Real-world outcomes after switching to cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a case series

Abstract Background Late-onset Pompe disease (LOPD) is a lysosomal disorder leading to progressive muscle weakness and respiratory compromise if untreated. Enzyme replacement therapy with alglucosidase alfa has been the standard of care, but long-term efficacy is limited by suboptimal lysosomal targeting. Next-generation therapies, avalglucosidase alfa and cipaglucosidase alfa plus miglustat, are designed to improve enzyme targeting to skeletal muscle. Methods We describe three adults with LOPD who transitioned from alglucosidase and/or avalglucosidase to cipaglucosidase plus miglustat. We summarize longitudinal motor and respiratory outcomes, biomarkers, immunogenicity, and patient-reported outcomes. Results Patient 1, treated with alglucosidase alfa for 12 years, experienced infusion-associated reactions (IARs), persistent antibody titers, declining endurance, and worsening forced vital capacity (FVC) despite above label dosing and premedication. She then received avalglucosidase for 2 years, during which IARs continued and antibody titers remained elevated; biomarkers (CK and uGlc4) improved, but standardized functional and respiratory outcome measures were not available. After switching to cipaglucosidase alfa plus miglustat at age 55, IARs resolved, biomarkers normalized, FVC improved, but functional outcomes were mixed. Patient 2, with longstanding sleep-disordered breathing requiring nocturnal non-invasive ventilation, received alglucosidase alfa for 5 years, and experienced fatigue, reduced endurance, elevated biomarkers, and reduced FVC. Following transition to cipaglucosidase alfa plus miglustat at age 58, she demonstrated improvements in endurance, biomarkers, FVC, fatigue and sustained functional independence over six years. However, objective functional measures began to decline by age 60 despite the patient reporting clinical stability. This decline progressed further after an intercurrent airway event at age 63.5, resulting in more pronounced deterioration on functional assessments. Patient 3 received alglucosidase alfa for 2 years before switching to cipaglucosidase alfa plus miglustat at age 41 and demonstrated improvement in endurance, biomarker normalization, stable FVC, and preserved functional independence over 6 years of follow-up. Conclusions Across three cases, switching to next generation therapy was associated with reduced IARs, improved biomarkers, and stabilization or improvement in respiratory and functional outcomes. Notably, the degree of functional improvement appeared inversely related to baseline disease severity: the patient with the least functional impairment at the time of switching demonstrated the most robust and sustained gains. Take-home message This case series provides real-world examples of adults with LOPD that derived clinical benefit from switching to next generation therapy (cipaglucosidase alfa + miglustat) following long-term treatment with alglucosidase alfa. The transition to a next generation therapy can reduce infusion burden and deliver durable real-world benefits in biomarkers, respiratory function, and patient-reported outcomes, with response shaped by disease stage and comorbid limitations.