Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study

Ploeg, Ans van der; Carlier, Pierre; Carlier, Robert; Kissel, John T.; Schöser, Benedikt; Wenninger, Stephan; Pestronk, Alan; Barohn, Richard J.; Dimachkie, Mazen M.; Göker-Alpan, Özlem; Mozaffar, Tahseen; Peña, Loren; Simmons, Zachary; Straub, Volker; Guglieri, Michela; Young, Peter; Boentert, Matthias; Baudin, Pierre Yves; Wens, S.C.A.; Shafi, Raheel; Bjartmar, Carl; Thurberg, Beth L.

doi:10.1016/j.ymgme.2016.05.013

Cited by 53 publications

(54 citation statements)

References 38 publications

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“…These data confirm that early starting ERT allows the best outcomes. A recent study on 16 patients (EMBASSY study) demonstrated a significant reduction in lysosomal glycogen after 6 months of ERT, confirming the stabilization of the disease in ERT-naïve LOPD patients [13]. Formation of anti-rhGAA antibodies is a well known side effect of ERT.…”

Section: Discussionmentioning

confidence: 74%

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

Menzella¹,

Codeluppi

Lusuardi³

et al. 2018

Multidiscip Respir Med

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BackgroundAcute respiratory failure can be triggered by several causes, either of pulmonary or extra-pulmonary origin. Pompe disease, or type II glycogen storage disease, is a serious and often fatal disorder, due to a pathological accumulation of glycogen caused by a defective activiy of acid α-glucosidase (acid maltase), a lysosomal enzyme involved in glycogen degradation. The prevalence of the disease is estimated between 1 in 40,000 to 1 in 300,000 subjects.Case presentationThis case report describes a difficult diagnosis of late-onset Pompe disease (LOPD) in a 52 year old Caucasian woman with acute respiratory failure requiring orotracheal intubation and subsequent tracheostomy for long-term mechanical ventilation 24 h/day. Despite a complex diagnostic process including several blood tests, bronchoscopy with BAL, chest CT, brain NMR, electromyographies, only a muscle biopsy allowed to reach the correct diagnosis.DiscussionThe most frequent presentation of myopathies, including LOPD, is proximal limb muscle weakness. Respiratory related symptoms (dyspnea on effort, reduced physical capacity, recurrent infections, etc.) and respiratory failure are often evident in the later stages of the diseases, but they have been rarely described as the onset symptoms in LOPD. In our case, a third stage LOPD, the cooperation between pulmonologists and neurologists was crucial in reaching a correct diagnosis despite a very complex clinical scenario due to different confounding co-morbidities as potential causes of respiratory failure and an atypical presentation. In this patient, enzyme replacement therapy with infusion of alglucosidase alfa was associated with progressive reduction of ventilatory support to night hours, and recovery of autonomous walking.

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Section: Discussionmentioning

confidence: 74%

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

Menzella¹,

Codeluppi

Lusuardi³

et al. 2018

Multidiscip Respir Med

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“…4 Indeed, the only previous study to demonstrate the clearance of accumulated glycogen in the skeletal muscle of LOPD had enrolled patients naive to ERT. 25 A recent short-term study with a pharmacologic chaperone plus ERT increased GAA activity in muscle without lowering glycogen content in patients with LOPD, demonstrating the need for a sustained effect to achieve biochemical correction. 26 Therefore, this is the first study to demonstrate improved biochemical correction of skeletal muscle in patients with LOPD who were previously treated with ERT.…”

Section: Discussionmentioning

confidence: 97%

Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease

et al. 2018

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This 52-week, phase I/II double-blind, randomized, placebo-controlled study investigated the novel use of clenbuterol in late-onset Pompe disease (LOPD) stably treated with ERT. Eleven of thirteen participants completed the study. No serious adverse events were related to clenbuterol, and transient minor adverse events included mild elevations of creatine kinase, muscle spasms, and tremors. At week 52, the 6-min walk test distance increased by a mean of 16 m (p = 0.08), or a mean of 3% of predicted performance (p = 0.03), and the maximum inspiratory pressure increased 8% (p = 0.003) for the clenbuterol group. The quick motor function test score improved by a mean of seven points (p = 0.007); and the gait, stairs, gower, chair test improved by a mean of two points (p = 0.004). Clenbuterol decreased glycogen content in the vastus lateralis by 50% at week 52. Transcriptome analysis revealed more normal muscle gene expression for 38 of 44 genes related to Pompe disease following clenbuterol. The placebo group demonstrated no significant changes over the course of the study. This study provides initial evidence for safety and efficacy of adjunctive clenbuterol in patients with LOPD (NCT01942590).

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“…In addition, glycogen content is generally low in adults with Pompe disease and there is limited longitudinal information regarding glycogen clearance from muscle with enzyme replacement therapy. In the Exploratory Muscle Biopsy Assessment Study (EMBASSY) of alglucosidase alfa in LOPD [21] , quadriceps biopsy glycogen was found both in lysosomes and cytoplasm at baseline (mean 5.3%; range 1.0-14.2%); after 24 weeks' therapy, lysosomal glycogen decreased in 10 patients and increased in 3 patients. Statistically significant changes were noted in 6 patients (4 had decreased glycogen and 2 increased glycogen), while cytoplasmic glycogen remained, and the total area of glycogen showed small reductions from baseline.…”

Section: Discussionmentioning

confidence: 99%

“…Response to GAA replacement is determined by the severity of damage at treatment initiation and extent of lysosomal glycogen accumulation [15,20,21] , and by the magnitude of muscle GAA uptake achieved on therapy [22,23] . Alglucosidase alfa is approved worldwide [24,25] for Pompe disease treatment.…”

Section: Introductionmentioning

confidence: 99%

Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study

Peña

Barohn

Byrne

et al. 2019

Neuromuscular Disorders

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This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.

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Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study

Cited by 53 publications

References 38 publications

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease

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