Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients

George A. Diaz, Andreas Schulze, Nicola Longo, William Rhead, Annette Feigenbaum, Derek Wong, J. Lawrence Merritt, William Berquist, Renata C. Gallagher, Dennis Bartholomew, Shawn E. McCandless, Wendy E. Smith, Cary O. Harding, Roberto Zori, Uta Lichter-Konecki, Jerry Vockley, Colleen Canavan, Thomas Vescio, Robert J. Holt, Susan A. Berry

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11 Scopus citations


INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB.

METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing.

RESULTS: A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure.

CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.

Original languageEnglish (US)
Pages (from-to)336-345
Number of pages10
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Aug 2019

Bibliographical note

Funding Information:
Horizon funded the development, conduct and analysis of the studies. Colleen Canavan, Thomas Vescio and Robert J. Holt are employees of and have stock in Horizon. Susan Berry, Nicola Longo, George Diaz, Shawn McCandless, J. Lawrence Merritt II, Wendy E. Smith, Roberto Zori and Jerry Vockley have served as Horizon Advisory Board members. The authors gratefully acknowledge and thank the efforts of the Study Coordinators and nursing staff who made these trials possible, including M. Mullins (Baylor College of Medicine, Howard Hughes Medical Institute), T. Carlson, S. Elsbecker (University of Minnesota), J. Crawford (Medical College of Wisconsin), K. Simpson (Children's National Medical Center), N. Schrager (Mount Sinai School of Medicine), S. Deward, J. Henry (Children's Hospital of Pittsburg of UPMC), L. Caspi, M. Ambreen, M. Mecija (Hospital for Sick Children), D. Naghmeh (UCLA Pediatrics/Genetics), L. Brody (Seattle's Children Hospital), C. Heggie (University Hospitals Case Medical Center), S. Mortensen (Maine Medical Center), C. Bailey (University of Utah), E. Merkel (Stanford University School of Medicine), S. Burr (Colorado Children's Hospital), J. Martin (Oregon Health & Science University), K. Regis (Nationwide Children's Hospital), M. Hunter (University of Florida), N. O'Donnell, M. Keuth (Long Beach Memorial). In addition, the authors would like to thank Megan Francis-Sedlak PhD and Teresa M.Y. Kok RPh, MBA from Horizon for data analysis, writing and editorial support. Some of the data in this report was previously presented in abstract form at the 2018 ACMG Annual Clinical Genetics Meeting (April 10–14, Charlotte, NC) and at the 2018 Southeastern Regional Genetics Group (SERGG) Annual Meeting (July 19–21, Asheville, NC).

Publisher Copyright:
© 2019 The Authors


  • Ammonia, glutamine
  • Glycerol phenylbutyrate
  • Long-term treatment
  • Urea cycle disorders


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