Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Nicola Longo; George A. Diaz; Uta Lichter-Konecki; Andreas Schulze; Michal Inbar-Feigenberg; Robert L. Conway; Allison A. Bannick; Shawn E. McCandless; Roberto Zori; Bryan Hainline; Nicholas Ah Mew; Colleen Canavan; Thomas Vescio; Teresa Kok; Marty H. Porter; Susan A. Berry

doi:10.1016/j.ymgme.2020.12.002

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Nicola Longo, George A. Diaz, Uta Lichter-Konecki, Andreas Schulze, Michal Inbar-Feigenberg, Robert L. Conway, Allison A. Bannick, Shawn E. McCandless, Roberto Zori, Bryan Hainline, Nicholas Ah Mew, Colleen Canavan, Thomas Vescio, Teresa Kok, Marty H. Porter, Susan A. Berry

Pediatric Genetics & Metabolism

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

11 Scopus citations

Abstract

BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.

METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.

RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.

CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

Original language	English (US)
Pages (from-to)	19-26
Number of pages	8
Journal	Molecular Genetics and Metabolism
Volume	132
Issue number	1
DOIs	https://doi.org/10.1016/j.ymgme.2020.12.002
State	Published - Jan 2021

Bibliographical note

Funding Information:
The authors gratefully acknowledge and thank the efforts of the study coordinators and nursing staff who made these trials possible, including Sara Elsecker, Liora Caspi, Ashley Wilson, Audrey Lynn, Ph.D. and Carrie Bailey. We would also like to thank Min Dong and Alexander Vinks for their work in conducting the pharmacokinetic analyses. In addition, the authors would like to thank Megan Francis-Sedlak Ph.D. Katie Obermeyer M.S. and Naina Barretto Ph.D. from Horizon for data analysis, writing, and editorial support. We wish to thank all patients and their families who took part in this study. Some of the data in this report was previously presented in abstract form at the 2019 (Society for Inherited Metabolic Disorders (SIMD) meeting (April 6?9, Bellevue, WA) and at the 2019 Southeastern Regional Genetics Group (SERGG) annual meeting (July 18?20, Asheville, NC). The authors have the following conflicts of interest: Colleen Canavan, Thomas Vescio, Teresa Kok, and Marty Porter are employees of, and have stock in, Horizon. None of the other authors have a financial interest in Horizon. For the following authors, payments were made by Horizon to their institutions for services provided in the conduct of the clinical studies upon which this report is based: Nicola Longo (University of Utah), George Diaz (Icahn School of Medicine at Mount Sinai), Uta Lichter-Konecki (Children's Hospital of Pittsburgh), Andreas Schulze (Hospital for Sick Children, Toronto), Robert Conway (Wayne State University), Shawn McCandless (University Hospitals of Cleveland and University of Colorado), Roberto Zori (University of Florida), Bryan Hainline (Indiana University School of Medicine), Nicholas Ah Mew (Children's National Medical Center), and Susan Berry (University of Minnesota). Nicola Longo, George Diaz, Uta Lichter-Konecki, Andreas Schulze, Robert Conway, Shawn McCandless, Roberto Zori, Bryan Hainline, and Susan Berry have served as Horizon advisory board members. Horizon Therapeutics plc funded the development, conduct and analysis of the study and participated in the preparation, review and approval of the manuscript.

Publisher Copyright:
© 2020 The Authors

Keywords

Diffusion tensor imaging
Glycerol phenylbutyrate
Hyperammonemia
Neonate
Pediatric
Urea cycle disorder
Phenylacetates/administration & dosage
Pediatrics
Humans
Ammonia/blood
Child, Preschool
Infant
Male
Glycerol/administration & dosage
Urea Cycle Disorders, Inborn/blood
Age of Onset
Female
Phenylbutyrates/administration & dosage
Infant, Newborn
Hyperammonemia/blood
Renal Dialysis

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article

UN SDGs

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

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10.1016/j.ymgme.2020.12.002

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Longo, N., Diaz, G. A., Lichter-Konecki, U., Schulze, A., Inbar-Feigenberg, M., Conway, R. L., Bannick, A. A., McCandless, S. E., Zori, R., Hainline, B., Ah Mew, N., Canavan, C., Vescio, T., Kok, T., Porter, M. H., & Berry, S. A. (2021). Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders. Molecular Genetics and Metabolism, 132(1), 19-26. https://doi.org/10.1016/j.ymgme.2020.12.002

Longo, N, Diaz, GA, Lichter-Konecki, U, Schulze, A, Inbar-Feigenberg, M, Conway, RL, Bannick, AA, McCandless, SE, Zori, R, Hainline, B, Ah Mew, N, Canavan, C, Vescio, T, Kok, T, Porter, MH & Berry, SA 2021, 'Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders', Molecular Genetics and Metabolism, vol. 132, no. 1, pp. 19-26. https://doi.org/10.1016/j.ymgme.2020.12.002

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title = "Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders",

abstract = "BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.",

keywords = "Diffusion tensor imaging, Glycerol phenylbutyrate, Hyperammonemia, Neonate, Pediatric, Urea cycle disorder, Phenylacetates/administration & dosage, Pediatrics, Humans, Ammonia/blood, Child, Preschool, Infant, Male, Glycerol/administration & dosage, Urea Cycle Disorders, Inborn/blood, Age of Onset, Female, Phenylbutyrates/administration & dosage, Infant, Newborn, Hyperammonemia/blood, Renal Dialysis",

author = "Nicola Longo and Diaz, {George A.} and Uta Lichter-Konecki and Andreas Schulze and Michal Inbar-Feigenberg and Conway, {Robert L.} and Bannick, {Allison A.} and McCandless, {Shawn E.} and Roberto Zori and Bryan Hainline and {Ah Mew}, Nicholas and Colleen Canavan and Thomas Vescio and Teresa Kok and Porter, {Marty H.} and Berry, {Susan A.}",

note = "Funding Information: The authors gratefully acknowledge and thank the efforts of the study coordinators and nursing staff who made these trials possible, including Sara Elsecker, Liora Caspi, Ashley Wilson, Audrey Lynn, Ph.D. and Carrie Bailey. We would also like to thank Min Dong and Alexander Vinks for their work in conducting the pharmacokinetic analyses. In addition, the authors would like to thank Megan Francis-Sedlak Ph.D. Katie Obermeyer M.S. and Naina Barretto Ph.D. from Horizon for data analysis, writing, and editorial support. We wish to thank all patients and their families who took part in this study. Some of the data in this report was previously presented in abstract form at the 2019 (Society for Inherited Metabolic Disorders (SIMD) meeting (April 6?9, Bellevue, WA) and at the 2019 Southeastern Regional Genetics Group (SERGG) annual meeting (July 18?20, Asheville, NC). The authors have the following conflicts of interest: Colleen Canavan, Thomas Vescio, Teresa Kok, and Marty Porter are employees of, and have stock in, Horizon. None of the other authors have a financial interest in Horizon. For the following authors, payments were made by Horizon to their institutions for services provided in the conduct of the clinical studies upon which this report is based: Nicola Longo (University of Utah), George Diaz (Icahn School of Medicine at Mount Sinai), Uta Lichter-Konecki (Children's Hospital of Pittsburgh), Andreas Schulze (Hospital for Sick Children, Toronto), Robert Conway (Wayne State University), Shawn McCandless (University Hospitals of Cleveland and University of Colorado), Roberto Zori (University of Florida), Bryan Hainline (Indiana University School of Medicine), Nicholas Ah Mew (Children's National Medical Center), and Susan Berry (University of Minnesota). Nicola Longo, George Diaz, Uta Lichter-Konecki, Andreas Schulze, Robert Conway, Shawn McCandless, Roberto Zori, Bryan Hainline, and Susan Berry have served as Horizon advisory board members. Horizon Therapeutics plc funded the development, conduct and analysis of the study and participated in the preparation, review and approval of the manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2021",

month = jan,

doi = "10.1016/j.ymgme.2020.12.002",

language = "English (US)",

volume = "132",

pages = "19--26",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "Academic Press Inc.",

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TY - JOUR

T1 - Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

AU - Longo, Nicola

AU - Diaz, George A.

AU - Lichter-Konecki, Uta

AU - Schulze, Andreas

AU - Inbar-Feigenberg, Michal

AU - Conway, Robert L.

AU - Bannick, Allison A.

AU - McCandless, Shawn E.

AU - Zori, Roberto

AU - Hainline, Bryan

AU - Ah Mew, Nicholas

AU - Canavan, Colleen

AU - Vescio, Thomas

AU - Kok, Teresa

AU - Porter, Marty H.

AU - Berry, Susan A.

N1 - Funding Information: The authors gratefully acknowledge and thank the efforts of the study coordinators and nursing staff who made these trials possible, including Sara Elsecker, Liora Caspi, Ashley Wilson, Audrey Lynn, Ph.D. and Carrie Bailey. We would also like to thank Min Dong and Alexander Vinks for their work in conducting the pharmacokinetic analyses. In addition, the authors would like to thank Megan Francis-Sedlak Ph.D. Katie Obermeyer M.S. and Naina Barretto Ph.D. from Horizon for data analysis, writing, and editorial support. We wish to thank all patients and their families who took part in this study. Some of the data in this report was previously presented in abstract form at the 2019 (Society for Inherited Metabolic Disorders (SIMD) meeting (April 6?9, Bellevue, WA) and at the 2019 Southeastern Regional Genetics Group (SERGG) annual meeting (July 18?20, Asheville, NC). The authors have the following conflicts of interest: Colleen Canavan, Thomas Vescio, Teresa Kok, and Marty Porter are employees of, and have stock in, Horizon. None of the other authors have a financial interest in Horizon. For the following authors, payments were made by Horizon to their institutions for services provided in the conduct of the clinical studies upon which this report is based: Nicola Longo (University of Utah), George Diaz (Icahn School of Medicine at Mount Sinai), Uta Lichter-Konecki (Children's Hospital of Pittsburgh), Andreas Schulze (Hospital for Sick Children, Toronto), Robert Conway (Wayne State University), Shawn McCandless (University Hospitals of Cleveland and University of Colorado), Roberto Zori (University of Florida), Bryan Hainline (Indiana University School of Medicine), Nicholas Ah Mew (Children's National Medical Center), and Susan Berry (University of Minnesota). Nicola Longo, George Diaz, Uta Lichter-Konecki, Andreas Schulze, Robert Conway, Shawn McCandless, Roberto Zori, Bryan Hainline, and Susan Berry have served as Horizon advisory board members. Horizon Therapeutics plc funded the development, conduct and analysis of the study and participated in the preparation, review and approval of the manuscript. Publisher Copyright: © 2020 The Authors

PY - 2021/1

Y1 - 2021/1

N2 - BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

AB - BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age.METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter.RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported.CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

KW - Diffusion tensor imaging

KW - Glycerol phenylbutyrate

KW - Hyperammonemia

KW - Neonate

KW - Pediatric

KW - Urea cycle disorder

KW - Phenylacetates/administration & dosage

KW - Pediatrics

KW - Humans

KW - Ammonia/blood

KW - Child, Preschool

KW - Infant

KW - Male

KW - Glycerol/administration & dosage

KW - Urea Cycle Disorders, Inborn/blood

KW - Age of Onset

KW - Female

KW - Phenylbutyrates/administration & dosage

KW - Infant, Newborn

KW - Hyperammonemia/blood

KW - Renal Dialysis

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M3 - Article

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Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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