15 research outputs found
A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.
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 registrationISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011
A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
Abstract 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. Trial registration ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011
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Simulated Adoption of 2019 Community-Acquired Pneumonia Guidelines Across 114 Veterans Affairs Medical Centers: Estimated Impact on Culturing and Antibiotic Selection in Hospitalized Patients.
BackgroundThe 2019 American Thoracic Society/Infectious Diseases Society of America guidelines for community-acquired pneumonia (CAP) revised recommendations for culturing and empiric broad-spectrum antibiotics. We simulated guideline adoption in Veterans Affairs (VA) inpatients.MethodsFor all VA acute hospitalizations for CAP from 2006-2016 nationwide, we compared observed with guideline-expected proportions of hospitalizations with initial blood and respiratory cultures obtained, empiric antibiotic therapy with activity against methicillin-resistant Staphylococcus aureus (anti-MRSA) or Pseudomonas aeruginosa (antipseudomonal), empiric "overcoverage" (receipt of anti-MRSA/antipseudomonal therapy without eventual detection of MRSA/P. aeruginosa on culture), and empiric "undercoverage" (lack of anti-MRSA/antipseudomonal therapy with eventual detection on culture).ResultsOf 115 036 CAP hospitalizations over 11 years, 17 877 (16%) were admitted to an intensive care unit (ICU). Guideline adoption would slightly increase respiratory culture (30% to 36%) and decrease blood culture proportions (93% to 36%) in hospital wards and increase both respiratory (40% to 100%) and blood (95% to 100%) cultures in ICUs. Adoption would decrease empiric selection of anti-MRSA (ward: 27% to 1%; ICU: 61% to 8%) and antipseudomonal (ward: 25% to 1%; ICU: 54% to 9%) therapies. This would correspond to greatly decreased MRSA overcoverage (ward: 27% to 1%; ICU: 56% to 8%), slightly increased MRSA undercoverage (ward: 0.6% to 1.3%; ICU: 0.5% to 3.3%), with similar findings for P. aeruginosa. For all comparisons, P < .001.ConclusionsAdoption of the 2019 CAP guidelines in this population would substantially change culturing and empiric antibiotic selection practices, with a decrease in overcoverage and slight increase in undercoverage for MRSA and P. aeruginosa
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Simulated Adoption of 2019 Community-Acquired Pneumonia Guidelines Across 114 Veterans Affairs Medical Centers: Estimated Impact on Culturing and Antibiotic Selection in Hospitalized Patients.
BackgroundThe 2019 American Thoracic Society/Infectious Diseases Society of America guidelines for community-acquired pneumonia (CAP) revised recommendations for culturing and empiric broad-spectrum antibiotics. We simulated guideline adoption in Veterans Affairs (VA) inpatients.MethodsFor all VA acute hospitalizations for CAP from 2006-2016 nationwide, we compared observed with guideline-expected proportions of hospitalizations with initial blood and respiratory cultures obtained, empiric antibiotic therapy with activity against methicillin-resistant Staphylococcus aureus (anti-MRSA) or Pseudomonas aeruginosa (antipseudomonal), empiric "overcoverage" (receipt of anti-MRSA/antipseudomonal therapy without eventual detection of MRSA/P. aeruginosa on culture), and empiric "undercoverage" (lack of anti-MRSA/antipseudomonal therapy with eventual detection on culture).ResultsOf 115 036 CAP hospitalizations over 11 years, 17 877 (16%) were admitted to an intensive care unit (ICU). Guideline adoption would slightly increase respiratory culture (30% to 36%) and decrease blood culture proportions (93% to 36%) in hospital wards and increase both respiratory (40% to 100%) and blood (95% to 100%) cultures in ICUs. Adoption would decrease empiric selection of anti-MRSA (ward: 27% to 1%; ICU: 61% to 8%) and antipseudomonal (ward: 25% to 1%; ICU: 54% to 9%) therapies. This would correspond to greatly decreased MRSA overcoverage (ward: 27% to 1%; ICU: 56% to 8%), slightly increased MRSA undercoverage (ward: 0.6% to 1.3%; ICU: 0.5% to 3.3%), with similar findings for P. aeruginosa. For all comparisons, P < .001.ConclusionsAdoption of the 2019 CAP guidelines in this population would substantially change culturing and empiric antibiotic selection practices, with a decrease in overcoverage and slight increase in undercoverage for MRSA and P. aeruginosa
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A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.
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 registrationISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011
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Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia
ImportanceUse of empirical broad-spectrum antibiotics for pneumonia has increased owing to concern for resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA). The association of empirical anti-MRSA therapy with outcomes among patients with pneumonia is unknown, even for high-risk patients.ObjectiveTo compare 30-day mortality among patients hospitalized for pneumonia receiving empirical anti-MRSA therapy vs standard empirical antibiotic regimens.Design, setting, and participantsRetrospective multicenter cohort study was conducted of all hospitalizations in which patients received either anti-MRSA or standard therapy for community-onset pneumonia in the Veterans Health Administration health care system from January 1, 2008, to December 31, 2013. Subgroups of patients analyzed were those with initial intensive care unit admission, MRSA risk factors, positive results of a MRSA surveillance test, and positive results of a MRSA admission culture. Primary analysis was an inverse probability of treatment-weighted propensity score analysis using generalized estimating equation regression; secondary analyses included an instrumental variable analysis. Statistical analysis was conducted from June 14 to November 20, 2019.ExposuresEmpirical anti-MRSA therapy plus standard pneumonia therapy vs standard therapy alone within the first day of hospitalization.Main outcomes and measuresRisk of 30-day all-cause mortality after adjustment for patient comorbidities, vital signs, and laboratory results. Secondary outcomes included the development of kidney injury and secondary infections with Clostridioides difficile, vancomycin-resistant Enterococcus species, or gram-negative bacilli.ResultsAmong 88 605 hospitalized patients (86 851 men; median age, 70 years [interquartile range, 62-81 years]), empirical anti-MRSA therapy was administered to 33 632 (38%); 8929 patients (10%) died within 30 days. Compared with standard therapy alone, in weighted propensity score analysis, empirical anti-MRSA therapy plus standard therapy was significantly associated with an increased adjusted risk of death (adjusted risk ratio [aRR], 1.4 [95% CI, 1.3-1.5]), kidney injury (aRR, 1.4 [95% CI, 1.3-1.5]), and secondary C difficile infections (aRR, 1.6 [95% CI, 1.3-1.9]), vancomycin-resistant Enterococcus spp infections (aRR, 1.6 [95% CI, 1.0-2.3]), and secondary gram-negative rod infections (aRR, 1.5 [95% CI, 1.2-1.8]). Similar associations between anti-MRSA therapy use and 30-day mortality were found by instrumental variable analysis (aRR, 1.6 [95% CI, 1.4-1.9]) and among patients admitted to the intensive care unit (aRR, 1.3 [95% CI, 1.2-1.5]), those with a high risk for MRSA (aRR, 1.2 [95% CI, 1.1-1.4]), and those with MRSA detected on surveillance testing (aRR, 1.6 [95% CI, 1.3-1.9]). No significant favorable association was found between empirical anti-MRSA therapy and death among patients with MRSA detected on culture (aRR, 1.1 [95% CI, 0.8-1.4]).Conclusions and relevanceThis study suggests that empirical anti-MRSA therapy was not associated with reduced mortality for any group of patients hospitalized for pneumonia. These results contribute to a growing body of evidence that questions the value of empirical use of anti-MRSA therapy using existing risk approaches