Pre-NDA Meeting Scheduled for December 7th
SOUTH SAN FRANCISCO, Calif.-- Hyperion Therapeutics, Inc. today announced that the Company’s phase III pivotal study of glycerol phenylbutyrate (HPN-100), an investigational drug for the treatment of urea cycle disorders (UCDs), met its primary endpoint. The non-inferiority study, conducted under a Special Protocol Assessment (SPA) granted by the U.S. Food and Drug Administration (FDA) in June 2009, evaluated the ammonia control of glycerol phenylbutyrate as compared to sodium phenylbutyrate (BUPHENYL®).
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 brain damage, coma, and/or death.
"These findings are an important step in evaluating glycerol phenylbutyrate as a potential treatment option for patients with UCDs,” said Brendan Lee, M.D., Ph.D., Howard Hughes Medical Institute Investigator and Professor Department of Molecular and Human Genetics, Baylor College of Medicine, who served as principal investigator.
“We appreciate the support we have received from the UCD community throughout our development program. This is an important milestone in our development of a therapy for patients with UCDs," said Donald J. Santel, Chief Executive Officer, Hyperion Therapeutics.
About the Study
The 4-week, multi-center, randomized, double-blind, cross-over phase III study was designed to evaluate the non-inferiority of glycerol phenylbutyrate to BUPHENYL® (sodium phenylbutyrate) in adults with urea cycle disorders. The primary efficacy measure was blood ammonia, assessed as 24-hour area under the curve on Days 14 and 28, the last day of each treatment period. Subjects were administered BUPHENYL or glycerol phenylbutyrate at equimolar doses (i.e. the same amount of active ingredient – phenylbutyric acid) equivalent to their prescribed dose of BUPHENYL before study enrollment. The drugs were administered TID with meals, and diet was strictly controlled. Day 14 and 28 measurements, the basis of comparison for the efficacy analysis, were carried out over 24 hours, including an overnight stay in a clinical study unit. All subjects completing the study were eligible to enter a 12-month, open label safety study which is on-going.
The study enrolled 46 adults at 19 sites in North America. 45 subjects received at least one dose of study drug and constituted the intent-to-treat (ITT) population; 44 completed the study. The mean daily dose was 13.49 g or 7.55 g/m2 for glycerol phenylbutyrate and 13.95 g or 7.8 g/m2 for BUPHENYL. Ninety-five percent confidence intervals for ammonia (24-hr AUC) on glycerol phenylbutyrate relative to BUPHENYL in the ITT population (0.799, 1.034) were below the predefined non-inferiority margin upper limit defined in the SPA (1.25). There were no statistically significant differences in ammonia levels between glycerol phenylbutyrate and BUPHENYL: mean (SD) = 34.7 (25.1) versus 38.4 (31.7) umol/L, and Cmax = 60.9 (46.2) versus 70.8 (66.7) umol/L, respectively.
At least one adverse event (AE) was reported by 23 subjects during BUPHENYL treatment and 27 subjects during glycerol phenylbutyrate treatment. The most common AEs reported during BUPHENYL treatment were dizziness, headache, nausea, diarrhea, dyspepsia, and abdominal discomfort. During the glycerol phenylbutyrate period, the most common AEs reported were diarrhea, flatulence, headache, vomiting, fatigue, decreased appetite, and abdominal pain. No deaths occurred during the study, and no clinically significant lab or ECG changes were observed for either treatment. One hyperammonemic crisis occurred on BUPHENYL, and one subject withdrew early from the study during BUPHENYL treatment because of high ammonia and headache.
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.
About Glycerol Phenylbutyrate
Glycerol phenylbutyrate (HPN-100), an investigational product, is a pre-pro-drug of phenylacetic acid, the active moiety of BUPHENYL®, 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. Glycerol phenylbutyrate holds orphan product designation in the US and Europe for maintenance treatment of patients with deficiencies in enzymes of the urea cycle. It also holds FDA Fast Track designation for this same indication.
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.