Defining the therapeutic corridor of stability in enzyme replacement therapy for Pompe disease: a position statement.

Abstract

Background: Pompe disease, also known as glycogen storage disease type II, is a rare, progressive lysosomal storage disorder caused by pathogenic variants in the GAA gene. Enzyme replacement therapy has transformed the natural history of the disease; however, with three agents now approved - alglucosidase alfa, avalglucosidase alfa, and cipaglucosidase alfa plus miglustat - clinicians lack a consensus quantitative framework for determining when a patient has left the zone of therapeutic stability and requires treatment reassessment, escalation, or switching.

Methods: A structured synthesis was conducted of Phase 2 and Phase 3 randomized controlled trials, open-label extension studies, registry analyses, real-world observational datasets, switching studies, scoping review evidence on global diagnostic and epidemiological variation, and consensus recommendations evaluating approved enzyme replacement therapies for Pompe disease, with an emphasis on late-onset Pompe disease. Outcome domains evaluated included forced vital capacity percentage predicted, six-minute walk test distance, urinary hexose tetrasaccharide, serum creatine kinase, maximal inspiratory and expiratory pressures, anti-drug antibody titers, functional motor scales, and patient-reported outcomes.

Results: Across LOTS, COMET and its 97- and 145-week extensions, PROPEL and ATB200-07, ATB200-02, the STIG real-world cohort, the International Pompe Registry, European Pompe Consortium start-switch-stop criteria, post hoc PROPEL switching analyses, real-world alglucosidase-to-avalglucosidase switching data, and the first multicenter real-world analysis of switching to next-generation enzyme replacement therapies, a coherent therapeutic corridor of stability emerges. Forced vital capacity change within approximately - 1% to + 5% per year defines the respiratory stability corridor; a confirmed decline exceeding 5% over 12 months constitutes an alarm threshold. For the six-minute walk test, stabilization within approximately ± 25 m of the peak is an adequate response, whereas a confirmed decline of more than 25 m from the peak is actionable. Biomarker improvement or normalization of urinary hexose tetrasaccharide and creatine kinase is achievable with next-generation enzyme replacement therapies and serves as an early surrogate of enhanced lysosomal glycogen clearance. Multicenter real-world switching data indicate that transitions between enzyme replacement therapy preparations are generally feasible and associated with clinical stability in late-onset Pompe disease.

Conclusions: This formal, multi-domain therapeutic corridor of stability for enzyme replacement therapy in Pompe disease is grounded in available Phase 2, Phase 3, extension, registry, consensus, and real-world evidence. The framework supports structured monitoring, timely reassessment of treatment, and personalized management for patients receiving long-term enzyme replacement therapy. Prospective validation with standardized monitoring is required.

Clinical trial number: Not applicable.