In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases.

Plastid-made biopharmaceuticals treat major metabolic or genetic disorders, including Alzheimer's, diabetes, hypertension, hemophilia, and retinopathy. Booster vaccines made in chloroplasts prevent global infectious diseases, such as tuberculosis, malaria, cholera, and polio, and biological threats, such as anthrax and plague. Recent advances in this field include commercial-scale production of human therapeutic proteins in FDA-approved cGMP facilities, development of tags to deliver protein drugs to targeted human cells or tissues, methods to deliver precise doses, and long-term stability of protein drugs at ambient temperature, maintaining their efficacy. Codon optimization utilizing valuable information from sequenced chloroplast genomes enhanced expression of eukaryotic human or viral genes in chloroplasts and offered unique insights into translation in chloroplasts. Support from major biopharmaceutical companies, development of hydroponic production systems, and evaluation by regulatory agencies, including the CDC, FDA, and USDA, augur well for advancing this novel concept to the clinic and revolutionizing affordable healthcare.

Response to Comments on "Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice".

We thank Dr. Weimer and her colleagues for their comments related to our recent work (Anding et al., 2023) and are grateful for the opportunity to further discuss the importance of efficient lysosomal targeting of enzyme-replacement therapies (ERT) for the treatment of Pompe disease. Patients with Pompe disease have mutations in the gene that encodes for acid α glucosidase (GAA), a lysosomal enzyme necessary for the breakdown of glycogen. The first-generation ERT, alglucosidase alfa, provides a lifesaving therapy for the severe form of the disease (infantile onset Pompe disease) and improves or stabilizes respiratory and motor function in patients with less severe disease (late onset Pompe disease). Despite these gains, significant unmet need remains, particularly in patients who display respiratory and motor decline following years of treatment. Poor tissue uptake and lysosomal targeting via inefficient binding of the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) in skeletal muscle contributed to this suboptimal treatment response, prompting the development of new ERTs with increased levels of M6P.

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial.

BACKGROUND: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. METHODS: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). RESULTS: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05). CONCLUSIONS: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease.

INTRODUCTION: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. METHOD: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. RESULTS: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DISCUSSION: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Establishing how much improvement in lung function and distance walked is clinically important for adult patients with Pompe disease.

BACKGROUND AND PURPOSE: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVCup) and the 6-min walk test (6MWT) after a year of treatment with enzyme replacement therapy. METHODS: Data were obtained from two prospective follow-up studies. Between-group and within-group MCIDs were estimated using anchor-based methods. Additionally, a distribution-based method was used to generate supportive evidence. As anchors, self-reported change in health and in physical functioning, shortness of breath and a categorization of the Short-Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category. RESULTS: In all, 102 patients had at least one FVCup or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between-group MCID for an improvement in FVCup ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18-46.61 m and 1.97-42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution-based method were within these ranges when applied to change in the outcome values. CONCLUSION: The MCIDs for FVCup and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies.

Real-life effectiveness 1 year after switching to avalglucosidase alfa in late-onset Pompe disease patients worsening on alglucosidase alfa therapy: A French cohort study.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by a progressive myopathy resulting from a deficiency of acid α-glucosidase enzyme activity. Enzyme replacement therapy has been shown to be effective, but long-term treatment results vary. Avalglucosidase alfa demonstrated non-inferiority to alglucosidase alfa in a phase 3 study, allowing in France compassionate access for advanced LOPD patients unresponsive to alglucosidase alfa. METHODS: Data from the French Pompe registry were analyzed for patients who benefited from a switch to avalglucosidase alfa with at least 1 year of follow-up. Respiratory (forced vital capacity [FVC]) and motor functions (Six-Minute Walk Test [6MWT]) were assessed before and 1 year after switching. Individual changes in FVC and 6MWT were expressed as slopes and statistical analyses were performed to compare values. RESULTS: Twenty-nine patients were included (mean age 56 years, 11 years of prior treatment). The FVC and 6MWT values remained stable. The individual analyses showed a stabilization of motor worsening: -1 m/year on the 6MWT after the switch versus -63 m/year the year before the switch (i.e., a worsening of 33%/year before vs. an improvement of 3%/year later). Respiratory data were not statistically different. DISCUSSION: At the group level, gait parameters improved slightly with a stabilization of previous worsening, but respiratory parameters showed limited changes. At the individual level, results were discordant, with some patients with a good motor or respiratory response and some with further worsening. CONCLUSION: Switching to avalglucosidase alfa demonstrated varied responses in advanced LOPD patients with failing alglucosidase alfa therapy, with a general improvement in motor stabilization.

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Long-term outcomes of very early treated infantile-onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme.

BACKGROUND: Starting enzyme replacement therapy (ERT) before severe irreversible muscular damage occurs is important in infantile-onset Pompe disease (IOPD). This long-term follow-up study demonstrates our diagnostic and treatment strategies for IOPD and compares our clinical outcomes with those of other medical centres. METHODS: In this long-term follow-up study, we analysed the outcomes of very early ERT with premedication hydrocortisone in patients with IOPD. Out of 1 228 539 infants screened between 1 January 2010 and 28 February 2021, 33 newborns had confirmed IOPD in Taipei Veterans General Hospital. Twenty-six were regularly treated and monitored at Taipei Veterans General Hospital. Echocardiographic parameters, biomarkers, IgG antibodies against alglucosidase alpha, pulmonary function variables and developmental status were all assessed regularly over an average follow-up duration of 6.18±3.14 years. We compared the long-term treatment outcomes of our patients with those of other research groups. RESULTS: The average age at ERT initiation was 9.75±3.17 days for patients with classic IOPD. The average of the latest antialglucosidase alpha IgG titre was 669.23±1159.23. All enrolled patients had normal heart sizes, motor milestones, cognitive function and pulmonary function that were near-normal to normal. Compared with patients in other studies, our patients had better outcomes in all aspects. CONCLUSION: Very early ERT using our rapid diagnostic and treatment strategy enabled our patients with IOPD to have better outcomes than patients in other medical centres.

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report.

PURPOSE: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3). METHODS: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months. RESULTS: In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3-avalglucosidase alfa [n = 5], and cohort 3-alglucosidase alfa [n = 6]). Median treatment compliance was 100%. None of the individuals discontinued treatment or died. Percentages of individuals with treatment-emergent adverse events were similar across dose and treatment groups. No serious or severe treatment-related treatment-emergent adverse events occurred. Trends for better motor function from baseline to week 25 were observed for 40 mg/kg every other week avalglucosidase alfa compared with either 20 mg/kg every other week avalglucosidase alfa or alglucosidase alfa up to 40 mg/kg weekly. CONCLUSION: These data support the positive clinical effect of avalglucosidase alfa in patients with infantile-onset Pompe disease previously declining on alglucosidase alfa.

Evaluating brain white matter hyperintensity, IQ scores, and plasma neurofilament light chain concentration in early-treated patients with infantile-onset Pompe disease.

PURPOSE: The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors. METHODS: Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores. RESULTS: A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (r2 = 0.8569; P < .001; n = 13). CONCLUSION: Our results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.

Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients.

Pompe disease is a rare lysosomal storage disorder arising from recessive mutations in the acid α-glucosidase gene and resulting in the accumulation of glycogen, particularly in the cardiac and skeletal muscle. The current standard of care is administration of enzyme replacement therapy in the form of alglucosidase alfa or the recently approved avalglucosidase alfa. In order to better understand the underlying cellular processes that are disrupted in Pompe disease, we conducted gene expression analysis on skeletal muscle biopsies obtained from late-onset Pompe disease patients (LOPD) prior to treatment and following six months of enzyme replacement with avalglucosidase alfa. The LOPD patients had a distinct transcriptomic signature as compared to control patient samples, largely characterized by perturbations in pathways involved in lysosomal function and energy metabolism. Although patients were highly heterogeneous, they collectively exhibited a strong trend towards attenuation of the dysregulated genes following just six months of treatment. Notably, the enzyme replacement therapy had a strong stabilizing effect on gene expression, with minimal worsening in genes that were initially dysregulated. Many of the cellular process that were altered in LOPD patients were also affected in the more clinically severe infantile-onset (IOPD) patients. Additionally, both LOPD and IOPD patients demonstrated enrichment across several inflammatory pathways, despite a lack of overt immune cell infiltration. This study provides further insight into Pompe disease biology and demonstrates the positive effects of avalglucosidase alfa treatment.

Effects of enzyme replacement therapy on bone density in late onset Pompe disease.

Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.

Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.

BACKGROUND AND OBJECTIVE: Pompe disease (PD) is an inherited lysosomal storage disease that progresses with glycogen accumulation in many tissues, due to the deficiency of the acid-alpha glucosidase enzyme. Recombinant alglucosidase alfa (rhGAA) is the only disease-specific treatment option, in the form of enzyme replacement therapy (ERT). Anaphylaxis can develop with rhGAA. There is no study evaluating anaphylaxis and its management in PD in the long term. We aimed to evaluate the development of anaphylaxis and rapid drug desensitization (RDD) with rhGAA in children with PD. MATERIALS AND METHODS: All children diagnosed and followed up in our institution with PD over 12 years between January 2009 and September 2021 were evaluated for development of anaphylaxis and RDD with rhGAA from medical records. RESULTS: Fourteen patients, 64% of whom were female and diagnosed with PD (1 juvenile, 13 infantile types) during the study period included in the study. The median age at diagnosis was 3.2 months (1-40 months). The median follow-up time of the patients was 20 months (1-129 months). Thirteen patients were given rhGAA, one died before ERT. Four (30.8%) patients developed moderate to severe anaphylaxis, and RDD was applied with rhGAA. A total of 390 RDDs have been performed so far without any serious breakthrough reactions during all RDDs. CONCLUSIONS: Anaphylaxis with rhGAA is not rare and RDD with rhGAA is safe and effective in the long term.

Association between changes in pulmonary function and in patient reported outcomes during enzyme therapy of adult patients with late-onset Pompe disease.

Pompe disease is a rare, progressive, and metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late-onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient-reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post hoc analysis of two cohort studies. Pulmonary function was assessed as forced vital capacity in the upright position (FVCup ). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36-item Short-Form Health Survey (SF-36) and daily life activities (Rasch-Built Pompe-Specific Activity [R-PACT] scale). We fitted Bayesian multivariate mixed-effects models. In the models of PROMs, we assumed a linear association with FVCup , and adjusted for time (nonlinear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R-PAct were positively associated with FVCup , while their relation with time was nonlinear (initial increase then decrease). A 1%-point increase in FVCup is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R-PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R-PAct scores by +0.42 and +0.80 points, and in the 5th year of +0.16 and +0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVCup increases during ERT.

Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

Population Pharmacokinetic Modeling and Determination of Individual Exposure to Avalglucosidase Alfa in Adolescent and Adult Patients With Late-Onset Pompe Disease: Analysis of Pooled Data From Phase I to III Clinical Trials.

BACKGROUND: Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. METHODS: The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. RESULTS: Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. CONCLUSIONS: A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.

Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-glucosidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease.

To discover small molecules as acid alpha-glucosidase (GAA) stabilizers for potential benefits of the exogenous enzyme treatment toward Pompe disease cells, we started from the initial screening of the unique chemical space, consisting of sixteen stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) to find out two primary stabilizers 17 and 18. Further external or internal structural modifications of 17 and 18 were performed to increase structural diversity, followed by the protein thermal shift study to evaluate the GAA stabilizing ability. Fortunately, pyrrolidine 21, possessing an l-arabino-typed configuration pattern, was identified as a specific potent rh-GAA stabilizer, enabling the suppression of rh-GAA protein denaturation. In a cell-based Pompe model, co-administration of 21 with rh-GAA protein significantly improved enzymatic activity (up to 5-fold) compared to administration of enzyme alone. Potentially, pyrrolidine 21 enables the direct increase of ERT (enzyme replacement therapy) efficacy in cellulo and in vivo.

Aggressive immunotherapy combined with bortezomib and rituximab for membranous nephropathy associated with enzyme replacement therapy in Pompe disease.

BACKGROUND: Pompe disease (PD) is a lysosomal glycogen storage disorder caused by a deficiency in acid α-glucosidase (GAA) activity. Various organs, including the skeletal muscle, cardiac muscle, and liver, are commonly involved. Early initiation of enzyme replacement therapy (ERT) with recombinant human α-glucosidase (rhGAA) can improve the outcome. However, some patients experience a poor clinical course despite ERT because of the emergence of anti-rhGAA antibodies that neutralize rhGAA. Treatment against anti-rhGAA antibodies is challenging. CASE-DIAGNOSIS/TREATMENT: A 14-year-old boy with late-onset PD was referred to our hospital with proteinuria detected by school urinalysis screening. He was diagnosed with PD at the age of 4 years based on muscle biopsy and decreased GAA activity. Treatment with rhGAA was initiated, but anaphylaxis occurred frequently. Anti-rhGAA antibodies were detected and immune tolerance therapy was therefore given, but his antibody titer remained high. Kidney biopsy revealed stage II membranous nephropathy. Immunohistochemistry staining revealed anti-rhGAA antibody/rhGAA immune complexes along the glomerular capillary loop. Aggressive immunotherapy combined with bortezomib and rituximab was then initiated. Serum levels of anti-rhGAA antibodies decreased significantly and his proteinuria finally resolved. CONCLUSIONS: There have been few reports of membranous nephropathy associated with ERT for PD. We clarified the cause in the current patient. Bortezomib and rituximab effectively suppressed anti-rhGAA antibody production resulting in the resolution of proteinuria and maintenance of ERT efficacy.

Enzyme replacement therapy for late-onset Pompe disease.

BACKGROUND: Pompe disease is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). People with infantile-onset disease have either a complete or a near-complete enzyme deficiency; people with late-onset Pompe disease (LOPD) retain some residual enzyme activity. GAA deficiency is treated with an intravenous infusion of recombinant human acid alglucosidase alfa, an enzyme replacement therapy (ERT). Alglucosidase alfa and avalglucosidase alfa are approved treatments, but cipaglucosidase alfa with miglustat is not yet approved. OBJECTIVES: To assess the effects of enzyme replacement therapies in people with late-onset Pompe disease. SEARCH METHODS: We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched MEDLINE OvidSP, clinical trial registries, and the reference lists of relevant articles and reviews. Date of last search: 21 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of ERT in people with LOPD of any age. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias and the certainty of the evidence (using GRADE). We resolved disagreements through discussion and by consulting a third author. MAIN RESULTS: We included six trials (358 randomised participants) lasting from 12 to 78 weeks. A single trial reported on each comparison listed below. None of the included trials assessed two of our secondary outcomes: need for respiratory support and use of a walking aid or wheelchair. Certainty of evidence was most commonly downgraded for selective reporting bias. Alglucosidase alfa versus placebo (90 participants) After 78 weeks, alglucosidase alfa probably improves the six-minute walk test (6MWT) distance compared to placebo (mean difference (MD) 30.95 metres, 95% confidence interval (CI) 7.98 to 53.92; moderate-certainty evidence) and probably improves respiratory function, measured as the change in per cent (%) predicted forced vital capacity (FVC) (MD 3.55, 95% CI 1.46 to 5.64; moderate-certainty evidence). There may be little or no difference between the groups in occurrence of infusion reactions (risk ratio (RR) 1.21, 95% CI 0.57 to 2.61; low-certainty evidence), quality of life physical component score (MD -1.36 points, 95% CI -5.59 to 2.87; low-certainty evidence), or adverse events (RR 0.94, 95% CI 0.64 to 1.39; low-certainty evidence). Alglucosidase alfa plus clenbuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus clenbuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 34.55 metres, 95% CI-10.11 to 79.21; very low-certainty evidence) and change in % predicted FVC (MD -13.51%, 95% CI -32.44 to 5.41; very low-certainty evidence). This study did not measure infusion reactions, quality of life, and adverse events. Alglucosidase alfa plus albuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus albuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 30.00 metres, 95% CI 0.55 to 59.45; very low-certainty evidence), change in % predicted FVC (MD -4.30%, 95% CI -14.87 to 6.27; very low-certainty evidence), and risk of adverse events (RR 0.67, 95% CI 0.38 to 1.18; very low-certainty evidence). This study did not measure infusion reactions and quality of life. VAL-1221 versus alglucosidase alfa (12 participants) Insufficient information was available about this trial to generate effect estimates measured at one year or later. Compared to alglucosidase alfa, VAL-1221 may increase or reduce infusion-associated reactions at three months, but the evidence is very uncertain (RR 2.80, 95% CI 0.18 to 42.80). This study did not measure quality of life and adverse events. Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo (125 participants) Compared to alglucosidase alfa plus placebo, cipaglucosidase alfa plus miglustat may make little or no difference to: 6MWT distance at 52 weeks (MD 13.60 metres, 95% CI -2.26 to 29.46); infusion reactions (RR 0.94, 95% CI 0.49 to 1.80); quality of life scores for physical function (MD 1.70, 95% CI -2.13 to 5.53) and fatigue (MD -0.30, 95% CI -2.76 to 2.16); and adverse effects potentially related to treatment (RR 0.83, 95% CI 0.49 to 1.40) (all low-certainty evidence). Cipaglucosidase alfa plus miglustat probably improves % predicted FVC compared to alglucosidase alfa plus placebo (MD 3.10%, 95% CI 1.04 to 5.16; moderate-certainty evidence); however, it may make little or no change in % predicted sniff nasal inspiratory pressure (MD -0.06%, 95% CI -8.91 to 7.71; low-certainty evidence). Avalglucosidase alfa versus alglucosidase alfa (100 participants) After 49 weeks, avalglucosidase alfa probably improves 6MWT compared to alglucosidase alfa (MD 30.02 metres, 95% CI 1.84 to 58.20; moderate-certainty evidence). Avalglucosidase alfa probably makes little or no difference to % predicted FVC compared to alglucosidase alfa (MD 2.43%, 95% CI -0.08 to 4.94; moderate-certainty evidence). Avalglucosidase alfa may make little or no difference to infusion reactions (RR 0.78, 95% CI 0.42 to 1.45), quality of life (MD 0.77, 95% CI -2.09 to 3.63), or treatment-related adverse events (RR 0.92, 95% CI 0.61 to 1.40), all low-certainty evidence. AUTHORS' CONCLUSIONS: 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.