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

Lancet Child Adolesc Health. 2022 Jan;6(1):28-37. doi: 10.1016/S2352-4642(21)00308-4

PMID: 34822769

Imke Anne Maartje Ditters, Hidde Harmen Huidekoper, Michelle Elisabeth Kruijshaar

Highlights: Patients with classic infantile Pompe disease treated with the high enzyme replacement therapy (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.

Abstract

Background: Patients with classic infantile Pompe disease, who die before the age of one year without treatment, have been found to benefit from enzyme replacement therapy (ERT) with alglucosidase alfa. Alternative dosing regimens have been developed as a result of varying responses to the conventional recommended dosage. We wanted to see how real-world ERT regimens affected these patients' survival and walking capacity.

Methods: In this observational cohort analysis, we used data from patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands who were diagnosed between October 26, 1998, and March 8, 2019, as part of a collaborative study within the European Pompe Consortium. Patients with hypertrophic cardiomyopathy and classic infantile Pompe disease with onset and verified diagnosis before the age of 12 months were eligible. A confirmed deficiency of -glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both, was defined as a proven diagnosis of classic infantile Pompe disease. Demographics, GAA variants, ERT dosage, death age, and walking ability were all collected. We used Cox regression, Kaplan-Meier curves, and log-rank tests to examine the effects of ERT dosage on survival and walking ability.

Findings: We studied 124 patients with classic infantile Pompe disease, 116 of whom were treated with ERT (median age at therapy initiation: 33 months [IQR 1,8-5,0, range 0,03-11,8)). 36 (31%) of 116 patients died during follow-up (mean duration 60,1 months [SD 57,3]; n=115). There were 39 different ERT dosage regimens used. At the last follow-up 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. The high dosage group had a considerably better survival rate than the regular dosage group (hazard ratio [HR] 0,17 [95% CI 0,04-0,76], p=002). There was no statistically significant difference in survival between the intermediate and standard dosage groups (HR 0,44 [0,13-1,51], p=019). 44 (51%) of the 86 patients who reached the age of 18 months learnt 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 learned to walk, however there were no statistically significant differences between groups.

Interpretation: When compared to patients with classic infantile Pompe disease who received the standard recommended ERT dosage of 20 mg/kg every other week, individuals with classic infantile Pompe disease who received the high ERT dosage of 40 mg/kg per week had significantly improved survival. Based on these findings, we recommend that the currently approved dosage be considered.

Keywords: Pompe, classic infantile Pompe disease, enzyme replacement therapy, ERT, alglucosidase alfa