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Reuters Health Information (2014-03-28): Glycerol phenylbutyrate improves hepatic encephalopathy outcomes


Glycerol phenylbutyrate improves hepatic encephalopathy outcomes

Last Updated: 2014-03-28 10:24:34 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Glycerol phenylbutyrate (GPB) lowers ammonia levels and reduces hepatic encephalopathy (HE) events, according to a new phase 2 trial.

"We are hopeful that GPB will be a candidate for first-line therapy for newly diagnosed patients as well as salvage treatment for patients failing other treatment," Dr. Bruce F. Scharschmidt, chief medical officer of Hyperion Therapeutics, Inc., South San Francisco, California, told Reuters Health by email. "This will of course depend on our phase 3 results."

Hyperion's GPB is approved for treatment of urea cycle disorders. It acts by providing an alternate pathway for ammonia removal and waste nitrogen excretion.

Dr. Scharschmidt and colleagues investigated the effects of GPB (6 mL twice daily by mouth for 16 weeks) in a double-blind, placebo-controlled trial of 178 patients with HE.

Significantly fewer patients in the GPB group (21%) than in the placebo group (36%) experienced an HE event during the study, the researchers report in Hepatology, online February 25.

The total number of HE events was significantly lower in the GPB arm (35 versus 57 in the placebo arm), and fewer patients in the GBP arm than in the placebo arm experienced dose interruptions (three patients with four interruptions versus 15 patients with 27 interruptions, respectively; p<0.01).

The treatment effect was much more pronounced among the 119 patients not taking rifaximin at entry, and there was no difference between GPB and placebo among the 59 patients who did take the antibiotic.

"Rifaximin is believed to act by lowering ammonia," Dr. Scharschmidt explained. "However, the data currently available suggest that GPB could be a more potent ammonia-lowering agent."

GPB patients also experienced fewer HE hospitalizations and fewer hospital days and had significantly lower ammonia levels, compared with placebo patients.

Adverse events occurred with similar frequency in the two groups and were as expected in a study population with clinically decompensated cirrhosis. All three deaths were attributed to the patients' advanced liver disease.

"The study has settled a question that has been debated for over a century," Dr. Scharschmidt said. "It has taught us that ammonia is a cause of hepatic encephalopathy."

"HE is a debilitating and humiliating problem for patients and their families and represents a huge cost (to) our healthcare system," Dr. Scharschmidt concluded. "We are proud of what this study has taught us about the cause of this important and growing medical problem."

"The study will become a hallmark because it initiates a new therapeutic approach to HE," write Dr. Juan Cordoba and Dr. Meritxell Ventura-Cots from Hospital Vall Hebron in Barcelona, Spain, in a related editorial.

"The results of the current study are very encouraging and provide a theoretical framework for better understanding the role of ammonia in HE," they conclude. "Next, it would be important to corroborate its preventive efficacy in different groups of patients and confirming the effects in episodic HE."

Hyperion funded the study and employed five of the 25 authors.


Hepatology 2014;59:1073-1083,764-766.

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