Glycerol phenylbutyrate significantly reduced the number of cirrhosis patients experiencing hepatic encephalopathy and the time to first event, a phase II trial has shown.
The randomized, double-blind placebo-controlled trial in 178 patients with cirrhosis found that only 21% of patients treated with glycerol phenylbutyrate (GPB) had a hepatic encephalopathy (HE) event compared with 36% of the placebo group (P =.02).
Treatment with 6 mL of oral GPB twice daily also significantly reduced the time to a first HE event (HR 0.56, 95% CI 0.32-0.99, P less than .05), in particular, more severe West Haven grade 2 events, according to a study published in the March issue of Hepatology.
The HE group also had significantly fewer total events (35 vs. 57, P less than .05), and treatment was associated with a nonsignificant reduction in HE hospitalizations (13 vs. 25; P = .06)
The treatment effect was more pronounced in the 119 patients not taking the antibiotic rifaximin at entry; among patients taking rifaximin there were no differences between the treatment arms in the number of patients experiencing an HE event, time to event, or total number of events (Hepatology 2014;59:1073-83).
Glycerol phenylbutyrate is currently approved for the treatment of urea cycle disorders and other inherited disorders characterized by an excess of ammonia in the blood.
This study followed a previous 4-week, open-label study that suggested this dose of GPB was well tolerated and lowered ammonia levels in patients with cirrhosis and HE.
"Though elevated blood ammonia has long been suspected as important, the evidence is largely correlative, other factors have been postulated, and evidence against ammonia has been reported," wrote Dr. Don C. Rockey of the Medical University of South Carolina, Charleston, and his colleagues.
In the current study, "GPB significantly lowered plasma ammonia and correlated strongly with HE events when assessed either at baseline or during the study."
Baseline ammonia levels were also higher among patients who subsequently experienced an HE event compared with those who did not, prompting the authors to suggest that elevated blood ammonia level does in fact play an important role in the pathogenesis of recurrent, overt HE.
Researchers reported similar types of adverse events in the two treatment arms and a similar frequency of these events, although serious adverse events and study drug discontinuations associated with adverse events occurred slightly more often in the GPB group.
"There were no treatment-related effects on liver biochemical tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, international normalized ratio (INR), or MELD [score]," the investigators wrote.
They concluced that "that GPB reduced the likelihood of HE events in patients with preexisting HE, and ... that it deserves further study as a potential therapeutic for these patients."
The study was funded by Hyperion Therapeutics. There were no other conflicts of interest declared.