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 Harding, Roberto Zori, Uta Lichter-Konecki, Jerry Vockley, Colleen Canavan, Thomas Vescio, Robert J. Holt, Susan A. Berry

Research output: Contribution to journalArticle

Abstract

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)
JournalMolecular Genetics and Metabolism
DOIs
StatePublished - Jan 1 2019

Fingerprint

Inborn Urea Cycle Disorder
Urea
Safety
Pediatrics
Ammonia
Therapeutics
glycerol phenylbutyrate
Glutamine
Population
Canada
Labels
Maintenance
Amino Acids

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. / Diaz, George A.; Schulze, Andreas; Longo, Nicola; Rhead, William; Feigenbaum, Annette; Wong, Derek; Merritt, J. Lawrence; Berquist, William; Gallagher, Renata C.; Bartholomew, Dennis; McCandless, Shawn E.; Smith, Wendy E.; Harding, Cary; Zori, Roberto; Lichter-Konecki, Uta; Vockley, Jerry; Canavan, Colleen; Vescio, Thomas; Holt, Robert J.; Berry, Susan A.

In: Molecular Genetics and Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

Diaz, GA, Schulze, A, Longo, N, Rhead, W, Feigenbaum, A, Wong, D, Merritt, JL, Berquist, W, Gallagher, RC, Bartholomew, D, McCandless, SE, Smith, WE, Harding, C, Zori, R, Lichter-Konecki, U, Vockley, J, Canavan, C, Vescio, T, Holt, RJ & Berry, SA 2019, 'Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients', Molecular Genetics and Metabolism. https://doi.org/10.1016/j.ymgme.2019.07.004
Diaz, George A. ; Schulze, Andreas ; Longo, Nicola ; Rhead, William ; Feigenbaum, Annette ; Wong, Derek ; Merritt, J. Lawrence ; Berquist, William ; Gallagher, Renata C. ; Bartholomew, Dennis ; McCandless, Shawn E. ; Smith, Wendy E. ; Harding, Cary ; Zori, Roberto ; Lichter-Konecki, Uta ; Vockley, Jerry ; Canavan, Colleen ; Vescio, Thomas ; Holt, Robert J. ; Berry, Susan A. / Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. In: Molecular Genetics and Metabolism. 2019.
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abstract = "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.",
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AU - Diaz, George A.

AU - Schulze, Andreas

AU - Longo, Nicola

AU - Rhead, William

AU - Feigenbaum, Annette

AU - Wong, Derek

AU - Merritt, J. Lawrence

AU - Berquist, William

AU - Gallagher, Renata C.

AU - Bartholomew, Dennis

AU - McCandless, Shawn E.

AU - Smith, Wendy E.

AU - Harding, Cary

AU - Zori, Roberto

AU - Lichter-Konecki, Uta

AU - Vockley, Jerry

AU - Canavan, Colleen

AU - Vescio, Thomas

AU - Holt, Robert J.

AU - Berry, Susan A.

PY - 2019/1/1

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N2 - 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.

AB - 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.

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