**Background:** Pompe disease is a rare autosomal-recessive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA), leading to lysosomal glycogen accumulation, progressive muscle weakness, respiratory dysfunction, and functional disabilities. Late-onset Pompe disease (LOPD) presents at any age with slower progression than infantile-onset disease. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has improved outcomes, but some patients decline during long-term treatment, particularly in respiratory function. Avalglucosidase alfa is a next-generation recombinant human GAA with approximately 15-fold higher mannose-6-phosphate (M6P) content than alglucosidase alfa, designed for enhanced cellular uptake. The phase 3 COMET trial previously demonstrated clinically meaningful improvements in respiratory function and functional endurance with avalglucosidase alfa vs alglucosidase alfa over 49 weeks in treatment-naive LOPD patients.
**Methods:** This was the open-label extension of the COMET trial. After the 49-week double-blind period, all participants received intravenous avalglucosidase alfa 20 mg/kg every other week. At data cutoff (February 10, 2021), patients had received ≥97 weeks of treatment. Efficacy outcomes were reported through week 97; patients initially randomized to avalglucosidase alfa had 97 weeks of treatment, while those switching from alglucosidase alfa had 48 weeks of avalglucosidase alfa. Efficacy assessments included upright FVC percent predicted, MIP percent predicted, MEP percent predicted, 6MWT distance, HHD, QMFT, GSGC, biomarkers (urinary hexose tetrasaccharide, creatine kinase), quality of life (SF-12, EQ-5D-5L), and patient-reported outcomes (R-PAct, PGIC, PDSS, PDIS). Safety monitoring included AEs, IARs, and immunogenicity (ADA and neutralizing antibodies). Statistical analysis used mixed models for repeated measures with LS means and SEs.
**Key Results:** Of 100 randomized participants, 95 completed the double-blind period and entered the extension; 86 (91%) continued through week 97 (46 continued avalglucosidase alfa, 40 switched). Mean age was 48.3 years (range 10-79); 54% were men. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) points for those continuing avalglucosidase alfa and by 0.36 (1.12) points for those switching. From week 49 to week 97, patients continuing avalglucosidase alfa sustained improvements in FVC, MIP, and MEP. For 6MWT distance, LS mean (SE) change from baseline to week 97 was +18.60 (12.01) m for continuing patients and +4.56 (12.44) m for switchers. Patients who switched showed continued improvement of +5.33 (10.81) m from week 49 to week 97. Biomarkers (urinary hexose tetrasaccharide, creatine kinase) improved to near-normal range by week 97. Quality of life (SF-12 PCS and MCS) improvements were maintained. Safety: AEs potentially related to treatment occurred in 56.9% of continuing patients and 56.8% of switchers. Protocol-defined IARs occurred in 39.2% of continuing patients vs 47.7% of switchers. Serious AEs occurred in 33.3% (continuing) and 22.7% (switchers); 7.8% and 4.5% were considered potentially treatment-related. Five patients discontinued due to AEs during extension. One death (pancreatic adenocarcinoma) was considered unrelated to treatment. Most common AEs were headache (32%), nasopharyngitis (31%), arthralgia (29%), back pain (28%), diarrhea (24%), and nausea (23%). ADA titers decreased or patients tolerized during extension.
**Clinical Implications:** This extension study demonstrates that avalglucosidase alfa maintains respiratory function, motor function, muscle strength, and quality of life over 97 weeks in LOPD patients, with a favorable safety profile. Patients switching from alglucosidase alfa achieved disease stabilization without increased safety or immunogenicity concerns. The small declines in functional endurance measures observed during weeks 73-97 may reflect age-related sarcopenia, COVID-19 pandemic effects on physical activity and treatment compliance (19 of 25 patients missing ≥2 consecutive infusions due to COVID-19), or both. These findings support early treatment with avalglucosidase alfa and the feasibility of safely switching patients from alglucosidase alfa. Limitations include the lack of a concurrent comparator group during the extension period and the potential confounding effects of the COVID-19 pandemic on functional assessments and treatment adherence.