Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start

David W Stockton,Karien Verhulst,Juan Llerena,Roberto Araujo,Ans Van Der Ploeg,Priya Kishnani,Sonia S Maruti,Matthias Boentert,Barry J Byrne,Kenneth I Berger,Mark Roberts,Nathan Thibault

doi:10.1007/s00415-020-09936-8

Abstract

ObjectiveTo examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation.MethodsLongitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models.ResultsAmong 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years.ConclusionFVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

Highlights

Pompe disease is a rare, autosomal recessive, progressive neuromuscular disorder caused by deficient lysosomal acid α-glucosidase (GAA), an enzyme that breaks down glycogen
The data indicate that respiratory function, assessed by upright forced vital capacity (FVC) % predicted, remained stable over the 5-year follow-up for Registry patients with late-onset Pompe disease (LOPD). These results extend the findings of previous studies, including the Dutch study of 102 adult LOPD patients [9], the Late-Onset Treatment Study (LOTS) [8], and the LOTS extension study [7] by studying a large global patient cohort over a long follow-up duration
Respiratory function remains stable in LOPD patients treated with alglucosidase alfa for up to 5 years

Summary

Introduction

Pompe disease is a rare, autosomal recessive, progressive neuromuscular disorder caused by deficient lysosomal acid α-glucosidase (GAA), an enzyme that breaks down glycogen. Resulting abnormal accumulation of lysosomal glycogen leads to cellular dysfunction; progressive respiratory, cardiac, skeletal, and smooth muscle damage; and functional disabilities. Enzyme replacement therapy (ERT) with alglucosidase alfa has been approved for the treatment of Pompe disease since 2006 [5, 6]. Alglucosidase alfa has been shown to improve and stabilize skeletal and respiratory muscle function within the first 2 years of treatment [1, 7, 8]. A more recent study reported that after 5 years of alglucosidase alfa treatment, muscle strength, respiratory muscle function, walking distance, and daily life activities showed improvement and often stability compared to baseline values and the expected natural course of the disease [9]

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