Authors' objectives: Late-onset Pompe disease is a rare inherited genetic condition that causes progressive muscle dysfunction and damage. As the disease advances, the progressive weakening of respiratory muscles significantly increases the risk of respiratory failure, which is a major contributor to premature mortality. Enzyme replacement therapy is the primary treatment for Pompe disease. To investigate the clinical impact of enzyme replacement therapies for the treatment and management of late-onset Pompe disease and establish the relative effectiveness of enzyme replacement therapy compared to best supportive care (in the absence of enzyme replacement therapy).

Authors' results and conclusions: The review included 60 studies: 38 on enzyme replacement therapy and 22 on best supportive care. Enzyme replacement therapy studies comprised 3 randomised controlled trials, 3 randomised controlled trial extensions, 7 registry studies and 25 single-group prospective studies. Two randomised controlled trials had a high risk of bias. Best supportive care studies included 14 longitudinal and 8 cross-sectional studies. In the network meta-analyses, after approximately 1 year, enzyme replacement therapy-naive patients showed significant 6-minute walk test improvements versus placebo: ~25 m with alglucosidase alfa and ~54 m with avalglucosidase alfa. No significant differences were found for forced vital capacity % predicted or comparisons with cipaglucosidase alfa, although very few enzyme replacement therapy-naive patients taking cipaglucosidase alfa were available for inclusion in the analyses. Intra-enzyme replacement therapy comparisons showed a significant 6-minute walk test advantage for avalglucosidase alfa. However, a sensitivity analysis adjusting for skewed data revealed no significant differences. Long-term enzyme replacement therapy effectiveness was assessed in single-group studies, showing initial gains maintained for 1–3 years, followed by gradual 10- to 15-year declines in 6-minute walk test and forced vital capacity % predicted. However, small sample sizes and missing data introduce uncertainty. Long-term evidence on best supportive care is limited, with most of the evidence focused on characterising basic demographic information and support needs. A small number of studies reported declines in forced vital capacity % predicted. Formal comparisons with long-term enzyme replacement therapy studies were not possible, but declines appear to be similarly gradual. The network meta-analyses shows enzyme replacement therapy modestly improves 6-minute walk test and forced vital capacity % predicted after 1 year versus placebo in enzyme replacement therapy-naive patients. However, there is limited evidence to suggest meaningful differences in outcomes between alglucosidase alfa, avalglucosidase alfa and cipaglucosidase alfa with miglustat. Observational data suggest declines beyond 2–3 years, lasting up to 15 years. Long-term comparative effectiveness remains uncertain, as does enzyme replacement therapy’s impact on disease progression and supportive care needs.

Authors' methods: A systematic review and network meta-analysis of published evidence on the clinical effectiveness of enzyme replacement therapy and best supportive care was undertaken. Comprehensive bibliographic database searches were conducted up to May 2024 to identify randomised controlled trials or any other prospective enzyme replacement therapy studies in patients with Pompe disease. Network meta-analyses of randomised controlled trials were undertaken to estimate indirect treatment effects for forced vital capacity % predicted and the 6-minute walk test. Other studies were summarised using narrative synthesis.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR161219

Year Published: 2026

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/published-articles/GJRH0730

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/GJRH0730

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk