Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial

Uma Ramaswami, Daniel G. Bichet, Lorne A. Clarke, Gabriela Dostalova, Alejandro Fainboim, Andreas Fellgiebel, Cassiano M. Forcelini, Kristina An Haack, Robert J. Hopkin, Michael Mauer, Behzad Najafian, C. Ronald Scott, Suma P. Shankar, Beth L. Thurberg, Camilla Tøndel, Anna Tylki-Szymanska, Bernard Bénichou, Frits A. Wijburg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalMolecular Genetics and Metabolism
DOIs
StatePublished - Jan 1 2019

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Fabry Disease
Pediatrics
Randomized Controlled Trials
Skin
Urine
Vascular Endothelium
Enzyme Replacement Therapy
Plasmas
Therapeutics
Galactosidases
Histology
Biopsy
Enzymes
Kidney
Podocytes
agalsidase beta
Labels
Vascular System Injuries
Abdominal Pain
Signs and Symptoms

Keywords

  • Agalsidase beta
  • Biopsy
  • Classic phenotype
  • Clinical outcomes
  • Enzyme replacement therapy
  • Fabry disease
  • Globotriaosylceramide
  • Pediatric
  • Podocytes
  • Superficial skin capillary endothelium
  • Symptoms

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Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease : A 5-year randomized controlled trial. / Ramaswami, Uma; Bichet, Daniel G.; Clarke, Lorne A.; Dostalova, Gabriela; Fainboim, Alejandro; Fellgiebel, Andreas; Forcelini, Cassiano M.; An Haack, Kristina; Hopkin, Robert J.; Mauer, Michael; Najafian, Behzad; Scott, C. Ronald; Shankar, Suma P.; Thurberg, Beth L.; Tøndel, Camilla; Tylki-Szymanska, Anna; Bénichou, Bernard; Wijburg, Frits A.

In: Molecular Genetics and Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

Ramaswami, U, Bichet, DG, Clarke, LA, Dostalova, G, Fainboim, A, Fellgiebel, A, Forcelini, CM, An Haack, K, Hopkin, RJ, Mauer, M, Najafian, B, Scott, CR, Shankar, SP, Thurberg, BL, Tøndel, C, Tylki-Szymanska, A, Bénichou, B & Wijburg, FA 2019, 'Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial' Molecular Genetics and Metabolism. https://doi.org/10.1016/j.ymgme.2019.03.010
Ramaswami, Uma ; Bichet, Daniel G. ; Clarke, Lorne A. ; Dostalova, Gabriela ; Fainboim, Alejandro ; Fellgiebel, Andreas ; Forcelini, Cassiano M. ; An Haack, Kristina ; Hopkin, Robert J. ; Mauer, Michael ; Najafian, Behzad ; Scott, C. Ronald ; Shankar, Suma P. ; Thurberg, Beth L. ; Tøndel, Camilla ; Tylki-Szymanska, Anna ; Bénichou, Bernard ; Wijburg, Frits A. / Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease : A 5-year randomized controlled trial. In: Molecular Genetics and Metabolism. 2019.
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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.",
keywords = "Agalsidase beta, Biopsy, Classic phenotype, Clinical outcomes, Enzyme replacement therapy, Fabry disease, Globotriaosylceramide, Pediatric, Podocytes, Superficial skin capillary endothelium, Symptoms",
author = "Uma Ramaswami and Bichet, {Daniel G.} and Clarke, {Lorne A.} and Gabriela Dostalova and Alejandro Fainboim and Andreas Fellgiebel and Forcelini, {Cassiano M.} and {An Haack}, Kristina and Hopkin, {Robert J.} and Michael Mauer and Behzad Najafian and Scott, {C. Ronald} and Shankar, {Suma P.} and Thurberg, {Beth L.} and Camilla T{\o}ndel and Anna Tylki-Szymanska and Bernard B{\'e}nichou and Wijburg, {Frits A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ymgme.2019.03.010",
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journal = "Molecular Genetics and Metabolism",
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TY - JOUR

T1 - Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease

T2 - 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.

PY - 2019/1/1

Y1 - 2019/1/1

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.

AB - 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.

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

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U2 - 10.1016/j.ymgme.2019.03.010

DO - 10.1016/j.ymgme.2019.03.010

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