Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study

Abstract

Background: Though enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome.

Methods: Eight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated.

Results: All eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3-5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation.

Conclusions: Our data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.

Fig. 1

Left-ventricular mass index (LVMI) z-scores and Alberta infant motor scale scores over time. The different symbols represent different patients. LVMI 20 mg/kg eow (a) and 40 mg/kg/week group (b); The dashed gray line represents the upper limit of normal (+2 z-scores). AIMS 20 mg/kg eow (c) and 40 mg/kg/week group (d). The different symbols represent different patients. Gray solid line: p50; dashed gray line: p90 and p10; dotted gray line: p5

Fig. 2

Antibody titers to alglucosidase alfa and enzyme activity in plasma using doses of either 20 mg/kg or 40 mg/kg. Antibody titers to alglucosidase alfa over time in 20 mg/kg eow (a) and 40 mg/kg/week group (b). Peak antibody titers in relation to age at start of ERT. Patients received either 20 mg/kg eow (squares) or 40 mg/kg/week (asterisks) (c). Enzyme activity (d): blood samples were collected just before the start of infusion (0 h) and at regular time intervals thereafter. A dose of 20 mg/kg (circles) and 40 mg/kg (squares) were given to the same patient (patient 3) at 1 week interval after 5.5 years of therapy (titer 1:6250). Closed symbols represent total acid α-glucosidase activity in the plasma; open symbols represent the amount of activity that was not antibody-bound. The activity in the supernatant was measured with MUGlc and is expressed in nmol 4 MU liberated per 10 μl supernatant per hour. NB: Even though the enzyme-activity assay is a standardized and validated assay there is always a slight variation in the figures obtained. All samples were analyzed as part of one experiment. The total set of analyses were performed three times with comparable results