Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences

Yin-Hsiu Chien,Wen-Hui Tsai,Chaw-Liang Chang,Pao-Chin Chiu,Yen-Yin Chou,Fuu-Jen Tsai,Siew-Lee Wong,Ni-Chung Lee,Wuh-Liang Hwu

doi:10.1016/j.ymgmr.2020.100591

Abstract

ObjectiveEnzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect. Study designA retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT. ResultsTwenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage (n = 23) or a high dosage exclusively (n = 5). At a median age of 8.3 years (0.8–17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline (p < .001). In patients with classical IOPD diagnosed through newborn screening, those late in ERT initiation (p = .006) or late in high-dosage ERT initiation (p = .044) had a higher risk of motor decline. At the latest assessment, both serum creatine kinase (CK) and urinary glucose tetrasaccharide (uGlc4) levels were lowest in the walkers. During follow up, the biomarker levels, once rose, never returned to normal. ConclusionLow CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients, although CK may be more fluctuated than uGlc4. High-dose ERT instituted immediately at newborn screening seems to give the best outcome, and a dosage increase is necessary upon – or, even better, before – a rise in biomarker levels.

Highlights

Pompe disease (PD), a rare autosomal recessive condition known as glycogen storage disease type II, is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA)
Six infantile-onset PD (IOPD) patients diagnosed after symptoms onset from our hospital were excluded due to no dosage change, and only one of them survived with invasive ventilation at age 12 years
Enzyme replacement therapy (ERT) above the labeled dose has been suggested to improve the outcome of IOPD patients, few studies can prove it because of the high heterogeneity of the patients and treatment conditions

Summary

Introduction

Pompe disease (PD), a rare autosomal recessive condition known as glycogen storage disease type II, is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). IOPD can present cardiomyopathy several months later. Enzyme replacement therapy (ERT) with recombinant human GAA (Myozyme®, alglucosidase alpha) is the only treatment currently available. ERT effectively reverses cardiomyopathy, improves motor development, and improves overall survival [1,2,3]. Both the introduction of ERT at a young age [4] and a low titer of anti-rhGAA antibodies [5] are critical to achieve a good treatment outcome.

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Results

Conclusion