Trial Outcomes & Findings for Avalglucosidase Alfa Extension Study (NCT NCT02032524)

The study was conducted at 17 centers in 7 countries. A total of 21 participants completed the open-label study TDR12857 (NCT01898364). Of which, 19 participants were enrolled in this study. There was no screening period in this study.

Participants who completed the open-label TDR12857 study were part of this study. This was an open-label study. As prespecified, data were analyzed and presented combinedly for studies TDR12857 and LTS13769.

Avalglucosidase Alfa Extension Study

An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An serious AE (SAE) is any untoward medical occurrence that results: death or life-threatening or inpatient hospitalization or prolongation of existing hospitalization or persistent or significant disability or congenital anomaly or medically important event. TEAEs are defined as AEs that develop or worsen during the on-treatment period (that is, from the time of first dose of IMP up to 4 weeks after the last administration of the IMP). Protocol-defined IARs were defined as AEs that occur during either the infusion or the post-infusion observation period (that is, up to 2 hours or longer following the infusion as per the Investigator's discretion) which were deemed to be related or possibly related to the IMP.

Physical examination included, at a minimum, an assessment of the participant's general appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral arterial pulse; and pupil, knee, achilles, and plantar reflexes.

Blood samples were collected to determine the clinical chemistry laboratory abnormalities.

Blood samples were collected to determine the hematology laboratory significant abnormalities.

Last on-treatment (LOT) values were collected at or just prior to the last IMP administration.

The LOT values were collected at or just prior to the last IMP administration.

The LOT values were collected at or just prior to the last IMP administration.

The LOT values were collected at or just prior to the last IMP administration.

The LOT values were collected at or just prior to the last IMP administration.

Participants vital signs were examined to determine the abnormalities. Vital signs included heart rate, systolic and diastolic blood pressure.

Body weight was measured in kilograms and collected in the electronic case report forms every 3 months throughout the duration of the study, as well as at the end of study visit.

Standard 12-lead ECGs were recorded after at least 15 minutes in the supine position using an electrocardiographic device. The following were assessed: heart rate, rhythm, interval between the peaks of successive QRS complexes (RR), interval from the beginning of the P wave until the beginning of the QRS complex (PR), interval from start of the Q wave to the end of the S wave (QRS), interval between the start of the Q wave and the end of the T wave (QT), QT interval corrected for heart rate (QTc) automatic correction evaluation (by the ECG device), QRS axis, R voltage V6, voltage V1, left ventricular hypertrophy criteria, right ventricular hypertrophy criteria, repolarization charges, and overall cardiac impression for each participant.

ADA negative was defined as ADAs are not detected (that is, negative in screening assay or reactive in screening but negative in confirmatory assay). ADA positive was defined as ADA was detected (that is, an assay signal equal to or greater than the cut-point in the screening assay and was tested positive in the confirmatory assay).

Cmax was defined as maximum plasma concentration observed. The non-compartmental pharmacokinetic (PK) analysis was performed.

AUClast was calculated using the trapezoidal method from time zero to the real time. The non-compartmental PK analysis was performed.

Tlast was defined as time corresponding to the last concentration above the limit of quantification, Clast. The non-compartmental PK analysis was performed.

t1/2z was calculated according to the following equation: t1/2z = 0.693/λz. Where, λz is the slope of the regression line of the terminal phase of the plasma concentration versus time curve. Half-life was calculated by taking the regression of at least 3 points. The non-compartmental PK analysis was performed.

CLss was calculated using the following equation: CLss= dose/AUC. The non-compartmental PK analysis was performed.

Vss was calculated using the following equation: Vz= CLss/λz. The non-compartmental PK analysis was performed.

Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The measured area of each muscle group, CSA was provided.

Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). Three-point dixon imaging provided quantification of fat content in muscles \[fat fraction (FF)\].

Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The FF was combined with the CSA measurements trophicity to provide an IRMM in mm\^2 (that is, IRMM = CSA x \[1 - FF\]). A negative change from baseline value in IRMM of skeletal muscle MRI indicates muscle loss (worse outcome) and a positive change from baseline value indicates muscle gain (better outcome).

Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The T2 multi-slice multi-spin echo and B1 mapping provided a quantitative measure of disease activity (edema, inflammation) within muscles.

Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The T2 multi-slice multi-spin echo and B1 mapping provided a quantitative measure of disease activity (edema, inflammation) within muscles.

Skeletal muscle needle or open biopsy was performed on the lower extremity (quadriceps) muscle to assess glycogen content. The MRI appearance of the muscle was used to determine the level (axial slice position) that the biopsy procedure should target (avoiding fatty replaced tissue). Glycogen content was measured by histomorphometric analysis or severity grading to determine how effectively avalglucosidase alfa was able to remove glycogen from muscle.

The Hex4, a tetraglucose oligomer, has been shown to be elevated in the urine of participants with Pompe disease. Hence, determination of Hex4 levels may be a means by which the efficacy of treatments were monitored. Urine samples were collected prior to IMP infusion for the assessment of urinary Hex4 concentrations.