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

doi:10.1016/j.ymgme.2019.03.010

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

Pediatric Nephrology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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 language	English (US)
Pages (from-to)	86-94
Number of pages	9
Journal	Molecular Genetics and Metabolism
Volume	127
Issue number	1
DOIs	https://doi.org/10.1016/j.ymgme.2019.03.010
State	Published - May 2019

Bibliographical note

Funding Information:
The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network) provided support (U54NS065768) for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11].

Funding Information:
The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network)provided support (U54NS065768)for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11].

Publisher Copyright:
© 2019 The Authors

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymgme.2019.03.010

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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, 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, vol. 127, no. 1, pp. 86-94. https://doi.org/10.1016/j.ymgme.2019.03.010

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

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.}",

note = "Funding Information: The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network) provided support (U54NS065768) for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11]. Funding Information: The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network)provided support (U54NS065768)for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11]. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = may,

doi = "10.1016/j.ymgme.2019.03.010",

language = "English (US)",

volume = "127",

pages = "86--94",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "Academic Press Inc.",

number = "1",

}

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.

N1 - Funding Information: The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network) provided support (U54NS065768) for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11]. Funding Information: The study was funded by Sanofi Genzyme; the sponsor had a role in the study design, data analysis, and data interpretation. The National Institutes of Health Lysosomal Disease Network (part of the ncATS Rare Diseases Clinical Research Network)provided support (U54NS065768)for development and performance of the methodology used in this manuscript and for EM measurement in kidney biopsy samples. The authors received editorial/writing support in the preparation of this manuscript, provided by Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme, but were responsible for all content and editorial decisions.Suma P. Shankar has been a site primary investigator in clinical trials, and has received research support and educational grants sponsored by Sanofi Genzyme, Shire, Protalix, Biomarin, and Amicus Therapeutics, and honoraria and travel support as speaker and for investigator meetings of Sanofi Genzyme, Shire, and Protalix (activities have been monitored and found to be in compliance with the conflict of interest policies at Emory University). The authors would like to thank the patients who agreed to participate in the study and their families, as well as all physicians and other hospital personnel involved in the conduct of this study. In addition, the authors would like to acknowledge all individuals who have been involved in skin and kidney biopsy reviews, production of biopsy slides, selection of the appropriate slides for review and scoring, iohexol measurement, retinal imaging reviews, and glycolipid assessments. The patient recruitment sites are described elsewhere [11]. Publisher Copyright: © 2019 The Authors

PY - 2019/5

Y1 - 2019/5

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

M3 - Article

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AN - SCOPUS:85064183980

SN - 1096-7192

VL - 127

SP - 86

EP - 94

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 1

ER -

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

Abstract

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Keywords

UN SDGs

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