Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate

Abstract

Background Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. Methods 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 4 studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Results Glycerol phenylbutyrate was non-inferior to NaPBA with respect to ammonia control in the pivotal study, with mean (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 3 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 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 patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297).

Switch from Sodium Phenylbutyrate to Glycerol Phenylbutyrate Improved Metabolic Stability in an Adolescent with Ornithine Transcarbamylase Deficiency

“…Following hydrolysis by pancreatic lipases, PBA is released and converted to the active moiety, phenylacetic acid (Lee et al 2010;McGuire et al 2010;Monteleone et al 2013). In clinical trials, GPB has been shown to provide effective ammonia control in adult and pediatric UCD patients (Lichter-Konecki et al 2011;Smith et al 2013;Diaz et al 2013;Berry et al 2014).…”

Orally administered sodium 4‑phenylbutyrate suppresses the development of dextran sulfate sodium‑induced colitis in mice

“…In the present study, orally administered PBA was demonstrated to delay the onset of experimental colitis. PBA treatment is not accompanied by the particular side effects of existing IBD therapeutics, and has the added benefit of an oral route of administration (15)(16)(17)(18)(19)(20)(21). PBA may therefore be one of a new type of therapeutic agents, which includes anti-TNF-α therapies (29)(30)(31)(32)(33).…”

“…Sodium 4-phenylbutyrate (PBA) is an aromatic fatty acid analog that is typically used to treat urea cycle disorders (15). PBA has also shown potential as a therapeutic treatment in many other diseases, including homozygous β-thalassemia, spinal muscular atrophy, and a variety of tumors (16,17).…”

Nutrition Management of Urea Cycle Disorders

“…Sodium phenylacetate is available as Buphenyl ® (Hyperion Therapeutics Inc., Brisbane, CA). Glycerol phenylacetate (Ravicti ® , Hyperion Therapeutics Inc.) works by the same mechanisms as sodium phenylacetate, and some fi nd it easier to administer because the dose is lower and the taste is better than sodium phenylacetate [ 32 ]. Ammonul ® (Ucyclyd Pharma, Inc., Scottsdale, AZ) is an IV form of nitrogen-scavenging medication that contains a combination of sodium phenylacetate and sodium benzoate.…”