Uma Ramaswami1, Daniel G Bichet2, Lorne A Clarke3, Gabriela Dostalova4, Alejandro Fainboim5, Andreas Fellgiebel6, Cassiano M Forcelini7, Kristina An Haack8, Robert J Hopkin9, Michael Mauer10, Behzad Najafian11, C Ronald Scott12, Suma P Shankar13, Beth L Thurberg14, Camilla Tøndel15, Anna Tylki-Szymanska16, Bernard Bénichou17, Frits A Wijburg18. 1. Lysosomal Disorders Unit, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, University College of London, London, United Kingdom. Electronic address: uma.ramaswami@nhs.net. 2. Nephrology Service, Research Center, Hôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada. 3. Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. 4. 2nd Department of Internal Medicine and Department of Cardiovascular Medicine, Charles University Prague, General University Hospital Prague, Prague, Czech Republic. 5. Hospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. 6. Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany. 7. Faculty of Medicine, Universidade de Passo Fundo, and Hospital São Vicente de Paulo, Passo Fundo, RS, Brazil. 8. Sanofi Genzyme, Chilly-Mazarin, France. 9. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College Medicine, Cincinnati, OH, USA. 10. Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN, USA. 11. Department of Pathology, University of Washington, Seattle, WA, USA. 12. Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. 13. Departments of Human Genetics and Ophthalmology, Emory University School of Medicine, Decatur, GA, USA. 14. Sanofi Genzyme, Framingham, MA, USA. 15. Departments of Pediatrics and Clinical Medicine, Haukeland University Hospital, Bergen, Norway. 16. Department of Pediatric Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland. 17. Formerly Sanofi Genzyme, Saint-Germain-en-Laye Cedex, France. 18. Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Academic Medical Center, University Hospital of Amsterdam, Amsterdam, the Netherlands.
Abstract
BACKGROUND: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. METHODS: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). RESULTS:The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. CONCLUSIONS: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
RCT Entities:
BACKGROUND:Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients. METHODS: In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE). RESULTS: The mean age was 11.6 (range: 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; P = .0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased. CONCLUSIONS: Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5 years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
Authors: Maria Helena Vaisbich; Luís Gustavo Modelli de Andrade; Cassiano Augusto Braga Silva; Fellype de Carvalho Barreto Journal: J Bras Nefrol Date: 2022 Apr-Jun
Authors: Derralynn A Hughes; Patricio Aguiar; Patrick B Deegan; Fatih Ezgu; Andrea Frustaci; Olivier Lidove; Aleš Linhart; Jean-Claude Lubanda; James C Moon; Kathleen Nicholls; Dau-Ming Niu; Albina Nowak; Uma Ramaswami; Ricardo Reisin; Paula Rozenfeld; Raphael Schiffmann; Einar Svarstad; Mark Thomas; Roser Torra; Bojan Vujkovac; David G Warnock; Michael L West; Jack Johnson; Mark J Rolfe; Sandro Feriozzi Journal: BMJ Open Date: 2020-10-10 Impact factor: 2.692
Authors: Andrea Frustaci; Behzad Najafian; Giuseppe Donato; Romina Verardo; Cristina Chimenti; Luigi Sansone; Manuel Belli; Enza Vernucci; Matteo Antonio Russo Journal: J Clin Med Date: 2022-02-28 Impact factor: 4.241
Authors: Sanne J van der Veen; Wytze J Vlietstra; Laura van Dussen; André B P van Kuilenburg; Marcel G W Dijkgraaf; Malte Lenders; Eva Brand; Christoph Wanner; Derralynn Hughes; Perry M Elliott; Carla E M Hollak; Mirjam Langeveld Journal: Int J Mol Sci Date: 2020-08-12 Impact factor: 5.923
Authors: Sanne J van der Veen; Carla E M Hollak; André B P van Kuilenburg; Mirjam Langeveld Journal: J Inherit Metab Dis Date: 2020-03-02 Impact factor: 4.982