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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 languageEnglish (US)
Pages (from-to)19-26
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number1
StatePublished - 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


  • 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


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