CLINICAL TRIAL: A PHASE 3, OPEN-LABEL STUDY OF THE SAFETY OF HPN-100 FOR THE LO

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT 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 or HPN-100), 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. HPN-100 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 long-term safety study of HPN-100 in adult subjects with urea cycle disorders. Subjects will be assessed regularly for safety and control of their venous ammonia. Hyperammonemic events will be characterized with respect to contributing factors such as intercurrent illness, diet, and noncompliance with medication. I. HYPOTHESIS HPN-100 is a safe and effective medication for the long-term treatment of adults with urea cycle disorders. II. SPECIFIC AIMS The specific aim of this study is to evaluate the long-term safety of HPN-100 and its control of venous ammonia in the management of UCDs.