17 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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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
Additional file 2: of A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
Mean anti-BMN 701 (reveglucosidase alfa) antibody titers (safety population). (DOCX 16Â kb
Thigh-length compression stockings and DVT after stroke
Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease
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Persistent and Stable Growth Promoting Effects of Vosoritide in Children With Achondroplasia for up to 2 Years: Results From the Ongoing Phase 3 Extension Study
Abstract Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions
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SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia
Abstract Background: Achondroplasia is a disorder caused by specific mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) protein. Open-label, phase 2 trials in children with achondroplasia showed that administration of vosoritide, an analogue of C-natriuretic peptide, resulted in sustained increases in annualized growth velocity. Methods: This international, randomized, double-blind, phase 3 trial compared once-daily subcutaneous administration of vosoritide, at a dose of 15 μg per kg of body weight, with placebo in children with achondroplasia aged 5 to <18 years. Eligible patients had participated, for at least 6 months, in an observational growth study in order to calculate their baseline annualized growth velocity. The primary efficacy endpoint was the change from baseline in annualized growth velocity at week 52 of treatment. The primary analysis of the change from baseline in annualized growth velocity was performed using an ANCOVA model. Results: A total of 121 patients were randomized, with 60 assigned to receive vosoritide and 61 to receive placebo. A total of 119 patients completed the 52-week trial. The adjusted mean difference in annualized growth velocity between patients administered vosoritide and those administered placebo was 1.57 cm per year in favor of vosoritide (95% CI: [1.22, 1.93], two-sided p-value <0.001). A total of 119 patients experienced at least one adverse event (vosoritide group, 59 [98.3%], placebo group, 60 [98.4%]). Conclusions: Daily, subcutaneous administration of vosoritide to children with achondroplasia resulted in a significant increase in mean annualized growth velocity and similar incidence of adverse events compared to placebo