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Hyperion Therapeutics Announces Presentation of Long Term Data on Ammonia Control in Pediatric Patients Treated With RAVICTI(R) at the 12th International Congress of Inborn Errors of Metabolism and the Urea Cycle Disorder Satellite Symposium

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Thursday, September 05, 2013

SOUTH SAN FRANCISCO, Calif. - Hyperion Therapeutics, Inc., announced several data presentations at the 12th International Congress of Inborn Errors of Metabolism (ICIEM) and the satellite symposium on urea cycle disorders (UCDs) held in Barcelona, Spain. Among the presentations, the company highlighted long term data regarding ammonia control in pediatric patients with UCDs who were treated with RAVICTI® (glycerol phenylbutyrate) Oral Liquid. UCD patients lack enzymes or transporters necessary for the conversion of ammonia to urea and experience heightened levels of ammonia in the bloodstream. Left untreated, UCDs can result in neurological damage, coma, and/or death.

The long term, prospectively collected, data, which were presented by Susan Berry, M.D., Professor of Pediatrics and Division Director for Genetics and Metabolism in the Department of Pediatrics at the University of Minnesota, were pooled from two studies with RAVICTI which involved 49 pediatric UCD patients less than 18 years of age, including 23 patients ages 2 months through 5 years. During 12-months of treatment with RAVICTI, mean monthly ammonia levels ranged from 17.2 to 24.8 umol/L and remained below the upper limit of normal (35 umol/L). In addition, patients' physical growth and development were similar to the normal population, as determined by Z scores for height and weight being within one standard deviation of the normal age-matched population. During the 12-month pre-study period, 45% of patients reported 38 hyperammonemic crises whereas 25% experienced 17 crises during the 12 months of open-label RAVICTI dosing. Common adverse events reported were gastrointestinal and upper respiratory tract infections. Four patients did not complete the 12-month treatment period with RAVICTI.

Pooled analysis of data from two previously reported short term trials that independently demonstrated RAVICTI to be non-inferior to BUPHENYL® (sodium phenylbutyrate) (Lichter 2011, Smith 2013) were also presented. Among the 26 patients ages 2 months through 17 years enrolled in these two switchover studies, mean daily ammonia exposure assessed as 24-hour area under the curve was 872 vs. 627 µmol/L*h (p = 0.008) for BUPHENYL and RAVICTI respectively. The percentage of abnormal ammonia values on BUPHENYL and RAVICTI were 35% and 15% (p = 0.02), respectively. All patients switched from BUPHENYL to RAVICTI in a single step and adverse events reported by more than one patient on RAVICTI were abdominal pain and vomiting, which generally decreased and/or resolved with continued treatment.

"Pediatric patients under the age of 18 account for approximately 60 percent of UCD patients in the U.S." commented Dr. Berry, "and we are particularly encouraged by the findings among young children participating in these studies."

Also presented were analyses on both the relationship between fasting ammonia and outcome in UCDs. The post hoc analyses of fasting ammonia involved over 1000 ammonia values from 100 clinically stable UCD patients ages 2 months to > 70 years who participated in the short term switchover and/or long term RAVICTI treatment protocols. Fasting ammonia correlated strongly with total daily ammonia exposure (r=0.79; 0 < 0.0001) assessed as 24-hour area under the curve in the short term studies and, during long term dosing, correlated significantly and inversely with time to first hyperammonemic crisis (p < 0.0091). After controlling for age, gender and race, patients with a baseline fasting ammonia > 1.0 x ULN experienced a rate of hyperammonemic crises approximately 15 times higher than those with a fasting ammonia < 0.5 ULN (p=0.0004).

Bruce Scharschmidt, CMO, Hyperion Therapeutics, commented, "We believe these are important new findings which warrant further investigation and suggest that management of UCD patients designed to achieve tight ammonia control may result in improved ammonia control and fewer hyperammonemic crises."

RAVICTI Indications, Usage and Safety Information

RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥two years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and in some cases, dietary supplements (e.g. essential amino acids, arginine, citrulline, protein-free calorie supplements).

Limitations of Use:

RAVICTI is not indicated for the treatment of acute hyperammonemia in patients with UCD because more rapidly acting interventions are essential to reduce plasma ammonia levels.

The safety and efficacy of RAVICTI for the treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established.

RAVICTI is Contraindicated in Patients:

Less than two months of age. Children less than two months of age may have immature pancreatic exocrine function which could impair hydrolysis of RAVICTI, leading to impaired absorption of phenylbutyrate and hyperammonemia.

With known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, shortness of breath, coughing, low blood pressure, flushing, nausea and rash.

The major metabolite of RAVICTI, PAA, is associated with neurotoxicity at levels ≥ 500 μg/mL. If symptoms of vomiting, nausea, headache, drowsiness, or confusion are present in the absence of high ammonia or other intercurrent illnesses, reduce the RAVICTI dosage.

Pancreatic insufficiency or intestinal malabsorption may result in reduced or absent digestion of RAVICTI and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Monitor ammonia levels closely in these patients.

Most common adverse reactions in ≥10% of patients are: diarrhea, flatulence, headache, nausea, vomiting, fatigue, decreased appetite, hyperammonemia, dizziness, headache, upper abdominal (stomach) pain and rash.

Corticosteroids, valproic acid, or haloperidol may increase plasma ammonia levels; monitor ammonia levels closely when used concomitantly with RAVICTI. Probenecid may affect renal excretion of metabolites of RAVICTI including PAGN and PAA.

The use of RAVICTI in pregnant women may cause fetal harm. Breastfeeding is not recommended during RAVICTI treatment.

Please see full prescribing information for Ravicti at ( ) and Medication Guide ( for Ravicti.

About BUPHENYL (sodium phenylbutyrate) Tablets and Powder

BUPHENYL is indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). BUPHENYL should not be administered to patients with known hypersensitivity to sodium phenylbutyrate or any component of this preparation. The most common adverse reactions associated with BUPHENYL were amenorrhea dysfunction, decreased appetite, body odor (probably caused by its metabolite phenylacetate) and bad taste or taste aversion. Patients with urea cycle disorders should not take valproic acid, haloperidol, or steroids as these drugs have been reported to increase blood ammonia levels, and probenecid may affect the kidneys' excretion. Use with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states where there is sodium retention with edema. Use caution when administering to patients with hepatic or renal insufficiency or inborn errors of beta oxidation. The safety or efficacy of doses in excess of 20 grams (40 tablets) per day has not been established.

Please see full Prescribing Information for BUPHENYL at

About Hyperion Therapeutics

Hyperion Therapeutics, Inc. is a commercial stage biopharmaceutical company committed to developing and delivering life-changing treatments for orphan diseases and hepatology. The company's first commercial product, RAVICTI® (glycerol phenylbutyrate) Oral Liquid, was approved in February 2013 and is currently being marketed in the United States. The company also owns and markets BUPHENYL® (sodium phenylbutyrate) Tablets and Powder worldwide. For more information, please visit


Sylvia Wheeler
Vice President, Investor Relations
(650) 745-7834
Source: Hyperion Therapeutics, Inc.
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