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Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial.
Mol Genet Metab. 2019 05; 127(1):86-94.MG

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.

Authors+Show Affiliations

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.Nephrology Service, Research Center, Hôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada.Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.2nd Department of Internal Medicine and Department of Cardiovascular Medicine, Charles University Prague, General University Hospital Prague, Prague, Czech Republic.Hospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.Faculty of Medicine, Universidade de Passo Fundo, and Hospital São Vicente de Paulo, Passo Fundo, RS, Brazil.Sanofi Genzyme, Chilly-Mazarin, France.Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College Medicine, Cincinnati, OH, USA.Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN, USA.Department of Pathology, University of Washington, Seattle, WA, USA.Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.Departments of Human Genetics and Ophthalmology, Emory University School of Medicine, Decatur, GA, USA.Sanofi Genzyme, Framingham, MA, USA.Departments of Pediatrics and Clinical Medicine, Haukeland University Hospital, Bergen, Norway.Department of Pediatric Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.Formerly Sanofi Genzyme, Saint-Germain-en-Laye Cedex, France.Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Academic Medical Center, University Hospital of Amsterdam, Amsterdam, the Netherlands.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30987917

Citation

Ramaswami, Uma, et al. "Low-dose Agalsidase Beta Treatment in Male Pediatric Patients With Fabry Disease: a 5-year Randomized Controlled Trial." Molecular Genetics and Metabolism, vol. 127, no. 1, 2019, pp. 86-94.
Ramaswami U, Bichet DG, Clarke LA, et al. Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial. Mol Genet Metab. 2019;127(1):86-94.
Ramaswami, U., Bichet, D. G., Clarke, L. A., Dostalova, G., Fainboim, A., Fellgiebel, A., Forcelini, C. M., An Haack, K., Hopkin, R. J., Mauer, M., Najafian, B., Scott, C. R., Shankar, S. P., Thurberg, B. L., Tøndel, C., Tylki-Szymanska, A., Bénichou, B., & Wijburg, F. A. (2019). Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial. Molecular Genetics and Metabolism, 127(1), 86-94. https://doi.org/10.1016/j.ymgme.2019.03.010
Ramaswami U, et al. Low-dose Agalsidase Beta Treatment in Male Pediatric Patients With Fabry Disease: a 5-year Randomized Controlled Trial. Mol Genet Metab. 2019;127(1):86-94. PubMed PMID: 30987917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial. AU - Ramaswami,Uma, AU - Bichet,Daniel G, AU - Clarke,Lorne A, AU - Dostalova,Gabriela, AU - Fainboim,Alejandro, AU - Fellgiebel,Andreas, AU - Forcelini,Cassiano M, AU - An Haack,Kristina, AU - Hopkin,Robert J, AU - Mauer,Michael, AU - Najafian,Behzad, AU - Scott,C Ronald, AU - Shankar,Suma P, AU - Thurberg,Beth L, AU - Tøndel,Camilla, AU - Tylki-Szymanska,Anna, AU - Bénichou,Bernard, AU - Wijburg,Frits A, Y1 - 2019/04/03/ PY - 2018/12/13/received PY - 2019/03/06/revised PY - 2019/03/30/accepted PY - 2019/4/17/pubmed PY - 2019/11/16/medline PY - 2019/4/17/entrez KW - Agalsidase beta KW - Biopsy KW - Classic phenotype KW - Clinical outcomes KW - Enzyme replacement therapy KW - Fabry disease KW - Globotriaosylceramide KW - Pediatric KW - Podocytes KW - Superficial skin capillary endothelium KW - Symptoms SP - 86 EP - 94 JF - Molecular genetics and metabolism JO - Mol Genet Metab VL - 127 IS - 1 N2 - 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. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/30987917/Low_dose_agalsidase_beta_treatment_in_male_pediatric_patients_with_Fabry_disease:_A_5_year_randomized_controlled_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(18)30766-2 DB - PRIME DP - Unbound Medicine ER -