Recombinant human acid α-glucosidase: Major clinical benefits in infantile-onset Pompe disease

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 infusionassociated 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.

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

“…This was largely due to a single patient that had had over 50 % of the total number of IARs. A similar pattern was observed in the pivotal trials (Kishnani et al 2007). The patient with most IARs in our study had recurrent episodes of exanthema, coughing and vomiting, occasionally accompanied by saturation drops.…”

“…It is unquestionable that the introduction of enzyme replacement therapy has significantly improved the life expectancy of patients with classic infantile Pompe disease (Van den Hout et al 2000Kishnanietal2007, 2009Chakrapani et al 2010). Nevertheless, nearly 50 % of the infants treated do not survive ventilator-free (Kishnani et al 2007. In this Even though the enzyme-activity assay is a standardized and validated assay there is always a slight variation in the figures obtained.…”

European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10‐year experience

“…In 2006, enzyme replacement therapy (ERT) with human recombinant acid a-glucosidase (Myozyme Ò ) became available for all patients in Europe and the USA. In infants, treatment generally improves cardiorespiratory function and motor function, and prolongs survival [3][4][5][6]. In older children and adults, ERT improves or stabilizes skeletal muscle strength, muscle function, respiratory function and also survival [7][8][9][10][11][12][13][14][15][16].…”

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease

“…The introduction of enzyme replacement therapy (ERT) changed the natural course of the infantile form because of the notable effect in cardiac muscle; however, the effect in skeletal muscle has been modest at best (Kishnani et al, 2007;Strothotte et al, 2010;Van der Ploeg et al, 2010;Prater et al, 2012). The pathophysiology of muscle damage involves enlargement and rupture of glycogen-filled lysosomes, disturbance of calcium homeostasis and endocytic trafficking, mitochondrial abnormalities, and autophagic defect (Thurberg et al, 2006;Lim et al, 2014Lim et al, , 2015Nascimbeni et al, 2015).…”