Conclusion: Glycerol phenylbutyrate exhibits favorable pharmacokinetics Pexidartinib 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) Urea cycle disorders (UCD) are rare inborn errors of metabolism which result from mutations in the genes encoding for one of six enzymes or two transporters necessary for normal function of the urea cycle and are characterized by hyperammonemia and life-threatening hyperammonemic crises.1, 2 Hyperammonemia-related neurologic injury ranges from lethal cerebral edema to mild or subclinical cognitive impairment among individuals

with milder genetic defects.3 Abnormalities in executive function manifested by difficulty in goal setting, planning, monitoring progress, and purposeful problem solving significantly impair day-to-day functioning among children INCB024360 solubility dmso with UCDs, even in those with milder disease who present beyond the neonatal period.4 Management of UCD patients typically involves dietary protein restriction, dietary supplements, and when dietary management alone is insufficient, sodium phenylbutyrate (NaPBA), the only approved drug (Ucyclyd Pharma, U.S. trade name: Buphenyl, EU: Ammonaps) for treatment of UCDs.2, 5 Glycerol phenylbutyrate is an investigational agent being developed for UCDs.6-8 Like NaPBA, it contains phenylbutyric acid (PBA), a prodrug that is converted by way of β-oxidation to the active moiety, phenylacetic acid (PAA), which conjugates with

glutamine to form phenylacetylglutamine (PAGN). PAGN is excreted in the urine and mediates waste nitrogen excretion. Unlike NaPBA, glycerol phenylbutyrate consists of three molecules of PBA joined to glycerol in ester linkage that is hydrolyzed in the small intestine by pancreatic lipases to release PBA, contains no sodium, has minimal taste medchemexpress and no odor, and 17.4 mL of glycerol phenylbutyrate contains the same amount of PBA as 40 tablets of NaPBA, the maximal approved daily dose.6, 7, 8 The development of glycerol phenylbutyrate for UCD, rare disorders with fewer than 500 patients currently estimated to be treated with NaPBA in the U.S., has involved a cooperative effort among investigators of the NIH-funded UCD Consortium, the National Urea Cycle Disorders Foundation and Hyperion Therapeutics.2, 9, 10 This report describes the results of the pivotal Phase 3 study of glycerol phenylbutyrate for UCD, as well as short- and long-term ammonia control and neurocognitive outcomes among a total of 91 UCD patients participating in four clinical trials.