Alglucosidase alfa demonstrates effectiveness and safety in Chinese patients with late-onset Pompe disease: A multi-center prospective study.

ObjectiveTo examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation.MethodsLongitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models.ResultsAmong 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years.ConclusionFVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

Background: Late-Onset Pompe disease (LOPD) is an inherited condition caused by glucogen accumulation due to deficiency of acid alfa- glucosidase and consequent muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT) with alglucosidase alfa has been considered useful to treat LOPD in clinical trials, case series and real-life studies. Recently, a new ERT with avalglucosidase has been demonstrated as non-inferior to alglucosidase, with the promise of better outcomes in the clearance of glycogen in the muscle. Objective: To describe the real-life experience in the switch from alglucosidase to avalglucosidase in LOPD patients treated with ERT. Methods: We retrospectively reviewed all medical records from LOPD patients followed in a tertiary neuromuscular center from Jan 2019 to May 2024. Patients who changed the ERT therapy were analyzed according to timed tests, forced vital capacity (FVC) before and after the ERT switch. Results: Fourteen LOPD patients with regular treatment with ERT were identified from the neuromuscular clinic records. Two of them switched from alglucosidase to avalglucosidase. One male patient, diagnosed at 41 years of age presented progressive worsening of respiratory symptoms and FVC, needing continuous non-invasive ventilation, despite alglucosidase treatment for four consecutive years. After two years of changing the treatment to avalglucosidase his FVC increased from 64% to 75% and 10m walk test improved from 25 seconds to 15 seconds. The other male patient, diagnosed at 46 years of age were using doble dosis of alglucosidase (20mg/kg weakly) over a period of two years, with stable respiratory and motor condition. After six months of switch to avalglucosidase, his FVC improved from 52% to 55% and his 6-minute walk-test increased from 390m to 460m. Conclusion: Two out 14 LOPD patients in our center switched ERT from alglucosidase to avalglucosidase, and this Brazilian single-center experience shows a trend of better motor e respiratory outcomes with the new generation ERT, like other real-life reported studies. Further studies are still needed to demonstrated the superiority of avalglucosidase over alglucosidade in treating Pompe disease.

Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial

One trial compared the effect of ERT to placebo in LOPD, showing that alglucosidase alfa probably improves 6MWT and respiratory function (both moderate-certainty evidence). Avalglucosidase alfa probably improves 6MWT compared with alglucosidase alfa (moderate-certainty evidence). Cipaglucosidase plus miglustat probably improves FVC compared to alglucosidase alfa plus placebo (moderate-certainty evidence). Other trials studied the adjunct effect of clenbuterol and albuterol along with alglucosidase alfa, with little to no evidence of benefit. No significant rise in adverse events was noted with all ERTs. The impact of ERT on some outcomes remains unclear, and longer RCTs are needed to generate relevant information due to the progressive nature of LOPD. Alternative resources, such as post-marketing registries, could capture some of this information.

Glycogen storage disease type 2, Pompe disease, is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of the enzyme acid alpha-glucosidase. Although only a few patients have been treated with recombinant human alpha-glucosidase from rabbit milk since 2004, enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease since 2006. Here, a systematic review [1] evaluates the clinical efficacy and safety of alglucosidase alfa treatment in juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment in patients with LOPD, published up to October 2012, were identified using an electronic search of the EMBASE and MEDLINE databases, and manual searches of the reference lists. Data on ERT outcomes were extracted from the selected papers and analyzed descriptively. No statistical analyses were performed owing to data heterogeneity. Twenty-two studies containing clinical data from 437 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or exhibited improvements in creatine kinase levels, and muscular and/or respiratory function following treatment with alglucosidase alfa. Enzyme replacement therapy was well tolerated; the majority of adverse events were mild or moderate infusion-related reactions. Alglucosidase alfa treatment offers an effective and well tolerated treatment that attenuates the progression of LOPD in the majority of patients. Although first insights are upcoming, further research is required to investigate reliable prognostic factors such as age at treatment start, phenotypic presentation, and genotypic characteristics, of which may enable better clinical and therapeutic management of LOPD patients.

The impact of antibodies in late-onset Pompe disease: A case series and literature review

Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial

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

Late-onset Pompe disease is a rare inherited genetic condition that causes progressive muscle dysfunction and damage. As the disease advances, the progressive weakening of respiratory muscles significantly increases the risk of respiratory failure, which is a major contributor to premature mortality. Enzyme replacement therapy is the primary treatment for Pompe disease. To investigate the clinical impact of enzyme replacement therapies for the treatment and management of late-onset Pompe disease and establish the relative effectiveness of enzyme replacement therapy compared to best supportive care (in the absence of enzyme replacement therapy). A systematic review and network meta-analysis of published evidence on the clinical effectiveness of enzyme replacement therapy and best supportive care was undertaken. Comprehensive bibliographic database searches were conducted up to May 2024 to identify randomised controlled trials or any other prospective enzyme replacement therapy studies in patients with Pompe disease. Network meta-analyses of randomised controlled trials were undertaken to estimate indirect treatment effects for forced vital capacity % predicted and the 6-minute walk test. Other studies were summarised using narrative synthesis. The review included 60 studies: 38 on enzyme replacement therapy and 22 on best supportive care. Enzyme replacement therapy studies comprised 3 randomised controlled trials, 3 randomised controlled trial extensions, 7 registry studies and 25 single-group prospective studies. Two randomised controlled trials had a high risk of bias. Best supportive care studies included 14 longitudinal and 8 cross-sectional studies. In the network meta-analyses, after approximately 1 year, enzyme replacement therapy-naive patients showed significant 6-minute walk test improvements versus placebo: ~25 m with alglucosidase alfa and ~54 m with avalglucosidase alfa. No significant differences were found for forced vital capacity % predicted or comparisons with cipaglucosidase alfa, although very few enzyme replacement therapy-naive patients taking cipaglucosidase alfa were available for inclusion in the analyses. Intra-enzyme replacement therapy comparisons showed a significant 6-minute walk test advantage for avalglucosidase alfa. However, a sensitivity analysis adjusting for skewed data revealed no significant differences. Long-term enzyme replacement therapy effectiveness was assessed in single-group studies, showing initial gains maintained for 1-3 years, followed by gradual 10- to 15-year declines in 6-minute walk test and forced vital capacity % predicted. However, small sample sizes and missing data introduce uncertainty. Long-term evidence on best supportive care is limited, with most of the evidence focused on characterising basic demographic information and support needs. A small number of studies reported declines in forced vital capacity % predicted. Formal comparisons with long-term enzyme replacement therapy studies were not possible, but declines appear to be similarly gradual. The network meta-analyses shows enzyme replacement therapy modestly improves 6-minute walk test and forced vital capacity % predicted after 1 year versus placebo in enzyme replacement therapy-naive patients. However, there is limited evidence to suggest meaningful differences in outcomes between alglucosidase alfa, avalglucosidase alfa and cipaglucosidase alfa with miglustat. Observational data suggest declines beyond 2-3 years, lasting up to 15 years. Long-term comparative effectiveness remains uncertain, as does enzyme replacement therapy's impact on disease progression and supportive care needs. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme as award number NIHR161219.

Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

Glycogen storage disease type 2/Pompe disease is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of acid alpha-glucosidase. Since 2004 only a limited number of patients have been treated with recombinant human alpha-glucosidase from rabbit milk whereas since 2006 enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease. This systematic review evaluates the clinical efficacy and safety of alglucosidase alfa treatment of juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment of LOPD patients-published up to January 2012-were identified by electronic searching of the EMBASE and MEDLINE databases, and manual searching of the reference lists. Data on ERT outcomes were extracted from selected papers and analyzed descriptively. No statistical analysis was performed owing to data heterogeneity. Twenty-one studies containing clinical data from 368 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or had improved creatine kinase levels and muscular and/or respiratory function following treatment with alglucosidase alfa. ERT was well tolerated; most adverse events were mild or moderate infusion-related reactions. In conclusion, alglucosidase alfa treatment is effective and well tolerated and attenuates progression of LOPD in most patients. Further research is required to investigate factors such as age at diagnosis, phenotypic presentation, and genotypic characteristics, identification of which may enable better clinical and therapeutic management of LOPD patients.

eP157: Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease: PROPEL study

In patients with late-onset Pompe disease (LOPD), the efficacy of the enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) is difficult to evaluate, due to the clinical heterogeneity and the small sample sizes in published studies. Therefore, we conduct a systematic literature review and meta-analysis of the literature to evaluate the efficacy of ERT in LOPD patients considering the walking distance, respiratory function and muscle strength. Particularly, six-minute walk test (6MWT), forced vital capacity (FVC), medical research council (MRC) grading, quantitative muscle testing (QMT), and quick motor function test (QMFT) were outcomes of interest. Overall, 619 studies were identified in PubMed, EMBASE and by manual search on July 18th, 2020. After an initial assessment, 16 studies were included in the meta-analysis, containing clinical data from 589 patients with LOPD. For the 6MWT, 419 patients were analyzed. Walking distance improved on average, 32.2 m greater during the observed period (p = 0.0003), compared to the distance at the baseline. The meta-analysis did not show any improvement in FVC and only a tendency towards better muscle strength after treatment with ERT, but the difference was not statistically significant. In conclusion, the available data showed that ERT has a significant beneficial efficacy in the improvement of walking distance in LOPD patients and a non-significant improvement of muscle strength. No improvement in respiratory capacity was found. More prospective and controlled trials are needed to demonstrate a clear clinical benefit of ERT.

Late-onset Pompe disease (LOPD) is the first genetic neuromuscular disease treated with enzyme replacement therapy (ERT) in 2006, with variable results over time. This study aimed to assess therapeutic efficacy and safety in a large national cohort of patients after 10 and 15years of treatment with alglucosidase alfa, all of them regularly evaluated in expert Centers. This retrospective study analyzed data from 15 Italian Centers, examining clinical-genetic features and motor and respiratory outcomes at baseline, 10years (T10, n = 85), and 15years (T15, n = 42) after ERT initiation. Patients were categorized by baseline 6-min walk test (6MWT: 1: < 150m, 2: 150-299m, 3: 300-449m, 4: ≥ 450m) or forced vital capacity (FVC: 0: < 80%, 1: ≥ 80%) to assess outcome differences based on initial functional status. All patients were ambulant at baseline. Motor performance, assessed by 6MWT, declined across all functional groups, but even the lowest-performing patients at baseline (Groups 1-2) were mostly ambulant by T15 (50% and 71% respectively). In the best performing patients at baseline (Group 4), subjects maintained quite high performance values also at T15, with a statistically significant decrement observed at T10, and a stabilization at T15; none of them lost ambulation at T15. Despite an overall FVC% reduction, 21/42 patients (50%) remained ventilator-free at T15. No ERT discontinuations or significant adverse events were reported. Alglucosidase alfa therapy showed variable results in a long-term perspective, confirming a reduction in mortality in all functional groups, and stabilization in several patients, without relevant safety concerns. Motor and respiratory function responses varied by functional groups and in single patients, underscoring the need for additional outcome measures. These long-term results will be useful for comparing the possible prolonged efficacy of the new therapies for Pompe disease.

Introduction: Pompe disease (PD) is a rare glycogen storage disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase, which affects approximately one every 40’000 people. Late onset Pompe disease (LOPD) is a particular and heterogeneous clinical form of Pompe disease whose symptoms appear after the first year of life. LOPD is characterized by progressive skeletal myopathy, followed by respiratory muscle weakness. Without treatment, LOPD leads typically to an early death. Since 2006, PD can be treated with enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA). However, the long-term effect of ERT in patients with LOPD remains so far not completely understood. The objective of this study is to provide a systematic review on the effectiveness of ERT in patients with LOPD concerning respiratory function, motor performance, and muscle strength. Methods: On July 18th, 2020 614 studies were systematically identified in the electronic databases PubMed and EMBASE. Outcomes of interest were: respiratory function, as assessed by the forced vital capacity (FVC); motor performance, as measured by the 6-min walk test (6MWT); and muscle strength, as tested with the medical research council grading (MRC), quantitative muscles testing (QMT) or quick motor function test (QMFT). Results: Overall, 16 studies containing clinical data from 589 patients with LOPD were included in the systematic review. Studies included were published between 2010 and 2020. Our findings show that in patients with LOPD treated with ERT, compared to their baseline values before initiation of the treatment, the walking distance improved in 13 of 14 studies (92.85%) as assessed by the 6MWT, the muscle strength improved in 7 of 10 studies (70%), and the FVC improved in 8 of 16 studies (50%). Conclusions: Our systematic review shows that most of the studies in patients with LOPD had a beneficial effect on improving motor performance and muscle strength after initiation of the ERT. However, only half of the studies included showed an improvement of the respiratory function. New meta-analyses are needed to correlate the findings of the studies considering the different observation times.