This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urea cycle disorders (UCDs) are inborn errors of metabolism that can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). These disorders prevent the conversion of waste nitrogen into urea and result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of Buphenyl? (sodium phenylbutyrate) with citrulline or arginine. Although an effective treatment, Buphenyl? has some disadvantages, such as a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20 kg child), unpleasant taste, and high sodium content. There is some evidence from clinical trials of PBA for other indications that the high pill burden may decrease the likelihood of compliance with the treatment regimen. Glyceryl tri (4-phenylbutyrate) (GT4P), a prodrug of phenylbutyrate (PBA) (Buphenyl?) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl? in patients with UCDs. GT4P is expected to provide similar nitrogen-scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden. This is a phase 2, open-label, switch-over, dose-escalation study in patients with UCDs who are taking Buphenyl? as maintenance therapy. For each patient, GT4P will be introduced as a replacement for Buphenyl? gradually over a dose-escalation phase of up to 9 weeks, which may include up to 10 inpatient visits. GT4P will be a safe, well-tolerated alternative to Buphenyl? for patients with urea cycle disorders.
SPECIFIC AIMS The primary objective of this study is to evaluate the safety and tolerability of GT4P compared to Buphenyl? in patients with urea cycle disorders (UCDs). Secondary objectives are to assess: ? plasma and urine pharmacokinetic (PK) characteristics of GT4P and Buphenyl? metabolites. ? preliminary evidence of efficacy (as assessed by venous ammonia levels and urinary excretion of phenylacetylglutamine [PAGN]). ? amino acid levels. ? convenience and comfort associated with drug treatment as assessed by the patient or caregiver. ? compliance with study drug treatment as assessed by diary data. BACKGROUND AND SIGNIFICANCE The urea cycle is required for excretion of excess nitrogen compounds generated by dietary intake and protein catabolism. Human genetic deficiencies of urea cycle enzymes are well known and usually present in the neonatal period or early infancy with metabolic crises and subsequent neurological impairment. Each disease has significant variability in severity based on the heterogeneity of mutations and other factors. Urea cycle disorders can result from decreased or absent activity of any of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase (ARG). Treatment of urea cycle disorders relies on two strategies. The first is reduction of nitrogen load through the use of a protein-restricted diet. The second approach uses """"""""alternative"""""""" or latent enzymatic pathways of the liver to conjugate glutamine or glycine to carrier molecules and arginine supplementation to increase urinary excretion of nitrogenous products. Nitrogen-scavenging drugs for UCDs include sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate (Buphenyl?). Sodium phenylacetate, together with sodium benzoate (10%/10%) are marketed as AMMUNOL? Injection, which is administered intravenously as an acute treatment for hyperammonemia in patients with UCDs. Most patients with UCDs are managed chronically either by diet alone or by dietary nitrogen restriction plus oral doses of sodium phenylbutyrate with citrulline or arginine. Patient with UCDs who are treated with sodium phenylbutyrate may still experience episodes of hyperammonemic encephalopathy requiring hospitalization and immediate aggressive metabolic intervention. Orthotopic liver transplantation may also be considered for patients with severe disease. Buphenyl? (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS. It is also indicated in all patients with neonatal-onset deficiency (enzyme deficiency presenting in the first 28 days of life) and in patients with late-onset disease who have a history of hyperammonemic encephalopathy.1 Buphenyl? is orally administered in these patients to increase the excretion of nitrogen through conjugation with glutamine, providing an alternative waste elimination pathway that circumvents the urea cycle. Following oral administration, phenylbutyrate is converted to phenylacetate, which is then conjugated with glutamine in the liver and kidneys and excreted as phenylacetylglutamine (PAGN).2 Phenylacetylglutamine is excreted by both renal glomerular filtration and tubular secretion. The nitrogen content of PAGN per mole is identical to that of urea (both contain 2 moles of nitrogen). Although an effective treatment, Buphenyl? has some disadvantages. It has a high pill burden (approximately 40 tablets [20 g] per day for an adult or 4 tsp of powder for a 20-kg child), unpleasant taste and high sodium content. Buphenyl? also has a short half-life and therefore must be administered 3 to 6 times per day. Glyceryl tri (4-phenylbutyrate) (GT4P), a prodrug of phenylbutyrate (PBA) (Buphenyl?) and a pre-prodrug of the active compound phenylacetate (PAA), is under development as an alternative therapy to Buphenyl? in patients with UCDs. In the gastrointestinal tract or following absorption, GT4P is very rapidly enzymatically hydrolyzed to glycerol and PBA. So like Buphenyl?, GT4P is expected to provide a means of waste nitrogen disposal that circumvents the urea cycle. In distinct contrast to Buphenyl?, GT4P is odorless, colorless, tasteless oil. Additionally, there is no sodium burden on the patients with GT4P and a substantially reduced pill burden due to the concentrated nature of the drug. Results from the one previous clinical study conducted with GT4P suggest that GT4P will be safe and well tolerated and may be preferred by patients and their caregivers.
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