Recombinant human acid α-glucosidase

Abstract

Abstract-Background:Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid ␣-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. Methods: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n ϭ 9) or 40 mg/kg (n ϭ 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. Results: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. Conclusions: Recombinant human acid ␣-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid ␣-glucosidase in which patients were older.

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

“…Outcome assessment in comparison to an appropriately matched natural history or historical control population has been used to support regulatory approval of several therapies targeted to ultra‐orphan populations over the past decade including Myozyme for Pompe disease46 and CEPROTIN for patients with severe congenital protein C deficiency 47. These present results indicate such an approach may also be appropriate for DMD, especially as it would spare declining patients from receiving placebo rather than potentially disease‐altering treatment.…”

Hypertrophic Cardiomyopathy in Pompe Disease Is Not Limited to the Classic Infantile-Onset Phenotype

“…ERT prolonged overall survival and ventilator-free survival and reversed cardiomegaly in infantile-onset Pompe disease (Kishnani et al 2007). Motor function was maintained when infants with classic infantile-onset Pompe disease were diagnosed through newborn screening and received very early treatment with ERT (Chien et al 2008;Chien et al 2009).…”

Response to de Vries et al.

“…It is noteworthy that even in cross-reactive immunologic material (CRIM)-negative IPD patients with high-sustained antibody titers, only a subset demonstrated neutralizing antibodies in in-vitro assays. 2,3 Even among those who had neutralizing antibodies, some demonstrated antibodies only to the catalytic domain and not to the uptake domain. However, irrespective of the presence/ type of neutralizing activity, they all experienced poor clinical outcomes.…”

“…We previously reported on the counteracting effect of high sustained antibodies in this particular patient. 3 Herbert and colleagues may have missed the fact that only a few adult patients develop high sustained antibodies, which is in contrast to the situation in classic infantile patients. A recent study by Masat et al 4 on behalf of the French Pompe Registry Study Group also concluded that antibodies are not a major concern in adults with Pompe disease.…”