A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

作者：Byrne Barry J^*; Geberhiwot Tarekegn; Barshop Bruce A; Barohn Richard; Hughes Derralynn; Bratkovic Drago; Desnuelle Claude; Laforet Pascal; Mengel Eugen; Roberts Mark; Haroldsen Peter; Reilley Kristin; Jayaram Kala; Yang Ke; Walsh Liron

来源：Orphanet Journal of Rare Diseases, 2017, 12(1): 144.

DOI：10.1186/s13023-017-0693-2

• Reveglucosidase alfa
• Late-onset Pompe disease
• Enzyme replacement therapy
• Pharmacokinetics
• Safety
• Efficacy
• Respiratory
• Pulmonary

Background: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh) GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA.
Results: Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1. 2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks.
Conclusions: Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease.

• 出版日期2017-8-24