Late Onset Pompe Disease

Primary Objective The primary objective of this study is to assess the long-term safety and tolerability of ATB200/AT2221 co-administration. Secondary Objectives The secondary objectives of this study are as follows: • to assess the long-term efficacy of ATB200/AT2221 co-administration on ambulatory function, as measured by the 6-minute walk test (6MWT) • to assess the long-term efficacy of ATB200/AT2221 co-administration on pulmonary function, as measured by sitting forced vital capacity (FVC) (% predicted) • to assess the long-term efficacy of ATB200/AT2221 co-administration on muscle strength • to assess the long-term efficacy of ATB200/AT2221 co-administration on health-related patient-reported outcomes • to assess the long-term efficacy of ATB200/AT2221 co-administration on motor function • to assess the long-term efficacy of ATB200/AT2221 co-administration on overall clinical impression, as assessed by both physician and subject • to assess the long-term efficacy of ATB200/AT2221 co-administration on measures of pulmonary function other than FVC (% predicted) • to assess the long-term effect of ATB200/AT2221 co-administration on biomarkers of muscle injury and disease substrate • to assess the immunogenicity of ATB200/AT2221 co-administration • to characterize the pharmacokinetics of ATB200 and AT2221 using plasma total GAA protein level by signature peptide and plasma AT2221 concentration assays in subjects at sites in Japan only • to explore the exposure-response relationship for ATB200/AT2221 in subjects at sites in Japan only

ATB200、AT2221

N-butyl-deoxynojirimycin (Miglustat)
recombinant human acid α-glucosidase (rhGAA)

Lyophilized powder
Hard gelatin capsule

105
65

Safety Endpoints
The long-term safety profile of ATB200/AT2221 will be characterized using incidence of
TEAEs, 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 (eg, clinical
laboratory tests, ECGs, vital signs). Immunogenicity to ATB200 will also be described.

Efficacy Endpoints
Efficacy endpoints are as follows:
• change from baseline in 6MWD
• change from baseline in sitting FVC (% predicted)
• change from baseline in the manual muscle test score for the lower extremities
• change from baseline in the total score for the PROMIS – physical function
• change from baseline in the total score for the PROMIS – fatigue
• change from baseline in the following variables related to motor function:
− GSGC total score
− 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
− change from baseline in the time to complete the TUG test
• change from baseline in the following variables related to muscle strength:
− manual muscle test score for the upper extremities
− manual muscle test total score (upper and lower extremities combined)
− quantitative muscle test value (kg) for the upper extremities
− quantitative muscle test value (kg) for the lower extremities
− quantitative muscle test total value (kg) (upper and lower extremities combined)
• change from baseline in the following variables from patient-reported outcome
measures:
− total score for the PROMIS – dyspnea
− 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, as measured by
the SGIC:
− overall physical well-being
− 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), as
measured by the PGIC
• change from baseline in the following measures of pulmonary function, as follows:
− sitting SVC (% predicted)
− MIP (cmH2O)
− MIP (% predicted)
− MEP (cmH2O)
− MEP (% predicted)
− SNIP (cmH2O)

Pharmacodynamic Endpoints
Pharmacodynamic endpoints are as follows:
• change from baseline in serum CK level
• change from baseline in urinary Hex4 level

Pharmacokinetic Endpoints
Pharmacokinetic endpoints are applicable for subjects at sites in Japan only.
Plasma total GAA protein PK parameters after intravenous administration of ATB200 will be
determined, as follows:
• maximum observed concentration (Cmax)
• time to reach Cmax (tmax)
area under the plasma concentration-time curve from time zero to the last quantifiable
concentration (AUC0-t)
• partial area under the plasma concentration-time curve from tmax to 24 hours
(AUCtmax-24h)
• area under the plasma concentration-time curve from time zero extrapolated to
infinity (AUC0-∞)
• alpha-phase (distribution) elimination half-life (alpha t½)
• total plasma clearance of drug after intravenous administration (CLT)
Plasma AT2221 pharmacokinetic parameters will also be determined, as follows:
• Cmax
• tmax
• AUC0-t
• AUC0-∞
• beta-phase or terminal t½
• apparent total clearance of drug after extravascular administration (CL/F)
• terminal phase volume of distribution (Vz/F)

Subjects Who Participated in Study ATB200-03
Inclusion Criteria
1. Subject must provide signed informed consent prior to any study-related procedures
being performed.
2. Subjects must have completed Study ATB200-03.
Note: Subjects who were forced to withdraw from Study ATB200-03 for a logistical
reason not related to the efficacy or safety of ATB200/AT2221 (eg, hospitalization for a
car accident or emergency surgery) and which resulted in several consecutive missed
doses may be eligible to participate in this study upon approval by the Amicus medical
monitor.
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.

New Subjects at Sites in Japan
Inclusion Criteria
1. Subject must provide signed informed consent prior to any study-related procedures
being performed.
2. Subjects are of Japanese descent.
3. Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
4. 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.
5. Subject must have a diagnosis of LOPD based on documentation of one of the following:
a. deficiency of GAA enzyme
b. GAA genotyping
6. 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) or at a
dose of 20 mg/kg based on lean or ideal body weight every 2 weeks for ≥ 24 months
b. ERT-naïve, defined as never having received investigational or commercially
available ERT
7. Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National
Health and Nutrition Examination Survey III) at screening.
8. 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

Subjects Who Participated in Study ATB200-03
Exclusion Criteria
1. Subject plans to receive gene therapy or participate in another interventional study for
Pompe disease.
2. 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.
3. Subject, if female, is pregnant or breastfeeding.
4. Subject, whether male or female, is planning to conceive a child during the study.

New Subjects at Sites in Japan
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 does not have documentation of diagnosis of Pompe disease and refuses to
undergo genetic testing.