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Hyperion Therapeutics Announces Results of Phase I Study in Patients With Liver Cirrhosis

- Company preparing to initiate phase II trial in hepatic encephalopathy -

SOUTH SAN FRANCISCO, Calif., June 2 /PRNewswire/ -- Hyperion Therapeutics, Inc. today announced top-line results from a phase I study of HPN-100 in patients with liver cirrhosis. The data were presented as part of the 2009 Digestive Disease Week meeting. The abstract is titled "Pharmacokinetic (PK) and Safety Analyses of a Novel Ammonia-Reducing Agent in Healthy Adults and Patients with Cirrhosis."


This open-label study was designed to determine the safety, tolerability, and PK and pharmacodynamic (PD) profiles of HPN-100 administered orally to subjects with hepatic impairment and cirrhosis and to subjects with normal hepatic function. A total of thirty-two subjects were enrolled, including twenty four with cirrhosis (eight each Child-Pugh score A, B, and C), and eight age- and gender-matched healthy subjects with normal hepatic function. Subjects received a single oral dose (100mg/kg/d) of HPN-100 on day 1, two doses of 100mg/kg on each of days 8-14 (total of 200mg/kg/d), and a single dose on day 15 (100mg/kg/d). In order to assess the effects of food on HPN-100 PK, the dose was given fasting on Day 1 and with a meal on Day 8.

HPN-100 was metabolized via the expected major pathway, from phenylbutyrate (PBA) to phenylacetic acid (PAA) and then to phenylacetylglutamine (PAGN). PAGN mediates waste nitrogen excretion and ammonia removal. The extent of plasma exposure to PAA significantly correlated with MELD score (r2= 0.15; p= 0.03), but did not correlate significantly with glomerular filtration rate (r2= 0.01; p= 0.54) or Child-Pugh score (r2= 0.10; p= 0.08). No consistent differences between cirrhotic subjects and healthy volunteers were seen for the plasma PK variables on days 1 or 15. There were no statistically significant differences in the PK characteristics when HPN-100 was given fasting on day 1 or with a meal on day 8. Excretion of the main metabolite PAGN was similar between healthy adults and cirrhotic subjects. Urinary PAGN after the first dose on Day 1 ranged from 42-49% of the administered dose, and the mean total excretion of PAGN after the last dose in the study (day 15) ranged from 25,152 to 31,431 umol in the four treatment groups

There were no SAEs or AEs leading to withdrawal during the study. The most common system organ class was "investigations" (32 events in 18 subjects), and of these the most frequent individual AEs were increased body temperature, which was reported in 10 subjects (all from Child-Pugh groups A, B, and C), and decreased platelet count, which was reported in 4 subjects in Child-Pugh group A and 1 subject in the healthy volunteer group. There were no overall consistent patterns across all subject groups in changes in mean hematology, biochemistry, and coagulation variables.

"Hepatic encephalopathy (HE) is a significant clinical problem," said Brendan M. McGuire, M.D. Medical Director of Liver Transplantation at the University of Alabama. "I am encouraged by the phase I study results and look forward to further clinical studies."

About HPN-100

HPN-100 is an investigational product that is a pre-pro-drug of phenylacetic acid, the active moiety of BUPHENYL(R), the only therapy currently FDA-approved as adjunctive therapy for the chronic management of patients with the most prevalent urea cycle disorders: carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC) and argininosuccinic acid synthetase (AS) deficiencies. HPN-100, which is dosed orally in liquid form, is under clinical investigation as providing a potential alternative pathway to the urea cycle for the disposal of waste nitrogen through the renal excretion of phenylacetylglutamine (PAGN), which is formed from phenylacetic acid (PAA) and glutamine. Hyperion has initiated a phase III clinical program for the use of HPN-100 in the treatment of urea cycle disorders and plans to initiate a phase II program for the use of HPN-100 in treating hepatic encephalopathy later this year.

About Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a serious but potentially reversible neurological disorder that can occur in patients with acute liver failure and, most commonly, in patients with cirrhosis of any etiology. It comprises a spectrum of neurological signs and symptoms ranging from mild (e.g. minimal disorientation) to severe (e.g. coma, death) and is believed to occur when the brain is exposed to gut-derived toxins such as ammonia that are normally removed from the blood by a healthy liver. There are no therapies currently FDA-approved for the treatment of HE.

About Urea Cycle Disorders

Urea cycle disorders are inherited, inborn errors of metabolism present in an estimated 1 in 10,000 births in the United States. Patients with urea cycle disorders are deficient in one of the key enzymes that comprise the urea cycle, the body's primary vehicle for removing ammonia, a potent neurotoxin, from the bloodstream. Onset may occur at any age depending on the severity of the disorder. Left untreated, urea cycle disorders can cause dangerously heightened levels of ammonia in the bloodstream (hyperammonemia) resulting in brain damage, coma, and/or death.


BUPHENYL is indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of CPS, OTC, or 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.

About Hyperion Therapeutics

Hyperion Therapeutics is a privately held specialty pharmaceutical company focused on the development of therapies that address critical unmet needs in the areas of gastroenterology and hepatology. Hyperion and Ucyclyd Pharma, Inc., a subsidiary of Medicis Pharmaceutical Corporation, entered into a collaboration agreement for HPN-100 in August 2007. Under the terms of the agreement, Hyperion is conducting ongoing research and development of HPN-100 for urea cycle disorders, hepatic encephalopathy, and other forms of hyperammonemia. Hyperion is headquartered in South San Francisco, CA. For additional information, visit

BUPHENYL is a registered trademark of Ucyclyd Pharma, Inc.

Full Prescribing Information for BUPHENYL is available at or by contacting Ucyclyd Pharma, Inc.

SOURCE Hyperion Therapeutics, Inc.
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