A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease

The efficacy of cipaglucosidase alfa/miglustat co-administration on pulmonary function was measured by sitting FVC (% predicted). FVC is a standard pulmonary function test used to quantify respiratory muscle weakness.

The total score for the MMT lower extremity strength included the following 8 body parts: right/left hip flexion, right/left hip abduction, right/left knee flexion and right/left knee extension. The MMT lower extremity score ranged from 0 to 40, with lower scores indicating weaker muscle strength. An increase from baseline indicated increased muscle strength.

The 6MWD, measured in meters, is the distance walked on the 6MWT.

Physical Function Short Form 20a (v2.0) consisted of 20 questions. The first 14 questions were 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 were 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. The total score was calculated by summing up scores (1 to 5) across all items. Total scores range from 20 to 100. A higher score represented a better outcome.

Fatigue Short Form 8a consisted of 6 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. The total score was calculated by summing up scores (1 to 5) across all items. A lower score represented lower fatigue symptoms.

The GSGC consisted of a 10-meter walk for evaluation of gait, a 4-stair climb, Gowers' maneuver, and arising from a chair. Results of the GSGC included the time required to complete the individual tests, individual scores for each of the tests (1 to 7 points for each of gait, 4-stair climb, and Gowers' maneuver, and 1 to 6 points for arising from a chair), and a total score. GSGC total score was the sum of the component scores from the 4 functional tests. The total score ranged from a minimum of 4 points (normal performance) to a maximum of 27 points (worst performance).

The R-PAct scale was an 18-item questionnaire to measure limitations in activities and restriction in social participation. Possible responses to questions were as follows: unable to perform, able to perform, but with difficulty, and able to perform without difficulty. The total score was calculated by summing up the observed scores across the 18 items and it ranged from 0 to 36, with higher values representing lower level of disease impact on the muscles.

The EuroQol Visual Analogue Scale (EQ VAS) is a vertical visual analogue scale that records the respondent's own assessment of his or her overall health status at the time of completion. Scores range from 0 (the worst health you can imagine) to 100 (the best health you can imagine). Higher EQ VAS scores represent an improved sense of overall health while lower scores represent a worsening of overall health.

SVC is a standard pulmonary function test used to quantify respiratory muscle weakness.

The percent predicted values of MIP were calculated as: % predicted = (actual result / predicted result)* 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).

The percent predicted values of MEP were calculated as: % predicted = (actual result / predicted result)

• 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).

The percent predicted values of SNIP were calculated as: % predicted = (actual result / predicted result) * 100, where the predicted results were obtained using the reference equations from Evans and Whitelaw (2009).

The % predicted 6MWD = (actual 6MWD / predicted 6MWD) * 100. The predicted values were calculated using Enright And Sherrill 1998 Reference Equations.

QMT was measured using the hand-held dynamometer. Larger values (in kg) indicated greater muscle strength.

Each manual muscle test was 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. Upper extremity score was the sum of scores for right/left shoulder abduction, right/left shoulder adduction, right/left elbow extension, and right/left elbow flexion, with the total score ranging from 0 to 40.

Proximal muscle group score, the sum of scores for 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. MMT total score was the sum of the lower and upper extremity scores and ranged from 0 to 80. Lower scores indicated lower overall muscle strength. An increase from baseline indicated improvement in muscle strength.

Maximum VC is the greater of the two VC values (FVC or SVC).

The Upper Extremities Short Form 7a consisted 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.

Dyspnea Severity Short Form 10a consisted of 10 items 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.

A total score was generated for each instrument by adding up each item. Total scores for upper extremities range from 7 to 35. Total scores for dyspnea range from 0 to 30. A higher score for upper extremities represented improvement in symptoms. A lower score for dyspnea severity represented improvement in symptoms.

Motor function test assessed the time to complete individual GSGC component tests (10-meter walk, 4- stair climb, Gowers' maneuver, and arise from a chair) and the TUG test. The TUG test assessed the time a subject needed to rise from a chair, walk 3 meters, turn around, walk back to the chair, and sit down.

Physician's Global Impression of Change is based on a single item that is scored on a 7-point rating scale ranging from 1 "very much worse" to 7 "very much improved".

A tertiary response variable (improving, declining, stable) was defined as follows: "Improving", which consisted of improved, moderately improved, and very much improved; "Declining", which consisted of worse, moderately worse, and very much worse; and "Stable", which equaled to no change.

The SGIC is designed to record the participants' impression of their functional status since starting study drug using a 7-point scale ranging from 1 "very much worse" to 7 "very much improved".

A tertiary response variable (improving, declining, stable) was defined as follows: "Improving", which consisted of improved, moderately improved, and very much improved; "Declining", which consisted of worse, moderately worse, and very much worse; and "Stable", which equaled to no change.

A composite subject-level response of the 2 relevant clinical outcomes, 6MWD and FVC (% predicted), was assessed. Prespecified thresholds were used for assessment of improvement consistent with published minimal clinically important difference values for comparable instruments in similar disease.

Treatment-emergent ADAs were defined as participants who had seroconverted or boosted their preexisting ADA during the study period.

Levels of urinary Hex4, a biomarker of disease substrate, were measured. The assay specifically targets Hex4, the glucose tetrasaccharide (Glc4), which is a biomarker of glycogen storage.

Change from baseline to Week 52 in serum CK level. CK levels were measured as part of the serum chemistry panel.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.

A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/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 cipaglucosidase alfa/alglucosidase alfa infusion for plasma total human acid α-glucosidase (GAA) protein signature peptide T09 and plasma miglustat determinations.

A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/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 cipaglucosidase alfa/alglucosidase alfa infusion for plasma total GAA protein signature peptide T09 and plasma miglustat determinations.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.

On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.