Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate

Abstract

Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved.

Conclusion: Glycerol phenylbutyrate exhibits favorable pharmacokinetics 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).

Copyright © 2012 American Association for the Study of Liver Diseases.

Figures

Figure 1

Short- and Long-Term Blood Ammonia Levels in UCD Patients. This figure depicts the pooled results of ammonia control during short term (2 to 4 week) treatment with sodium phenylbutyrate (NaPBA) or glycerol phenylbutyrate (GPB) (left panel) as well as of long term (up to 1 year) treatment with glycerol phenylbutyrate (right panel). The vertical bars represent standard error (SE). All ammonia values were normalized to a standard range of 9–35 umol/L, and the numbers at the bottom of the right panel indicate the number of patients for whom data were available at each timepoint.

Figure 2

Pooled Analysis of Blood Ammonia Across Subpopulations. The ratio of geometric means for blood ammonia, assessed as 24 hour area under the curve, during treatment with glycerol phenylbutyrate relative to treatment with NaPBA is depicted along with respective upper and lower 95% confidence intervals. An upper 95% CI of less than 1.25 was pre-specified as demonstrating non-inferiority. An upper 95% CI of less than 1.0 was pre-specified as indicating superiority.

Figure 3

UCD Patient Disposition. Forty of 44 patients completing Protocol HPN-100-006 enrolled into the 12-month safety protocol, HPN-100-007, in addition to 11 adult and 9 pediatric patients, for a total of 60. All patients completing the switchover part of Protocol HPN-100-005 entered the safety extension of this protocol, HPN-100-005SE, along with 9 additional pediatric patients who enrolled directly into HPN-100-005SE. Of the 77 patients total who enrolled in either HPN-100-007 or HPN-100-005SE, 69 completed, including 45 adult and 24 pediatric patients.

Figure 4

BRIEF Domain T scores in Pediatric Patients (6–17 yr) Treated with Glycerol Phenylbutyrate for 12 Months Scores are shown at baseline (grey symbols) and at the end of 12 months of glycerol phenylbutyrate treatment (black symbols) for pediatric patients ages 6–17. The T scores of 50 with a standard deviation (SD) of 10 are considered normative means for all BRIEF clinical scales, and a T score of 65 is generally considered clinically significant executive dysfunction (Krivitzky 2009). An asterisk indicates statistically significant improvement (*p