Change in forced vital capacity (FVC) upright from Baseline to Week 24 has been changed from a tertiary endpoint to a secondary endpoint. The measurements of IGF-1, IGF-2, and IGF-BP3 will now be performed at the same visits as the immunogenicity assessments (Baseline and Weeks 2, 4, 8, 12, 16, 20, and 24) instead of at Baseline, Week 12 and Week 24 as previously scheduled. The repeated measures analysis of MIP (and likewise of the secondary efficacy endpoints) has been replaced with an analysis of covariance (ANCOVA) approach. Separate assessments of the 6MWT are now used for Screening (to determine eligibility) vs. Baseline (used for statistical analysis). It has been emphasized that Baseline, not Screening, values will be used to calculate the change values used in statistical analyses. The use of antihistamines in the desensitization protocol has been clarified as optional. The use of any form of ventilatory assistance will now be captured as part of the assessment of concomitant medications before study and at each study visit. The Borg scale, rather than the modified Borg scale, will now be used. The patient-reported outcome (PRO) instruments have been removed as Appendices to the protocol. The collection of exploratory blood and urine samples has been clarified as an optional assessment. Administrative updates have been made to improve consistency and clarity.

An extension phase of up to 240 weeks has been added to the study. The neutralizing antibody for BMN 701 activity has been removed. Sleep assessments and analyses have been added to the study. References to a “light meal” to be eaten prior to BMN 701 infusions have been changed to a “meal.” The Week 12 magnetic resonance imaging (MRI) assessment has been removed. Chest X-rays taken within 12 months of study enrollment will now satisfy the requirement for a Screening chest X-ray (previously the X-ray must have been within 2 months of study enrollment). The requirement for both a posterior-anterior (PA) and lateral chest X-ray views has been removed. A PA view alone will suffice. The Baseline genomic sampling will be tested looking for angiotensin converting enzyme (ACE) polymorphisms. The collection of exploratory blood and urine samples has been clarified a required assessment; the genetic/genomic testing of these samples is optional. Language regarding assessments which may be necessary upon transition of the product to a new clinical lot has been added. Administrative updates have been made to improve consistency and clarity.

The interval of assessment between the pulmonary function tests and the 6-minute walk test (6MWT) has been reduced from 2 hours to 30 minutes, the interval between consecutive 6MWTs has been reduced to a minimum of one hour, and the interval between the 6MWT and the Quick Motor Function Test (QMFT) has been reduced from 4 hours to 1 hour. The QMFT assessments have been removed from the Week 6 and Week 18 visits. The post-infusion observation time has been reduced from 3 hours to 2 hours. The Screening window may be extended, upon approval by the Medical Monitor. The window for last rhGAA administration prior to the start of treatment BMN 701 has been changed from 14-28 days to 10-31 days. The window for assessment of GAA activity following an rhGAA treatment has been reduced from ≥ 14 days to ≥ 12 days. The timing of pharmacokinetic (PK) assessments for subjects receiving the complete PK analysis has been changed to remove the 8 hour post-infusion collection timepoint and add a timepoint 5 hours post-infusion, with the final collection at 6 hours. Administrative updates have been made to improve consistency and clarity.

The anticipated number of patients in the study has been increased to up to approximately 70. An additional pharmacokinetic (PK) and immunogenicity assessment visit has been added to the Transition Period (after the subject starts to receive study drug from the new clinical lot). Subjects in the complete PK cohort will also have complete PK testing at weeks 12 and 24 following the clinical lot transition. Blood glucose monitoring has been added to the transition period visits. The sleep study inclusion criteria have been modified. Visit windows ( ± 7 days) have been added to each of the visits during the Extension Period. Language was added to make it clear that all infusions should be administered with a minimum of 7 days between consecutive infusions. Language regarding PK sampling at the time of infusion end has been modified to change “prior to line flush” to “after all the drug has infused, including that within the tubing”. Language regarding “infusion-associated” reactions has been changed to reference “hypersensitivity” reactions. Clarified what was meant by the need to have ACLS-certified personnel and emergency equipment “readily available” during infusions. Clarified that the Appendix 1 guidance for medical management of subjects with hypoglycemia are intended as a suggested course of action, not a requirement. Added language to allow for discretionary home blood glucose monitoring. Reference to subjects transitioning to a new clinical lot prior to Week 24 of the study have been removed. Section 7 has been updated to reflect the latest information available in the Investigator’s Brochure. The Appendix 1 hypoglycemia management guidelines have been updated to provide more complete guidance. The adverse event reporting language has been updated to clarify that all AEs with severity of grade 3 or higher should be reported as serious AEs, and conform with BioMarin's internal processes. The identity of the medical monitor has been updated.

Expanded inclusion criteria to permit enrollment of subjects aged 12-17. Added as an exclusion criterion the need for invasive ventilatory support to exclude subjects with invasive ventilator support based on complete respiratory muscle paralysis. Added as an exclusion criterion moderate to severe respiratory or cardiac disease not related to Pompe, including, but not limited to, symptomatic asthma, angina, congestive heart failure, or chronic obstructive pulmonary disease (COPD), causing respiratory and functional limitations requiring concurrent treatment. Added as an exclusion criterion a history of limb fracture which impairs ambulation at the time of consent. Added as an exclusion criterion the concurrent use of smoking tobacco within 6 months prior to study enrollment due to significant comorbid conditions not related to LOPD that would limit ability to adequately ascertain efficacy of reveglucosidase alfa on respiratory function and endurance. Subjects who have experienced reductions in blood glucose with CTCAE severity ≥ grade 2 or AEs of “hypoglycemia” or “blood glucose decreased” during the Treatment Period should have glucose monitoring during Extension Period infusions at the same intervals indicated for the initial 24-week Treatment Period (every 30 minutes) until 12 weeks have passed without hypoglycemia more severe than CTCAE grade 1. At that point, monitoring may return to every 1 hour (±10 minutes) after the start of the infusion, for at least 2 hours following completion of the infusion. Clarified that the subject’s blood glucose level must be stable and ≥72 mg/dL (≥4.0 mmol/L) on the last two measurements prior to discharge. Clarified that blood glucose must be within normal limits (≥ 72 mg/dL [≥ 4.0 mmol/L]) before the infusion may be started.