Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.
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2020-05
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Abstract
Purpose
Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease.Methods
We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated.Results
Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses.Conclusion
Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.Type
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Khan, Aleena A, Laura E Case, Mrudu Herbert, Stephanie DeArmey, Harrison Jones, Kelly Crisp, Kanecia Zimmerman, Mai K ElMallah, et al. (2020). Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature. Genetics in medicine : official journal of the American College of Medical Genetics, 22(5). pp. 898–907. 10.1038/s41436-019-0738-0 Retrieved from https://hdl.handle.net/10161/27300.
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Scholars@Duke
Laura Elizabeth Case
Laura E Case, PT, DPT, MS, PhD, PCS, C/NDT is a board-certified clinical specialist in pediatric physical therapy. She has dedicated her career to teaching and research in childhood-onset neuromusculoskeletal disorders, and to the lifelong treatment of people with childhood-onset neurological and neuromuscular disorders such as cerebral palsy, traumatic brain injury, Duchenne muscular dystrophy, spinal muscular atrophy, Pompe disease, myelodysplasia, juvenile rheumatoid arthritis, and brachial plexus injury.
She has been involved in numerous clinical trials for the treatment of disorders including Pompe disease and other metabolic disorders, cerebral palsy, Duchenne muscular dystrophy, and spinal muscular atrophy. Dr. Case has participated in the development of international guidelines for the management of Duchenne muscular dystrophy, Pompe disease, and other glycogen storage diseases.
She teaches and consults internationally, has worked on a number of Center for Disease Control (CDC) task forces, has served on numerous committees and task forces in the pediatric section of APTA, served two terms as NC State Representative to the APTA Section on Pediatrics, and is a member of the North American Pompe Registry Board of Advisors.
Kanecia Obie Zimmerman
Mai ElMallah
Our laboratory focuses on the control of breathing and pulmonary mechanics in murine models of several genetic diseases. These genetic diseases include Duchenne Muscular Dystrophy, Pompe Disease, ALS, and Spino-cerebellar ataxia Type 7. We also investigate the ability of gene therapy and neuromodulation to treat respiratory insufficiency in neuromuscular diseases. As a clinician-scientist, my goal is to bring therapy from the bench to the bedside and enhance our research at the bench through observations at the bedside.
Our clinical research focus is on the impact of novel therapies on respiratory function in Duchenne Muscular Dystrophy and Pompe Disease. We study the impact of recent therapies on breathing in these disorders and the impact of social determinants of health on clinical outcome measures.
Sarah Phyllis Young
As an ABMGG-certified clinical biochemical geneticist and Co-Director of the DUHS Biochemical Genetics Laboratory, my research focuses on advancing laboratory diagnostics for rare inherited metabolic disorders. I lead efforts to develop and implement mass spectrometry–based assays to improve the detection, characterization, and monitoring of these conditions in both clinical and research settings. My work has a particular emphasis on biomarker validation for lysosomal disorders, including Pompe disease, Fabry disease, and the mucopolysaccharidoses. Through longitudinal biomarker studies, I contribute to the assessment of disease burden and therapeutic response, including enzyme replacement therapy, gene therapy, and emerging in utero interventions. I am also actively involved in translational research supporting newborn screening and diagnostic algorithms, with the goal of enabling earlier detection and more precise follow-up testing for metabolic diseases.
Priya Sunil Kishnani
RESEARCH INTERESTS
A multidisciplinary approach to care of individuals with genetic disorders in conjunction with clinical and bench research that contributes to:
1) An understanding of the natural history and delineation of long term complications of genetic disorders with a special focus on liver Glycogen storage disorders, lysosomal disorders with a special focus on Pompe disease, Down syndrome and hypophosphatasia
2) ) The development of new therapies such as AAV gene therapy, enzyme therapy, small molecule and other approaches for genetic disorders through translational research
3) The development and execution of large multicenter trials to confirm safety and efficacy of potential therapies
4) Role of antibodies/immune response in patients on therapeutic proteins and AAV gene therapy
. Glycogen Storage Disease (GSD): We are actively following subjects with all types of Glycogen Storage Disease, with particular emphasis on types I, II, III, IV, VI and IX. The goal of the treatment team is to better determine the clinical phenotype and long term complications of these diseases. Attention to disease manifestations observed in adulthood, such as adenomas and risk for HCC, is of paramount importance in monitoring and treating these chronic illnesses. We are establishing clinical algorithms for managing adenomas, and the overall management of these patients including cardiac, bone, muscle and liver issues. A special focus is biomarker discovery, an Omics approach including metabolomics and immune phenotyping. We are working on AAV gene therapy for several hepatic GSDs
.Lysosomal Storage Disease: The Duke Lysosomal Storage Disease (LSD) treatment center follows and treats patients with Pompe, Gaucher, Fabry, Mucopolysaccharidosis, Niemann Pick, LAL-D and other LSD's. The Duke Metabolism Clinical Research Team is exploring many aspects of enzyme replacement therapy (ERT), including impact on different systems, differential response, and long term effects. Other symptomatic and treatment interventions for this category of diseases are also being explored in the context of clinical care.
. Pompe Disease: The care team has extensive experience in the care of infants and adults with Pompe disease and was instrumental in conducting clinical trials and the bench to bedside work that led to the 2006 FDA approval of alglucosidase alfa, the first treatment for this devastating disease. We are currently focusing on role of antibodies/immune response on patient outcome and role of immune modulation/immune suppression as an adjunct to ERT. Our team is also working on AAV gene therapy for Pompe disease. A focus is on newborn screening (NBS) and understanding the clinical phenotype and management approaches for babies identified via NBS
. Hypophosphatasia: We follow a large cohort of patients with HPP. The goal is to understand the features of the disease beyond bone disease, development of biomarkers, role of ERT and immune responses in HPP
. Neuromuscular disorders: We are collaborating with neurologists, cardiologists and neuromuscular physicians to serve as a treatment site for clinical trials in these diseases. We are currently involved in trials of DMD and are working closely on setting up collaborations for studies in SMA.
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