Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial

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Abstract

Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy. We report on the results of a phase II clinical trial including two patients with classical infantile Pompe disease receiving enzyme replacement therapy over a period of 48 weeks by weekly infusions. Recombinant acid alpha-glucosidase was derived from the milk of transgenic rabbits. Safety was evaluated by recording adverse events while clinical efficacy was evaluated by ventilator-free survival, left ventricular mass index, motor development as well as histologic and biochemical analysis of muscle biopsies. This therapy was in general well-tolerated. There was an overall improvement in left ventricular mass, cardiac function, skeletal muscle function and histological appearance of skeletal muscle.

Introduction

Pompe disease (Glycogen storage disease II/GSD II) is an autosomal recessive muscle wasting disorder with an incidence of approximately 1:40,000 [1], [2], [3]. It is caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leading to lysosomal glycogen accumulation in different tissues, most severely affecting skeletal and mainly in the infantile form also cardiac muscle. Besides mechanical impairment of muscle fibres, lysosomal accumulation of glycogen leads to rupture of the lysosomes causing secondary damage to the cell [4], [5].

Classical infantile Pompe disease is characterised by progressive, hypertrophic cardiomyopathy, muscular weakness, respiratory insufficiency and death normally within the first year of life [3]. Depending on residual GAA activity, an infantile, a juvenile, and an adult form can be distinguished [6].

In the latter forms, cardiac muscle is usually not affected whereas respiratory impairment and limb girdle muscular weakness are the main clinical features. At present there is no causal therapy available for patients with Pompe disease.

In the development of enzyme replacement therapy, recombinant precursor human acid alpha-glucosidase (rhGAA) was produced in CHO cell cultures [7], [8] and from milk of transgenic rabbits [9], [10]. First data on safety and efficacy of enzyme replacement therapy in classical infantile Pompe disease administering CHO cell derived and a transgenically derived enzyme have been published with encouraging results [11], [12], [13]. In this article we report on data from a phase II clinical trial evaluating safety and efficacy of rhGAA. RhGAA was derived from the milk of transgenic rabbits and administered in weekly infusions with a dosage of 40 mg/kg over a period of 48 weeks.

Section snippets

Materials and methods

This study was designed as a phase II, open-label, single-center, single-dose study. RhGAA was infused once weekly inravenously with 40 mg/kg in two patients. The study was approved by the institutional Ethics Committee, and written informed consent was obtained from the parents prior to any study-related procedure.

Safety

In a total of 96 infusions, eight mild infusion-associated reactions were observed. Patient 1 showed infusion-associated reactions in week 6, 9, and 10 with facial erythema and vomiting. Patient 2 showed a rise in temperature in week 1, 5, 7, tachycardia in week 8 and facial erythema in week 9. Vital parameters were within normal limits at all times besides the mentioned tachycardia. Symptoms resolved quickly after interruption of the infusion and the administration of antihistamines and

Discussion

Enzyme replacement therapy with 40 mg/kg rhGAA weekly enabled survival of the two patients with classical infantile Pompe disease.

At time of enrolment, both patients displayed the typical clinical findings of classical infantile Pompe disease with generalized muscular hypotonia, global delay in motor function and severe cardiomyopathy which necessitated anticongestive medication and intermittent application of additional oxygen via nasal canula. During the course of therapy patient 1 achieved

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