Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: Safety, pharmacokinetics and ammonia control

Abstract

Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-hour blood ammonia.Methods-An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after ClinicalTrials.gov: NCT00551200Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMol Genet Metab. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Mol Genet Metab. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA).Results-Ten subjects completed the study. Adverse events were comparable for the two drugs; two subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were ~30% lower than on NaPBA (time normalized AUC = 26.2 vs. 38.4 μmol/L; Cmax = 56.3 vs. 79.1 μmol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time normalized AUC) by post hoc analysis. Systemic exposure (AUC 0-24 ) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 μg•h/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 μg•h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 μg•h/mL) were similar. Urinary PAGN excretion accounted for ~54% of PBA administered for both NaPBA and GPB; other metabolites accounted for < 1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=−0.82; p<0.0001) but weakly or not at all with blood metabolite levels.Conclusions-Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.

Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle

“…This compound has been shown to reduce protein mislocalization in diseases such as cystic fibrosis, cerebral ischemic injury, diabetes, Alzheimer's disease, and familial Parkinson's disease (28)(29)(30)(31)(32), and it has been approved for clinical use in patients with cystic fibrosis and to treat urea cycle disorders (28,33). Our results have potential clinical relevance, as they point out a pathological mechanism of desmin protein aggregation effected by plectin deficiency.…”

Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease

“…113 It also functions as a chemical chaperone because of the preferential hydration of the exposed polypeptide backbones and side chains of partially unfolded structures. 114,115 PBA is now used in the clinical setting for the treatment of diseases associated with protein misfolding, such as ␣1-antitrypsin deficiency and cystic fibrosis. 114,115 Ozcan et al have shown that chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.…”

“…114,115 PBA is now used in the clinical setting for the treatment of diseases associated with protein misfolding, such as ␣1-antitrypsin deficiency and cystic fibrosis. 114,115 Ozcan et al have shown that chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. 116 Erbay et al have shown that ER modification by chemical chaperones in macrophages and adipocytes has therapeutic efficacy against atherosclerosis in mouse models.…”

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

“…GPB has the same mechanism of action as sodium PB, but is a pre-pro drug consisting of phenylbutyric acid (PBA) linked to glycerol. 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).…”