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

Abstract

BackgroundLate-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.ResultsReveglucosidase 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.ConclusionsAdditional 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.Trial registration ISRCTN01435772 and ISRCTN01230801, registered 27 October 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0693-2) contains supplementary material, which is available to authorized users.

Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease

“…Other approaches are in phase of preclinical or clinical development. These include new‐generation recombinant enzymes with improved muscle‐targeting properties (neo‐rhGAA, AT‐GAA) (Zhu et al , 2009; Byrne et al , 2017; Xu et al , 2019), enhancement or stabilization of rhGAA by co‐dosing with a pharmacological chaperone (Porto et al , 2009; Parenti et al , 2014; Kishnani et al , 2017) or with beta‐2 agonist drugs (Koeberl et al , 2020), antisense oligonucleotide technologies (Goina et al , 2017; van der Wal et al , 2017), and gene therapy‐based strategies exploiting different viral vectors and gene expression cassettes (van Til et al , 2010; Wagemaker, 2014; Corti et al , 2017; Puzzo et al , 2017; Byrne et al , 2019; Doyle et al , 2019; Cagin et al , 2020). An approach based on reducing the synthesis of substrate (substrate reduction therapy) was also proposed (Douillard‐Guilloux et al , 2008).…”

“…Other approaches are in phase of preclinical or clinical development. These include new-generation recombinant enzymes with improved muscle-targeting properties (neo-rhGAA, AT-GAA) (Zhu et al, 2009;Byrne et al, 2017;Xu et al, 2019), enhancement or stabilization of rhGAA by co-dosing with a pharmacological chaperone (Porto et al, 2009;Parenti et al, 2014;Kishnani et al, 2017) ). An approach based on reducing the synthesis of substrate (substrate reduction therapy) was also proposed (Douillard-Guilloux et al, 2008).…”

Screening of Chimeric GAA Variants in a Preclinical Study of Pompe Disease Results in Candidate Vector for Hematopoietic Stem Cell Gene Therapy

“…To address limitations of ERT and to enhance delivery to the skeletal muscle, a GILT tag based on the IGF2 sequence that binds with high affinity to the IGF2R was fused to a truncated catalytic domain of GAA (reveglucosidase alfa) and demonstrated to be more effective 4 in clearing glycogen in skeletal muscle in a Gaa -/mice (3). Reveglucosidase alfa infusions in LOPD patients were reasonably well tolerated and initial improvements of respiratory strength and ventilatory function were observed, but with limited effect on walking endurance (8) (ClinicalTrials.gov ID: NCT01230801).…”

Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies

“…Although no clear guidelines exist regarding the management of antibodies in Fabry disease patients treated with agalsidase beta [18], routine antibody testing in patients undergoing ERT [31,32], and close monitoring of patients with elevated antibody titers [33], particularly during the infusion process, are recommended. More recently, the application of immune tolerance induction protocols used in other lysosomal storage diseases for Fabry disease have been suggested as a possible means of preventing ADA formation in ERT-naïve patients and decreasing or saturating existing antibody titers in antibody-positive patients, although the benefit remains to be established [31,34].…”