GT4P COMPARED TO SODIUM PHENYLBUTYRATE IN UREA CYCLE DISORDERS

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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 (UCD's) represent a group of inherited diseases that usually present catastrophically with elevations of blood ammonia levels (hyerammonemia) in the newborn period and have a high mortality and morbidity due toa deficiency in or lack of an essential urea cycle enzyme. Current pharmacological treatment involves the use of alternative pathway therapy with phenylbutyrate (PBA) (Buphenyl¿) to scavenge nitrogen, combined with supplementation of the amino acids L citrulline or L-arginine. Buphenyl must be administered in large doses and has the complications of bad taste, sodium content and odor. GT4P is a pro-drug of Buphenyl, and is expected to provide similar nitrogen-scavenging abilities while eliminating the current issues associated with the drug. To further evaluate the safety and tolerabilty of GT4P as a replacement for Buphenyl, this will be a phase II, open-label, switch-over dose escalation study. For patients currently on Buphenyl, GT4P will be gradually phased in while Buphenyl is phased out, and then a switch will be made back to Buphenyl. Patients will be closely monitored for hyperammonemia during the transition to and from GT4P and a number of safety lab tests will be conducted. Results from the one previous clinical study indicate that GT4P will be safe and well tolerated and may be preferred by patients and their caregivers. Hopefully, with favorable results from this study, the next step will be phase III efficacy studies and the further establishment of GT4P as an alternative therapy to Buphenyl in patients with UCDs. Hypothesis: GT4P will be as safe and more tolerable than Buphenyl as a UCD treatment.