 13.1.2) must also be immediately reported 
by the investigator to Amicus or Amicus’ representative but no later than 24 hours after any 
study site personnel is aware of the event. 
If a nonserious event becomes serious, the event must be reported as described above. 
If the investigator becomes aware of an SAE in a subject or receives an unsolicited report of an 
SAE from a subject more than 30 days after the last treatment, and considers the event possibly, 
probably, or definitely related to previous study treatment, he or she should contact the Amicus 
medical monitor to determine how the SAE should be documented and reported.  
The Amicus medical monitor will determine the expectedness of AEs according to current safety 
reference document (eg, current Investigator’s Brochure or other safety-related information as 
available). 
13.3.1. 
Additional Reporting Requirements for Suspected Unexpected Serious Adverse 
Reaction 
Any AE that is serious, unexpected, and associated with the use of the study drug (suspected 
unexpected serious adverse reaction [SUSAR], also referred to as Expedited Safety Report and 
Investigational New Drug Safety Report) has additional reporting requirements. All investigators 
conducting clinical studies with the study drug will be notified of such events and must inform 
their IRBs/IECs/REBs as required in accordance with local law. Amicus will ensure that 
SUSARs are reported to regulatory agencies in accordance with local law in each country where 
study sites are located. 
•
If the SUSAR is fatal or life-threatening, associated with the use of the study drug,
and unexpected, regulatory authorities and IRBs/IECs/REBs will be notified within
7 calendar days after Amicus learns of the event.
•
If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with
the use of the study drug, and unexpected, regulatory authorities and
IRBs/IECs/REBs will be notified within 15 calendar days after Amicus learns of the
event.
Safety updates will be provided periodically to the regulatory authorities and IRBs/IECs/REBs 
responsible for the study according to the rules in effect in each country where study sites are 
located. These updates will include information on SUSARs and other relevant safety findings. 
13.3.2. 
Overdose/Under Dose 
Any event associated with, or observed in conjunction with, a product overdose/under dose 
(whether accidental or intentional) is considered by Amicus to be an AE and must be reported as 
such. If a subject experiences an overdose (defined as ≥ 20% higher than the assigned dose of 
study drug for that period in the protocol) or an under dose (defined as ≥ 20% lower than the 


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assigned dose of the study drug for that period in the protocol) during the course of the study 
(whether symptomatic or not), the Amicus medical monitor must be notified within 5 working 
days of the investigator or study personnel first becoming aware of the overdose/under dose. 
Follow-up information must be forwarded on the outcome as applicable. If an SAE occurs in 
conjunction with the overdose/under dose, the same SAE reporting requirements described in 
Section 13.3 apply. 
13.3.3. 
Missed Dose 
If a subject is unable to schedule a treatment (infusion) up to 7 days after the scheduled date, this 
is considered as a missed dose. The subject will receive his or her next dose per his or her 
schedule, ie, approximately 4 weeks following the previous dose, since the subject missed a dose 
at 2 weeks following the last dose. This is recorded as a protocol deviation. Any AE that occurs 
as a result of missed dose should be recorded as such. The Amicus medical monitor must be 
notified within 5 working days of the investigator or study personnel first becoming aware of the 
missed dose. Follow-up information on the outcome must be forwarded as applicable. If an SAE 
occurs in conjunction with the missed dose, the same SAE reporting requirements described in 
Section 13.3 apply.  
During the conduct of the study, the COVID-19 pandemic emerged and impeded the conduct of 
site visits and laboratory testing due to quarantines, travel restrictions, and risk of infection. 
Study subjects who missed infusions close to their scheduled assessments on Weeks 26, 38, or 
52 should postpone the assessments and receive a sufficient number of “catch-up” infusions prior 
to undergoing the study assessments. Each instance of missed infusion should be discussed with, 
and course of action approved by, the medical monitor. If a subject misses 5 consecutive 
infusions at any time during the study, the subject must withdraw from the study. Depending on 
the circumstances of the missed infusions, the subject may still be eligible to participate in the 
ATB200-07 study. If a visit was missed due to COVID-19 related quarantines, travel restrictions, 
and risk of infection, it should be recorded as such in the Interactive Voice/Web Response 
System and EDC. A reason for the missed visit should be entered into the EDC as COVID-19 
related. The relevant IRBs, IECs, and REBs should be notified of any deviations from the 
protocol. If 5 or more consecutive infusions are missed due to any circumstance, including 
COVID-19, the subject must be discontinued from this protocol. Any subjects discontinued due 
to COVID-19 may be eligible for ATB200-07 with Amicus approval. 
13.4. 
Reporting of Pregnancy 
Pregnancy information for female subjects and female partners of male subjects participating in 
the study is collected by Amicus. Pregnancy, in and of itself, is not regarded as an AE (unless 
there is a suspicion that study drug may have interfered with the effectiveness of a contraceptive 
medication).  
If a female subject becomes pregnant during the course of this study, or if the female partner of a 
male subject becomes pregnant during the subject’s participation in the study, the event must be 
reported within 5 working days of the investigator or study personnel becoming aware of the 
pregnancy. Study drug will be discontinued, and the subject’s treatment assignment will be 
unblinded. The subject will be monitored for the duration of pregnancy and the baby for 
6 months following birth. If an SAE occurs in conjunction with the pregnancy, the SAE must be 


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reported as described in Section 13.3. Amicus will provide pregnancy report forms and 
instructions to study personnel regarding collection of pregnancy and outcome information 
(subject to receipt of data privacy release approvals where required under local privacy laws). 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was withdrawn 
from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
13.5. 
Data Monitoring Committee 
A DMC will be constituted prior to first subject first visit (date of consent). The DMC will be 
responsible for reviewing safety data and will provide input on trial stopping or modifications. A 
meeting will be held with the DMC prior to first subject first visit to describe the board’s roles 
and responsibilities, discuss potential data format and process, and agree upon a charter. A 
description of the DMC membership and meeting frequency will be outlined in the DMC charter. 
Additional safety analyses may be performed at the discretion of the DMC. 
The DMC may make any of the following recommendations: 
•
no safety issues, ethical to continue the study as planned
•
serious safety concerns precluding further study treatment for individual subjects
•
recommendation to continue the study with amendment to the protocol
•
recommendation for trial stopping or modification based on safety


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14.
DATA MANAGEMENT
For this study, subject data will be entered into an electronic data capture system managed by 
Amicus (or designee). The data will be transmitted via a secure electronic method to Amicus (or 
designee) as defined in the Data Management Plan. 
Management of clinical data will be performed in accordance with applicable Amicus standards 
and data cleaning procedures to ensure the integrity of the data (eg, determining errors and 
inconsistencies in the data and ensuring data are corrected by site personnel or designees).  
After database lock, each study site will receive an electronic file containing all of their 
site-specific eCRF data as entered into the electronic data capture system for the study, including 
full discrepancy and audit history. Additionally, an electronic copy of all of the study site’s data 
from the study will be retained by Amicus and designee for storage. In the event that the subject 
revokes authorization to collect or use protected health information, the investigator retains the 
ability to use all information collected prior to the revocation of subject authorization. 


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15.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
15.1. 
Endpoints 
15.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Week 52 in 6MWD. 
15.1.2. 
Secondary Efficacy Endpoints 
Key secondary efficacy endpoints are as follows: 
•
change from baseline to Week 52 in sitting FVC (% predicted)
•
change from baseline to Week 52 in the manual muscle test score for the lower
extremities
•
change from baseline to Week 52 in the total score for the PROMIS – physical
function
•
change from baseline to Week 52 in the total score for the PROMIS – fatigue
•
change from baseline to Week 52 in GSGC total score
•
change from baseline to Week 26 in 6MWD
Other secondary efficacy endpoints are as follows: 
•
change from baseline to Week 52 in the following variables related to motor function:
−
time to complete the 10-meter walk (ie, assessment of gait) of the GSGC test
−
time to complete the 4-stair climb of the GSGC test
−
time to complete the Gower’s maneuver of the GSGC test
−
time to arise from a chair as part of the GSGC test
−
time to complete the TUG test
•
change from baseline to Week 52 in the following variables related to muscle
strength:
−
manual muscle test score for the upper extremities
−
manual muscle test total score
−
quantitative muscle test value (kg) for the upper extremities
−
quantitative muscle test value (kg) for the lower extremities
−
quantitative muscle test total value (kg)
•
change from baseline to Week 52 in the following variables from patient-reported
outcome measures:
−
total score for the PROMIS – dyspnea
−
total score for the PROMIS – upper extremity


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−
R-PAct Scale total score
−
EQ-5D-5L health status
•
actual value of the subject’s functional status (improving, stable, or declining)
pertaining to the effects of study drug in the following areas of life at Week 52, as
measured by the Subject’s Global Impression of Change:
−
overall physical wellbeing
−
effort of breathing
−
muscle strength
−
muscle function
−
ability to move around
−
activities of daily living
−
energy level
−
level of muscular pain
•
actual value of the subject’s functional status (improving, stable, or declining) at
Week 52, as measured by the Physician’s Global Impression of Change
•
change from baseline to Week 52 in the following measures of pulmonary function,
as follows:
−
sitting SVC (% predicted)
−
MIP (cmH2O)
−
MIP (% predicted)
−
MEP (cmH2O)
−
MEP (% predicted)
−
SNIP (cmH2O)
15.1.3. 
Pharmacodynamic Endpoints 
Pharmacodynamic endpoints are as follows: 
•
change from baseline to Week 52 in serum CK level
•
change from baseline to Week 52 in urinary Hex4 level
15.1.4. 
Pharmacokinetic Endpoints 
15.1.4.1. Population Pharmacokinetic Analysis (ERT-Experienced Subjects) 
After sparse sampling in ERT-experienced subjects (Day 1 and Week 52) and ERT-naïve 
subjects (Week 52 only), PK endpoints from a population PK analysis of total GAA protein and 
AT2221 concentrations will be provided in a separate modeling and simulation plan. Plasma 
GAA activity levels may be evaluated during the terminal phase only. 


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15.1.4.2. Pharmacokinetic Subanalysis (ERT-naïve Subjects) 
After serial blood sampling in ERT-naïve subjects, PK parameters for plasma total GAA protein 
concentration will be calculated as follows:  
•
Cmax: maximum observed concentration obtained directly from the concentration
profile
•
tmax: time of the first occurrence of the maximum observed concentration obtained
directly from the concentration profile
•
Kel or λz: the apparent terminal phase elimination rate constant will be estimated by
linear regression of logarithmically transformed concentration versus time data; only
those data points which are judged to describe the terminal log-linear decline will be
used in the regression
•
AUC0-t: area under the plasma drug concentration-time curve from 0 time (predose)
to the time of last quantifiable concentration (t), calculated with the linear
up/log-down trapezoidal method
•
AUC0-∞: the area under the plasma drug concentration-time curve from 0 time
(predose) extrapolated to infinite time will be calculated as follows:
AUC0-∞ = AUC0-t + Ct/λz 
where Ct is the last observed quantifiable concentration 
•
AUCtmax-24h: partial area under the plasma drug concentration-time curve from the
time of maximum concentration (tmax) to 24 hours post initiation of ATB200 infusion
•
t½α: the alpha-phase terminal half-life, calculated as ln(2)/λz from the first 3 or more
quantifiable concentrations after Cmax; estimated for plasma total GAA protein
concentration only
•
CLT: total plasma clearance after IV administration, calculated as dose/AUC0-∞
Plasma GAA activity levels may be evaluated during the terminal phase only. 
Plasma AT2221 PK parameters will be calculated as follows:  
•
Cmax: maximum observed concentration obtained directly from the concentration
profile
•
tmax: time of the first occurrence of the maximum observed concentration obtained
directly from the concentration profile
•
Kel or λz: the apparent terminal phase elimination rate constant will be estimated by
linear regression of logarithmically transformed concentration versus time data; only
those data points which are judged to describe the terminal log-linear decline will be
used in the regression
•
AUC0-t: area under the plasma drug concentration-time curve from 0 time (predose)
to the time of last quantifiable concentration (t), calculated with the linear
up/log-down trapezoidal method


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•
AUC0-∞: the area under the plasma drug concentration-time curve from 0 time
(predose) extrapolated to infinite time will be calculated as follows:
AUC0-∞ = AUC0-t + Ct/λz 
where Ct is the last observed quantifiable concentration 
•
t½β: the beta-phase terminal elimination half-life, calculated as natural log ln(2)/λz
from the last 3 or more quantifiable concentrations from the beta phase of elimination
•
CLT/F: total plasma clearance from an oral administration, calculated as dose/AUC0-∞
•
Vz/F: volume of distribution based on the terminal elimination phase from an oral
administration, calculated as dose/(AUC0-∞ • λz)
15.1.5. 
Safety Endpoints 
The safety profile of ATB200/AT2221 will be characterized using incidence of 
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and AEs leading to 
discontinuation of study drug, frequency and severity of immediate and late IARs, and any 
abnormalities noted in other safety assessments. The impact of immunogenicity to ATB200 and 
alglucosidase alfa on safety and efficacy will also be described. 
15.2. 
Sample Size Considerations 
A 2-group t-test with a 2-sided significance level of 0.05 and a 2:1 randomization scheme 
(66 subjects in the ATB200/AT2221 group and 33 subjects in the alglucosidase alfa/placebo 
group, for a total sample size of 99 subjects) will have approximately 90% power to detect a 
standardized effect size of 0.7 between the 2 groups in a superiority test. This calculation was 
performed using NQuery 8©®. Assuming a 10% dropout rate, the sample size will be 
approximately 110 subjects. 
Further details of the sample size calculation will be provided in a separate statistical analysis 
plan (SAP). 
15.3. 
Data Analysis Considerations 
The Statistical Analysis System (SAS®) version 9.4 (or latest version at the time of the analysis) 
and R© software will be used for all statistical procedures and analyses. 
Full details of the analysis plan will be provided in the SAP. 
15.3.1. 
Analysis Populations 
Safety Population: The safety population is defined as all subjects who receive at least 1 dose of 
study drug (ATB200/AT2221 or alglucosidase alfa/placebo). This population will be used in the 
assessment and reporting of safety data, and subjects will be analyzed according to the actual 
treatment received. 
Intent-to-Treat Population: The intent-to-treat (ITT) population consists of all randomized 
subjects (regardless of whether they took a dose of study drug). This population will be analyzed 
according to the planned treatment groups. The ITT population is the primary population for 
efficacy analyses.   


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Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) population consists 
of all randomized subjects who took at least 1 dose of study drug and have both a 6MWD 
baseline (ie, average of 2 screening 6MWD values) and at least one post-baseline 6MWD. This 
population will be analyzed according to the planned treatment groups. The mITT population 
will be used for supportive/sensitivity analyses of the primary and key secondary efficacy 
endpoints, as well as for baseline and demographic summaries. 
Per-Protocol Population: The per-protocol population is a subset of the ITT population that 
consists of subjects who have no major protocol or site deviations that impact the analyses of the 
primary endpoints or the integrity of the study, and took only the study drug to which they were 
randomized. This population will be analyzed according to the planned treatment groups. The 
per-protocol population may be used in supportive/sensitivity analyses of the primary and/or key 
secondary endpoints. 
Pharmacokinetic population(s) will be described in a separate modeling and simulation plan. 
15.3.2. 
Statistical Methods 
15.3.2.1. Randomization 
The following 2 factors have been identified as design stratification variables: 
1.
baseline 6MWD (75 to < 150 meters, 150 to < 400 meters, ≥ 400 meters)
2.
ERT status (ERT-experienced, ERT-naïve)
These 2 factors form 6 factorial combinations (ie, levels, strata).
A centralized block randomization procedure will be used to balance the above factors, 1) to 
reduce bias and increase the precision of statistical inference, and 2) to allow various planned 
and unplanned subset analyses. The block randomization scheme will be performed for each of 
the 6 strata. The randomization ratio is 2:1 ATB200/AT2221 to alglucosidase alfa/placebo, fixed. 
15.3.2.2. Missing Data Handling 
Missing data may be imputed using methods of multivariate imputation by chained equations. 
Both missing-at-random and missing-not-at-random patterns will be considered and their impacts 
on robustness of the primary and/or key secondary analysis results will be assessed with a 
tipping point analysis. Further details of the approach will be provided in the full SAP. 
Similarly, missing attributes for AEs will be imputed with the worst possible outcome, for 
summary purposes. 
15.3.2.3. Efficacy Analyses 
For functional assessments, screening results will serve as the baseline values. For 6MWD, the 
2 values for 6MWD obtained at screening will be averaged to get the baseline value. For FVC, 
the higher of the 2 screening values will be the baseline value, and baseline values for all other 
pulmonary function tests (SVC, MIP, MEP, and SNIP) will be those obtained at the same visit 
during which the higher value for FVC was obtained. 


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15.3.2.3.1. Analyses of the 6MWT 
The primary efficacy endpoint (ie, change from baseline to Week 52 in 6MWD) will be analyzed 
using a parametric analysis of covariance (ANCOVA) model to compare between the new 
treatment and the control. This model would typically adjust for baseline 6MWD (as a 
continuous covariate), and the 2 factors used to stratify randomization: ERT status (ERT-naïve 
vs. ERT-experienced) and baseline 6MWD (75 to < 150 meters, 150 to < 400 meters, 
≥ 400 meters). However, the baseline 6MWD cannot be used in the model twice (both as a 
continuous and a categorical variable) due to the expected high point-biserial correlation between 
them. Thus, the 6MWD continuous variable will remain in the model but the categorical 6MWD 
will be removed. The ANCOVA model then has terms for treatment, baseline 6MWD 
(continuous), and ERT status (categorical).  
Additionally, potential treatment-by-covariate interactions (ie, TREATMENT-by-ERT-STATUS 
and TREATMENT-by-BASELINE 6MWD continuous) will be examined. If an interaction term 
is statistically significant (eg, p < 0.10, 2-sided), and there is logical biological interpretation, 
then the interaction term can potentially be added in the final ANCOVA model that will be used 
for the primary endpoint analysis. The data would then be analyzed based on the ANCOVA 
model, and all the relevant estimates (eg, LS means for each treatment group, LS means 
difference, 95% confidence intervals [CIs] for the LS mean difference, and p-value for 
comparing between the 2 treatment groups) would be provided. 
To support the interpretation of clinical benefit, a composite subject-level response will be 
defined based on the totality of the treatment outcome data. Subjects will be classified by an 
ordinal response variable consisting of significant improvement, moderate improvement, or 
minor/no improvement based on treatment outcomes. 
This defines a hierarchical ordinal categorical response variable, for which a continuation logit 
model will be used to perform separate logistical regression analyses adjusting for baseline 
factors like duration of prior alglucosidase alfa, gender, and mutation type. The results of these 
separate logistic regression analysis are then pooled to test the overall null hypothesis that 
treatment with ATB200/AT2221 is more effective than alglucosidase alfa with respect to either 
the positive response (ie, significant improvement) or the negative response (ie, minor/no 
improvement).  
Details of the methodology with regards to the definition of improvement criteria, intergroup 
comparisons, test against the overall null hypothesis, and use of assistive devices while 
performing the 6MWT will be provided in the SAP. 
15.3.2.3.2. Key Secondary Endpoint Analyses 
Key secondary endpoints will be analyzed according to the hierarchical order as specified in 
Section 15.1.2, using stepwise closed testing procedure to control the type I error rate. Key 
secondary and other secondary endpoints will be analyzed separately with a similar method used 
for the primary endpoint analysis. 


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15.3.2.3.3. Other Secondary Endpoint Analyses 
15.3.2.3.3.1. Functional Assessments 
Endpoints for motor function tests, muscle strength tests, and pulmonary function tests will be 
summarized by treatment group and visit. In addition, the change from baseline to Week 52 for 
each endpoint measure will be analyzed and compared between the 2 treatment groups using 
similar analysis as for the primary endpoint. 
15.3.2.3.3.2. Patient-Reported Outcomes and Physician’s Global Impression of Change 
The mITT population will be used for patient-reported outcome analyses. Summary of each item 
as well as total score (raw total score and change from baseline in total score) for R-PAct scale, 
EQ-5D-5L (descriptive scores), and PROMIS instruments will be summarized by treatment 
group and visit. The change from baseline to Week 52 in the total scores will be analyzed using 
an ANCOVA to compare between the 2 treatment groups. 
Each item of the Subject Global Impression of Change will be summarized by treatment group 
and visit. Additionally, the response scale for each item at Week 52 will be divided into 
3 categories (improving, stable, or declining) which reflect the functional status, and these will 
be summarized by treatment group.  
Summary of response score for actual values for Physician’s Global Impression of Change will 
be summarized by treatment group and visit. 
15.3.2.3.3.3. Biomarker Analyses 
The mITT population will be used for biomarker analyses involving CK or urinary Hex4. 
Specific analyses include but not limited to intergroup comparisons of ATB200/AT2221 to 
alglucosidase alfa/placebo, description of relationships between biomarkers, and mediation 
analysis to establish surrogacy of biomarkers for clinical or patient-reported outcome endpoints 
with intergroup comparisons. 
15.3.2.4. Pharmacokinetic Analyses 
15.3.2.4.1. Population Pharmacokinetic Analysis (ERT-experienced Subjects) 
Population PK analyses for repeated-measures endpoints will be conducted with NONMEM 
software, Version 7.3 or higher (ICON Development Solutions, Hanover, MD). Data from the 
current study will be added to the existing data set for Study ABT200-02, and the previously 
developed population PK models will be used as the starting point for updated analyses. The 
models will be refined as necessary to describe ATB200 and AT2221 disposition given the 
updated data set (eg, testing alternative structural models, random effects structure, covariate 
models). 
The effects of demographic and clinical factors on variability of ATB200 and AT2221 
pharmacokinetics will be investigated throughout the modeling process. Covariate effects to be 
investigated include, but are not limited to, body size, ERT status (ERT-experienced, 
ERT-naïve), gender, age, and the presence of antidrug Abs. 


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Exposure-response relationships will also be explored. Initially, plots of PD endpoints versus 
ATB200 exposures will be constructed to investigate potential exposure-response correlations. 
Any potential relationships will be explored further using longitudinal and/or landmark 
exposure-response analyses to characterize the effects of ATB200 exposure on PD endpoints. 
Additional details will be provided in a separate modeling and simulation plan to be finalized 
prior to population PK and PK/PD modeling, and a separate report will be provided to 
summarize all modeling analyses. 
15.3.2.4.2. Noncompartmental Pharmacokinetic Analysis (ERT-naïve Subjects) 
Plasma PK parameters will be computed by noncompartmental analysis with Phoenix® 
WinNonlin® version 8.0 or higher. For the purpose of calculating PK parameters, values below 
the limit of quantification (BLQ) will be set to 0 when a BLQ occurs before the first measurable 
concentration. If a BLQ occurs after a measurable concentration in a profile and is followed by a 
value above the lower limit of quantification, then the BLQ will be treated as “missing”. If a 
BLQ value occurs at the end of the blood sampling interval (after the last quantifiable 
concentration) it will also be treated as “missing”. For descriptive statistics of plasma 
concentration data, all BLQs will be set to 0 and included in designated statistical calculations. 
Pharmacokinetic analyses performed on preliminary quality checked concentration data will use 
nominal time points; PK analyses performed on final concentration data will use actual time 
points. Pharmacokinetic endpoints are described in Section 15.1.4. 
15.3.2.5. Safety Analyses 
Safety analyses will be based the safety population. Safety data will be summarized using counts 
and percentages for categorical data and descriptive statistics (mean, standard deviation, median, 
minimum, maximum) for continuous data.  
Exposure to study drug will be summarized using descriptive statistics. 
Summaries of AEs will include an overall summary of incidence and summaries by relationship 
and by severity. Summaries and/or listings will be provided for deaths, SAEs, and AEs leading to 
discontinuation. Infusion-associated reactions in the ATB200/AT2221 arm will be compared in 
frequency to the alglucosidase alfa/placebo group in this study. Adverse events will be coded 
using Medical Dictionary for Regulatory Activities version 18 or higher. 
Clinical laboratory results, ECG parameters, and vital signs will be summarized using descriptive 
statistics (number, mean, median, standard deviation, minimum, and maximum) by treatment 
group and visit for actual values and changes from baseline. The proportion of subjects with 
abnormalities will be provided for clinical laboratory results, ECGs, and vital signs. Shift tables 
will also be provided for clinical laboratory results. 
Prior and concomitant medications and nondrug therapies will be summarized by treatment 
group. Concomitant medications terms will be coded using the World Health Organization Drug 
Dictionary (September 2013 DDE). 
15.3.2.6. Immunogenicity Analyses 
The effect of immunogenicity results on efficacy, pharmacokinetics, and safety will be explored. 


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16.
STUDY CONDUCT CONSIDERATIONS
This global study will include both US sites operating under the Investigational New Drug (IND) 
application (ie, IND sites) and foreign sites (ie, non-IND sites). All investigators will be required 
to certify their compliance with both International Conference on Harmonisation (ICH) E6 Good 
Clinical Practice (GCP) and their respective country’s applicable laws and regulations. Both IND 
and non-IND sites will be operating under a single protocol (ie, there will not be a separate 
protocol for non-IND sites). The sponsor will ensure the conduct, monitoring, auditing, 
recording, analysis, and reporting of clinical trial results are in accordance with ICH GCP, 
providing assurance that the data and reported results are credible and accurate and that the 
rights, safety, and well-being of trial subjects are protected. 
16.1. 
Posting of Information on Publicly Available Clinical Trial Registers 
Amicus will be responsible for registering this clinical study in global public registries that meet 
the requirements specified by the International Council of Medical Journal Editors, such as 
www.clinicaltrials.gov, and for publication of study results. Investigators will provide contact 
information to Amicus for the study listing.  
16.2. 
Regulatory and Ethical Considerations 
16.2.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
current version of the Declaration of Helsinki and are consistent with International Council on 
Harmonisation/GCP, applicable regulatory requirements, and Amicus’ policy on bioethics. 
16.2.2. 
Independent Ethics Committees/Institutional Review Boards Approval and 
Study Compliance 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC/REB, as appropriate. The investigator must submit 
written approval to Amicus (or designee) before he or she can recruit any subject into the study. 
The principal investigator is responsible for informing the IRB/IEC/REB of any amendment to 
the protocol in accordance with local requirements. In addition, the IRB/IEC/REB must approve 
all advertising used to recruit subjects for the study. The protocol must be re-approved by the 
IRB/IEC/REB upon receipt of amendments and annually, if applicable, as local regulations 
require. 
16.2.3. 
Ongoing Information for Independent Ethics Committees/Institutional Review 
Boards 
The information listed below must be submitted to the IRBs/IECs/REBs according to timelines 
specified by individual IRB/IEC/REB-documented submission policies and procedures, or by 
local law: 
•
Adverse event information
•
Expedited safety reports


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•
Periodic reports on the progress of the study
Submissions may be made by Amicus (or designee) or by the investigator. 
16.2.4. 
Subject Information and Informed Consent 
Signed written informed consent is to be obtained from each subject prior to any study-related 
procedures being performed. Consent must be in a language understandable to the subject and 
must specify who informed the subject. Informed consent process must follow local regulations. 
Where required by local law, the person who informs the subject must be a physician. 
The subject must be given the opportunity to read the ICF and have all their questions and 
concerns addressed before giving consent in writing. If the subject is unable to read, oral 
presentation and explanation of the written ICF and information to be supplied to the subject 
must take place in the presence of an impartial witness. Consent must be confirmed at the time of 
consent orally and by the personally dated signature of the subject (eg, subject’s thumbprint or 
mark). Details about why oral presentation was used, how the information was presented, and 
how the subject provided consent must be described in the medical records. In addition, subjects 
are not allowed to share, discuss, or comment on social media about their participation in this 
study. 
A copy of the signed ICF will be given to the subject, and the original will be retained by the 
site. An entry must be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a copy 
of the signed ICF. 
The witness and the person conducting the informed consent discussions must also sign and 
personally date the ICF. Until a signed written consent has been obtained, the investigator will 
not undertake any measures specifically required for this study. 
If informed consent is obtained by telephone (as allowed by individual IRBs/IECs/REBs), the 
subject must be provided a copy of the informed consent document in advance of a telephone 
discussion with the investigator. The investigator must explain the research and assess subject 
comprehension of the study according to site consent procedures. If the subject agrees to 
participate, the subject signs the consent form and returns it to the investigator (eg, via fax) for 
signature before any study assessments begin. When the subject is seen at the site, an updated 
in-person consent form will be obtained before any additional study procedures are performed. 
16.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Amicus procedures, Amicus monitors or 
designee will contact the site prior to the start of the study to review with the site personnel the 
protocol; study requirements; and their responsibilities to satisfy regulatory, ethical, and Amicus’ 
or its designee’s requirements. When reviewing data collection procedures, the discussion will 
include identification, agreement, and documentation of data items for which the eCRF will 
serve as the source document. 


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Risk-based monitoring will be performed on the primary characteristics of the study, as detailed 
in the Monitoring Plan. Amicus or its designee will monitor the study as indicated to ensure the 
following: 
•
Data are authentic, accurate, and complete.
•
Safety and rights of subjects are being protected.
•
Study is conducted in accordance with the currently approved protocol and any other
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agree to allow the 
monitor direct access to all relevant documents. 
16.3.1. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Amicus may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the study. 
In the event of an assessment, audit, or inspection, the investigator (and institution) must agree to 
grant the advisor(s), auditor(s), and inspector(s) direct access to all relevant documents and to 
allocate their time and the time of their personnel to discuss the conduct of the study and any 
findings/relevant issues and to implement any corrective and/or preventative actions to address 
any findings/issues identified. 
16.3.2. 
Confidentiality 
Subject names will not be supplied to Amicus. A unique subject number will be recorded in the 
eCRF, and if the subject’s name appears on any other document (eg, a laboratory report), it must 
be obliterated on the copy of the document to be supplied to Amicus. Study findings stored on a 
computer will be stored in accordance with local data protection laws (eg, European Union [EU] 
Directive 95/46/EC, EU Directive 94/45/EC, and the General Data Protection Regulation 
(GDPR) (EU) 2016/679]). The subject will be informed that representatives of Amicus, the 
IRB/IEC/REB, or regulatory authorities may inspect their medical records to verify the 
information collected and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
16.3.3. 
Protocol Amendments and Deviations 
If a clarification on a procedure or an error is found in the protocol, a protocol clarification 
memo will be sent to all sites and the IRB/IEC/REB before an amendment is issued. 
Changes to the administrative aspects of the study (eg, changes in contact information or study 
personnel) will not require formal protocol amendments or IRB/IEC/REB approval but can be 
treated as administrative amendments. However, the IRB/IEC/REB should be kept informed of 
such changes.  
Nonadministrative changes to the protocol, initiated either by Amicus or the investigator, will 
require a formal amendment procedure. Approval of all amendments must be obtained from 


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Amicus, relevant IRB/IEC/REB, and regulatory authorities (in accordance with local 
requirements) prior to implementation.  
Protocol deviations that may significantly impact subject safety or scientific integrity 
(eg, changes to eligibility criteria, addition or deletion of tests, dosing, duration of treatment, 
and/or other aspects of study design) are not permitted under GCP or by Amicus, unless 
necessary to eliminate an immediate hazard to the subject(s). Where Amicus and/or the 
investigator must take urgent safety measures to protect subjects from an immediate hazard, a 
protocol deviation may be allowed prior to obtaining approval from the relevant IRB/IEC/REB 
(and/or regulatory authorities) according to 21 Code of Federal Regulations 312.30(b) (2). In 
such cases, Amicus and the IRB/IEC/REB must be notified within 1 business day. 
Amicus and the relevant IRB/IEC/REB, where required by local law, must be informed of all 
protocol deviations and violations, and the investigators shall document such protocol deviations 
and violations in subject source documents and eCRFs. 
16.3.4. 
Delegation of Investigator Duties 
The investigator should ensure that all persons assisting with this study are adequately qualified 
and informed about their study-related duties and functions, the protocol, any amendments to the 
protocol, and the study treatment.  
Amicus will select a coordinating investigator as a representative of all investigators for this 
study. Each investigator must maintain a list of sub-investigators and other appropriately 
qualified persons to whom they delegate significant study-related duties.  
Should the investigator delegate the supervision of the administration of the study drugs, the 
designee should have the appropriate medical qualifications to effectively conduct or supervise 
any potential resuscitation procedures. 
16.3.5. 
Study and Site Closure 
Upon completion or termination of the study, the Amicus monitor or its designee will conduct 
site closure activities with the investigator or site personnel (as appropriate), in accordance with 
applicable regulations, GCP, and standard operating procedures of Amicus or its designee. 
Amicus reserves the right to temporarily suspend or terminate the study at any time for reasons 
including (but not limited to) safety issues, ethical issues, or severe noncompliance. If Amicus 
determines that such action is required, Amicus will discuss the reasons for taking such action 
with the investigator or head of the medical institution (where applicable). When feasible, 
Amicus will provide advance notice to the investigator or head of the medical institution of the 
impending action. 
If a study is suspended or terminated for safety reasons, Amicus will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions conducting 
the study. Amicus or its designee will also promptly inform the relevant regulatory authorities of 
the suspension/termination along with the reasons for such action. Where required by applicable 
regulations, the investigator or head of the medical institution must inform the IRB/IEC/REB 
promptly and provide the reason(s) for the suspension/termination. 


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16.4. 
Legal and Financial Aspects 
16.4.1. 
Liability and Insurance 
Liability and insurance provisions for this study are provided in separate agreements. 
16.4.2. 
Financial Disclosure 
Before the start of the study, the investigator will disclose to Amicus any proprietary or financial 
interests he or she might hold in the investigational products, miglustat (as in Zavesca®), 
Myozyme, Lumizyme, or Amicus, as outlined in the financial disclosure form provided by 
Amicus. The investigator agrees to update this information in case of significant changes during 
the study or within 1 year of its completion. The investigator also agrees that, where required by 
law or regulation, Amicus may submit this financial information to domestic or foreign 
regulatory authorities in applications for marketing authorizations.  
Where required by regulation: 
•
The investigator will disclose his/her financial interests to the subjects in the informed
consent information.
•
The investigator or Amicus, on behalf of the investigator, will submit the financial
arrangements for the study to the regulatory authorities or to the IRB/IEC/REB.
Each sub-investigator to whom the investigator delegates significant study-related 
responsibilities will provide financial disclosures. 
16.5. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations to 
be maintained elsewhere) in a safe and secure location. The records must be easily accessible 
when needed (eg, for a sponsor audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant site personnel. 
Where permitted by local laws/regulations or institutional policy, some or all of the records may 
be maintained in a format other than hard copy (eg, microfiche, scanned, and electronic); 
however, caution must be exercised before such action is taken. The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original. In addition, 
they must meet accessibility and retrieval standards, including regeneration of a hard copy, if 
required. The investigator must also ensure that an acceptable back-up of the reproductions exists 
and that there is an acceptable quality control procedure in place for creating the reproductions. 
Amicus (or designee) will inform the investigator of the time period for retaining the site records 
in order to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, 
Amicus’ standard operating procedures, and/or institutional requirements. 
The investigator must notify Amicus of any changes in the archival arrangements, including, but 
not limited to, archival of records at an off-site facility or transfer of ownership of the records in 
the event that the investigator is no longer associated with the site. 


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16.6. 
Use of Study Findings 
All information concerning the operation of Amicus that has been provided by Amicus and is 
unpublished is confidential and must remain the sole property of Amicus. The investigator agrees 
to use the information only for the purposes of carrying out this study and for no other purpose 
unless prior written permission from Amicus is obtained. 
Amicus has full ownership of the data collected as part of the study. 
By signing the clinical study protocol and the confidentiality agreement, the investigator agrees 
that the results of the study may be used for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. The 
authorities will be notified of the investigator’s name, address, qualifications, and extent of 
involvement. 
Amicus will ensure that a final report on the study is prepared and will ensure that the study 
findings are reported in a manner that complies with applicable requirements for reporting 
clinical study results.  


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17.
REFERENCES
ATS Statement: Guidelines for the Six-Minute Walk Test (2002). Am J Respir Crit Care Med 
166: 111-117. 
Bohannon R.W., Crouch R. (2017). “Minimal clinically important difference for change in 
6-minute walk distance of adults with pathology: a systemic review.” J. Eval. Clin. Prac.
23(2):377-381.
Clinical Outcome Assessment Compendium, Version 1. Information Based on Drug Labeling 
Approved From 2003 to 2014: December 31, 2014; and CDER’s DDT COA Qualification 
Program: December 31, 2015. 
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/U
CM481225.pdf 
Doerfler, P. A., J. S. Kelley, et al. (2014). "Pharmacological chaperones prevent the precipitation 
of rhGAA by anti-GAA antibodies during enzyme replacement therapy." Mol. Genet. Metab. 
111(2): S38. 
Enright, P.L., Sherrill D.L. (1998). “Reference equations for the six-minute walk in healthy 
adults.” Am. J. Respir. Crit. Care Med. 158(5 Pt 1):1384-1387. 
Hagemans, M. L. C., A. C. J. W. Janssens, et al. (2004). "Late-onset Pompe disease primarily 
affects quality of life in physical health domains." Neurology 63(9): 1688-1692. 
Hagemans, M. L., L. P. Winkel, P. A. Van Doorn, W. J. Hop, M. C. Loonen, A. J. Reuser and 
A. T. Van der Ploeg (2005). "Clinical manifestation and natural course of late-onset Pompe's 
disease in 54 Dutch patients." Brain. 128(Pt 3): 671-677 Epub 2005 Jan 2019. 
Hirschhorn, R. and A. J. J. Reuser (2001). Glycogen Storage Disease Type II: Acid 
α-Glucosidase (Acid Maltase) Deficiency. The Metabolic and Molecular Bases of Inherited 
Disease. C. Scriver, A. Beaudet, W. Sly and D. Valle. New York, McGraw-Hill. 2006: 
3389-3420. 
Kishnani, P. S., R. D. Steiner, D. Bali, K. Berger, B. J. Byrne, L. E. Case, J. F. Crowley, 
S. Downs, R. R. Howell, R. M. Kravitz, J. Mackey, D. Marsden, A. M. Martins,
D. S. Millington, M. Nicolino, G. O'Grady, M. C. Patterson, D. M. Rapoport, A. Slonim,
C. T. Spencer, C. J. Tifft and M. S. Watson (2006). "Pompe disease diagnosis and management
guideline." Genet. Med. 8(5): 267-288.
Leslie, N. and L. Bailey. Pompe Disease. August 31, 2007; Last Update: May 11, 2017 In: 
R. A. Pagon, M. P. Adam, H. H. Ardinger et al., editors. GeneReviews® [Internet]. Seattle (WA): 
University of Washington, Seattle; 1993-2017. 
Parenti, G., G. Andria, et al. (2015). "Lysosomal Storage Diseases: From Pathophysiology to 
Therapy." Annu. Rev. Med. 66(1): 471-486. 
Raben, N., P. Plotz and B. J. Byrne (2002). "Acid α-Glucosidase deficiency (glycogenosis type 
II, Pompe disease)." Current Molecular Medicine 2(2): 145-166. 


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Regnery, C., C. Kornblum, F. Hanisch, S. Vielhaber, N. Strigl-Pill, B. Grunert, 
W. Müller-Felber, F. Glocker, M. Spranger, M. Deschauer, E. Mengel and B. Schoser (2012).
"36 months observational clinical study of 38 adult Pompe disease patients under alglucosidase
alfa enzyme replacement therapy." Journal of Inherited Metabolic Disease 35(5): 837-845.
Sampson, H. A., A. Muñoz-Furlong, et al. (2006). "Second symposium on the definition and 
management of anaphylaxis: Summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium." J. Allergy Clin. 
Immunol. 117(2): 391-397. 
Schoser, B., A. Stewart, S. Kanters, A. Hamed, J. Jansen, K. Chan, M. Karamouzian and 
A. Toscano (2017). "Survival and long-term outcomes in late-onset Pompe disease following
alglucosidase alfa treatment: a systematic review and meta-analysis." J Neurol 264(4): 621-630.
Toscano, A. and B. Schoser (2013). "Enzyme replacement therapy in late-onset Pompe disease: a 
systematic literature review." J Neurol 260(4): 951-959. 
van der Ploeg, A. T., P. R. Clemens, D. Corzo, D. M. Escolar, J. Florence, G. J. Groeneveld, 
S. Herson, P. S. Kishnani, P. Laforet, S. L. Lake, D. J. Lange, R. T. Leshner, J. E. Mayhew,
C. Morgan, K. Nozaki, D. J. Park, A. Pestronk, B. Rosenbloom, A. Skrinar, C. I. van Capelle,
N. A. van der Beek, M. Wasserstein and S. A. Zivkovic (2010). "A Randomized Study of
Alglucosidase Alfa in Late-Onset Pompe's Disease." N Engl J Med 362(15): 1396-1406.
van der Ploeg, A. T., M. E. Kruijshaar, A. Toscano, P. Laforêt, C. Angelini, R. H. Lachmann, 
S. I. Pascual, M. Roberts, K. Rösler, T. Stulnig, P. A. van Doorn, P. Y. K. Van den Bergh,
J. Vissing, B. Schoser and C. the European Pompe (2017). "European consensus for starting and
stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year
experience." European Journal of Neurology: n/a-n/a.
Vogel, WH (2010). “Infusion reactions: diagnosis, assessment, and management.” Clin J Oncol 
Nurs Apr; 14(2):E10-21 
Wraith, J. E. and J. Imrie (2009). "New therapies in the management of Niemann-Pick type C 
disease: clinical utility of miglustat." Ther Clin Risk Manag 5: 877-887. 
Wyatt, K., W. Henley, L. Anderson, R. Anderson, V. Nikolaou, K. Stein, L. Klinger, D. Hughes, 
S. Waldek, R. Lachmann, A. Mehta, A. Vellodi and S. Logan (2012). "The effectiveness and
cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of
people with lysosomal storage disorders." Health Technology Assessment 16(39): 1-543.


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APPENDIX 1. SAMPSON CRITERIA FOR ANAPHYLAXIS 
Source: Sampson et al 2006


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APPENDIX 2. POTENTIALLY CLINICALLY SIGNIFICANT 
GUIDELINES 
Criteria for identifying abnormalities as potentially clinically significant are based on the 
Guidelines for the Division of Neuropharmacological Drug Products, US Food and Drug 
Administration (revised on 2 April 1987). The laboratory values identified below are not 
inclusive of all the safety laboratory analytes that will be assessed during this clinical trial. Safety 
laboratory analytes that are known to be elevated in some adults with Pompe disease 
(eg, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase) and safety 
laboratory analytes which are not listed below will be reviewed to determine if they are to be 
noted as potentially clinically significant based on the magnitude of the out of range value as 
compared to the normal range and the subject’s baseline value, and whether the out of range 
value is coded as clinically significant by the principal investigator. 


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Laboratory Values 
Variable 
Criterion Values 
Standard Units 
SI Units 
Chemistry 
SGOT (AST) 
≥ 3 x Upper Limit Normal 
SGPT (ALT) 
≥ 3 x Upper Limit Normal 
Alkaline Phosphatase 
≥ 3 x Upper Limit Normal 
LDH 
≥ 3 x Upper Limit Normal 
BUN 
≥ 30 mg/dL 
≥ 10.7 µM 
Creatinine 
≥ 2.0 mg/dL 
≥ 176.8 µM 
Uric Acid 
Male 
≥ 10.5 mg/dL 
≥ 624.6 µM 
Female 
≥ 8.5 mg/dL 
≥ 505.6 µM 
Bilirubin (Total) 
≥ 2.0 mg/dL 
≥ 34.2 µM 
Hematology 
Hematocrit 
Male 
≤ 37% 
Female 
≤ 32% 
Hemoglobin 
Male 
≤ 11.5 g/dL 
Female 
≤ 9.5 g/dL 
Platelets 
≤ 75,000/mm3 or ≥ 700,000/mm3 ≤ 75 x 109/L or ≥ 700 x 109/L 
Leukocytes 
≤ 2,800/mm3 or ≥ 16,000/mm3 
≤ 2.8 x 109/L or ≥ 16 x 109/L 
Eosinophils 
≥ 10% 
Neutrophils 
≤ 15% 
Urinalysis 
Protein 
Increase of ≥ 2 units 
Glucose 
Increase of ≥ 2 units 
Casts 
Increase of ≥ 2 units 
Abbreviations: BUN = blood urea nitrogen; LDH = lactate dehydrogenase; SGOT (AST) = serum glutamic 
oxaloacetic transaminase (aspartate aminotransferase); SGPT (ALT) = serum glutamic pyruvic transaminase 
(alanine aminotransferase) 


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Vital Sign Values 
Variable 
Criteria 
Change Relative to 
Baseline 
Heart Rate 
≥ 120 bpm 
and an 
increase of ≥ 15 bpm 
≤ 50 bpm 
and a 
decrease of ≥ 15 bpm 
Systolic 
Blood Pressure 
≥ 180 mmHg 
and an 
increase of ≥ 20 mmHg 
≤ 90 mmHg 
and a 
decrease of ≥ 20 mmHg 
Diastolic 
Blood Pressure 
≥ 105 mmHg 
and an 
increase of ≥ 15 mmHg 
≤ 50 mmHg 
and a 
decrease of ≥ 15 mmHg 
Weight 
change of ≥ 7% body weight 
ECG Values 
ECG parameter 
Low 
High 
PR interval (ms) 
< 120 ms 
≥ 210 ms 
QRS duration (ms) 
≤ 50 ms 
> 120 ms
QTcB interval (ms) 
Not applicable 
> 450 ms for males and > 470 ms
for females and QTcB increases
from baseline > 60 ms (males and
females)
Ventricular rate (bpm) 
A decrease from referencea 
≥ 15 bpm, and an absolute value 
< 50 bpm
An increase from referencea 
≥ 15 bpm, and an absolute value 
> 120 bpm 
Abbreviation: QTcB = QT interval for corrected heart rate 
a Reference value: baseline or initial visit value, as appropriate. 

SAP_001.pdf: 
Official Title: 
Statistical Analysis Plan:  A Phase 3 Double-blind 
Randomized Study to Assess the Efficacy and 
Safety of Intravenous ATB200 Co-administered 
With Oral AT2221 in Adult Subjects With  
Late-Onset Pompe Disease Compared With 
Alglucosidase Alfa/Placebo  
 
 
NCT Number: 
NCT03729362 
 
 
Document Date: 
Final SAP v3.0:  14 January 2021 
 


STATISTICAL ANALYSIS PLAN  
 
VERSION: Final SAP v3.0 
DATE OF PLAN: 
14 January 2021 
 
STUDY TITLE: 
A PHASE 3 DOUBLE-BLIND RANDOMIZED STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF INTRAVENOUS ATB200 CO-ADMINISTERED 
WITH ORAL AT2221 IN ADULT SUBJECTS WITH LATE-ONSET POMPE 
DISEASE COMPARED WITH ALGLUCOSIDASE ALFA/PLACEBO 
 
PROTOCOL NUMBER: ATB200-03 
Protocol Amendment 3, Dated: 14 August 2020  
 
COMPOUNDS: ATB200 and AT2221 (ie, ATB200/AT2221) 
 
 
SPONSOR: 
Amicus Therapeutics, Inc. 
1 Cedar Brook Drive 
Cranbury, NJ 08512, USA 
Phone: +1 609-662-2000 
 
The information in this document is the property of Amicus Therapeutics and is strictly 
confidential. Neither the document nor the information contained herein may be reproduced or 
disclosed outside of Amicus Therapeutics without the prior written consent of the company, 
except to the extent required under applicable laws or regulations.  


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
1. 
LIST OF ABBREVIATIONS .......................................................................................8 
2. 
INTRODUCTION ......................................................................................................10 
3. 
STUDY OBJECTIVES ..............................................................................................11 
3.1. 
Primary Objective .......................................................................................................11 
3.2. 
Secondary Objectives .................................................................................................11 
3.3. 
Study Endpoints ..........................................................................................................12 
3.3.1. 
Primary Endpoint ........................................................................................................12 
3.3.2. 
Key Secondary Efficacy Endpoints ............................................................................12 
3.3.3. 
Other Secondary Efficacy Endpoints ..........................................................................12 
3.3.4. 
Pharmacodynamic Endpoints .....................................................................................14 
3.3.5. 
Pharmacokinetic Endpoints ........................................................................................14 
3.3.5.1. 
Population Pharmacokinetic Analysis ........................................................................14 
3.3.5.2. 
Pharmacokinetic Sub-analysis (ERT-naïve Subjects) ................................................14 
3.3.5.3. 
Immunogenicity Endpoints .........................................................................................15 
3.3.6. 
Safety Endpoints .........................................................................................................15 
4. 
STUDY DESIGN .......................................................................................................16 
4.1. 
Summary of Study Design ..........................................................................................16 
4.2. 
Definition of Study Drugs ..........................................................................................16 
4.3. 
Sample Size and Power Considerations .....................................................................16 
4.4. 
Randomization and Stratification ...............................................................................16 
4.5. 
Clinical Assessments ..................................................................................................17 
4.5.1. 
Impact of COVID-19 Pandemic .................................................................................17 
5. 
INTERIM ANALYSES ..............................................................................................18 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................19 
6.1. 
Analysis Populations ..................................................................................................19 
6.1.1. 
Screen Failures ............................................................................................................19 
6.1.2. 
Safety Population ........................................................................................................19 
6.1.3. 
All Randomized Population ........................................................................................19 
6.1.4. 
ITT Population ............................................................................................................19 


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6.1.4.1. 
ITT-OBS .....................................................................................................................19 
6.1.4.2. 
ITT-LOCF ...................................................................................................................19 
6.1.5. 
Modified ITT Population ............................................................................................20 
6.1.6. 
Per-protocol Population ..............................................................................................20 
6.1.7. 
Completers ..................................................................................................................21 
6.1.8. 
PK Population .............................................................................................................21 
6.2. 
Derived and Transformed Data ..................................................................................22 
6.2.1. 
Study Day ...................................................................................................................22 
6.2.2. 
Baseline Definition .....................................................................................................22 
6.2.3. 
Baseline Age ...............................................................................................................22 
6.2.4. 
Week 52/ET Assessments ...........................................................................................22 
6.2.5. 
Change and Percent Change from Baseline ................................................................23 
6.2.6. 
Analysis Visit Windows .............................................................................................23 
6.2.6.1. 
Visit Windows ............................................................................................................23 
6.2.6.2. 
Impact of COVID-19 on the Visit Windows ..............................................................24 
6.2.7. 
Multiple Assessments in a Visit Window ...................................................................25 
6.2.7.1. 
For Efficacy Data ........................................................................................................25 
6.2.7.2. 
For Safety Data ...........................................................................................................25 
6.3. 
Handling of Missing Data for Key Endpoints ............................................................25 
6.3.1. 
Imputation for Missing Baseline Values ....................................................................25 
6.3.2. 
Imputation for Missing Post-baseline Values .............................................................26 
6.4. 
Handling of Intercurrent Events .................................................................................26 
6.4.1. 
Missing AE Attributes ................................................................................................28 
6.4.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................28 
6.4.3. 
Missing Start and Stop Dates for Adverse Events ......................................................28 
7. 
CHARACTERISTICS OF STUDY POPULATION .................................................29 
7.1. 
Subject Disposition .....................................................................................................29 
7.2. 
Screen Failures ............................................................................................................29 
7.3. 
Protocol Deviations ....................................................................................................29 
7.4. 
Demographic and Baseline Characteristics ................................................................30 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................31 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................31 
7.7. 
Handling the Use of Assistive Device During the 6MWT .........................................31 


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7.8. 
Prior and Concomitant Medications and Nondrug Therapies ....................................31 
7.8.1. 
Non-diagnosis Related Prior Medication History .......................................................32 
7.8.2. 
Prior Diagnosis Related Medication History ..............................................................32 
7.9. 
Baseline Physical Examination ...................................................................................32 
7.10. 
Baseline Vital Signs ....................................................................................................32 
7.11. 
Baseline Laboratory Data ...........................................................................................32 
7.12. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................32 
8. 
ANALYSIS OF EFFICACY ......................................................................................33 
8.1. 
General Considerations ...............................................................................................33 
8.2. 
Testing Statistical Assumptions and Alternative Analysis .........................................33 
8.3. 
Statement of the Null and Alternative Hypotheses .....................................................34 
8.3.1. 
Primary Null and Alternative Hypotheses ..................................................................34 
8.3.2. 
Key Secondary Null and Alternative Hypotheses ......................................................34 
8.4. 
Multiple Comparisons and Multiplicity ......................................................................35 
8.5. 
Analysis of the Primary Efficacy Endpoint ................................................................35 
8.5.1. 
Primary Efficacy Analysis ..........................................................................................35 
8.5.1.1. 
Supportive Analyses for the Primary Efficacy Endpoint and % Predicted 
FVC .............................................................................................................................36 
8.5.1.2. 
Sensitivity Analysis for the Primary Endpoint and % Predicted FVC .......................37 
8.6. 
Analysis of the Key Secondary Endpoints .................................................................39 
8.7. 
Composite Subject-level Response Analysis ..............................................................40 
8.8. 
Analysis of Other Secondary Endpoints .....................................................................42 
8.8.1. 
Motor Function Test ...................................................................................................42 
8.8.2. 
Muscle Strength Tests .................................................................................................42 
8.8.3. 
Other Pulmonary Function Tests ................................................................................43 
8.8.4. 
Patient-reported Outcomes .........................................................................................43 
8.8.5. 
Proportion Improving on Both 6MWD and % Predicted FVC ..................................44 
8.8.6. 
Analysis of Pharmacodynamic Endpoints ..................................................................44 
8.8.7. 
Immunogenicity ..........................................................................................................44 
8.9. 
Subgroup Analyses .....................................................................................................45 
9. 
ANALYSIS OF SAFETY ..........................................................................................47 
9.1. 
Treatment-emergent Adverse Events .........................................................................47 
9.1.1. 
Adverse Event Reporting Period ................................................................................47 


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9.1.2. 
Summary of Treatment-emergent Adverse Events .....................................................48 
9.1.3. 
TEAEs Reported as Infusion-associated Reaction .....................................................48 
9.1.4. 
Additional Analysis of IARs ......................................................................................49 
9.1.4.1. 
Analysis of Time to First IAR-TEAE .........................................................................49 
9.1.4.2. 
Analysis of IARs by Onset Intervals ..........................................................................49 
9.1.4.3. 
Analysis by Time After Infusion Start ........................................................................50 
9.1.5. 
Describing Relationship to Study Drug ......................................................................50 
9.1.6. 
Missing AE Onset Date, Severity, and Relationship ..................................................51 
9.1.6.1. 
Missing or Partial AE Onset or Medication Start Date ..............................................51 
9.1.6.2. 
Missing or Partial Medication Stop Date ....................................................................51 
9.1.6.3. 
Missing Severity .........................................................................................................52 
9.1.6.4. 
Missing Relationship ..................................................................................................52 
9.2. 
Clinical Safety Laboratory Data .................................................................................52 
9.3. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............54 
9.3.1. 
Vital Signs ..................................................................................................................54 
9.3.2. 
Physical Examination .................................................................................................55 
9.3.3. 
Electrocardiograms .....................................................................................................55 
9.4. 
Duration of Therapy and Missing Medication Start and Stop Dates ..........................56 
9.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........56 
9.4.2. 
Duration of Therapy and Treatment Compliance .......................................................57 
10. 
REFERENCES ...........................................................................................................58 
APPENDIX 1. SAMPLE SIZE JUSTIFICATION .....................................................................60 
APPENDIX 2. DESCRIPTIONS OF EFFICACY ENDPOINTS ..............................................62 
APPENDIX 3. SAMPLE SAS PROGRAMS .............................................................................67 
 
LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................8 
Table 2: 
Pre-specified Important Protocol Deviations Leading to Exclusion from 
Per-protocol Populations (PP1 and PP2) ....................................................................21 
Table 3: 
Visit Windows for Functional Assessments, PROs, ECG, and CPE (as 
applicable) ...................................................................................................................23 
Table 4: 
Visit Windows for Vital Signs, Lab Measurements, and BPE (as applicable) ...........24 
Table 5: 
Accounting for Intercurrent Events ............................................................................27 


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Table 6: 
Supportive Analyses for the 6MWD and % Predicted FVC ......................................36 
Table 7: 
Sensitivity Analyses for the 6MWD and % Predicted FVC .......................................37 
Table 8: 
Threshold for Defining Clinically Meaningful Within-subject Change .....................40 
Table 9: 
Pre-defined Limits of Change Criteria for Clinical Safety Laboratory Data ..............53 
Table 10: Pre-defined Limits of Change Criteria for Vital Signs ...............................................55 
Table 11: Pre-defined Limits of Change Criteria for ECG Values .............................................56 
Table 12: Predicted Equations for MIP, MEP, and SNIP ...........................................................62 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical classification 
CI 
confidence interval 
CI-MPR 
cation-independent mannose 6-phosphate receptor 
CK 
creatine kinase 
COVID-19 
coronavirus disease 2019 that is caused by the SARS-Cov-2 virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life-5 Dimensions 5 Response Levels 
ERT 
enzyme replacement therapy 
ET 
early termination 
FVC 
forced vital capacity 
GAA 
human acid α-glucosidase 
GSGC 
Gait, Stairs, Gowers’ maneuver, Chair 
Hex4 
hexose tetrasaccharide 
IAR 
infusion-associated reaction 
ITT 
intent-to-treat population 
ITT-LOCF 
intent-to-treat population with missing data replaced by the last available value 
ITT-OBS 
intent-to-treat population that includes all available, observed data without any 
missing data imputation at Week 52 
LOPD 
late-onset Pompe disease 
LS 
least squares 
MEP 
maximal expiratory pressure 
MIP 
maximal inspiratory pressure 
MMRM 
mixed-effect model for repeated measures 
mITT 
modified intent-to-treat population 


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Table 1: 
List of Abbreviations (Continued) 
Abbreviation 
Term 
MMT 
manual muscle test 
NAb 
neutralizing antibody 
PDLC 
pre-defined limits of change 
PGIC 
Physician’s Global Impression of Change 
PK 
pharmacokinetic 
PP 
per-protocol population 
PP1 
per-protocol population for sensitivity analysis of the 6MWD 
PP2 
per-protocol population for sensitivity analysis of the percent predicted FVC 
PRO 
patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
preferred term 
QMT 
quantitative muscle test 
rhGAA 
recombinant human acid α-glucosidase 
R-PAct 
Rasch-built Pompe-specific Activity scale 
SAP 
statistical analysis plan 
SGIC 
Subject’s Global Impression of Change 
SD 
standard deviation 
SNIP 
sniff nasal inspiratory pressure 
SOC 
system organ class 
SVC 
slow vital capacity 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TUG 
Timed Up and Go 
VC 
vital capacity 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned data derivations, analyses, and 
statistical methods to be performed for Study ATB200-03. It is based on:  
• Protocol for ATB200-03 Amendment 3 dated 14 August 2020 
• Amicus standard operating procedure (SOP) ATCRA-SOP-AT-008 
• Good Clinical Practices (GCP) and International Conference on Harmonisation (ICH) 
guidelines E9 (Statistical Principles for Clinical Trials) 
• Discussions with Regulatory Authorities 
The purpose of this document is to provide details on study populations and on how the variables 
will be derived, how missing data and intercurrent events will be handled, as well as details on 
statistical methods to be used to analyze the efficacy and safety data from Study ATB200-03. 
The document may evolve over time to reflect protocol amendments, regulatory discussions, and 
other important changes. However, the final SAP will be finalized, approved by the Sponsor, and 
placed on file before the database is locked. The data analyses and statistical methods specified 
in the final SAP supersede those described in the study protocol. Deviations from the final 
approved plan will be noted in the clinical study report.  
Pharmacokinetic (PK) and immunogenicity analyses will be covered in separate analysis plans.  


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3. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the efficacy, safety, patient-reported outcomes 
(PROs), and pharmacodynamics (PD) of ATB200/AT2221 co-administration in subjects with 
late-onset Pompe disease (LOPD) compared with alglucosidase alfa/placebo. The primary and 
the secondary objectives are stated below.  
3.1. 
Primary Objective 
• To assess the efficacy of ATB200/AT2221 co-administration on ambulatory function, 
as measured by the 6-minute walk test (6MWT), compared with alglucosidase 
alfa/placebo 
3.2. 
Secondary Objectives 
• To assess the efficacy of ATB200/AT2221 co-administration on pulmonary function, 
as measured by sitting forced vital capacity (FVC) (% predicted), compared with 
alglucosidase alfa/placebo  
• To assess the efficacy of ATB200/AT2221 co-administration on muscle strength, 
compared with alglucosidase alfa/placebo 
• To assess the efficacy of ATB200/AT2221 co-administration on health-related PROs, 
compared with alglucosidase alfa/placebo 
• To assess the efficacy of ATB200/AT2221 co-administration on motor function, 
compared with alglucosidase alfa/placebo  
• To assess the efficacy of ATB200/AT2221 co-administration on overall clinical 
impression as assessed by both the physician and subject, compared with 
alglucosidase alfa/placebo 
• To assess the safety, tolerability, and immunogenicity of ATB200/AT2221 
co-administration compared with alglucosidase alfa/placebo 
• To assess the effect of ATB200/AT2221 co-administration on biomarkers of muscle 
injury and disease substrate compared with alglucosidase alfa/placebo 
• To characterize the population PK of ATB200 and alglucosidase alfa in enzyme 
replacement therapy (ERT)-experienced subjects using plasma total acid 
α-glucosidase (GAA) protein level by signature peptide assay and plasma AT2221 
concentration 
• To characterize the PK of ATB200, alglucosidase alfa, and AT2221 in ERT-naïve 
subjects using noncompartmental analysis 
• To explore the exposure-response relationship for ATB200/AT2221 and 
alglucosidase alfa/placebo co-administration  


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3.3. 
Study Endpoints 
3.3.1. 
Primary Endpoint 
The primary efficacy endpoint of this study is the change from baseline to Week 52 in 6-minute 
walk distance (6MWD) measured in meters, which is the distance walked in the 6MWT. 
3.3.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints, in hierarchical order of importance, are: 
• Change from baseline to Week 52 in sitting FVC (% predicted) 
• Change from baseline to Week 52 in the manual muscle test (MMT) score for the 
lower extremities 
• Change from baseline to Week 26 in 6MWD 
• Change from baseline to Week 52 in the total score for the Patient-Reported 
Outcomes Measurement Information System (PROMIS®) – Physical Function 
• Change from baseline to Week 52 in the total score for the PROMIS – Fatigue 
• Change from baseline to Week 52 in the total score for the GSGC (Gait, Stairs, 
Gowers’ maneuver, Chair)  
Note: See Appendix 2 for further descriptions/definitions of the efficacy endpoints. 
3.3.3. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
• Change from baseline to Week 52 in % predicted 6MWD (where the predicted values 
are calculated using Enright and Sherrill 1998 reference equations) 
• Proportion of subjects improving on both 6MWD and % predicted FVC (where the 
definition of improvement is provided in Section 8.7).  
• Change from baseline to Week 52 in the following variables related to motor 
function: 
− time to complete the 10-meter walk (ie, assessment of gait) of the GSGC test 
− time to complete the 4-stair climb of the GSGC test 
− time to complete the Gower’s maneuver of the GSGC test 
− time to arise from a chair as part of the GSGC test 
− time to complete the Timed Up and Go (TUG) test 
• Change from baseline to Week 52 in the following variables related to muscle 
strength: 
− MMT score for the upper extremities 
− MMT total score 


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− Proximal muscles MMT score 
− Quantitative muscle test (QMT) value (kg) for the upper extremities 
− QMT value (kg) for the lower extremities 
− QMT total value (kg)  
• Change from baseline to Week 52 in the following variables from PRO measures: 
− Total score for the PROMIS – Dyspnea 
− Total score for the PROMIS – Upper Extremities 
− Total score for the Rasch-built Pompe-specific Activity (R-PAct) Scale 
− European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L) based on 
the EQ-VAS quantitative score 
• Actual value of the subject’s functional status (improving, stable, or declining) 
pertaining to the effects of study drug in the following areas of life at Week 52, as 
measured by the Subject’s Global Impression of Change (SGIC): 
− overall physical wellbeing 
− effort of breathing 
− muscle strength 
− muscle function 
− ability to move around 
− activities of daily living 
− energy level 
− level of muscular pain 
• Actual value of the subject’s functional status (improving, stable, or declining) at 
Week 52, as measured by the Physician’s Global Impression of Change (PGIC) 
• Change from baseline to Week 52 in the following measures of pulmonary function, 
as follows:  
− Sitting slow vital capacity (SVC) (% predicted) 
− Maximum vital capacity (maximum VC) (% predicted), where maximum VC is 
defined as the larger of the sitting FVC and the sitting SVC 
− Maximal inspiratory pressure (MIP) (% predicted) 
− Maximal expiratory pressure (MEP) (% predicted) 
− sniff nasal inspiratory pressure (SNIP) (% predicted)  
Note: See Appendix 2 for further descriptions of the efficacy endpoints. 


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3.3.4. 
Pharmacodynamic Endpoints 
Pharmacodynamic endpoints are as follows:  
• Change from baseline to Week 52 in serum creatine kinase (CK) level 
• Change from baseline to Week 52 in urinary hexose tetrasaccharide (Hex4) level 
3.3.5. 
Pharmacokinetic Endpoints 
3.3.5.1. 
Population Pharmacokinetic Analysis 
Population PK from sparse sampling in ERT-experienced subjects (Day 1 and Week 52) and 
ERT-naïve subjects will be performed. The population PK analysis of total GAA protein and 
AT2221 concentrations will be provided in a separate PK analysis plan.  
3.3.5.2. 
Pharmacokinetic Sub-analysis (ERT-naïve Subjects)  
The ERT-naïve subjects will undergo rich PK sampling to enable a noncompartmental analysis 
in the naïve subjects. After serial blood sampling in ERT-naïve subjects, PK parameters for 
plasma total GAA protein concentration will be calculated as follows: 
• Cmax: maximum observed concentration obtained directly from the concentration 
profile 
• tmax: time of the first occurrence of Cmax obtained directly from the concentration 
profile 
• Kel or λz: the apparent terminal phase elimination rate constant will be estimated by 
linear regression of logarithmically transformed concentration versus time data; only 
those data points which are judged to describe the terminal log-linear decline will be 
used in the regression 
• AUC0-t: the area under the plasma drug concentration-time curve from 0 time 
(predose) to the time of last quantifiable concentration (t), calculated with the linear 
up/log-down trapezoidal method  
• AUC0-∞: the area under the plasma drug concentration-time curve from 0 time 
(predose) extrapolated to infinite time will be calculated as follows: 
AUC0-∞ = AUC0-t + Ct/λz 
where Ct is the last observed quantifiable concentration 
• AUCtmax-24h: partial area under the plasma drug concentration-time curve from tmax to 
24 hours post initiation of ATB200 infusion 
• t1/2α: the alpha-phase terminal elimination half-life, calculated as ln(2)/λz from the 
first 3 or more quantifiable concentrations after Cmax; estimated for plasma total GAA 
protein concentration only 
• CLT: total plasma clearance after IV administration, calculated as dose/AUC0-∞ 


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Plasma AT2221 PK parameters will be calculated as follows: 
• Cmax 
• tmax 
• Kel or λz 
• AUC0-t 
• AUC0-∞ 
• t½β: the beta-phase terminal elimination half-life, calculated as ln(2)/λz from the last 
3 or more quantifiable concentrations from the beta phase of elimination 
• CLT/F: total plasma clearance from an oral administration, calculated as dose/AUC0-∞ 
• Vz/F: volume of distribution based on the terminal elimination phase from an oral 
administration, calculated as dose/(AUC0-∞ • λz) 
The details of the PK analyses will be described in a separate PK analysis plan. 
3.3.5.3. 
Immunogenicity Endpoints 
Immunogenicity endpoints are:  
• Total anti-drug antibodies (ADAs), including titers 
• Neutralizing antibodies (NAbs): 
− Inhibition of recombinant human acid α-glucosidase (rhGAA) binding to 
cation-independent mannose-6-phosphate receptor (CI-MPR) 
− Inhibition of rhGAA-mediated hydrolysis of 4-MU-glucoside  
− Inhibition of rhGAA-mediated hydrolysis of glycogen 
• Anti-rhGAA cross-reactive with alglucosidase alfa 
• Anti-rhGAA-specific Immunoglobulin E (IgE) 
The details of the immunogenicity analyses will be described in a separate document: “Modeling 
and Simulation Plan (MSP): Population Pharmacokinetics and Immunogenicity Analyses for 
ATB200/AT2221 in Patients with Pompe Disease Enrolled in Study ATB200-03.” 
3.3.6. 
Safety Endpoints 
The safety profile of ATB200/AT2221 will be characterized using incidence of 
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events 
(AEs) leading to discontinuation of study drug, frequency and severity of immediate and late 
infusion-associated reactions (IARs), and any abnormalities noted in other safety assessments. 
The impact of immunogenicity to ATB200 and alglucosidase alfa on safety and efficacy will also 
be described. The immunogenicity analyses will also be performed by ERT status subgroups 
(ERT-naïve and ERT-experienced).  


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a Phase 3 double-blind, randomized, parallel-group, multicenter, international study of 
ATB200/AT2221 in adult subjects with LOPD compared with alglucosidase alfa/placebo. 
Subjects enrolled will be either ERT-experienced or ERT-naïve. 
The study consists of a 12-month double-blind treatment period during which eligible subjects 
are randomly assigned in a 2:1 ratio to receive either ATB200/AT2221 co-administration or 
alglucosidase alfa/placebo co-administration.  
Subjects who complete 12 months of treatment in this study will have the option to participate in 
an open-label extension (OLE) study (ATB200-07) to receive ATB200/AT2221 under a separate 
protocol. 
4.2. 
Definition of Study Drugs 
Study drugs defined in this protocol are ATB200/AT2221 co-administration and alglucosidase 
alfa/placebo combination. The study drugs will be administered every 2 weeks (QOW). 
The dose for ATB200 as well as alglucosidase alfa will be 20 mg/kg, and both are administered 
via infusion. The dose for AT2221 will be 260 mg (4 x 65 mg oral capsules) for subjects who 
weigh ≥ 50 kg, and 195 mg (3 x 65 mg oral capsules) for subjects who weigh ≥ 40 to < 50 kg. 
The AT2221 and placebo are to be taken orally 1 hour prior to the start of the infusion.  
4.3. 
Sample Size and Power Considerations 
The primary endpoint for this study is the change from baseline to Week 52 in the 6MWD.  
Using a 2-group t-test with a 1-sided significance level of 0.025 and a 2:1 randomization ratio, a 
total of 99 subjects (66 subjects in the ATB200/AT2221 group and 33 subjects in the 
alglucosidase alfa/placebo group) would yield approximately 90% power to detect a clinically 
meaningful standardized effect size of 0.7 between the 2 groups in a superiority test for the 
primary endpoint. This calculation was performed using nQuery 8©. 
Assuming a 10% dropout rate (after randomization), a total of approximately 110 subjects were 
planned to be randomized to ensure 99 evaluable patients.  
Details of the sample size justification are described in Appendix 1. 
4.4. 
Randomization and Stratification 
Although this is a multicenter trial, the randomization was not stratified by center. The following 
2 risk factors were identified as key prognostic factors, and therefore randomization was 
stratified according to these: 
1. Baseline 6MWD (categorized as: 75 to < 150 meters, 150 to < 400 meters, ≥ 400 meters)  
2. ERT status (categorized as: ERT-experienced versus ERT-naïve) 
The randomization schedule was generated and administered centrally by Almac Clinical 
Technologies (Almac), independent of the sponsor’s project team. This centralized block 


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randomization procedure was used to balance the above risk factors, (1) to reduce bias and 
increase the precision of statistical inference, and (2) to allow various planned and unplanned 
subset analyses. The randomization ratio was 2:1 (ATB200/AT2221 to alglucosidase 
alfa/placebo), fixed. Approximately 30 ERT-naïve subjects were planned to be enrolled. 
4.5. 
Clinical Assessments 
Study assessments were to be performed in accordance with the Schedule of Assessments of the 
ATB200-03 protocol. 
4.5.1. 
Impact of COVID-19 Pandemic 
The emergence of the coronavirus disease 2019 (COVID-19) during the conduct of study and the 
related travel restrictions and quarantines resulted in some subjects experiencing missed 
infusions, missed assessments, delayed visits, and early withdrawals. These could potentially 
alter the subject’s response to treatment, confound the assessment of the 6MWD and FVC, and 
impact the analyses.  
Assessment and infusion visits that were missed due to COVID-19 related reasons were to be 
recorded as protocol deviations in the electronic data capture (EDC) and the reasons attributed to 
COVID-19. Infusions that were missed near the scheduled assessments visits at Weeks 26, 38, 
and 52 were to be examined on a case-by-case basis to determine whether catch-up infusions 
were needed, and if so, how many catch-up infusions were needed, prior to rescheduling the 
visits to perform make-up assessments. As a result, subjects who missed visits due to COVID-19 
related reasons could be enrolled longer than 12 months in the study due to delayed visits.  
As a general rule, a subject missing at least 2 consecutive infusions just prior to the Week 52 
assessments (or between Week 38 and Week 52) due to COVID-19 was required to receive 
make-up infusions prior to the EOS assessments. The make-up infusions required 4 consecutive 
infusions to be administered regardless of the number of infusions missed. For example: if a 
subject missed 3 consecutive infusions at Week 42, 44 and 46, then the subject was required to 
receive make-up infusions at Week 48, 50, 52 and 54, and the EOS assessments were to be 
conducted thereafter, prior to Week 56. A subject missing 5 consecutive infusions was to be 
withdrawn from the study. 
Analyses will be performed to assess whether the number of subjects with missing data due to 
COVID-related reasons are comparable between the 2 groups (at Week 52 and across the study).  


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5. 
INTERIM ANALYSES 
There is no interim analysis planned for this study. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
Analysis Populations 
The total number of subjects screened, number who screen-failed, and the number randomized 
(including subjects randomized after rescreening) will be tabulated. 
6.1.1. 
Screen Failures 
Subjects who signed an informed consent form (ICF) but failed to qualify for the study and were 
therefore not randomized, will be considered screen failures.  
Information on screen failures will be presented in a data listing. 
6.1.2. 
Safety Population 
The safety population is defined as all subjects who received at least 1 dose of study drug 
(ATB200/AT2221 or alglucosidase alfa/placebo). This population will be used in the assessment 
and reporting of safety data. Subjects will be analyzed according to the actual treatment received. 
6.1.3. 
All Randomized Population 
The ‘All Randomized’ population consists of all subjects who were randomized, regardless of 
whether they took a dose of study drug. This population will be used only for subject accounting 
purposes, and it will be analyzed according to the planned treatment groups.  
6.1.4. 
ITT Population 
The intent-to-treat (ITT) population consists of all randomized subjects who received at least 
1 dose of study drug. This population will be analyzed according to the planned treatment 
groups. The ITT population will be used for additional baseline and demographic summaries. 
For the purpose of efficacy analysis, the ITT population has been characterized in 2 different 
ways (ITT-observed [OBS] and ITT-last observation carried forward [LOCF]) (see Section 8.2 
and Section 6.3.2 for further descriptions).  
6.1.4.1. 
ITT-OBS 
The ITT-OBS is the ITT population using all available, observed data without imputation for 
missing post-baseline data. That is, missing data at Week 52 and at other visits are not replaced.  
The ITT-OBS population is identical to the ITT population as defined above. The mixed-effect 
model for repeated measures (MMRM) analysis will be performed on the ITT-OBS population. 
6.1.4.2. 
ITT-LOCF 
The ITT-LOCF is the ITT population with missing data replaced with the last available value 
from post-baseline results. That is, the LOCF replaces missing data at Weeks 26, 38, and 52 with 
the last available endpoint value. Where applicable, the observed baseline result will be used to 
replace a missing post-baseline result at the Week 12 visit. Imputed baseline value cannot be 
used to replace missing Week 12 result. The missing value at Week 52 is replaced with the last 


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available value from the subject in the study. This can be the value from the early termination 
(ET)/end of study (EOS) visit if available. If not available, the last available value from prior 
post-baseline visits (Week 38, Week 26, or Week 12, whichever is available) will be used to 
replace the missing value at Week 52. 
Example for visits earlier than Week 52: Suppose the subject only missed the assessment at 
Week 12 but had assessments at some other visits after Week 12 (ie, Week 26 and/or Week 38 
and/or Week 52). Then the missing assessment at Week 12 is replaced with the last available 
value on/prior to Week 12 (eg, the observed baseline value). If the subject missed the Week 12 
visit due to discontinuation/withdrawal from the study and had follow-up assessments at the 
ET/EOS visit, then the last available value from the ET/EOS visit will be used to replace the 
missing Week 12 value. This EOS value is then carried forward to replace missing values at 
Weeks 26, 38, and 52 as the subject had withdrawn from the study since Week 12.  
Note: The observed baseline result can only be used to replace missing data at Week 12, where 
applicable (ie, if the subject has other post-baseline data). It will not be carried forward to replace 
missing values at Week 26, 36 or 52. In addition, imputed baseline values cannot be used to 
replace missing post-baseline values. 
6.1.5. 
Modified ITT Population 
The modified intent-to-treat (mITT) population is a subset of the ITT population consisting of all 
randomized subjects who took at least 1 dose of study drug and have both baseline and at least 
1 post-baseline assessment for the 6MWD. This population will be analyzed according to the 
planned treatment groups. The mITT population will be used for subject accounting purposes. 
6.1.6. 
Per-protocol Population 
The per-protocol population (PP) is a subset of the mITT population consisting of any mITT 
subjects who do not have pre-specified protocol deviations that are considered important, as they 
potentially may have altered the subject’s response to study treatment or confounded the study 
assessments, thereby impacting the analyses of the primary endpoint (6MWD) and the FVC. 
This population will be analyzed according to the actual treatment received.  
The PP population will be characterized separately for sensitivity analyses for the 6MWD and 
% predicted FVC. The per-protocol population 1 (PP1) will be used for the sensitivity analyses 
of the 6WMD, while per-protocol population 2 (PP2) will be used for sensitivity analyses of the 
% predicted FVC.  
Pre-specified important protocol deviations leading to exclusion from the PP1 and PP2 
populations include those in Table 2. These populations will be determined and finalized before 
locking the database. 


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Table 2: 
Pre-specified Important Protocol Deviations Leading to Exclusion from 
Per-protocol Populations (PP1 and PP2) 
Item 
Important Protocol Deviation Description 
(Excluded from PP1: for 6MWD)  
Important Protocol Deviation Description 
(Excluded from PP2: for FVC) 
1. 
Subject did not have sufficient treatment 
exposure (ie, subject did not have at least 
80% compliance with study treatment)  
Subject did not have sufficient treatment 
exposure (ie, subject did not have at least 
80% compliance with study treatment) 
2. 
Subject did not have the primary endpoint 
(6MWD) assessment at the Week 52 visit 
(including catch-up assessment or delayed 
visit) due to COVID-19 pandemic or other 
reasons 
Subject did not have FVC assessment at the 
Week 52 visit (including catch-up assessment 
or delayed visit) due to COVID-19 pandemic 
or other reasons 
3. 
Subject was discontinued from the study for 
missing at least 5 infusions 
Subject was discontinued from the study for 
missing at least 5 infusions 
4. 
Subject withdrew consent and/or 
discontinued from the study 
Subject withdrew consent and/or 
discontinued from the study 
5. 
Subject was unblinded (accidentally or 
otherwise) before database lock 
Subject was unblinded (accidentally or 
otherwise) before database lock 
6. 
Subject was inconsistent in the use/non-use 
of assisted devices during 6MWT 
 
Abbreviations: 6MWD = 6-minute walk distance; 6MWT = 6-minute walk test; FVC = forced vital capacity; 
PP1 = per-protocol population 1 is used for the sensitivity analyses of the 6WMD; PP2 = per-protocol population 2 
(PP2) is used for the sensitivity analyses of the percent predicted FVC 
6.1.7. 
Completers 
The Completers population consists of subjects who completed the Week 52 visit and have both 
6MWD and FVC assessments at the Week 52 visit (including make-up assessments or delayed 
visits). Subjects who completed the Week 52 visit and were able to do only 1 6MWT (instead of 
2) at Week 52 will still be considered as completers. This population will be used for subject 
accounting purposes. 
A subject who withdraws/discontinues from the study and returns for the end of study or early 
termination visit is not a completer and does not belong in the Completers population.  
6.1.8. 
PK Population 
The PK population consists of those randomized subjects who have been exposed to at least 
1 dose of the study drug (ATB200/AT2221 or alglucosidase alfa/placebo) and have at least 1 PK 
assessment. For ERT-naïve subjects who undergo serial PK sampling, noncompartmental PK 
analysis is described in Section 3.3.5.2. For all other subjects who undergo sparse PK sampling, 
population PK analysis will be described in a separate Modeling and Simulation Plan. 


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6.2. 
Derived and Transformed Data 
6.2.1. 
Study Day 
The study has no Study Day 0. The date of first dose of study drug (First Dose Date) is labeled as 
“Day 1” for analysis purposes; it will serve as the reference start date.  
Total duration of treatment will be calculated as the difference between the dates of last and first 
dose of study drug plus 1. 
If the date of interest occurs on or after the first dose/randomization date, then study day will be 
calculated as (date of interest – date of first dose) + 1. If the date of interest occurs prior to the 
first dose/randomization date, then study day will be calculated as (date of interest – date of first 
dose). 
6.2.2. 
Baseline Definition 
In general, baseline is defined as the last non-missing measurement prior to the administration of 
the first dose of study drug, unless otherwise specified. It is understood that baseline may be 
different for different efficacy and safety endpoints. 
• For the 6MWD, FVC, and SVC, the average of the last 2 values obtained on or prior 
to the first dose date will be used as the baseline value. 
• For other functional assessments (such as the MMT, QMT, TUG, GSGC, PROMIS 
instruments, EQ-5D-5L (quantitative EQ-VAS score and descriptive health status), 
and R-PAct scale), the screening results will serve as the baseline values. 
• For all other pulmonary function tests (MIP, MEP, and SNIP), baseline will be the 
last available value obtained on or prior to the first dose date. 
• For safety data (including all lab assessments, physical examinations, ECG, vital 
signs, weight, etc), the last available result on or prior to the first dose date will be 
used as the baseline value (without considering the time of assessment on Day 1). If 
this value is missing, then the screening value will be used instead. 
6.2.3. 
Baseline Age 
Calculation of subject’s age in years is based on the date of informed consent, using the 
following formula: Age (year) = FLOOR ([date of informed consent – date of birth] / 365.25), 
where the FLOOR ( ) function returns the integer part of the result. 
6.2.4. 
Week 52/ET Assessments 
Subjects who discontinue study drug or who are withdrawn from the study are required to return 
for an EOS or ET visit. The muscle strength tests, pulmonary function tests, motor function tests, 
PRO assessments, and pharmacodynamic endpoints (Hex4 and CK) performed at the ET visit 
will be used as the final values at the Week 52 visit for statistical analysis. The 6MWT is to be 
performed twice at the Week 52/ET visit, and the average of the 2 test values will be used as the 
final value at Week 52 for statistical analysis. 


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Note: As a result of the COVID-19 related policies and restrictions, the Week 52 visit (and/or the 
ET/EOS visit) may be delayed. Even if that happens, the delayed visit assessments will still be 
used for analyses. The make-up assessments at Week 52 will be used as the Week 52 results. In 
addition, some subjects were only able to have 1 assessment of 6MWD at Week 52. For these 
subjects, the single assessment will still be used as the Week 52 value.  
6.2.5. 
Change and Percent Change from Baseline 
Change from baseline is calculated as:  
Value at a visit – Baseline value. 
Percent change from baseline is calculated as:  
100 * (Value at a visit – Baseline value) / Baseline value. 
6.2.6. 
Analysis Visit Windows 
6.2.6.1. 
Visit Windows 
Analysis visit windows will be used for all by-visit analyses, as provided for in Table 3 and 
Table 4.  
Table 3: 
Visit Windows for Functional Assessments, PROs, ECG, and CPE (as 
applicable) 
Visit 
Week 
Target Day 
Analysis Visit Window 
Visit 1 
Week -2a 
Day -15/-14 
Screening/Baseline for efficacy 
Visit 1.10b 
< Week 0 
Day -10 
Randomization 
Visit 6 
Week 12 
Day 85 
Day 2 – 134 
Visit 7 
Week 26 
Day 183 
Day 135 – 225 
Visit 8 
Week 38 
Day 267 
Day 226 – 316 
Visit 9 (EOS/ET) 
Week 52 
Day 365 
> Day 316 
Visit 10 (F/U)c 
Week X.10 
N/A 
N/A 
Abbreviations: AE = adverse event; CPE = complete physical exam; ECG = electrocardiogram; EOS = end of study; 
ET = early termination; F/U = follow-up; IRT = Interactive Response Technology; N/A = not applicable; 
PRO = Patient-reported outcome 
a Denotes Day -15/-14 in the screening period. 
b Denotes the randomization day. Randomization is carried out via the IRT system and subjects do not need to be 
present. Hence, ‘randomization day’ is not a scheduled visit in the study protocol. Using the ‘Visit 1.10’ 
designation can help with data programming for analysis purposes. 
c Denotes follow-up visits occurring at Week X.10 (AEs and concomitant medications are to be collected up to 
30 days after last dose date). 


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Table 4: 
Visit Windows for Vital Signs, Lab Measurements, and BPE (as applicable) 
Visit 
Week 
Target Day 
Analysis Visit Window 
Visit 1 
Week -2a 
Day -15/-14 
Screening/Baseline for efficacy 
Visit 1.10b 
< Week 0 
Day -10 
Randomization 
Visit 2 
Week 0c 
Day 1 
Baseline for safety 
Visit 3 
Week 2 
Day 15  
Day 2 – 22 
Visit 4 
Week 4 
Day 29 
Day 23 – 36 
Visit 5 
Week 6 
Day 43 
Day 37 – 64  
Visit 6 
Week 12 
Day 85 
Day 65 – 134 
Visit 7 
Week 26 
Day 183 
Day 135 – 225 
Visit 8 
Week 38 
Day 267 
Day 226 – 316 
Visit 9 (EOS/ET) 
Week 52 
Day 365 
> Day 316 
Visit 10 (F/U)d 
Week X.10 
N/A 
N/A 
Abbreviations: AE = adverse event; BPE = brief physical exam; EOS = end of study; ET = early termination; 
F/U = follow-up; IRT = Interactive Response Technology; N/A = not applicable; PRO = patient-reported outcome 
a Denotes Day -15/-14 in the screening period. 
b Denotes the randomization day. Randomization is carried out via the IRT system and subjects do not need to be 
present. Hence, ‘randomization day’ is not a scheduled visit in the study protocol. Using the ‘Visit 1.10’ 
designation can help with data programming for analysis purposes. 
c Denotes study visit Day 1, at which baseline safety assessments are performed. 
d Denotes follow-up visits occurring at Week X.10 (AEs and concomitant medications are to be collected up to 
30 days after last dose date). 
6.2.6.2. 
Impact of COVID-19 on the Visit Windows  
Due to the COVID-19 related policies and restrictions, sites were allowed to perform make-up 
assessments at a later date when feasible. This resulted in some delayed visits, and some of this 
may appear in the Study Data Tabulation Model (SDTM) datasets as unscheduled visits or 
multiple assessments at some specified visits.  
Delayed visits and make-up assessments that go beyond the stated visit windows will be 
remapped to the planned study visit. For example, the visit window for Week 26 is Day 135 to 
Day 225, and the window for Week 38 is Day 226 to Day 316. Suppose a subject had a 
COVID-19 related situation leading to a delay in the Week 26 assessment such that the delayed 
visit / make-up assessment for Week 26 occurs on Day 261 (which is 36 days outside of the 
planned visit window for Week 26, and it’s inside the Week 38 visit window), followed by the 
Week 38 assessment on Day 300 (which is right within the Week 38 visit window). Here, the 
delayed assessment occurring on Day 261 will be remapped to the Week 26 visit (which was the 
intended visit).  


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6.2.7. 
Multiple Assessments in a Visit Window 
6.2.7.1. 
For Efficacy Data  
In general, for all post-baseline efficacy and other functional by-visit analyses, if multiple 
assessments (from both scheduled and unscheduled visits) occur in the same visit window, the 
visit dates should first be examined to see if they are part of the COVID-19 related delayed visits 
or make-up assessments that require visit windows to be adjusted or remapped (as discussed in 
Section 6.2.6.2) in order for the data to be in the appropriate study visits. 
• If they are part of COVID-19 related delayed visits or make-up assessments, then the 
assessments should be handled in accordance with the handling of delayed visits and 
make-up assessments in Section 6.2.4 and the visit window remapping described in 
Section 6.2.6.2. 
• If they are not part of COVID-19 related delayed visits or make-up assessments that 
require visit window adjustment per Section 6.2.4 and Section 6.2.6.2, then the usual 
visit window rules apply.  
That is, if they are not COVID-19 related (or even if they are COVID-19 related but do not 
require any visit window adjustment or remapping), then for multiple assessments in the same 
visit window, the value closest to the planned target visit day will be used for analysis at that 
visit. If two assessments are equidistant from the target day, or if two assessments occur on the 
exact same day but at different times, the last value in chronological order will be used.  
6.2.7.2. 
For Safety Data  
For all post-baseline safety by-visit analyses, if multiple assessments (from both scheduled and 
unscheduled visits) occur in the same visit window, the value closest to the planned target visit 
day will be used for that visit (unless these are COVID-19 related delayed visits for which visit 
window adjustment or remapping is required). If two assessments are equidistant from the target 
day or occur on the same day but at different times, the last assessment in chronological order 
will be used (unless these are COVID-19 related delayed visits for which visit window 
adjustment or remapping is required).  
Note: See Section 6.2.6.2 regarding the handling of the impact of COVID-19 related delayed 
visits and assessments on the analysis visit windows. 
6.3. 
Handling of Missing Data for Key Endpoints 
6.3.1. 
Imputation for Missing Baseline Values 
All available subjects in the ITT population have baseline values for both 6MWD and FVC. 
Hence, no baseline imputation is needed for these 2 key efficacy endpoints.  
For the multi-component/multi-item endpoints (such as GSGC and MMT), a subject could be 
missing either specific items or the entire assessment. If the baseline value is partially missing 
(subject is missing only specific items at baseline), the average value using all subjects with 
non-missing values for that item across the 2 treatment groups combined will be used to replace 
the missing item score. If the baseline total score is completely missing, the average score using 
all subjects with non-missing total scores for the endpoint across the 2 treatment groups 


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combined will be used to replace the missing baseline total score. See Section 8.8.4 for the 
handling of missing baseline values for PROs including PROMIS instruments. 
6.3.2. 
Imputation for Missing Post-baseline Values  
For this study, subjects who permanently discontinued the assigned study drug are subsequently 
discontinued from the study. However, these subjects are required to return for the EOS/ET visit. 
Efficacy assessments collected at the EOS/ET visit will be used to replace the missing endpoint 
value at Week 52 in the ITT-LOCF population. That is, the last available observation will be 
carried forward to replace the missing value at Week 52 (see Section 6.1.4.2).  
The MMRM analysis is the primary analysis for the primary endpoint (6MWD), and it will be 
performed as an ITT-OBS (observed cases) analysis. That is, all available, observed values will 
be used without imputation, and missing data at Week 52 are not replaced. 
6.4. 
Handling of Intercurrent Events 
Intercurrent events are defined as events that occur after treatment initiation and either preclude 
observation of the primary endpoint or affect its interpretation (eg, discontinuation of treatment, 
terminal events such as death, etc), per ICH E9 R1. 
The potential intercurrent events for this study are listed in Table 5 together with the proposed 
strategy and handling of such events for the mixed-effect model repeated measures (MMRM) 
analysis and the analysis of covariance (ANCOVA). 


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Table 5: 
Accounting for Intercurrent Events 
Intercurrent Event 
Treatment Strategy for 
Handling Event 
Handling of Event 
Intervention for AEs, SAEs 
and IARsa;  
Incorrect treatment assigned; 
Prespecified important major 
protocol deviations that can 
potentially affect the 
assessment of 6MWD. 
Treatment policy strategy 
(based on ITT principle): 
• If subject continues in 
the study and dosing 
is resumed  
For the ITT-OBS population: Value of 
interest (eg, 6MWD result observed at a 
given visit) will be used, regardless of 
whether the intercurrent event occurred. 
Note: No imputation will be performed 
for missing values at Week 52 (and other 
post-baseline visits). This is for the 
MMRM analysis. 
For the ITT-LOCF population: Value of 
interest will be used, regardless of 
whether the intercurrent event occurred. 
Note: Missing values at Week 52 (and 
other post-baseline visits) will be imputed 
with the last available post-baseline 
assessment value. This is for the 
ANCOVA analysis. 
Example: Compare “Treat A + Use of 
prohibited concomitant medication as 
needed” versus “Treat B + Use of 
prohibited concomitant medication as 
needed.” 
• If subject permanently 
discontinues from 
study drug (and is 
withdrawn from the 
study) 
For the ITT-OBS population: Observed 
value at time of discontinuation will be 
used. Note: No imputation will be 
performed for missing values at Week 52 
and other post-baseline visits. Data after 
study discontinuation will be considered 
missing and will be handled by the MAR 
assumption in the MMRM analysis. 
For the ITT-LOCF population: The last 
available assessment value will be used 
(regardless of whether the intercurrent 
event occurred). This setup is for the 
ANCOVA analysis. 


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Table 5: 
Accounting for Intercurrent Events (Continued) 
Intercurrent Event 
Treatment Strategy for 
Handling Event 
Handling of Event 
Withdrawn at subject’s own 
request (eg, subject withdrew 
consent); 
Withdrawn based on 
investigator’s opinion; 
Withdrawn for persistent 
noncomplianceb; 
Withdrawn due to SAEs or 
COVID-19 related reasons.  
Withdrawn due to IARs 
Treatment policy strategy 
(based on ITT principle) 
Here, subject is 
permanently discontinued 
from study drug (and is 
withdrawn from the 
study). 
For the ITT-OBS population: The 
observed value available at time of 
discontinuation will be used. No 
imputation will be performed for missing 
values at Week 52 and other post-baseline 
visits. Data after study discontinuation 
will be considered missing and will be 
handled by the MAR assumption in the 
MMRM analysis; 
For the ITT-LOCF population: The last 
available assessment value will be used, 
regardless of whether the intercurrent 
event occurred.  
Note: This setup is for the ANCOVA 
analysis. 
Abbreviations: 6MWT = 6-minute walk test; AE = adverse event; IAR = infusion-associated reaction; 
ITT = intent-to-treat; MAR = missing at random 
Note: A subject who permanently discontinues study drug is subsequently withdrawn from this study.  
a Intervention for AEs and IARs includes concomitant medications, dose modifications, interruptions, or 
withdrawal. 
b Withdrawn for persistent noncompliance with study drug, study requirements, or failure to return to the study site 
for infusion visits. Eg, subject missed 5 or more infusions; or subject’s calculated compliance value < 80%. 
6.4.1. 
Missing AE Attributes 
Adverse events with missing attributes will be imputed with the worst possible outcome, for 
summary purposes. For example, if an AE is missing relationship to study drug, it will be 
imputed as being ‘related’ to the study drug; if an AE is missing the severity level, it will be 
imputed as being ‘severe.’ 
Nonetheless, in the data listings, the actual observed values will be reported. That is, if the 
response is missing, it will show as missing in the data listings. 
6.4.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Missing start and stop dates for prior and concomitant medications will be imputed in accordance 
with the rules described in Section 9.4.1.  
6.4.3. 
Missing Start and Stop Dates for Adverse Events 
Missing start and stop dates for AEs will be imputed in accordance with the rules described in 
Section 9.1.6. 


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7. 
CHARACTERISTICS OF STUDY POPULATION 
7.1. 
Subject Disposition 
For each analysis population (Screened, All Randomized, ITT, ITT-OBS, ITT-LOCF, mITT, 
Safety, PP, Completers, and PK), the study enrollment and completion status will be summarized 
by the number and percent of subjects who completed the study, who discontinued the study 
early for each treatment group, and for all subjects combined. The number of subjects who were 
randomized following rescreening will be included in the disposition table. 
The number and percent of subjects, by the reason for discontinuing the study early, will also be 
presented for each treatment group and for all subjects combined. The categories classifying the 
subjects’ study completion status are derived from the end of study electronic case report form 
(eCRF) page and include categories such as “Lost to Follow-Up,” “Adverse Event,” and 
“Death.” The reasons for early study termination will likely provide some insight into how the 
trial was conducted and some understanding of the potential dropout pattern. 
Study Completion/Termination Status: 
The completion status of subjects at the end of the study will be categorized and summarized by 
treatment group with respect to the number of subjects who:  
• Completed the study (based on the ‘Yes’ checked box on the eCRF) 
• Discontinued the study prematurely 
Note that the ‘Yes’ checked box on the eCRF does not necessarily indicate that the subject 
belongs to the Completers population. The Completers population is defined in Section 6.1.7. 
The reasons for early study termination will be summarized as recorded on the eCRF (eg, AE, 
protocol violation, administrative, lost to follow-up, death, COVID-19 related, etc). 
7.2. 
Screen Failures 
The number of subjects who failed screening will be presented in an individual subject data 
listing, which will include ERT status (ERT-naïve or ERT-experienced) and other demographic 
data.  
7.3. 
Protocol Deviations 
Protocol deviations data are collected and consolidated into a deviation log, and transferred to 
Amicus for review on an ongoing basis throughout the course of the study to identify trends and 
determine the type (eg, inclusion/exclusion criteria, study procedures) and the category 
(eg, minor or major) of each deviation. The number and percent of subjects with protocol 
deviations will be presented for each treatment group and summarized by deviation type (major 
or important). A listing of subjects with all protocol deviations (minor, major, and important) 
will be provided.  


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7.4. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized with descriptive statistics defined 
in Section 8.1 by treatment group for the ITT, mITT, and safety populations. Demographic and 
baseline characteristics to be presented include:  
• Gender; race; ERT status (naïve or experienced); subjects using assistive devices at 
baseline; subjects with a history of falls (Yes, No); and subjects with a history of 
IARs (Yes, No) will be summarized by treatment group and overall using number and 
percentage as described in Section 8.1. 
• The continuous variables height (cm), weight (kg), CK, Hex4, ALT, AST, and body 
mass index (BMI) (kg/m2) will be summarized using descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum as described in Section 8.1.  
Other baseline variables to be summarized will include: 
• Age at informed consent date (in years), as a continuous variable; 
− Categorized as: ≥ 18 to < 35 years, ≥ 35 to < 50 years, ≥ 50 to < 65 years, 
≥ 65 years 
• Age at diagnosis (in years) as a continuous variable; 
− Categorized as: < 18 years, ≥ 18 to < 35 years, ≥ 35 to < 50 years, ≥ 50 years  
• Age at first ERT dose in years (for subjects who are ERT-experienced only) as a 
continuous variable; 
− Categorized as: < 18 years, ≥ 18 to < 35 years, ≥ 35 to < 50 years, ≥ 50 years  
• ERT duration (for ERT-experienced subjects) as a continuous variable, calculated as: 
ROUND([date of randomization – date of first dose of ERT] / 365.25);  
− Categorized as: 2 to < 3 years, 3 to < 5 years, ≥ 5 years. 
For partial dates involving age at diagnosis and age at first dose of ERT, missing Day will be 
imputed as ‘01,’ and missing Month will be imputed as ‘JANUARY.’  
Other baseline characteristics include the baseline 6MWD (that is, the average of the 2 screening 
values), and the corresponding % predicted 6MWD, baseline FVC and other pulmonary function 
parameters, baseline motor function tests, muscle strength tests, and PROs.  
The total number of subjects enrolled by country and by region will be presented by treatment 
group and overall. The 3 specified regions are: North/South America, Europe, and Asia Pacific. 
The demographic and baseline characteristics summary will also be presented by ERT status 
(naïve vs experienced). 
The Pompe disease history information will be summarized for subjects who are ERT-naïve, 
ERT-experienced, have baseline 6MWD categorized as: 75 to < 150 m, 150 to < 400 m, and 
≥ 400 m, based on the descriptive statistics defined in Section 8.1, for the ITT, and safety 
populations.  
A listing of baseline data will be provided.  


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7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
For screen failures, a listing for all subjects will be provided showing which specific eligibility 
criteria were not met. 
7.6. 
Medical History and Medical Conditions Present at Entry 
The medical history (captured on the eCRF) will be coded using version 20.1 or later of the 
Medical Dictionary for Regulatory Activities (MedDRA) into system organ class and preferred 
term. The frequency of subjects with medical history by system organ class and preferred term 
will be presented on the safety population.  
7.7. 
Handling the Use of Assistive Device During the 6MWT 
Subjects using a permitted assistive device during the Screening/Baseline 6MWT should use the 
same assistive device for all follow-up 6MWT assessments in the study. If the subject added a 
new device, changed the device at certain visits, or did not use the assistive device, then that will 
be considered a protocol deviation as the change can affect the primary endpoint and the results 
of these assessments. See Section 6.1.6 and Section 6.4 for the listing of pre-defined major 
protocol deviations and the listing of intercurrent events.  
7.8. 
Prior and Concomitant Medications and Nondrug Therapies 
Prior medications and nondrug therapies are defined as any medication or nondrug therapy taken 
or occurring before the first dose of study drug. Concomitant medications and nondrug therapies 
include medications and nondrug therapies with start dates (and times) on or after the first dose 
of study drug, medications and nondrug therapies with onset dates (and times) prior to the first 
dose of study drug without a stop date, or medications and nondrug therapies with a stop date 
(time) after the first dose of study drug. Medications starting after the last dose of study drug will 
not be considered as concomitant but will be flagged as post medications in the listing of 
medications. Nondrug therapies include physiotherapy and occupational therapy, procedures, 
surgery, or use of assistive devices. 
Prior and concomitant medications are coded to indication-specific Anatomical Therapeutic 
Chemical classification (ATC) and preferred name using the World Health Organization Drug 
Dictionary (WHO DDE, September 2013 or later). 
Prior and concomitant medication use will be summarized by level 4 ATC and preferred name 
using the number and percentage of subjects by treatment group. Medications will be sorted 
alphabetically by ATC and preferred name within ATC, and in decreasing order of the total 
number of subjects who took each medication within each ATC class. Subjects with multiple 
occurrences of a medication in ATC and preferred name will only be counted once within each 
ATC and preferred name. In addition, the total number of subjects to ever take any concomitant 
medications will be presented. Since medications are coded to ATC by indication, preferred 
names may appear under multiple ATCs.  
A listing of all medications, both prior to infusions and concomitant, and nondrug therapies will 
be presented. Investigator verbatim descriptions as well as coded terms will be included in the 
listings. Any abbreviations and codes will be clearly explained on each page of the listing. The 
listing will be sorted by treatment group and subject identifier, and will include level 4 ATC, 


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preferred name, reported name, dose, route of administration, dosing frequency, start date, end 
date, indication, and period of medication (prior only, concomitant only, prior and concomitant), 
and nondrug therapy. Pre-medications (which are a subset of all medications) will be listed in a 
separate data listing, and this listing will include a flag indicating whether the specified 
medication is a new pre-medication and whether there were changes in the subject’s 
pre-medication (eg, changed to a different pre-medication change in dose of the pre-medication) 
prior to infusions.  
Prior and concomitant medications and nondrug therapies will be summarized by treatment 
group. 
7.8.1. 
Non-diagnosis Related Prior Medication History 
Non-diagnosis related medications are medications taken for conditions other than the one under 
study. These medications will be identified, and a supportive listing will be provided to include 
the unique data associated with the medication start and stop dates, whether the medication is 
ongoing, dose, frequency of administration, route of administration, trade name, generic name, 
and why it was prescribed. 
7.8.2. 
Prior Diagnosis Related Medication History 
Prior diagnosis related medication history, if available, will be flagged in the listing discussed 
above in Section 7.8.1.  
7.9. 
Baseline Physical Examination 
Overall assessment of baseline physical exam (categorized as normal, abnormal, or not 
performed) will be summarized by number and percent, together with post-baseline data. 
7.10. 
Baseline Vital Signs 
Baseline vital signs including systolic and diastolic blood pressures (mmHg), heart rate (bpm), 
and body temperature (°C) will be summarized using descriptive statistics, together with 
post-baseline data. 
7.11. 
Baseline Laboratory Data 
Baseline laboratory results will be summarized with descriptive statistics, together with the 
post-baseline lab data. See Section 9.2 for analysis of clinical laboratory data.  
7.12. 
Baseline Primary and Secondary Efficacy Evaluations 
The results from the primary and secondary efficacy evaluations obtained at baseline will be 
summarized with appropriate descriptive statistics, together with post-baseline data.  


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8. 
ANALYSIS OF EFFICACY 
8.1. 
General Considerations 
The Statistical Analysis System (SAS©) software version 9.4 (or the latest version at the time of 
the analysis) and R software will be used for all statistical procedures and analyses. 
In general, where basic summary statistics are needed, continuous variables will be summarized 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum); categorical 
variables will be summarized using number and percentage. For basic summaries involving the 
change from baseline, a 95% confidence interval (CI) for the mean difference will also be 
provided.  
All inferential statistical tests for the primary and key secondary efficacy endpoints will be 
1-sided and will be performed at the alpha level of 0.025, unless otherwise specified. 
8.2. 
Testing Statistical Assumptions and Alternative Analysis 
Estimated treatment effects such as the least squares (LS) means estimate from linear mixed 
models (eg, MMRM) and linear model (eg, ANCOVA) are known to be robust against moderate 
to high deviations from the normality assumption. 
The underlying assumptions for the primary efficacy model will still be checked. The MMRM 
analysis will be used as the primary efficacy analysis for the 6MWD regardless of the results of 
the normality checks, as the MMRM model is believed to be robust against deviations from 
normality (Bartlett 2014). The nonparametric randomization-based covariance analysis described 
in Section 8.5.1.2 will be performed as a sensitivity analysis only if the normality assumption is 
notably violated with the Shapiro-Wilk test p-value < 0.01. The MMRM analysis assumes that 
data are missing at random (MAR). For this study, a lot of effort has been (and will continue to 
be) made to follow up all subjects so as to try to reduce the number of dropouts in the study. 
Despite all this, it is still possible to have subjects who could not do the 6MWD and/or FVC 
assessment due to COVID-19 related reasons. In view of the potential impact this can have on 
the efficacy assessments and analysis, the following analyses are considered: 
• The MMRM analysis will be used as the primary efficacy analysis for the 6MWD, 
based on the ITT-OBS population. 
The MMRM analysis uses all available data without imputation for missing data, and 
the amount of missing data for 6MWD at Week 52 is expected to be small (< 10%). 
Under these conditions, the MMRM is preferable to the ANCOVA (White, Carpenter 
et al. 2012; Siddiqui, Hung, et al. 2009). 
• The ANCOVA model remains the main analysis for the % predicted FVC and other 
continuous endpoints, based on the ITT-LOCF population, unless otherwise specified. 
The MMRM is a likelihood-based method that does not require a complete dataset; it uses all 
available data across visits, allowing it to account for differences in variability between visits; 
and it can model the within-subject variability. These features of the MMRM may be important 
now in view of the COVID-related interruptions at study sites resulting in delayed visits and 
make-up assessments, with potentially high between-visit variability. This can also be helpful 


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given that this study enrolled both ERT-naïve and ERT-experienced subjects who potentially 
differ in variability.  
The validity of the MAR assumption in this study will be assessed by examining the amount and 
reason of the missing data and assessing whether they are balanced between the treatment 
groups. If the amount of missing data is small (eg, less than 10% of the total sample size), and/or 
are balanced between the treatment groups by reason of the missing data, then the impact of the 
missing data will be expected to be small.  
In addition, a ‘control group imputation’ algorithm based on data sampled from the control group 
(alglucosidase alfa/placebo) will be implemented to replace missing data at the post-baseline 
visit. For example: For each instance of a missing 6MWD result at Week 52 in either treatment 
group (ie, active control or new treatment), a random sample of 15 values will be selected (with 
replacement) from the available set of data in the control group at Week 52. The average of these 
15 values will then be used to replace the missing value. These steps will be carried out until all 
missing data at Week 52 have been replaced. The planned analysis (eg, MMRM) will then be 
performed on these newly imputed data. Consistency in the results with the original analysis 
(that is, the treatment effects are in the same direction, and the conclusions are similar) will 
suggest that the MAR assumption is valid.  
8.3. 
Statement of the Null and Alternative Hypotheses 
8.3.1. 
Primary Null and Alternative Hypotheses 
The primary endpoint is the change from baseline to Week 52 in 6MWD, measured in meters. 
The primary endpoint analysis is based on a comparison of the change in 6MWD between 
ATB200/AT2221 (‘new treatment’) and alglucosidase alfa/placebo (‘control’).  
H0: the new treatment is less effective than the control, with respect to the primary efficacy 
endpoint 
HA: the new treatment is more effective than the control, with respect to the primary efficacy 
endpoint 
The primary null hypothesis will be tested at the 1-sided significance level of 0.025, unless 
otherwise stated. 
8.3.2. 
Key Secondary Null and Alternative Hypotheses 
There are 6 key secondary endpoints in hierarchical order of importance, as follows: 
• Change from baseline to Week 52 in sitting FVC (% predicted) 
• Change from baseline to Week 52 in the MMT score for the lower extremities 
• Change from baseline to Week 26 in 6MWD 
• Change from baseline to Week 52 in the total score for the PROMIS – Physical 
Function 
• Change from baseline to Week 52 in the total score for the PROMIS – Fatigue 
• Change from baseline to Week 52 in GSGC total score 


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The null and alternative hypotheses for superiority testing of all the key secondary endpoints are 
as follows: 
H0i: the new treatment is less effective than the control, with respect to the ith key secondary 
efficacy endpoint 
HAi: the new treatment is more effective than the control, with respect to the ith key secondary 
efficacy endpoint  
8.4. 
Multiple Comparisons and Multiplicity 
The primary analysis is based on a single inter-group comparison of the primary efficacy 
endpoint between the new treatment and control at the 1-sided significance level of 0.025. The 
study has 6 key secondary efficacy endpoints which are ordered. The family-wise Type I error 
rate (FWER) for the statistical tests of the primary and key secondary endpoints will be 
controlled at 0.025. The p-value for comparing the primary and each key secondary endpoint will 
be calculated irrespective of its statistical significance. 
To strongly control the FWER at this level, a gate-keeping approach will be utilized in which 
each family of statistical tests (family of primary and family of key secondary) will be conducted 
in a sequential manner. The test for the primary endpoint will be conducted first at the 
0.025 significance level and, if significant, the ordered key secondary endpoints will be similarly 
tested at the 0.025 significance level. The statistical significance of the key secondary endpoints 
will be interpreted following a hierarchical testing order, each at the 1-sided alpha level of 0.025. 
If at any point the null hypothesis fails to be rejected, then that comparison and any other 
comparison below it cannot be claimed as successful. 
The hypothesis tests included in the other secondary endpoints are not controlled, and each will 
be tested at the 1-sided alpha level of 0.025.  
8.5. 
Analysis of the Primary Efficacy Endpoint 
8.5.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint (change from baseline to Week 52 in 6MWD) will be analyzed 
using an MMRM model to compare between treatment and control on the ITT-OBS population.  
For this analysis, the dependent variable is the change from baseline to all post-baseline visits. 
Independent variables in the model are the fixed, categorical effects of treatment, time (ie, visit), 
treatment-by-time interaction, ERT status, and gender, as well as the fixed, continuous covariates 
of baseline 6MWD, baseline age, baseline weight, and baseline height. SAS PROC MIXED will 
be used for the analysis, with restricted maximum likelihood estimation (REML) and 
unstructured within-subject covariance structure. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom and adjust standard errors for the tests of fixed 
effects. If this model fails to converge, a compound symmetry (CS) covariance structure will be 
used instead. The OBSMARGINS (OM) option in the LSMEANS statement will be specified to 
allow for the use of the observed marginal distributions of the categorical variable rather than 
assuming a balance among the levels of the categorical variable. The E option will also be 
specified to check for estimability of LS means.  


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All the relevant estimates from this model, including LS means, standard errors (SE), treatment 
differences in LS means, and the corresponding 95% CIs will be estimated for each time point. 
The main variable to be estimated (ie, the estimand) in the primary comparison is the difference 
between ATB200/AT2221 and alglucosidase alfa/placebo in mean change in 6MWD from 
baseline to Week 52, regardless of whether intercurrent events have occurred. The significance 
test will be based on the treatment comparison of LS means at Week 52 and a p-value will be 
presented for this time point only. Estimated LS means (± SE) for the change from baseline by 
treatment group will be plotted over time. 
Exploratory Interaction Tests:  
The study is not powered to detect any interaction. However, the following interactions will be 
explored. 
Time-based interactions (ie, time-by-baseline 6MWD, time-by-baseline age, time-by-baseline 
weight, time-by-ERT status) will be examined separately (one at a time) in separate MMRM 
models to understand the changes over time.  
Similarly, treatment-by-covariate interactions (treatment-by-ERT status, treatment-by-baseline 
6MWD, treatment-by-age, treatment-by-gender, treatment-by-weight, and treatment-by-height) 
will be explored. Each interaction term will be explored using a separate MMRM model that 
includes the full set of covariates of model terms (time, treatment-by-time interaction, gender, 
baseline 6MWD [continuous], baseline age [continuous], baseline weight [continuous], and 
baseline height [continuous]) as well as the added interaction term. The treatment-by-covariate 
interaction terms with a 2-sided p < 0.10 will be further examined clinically. Forest plots will be 
used to present the subgroups defined by the baseline covariates. 
Secondary analyses of the primary endpoint and % predicted FVC (including supportive and 
sensitivity analyses) are described in Section 8.5.1.1 and Section 8.5.1.2. Analysis of the key 
secondary endpoints are described in Section 8.6, other secondary endpoints in Section 8.8, and 
subgroup analyses in Section 8.9. In all analyses involving the use of the LSMEANS, the OM 
option (as described above) will be used where applicable. If the LS means are not estimable 
with the OM option but they are without it, then the analysis without the OM option will be used. 
This will be footnoted accordingly. 
8.5.1.1. 
Supportive Analyses for the Primary Efficacy Endpoint and % Predicted FVC 
The following supportive analyses will be performed: 
Table 6: 
Supportive Analyses for the 6MWD and % Predicted FVC 
 
Primary Endpoint (6MWD) 
% Predicted FVC 
1 
ANCOVA at Week 52 on ITT-LOCF 
MMRM analysis on ITT-OBS 
2 
Rate of change in 6MWD based on 12-month 
slopes 
Rate of change in % predicted FVC based on 
12-month slopes 
Abbreviations: 6MWD = 6-minute walk distance; ANCOVA = analysis of covariance; FVC = forced vital capacity; 
ITT-LOCF = intent-to-treat population with missing data replaced by the last available value; 
ITT-OBS = intent-to-treat population that includes all available, observed data without any missing data imputation 
at Week 52; MMRM = mixed-effect model for repeated measures 


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In addition, note that as a supportive analysis, each of the other key secondary endpoints will be 
analyzed using an MMRM analysis on the ITT-OBS population as described in Section 8.3.2. 
Details for the supportive analyses are as follows: 
• MMRM analysis: This is based on the ITT-OBS population, similar to what has been 
described for the primary endpoint analysis in Section 8.5.1. There is no need to 
explore the treatment-by-covariate interaction tests in using MMRM as supportive 
analysis for the key secondary endpoints.  
• Rate of change using ANCOVA on the ITT-OBS population based on the 12-month 
slopes of the 6MWD assessments (ie, change in 6MWD per month), where the slope 
is estimated for each subject using a simple linear regression of the observed values. 
The mean slopes are then compared between the 2 treatment groups adjusting for the 
baseline value (continuous) and ERT status, as well as baseline age, gender, baseline 
height, and baseline weight. All the relevant LS estimates (including the LS means 
for each treatment group, LS mean difference, 95% CI for the LS mean difference, 
SE, and p-value for comparing the 2 treatment groups) will be provided.  
8.5.1.2. 
Sensitivity Analysis for the Primary Endpoint and % Predicted FVC 
The following sensitivity analyses will be considered for the primary endpoint and % predicted 
FVC.  
Table 7: 
Sensitivity Analyses for the 6MWD and % Predicted FVC 
 
Primary Endpoint (6MWD) 
First Key Secondary Endpoint 
(% Predicted FVC) 
1 
Nonparametric randomization-based 
covariance analysis on ITT-LOCF at Week 52 
(if Shapiro-Wilk p-value < 0.01) 
Nonparametric randomization-based 
covariance analysis on ITT-LOCF at Week 52 
(if Shapiro-Wilk p-value < 0.01) 
2 
MMRM analysis incorporating the handling 
of intercurrent events 
ANCOVA incorporating the handling of 
intercurrent events 
3 
ANCOVA on the per-protocol population 1 
(PP1) 
ANCOVA on the per-protocol population 2 
(PP2) 
4 
ANCOVA on ITT-OBS, using the 
% predicted 6MWD 
ANCOVA on ITT-LOCF for the subset of 
subjects with baseline % predicted FVC value 
< 85%, vs ≥ 85%; 
MMRM analyses in ITT-OBS for the subset 
of subjects with baseline % predicted FVC 
value < 85%, vs ≥ 85%  
5 
Randomization test applied to test statistics 
from the ANCOVA model 
Randomization test applied to test statistics 
from the ANCOVA model 


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Table 7: 
Sensitivity Analyses for the 6MWD and % Predicted FVC (Continued) 
 
Primary Endpoint (6MWD) 
First Key Secondary Endpoint 
(% Predicted FVC) 
6 
ANCOVA based on ITT-LOCF where 
externally studentized residuals that are large 
(eg, > 3) in magnitude (absolute value) are 
considered as outliers and are removed from 
the analysis 
ANCOVA based on ITT-LOCF where 
externally studentized residuals that are large 
(eg, > 3) in magnitude (absolute value) are 
considered as outliers and are removed from 
the analysis 
Abbreviations: 6MWD = 6-minute walk distance; ANCOVA = analysis of covariance; FVC = forced vital capacity; 
ITT-LOCF = intent-to-treat population with missing data replaced by the last available value; 
ITT-OBS = intent-to-treat population that includes all available, observed data without any missing data imputation 
at Week 52 
Details of the sensitivity analyses are as follows: 
• Nonparametric randomization-based covariance analysis (nonparametric ANCOVA): 
This analysis is based on Koch, Tangen et al. 1998 and LaVange, Durham et al. 2005. 
The SAS/IML® (Interactive Matrix Language) implementation of this procedure via 
the NPARCOV3 macro (Zink and Koch 2012) will be used. For this method, the ERT 
status (naïve or experienced) will be specified as STRATA, and baseline value, 
baseline age, gender, height, and weight will be specified as COVARIATES. The 
categorical variable (ie, gender) will be recoded as a numeric variable. No missing 
values are allowed in this macro. Due to the potential for smaller ERT-naïve stratum 
size, the weighted estimates will be combined across strata prior to covariance 
adjustment. The covariance matrix calculated under the alternative hypothesis will be 
used for statistical test to compare between the treatment groups. The relevant results 
including estimates of the treatment difference, SE, p-value for the treatment 
comparison, and the 95% confidence interval for the treatment difference will be 
provided. This is an ITT-LOCF analysis at Week 52, unless otherwise specified.  
− As stated in Section 8.2, this nonparametric method will be used as a sensitivity 
analysis for the primary endpoint only if the normality assumption for the primary 
MMRM analysis model is notably violated with the Shapiro-Wilk test p-value 
< 0.01.  
− This sensitivity analysis will also be used for the % predicted FVC if the 
normality assumption for the ANCOVA model on the ITT-LOCF population is 
violated with the Shapiro-Wilk test p-value < 0.01.  
− This nonparametric method will be used to compare the biomarker endpoints at 
Week 52 between the treatment groups based on the ITT-LOCF population. 
• ANCOVA that incorporates the handling of the intercurrent events: This model will 
be adjusted for the baseline value (continuous) and ERT status, as well as baseline 
age, gender, baseline height, and baseline weight. See Section 6.4 for the list of 
intercurrent events. 
• ANCOVA applied to the PP population: This model will be adjusted for the baseline 
value (continuous) and ERT status, as well baseline age, gender, baseline height, and 
baseline weight to compare between the 2 treatment groups. 


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• ANCOVA for % predicted 6MWD: ANCOVA using the change from baseline to 
Week 52 in % predicted 6MWD, where the % predicted 6MWD is calculated using 
the Enright and Sherrill 1998 reference equations. This analysis will be performed on 
observed data (ITT-OBS) and the model will be adjusted for baseline 6MWD (as a 
continuous variable) and ERT status to compare between the 2 treatment groups. The 
baseline age, gender, height, and weight will not be included as covariates in this 
ANCOVA analysis because they are already incorporated in the calculation of the 
% predicted 6MWD values.  
• ANCOVA for the subset of subjects with baseline % predicted FVC value < 85% and 
the subset with baseline value ≥ 85%. This analysis will be performed on the 
ITT-LOCF population. 
• MMRM analysis for the subset of subjects with baseline % predicted FVC value 
< 85% and the subset with baseline value ≥ 85%. This analysis will be performed on 
the ITT-OBS population. 
• Randomization test applied to ANCOVA: Analysis using a randomization test applied 
to test statistics obtained from the ANCOVA model adjusted for baseline 6MWD (as 
a continuous variable), ERT status, baseline age, gender, baseline height, and baseline 
weight to compare between the 2 treatment groups. The p-value for comparing 
between the 2 treatment groups will be provided. This analysis will be performed on 
the ITT-LOCF population. 
8.6. 
Analysis of the Key Secondary Endpoints 
Key secondary endpoints will be analyzed according to the hierarchical order specified in 
Section 8.3.2 using a stepwise closed testing procedure to control the overall Type 1 error rate.  
Each key secondary endpoint will be analyzed using an ANCOVA model on the ITT-LOCF 
population. The model will be adjusted for the baseline value (as a continuous covariate) and 
ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline 
height, and baseline weight to compare between the 2 treatment groups. The OBSMARGINS 
(OM) option in the LSMEANS statement will be specified to allow for the use of the observed 
marginal distributions of the categorical variable rather than assuming a balance among the 
levels of the categorical variable. The E option will also be specified to check for estimability of 
LS means. If the LS means are not estimable with the OM option but they are without it, then the 
analysis without the OM option will be used. 
All the relevant estimates from the ANCOVA (including LS means for each treatment group, 
LS mean difference, standard error of the estimate, 95% CI for the LS mean difference, and 
p-value for comparing between the 2 treatment groups) will be provided.  
The treatment-by-covariate interactions (ie, treatment-by-ERT status, treatment-by-baseline 
value, treatment-by-age, treatment-by-gender, treatment-by-weight, and treatment-by-height) 
will be explored. Each interaction term will be explored using a separate ANCOVA model that 
includes the full set of covariates (ie, treatment, baseline value (as a continuous variable), ERT 
status, baseline age, gender, height, and weight) as well as the interaction term. Interaction terms 
with a 2-sided p < 0.10 will be further examined clinically. Forest plots will be used to present 


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the subgroups defined by the baseline covariates. A plot of the LS mean (± SE) change from 
baseline over time will be provided for each key secondary endpoint.  
As a supportive analysis, each of the key secondary endpoints will be analyzed using an MMRM 
analysis on the ITT-OBS population. See further description in Section 8.5.1.1.  
For the % predicted FVC, additional supportive and sensitivity analyses will be performed as 
specified in Section 8.5.1.1 and Section 8.5.1.2, respectively. 
If the superiority tests based on the ANCOVA analysis using ITT-LOCF specified for 6MWD 
and % predicted FVC fail, an informal determination for non-inferiority (NI) for the % predicted 
FVC will be made based on the 2-sided 95% CI for the treatment difference 
(new treatment – control). That is, if the lower bound of the 95% CI is equal to or greater 
than -1.1% (which is the assumed NI margin), then NI would be deemed to have been met. 
8.7. 
Composite Subject-level Response Analysis 
As a supplementary analysis to the primary and key secondary endpoints for the study, and to 
support the interpretation of further clinical benefit, an analysis using a composite subject-level 
response will be performed based on a multi-domain responder index (MDRI). This MDRI will 
be defined to capture the totality of evidence using the 3 relevant clinical outcomes, 6MWD, 
FVC (% predicted), and MMT lower extremity score. The MDRI approach provides a 
framework for presenting the totality of data combining the 3 components which measure motor 
function, pulmonary function, and muscle strength, which are the domains that are impacted in 
individuals with LOPD. A clinically meaningful threshold for within-subject changes in each 
clinical outcome and the categorization of each outcome are provided in Table 8. 
Table 8: 
Threshold for Defining Clinically Meaningful Within-subject Change 
Clinical Outcome 
Declining 
Stable 
Improving 
6MWDa 
< -6% 
-6% to < +6% 
≥ +6% 
% predicted FVCb 
< -3% 
-3% to < +3% 
≥ +3% 
MMT lower extremity scorea 
< -7% 
-7% to < +7% 
≥ +7% 
a Threshold is based on the percentage change from baseline. 
b Threshold is based on the change from baseline.  
The above thresholds are consistent with published MCID (minimal clinically important 
differences) values for comparable instruments in similar disease populations (Schrover, Evans 
et al. 2017; du Bois, Weycker et al. 2011; Baschung Pfister, de Bruin et al. 2018). 
The ordinal composite response across all 3 ternary outcomes is defined as follows: 
• 3 = significant improvement: subject is either improving on all 3 outcomes, or is 
improving on both 6MWD and % predicted FVC; 
• 2 = moderate improvement: subject is improving on either 6MWD only, or 
% predicted FVC only, or both 6MWD and MMT lower extremity, or both 
% predicted FVC and MMT lower extremity;  
• 1 = minor: subject is improving on MMT lower extremity score only; 


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• 0 = no improvement: subject is not improving on any of the 3 clinical outcomes.  
The main interest for this analysis is the inter-group comparison. There is no intra-subject 
comparison for the MDRI approach.  
This method defines a hierarchical ordinal categorical response variable, for which a 
continuation logit model (Agresti 2002) will be used to perform separate logistical regression 
analyses adjusting for baseline risk factors including ERT status (ERT-naïve or 
ERT-experienced), duration of prior alglucosidase alfa (only for ERT-experienced subjects), 
gender, and baseline age.  
The results of these separate logistic regression analyses are then pooled to test the overall null 
hypothesis that treatment with ATB200/AT2221 is less effective than alglucosidase alfa/placebo 
with respect to either the positive composite response (ie, significant improvement) or the 
negative response (ie, minor/no improvement). The inter-group comparison will be based on the 
combined analysis of comparisons of the positive response rates of significant improvements and 
the negative response rates of minor/no improvement.  
Additional details regarding the separate logistic regression analyses and test against the overall 
null hypothesis are described below. 
The “significant improvement” response category is considered as positive response, the 
“moderate improvement” category is considered as stable response, and “minor/no 
improvement” is considered as negative response. Treatment (ie ATB200/AT2221) is expected 
to have high positive responses and low negative responses, while the control (ie, alglucosidase 
alfa/placebo) is expected to have high negative responses and low positive responses). Separate 
logistic regression models are used to analyze and test (1) positive responses vs. not positive 
responses (where “not positive responses” includes the “moderate improvement” and “minor/no 
improvement” categories; (2) negative responses vs. stable responses, conditional on subjects 
who are not positive responders.  
The respective hypotheses for Test 1 and Test 2 are stated as follows: H10: ⸹1 ≤ 0 vs. H1A: ⸹1 > 0 
and H20: ⸹2 ≤ 0 vs. H2A: ⸹2 > 0, where ⸹1 and ⸹2 are the effect sizes for comparing treatment to 
control for Test 1 and Test 2 respectively.  
Let the logistic regression model for Test 1 be:  
logit൫𝑝𝑝1,𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃൯= ln
𝑝𝑝1,𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
𝑝𝑝1,𝑁𝑁𝑁𝑁𝑁𝑁 𝑝𝑝𝑝𝑝𝑝𝑝= 𝛽𝛽1,0 + 𝛽𝛽1,1TRT + 𝛽𝛽1,2ERT + 𝛽𝛽1,3 DUR + 𝛽𝛽1,4 SEX + 𝛽𝛽1,5 AGE 
and Test 2 be: 
logit൫𝑝𝑝2,𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁൯= ln
𝑝𝑝2,𝑁𝑁𝑁𝑁𝑁𝑁
𝑝𝑝2,𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆= 𝛽𝛽2,0 + 𝛽𝛽2,1TRT + 𝛽𝛽2,2ERT + 𝛽𝛽2,3 DUR + 𝛽𝛽2,4 SEX + 𝛽𝛽2,5 AGE 
For any coefficient β, the Wald statistic is given by Wald = b/seb, where b is the estimate for β 
and seb is the standard error for β, and the Wald statistic is approximately normally distributed. 
Therefore, in testing the null hypothesis about the treatment effect, say β1,2 = 0 (for Test 1), the 
test statistic for treatment effect is: (b1,2 - 0)/seb = b1,2 /seb. 


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Let Z1 = b1/seb1 and Z2/1 = b2/1/seb2/1 be the test statistics for testing treatment effect in Test 1 and 
Test 2 respectively, where Z1 and Z2/1 are standardized to have standard normal distributions (so 
that each has mean = 0 and variance = 1). 
The inter-group comparison is based on the combined analysis of the positive response rates of 
significant improvements and the negative response rates of minor/no improvement. The overall 
null and alternative hypothesis (H0: H10 ∩ H20) is tested against the alternative hypothesis 
(HA: H1A U H2A) based on the combination test statistic: 
𝑍𝑍=
𝑤𝑤1
𝑤𝑤1+𝑤𝑤2  𝑍𝑍1  + 
𝑤𝑤2
𝑤𝑤1+𝑤𝑤2 𝑍𝑍2/1, where 𝑤𝑤1 and 𝑤𝑤2 are weights (constants) for the random  
variables Z1 and Z2/1 respectively (Rpatel 2019). The weights, wi, represent the information 
fraction in test i. The expected value of Z is given by:  
𝐸𝐸(𝑍𝑍) =
𝑤𝑤1
𝑤𝑤1+𝑤𝑤2  𝐸𝐸(𝑍𝑍1) + 
𝑤𝑤2
𝑤𝑤1+𝑤𝑤2  𝐸𝐸(𝑍𝑍2/1) =  0, under H0. 
Assuming independence of Z1 and Z2/1, the variance of Z is given as: 
𝑉𝑉𝑉𝑉𝑉𝑉(𝑍𝑍) = ൬
𝑤𝑤1
𝑤𝑤1 + 𝑤𝑤2
൰
2
𝑉𝑉𝑉𝑉𝑉𝑉( 𝑍𝑍1) + ൬
𝑤𝑤2
𝑤𝑤1 + 𝑤𝑤2
൰
2
𝑉𝑉𝑉𝑉𝑉𝑉൫𝑍𝑍2/1൯  
= ൬
𝑤𝑤1
𝑤𝑤1 + 𝑤𝑤2
൰
2
+ ൬
𝑤𝑤2
𝑤𝑤1 + 𝑤𝑤2
൰
2
 
Inference is based on the standardized score ZW, where  
𝑍𝑍𝑊𝑊= 
𝑤𝑤1
𝑤𝑤1 + 𝑤𝑤2  𝑍𝑍1  + 
𝑤𝑤2
𝑤𝑤1 + 𝑤𝑤2 𝑍𝑍2/1
൤ቀ
𝑤𝑤1
𝑤𝑤1 + 𝑤𝑤2ቁ
2
+ ቀ
𝑤𝑤2
𝑤𝑤1 + 𝑤𝑤2ቁ
2
൨
1/2 
follows the standard normal distribution under the null hypothesis. A 1-sided p-value for testing 
against the overall null hypothesis H0 is given by p = 1 – Φ(zw), where Φ(.) is the cumulative 
distribution function of a random variable that follows the standard normal distribution. 
8.8. 
Analysis of Other Secondary Endpoints 
8.8.1. 
Motor Function Test 
Motor function test endpoints (including % predicted 6MWD time to complete TUG, and time to 
complete individual GSGC components) will be summarized by treatment group and visit. The 
change from baseline to Week 52 will be analyzed and compared between the 2 treatment groups 
using an ANCOVA model on the ITT-LOCF population, similar to that for the key secondary 
endpoints. No supportive and/or sensitivity analyses will be performed for these motor function 
tests. 
8.8.2. 
Muscle Strength Tests  
Muscle strength test endpoints (including MMT and QMT) will be summarized by treatment 
group and visit for the lower extremity score, upper extremity score, total MMT score, and the 
proximal muscle group score. In addition, the change from baseline to Week 52 for each 
endpoint measure will be analyzed and compared between the 2 treatment groups using an 


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ANCOVA model on the ITT-LOCF population, similar to that for the key secondary endpoints. 
A plot of the LS mean (± SE) change from baseline over time will be provided by treatment 
group. 
A supportive analysis for the MMT lower extremity (right/left hip flexion, right/left hip 
abduction, right/left knee flexion, and right/left knee extension) will be conducted. For this 
analysis, the number of subjects with changes in score of ≤ -3, -2, -1, 0, 1, 2, or ≥ 3 (from 
baseline to the Week 52 visit) will be tabulated for each body part, and then summed across all 
8 body parts for each treatment group. For this analysis, subjects must have tested on the same 
muscles (right or left) at both baseline and post-baseline visit in order to determine the point 
change. The summed changes in scores by categories across the 8 body parts will then be 
summarized (by number and percentage) for each treatment group. No inferential comparisons 
will be performed. Similar summaries will be performed for the body parts associated with upper 
extremity (right/left shoulder abduction, right/left shoulder adduction, right/left elbow extension, 
and right/left elbow flexion), overall MMT (lower extremity and upper extremity combined), and 
the proximal muscle group.  
No supportive or sensitivity analysis will be performed for the QMT scores. 
8.8.3. 
Other Pulmonary Function Tests 
The other pulmonary function test endpoints (ie, % predicted SVC, maximum VC [% predicted], 
% predicted MIP, % predicted MEP, and SNIP [% predicted]) will be summarized by treatment 
group and visit. In addition, the change from baseline to Week 52 for each endpoint will be 
analyzed and compared between the 2 treatment groups using an ANCOVA model on the 
ITT-LOCF population, similar to that for the key secondary endpoints. No sensitivity or 
supportive analyses will be conducted for these. 
A plot of the LS mean (± SE) change from baseline over time will be provided for the pulmonary 
function test (PFT) endpoints by treatment group. In addition, the difference between sitting 
FVC and supine FVC results will be summarized by visit.  
The % predicted SVC will be calculated as: (observed SVC results / predicted value)*100, where 
the predicted value is obtained from the corresponding VCMax predicted value in the dataset 
8.8.4. 
Patient-reported Outcomes 
The total score and change from baseline in total score will be summarized for the R-PAct scale, 
EQ-5D-5L (ie, based on the quantitative EQ-VAS score), and PROMIS instruments. The change 
from baseline to Week 52 in the total score and the EQ-VAS score will be analyzed using an 
ANCOVA model on the ITT-LOCF population, similar to that for the key secondary endpoints. 
A plot of the LS mean (± SE) change from baseline over time will be provided for each of these 
PROs by treatment group. The EQ-5D categorical responses and the changes in the responses 
will be summarized by visit for each of the 5 dimensions.  
Handling Baseline Missing Data for PROs: 
For the PROs, missing baseline total scores will be handled similarly to that described for the 
multi-item endpoints in Section 6.3.1. That is, a missing baseline total score will be imputed with 
the average of all non-missing baseline total scores (from both treatment groups combined). If 


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the subject is only missing specific item(s) at baseline, the average of all non-missing values for 
that specific item (from both treatment groups combined) will be used.  
Note: a missing baseline total score (or a missing individual item score) will only be imputed if 
the subject has at least 1 non-missing post-baseline total score (or individual item score).  
Handling Post-baseline Missing Data for PROs: 
For any PRO with a total score based on multiple items/questions, a missing post-baseline total 
score at a given visit will be handled using the “50% prorating rule” described below: 
• If ≥ 50% of items are available, the total score will be calculated and prorated as the 
average of the non-missing items multiplied by the total number of items expected 
(Haywood, Garratt et al. 2004);  
• If < 50% of items are available, the total score will not be calculated, and it will be set 
to missing (in the ITT-OBS population). For the ITT-LOCF population, missing data 
will be imputed as described in Section 6.1.4.1 and Section 6.3.2.  
For the SGIC, the responses for each of the 8 items will be summarized by treatment group and 
visit. Additionally, the response scale for each item at Week 52 will be divided into 3 categories 
(improving, stable, or declining) which reflect the functional status, and these will be 
summarized by treatment group. 
For the PGIC, a summary of the response score will be provided by treatment group and visit.  
8.8.5. 
Proportion Improving on Both 6MWD and % Predicted FVC 
The proportion of subjects improving on both 6MWD and % predicted FVC (where definition of 
improvement is provided in Section 8.7) will be compared between the 2 treatment groups using 
a logistic regression model adjusting for baseline age, ERT status, gender, baseline height, and 
baseline weight. The number and percent of subjects improving will be presented for each 
treatment group, and the p-value for comparing between the 2 treatment groups and the 
95% confidence interval for the treatment difference will be calculated from the logistic 
regression model. 
8.8.6. 
Analysis of Pharmacodynamic Endpoints  
For the pharmacodynamic endpoints/biomarkers (CK and urinary Hex4), the change from 
baseline and percent change from baseline at each visit will be summarized by treatment group. 
A line plot over time of the mean ± SE for the change and percent change from baseline will be 
provided by treatment group. The change from baseline to Week 52 will be compared between 
treatment groups using the nonparametric randomization-based covariance analysis described in 
Section 8.5.1.2. Analysis will be performed on the ITT-LOCF population. 
8.8.7. 
Immunogenicity 
This study will assess anti-rhGAA antibodies and NAbs in subjects treated with 
ATB200/AT2221 and alglucosidase alfa. The effect of immunogenicity results on PK, efficacy, 
safety, and PD will be explored. Further details will be provided in the MSP mentioned in 
Section 3.3.5.3 for the analysis of immunogenicity and PD data. 


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• Total ADA, including titers, will be assessed using the ATB200 assay, regardless of 
what treatment arm the subject is in, because the assay is set up for use with either 
treatment.  
• NAbs (inhibition of rhGAA-mediated hydrolysis of 4-MU glucoside, inhibition of 
rhGAA-mediated hydrolysis of glycogen, and inhibition of rhGAA binding to 
CI-MPR (for ATB200 analysis only) will be assessed using ATB200 in the assays, 
regardless of the treatment arm, because the assays are set up for use with either 
treatment (with the exception of the CI-MPR assay).  
• CI-MPR will be handled slightly differently as follows: All samples will be analyzed 
in the CI-MPR assay regardless of treatment arm, but data will be reported/used for 
further analysis only for subjects treated with ATB200 (the assay cannot be set up for 
use with alglucosidase alfa). 
• GAA cross-reactivity (anti-rhGAA antibodies cross-reactive to alglucosidase alfa) is 
also included in the protocol and will be assessed regardless of treatment arm 
(Screen/confirm analysis only; ie, no titers will be assessed with the GAA assay). 
• Anti-rhGAA IgE will be assessed as needed regardless of treatment arm. 
8.9. 
Subgroup Analyses 
Subgroup analyses by age group, gender, and race (using all available categories) will be 
performed for the primary endpoint and the change from baseline to Week 52 in % predicted 
FVC.  
In addition, the following subgroups will be analyzed for the primary endpoint and the change 
from baseline to Week 52 in % predicted FVC, unless otherwise specified: 
• ERT status (categorized as: ERT-experienced versus ERT-naïve) 
This subgroup analysis will apply to the primary and key secondary endpoints, 
% predicted SVC, as well as for the overall adverse event (AE) overview table, 
summary of treatment-emergent AEs by system organ class and by preferred term, 
and PD endpoints. 
• Baseline 6MWD (categorized as: 75 to < 150 meters, 150 to < 400 meters, 
≥ 400 meters) 
Note that for this subgroup analysis, categories may be collapsed depending on the 
actual number of subjects in each category, eg, 75 to < 150 meters and 150 to 
< 400 meters may be combined into 75 to < 400 meters.  
• Baseline 6MWD < median value, baseline 6MWD ≥ median value  
• Baseline FVC < median value, baseline FVC ≥ median value 
• Regions (North/South America, Europe, Asia Pacific) 
• ERT duration categorized as: 2 to < 3, 3 to < 5, and ≥ 5 years 
• History of IARs (Yes, No) 


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All subgroup analysis results will be presented by forest plots. The p-values for the 
treatment-by-subgroup interactions will be presented together in a tabular form.  
Note that subgroup analyses will not be performed if the size of the specified subgroup category 
is small and the analyses will not be meaningful. 


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9. 
ANALYSIS OF SAFETY 
Safety will be evaluated through the analyses of AEs, clinical safety laboratory data, vital signs, 
physical examination, electrocardiogram (ECG), and concomitant medications.  
Safety analyses will be based on the safety population. Safety data will be summarized using 
counts and percentages for categorical data and using descriptive statistics (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) for continuous data. No formal statistical tests will be 
performed. 
Infusion-associated reactions in the ATB200/AT2221 arm will be compared in frequency to the 
alglucosidase alfa/placebo arm in this study. 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using 
MedDRA version 20.1 or higher.  
Concomitant medications and nondrug therapies will be summarized by treatment group. 
Concomitant medications and nondrug therapies will be coded using WHO DDE, March 2017 or 
later. 
9.1. 
Treatment-emergent Adverse Events 
Summary of adverse events will be based on TEAEs. A TEAE is defined as any event that 
started or changed in the severity on or after the first dose of study drug.  
For AEs occurring on Day 1, if the start time of the event is missing or after the administration of 
the first dose of study drug, the event will be considered a TEAE.  
9.1.1. 
Adverse Event Reporting Period 
In general, TEAEs that occur more than 30 days from the last dose of study drug will not be 
counted. 
• For subjects who permanently discontinue study drug prematurely or who complete 
the treatment period and do not continue or enter the optional OLE study, 
ATB200-07, their AEs will be tabulated up to 30 days after the last treatment visit in 
Study ATB200-03. Their TEAE tabulation period (days) is calculated as:  
(last dose date of study drug + 30 days) – first dose date + 1. 
• For subjects who are confirmed to have a positive result for anti-rhGAA antibodies at 
the time of discontinuation and up to the 30-day safety follow-up visit, they will 
continue to have follow-up immunological testing for up to 12 months (ie, at 
6 months and 12 months) after the last dose date of study drug, but the AE collection 
will be up to 30 days from the time of study discontinuation. 
In order to generate summary results for the clinical study report (CSR), the summary 
will use only the events (ie, AEs and immunogenicity) that occurred within the first 
30 days after the last dose of study drug in Study ATB200-03. The additional 
potential immunogenicity events from Month 1 to Month 12 post the date of last dose 
of study drug will be reported as an addendum to the ATB200-03 CSR.  


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9.1.2. 
Summary of Treatment-emergent Adverse Events 
The overall summary of TEAEs table will be presented by treatment group and for all treated 
subjects using the number and percentage of subjects. The following events will be summarized: 
• Any treatment-emergent adverse events (any TEAE)  
• Treatment-emergent serious adverse events (TESAEs) 
• TEAEs leading to study drug discontinuation 
• TEAEs related to study drug (ie, treatment related TEAEs) 
• TEAEs related to study drug and leading to study drug discontinuation 
• TESAEs leading to study drug discontinuation 
• TESAEs related to study drug (ie, treatment related TESAEs) 
• TESAEs related to study drug and leading to study drug discontinuation 
• Deaths 
In addition, summary tables will be presented for each of the individual bulleted items listed 
above.  
The number and percentage of subjects who experienced TEAEs will be presented by SOC and 
by PT within SOC for each treatment group. The table by SOC and PT will be repeated, one with 
the PTs within SOC sorted according to descending order of the ATB200/AT2221 group, and 
another the PTs sorted alphabetically within the SOCs. A subject will be counted only once 
within the same SOC and within the same PT. 
The cumulative number and percentage of subjects with TEAEs will be summarized by severity 
(mild, moderate, severe) for each treatment group, and by relationship to study drug (‘related’ vs 
‘not related’) for each treatment group. If a subject experienced more than 1 TEAE within 
different severity or relationship categories within the same SOC/PT, only the worst case (worst 
severity and related TEAE) will be reported.  
All AEs will be provided in a listing that will include the subject identifier, SOC, PT, and the 
reported term, date of onset and study day, date of resolution and study day, the seriousness, the 
severity, the relationship to each individual study drug (for TEAEs), duration, the action taken, 
and the outcome. All TEAEs will be flagged in the listing.  
Listings will also be generated for deaths, SAEs, and discontinuations due to TEAEs. 
9.1.3. 
TEAEs Reported as Infusion-associated Reaction 
For any AE, the reporting investigator is requested to enter on the AE eCRF whether the AE is 
deemed to be an infusion-associated reaction and determine the relationship to each of the study 
drug components (ATB200, AT2221, alglucosidase alfa, and placebo). 
To further characterize TEAEs considered by the reporting investigator to be IARs, a summary 
table of TEAEs reported as IARs will be provided. The number and percentage of subjects who 
experienced IARs will be presented by SOC and by PT within SOC for each treatment group. A 
subject will be counted only once within the same SOC and within the same PT. 


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Summary of IARs will also be presented by severity, and for relationship to each treatment 
component (ATB200, AT2221, alglucosidase alfa, and placebo) as well as for the 
co-administration. Additional summary tables/plots will be provided to describe the clinical 
characteristics of the IARs by treatment group, including the event rates, changes in severity over 
time, and time to first IAR (see Section 9.4.1). The IAR summary will also be presented by prior 
history of IARs (yes/no), and by ERT status (experienced/naïve). 
A listing of treatment-emergent IARs, serious IARs, IAR-related deaths, and IARs leading to 
study drug discontinuation will be provided. A listing displaying the summary of number of 
infusions and infusions associated with IARs by each individual subject who had an IAR will 
also be provided. For each subject, this listing provides subject ID, number of infusions received, 
number of infusions associated with IARs, percentage of infusions associated with IARs, the 
TEAEs that are IARs (IAR-TEAEs) occurring in each of the time intervals (see Section 9.1.4.2 
and Section 9.1.4.3), and the event severity of the IARs corresponding to (or associated with) 
each infusion.  
A summary of IAR-TEAEs by subjects with IARs, and the number of subjects with 1, 2, 3, 4 to 
6, 7 to 10, 11 to 19, and ≥ 20 IARs will be summarized for each treatment group. A summary of 
the number of infusions and IARs associated with the infusions will be provided for all subjects 
as well as only for subjects who had IARs. 
9.1.4. 
Additional Analysis of IARs 
Additional summary tables/plots will be provided to describe the clinical characteristics of the 
IARs by treatment group, including the event rates, changes in severity over time, and time to 
first IAR. 
9.1.4.1. 
Analysis of Time to First IAR-TEAE 
This calculation is only performed for subjects who have IARs. For these subjects, the time (in 
weeks) from the first dose of study drug to the onset of the first TEAE that is an IAR 
(ie, IAR-TEAE) will be calculated for each subject as:  
Time to first IAR-TEAE (Weeks) = (date of the first IAR-TEAE – date of first dose of study 
drug + 1) / 7.  
The calculated times will also be presented in a subject listing.  
9.1.4.2. 
Analysis of IARs by Onset Intervals 
The IARs will also be analyzed by onset intervals categorized as follows:  
• 1 to 3 days, 4 to 7 days, 8 to 14 days, 15 to 28 days, 29 days to ≤ 3 months, 
> 3 months to ≤ 6 months, > 6 months to ≤ 12 months, and > 12 months. 
The event rates and changes in severity over time (over these intervals) will be summarized for 
each treatment group. This analysis will further describe the clinical characteristics of IARs and 
help determine whether the IARs disappear over time or appear late.  


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9.1.4.3. 
Analysis by Time After Infusion Start 
IARs and anaphylactic reactions will be analyzed by the time after infusion start. Based on 
protocol descriptions of immediate-type IARs and late-type infusion reactions, the following 
time after infusion start will be used: 
• 0 to < 2 hours, 2 to < 4 hours, 4 to < 6 hours, 6 to < 12 hours, 12 to < 24 hours 
(1 day), 1 to < 4 days (96 hours). 
The event rates and changes in severity over time (over these intervals) will be summarized to 
help describe the clinical characteristics of IARs and anaphylactic reactions. 
9.1.5. 
Describing Relationship to Study Drug 
For each AE entered on the AE eCRF, the reporting investigator was asked to assess relationship 
to both infusion drug (ATB200 or alglucosidase alfa) and capsule (AT2221 or placebo). The 
relationship to each study drug will be presented by 2 categories:  
• “related,” which includes possibly related, probably related, and definitely related, as 
reported by the investigator 
• “not-related,” which includes unrelated and unlikely related, as reported by the 
investigator 
To describe the overall relationship to study drug, two approaches will be presented: 
1. Based on the pooling into one designation of the two individual relationships to ATB200 
or alglucosidase alfa and AT2221 or placebo 
a. If the two categories of the individual relationships are discordant (ie, “related” to one 
and “not related” to the other), the pooled designation will be considered “related” 
b. If the two categories of the individual relationships are concordant (ie, “related” to 
both or “not related” to both), the pooled designation will be concordant with the 
individual categories 
2. Based on the assessment of causality to the individual component, yielding these possible 
combinations 
a. “Related” to ATB200 – “related” to AT2221 
b. “Related” to ATB200 – “not related” to AT2221 
c. “Not related” to ATB200 – “related” to AT2221 
d. “Not related” to ATB200 – “not related” to AT2221 
e. “Related” to alglucosidase alfa – “related” to placebo 
f. “Related” to alglucosidase alfa – “not related” to placebo 
g. “Not related” to alglucosidase alfa – “related” to placebo 
h. “Not related” to alglucosidase alfa – “not related” to placebo 


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9.1.6. 
Missing AE Onset Date, Severity, and Relationship 
9.1.6.1. 
Missing or Partial AE Onset or Medication Start Date 
Complete dates are very important to correctly describe safety events such as TEAEs and 
designation of unique AE occurrences. When dates are completely missing or partially missing, 
they will be imputed.  
The following algorithm will be used to impute partial or missing AE start dates: 
1. If Year is not missing and is after the year of first application of study drug: 
If Month is missing, then Month will be imputed as January. 
If Day is missing, then Day will be imputed as the first of the month. 
2. If Year is not missing and is the same as the year of the first application of study drug: 
If Month is missing, then impute the Month as the month of the first application of 
study drug. 
If Day is missing but Month is the same as the month of first application of study 
drug, then impute Day as the first day of study drug application. 
If Day is missing but Month is after the month of first application of study drug, then 
impute Day as the first of the month. 
3. If Year is missing, then impute the year as the year of the first application of study drug: 
If Month is missing, then impute the Month as the month of the first application of 
study drug. 
If Day is missing, then impute the Day as the day of the first application of study 
drug. 
4. If the start date is completely missing, but the AE is either ongoing or the stop date is 
after the first date of drug application, then impute the start date as the first application of 
study drug. 
5. If using the above rules, the stop date is before the start date, then leave the start date 
missing and assume that the AE is treatment-emergent for the purpose of the analysis. 
No imputations will be applied to AE stop dates. 
9.1.6.2. 
Missing or Partial Medication Stop Date 
References to year and month are the year and month of the stop date: 
1. If year and month are known and study medication stopped during that month and year, 
use the stop date of study medication.  
2. If year and month are known and informed consent was provided during that month and 
year, use the date of informed consent.  
3. If year and month are known and study medication stopped after the date of informed 
consent and not in the month that medication stopped, use the last day of the month.  


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4. If year and month are known and are prior to the month of informed consent, use the first 
day of the month.  
5. If only year is known and study medication stopped during that year, use the stop date of 
study medication.  
6. If only year is known and study medication stopped after that year, use December 31st of 
that year.  
7. If only year is known and study medication stopped prior to that year, use the first day of 
the year.  
8. Should any of the previous stop dates be created before a start date, either a complete 
date or an imputed one, use the (imputed) start date instead of the date that would 
otherwise be created.  
9. Otherwise, if stop date is unknown, leave as missing.  
9.1.6.3. 
Missing Severity 
If severity is missing for any AE/TEAE, then its severity will be classified as “severe” in the 
summary tables. 
9.1.6.4. 
Missing Relationship 
If the assessment of relationship of the TEAE to study drug is missing, then it will be classified 
as “related” in the summary tables. 
9.2. 
Clinical Safety Laboratory Data 
Laboratory data will be presented using the Système International (SI) unit. Descriptive statistics 
for clinical safety laboratory data will be presented by treatment group and by visit, starting at 
the Baseline visit. Analyses will be based on the safety population. Change from baseline and 
percent change from baseline to post-baseline visit will also be presented. No formal statistical 
comparisons will be performed. Data will be attributed to visits according to the visit windows in 
Table 4. 
Summary tables by treatment group will be presented for each category of data separately. 
Routine clinical laboratory data will include hematology, serum chemistry, and urinalysis. 
Quantitative laboratory test results will be summarized using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum). Line plots (for ALT and AST) over time will be 
provided by treatment group using the mean ± SE for the change from baseline and percent 
change from values. Qualitative tests (eg, some urinalysis assessments) will be categorized 
accordingly. The set of laboratory parameters included in each table will correspond to those 
requested in the study protocol.  
The percentage of subjects with specific treatment-emergent laboratory values that meet 
pre-defined limits of change (PDLC) will be summarized for these laboratory parameters.  
The incidence rates of PDLC values will be compared descriptively between treatment groups, 
without any statistical testing. 


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If a subject has even 1 post-baseline value that meets the PDLC criteria for any lab parameter, 
then all values of that parameter for that subject will be listed.  
Table 9: 
Pre-defined Limits of Change Criteria for Clinical Safety Laboratory Data 
Laboratory Test 
Parameter for ANY Value and LAST Value 
Chemistry 
Albumin 
Composite: < LLN and > 25% decrease from BL 
Bilirubin 
Composite: > ULN and > 25% increase from BL 
Absolute Value: > 2X ULN 
Bicarbonate 
Absolute Value: < 16 mEq/L 
Calcium 
Composite: > ULN and > 10% increase from BL 
Phosphorus 
Composite: < LLN and > 25% decrease from BL 
Composite: > ULN and > 25% increase from BL 
Potassium 
Composite: < LLN and > 15% decrease from BL 
Composite: > ULN and > 15% increase from BL 
Sodium 
Composite: < LLN and decrease > 5 mEq/L or more from BL 
Composite: > ULN and increase > 5 mEq/L or more from BL 
Uric Acid 
Male: absolute value ≥ 624.6 µM 
Female: absolute value ≥ 505.6 µM 
Composite: < LLN and > 25% decrease from BL 
Composite: > ULN and > 25% increase from BL 
ALT 
Absolute Value: > 3X ULN 
Absolute Value: > 5X ULN 
Absolute Value: > 8X ULN 
AST 
Absolute Value: > 3X ULN 
Absolute Value: > 5X ULN 
Absolute Value: > 8X ULN 
ALT > 3X ULN and Tbili 
> 2X ULN  
Composite: ALT > 3X ULN and Tbili > 2X ULN (with the Tbili 
elevation > 2 X ULN within 30 days of the ALT elevation > 3X ULN) 
AST > 3X ULN and Tbili 
> 2X ULN 
Composite: AST > 3X ULN and Tbili > 2X ULN (with the Tbili 
elevation > 2X ULN within 30 days of the AST elevation > 3X ULN) 
CK 
Absolute CK ≥ 2X ULN or 2X baseline value 


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Table 9: 
Pre-defined Limits of Change Criteria for Clinical Safety Laboratory Data 
(Continued) 
Laboratory Test 
Parameter for ANY Value and LAST Value 
Hematology 
Hemoglobin 
Male: absolute value ≤ 11.5 g/dL 
Female: absolute value ≤ 9.5 g/dL 
Change: ≥ 2 g/dL decrease from BL 
Change: ≥ 2 g/dL increase from BL 
Platelets 
Absolute value: ≤ 75 x 109/L  
Absolute value: ≥ 700 x 109/L 
Composite: > ULN and increase > 25% from BL 
Composite: < LLN and > 25% decrease from BL 
White Blood Count 
Composite: < LLN and > 25% decrease from BL 
Composite: > ULN and > 50% increase from BL 
Eosinophils  
Absolute value: > 10% 
Abbreviations: BL = baseline; LDH = lactate dehydrogenase; LLN = lower limit of normal; PDLC = pre-defined 
limit of change; SGOT (AST) = serum glutamic oxaloacetic transaminase (aspartate aminotransferase); 
SGPT (ALT) = serum glutamic pyruvic transaminase (alanine aminotransferase); Tbili = total bilirubin; 
ULN = upper limit of normal 
Supportive data listings for all laboratory results will be generated by laboratory type 
(hematology, serum chemistry, and urinalysis). Subject data listings will include the type of visit 
(eg, scheduled test, retest, or unscheduled), age, sex, laboratory test, test units, laboratory test 
result, and the laboratory standard normal ranges adjusted as appropriate for age and sex, if 
available. Laboratory values outside of the normal range will be flagged in the data listings. 
Results of urine pregnancy tests will be presented in a listing only.  
9.3. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.3.1. 
Vital Signs 
Descriptive statistics for vital signs will be presented by treatment group for systolic blood 
pressure, diastolic blood pressure, heart rate, and body weight at each visit starting at baseline. 
Change from baseline to post-baseline visit will be presented. No formal statistical comparisons 
will be performed. Data will be attributed to visits as described in Section 6.2.6. 
The incidence rates of PDLC for vital sign by parameter will be summarized (altogether, not by 
visit).  
The incidence rates will be presented by treatment group. There will be no formal statistical 
testing. 


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A listing will present all values for a subject and vital sign parameter if at least 1 post-baseline 
value for that subject and parameter meets the PDLC criterion. 
Table 10 presents criteria for categorizing the change from baseline in vital signs as PDLC. 
Table 10: 
Pre-defined Limits of Change Criteria for Vital Signs 
Vital Sign  
Criteria  
Pulse rate 
≥ 120 bpm at any time post-dose and ≥ 15 bpm increase from baseline at 
any time post-dose  
≤ 50 bpm at any time post-dose and ≥ 15 bpm decrease from baseline at 
any time post-dose 
Systolic blood pressure 
≥ 180 mm Hg at any time post-dose and ≥ 20 mm Hg increase from 
baseline at any time post-dose  
≤ 90 mm Hg at any time post-dose and ≥ 20 mm Hg decrease from 
baseline at any time post-dose 
Diastolic blood pressure 
≥ 105 mm Hg at any time post-dose and ≥ 15 mm Hg increase from 
baseline at any time post-dose  
≤ 50 mm Hg at any time post-dose and ≥ 15 mm Hg decrease from 
baseline at any time post-dose 
Weight 
Change: > 5% increase from BL 
Change: > 5% decrease from BL 
Abbreviations: bpm = beats per minute; mm Hg = millimeters mercury; PDLC = pre-defined limit of change 
9.3.2. 
Physical Examination 
Complete physical exams are performed at screening and the Week 52 visit. Brief physical 
exams are performed at Day 1, Weeks 2, 4, 6, 12, 26, and 38. Baseline physical examination 
results will be presented for each body system/category examined. The number and percentage 
of subjects judged to be normal, abnormal, or not performed will be summarized. 
Further, the results of the physical examinations will be summarized by visit for subjects in the 
safety population who had an examination post-baseline. Each site/system will be summarized 
with respect to being normal or abnormal, or not performed.  
The supportive data listing will include the information collected on the eCRF (eg, body 
system/category, result of the observation [eg, normal or abnormal] or not performed, and any 
investigator comment). 
9.3.3. 
Electrocardiograms 
Electrocardiogram data including heart rate [HR] (beats/min), PR interval [PR] (msec), QRS 
duration (msec), QT interval (msec), QTcB interval (msec), QTcF interval (msec), and R-R 
interval [RR] (msec) will be summarized at baseline.  
The ECG parameters will be summarized by treatment group and visit. Frequency counts will be 
presented per treatment for both change and absolute values, with changes categorized as per the 


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bullets below. Individual listings presenting subjects with flags will be created for both change 
and absolute values. The summary will be tabulated by treatment group. 
Additionally, the number and percentage of subjects with the following overall ECG result will 
be presented:  
• Normal  
• Abnormal, not clinically significant 
• Abnormal, clinically significant  
The PDLCs for quantitative ECG data will be summarized by parameter and treatment group. 
The summary will indicate the number and percentage of subjects with PDLCs at any time 
during the study and will not be presented by visit. Unscheduled visits will be included in this 
summary. It is possible for subjects to appear in both categories for any parameters.  
The incidence rates will be compared descriptively between treatment groups. There will be no 
statistical testing. 
Table 11 indicates the PDLC criteria for ECG data. All ECG data will be presented in listings. 
Table 11: 
Pre-defined Limits of Change Criteria for ECG Values 
ECG Parameter 
Criteria 
PR interval (msec) 
< 120 msec or ≥ 210 msec  
QRS duration (msec) 
≤ 50 msec or > 120 msec 
QTcF interval (msec) and 
QTcB interval (msec)  
Absolute post-baseline QTcB, QTcF, and uncorrected QT interval: 
≤ 450 msec or > 450 msec  
≤ 480 msec or > 480 msec  
≤ 500 msec or > 500 msec  
Change from baseline for QTcB, QTcF, and uncorrected QT: 
≤ 30 msec or > 30 msec; ≤ 60 msec or > 60 msec  
Abbreviations: bpm = beats per minute; ECG = electrocardiogram; msec = millisecond; PDLC = pre-defined limit 
of change; QTcB = QT interval for corrected heart rate (based on Bazett’s formula: QT/(RR1/2)); QTcF = QT 
interval for corrected heart rate (based on Fridericia’s formula: QT/(RR1/3)). If the RR is not collected, it will be 
derived as follows: RR = (60/HR). 
9.4. 
Duration of Therapy and Missing Medication Start and Stop Dates  
9.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Incomplete concomitant medication start dates will be imputed in the same manner as imputation 
of AE start dates described in Section 9.1.6.1. No imputations will be applied to the medication 
stop date. If, when using those rules, the stop date is before the start date, then the start date will 
be left as missing and it will be assumed that the medication is concomitant for the purpose of 
the analysis. Imputed dates will be flagged in the subject data listings. 


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9.4.2. 
Duration of Therapy and Treatment Compliance 
Study drug exposure and compliance will be summarized for ATB200 and AT2221 separately. 
Dose completion (number of administered doses), treatment duration, and treatment compliance 
will be tabulated. A frequency distribution for the number of treated subjects, and descriptive 
statistics for the duration of treatment (months) and compliance will be provided by treatment 
group and for all treated subjects. A summary of treatment duration will also be provided by 
ERT status. 
Duration of treatment (extent of exposure) in months is defined as the number of months on 
treatment. This will be calculated as: (date of last dose – date of first dose + 1) / 30.4. 
The number and percentages of subjects will be tabulated by the extent of exposure categorized 
into months as: ≤ 3, 3 to ≤ 6, 6 to ≤ 9, 9 to ≤ 12, and > 12. 
Note: Due to the potential for delayed visits and catch-up infusions, it is possible that some 
subjects may stay in the study longer than 12 months. 
Compliance for each subject taking ATB200 will be calculated based on the number of infusions 
as well as the actual infusion dose administered. Compliance based on infusion dose is calculated 
as:  
100 * (total infusion dose administered [mg] / total infusion dose planned or intended [mg]).  
Compliance based on number of infusions is calculated as:  
100 * (number of infusions administered / number of infusions planned or intended), 
where the number of infusions planned is obtained as: 
(subject’s last date in study while on treatment – date of first infusion + 14) / 14.  
Note: Missed infusions due to COVID-19 related policies must be subtracted to ensure accurate 
compliance.  
Compliance for each subject taking AT2221 will be calculated as: 
100 * (total dose administered [mg] / scheduled or planned dose [mg]). 
Dose compliance rate will be classified as under-compliance: < 80%, within compliance: (80%, 
120%), and over-compliance: > 120%. 


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10. 
REFERENCES 
Agresti, A. (2002). Categorical Data Analysis. Second Edition. New York: Wiley.  
Bartlett, J. (2014). “Robustness of linear mixed models.” 
https://thestatsgeek.com/2014/08/17/robustness-of-linear-mixed-models/. 
Baschung Pfister, P., E. D. de Bruin, I. Sterkele, B. Maurer, R. A. de Bie and R. H. Knols (2018). 
“Manual muscle testing and hand-held dynamometry in people with inflammatory myopathy: An 
intra- and interrater reliability and validity study.” PLoS One 13(3): e0194531. 
Bohannon, R. W. and R. Crouch (2017). “Minimal clinically important difference for change in 
6-minute walk test distance of adults with pathology: a systematic review.” J Eval Clin Pract 
23(2): 377-381. 
du Bois, R. M., D. Weycker, C. Albera, W. Z. Bradford, U. Costabel, A. Kartashov et. al. (2011). 
“Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal 
clinically important difference.” Am J Respir Crit Care Med 184(12): 1382-1389. 
Enright, P. L. and D. L. Sherrill (1998). “Reference equations for the six-minute walk in healthy 
adults.” Am J Respir Crit Care Med 158(5 Pt 1): 1384-1387. 
Evans, J. A. and W. A. Whitelaw (2009). “The assessment of maximal respiratory mouth 
pressures in adults.” Respiratory Care 54(10): 1348-1359. 
Haywood K. L., A. M. Garratt, L. J. Schmidt, A. E. Mackintosh and R. Fitzpatrick (2004). 
Health Status and Quality of Life in Older People: A Structured Review of Patient-reported 
Health Instruments Report from the Patient-reported Health Instruments Group (formerly the 
Patient-assessed Health Outcomes Programme) to the Department of Health. 
Koch G. G., C. M. Tangen, J. W. Jung and I. A. Amara (1998). “Issues for covariance analysis of 
dichotomous and ordered categorical data from randomized clinical trials and non-parametric 
strategies for addressing them.” Stat Med 17(15-16): 1863-92.  
LaVange L. M., T. A. Durham and G. G. Koch (2005). “Randomization-based nonparametric 
methods for the analysis of multicentre trials.” Stat Methods in Med Res 14(3): 281-301. 
nQuery Advisor Sample Size Calculator, Version 8.2.1.0 (2018). Statistical Solutions Ltd., One 
International Place, 100 Oliver Street, Suite 1400, Boston, MA 02110. 
Rpatel. “Combining Z Scores by Weighted Average. Sanity Check Please?” 
URL (version: 2019-04-27): https://stats.stackexchange.com/q/348605. 
Schrover, R, K. Evans, R. Giugliani, I. Noble and K. Bhattacharya (2017). “Minimal clinically 
important difference for the 6-min walk test: literature review and application to Morquio A 
syndrome.” Orphanet Journal of Rare Diseases 12: 78. 
Siddiqui, O., J. H. M. Hung, and R. O’Neill (2009). “MMRM vs. LOCF: a comprehensive 
comparison based on simulation study and 25 NDA datasets.” Journal of Biopharmaceutical 
Statistics 19(2): 227-246. 
Uldry, C. and J-W. Fitting (1995). “Maximal values of sniff nasal inspiratory pressure in healthy 
subjects.” Thorax 50: 371-375.  


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van der Ploeg, A. T., P. R. Clemens, R. J. Hopkin, K. Kacena, B.-J. Sanson and P. Lafôret 
(2017). Poster: Long-term Efficacy of Alglucosidase Alfa in Late-onset Pompe Disease. 
WORLD. San Diego, CA, Sanofi Genzyme.  
White, I. R., J. Carpenter and N. J. Horton (2012). “Including all individuals is not enough: 
lessons for intention-to-treat analysis.” Clin Trials 9(4): 396-407. 
Zink, R. C. and G. G. Koch (2012). “A SAS/IML macro for nonparametric randomization-based 
analysis of covariance.” Journal of Statistical Software 50(3). 


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APPENDIX 1. SAMPLE SIZE JUSTIFICATION 
The data used for the sample size calculations came from 2 sources:  
a. Data for alglucosidase alfa came from the LOTS extension (NCT00455195) which is 
a long-term extension study in which subjects were treated with the standard of care 
ERT (alglucosidase alfa) for up to 9 years; and  
b. Data for ATB200/AT2221 came from Amicus’ ongoing single-arm study, 
ATB200-02, which enrolled 4 cohorts of subjects. Of these, 2 cohorts had relevant 
data for use in the sample size calculations: Cohort 1 – ambulatory subjects who had 
been on ERT treatment for 2 to < 7 years; and Cohort 3 – ambulatory subjects who 
had not been previously treated with ERT (ie, ERT-naïve). 
Firstly, effect sizes were estimated using % predicted 6MWD data from ATB200-02 Cohort 1 
subjects (n = 10) treated with alglucosidase alfa for 2 to 6 years before switching to 
ATB200/AT2221, ATB200-02 Cohort 3 subjects (n = 5) who were ERT-naïve before starting 
ATB200/AT2221, and from a LOTS extension study (n = 22) where subjects were treated with 
alglucosidase alfa for up to 9 years (van der Ploeg, Clemens et al. 2017). Longitudinal percent 
predicted 6MWD data were extracted from Figure 5 of van der Ploeg, Clemens et al. 2017 and 
subjects were 1:1 matched to ATB200-02 subjects on the basis of treatment duration and 
baseline % predicted 6MWD. A treatment duration window was specified for each ATB200-02 
subject extending from the time of switching from alglucosidase alfa to ATB200/AT2221 
(eg, 4.4 years) to the end of the 9 or 12-month treatment period with ATB200/AT2221 
(eg, 5.4 years). In order to be eligible for matching to a given ATB200-02 subject, a LOTS 
extension study subject had to have at least one 6MWD value within the corresponding treatment 
duration window and one 6MWD value before and after the window. The LOTS extension 
subjects were then sequentially matched to ATB200-02 subjects based on having the smallest 
difference in baseline % predicted 6MWD at the corresponding treatment duration starting point. 
Once the LOTS extension subject with the closest baseline 6MWD was matched to a given 
ATB200-02 subject, that subject was removed from the pool and the remaining subjects were 
matched. Calculation of the slope of change in % predicted 6MWD for each matched LOTS 
extension subject was then based upon cubic spline values extracted every 3 months across the 
corresponding 9 or 12-month treatment duration window ± 6 months on each side.  
Based on this analysis, ATB200-02 Cohort 1 subjects switching from alglucosidase alfa to 
ATB200/AT2221 had a mean 12-month slope of change of +5.87% predicted 6MWD compared 
to a mean 12-month slope of -2.15% for matched subjects in the LOTS extension remaining on 
alglucosidase alfa. The mean difference between groups was +8.01%, favoring 
ATB2200/AT2221 with a standard deviation of +8.49%. For the ATB200-02 Cohort 3 subjects 
who were ERT-naïve before starting on ATB200/AT2221, the mean 12-month slope of change 
was +12.61% predicted 6MWD compared to a mean 12-month slope of -0.65% for matched 
subjects in the LOTS extension remaining on alglucosidase alfa. The mean difference between 
groups was +13.26%, favoring ATB2200/AT2221 with a standard deviation of +2.85%. Thus, 
the effect size of ATB200/AT2221 in ERT-naïve subjects was larger than the effect size in 
ERT-switch subjects. 
Secondly, when the subjects in ATB200-02 Cohort 1 (ERT-switch subjects) were combined with 
Cohort 3 (ERT-naïve subjects) into a single LOPD sample (n = 15), the overall mean 12-month 
slope of change for subjects receiving ATB200/AT2221 in ATB200-02 was +8.11% predicted 


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6MWD compared to a mean 12-month slope of -1.65% for the matched subjects in the LOTS 
extension on alglucosidase alfa. The mean difference between groups was +9.76% favoring 
ATB2200/AT2221 with a standard deviation of +7.43%. The resulting estimated standardized 
effect size (mean difference divided by standard deviation of difference) is then 
1.31 (95% CI: 0.60, 2.00) for subjects switching from alglucosidase alfa to ATB200/AT2221. 
Thirdly, the sample size calculation used a conservative standardized effect size of 0.7 for the 
inter-group analysis in the combined ERT-switch and ERT-naïve population. This reduction 
from the estimated 1.31 effect size was intended to help account for uncertainty of the effect size 
estimate due to the relatively small sample size, potential selection bias in ATB200-02 versus 
LOTS study extension data, other potential biases in period effects in combining ERT-switch and 
ERT-naïve subjects, as well as imbalance in known and unknown risk factors, outliers, 
informative missing data, and dropout patterns. The standard effect size of 0.7, which is close to 
the lower confidence limit, constitutes about one-half of the originally calculated standardized 
effect size of 1.31, thus making it quite conservative. Of note, the standard effect size of 
0.7 corresponds to a % predicted 6MWD of 5.0. In the range of expected subject age, weight, 
and height (using Enright and Sherrill 1998 for % predicted 6MWD calculation), a % predicted 
value of 5.0 equates to a measured 6MWD value of between 20 to 40 meters. Such a 6MWD 
range is within the minimal clinically important difference in 6MWD for adults with pathology, 
and it may also be clinically important across multiple subject groups (Bohannon and Crouch 
2017). In addition, 20 to 40 meters is within the range of group-level 6MWD differences 
(investigational treatment versus comparator) that served as the basis for regulatory approval. 


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APPENDIX 2. DESCRIPTIONS OF EFFICACY ENDPOINTS 
1. 6MWD: The 6-minute walk distance, measured in meters (m), is the distance walked on 
the 6MWT.  
2. Percent predicted 6MWD is calculated as: 
% predicted 6MWD = (actual 6MWD / predicted 6MWD) * 100, 
(rounded up or down based on standard rounding rules), where the predicted values 
are derived for males and females using the following Enright and Sherill 1998 
equations:  
Males: 6MWD = (7.57 x Height in cm) - (5.02 x Age in years) - (1.76 x Weight in 
kg) - 309 m; 
Females: 6MWD = (2.11 x Height in cm) - (5.78 x Age in years) - (2.29 x Weight in 
kg) + 667 m. 
3. Pulmonary function tests (PFTs): 
• Sitting forced vital capacity (FVC): FVC (L) and percent predicted FVC (%) 
• Supine forced vital capacity: FVC (L) and percent predicted FVC (%) 
• Maximum inspiratory pressure (MIP): MIP (cm of water [cm H2O]) and 
% predicted MIP (%) 
• Maximum expiratory pressure (MEP): MEP (cm of water [cm H2O]) and 
% predicted MEP (%)  
• SNIP (cm of water [cm H2O]) and % predicted SNIP (%) 
The percent predicted values of MIP, MEP, and SNIP will be calculated as: 
% predicted = (actual result / predicted result) * 100, 
where the predicted results are obtained using the reference equations in Table 12. The 
equations for MIP and MEP are from Uldry and Fitting 1995; the equation for SNIP is 
from Evans and Whitelaw 2009. 
Table 12: 
Predicted Equations for MIP, MEP, and SNIP 
PFT 
Male 
Female 
MIP 
120 – (0.41 x Age in years) 
108 – (0.61 x Age in years) 
MEP 
174 – (0.83 x Age in years) 
131 – (0.86 x Age in years) 
SNIP 
126.8 – (0.42 x Age in years) 
94.9 – (0.22 x Age in years) 
4. Manual muscle testing (MMT): 
− Right/left shoulder adduction 
− Right/left shoulder abduction 
− Right/left elbow flexion 


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− Right/left elbow extension 
− Right/left hip flexion  
− Right/left hip abduction  
− Right/left knee flexion  
− Right/left knee extension  
Each manual muscle test is evaluated on a scoring scale from 0 to 5, as follows: 0 = no 
muscle movement; 1 = visible muscle movement, but no movement at the joint; 
2 = movement at the joint, but not against gravity; 3 = movement against gravity, but not 
against added resistance; 4 = movement against resistance, but less than normal; 
5 = normal strength.  
• MMT Lower Extremity score: The total score for MMT lower extremity strength is 
obtained by summing the test scores across the following 8 body parts: right/left hip 
flexion, right/left hip abduction, right/left knee flexion, and right/left knee extension. 
The total score ranges from 0 to 40, with lower scores indicating lower muscle 
strength. That is, Lower = Hip scores + Knee scores. 
• MMT Upper Extremity score: The total score for MMT upper extremity strength is 
obtained by summing the test scores across the following 8 body parts: right/left 
shoulder abduction, right/left shoulder adduction, right/left elbow extension, and 
right/left elbow flexion. The total score ranges from 0 to 40, with lower scores 
indicating lower muscle strength. That is, Upper = Shoulder scores + Elbow scores. 
• MMT Total score: The MMT total score is the sum of the lower extremity score and 
the upper extremity score. The total score ranges from 0 to 80, with lower scores 
indicating lower overall muscle strength. That is, Total = Upper extremity + Lower 
extremity. 
• Proximal body muscle groups include right/left hip flexion, right/left hip abduction, 
right/left shoulder abduction, and right/left shoulder adduction with the total score 
ranging from 0 to 40, based on these 8 muscle groups. That is, Proximal = Shoulder 
scores + Hip scores. 
5. Quantitative muscle test (QMT) was measured using the hand-held dynamometer (HHD). 
Larger values/scores (in kg) indicate greater muscle strength.  
− Right/left shoulder adduction 
− Right/left shoulder abduction 
− Right/left elbow flexion 
− Right/left elbow extension 
− Right/left hip flexion  
− Right/left hip adduction  
− Right/left hip abduction  


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− Right/left knee flexion 
− Right/left knee extension  
• QMT value for upper extremities (kg) is obtained by summing up the values/scores 
from the following: right/left shoulder abduction, right/left shoulder adduction, 
right/left elbow extension, and right/left elbow flexion. 
• QMT value for lower extremities (kg) is obtained by summing up the values/scores 
from the following: right/left hip flexion, right/left hip abduction, right/left hip 
adduction, right/left knee flexion, and right/left knee extension. 
• QMT total value (kg) is obtained by adding up the QMT upper extremity and QMT 
lower extremity values/scores.  
• QMT proximal body value (kg) is obtained by adding up the scores/values from the 
following: right/left shoulder abduction, right/left shoulder adduction, right/left hip 
flexion, right/left hip abduction, and right/left hip adduction. 
6. PROMIS Short Forms 
• PROMIS – Physical Function Short Form 20a (v2.0) consists of 20 questions. The 
first 14 questions are each scored on a scale from 1 to 5 as follows: 1 = unable to do; 
2 = with much difficulty; 3 = with some difficulty; 4 = with a little difficulty; 
5 = without any difficulty; the next 6 questions are each scored on a scale from 1 to 
5 as follows: 1 = cannot do; 2 = quite a lot; 3 = somewhat; 4 = very little; 5 = not at 
all. 
• PROMIS – Fatigue Short Form 8a consists of 8 questions, each scored on a scale 
from 1 to 5 as follows: 1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; 
5 = very much; and 2 questions, each scored on a scale from 1 to 5 as follows: 
1 = never; 2 = rarely; 3 = sometimes; 4 = often; 5 = always.  
• PROMIS – Upper Extremity Short Form 7a consists of 7 items each scored on a 
decreasing scale from 1 to 5 as follows: 1 = unable to do; 2 = with much difficulty; 
3 = with some difficulty; 4 = with a little difficulty; 5 = without any difficulty. 
• PROMIS – Dyspnea Severity Short Form 10a consists of 10 questions each scored on 
a scale from 0 to 3 as follows: 0 = no shortness of breath; 1 = mildly short of breath; 
2 = moderately short of breath; 3 = severely short of breath. 
7. Gait, Stairs, Gowers’ maneuver, Chair (GSGC total score is the sum of the component 
scores from the following 4 functional tests: 
• 10-meter walk test (10MWT) is the time in seconds (s) it takes for the subject to walk 
10 meters. The test is scored as: 1 = normal; 2 = mild waddling, lordosis and/or toe 
walking; 3 = moderate waddling, lordosis and/or toe walking; 4 = severe waddling, 
lordosis and/or toe walking; 5 = walks only with assistance (ie, braces, cane, 
crutches); 6 = stands, but unable to walk; 7 = confined to wheelchair. The score from 
this test is used as the Gait score in GSGC. 


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• Stairs score (based on the subject climbing 4 stairs). This is scored as: 1 = climbs four 
stairs without assistance; 2 = supports one hand on thigh; 3 = supports both hands on 
thighs; 4 = climb stairs in upright position but with aid of railing; 5 = climbs while 
clinging to the railing with both hands; 6 = manages to climb only a few steps; 
7 = unable to climb steps. 
• Gowers’ maneuver score (based on the subject lying down on the floor, then rising 
from the floor to get to a standing position). This is scored as: 1 = normal; 2 = butt 
first maneuver, one hand on floor; 3 = butt first maneuver, two hands on floor; 
4 = unilateral hand support on thigh; 5 = bilateral hand support on thighs; 6 = arises 
only with aid of an object (table, chair, cane, etc); 7 = unable to rise.  
• Chair score (based on the subject arising from a sitting position in a chair to a 
standing position). This is scored as: 1 = normal; 2 = with wide base and/or difficulty 
but without support; 3 = with support on one thigh; 4 = with support on both thighs; 
5 = with support on arms of chair or on a table; 6 = not possible. 
For each of the above motor function tests, the actual time (in seconds [s]) that the 
subject takes to perform the test is also recorded for analysis.  
The total GSGC score ranges from 4 (normal performance) to 27 (worst performance).  
8. Timed Up and Go [TUG] test represents the time it takes the subject to stand up from the 
chair, walk to the line on the floor (about 3 meters), turn around, walk back to the chair, 
and sit down, all at the regular pace. 
9. R-PAct Scale total score: The Rasch-built Pompe-specific Activity (R-PAct) scale 
consists of 18 questions, each scored on a scale from 0 to 2 as follows: 0 = no; 1 = yes, 
but with difficulty; 2 = yes, without difficulty. 
The total score is calculated simply by summing up the observed scores across the 
18 items and it ranges from 0 to 36, with higher values representing lower level of 
disease impact on the muscles. 
10. EQ-5D-5L: European Quality of Life-5 Dimensions 5 Response Levels health status: 
The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ-VAS (visual 
analogue scale). Each of the 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) has 5 categorical responses/levels of perceived 
problems coded as follows:  
Level 1 = indicating no problem; Level 2 = indicating slight problems; 
Level 3 = indicating moderate problems; Level 4 = indicating severe problems; 
Level 5 = indicating extreme problems (for pain and anxiety) or indicating unable to (for 
mobility, self-care, and activity). 
The EQ-VAS is a quantitative measure of health outcome that reflects the patient’s own 
judgement. The EQ-5D is a 5-digit number (a categorical variable) that describes the 
subject’s health state. 


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11. SGIC: The Subject’s Global Impression of Change consists of the following 8 items (or 
functional areas):  
• overall physical wellbeing  
• effort of breathing  
• muscle strength  
• muscle function  
• ability to move around  
• activities of daily living  
• energy level  
• level of muscular pain  
Each of the 8 functional items is scored on a 7-point rating scale that ranges from 
‘1 = very much worse’ to ‘7 = very much improved.’ 
For each functional item, a tertiary response variable (improving, declining, stable) will 
be defined as: “Improving” which consists of improved, moderately improved, and very 
much improved; “Declining” consists of worse, moderately worse, and very much worse; 
and “Stable” equals no change. 
12. PGIC: The Physician’s Global Impression of Change is based on a single item that is 
scored on a 7-point rating scale. The response options/category are similar to the SGIC 
described above. 


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APPENDIX 3. SAMPLE SAS PROGRAMS 
All analysis programs will be submitted. Three sample SAS codes are provided below to 
illustrate the MMRM analysis (based on ITT-OBS), ANCOVA (based on ITT-LOCF) and the 
composite endpoint analysis that combines two separate logistic regression analyses. 
Sample Code for the MMRM Analysis  
/************************************************************************/ 
/** Description: Sample program for implementing the MMRM Analysis.     */ 
/** This sample program applies to the primary analysis of the primary  */ 
/** endpoint(6MWD), and can be adapted to all other MMRM analyses       */ 
/** specified in the SAP.                                               */ 
/*                                                                      */ 
/*  Response variable(CHG): Change from baseline at each visit timepoint*/ 
/** Explanatory variables in the model are:                             */ 
/**       TRTPN AVISIT TRTPN*AVISIT SEX BASE ERTEXP AGEBL HGTBL WGTBL   */ 
/*                                                                      */ 
/*  Assume that the 6MWD dataset is called ANADAT                       */ 
/*                                                                      */ 
/*  Some Definitions:                                                   */ 
/**     TRTPN  = Treatment group (1 = new treatment, 2 = control)       */ 
/**     AVISIT = Analysis Visit                                         */ 
/**     ERTSTA = ERT status (Experienced or Naïve)                      */ 
/************************************************************************/ 
 
/************************************************************************/ 
/* Perform the analysis. Then obtain treatment means and differences at */ 
/* each visit, with p-values and CIs.                                   */ 
/************************************************************************/ 
 
ods output LSMeans=lsm LSMEstimate=lsmest; 
proc mixed data = anadat method = reml; 
   class TRTPN AVISIT ERTSTA SEX USUBJID; 
   model CHG = TRTPN AVISIT TRTPN*AVISIT SEX BASE ERTSTA AGEBL HGTBL WGTBL / 
               ddfm=kr; 
   repeated AVISIT / type=UN subject=USUBJID;   
   lsmeans TRTPN*AVISIT / slice=AVISIT alpha=0.05 OM diff cl s;  *** Obtain 
      treatment means and differences at each visit, with CIs.**; 
  
   lsmestimate TRTPN*AVISIT "Treat vs. Control at Week 52" 0 0 0 1 0 0 0 -1  
      / upper testvalue=0; *** Get treatment diff and 1-sided p-value  **; 
 
   lsmestimate TRTPN*AVISIT ‘Treat vs. Control at Week 52’ 0 0 0 1 0 0 0 -1 / 
      testvalue=0 alpha=0.05 cl; **Get treatment diff and 2-sided p-value *; 
 
 
 
 
 
 
 
 
 


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Sample Code for the ANCOVA 
/************************************************************************/ 
/* ANCOVA is based on the ITT-LOCF population. This sample program can  */ 
/* be adapted to other ANCOVA analyses for the 6MWD, percent predicted  */ 
/* FVC, and all others specified in the SAP.                            */ 
/************************************************************************/ 
 
/* Perform the ANCOVA, obtain estimates of the treatment means, treatment */ 
/* differences, p-values and 95% CIs.                                     */ 
                                                                      
ods output LSMeans=lsm LSMEstimate=lsmest; 
proc mixed data = anadat; 
   class TRTPN ERTSTA SEX; 
   model CHG = TRTPN SEX BASE ERTSTA AGEBL HGTBL WGTBL /ddfm=kr; 
   lsmeans TRTPN / OM s alpha=0.05 cl diff;  ** Obtain lsmeans and lsmean 
differences; 
  
   lsmestimate TRTPN "Treat vs. Control at Week 52" 1 -1 / upper  
       testvalue=0; **Get treatment diff and 1-sided p-value at W52 *; 
 
   lsmestimate TRTPN ‘Treat vs. Control at Week 52’ 1 -1 / testvalue=0  
       alpha=0.05 cl; **Get treatment diff, 2-sided p-value, 95% CIs at W52*; 
 
Sample Code for the Analysis of Composite Endpoint 
*********************************************************************** 
* Implement separate logistic analyses for positive responses and     * 
* negative responses, and then combine the two results using weights. * 
*                                                                     * 
*  Assume input dataset (COMPOS) is structured as below, and has the  * 
*  following variables: RESPONSE, TRTPN, ERTSTA, DUR, SEX, AGEBL      * 
*                                                                     * 
  1 1 N 2.4 F 0 
  3 1 N 3.5 M 0 
  1 1 E 2.7 M 37 
  0 2 N 5.6 F 0 
  3 1 E 7.0 M 67 
  3 2 N 2.0 F 0 
  2 1 E 4.1 M 64 
  1 2 N 4.8 M 0 
  0 2 E 7.7 F 28 
  3 1 E 5.5 F 32 
  2 2 E 6.3 F 48 
   . . .  .  . . 
 
*   RESPONSE variable = composite response with values 0, 1, 2, 3     * 
*   TRTPN = Treatment group (1 = new treatment, 2 = control)          * 
*   ERTSTA = ERT status (Experienced or Naïve)                        * 
*   DUR = duration of ERT: value for ERT-experienced, and 0 for naïve.* 
***********************************************************************; 
 
** Analysis of positive responses vs. not positive responses **; 


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data comp1; 
  set compos; 
  if response=3 then resp1='Y';  
  else resp1='N'; 
run; 
 
** Analysis of stable responses vs. negative responses; 
data comp2; 
  set compos; 
  if response=3 then delete; 
  if response=2 then resp2='Y';  
  else resp2='N'; 
run; 
 
** Run two separate logistic regression models **; 
ods output ParameterEstimates=test1; 
proc genmod data=comp1;  
  class TRTPN ERTSTA SEX; 
  model resp1(event='Y') = TRTPN ERTSTA DUR SEX AGEBL / dist=binomial  
                             link=logit type3; 
run; 
 
ods output ParameterEstimates=test2; 
proc genmod data=comp2;  
  class trt ert; 
  model resp2(event='Y') = TRTPN ERTSTA DUR SEX AGEBL / dist=binomial  
                             link=logit type3; 
run; 
 
data combo; 
  merge test1(where=(level1='1') keep=level1 estimate stderr 
            rename=(estimate=estimate1 stderr=stderr1))  
 
  test2(where=(level1='1') keep=level1 estimate stderr  
            rename=(estimate=estimate2 stderr=stderr2)); 
run; 
 
** Calculate the weights, combine the test statistics and obtain the **; 
** p-value using weight as the inverse of the standard error estimate *; 
data combo2; 
  set combo; 
  w1=1/stderr1**2; 
  w2=1/stderr2**2; 
  z1=estimate1/stderr1; 
  z2=estimate2/stderr2; 
  zw=(w1/(w1+w2)*z1 + w2/(w1+w2)*z2)/sqrt((w1/(w1+w2))**2+(w2/(w1+w2))**2); 
  pvalue=1-cdf('normal',zw); 
run;