The Experts below are selected from a list of 945 Experts worldwide ranked by ideXlab platform
Priya S Kishnani - One of the best experts on this subject based on the ideXlab platform.
-
Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start
Journal of neurology, 2020Co-Authors: David W Stockton, Ans T. Van Der Ploeg, Priya S Kishnani, Barry J. Byrne, Matthias Boentert, Mark Roberts, Roberto Araujo, Sonia S. Maruti, Juan Clinton Llerena, Nathan ThibaultAbstract:To 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. Longitudinal 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. Among 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. FVC 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.
-
Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.
Genetics in medicine : official journal of the American College of Medical Genetics, 2019Co-Authors: Priya S Kishnani, Nancy D Leslie, Loren D.m. Pena, David Kronn, Pranoot Tanpaiboon, Michael J Gambello, James B Gibson, Richard Hillman, David W Stockton, John W. DayAbstract:To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale Alglucosidase Alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date. Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L Alglucosidase Alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments. Of 113 enrollees (60 male/53 female) aged 1–18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.−32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material–negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.−32−13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0–100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0–99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0–100.0%). ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.
-
Enzyme replacement therapy with Alglucosidase Alfa in Pompe disease: Clinical experience with rate escalation.
Molecular genetics and metabolism, 2017Co-Authors: Ankit K. Desai, Stephanie Dearmey, Crista Walters, Heidi L. Cope, Zoheb B. Kazi, Priya S KishnaniAbstract:Abstract Patients with Pompe disease have realized significant medical benefits due to enzyme replacement therapy (ERT) infusions with Alglucosidase Alfa. However, regular infusions are time-consuming. Utilizing recommended infusion rates, infusion duration is 3 h 45 min for a patient receiving the standard dose of 20 mg/kg, not including additional time needed for preparation of ERT, assessment of vital signs, intravenous access, and post-infusion monitoring. Recent studies have demonstrated increased effectiveness of higher dose of ERT (40 mg/kg) in infantile-onset Pompe disease (IOPD), which increases the infusion duration to 6 h 36 min. Increased infusion durations compound the psychosocial burden on patients and families and potentially further disrupt family activities and obligations. We developed a stepwise infusion rate escalation protocol to administer higher dose ERT safely while decreasing infusion duration, which has been implemented in 15 patients to date. Reported here in detail are five patients with IOPD on 40 mg/kg/weekly ERT in whom infusion duration was decreased with individualized, stepwise rate escalation. All patients tolerated rate escalations above the recommended rates without experiencing any infusion associated reactions and experienced a reduction in infusion duration by 1 h and 24 min with a corresponding increase in reported satisfaction. Our experience with ERT rate escalation is presented. Synopsis A careful stepwise method of enzyme replacement therapy (ERT) rate escalation can safely reduce infusion duration in patients with Pompe disease.
-
Alglucosidase Alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation.
Molecular genetics and metabolism, 2016Co-Authors: Stephanie L Austin, Laura E. Case, Baodong Sun, Andrew Chiou, Kenny Govendrageloo, Perrin Hansen, Priya S KishnaniAbstract:PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with Alglucosidase-Alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. At 2.5months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11months. However, 1month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. This report outlines the benefits of ERT with Alglucosidase Alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Alglucosidase Alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation
Molecular Genetics and Metabolism, 2016Co-Authors: Stephanie Austin, Laura E. Case, Baodong Sun, Andrew Chiou, Kenny Govendrageloo, Perrin Hansen, Priya S KishnaniAbstract:Abstract Objective PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with Alglucosidase-Alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. Case report At 2.5 months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11 months. However, 1 month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. Conclusion This report outlines the benefits of ERT with Alglucosidase Alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.
Ans T. Van Der Ploeg - One of the best experts on this subject based on the ideXlab platform.
-
Respiratory function during enzyme replacement therapy in late-onset Pompe disease: longitudinal course, prognostic factors, and the impact of time from diagnosis to treatment start
Journal of neurology, 2020Co-Authors: David W Stockton, Ans T. Van Der Ploeg, Priya S Kishnani, Barry J. Byrne, Matthias Boentert, Mark Roberts, Roberto Araujo, Sonia S. Maruti, Juan Clinton Llerena, Nathan ThibaultAbstract:To 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. Longitudinal 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. Among 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. FVC 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.
-
Cost-effectiveness of enzyme replacement therapy with Alglucosidase Alfa in adult patients with Pompe disease.
Orphanet journal of rare diseases, 2017Co-Authors: Tim A. Kanters, Ans T. Van Der Ploeg, Michelle E. Kruijshaar, Dimitris Rizopoulos, W. Ken Redekop, Maureen P. M. H. Rutten-van Mӧlken, Leona Hakkaart-van RoijenAbstract:Pompe disease is a rare, progressive, metabolic disease, and the first treatable inheritable muscle disorder. Enzyme replacement therapy (ERT) with Alglucosidase Alfa is disease specific and the only medicinal product authorized for the treatment of Pompe disease. Costs of ERT are very high as for most orphan drugs. This study investigates the cost-effectiveness of ERT compared to supportive treatment in adult patients with Pompe disease. Survival probabilities were estimated from an international observational dataset (n = 283) using a time-dependent Cox model. Quality of life was estimated on a Dutch observational dataset using a previously developed conceptual model which links clinical factors to quality of life. Costs included costs of ERT, costs of drug administration and other healthcare costs. Cost-effectiveness was estimated using a patient-level simulation model (n = 90), synthesising the information from underlying models for survival, quality of life and costs. The cost-effectiveness model estimated the (difference in) lifetime effects and costs for both treatments. Two scenarios were modelled: (1) a worse case scenario with no extrapolation of the survival gain due to ERT beyond the observed period (i.e. from 10 years onwards); and (2) a best case scenario with lifetime extrapolation of the survival gain due to ERT. Effects were expressed in (quality adjusted) life years (QALYs). Costs were discounted at 4.0% and effects at 1.5%. Substantial increases in survival were estimated – discounted incremental life years of ERT ranged from 1.9 years to 5.4 years in the scenarios without and with extrapolation of survival gains beyond the observed period. Quality of life was also significantly better for patients receiving ERT. Incremental costs were considerable and primarily consisted of the costs of ERT. Incremental costs per QALY were €3.2 million for scenario 1 and €1.8 million for scenario 2. The availability of extended, prospectively collected, longitudinal observational data on the most important input parameters required to construct a cost-effectiveness model is quite exceptional for orphan diseases. The cost-effectiveness model showed substantial survival gains from ERT. Despite these substantial gains, ERT was not cost-effective in the treatment of adult Pompe disease because of the high cost of treatment.
-
Long-Term Efficacy of Alglucosidase Alfa in Late-Onset Pompe Disease (P1.120)
Neurology, 2017Co-Authors: Paula R. Clemens, Pascal Laforêt, Katherine Kacena, Bernd-jan Sanson, Robert J. Hopkin, Ans T. Van Der PloegAbstract:Objective: To examine the long-term effects of Alglucosidase Alfa on ambulatory function, respiratory function, and survival in LOPD patients. Background: Alglucosidase Alfa has been shown to improve survival as well as respiratory and muscle function in patients with infantile-onset (IOPD) and late-onset Pompe disease (LOPD). However, there is relatively little data on long-term efficacy. Design/Methods: Data was integrated from 68 (32 F, 36 M) patients receiving up to 9 years of treatment with Alglucosidase Alfa during participation in 2 sequential clinical studies with Alglucosidase Alfa, a randomized, double blind, placebo-controlled study (LOTS, NCT00158600) and its open-label extension (NCT00455195), and in the ongoing observational Pompe Registry. Results: Mean age at symptom onset was 28.7 years (range: 2.7–53.6) and mean age at diagnosis was 34.9 years (range: 5.8–61.3). Mean age at first infusion of Alglucosidase Alfa was 45.8 years (range: 16–70). 71% of the 42 patients who were ventilator free at baseline remained ventilator free during follow-up. The estimated annual decline in % predicted upright forced vital capacity (FVC) prior to initiation of Alglucosidase Alfa was 1.3% per year, while that observed during the follow-up period was 0.78%. 53% of the 34 patients who were not using ambulatory support at baseline maintained independent ambulation during follow-up. Percent predicted 6WMD increased for the first 2–3 years after initiation of Alglucosidase Alfa, followed by a relatively modest decline over the next 3 years, for an absolute decrease of 6.4% over the first 6 years of treatment. 4 (5.9%) patients died during the follow-up period. Conclusions: Long-term treatment with Alglucosidase Alfa was associated with stabilization of respiratory and ambulatory function during the first 6 years of treatment. These data support the ability of Alglucosidase Alfa to slow disease progression and the long-term use of Alglucosidase Alfa in patients with LOPD. Study Supported by: Sanofi Genzyme Disclosure: Dr. Clemens has received personal compensation for activities with Sanofi Genzyme. Dr. Laforet has received personal compensation for activities with Sanofi Genzyme and Amicus Therapeutics for serving on a scientific advisory board. Dr. Kacena has received personal compensation for activities with Sanofi Genzyme as an employee. Dr. Sanson has received personal compensation for activities with Sanofi Genzyme as an employee. Dr. Hopkin has nothing to disclose. Dr. Van Der Ploeg has received personal compensation for activities with Sanofi Genzyme as a consultant.
-
prospective exploratory muscle biopsy imaging and functional assessment in patients with late onset pompe disease treated with Alglucosidase Alfa the embassy study
Molecular Genetics and Metabolism, 2016Co-Authors: Ans T. Van Der Ploeg, Benedikt Schoser, Richard J. Barohn, Pierre G. Carlier, John T. Kissel, Alan Pestronk, Robert Carlier, Stephan Wenninger, Mazen M Dimachkie, Ozlem GokeralpanAbstract:Abstract Background Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with Alglucosidase Alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatmen t -naive adults after ERT have not been extensively examined. Methods This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- Alglucosidase Alfa treatment in treatment-naive adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. Results Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate. Conclusions This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naive patients with late-onset Pompe disease.
-
Phase 1 Safety and Pharmacokinetics of the Novel Enzyme Replacement Therapy neoGAA in Treatment-Naïve and Alglucosidase Alfa-Treated Late-Onset Pompe Disease Patients (S38.005)
Neurology, 2016Co-Authors: Jaya Trivedi, Pascal Laforêt, Ans T. Van Der Ploeg, Richard J. Barohn, Barry J. Byrne, Ozlem Goker-alpan, Claude Desnuelle, Shafeeq Ladha, Eugen Mengel, Alan PestronkAbstract:OBJECTIVE: This randomized open-label, ascending-dose study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and exploratory efficacy of the second-generation, recombinant acid alpha-glucosidase replacement, neoGAA, in treatment-naive (Grp 1) and Alglucosidase Alfa-treated (Grp 2) patients with late-onset Pompe disease (NCT01898364). BACKGROUND: The primary study objectives, safety profile and PK, are reported here. DESIGN/METHODS: Patients aged ≥18 years with acid α-glucosidase enzyme deficiency received IV neoGAA (5, 10, or 20mg/kg every other week) for 24 wks. RESULTS: 10 patients were treated in Grp 1; 9 completed (5mg/kg, n=3; 10mg/kg, n=3; 20mg/kg, n=3). 14 patients were treated in Grp 2; 12 completed (5mg/kg, n=3; 10mg/kg, n=4; 20mg/kg, n=5). There were no deaths or life-threatening SAEs. One Grp 1 patient had drug- and infusion-related SAEs (respiratory distress and chest discomfort); whereas in Grp 2, there were no drug-related SAEs. 4/10 Grp 1 patients had 11 infusion-associated reactions (IARs); 4 of 14 Grp 2 patients had 14 IARs. The majority of treatment-emergent AEs and IARs were non-serious and mild to moderate in intensity. In Grp 1, 9/10 patients developed anti-neoGAA antibodies, which inhibited uptake in 1 patient. In Grp 2, 5/14 patients had anti-neoGAA antibodies at screening/wk 1 although they had only been exposed to rhGAA. 2 of the 9 without baseline anti-neoGAA seroconverted without uptake inhibition. No enzyme-inhibitory antibodies or development of IgE antibodies occurred. NeoGAA plasma concentrations declined monoexponentially after infusion; mean t1/2 was 1.0 h in both groups. NeoGAA PK was similar in Grps 1 and 2 and remained largely unchanged between weeks 1, 13, and 25. 19/21 study completers entered the extension study and continue participating. CONCLUSIONS: NeoGAA had a well-tolerated safety profile in treatment-naive and previously treated patients with late-onset Pompe disease. These findings support further development of neoGAA in Pompe disease. Study Supported by: Genzyme, a Sanofi Company Disclosure: Dr. Trivedi has nothing to disclose. Dr. Van der Ploeg has received personal compensation for activities with Genzyme Corporation as a consultant. Dr. Barohn has received personal compensation for activities with Grifols & Genzyme, Speakers Bureau, NuFactor as speaker and consultant. Dr. Byrne has nothing to disclose. Dr. Desnuelle has nothing to disclose. Dr. Goker-Alpan has received personal compensation for activities with Genzyme, Shire HGT, Actelion, and Biomarin. Dr. Ladha has received personal compensation for activities with Genzyme and Biogen as a speaker and/or consultant. Dr. Ladha received a research support from Genentech. Dr. Laforet has received personal compensation for activities with Amicus Therapuetics as an advisory board participant. Dr. Mengel has received personal compensation for activities with Genzyme, Synageva, Orphazyme, Actelion, and Biomarin as a speaker and/or consultant. Dr. Pestronk has received personal compensation for activities with Athena Diagnostics. Dr. Pouget has nothing to disclose. Dr. Schoser has received personal compensation for activities with Genzyme, BioMarin Pharmaceuticals, Audentes Therapeutics, and Amicus Therapeutics. Dr. Straub has received personal compensation for activities with Genzyme, Audentes Therapeutics, ItAlfarmaco S.p.A., Summit Therapeutics and TrophyNOD as a speaker an advisory board member. Dr. Van Damme has nothing to disclose. Dr. Vissing has received personal compensation for activities with Alexion Pharmaceuticals and Ultragenyx as an advisory board member. Dr. Young has received personal compensation for activities with Genzyme, Biomarin, UCB, Heinen und Lowenstein, and Medice. Dr. Shafi has received personal compensation for activities with Genzyme as an employee. Dr. Culm-Merdek has received personal compensation for activities with Genzyme as an employee. Dr. Short holds stock and/or stock options in Sanofi-Aventis Pharmaceuticals, Inc. Dr. Pena has received personal compensation for activities with Sanofi-Genzyme as an advisory board member.
Stephanie Dearmey - One of the best experts on this subject based on the ideXlab platform.
-
Enzyme replacement therapy with Alglucosidase Alfa in Pompe disease: Clinical experience with rate escalation.
Molecular genetics and metabolism, 2017Co-Authors: Ankit K. Desai, Stephanie Dearmey, Crista Walters, Heidi L. Cope, Zoheb B. Kazi, Priya S KishnaniAbstract:Abstract Patients with Pompe disease have realized significant medical benefits due to enzyme replacement therapy (ERT) infusions with Alglucosidase Alfa. However, regular infusions are time-consuming. Utilizing recommended infusion rates, infusion duration is 3 h 45 min for a patient receiving the standard dose of 20 mg/kg, not including additional time needed for preparation of ERT, assessment of vital signs, intravenous access, and post-infusion monitoring. Recent studies have demonstrated increased effectiveness of higher dose of ERT (40 mg/kg) in infantile-onset Pompe disease (IOPD), which increases the infusion duration to 6 h 36 min. Increased infusion durations compound the psychosocial burden on patients and families and potentially further disrupt family activities and obligations. We developed a stepwise infusion rate escalation protocol to administer higher dose ERT safely while decreasing infusion duration, which has been implemented in 15 patients to date. Reported here in detail are five patients with IOPD on 40 mg/kg/weekly ERT in whom infusion duration was decreased with individualized, stepwise rate escalation. All patients tolerated rate escalations above the recommended rates without experiencing any infusion associated reactions and experienced a reduction in infusion duration by 1 h and 24 min with a corresponding increase in reported satisfaction. Our experience with ERT rate escalation is presented. Synopsis A careful stepwise method of enzyme replacement therapy (ERT) rate escalation can safely reduce infusion duration in patients with Pompe disease.
-
Immunological Factors in Pompe Disease Management: Clinical Experience and Implications for Newborn Screening.
Journal of neuromuscular diseases, 2015Co-Authors: Priya S Kishnani, Stephanie Dearmey, Deeksha Bali, Zoheb B. Kazi, Kathryn L. Berrier, Amy S. RosenbergAbstract:Enzyme replacement therapy (ERT) with Alglucosidase Alfa has improved clinical outcomes and prolonged survival for patients with infantile Pompe disease (IPD). However, patients characterised as Cross-Reactive Immunological Material (CRIM)negative (CN) mount an immune response against ERT resulting in clinical decline and, ultimately, death. A prophylactic immune tolerance induction (ITI) protocol has been successful in preventing the development of antibody titres for these patients. A subset of (CP) patients also mount an immune response with poor clinical outcomes, these at-risk patients are diffi cult to identify. With the advent of newborn screening for Pompe disease, preventative treatment to circumvent an immune response is warranted; therefore, our study aimed to assess the safety and effi cacy of prophylactic ITI in the naive setting for both CP and CN IPD patients.
-
Safety and efficacy of alternative Alglucosidase Alfa regimens in Pompe disease
Neuromuscular disorders : NMD, 2014Co-Authors: Laura E. Case, John P Clancy, Joel Charrow, Claire Morgan, Stephanie Dearmey, Carl Bjartmar, Robin Casey, Majed Dasouki, Khan Nedd, Mary NevinsAbstract:Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (Alglucosidase Alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of Alglucosidase Alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.
-
The emerging phenotype of long-term survivors with infantile Pompe disease
Genetics in medicine : official journal of the American College of Medical Genetics, 2012Co-Authors: Sean N. Prater, Stephanie Dearmey, Laura E. Case, Raymond Y Wang, Suhrad G. Banugaria, Eleanor G. Botha, Erin M. Stege, Harrison N. Jones, Chanika Phornphutkul, Sarah P. YoungAbstract:Purpose Enzyme replacement therapy with Alglucosidase Alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.
-
An individually, modified approach to desensitize infants and young children with Pompe disease, and significant reactions to Alglucosidase Alfa infusions.
Molecular genetics and metabolism, 2011Co-Authors: Areeg H El-gharbawy, Joanne Mackey, Stephanie Dearmey, Greg Westby, Sherry G Grinnell, Peggy Malovrh, Robert Conway, Priya S KishnaniAbstract:Pompe disease (PD) is a progressive metabolic myopathy for which the only available treatment is Alglucosidase Alfa (Myozyme®). Enzyme replacement therapy (ERT) has improved ventilator-free survival, and cardiac and motor functions in patients with infantile PD. However, for an adequate response to occur, a large amount of enzymes must be infused. In some patients, this may be problematic due to infusion-associated reactions (IARs) occurring in approximately 50% of patients receiving Alglucosidase Alfa infusions. Whilst the majority of these reactions are mild, life threatening hypersensitivity reactions may occur in some patients. In these patients desensitization is indicated to enable continued ERT safely. Infants and young children with PD and significant infusion reactions pose unique management challenges because of their young age, limited communication skills, variable presentation and underlying cardiomyopathy. In 2 patients with PD who experienced significant ERT-related reactions: an infant (IgE positive) and a young child (IgE negative), we implemented a desensitization protocol, that started by administering a reduced dose of Alglucosidase Alfa (10 mg/kg weekly) instead of the standard (20 mg/kg bi-weekly) using serial micro-dilutions that were individually prepared and delivered in a highly regulated manner based on patients' clinical manifestations and tolerance. Successful desensitization was achieved in both patients, allowing them to eventually continue to receive the full dose of ERT safely. Therapeutic demands in infants and young children with PD need to be tailored according to the patient presentation, and underlying cardiac and fluid-volume status. Desensitization allowed both patients to continue Alglucosidase Alfa treatment at the recommended dose without prolonged interruption of therapy, or further reactions. Copyright © 2011 Elsevier Inc. All rights reserved.
Laura E. Case - One of the best experts on this subject based on the ideXlab platform.
-
Alglucosidase Alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation.
Molecular genetics and metabolism, 2016Co-Authors: Stephanie L Austin, Laura E. Case, Baodong Sun, Andrew Chiou, Kenny Govendrageloo, Perrin Hansen, Priya S KishnaniAbstract:PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with Alglucosidase-Alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. At 2.5months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11months. However, 1month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. This report outlines the benefits of ERT with Alglucosidase Alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Alglucosidase Alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation
Molecular Genetics and Metabolism, 2016Co-Authors: Stephanie Austin, Laura E. Case, Baodong Sun, Andrew Chiou, Kenny Govendrageloo, Perrin Hansen, Priya S KishnaniAbstract:Abstract Objective PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with Alglucosidase-Alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. Case report At 2.5 months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11 months. However, 1 month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. Conclusion This report outlines the benefits of ERT with Alglucosidase Alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.
-
Safety and efficacy of alternative Alglucosidase Alfa regimens in Pompe disease
Neuromuscular disorders : NMD, 2014Co-Authors: Laura E. Case, John P Clancy, Joel Charrow, Claire Morgan, Stephanie Dearmey, Carl Bjartmar, Robin Casey, Majed Dasouki, Khan Nedd, Mary NevinsAbstract:Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (Alglucosidase Alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of Alglucosidase Alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.
-
The emerging phenotype of long-term survivors with infantile Pompe disease
Genetics in Medicine, 2012Co-Authors: Sean N. Prater, Laura E. Case, Raymond Y Wang, Suhrad G. Banugaria, Eleanor G. Botha, Erin M. Stege, Harrison N. Jones, Chanika Phornphutkul, Stephanie M. Dearmey, Sarah P. YoungAbstract:Genet Med 2012:14(9):800–810. Purpose: Enzyme replacement therapy with Alglucosidase Alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors. Methods: Inclusion criteria included ventilator-free status and age ≤6 months at treatment initiation, and survival to age ≥5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status. Results: Eleven of 17 patients met study criteria. All were cross-reactive immunologic material-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4–12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-Alglucosidase Alfa antibody titers. Conclusion: Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings.
-
The emerging phenotype of long-term survivors with infantile Pompe disease
Genetics in medicine : official journal of the American College of Medical Genetics, 2012Co-Authors: Sean N. Prater, Stephanie Dearmey, Laura E. Case, Raymond Y Wang, Suhrad G. Banugaria, Eleanor G. Botha, Erin M. Stege, Harrison N. Jones, Chanika Phornphutkul, Sarah P. YoungAbstract:Purpose Enzyme replacement therapy with Alglucosidase Alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors.
Yuan-tsong Chen - One of the best experts on this subject based on the ideXlab platform.
-
Alglucosidase Alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III.
Molecular genetics and metabolism, 2012Co-Authors: Baodong Sun, Beth L. Thurberg, Keri Fredrickson, Stephanie Austin, Adviye A. Tolun, William E. Kraus, Deeksha Bali, Yuan-tsong Chen, Priya S KishnaniAbstract:We investigated the feasibility of using recombinant human acid-α glucosidase (rhGAA, Alglucosidase Alfa), an FDA approved therapy for Pompe disease, as a treatment approach for glycogen storage disease type III (GSD III). An in vitro disease model was established by isolating primary myoblasts from skeletal muscle biopsies of patients with GSD IIIa. We demonstrated that rhGAA significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells (by 17% and 48%, respectively) suggesting that rhGAA could be a novel therapy for GSD III. This conclusion needs to be confirmed in other in vivo models.
-
glycogen storage disease types i and ii treatment updates
Journal of Inherited Metabolic Disease, 2007Co-Authors: Dwight D. Koeberl, Priya S Kishnani, Yuan-tsong ChenAbstract:Prior to 2006 therapy for glycogen storage diseases consisted primarily of dietary interventions, which in the case of glycogen storage disease (GSD) type II (GSD II; Pompe disease) remained essentially palliative. Despite improved survival and growth, long-term complications of GSD type I (GSD I) have not responded to dietary therapy with uncooked cornstarch or continuous gastric feeding. The recognized significant risk of renal disease and liver malignancy in GSD I has prompted efforts towards curative therapy, including organ transplantation, in those deemed at risk. Results of clinical trials in infantile Pompe disease with Alglucosidase Alfa (Myozyme) showed prolonged survival reversal of cardiomyopathy, and motor gains. This resulted in broad label approval of Myozyme for Pompe disease in 2006. Furthermore, the development of experimental therapies, such as adeno-associated virus (AAV) vector-mediated gene therapy, holds promise for the availability of curative therapy in GSD I and GSD II/Pompe disease in the future.
