Susan A Berry1, Uta Lichter-Konecki2, George A Diaz3, Shawn E McCandless4, William Rhead5, Wendy Smith6, Cynthia Lemons7, Sandesh C S Nagamani8, Dion F Coakley9, Masoud Mokhtarani9, Bruce F Scharschmidt9, Brendan Lee8. 1. University of Minnesota, Minneapolis, MN, USA. Electronic address: berry002@umn.edu. 2. Children's National Medical Center, Washington, DC, USA. 3. Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Department of Pediatrics, New York, NY, USA. 4. Case Western Reserve University, Cleveland, OH, USA. 5. The Medical College of Wisconsin, Milwaukee, WI, USA. 6. Maine Medical Center, Portland, ME, USA. 7. National Urea Cycle Disorders Foundation, 75 S. Grand Ave., Pasadena, CA 91105, USA. 8. Baylor College of Medicine, Houston, TX, USA. 9. Hyperion Therapeutics, South San Francisco, CA, USA.
Abstract
OBJECTIVE: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.
OBJECTIVE: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.
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Authors: Sandesh C S Nagamani; George A Diaz; William Rhead; Susan A Berry; Cynthia Le Mons; Uta Lichter-Konecki; James Bartley; Annette Feigenbaum; Andreas Schulze; Nicola Longo; William Berquist; Renata Gallagher; Dennis Bartholomew; Cary O Harding; Mark S Korson; Shawn E McCandless; Wendy Smith; Jerry Vockley; David Kronn; Robert Zori; Stephen Cederbaum; J Lawrence Merritt; Derek Wong; Dion F Coakley; Bruce F Scharschmidt; Klara Dickinson; Miguel Marino; Brendan H Lee; Masoud Mokhtarani Journal: Mol Genet Metab Date: 2015-08-05 Impact factor: 4.797
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Authors: Brendan Lee; George A Diaz; William Rhead; Uta Lichter-Konecki; Annette Feigenbaum; Susan A Berry; Cindy Le Mons; James A Bartley; Nicola Longo; Sandesh C Nagamani; William Berquist; Renata Gallagher; Dennis Bartholomew; Cary O Harding; Mark S Korson; Shawn E McCandless; Wendy Smith; Stephen Cederbaum; Derek Wong; J Lawrence Merritt; Andreas Schulze; Jerry Vockley; Gerard Vockley; David Kronn; Roberto Zori; Marshall Summar; Douglas A Milikien; Miguel Marino; Dion F Coakley; Masoud Mokhtarani; Bruce F Scharschmidt Journal: Genet Med Date: 2014-12-11 Impact factor: 8.822