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- Title
Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
- Authors
Diaz, George A; Krivitzky, Lauren S; Mokhtarani, Masoud; Rhead, William; Bartley, James; Feigenbaum, Annette; Longo, Nicola; Berquist, William; Berry, Susan A; Gallagher, Renata; Lichter-Konecki, Uta; Bartholomew, Dennis; Harding, Cary O; Cederbaum, Stephen; McCandless, Shawn E; Smith, Wendy; Vockley, Gerald; Bart, Stephen A; Korson, Mark S; Kronn, David; Zori, Roberto; Merritt, J Lawrence, 2nd; C S Nagamani, Sandesh; Mauney, Joseph; Lemons, Cynthia; Dickinson, Klara; Moors, Tristen L; Coakley, Dion F; Scharschmidt, Bruce F; Lee, Brendan
- Abstract
Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved.
- Publication
Hepatology (Baltimore, Md.), 2013, Vol 57, Issue 6, p2171
- ISSN
1527-3350
- Publication type
Journal Article
- DOI
10.1002/hep.26058