Effect of alglucosidase alfa dosage on survival and walking ability in patients with classic infantile Pompe disease: a multicentre observational cohort study from the European Pompe Consortium.

BACKGROUND

Enzyme replacement therapy (ERT) with alglucosidase alfa has been found to improve outcomes in patients with classic infantile Pompe disease, who without treatment typically die before the age of 1 year. Variable responses to the standard recommended dosage have led to alternative dosing strategies. We aimed to assess the effect of real-world ERT regimens on survival and walking ability in these patients.

METHODS

In this observational cohort study, we obtained data collected as part of a collaborative study within the European Pompe Consortium on patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands diagnosed between Oct 26, 1998 and March 8, 2019. Eligible patients had classic infantile Pompe disease with a disease onset and proven diagnosis before age 12 months, and a hypertrophic cardiomyopathy. A proven diagnosis of classic infantile Pompe disease was defined as a confirmed deficiency of α-glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both. We collected data on demographics, GAA variants, ERT dosage, age at death, and walking ability. We analysed the effects of ERT dosage on survival and walking ability using Cox regression, Kaplan-Meier curves, and log-rank tests.

FINDINGS

We included 124 patients with classic infantile Pompe disease, of whom 116 were treated with ERT (median age at start of treatment 3·3 months [IQR 1·8-5·0, range 0·03-11·8]). During follow-up (mean duration 60·1 months [SD 57·3]; n=115), 36 (31%) of 116 patients died. 39 different ERT dosing regimens were applied. Among the 64 patients who remained on the same dosage, 16 (52%) of 31 patients on the standard dosage (20 mg/kg every other week), 12 (80%) of 15 patients on an intermediate dosage (20 mg/kg per week or 40 mg/kg every other week), and 16 (89%) of 18 patients on the high dosage (40 mg/kg per week) were alive at last follow-up. Survival was significantly improved in the high dosage group compared with the standard dosage group (hazard ratio [HR] 0·17 [95% CI 0·04-0·76], p=0·02). No significant difference in survival was identified between the intermediate dosage group and the standard dosage group (HR 0·44 [0·13-1·51], p=0·19). Of the 86 patients who reached 18 months of age, 44 (51%) learned to walk. Ten (53%) of 19 patients on the standard dosage regimen, six (67%) of nine patients on intermediate dosage regimens, and 14 (93%) of 15 patients on high dosage regimens learnt to walk, but the differences between groups were not statistically significant.

INTERPRETATION

Patients with classic infantile Pompe disease treated with the high ERT dosage of 40 mg/kg per week had significantly improved survival when compared with patients treated with the standard recommended ERT dosage of 20 mg/kg every other week. Based on these results, we suggest that the currently registered dosage should be reconsidered.

FUNDING

Prinses Beatrix Spierfonds and Wishdom Foundation.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests HHH reports advisory board fees, speaker fees, and a clinical trial agreement from BioMarin International to his institution, outside the submitted work. FL reports travel expenses from Sanofi-Genzyme. MT reports personal fees from Sanofi Genzyme, outside the submitted work; and travel expenses from Sanofi-Genzyme. RP reports personal fees from Sanofi-Genzyme and personal fees from BioMarin, outside the submitted work. NAMEvdB received funding for research, clinical trials, and advisory fees from Sanofi-Genzyme and Amicus Therapeutics under agreements between these companies and Erasmus MC University Medical Center. ATvdP received funding for research, clinical trials, and advisory fees from Sanofi-Genzyme, Amicus Therapeutics, Biomarin, Ultragenix, Sarepta, Audentes, and Spark Therapeutics working on enzyme replacement therapy or next-generation therapies in the field of Pompe disease, other lysosomal storage diseases or neuromuscular disorders, under agreements with Erasmus MC University Medical Center and the relevant industry. JMPvdH received funding for research, clinical trials, and advisory fees from Sanofi-Genzyme, Amicus Therapeutics, Biomarin, Sarepta, and Chiesi working on enzyme replacement therapy or next-generation therapies in the field of Pompe disease, other lysosomal storage diseases or neuromuscular disorders, under agreements with Erasmus MC University Medical Center and the relevant industry. All other authors declare no competing interests.