Background: Pompe disease is a rare autosomal recessive disorder characterized by progressive loss of muscle and respiratory function due to acid α-glucosidase (GAA) deficiency. The approved treatment is enzyme-replacement therapy (ERT) with recombinant human GAA (rhGAA) alglucosidase alfa. AT-GAA is an investigational, 2-component therapy comprising cipaglucosidase alfa, a novel rhGAA with enhanced glycosylation for improved uptake and processing, and miglustat, an enzyme stabilizer. Objectives: Comparison of AT-GAA versus alglucosidase alfa/placebo in a double-blind, parallel-group study (NCT03729362) of adults (aged ≥18 years) with LOPD. ERT-experienced and -naive patients were randomized 2:1 to co-administration of intravenous cipaglucosidase (20 mg/kg)/miglustat or alglucosidase alfa (20 mg/kg)/placebo every 2 weeks. The primary and first key secondary endpoints were mean change from baseline to week 52 in 6-minute walk distance (6MWD) and % predicted forced vital capacity (FVC; sitting), respectively. Other key secondary endpoints included lower extremities manual muscle test (MMT), GSGC (gait, stairs, Gower, chair), PROMIS-physical function, and PROMIS-fatigue. Results: 123 patients were randomized in 62 sites across 24 countries; AT-GAA, n=85; alglucosidase alpha, n=38 (intention-to-treat population). Baseline characteristics were similar between arms. At week 52, 6MWD showed clinical improvement with AT-GAA versus approved therapy but did not reach statistical superiority (mean [SE]: +20.8 [4.6] versus +7.2 [6.6] meters; P=0.072). AT-GAA demonstrated a nominally statistically significant and clinically meaningful improvement in FVC for superiority over approved therapy (-0.9 [0.7] versus -4.0 [0.8]; P=0.023). A clinically significant improvement in GSGC and numerical trends in favor of AT-GAA versus approved therapy in lower MMT, PROMIS-physical function, and fatigue were also observed. Biomarkers showed significant improvements with AT-GAA versus approved therapy (creatine kinase: -22.4% versus +15.6%, P<0.05; urine hexose tetrasaccharide: -31.5% versus +11.0%, P<0.001). Additional endpoints including % predicted 6MWD, GSGC component scores, MIP, MEP, total and upper MMT will be presented. The safety profile was similar between arms. Conclusion: In this study population, AT-GAA showed positive trends or clinically meaningful improvements on motor and respiratory functions and biomarkers, compared with approved ERT.