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Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

ABSTRACT: PURPOSE:Enzyme replacement therapy (ERT) with recombinant human acid-? glucosidase (rhGAA) at standard dose of 20?mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease. METHODS:We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ?12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated. RESULTS:Eleven patients with IPD (n?=?7) or LOPD (n?=?4) were treated with higher doses of up to 40?mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40?mg/kg weekly compared with lower doses (p?

SUBMITTER: Khan AA

PROVIDER: S-EPMC7469631 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

Khan Aleena A AA Case Laura E LE Herbert Mrudu M DeArmey Stephanie S Jones Harrison H Crisp Kelly K Zimmerman Kanecia K ElMallah Mai K MK Young Sarah P SP Kishnani Priya S PS

Genetics in medicine : official journal of the American College of Medical Genetics 20200106 5

<h4>Purpose</h4>Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease.<h4>Methods</h4>We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long ...[more]

PMID: 31904026

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Project description:BackgroundChronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted.MethodsTo assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation.FindingsAmong 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively.ConclusionThese real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined.Trial registrationThis study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.

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Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

Publications

Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

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