title: Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
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.
  
  
  CONCLUSIONS
  Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).
authors.affiliation: Mount Sinai School of Medicine, Department of Genetics and Genomic Sciences, Department of Pediatrics, New York, NY, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Krivitzky
authors.forename: Masoud
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: William
authors.initials: W
authors.lastname: Rhead
authors.forename: James
authors.initials: J
authors.lastname: Bartley
authors.forename: Annette
authors.initials: A
authors.lastname: Feigenbaum
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: William
authors.initials: W
authors.lastname: Berquist
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
authors.forename: Renata
authors.initials: R
authors.lastname: Gallagher
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.forename: Dennis
authors.initials: D
authors.lastname: Bartholomew
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
authors.forename: Stephen
authors.initials: S
authors.lastname: Cederbaum
authors.forename: Shawn E
authors.initials: SE
authors.lastname: McCandless
authors.forename: Wendy
authors.initials: W
authors.lastname: Smith
authors.forename: Gerald
authors.initials: G
authors.lastname: Vockley
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bart
authors.forename: Mark S
authors.initials: MS
authors.lastname: Korson
authors.forename: David
authors.initials: D
authors.lastname: Kronn
authors.forename: Roberto
authors.initials: R
authors.lastname: Zori
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Merritt
authors.forename: Sandesh
authors.initials: S
authors.lastname: C S Nagamani
authors.forename: Joseph
authors.initials: J
authors.lastname: Mauney
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lemons
authors.forename: Klara
authors.initials: K
authors.lastname: Dickinson
authors.forename: Tristen L
authors.initials: TL
authors.lastname: Moors
authors.forename: Dion F
authors.initials: DF
authors.lastname: Coakley
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Scharschmidt
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000641:Ammonia / Q000097:blood*; D002648:Child; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005973:Glutamine / Q000097:blood; D005990:Glycerol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010654:Phenylbutyrates / Q000627:therapeutic use*; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D010654:Phenylbutyrates; D005973:Glutamine; D000641:Ammonia; C075773:4-phenylbutyric acid; D005990:Glycerol; C570223:glycerol phenylbutyrate