CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Comments on N203284 Ravicti glycerol phenyl butyrate
`
` From A. Jacobs, AD
`
` Date: Dec 10, 2012
`
`
`
`
`
`1. I concur that there are no pharm/tox approval issues and that the pregnancy category
`should be C. I concur with the Team leader that the nonstatistically significant tail effects
`in rat fetuses could be eliminated from the labeling
`
`2. I have conveyed other comments to the Team leader and they will be addressed as
`appropriate
`
`Reference ID: 3228387
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ABIGAIL C JACOBS
`12/10/2012
`
`Reference ID: 3228387
`
`

`

`ADDENDUM TO PHARMACOLOGY TEAM LEADER MEMORANDUM FOR
`NDA 203,284 DATED DECEMBER 10, 2012
`
`
`In the Pharmacology/Toxicology review by Dr. Ke Zhang (dated November 28, 2012),
`the following recommendation appears in the evaluation of the proposed labeling:
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Evaluation: The sponsor omitted this section from the proposed labeling. However, in
`the label for Buphenyl (sodium phenylbutyrate), the following paragraph is included
`under “PRECAUTIONS”:
`
`“Neurotoxicity of Phenylacetate in Animals”
`“When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused
`decreased proliferation and increased loss of neurons, and it reduced CNS myelin.
`Cerebral synapse maturation was retarded, and the number of functioning nerve
`terminals in the cerebrum was reduced, which resulted in impaired brain growth.
`Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the
`cortical pyramidal cells; dendritic spines were longer and thinner than normal and
`reduced in number.”
`
`Since phenylacetate is a major metabolite of glycerol phenylbutyrate, the same
`information should be included in the label for Ravicti.
`
`Recommended Version:
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Neurotoxicity of Phenylacetate in Animals
`
`When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused
`decreased proliferation and increased loss of neurons, and it reduced CNS myelin.
`Cerebral synapse maturation was retarded, and the number of functioning nerve
`terminals in the cerebrum was reduced, which resulted in impaired brain growth.
`Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the
`cortical pyramidal cells; dendritic spines were longer and thinner than normal and
`reduced in number.
`
`
`Comments:
`
`Dr. Zhang provided a reasonable argument for including this animal data in the Ravicti
`label, and I concurred with all of Dr. Zhang’s labeling recommendations in my Team
`Leader memorandum. However, I have reconsidered my view on this issue. First, it
`should be noted that the animal data summary, which originates from the Buphenyl®
`label, was based on data from an unidentified publication (see Pharmacology/
`
`Reference ID: 3253702
`
`

`

`Toxicology review of NDA 20,572 and 20,573 dated April 23, 1996). The study methods
`were not described in this review. However, the data summary in the Buphenyl® label
`does indicate that the active metabolite, phenylacetate (PAA), which is known to be
`neurotoxic, was injected subcutaneously in rat pups and presumably in pregnant rats for
`the prenatal exposure evaluation.
`
`The subcutaneous dosing of PAA in this study may have produced plasma levels higher
`than that achievable through oral administration of glycerol phenylbutyrate at an
`equivalent dose. Therefore, the relevance of the study results to the risk of
`neurotoxicity with orally administered glycerol phenylbutyrate is unknown. Furthermore,
`given that no detailed information about the study methods is available, the suitability of
`this data for inclusion in the Ravicti label is uncertain. Based on these considerations, it
`is appropriate to omit this nonclinical information in the Ravicti label.
`
`
`Recommendations:
`
`The nonclinical information from the Buphenyl® label, as shown above, should not be
`included in the Ravicti label.
`
`
`
`
` __________________________________ ____________
` David B. Joseph, Ph.D. Date
` Pharmacology Team Leader
`
`Division of Gastroenterology and Inborn Errors Products
`
`
`
`
`
`
`cc:
`NDA 203,284
`DGIEP
`DGIEP/PM
`DGIEP/Dr. Joseph
`DGIEP/Dr. Zhang
`DGIEP/Dr. Blank
`DGIEP/Dr. Griebel
`
`
`
`Reference ID: 3253702
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DAVID B JOSEPH
`01/31/2013
`
`Reference ID: 3253702
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`MEMORANDUM
`
`
`
`
`
`FROM: David B. Joseph
`
`Pharmacology Team Leader
`
`DATE: December 10, 2012
`
`SUBJECT: NDA 203,284 (SD # 1 dated December 23, 2011)
`
`Sponsor: Hyperion Therapeutics Inc.
`
`Drug Product: Ravicti™ (glycerol phenylbutyrate)
`
`Comments:
`
`1. Ravicti™ (glycerol phenylbutyrate) is a
`for oral administration, and is indicated for adjunctive therapy for chronic
`management of adult and pediatric patients with UCDs (urea cycle disorders).
`Glycerol phenylbutyrate is a triglyceride containing three molecules of 4-phenyl-
`butyric acid (PBA) linked to a glycerol backbone. The drug is metabolized to PBA
`and then PAA (phenylacetic acid), which is conjugated with glutamine to form PAGN
`(phenylacetylglutamine). PAGN is excreted in urine, thereby acting as a substitute
`for urea by mediating nitrogen excretion. Glycerol phenylbutyrate and sodium
`phenylbutyrate (Buphenyl®) are metabolized to the same active metabolite (PAA),
`therefore both drugs share the same mechanism of action. Buphenyl® is approved
`for adjunctive therapy in the chronic management of adult and pediatric patients with
`UCDs.
`
`)
`
`
`2. In the 2-year rat carcinogenicity study, glycerol phenylbutyrate produced an
`increased incidence of pancreatic acinar cell adenoma, carcinoma and combined
`adenoma or carcinoma, and Zymbal’s gland carcinoma in both male and female
`rats, and thyroid follicular cell adenoma, carcinoma and combined adenoma or
`carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial
`stromal polyp and combined polyp or sarcoma in female rats.
`
`
`3. Glycerol phenylbutyrate and its major metabolites are not genotoxic. Therefore, the
`drug-induced tumors in rats appear to be mediated by a non-genotoxic
`mechanism(s). A common mechanism for induction of thyroid follicular cell tumors
`in rodents is through hepatic microsomal enzyme induction (Capen, Toxicologic
`Pathology, 25(1), pg. 39-48, 1997). The metabolites PBA and PAA were shown to
`be P450 enzyme inducers in cultured human hepatocytes, and hepatocellular
`hypertrophy (indicative of enzyme induction) was observed in mice and monkeys in
`
`Reference ID: 3228212
`
`(b) (4)
`
`

`

`repeat-dose toxicity studies with glycerol phenylbutyrate. Although thyroid tumors
`occurred in rats in the 2-year carcinogenicity study, the available data from all rat
`studies does not clearly indicate whether glycerol phenylbutyrate or its metabolites
`produce enzyme induction. The Sponsor did not provide any study that evaluated
`enzyme induction in rats. However, a dose-dependent increase in liver weight
`occurred in the 3-month oral toxicity study in rats (up to 31% in females), but this
`effect was not associated with histological findings. Although hepatocellular
`hypertrophy was not observed in rats, the increased liver weight is consistent with
`enzyme induction. Therefore, the weight of evidence from rats and other species
`suggests that the thyroid tumors in rats were secondary to hepatic enzyme
`induction, a mechanism that does not appear to be relevant to the risk of thyroid
`tumor development in humans (Capen, Toxicologic Pathology, 25(1), pg. 39-48,
`1997). However, in the absence of additional studies (e.g. hepatic enzyme induction
`in rats, effects on TSH levels in rats), a final conclusion cannot be made regarding
`the mechanism of the thyroid follicular cell tumors produced by glycerol
`phenylbutyrate.
`
`
`
`Recommendations:
`
`There are no nonclinical issues which preclude the approval of Ravicti™. I concur with
`Dr. Zhang’s recommendation for approval, and his recommendations for labeling
`revisions.
`
`
`
`
`
` __________________________________ ____________
` David B. Joseph, Ph.D. Date
` Pharmacology Team Leader
`
`Division of Gastroenterology and Inborn Errors Products
`
`
`
`
`
`
`cc:
`NDA 203,284
`DGIEP
`DGIEP/PM
`DGIEP/Dr. Joseph
`DGIEP/Dr. Zhang
`DGIEP/Dr. Blank
`OND IO/Dr. Jacobs
`
`
`
`Reference ID: 3228212
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DAVID B JOSEPH
`12/10/2012
`
`Reference ID: 3228212
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Review Division:
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`
`203,284
`000
`December 23, 2011
`December 23, 2011
`Ravicti™ / glycerol phenylbutyrate
`Urea cycle disorders
`Hyperion Therapeutics
`South San Francisco, CA
`Division of Gastroenterology and Inborn Errors
`Products (DGIEP)
`Ke Zhang, Ph.D.
`Reviewer:
`David Joseph, Ph.D.
`Supervisor/Team Leader:
`Donna Griebel, M.D.
`Division Director:
`Jessica Benjamin
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203,284 are owned by Hyperion Therapeutics or are
`data for which Hyperion Therapeutics has obtained a written right of reference. Any
`information or data necessary for approval of NDA 203,384 that Hyperion Therapeutics
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`203,284.
`
`Reference ID: 3222607
`
`1
`
`

`

`NDA 203,284
`
`
`
`
`Ke Zhang
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 4
`2 DRUG INFORMATION ............................................................................................ 8
`2.1 DRUG................................................................................................................. 8
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 8
`2.3 DRUG FORMULATION ........................................................................................... 8
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 9
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 9
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 9
`2.7 REGULATORY BACKGROUND ................................................................................ 9
`3 STUDIES SUBMITTED.......................................................................................... 10
`3.1
`STUDIES REVIEWED........................................................................................... 10
`3.2
`STUDIES NOT REVIEWED ................................................................................... 13
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 13
`4 PHARMACOLOGY................................................................................................ 14
`PRIMARY PHARMACOLOGY................................................................................. 14
`4.1
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 17
`4.3
`SAFETY PHARMACOLOGY................................................................................... 17
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 19
`5.1
`PK/ADME........................................................................................................ 19
`TOXICOKINETICS ............................................................................................... 26
`5.2
`6 GENERAL TOXICOLOGY..................................................................................... 26
`SINGLE-DOSE TOXICITY..................................................................................... 26
`6.1
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 28
`7 GENETIC TOXICOLOGY ...................................................................................... 88
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 88
`IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 93
`7.2
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 99
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 101
`8 CARCINOGENICITY ........................................................................................... 132
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 178
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 178
`9.1
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 182
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 198
`9.3
`
`Reference ID: 3222607
`
`2
`
`

`

`NDA 203,284
`
`10
`
`SPECIAL TOXICOLOGY STUDIES................................................................. 211
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 211
`
`
`
`Ke Zhang
`
`APPENDIX/ATTACHMENTS........................................................................... 217
`
`Executive Summary
`Introduction
`
`12
`
`
`1.
`1.1
`
`Glycerol phenylbutyrate is a triglyceride containing three molecules of 4-phenylbutyric
`acid (PBA) linked to a glycerol backbone. Glycerol phenylbutyrate is hydrolyzed by
`lipases in the GI tract to glycerol and PBA following oral administration. PBA is then
`absorbed and metabolized to phenylacetic acid (PAA), which is subsequently
`conjugated with glutamine in the liver and kidneys to form phenylacetylglutamine
`(PAGN). PAGN is excreted in urine, thereby eliminating two moles of nitrogen on molar
`basis. Thus, PAGN is utilized as an alternate means for metabolic disposal of nitrogen
`waste in patients with genetic defects in their urea cycle. Buphenyl (sodium
`phenylbutyrate) is approved for treatment of urea cycle disorders. The current sponsor
`seeks market approval for glycerol phenylbutyrate as adjunctive therapy for chronic
`management of adult and pediatric patients ≥ 6 years of age with urea cycle disorders.
`
`1.2 Brief Discussion of Nonclinical Findings
`
`
`)
`Ravicti™ (glycerol phenylbutyrate) is a
`for oral administration. Glycerol phenylbutyrate was tested as a neat liquid in the
`nonclinical studies. The results of the repeated-dose oral toxicity studies revealed that
`the central nervous system was the target organ of toxicity based on clinical signs
`including hypoactivity, impaired equilibrium, ptosis, and shallow or labored respiration in
`mice, hypoactivity, impaired equilibrium, and rigid muscle tone in rats, and hypoactivity,
`impaired equilibrium, hunched posture, recumbency, labored respiration, and tremor in
`monkeys. Histopathologic examination revealed hepatocellular hypertrophy in 13-week
`oral toxicity studies in mice and monkeys and in the 52-week oral toxicity study in
`monkeys. Minimal to mild periductal mixed cellular infiltrates in liver were observed in a
`neonatal rat toxicity study after 7 weeks of treatment.
`
`
`Glycerol phenylbutyrate was not genotoxic in the Ames test, the in vitro
`chromosomal aberration test, or the in vivo rat micronucleus test. The metabolites PBA,
`PAA, PAGN, and phenylacetylglycine (PAG) were not genotoxic in the Ames test or the
`in vitro chromosomal aberration test.
`
`
`Glycerol phenylbutyrate was not tumorigenic in the 26-week carcinogenicity
`study in Tg.rasH2 mice at oral doses of 600 and 1000 mg/kg/day. In the 2-year
`carcinogenicity study in rats, glycerol phenylbutyrate increased the incidence of
`
`Reference ID: 3222607
`
`3
`
`(b) (4)
`
`

`

`
`
`Ke Zhang
`
`NDA 203,284
`
`pancreatic acinar cell adenoma, carcinoma and combined adenoma or carcinoma, and
`Zymbal’s gland carcinoma in both male and female rats, and thyroid follicular cell adenoma,
`carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or
`carcinoma, uterine endometrial stromal polyp and combined polyp or sarcoma in female
`rats. The exposure multiples which produced tumors were 4.7 in male rats and 8.4 in
`female rats relative to adult patients, and 3 in male rats and 5.5 in female rats relative to
`pediatric patients.
`
`
`Glycerol phenylbutyrate did not have adverse effects on fertility or reproductive
`function in rats at oral doses up to 0.9 g/kg/day, but did produce an increase in the
`number of non-viable embryos at 1.2 g/kg/day in the fertility and general reproduction
`toxicity study in rats.
`
`Glycerol phenylbutyrate had no adverse effects on embryo-fetal development in
`
`the oral developmental Segment II toxicity study in rabbits. In the oral developmental
`Segment II toxicity study in rats, the most common fetal effect was the presence of a
`cervical rib at the 7th cervical vertebra in the drug-treated rats. This effect was dose-
`dependent. Increased resorptions and reduced litter size were observed in the neonatal
`rat toxicity study.
`
`
`1.3 Recommendations
`
`1.3.1 Approvability
`From a nonclinical standpoint, the NDA application is approvable for the proposed
`indication.
`
`
`1.3.2 Additional Non Clinical Recommendations
`
`None
`
`1.3.3 Labeling
`
`Sponsor’s Version:
`
`8.1. Pregnancy
`Pregnancy Category C
`
`Reference ID: 3222607
`
`4
`
`(b) (4)
`
`

`

`NDA 203,284
`
`
`
`
`Ke Zhang
`
`Evaluation: The animal to human exposure ratios should be calculated using the
`combined AUCs for PBA and PAA, given that the human AUCs for these metabolites
`are similar. The incidence of cervical ribs at the 7th cervical vertebra in rat fetuses
`should be stated since this effect was dose-dependent and statistically significant. The
`description of
` should be
`deleted, since these findings were not statistically significant and occurred with low
`incidence. Adverse embryo-fetal effects (i.e. increased resorptions and reduced litter
`size) that were observed only in the reproduction phase of the neonatal rat toxicity study
`should also be stated.
`
`Recommended Version:
`
`8.1. Pregnancy
`
`Pregnancy Category C
`
`The potential for glycerol phenylbutyrate to cause teratogenic effects was studied in rats
`and rabbits. Oral administration of glycerol phenylbutyrate up to 350 mg/kg/day in
`rabbits produced maternal toxicity, but no effects on embryo-fetal development. In rats,
`oral doses of 650 mg/kg/day and higher produced maternal toxicity and adverse effects
`on embryo-fetal development including reduced fetal weights, and cervical ribs at the 7th
`cervical vertebra. The dose of 650 mg/kg/day in rats is approximately 5.7 times the
`dose of 6.87 ml/m2/day in adult patients, based on combined AUCs for PBA and PAA.
`No adverse effects were observed in rat fetuses at 300 mg/kg/day (1.9 times the dose
`of 6.87 ml/m2/day in adult patients, based on combined AUCs for PBA and PAA). In a
`neonatal rat study with daily dosing performed on post partum day 2 through mating and
`pregnancy after maturation, embryotoxicity (increased resorptions) occurred at 650
`mg/kg/day and litter size was reduced at 900 mg/kg/day. There are no adequate and
`well-controlled studies in pregnant women. Ravicti should be used during pregnancy
`only if the potential benefit justifies the potential risk to the fetus.
`
`
`Sponsor’s Version:
`
`
`Reference ID: 3222607
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 203,284
`
`
`
`
`Ke Zhang
`
`
`
`Evaluation: The description of tumor incidences in rats should be changed to conform
`to the conclusions of the FDA review of the rat carcinogenicity study. The animal to
`human exposure ratios should be calculated using the combined AUCs for PBA and
`PAA, given that the human AUCs for these metabolites are similar. The exposure ratios
`for both adult and pediactric patients should be stated.
`
`
`Recommended Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`In a 26-week study in transgenic (Tg.rasH2) mice, glycerol phenylbutyrate was not
`tumorigenic at doses up to 1000 mg/kg/day. In a two-year study in Sprague-Dawley
`rats, glycerol phenylbutyrate caused a statistically significant increase in the incidence
`of pancreatic acinar cell adenoma, carcinoma and combined adenoma or carcinoma at
`650 mg/kg/day in males (4.7 times the dose of 6.87 ml/m2/day in adult patients, based
`on combined AUCs for PBA and PAA) and 900 mg/kg/day in females (8.4 times the
`dose of 6.87 ml/m2/day in adult patients, based on combined AUCs for PBA and PAA).
`The incidence of the following tumors was also increased in female rats at 900
`mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or
`carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial
`stromal polyp and combined polyp or sarcoma. The dose of 650 mg/kg/day in male rats
`is 3 times the dose of 7.45 ml/m2/day in pediatric patients, based on combined AUCs for
`PBA and PAA. The dose of 900 mg/kg/day in female rats is 5.5 times the dose of 7.45
`ml/m2/day in pediatric patients, based on combined AUCs for PBA and PAA.
`
`Reference ID: 3222607
`
`6
`
`(b) (4)
`
`

`

`
`
`Ke Zhang
`
`NDA 203,284
`
`Mutagenesis
`Glycerol phenylbutyrate was not genotoxic in the Ames test, the in vitro chromosomal
`aberration test in human peripheral blood lymphocytes, or the in vivo rat micronucleus
`test. The metabolites PBA, PAA, PAGN, and phenylacetylglycine were not genotoxic in
`the Ames test or in vitro chromosome aberration test in Chinese hamster ovary cells.
`Impairment of Fertility
`Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and
`female rats at oral doses up to 900 mg/kg/day. However, the number of non-viable
`embryos was increased at 1200 mg/kg/day (approximately 7 times the dose of 6.87
`ml/m2/day in adult patients, based on combined AUCs for PBA and PAA).
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Evaluation: The sponsor omitted this section from the proposed labeling. However, in
`the label for Buphenyl (sodium phenylbutyrate), the following paragraph is included
`under “PRECAUTIONS”:
`
`“Neurotoxicity of Phenylacetate in Animals”
`“When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused
`decreased proliferation and increased loss of neurons, and it reduced CNS myelin.
`Cerebral synapse maturation was retarded, and the number of functioning nerve
`terminals in the cerebrum was reduced, which resulted in impaired brain growth.
`Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the
`cortical pyramidal cells; dendritic spines were longer and thinner than normal and
`reduced in number.”
`
`Since phenylacetate is a major metabolite of glycerol phenylbutyrate, the same
`information should be included in the label for Ravicti.
`
`Recommended Version:
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Neurotoxicity of Phenylacetate in Animals
`
`
`When given subcutaneously to rat pups, 190–474 mg/kg phenylacetate caused
`decreased proliferation and increased loss of neurons, and it reduced CNS myelin.
`Cerebral synapse maturation was retarded, and the number of functioning nerve
`terminals in the cerebrum was reduced, which resulted in impaired brain growth.
`Prenatal exposure of rat pups to phenylacetate produced lesions in layer 5 of the
`cortical pyramidal cells; dendritic spines were longer and thinner than normal and
`reduced in number.
`
`
`
`Reference ID: 3222607
`
`7
`
`

`

`NDA 203,284
`
`
`
`Ke Zhang
`
` 2
`
` Drug Information
`
`2.1 Drug
`
`Trade Name: Ravicti™
`
`Code Name: HPN-100
`
`Chemical Name: Glycerol phenylbutyrate (GPB) / Glyceryl Tri-(4-phenylbutyrate)
`(GT4P)
`
`Note: The code name, HPN-100, and abbreviations for the drug name, GPB and GT4P,
`are used in this review interchangeably.
`
`
`Molecular Formula/Molecular Weight:
`
`
`
`Structure or Biochemical Description:
`
`
`
`
`
`
`
`
`Pharmacologic Class: Nitrogen scavenging agent for hyperammonemia
`
`2.2 Relevant INDs, NDAs, and DMFs: IND 73,480
`
`2.3 Drug Formulation
`
`
`Reference ID: 3222607
`
`8
`
`

`

`NDA 203,284
`
`Ke Zhang
`
`RavictiTM is a
`colorless to pale yellow, and odorless.
`
`"M" for oral administration.
`There are
`
`It is
`“m
`
`2.4
`
`Comments on Novel Excipients: None
`
`2.5
`
`Comments on Impurities/Degradants of Concern: None
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`is adjunctive therapy for chronic management of
`The proposed indication for Ravicti
`adult and pediatric patients 2 6 years of age with urea cycle disorders involving
`deficiencies of the following enzymes: carbamyl phosphate synthetase (CPS), ornithine
`transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase
`(ASL) or arginase (ARG) as well as the mitochondrial transporter ornithine translocase
`(hyperornithinemia—hyperammonemia—homocitrullinuria [HHH] syndrome, also referred
`to as ornithine translocase deficiency).
`
`divided into 3
`m“)
`The recommended starting dose for an adult is
`doses. The recommended starting dose for pediatric patients is summarized in a table
`below taken from the sponsor's label.
`
`Table 1: Recommended Starting Dose for Pediatric Patient (6-17 years of age)
`
`BSA
`
`Recommended Startlng Dose
`
`0!) (4)
`
`The recommended dosing range for both adults and patients 6-17 years of age is 4.5 to
`11.2 mUm2/day (5.0 to 12.4 glm2/day). Total daily dose is not to exceed 17.5 mL (19.3
`9)-
`
`Regulatory Background
`
`In the pre-NDA
`Glycerol phenylbutyrate (RavictiTM) was developed under IND 73,480.
`meeting on December 7, 2010, the sponsor agreed to submit final study reports of all
`required nonclinical studies, including the statistical analysis of the tumor datasets from
`the rat and mouse carcinogenicity studies, in the NDA submission. All needed study
`reports are submitted to this NDA (see below).
`
`Reference ID: 3222607
`
`

`

`NDA 203,284
`
`Ke Zhang
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`Pharmacology
`
`Safety pharmacology
`
`
`Overview
`Test Article: Phenylacetlc Add (FAA),
`
`
`Lphenylbutrylc acid (PEA), Glycerol Pheuylbutyrate (GPB)1
`
`Location
`Testing Facility
`
`Vol. Page
`
`
`
`
`
`(b) (4)
`
`_
`)
`501-09 1
`7
`
`b
`
`b
`
`001094
`
`283-08011"
`
`L'CY
`0049053 0641‘
`L'CY
`003052669“
`
`
`
`
`
`
`
`Method of
`Type of Study
`Test System
`
`
`Administration
`
`Safety Phlrmncology
`)
`.
`~
`1..
`‘
`.
` Cardiovascular _ _
`
`
`hERG assay
`HEK-93 Translcctcd Lclls
`In rm 0
`Cardiovascular:
`‘
`'
`M
`.
`.
`
`Myocardial clamp
`Rabbtt mymytcs
`In m1 0
`Cardiovascular.
`
`.‘kn'hythmogenic potential
`via the Carlsson Model
`
`Rabbitd
`
`Oral
`
`,ll
`
`
`
`.
`.
`.
`-
`.
`‘
`Cynomolgus Monkey
`Cmdlox aswlar
`v.1
`‘
`Central Nervous System
`0“”
`CY“°“‘°15“5 Mm“)
`& Rcspimtion
`11ERG= human ether-a-go-go related gene. HEKfi-93=humm1emb1me kidney cells. line 293
`' Test mmle=phenylacenc acid [,PAAD
`1' Study report commits a GLP Compliante statement
`‘ Test artxc19:4-plleuy1buuylc acid (PBA)
`‘Teet mmle=glycerol phenylbutyrate (GPB). formerly referred to as glycet'yl III-(4 phenylbmyare) :‘GT4PW,
`
`Oral
`
`Pharmacokinetics
`
`Reference ID: 3222607
`
`1 0
`
`

`

`NDA 203,284
`
`Ke Zhang
`
`Table 2.4-2: Phal'macokinetic and Metabolism Studies Conducted with GPB
`
`Study
`
`Abso tion
`‘1’
`
`Monkey
`-
`
`0 6 91: of GPB (reat)
`'
`~‘ g
`‘
`
`U: i
`0025043564
`
`0-6 gkg of “C-GPB
`——m 0‘6 g PBA equivalents-kg
`——m- 06 g'kg of ‘C-GPB
`_
`a
`.
`Rat mouse dog rabbit
`l1000 11gmLJCPBA
`Protem bmdmg
`incl1k“; lnunan
`5-1000 ugmL C-PAA or
`,-
`1—250 pgmL “CPAGN
`Ra“ “1°“Se' d°g' rabb‘“
`1 pM—io mM of ”C-PBA
`monkey. human
`
`'
`
`In virro
`
`In vitro
`
`
`
`
`CFU0007
`UCY0008
`
`CFU0003
`
`PAJ 005
`
`.. ,
`Lo“ e_009
`
`Pancreatic lipase
`actixity against
`GPB
`
`Recombinant human
`PTL. PLRPZ. colipase.
`and CEL p .5ed from
`yeast
`
`.-
`In \ItTO
`
`0.5 mL of GPB
`
`Metabolism-
`
`Metabolism—
`inhibition
`
`Human Waves
`Human liver nncrosomes
`
`.-
`
`In vitro
`
`0 6 else. of 406912
`0.0287—86 mM PBA. or
`
`mm mm m m
`5 mM GPB or PBA
`CFUOOOS
`
`T
`
`Table 2.4-2: Pharmacokinetic and Metabolism Studies Conducted with GPB (Continued)
`
`_
`
`‘
`
`Study
`
`Drug—drug
`interaction:
`
`in mm enzymatic
`hydrolysis 0f GPB
`
`Human plasma
`Human liver microsomes
`Human intestinal
`
`microsomes
`Purified porcme lipase in
`simulated intestinal fluid
`
`9.4 or 25 uM of GPB
`
`——im 06 kzofI‘CGPB
`
`UCY0008
`
`1:11c:nlvsls of€633)
`
`Simulated intestinal fluid
`
`GPB loo—100000 H34“)
`
`A5195
`
`GPB = glycerol phenylbutymte; PBA = phenylbutymte; PAA= phenylacetic acid; 14C: carbon radiolabel;
`PTL = pancreatic triglyceride lipase; PLRPZ = pancreatic lipase related protein 2; CEL = carboxyl ester lipase.
`
`Reference ID: 3222607
`
`1 1
`
`

`

`NDA 203,284
`
`Toxicology
`
`Ke Zhang
`
`Table 2.4-3: Toxicology Studies Conducted with GPB
`
`_
`
`,
`
`GPB Doses
`
`Dosing
`
`,
`
`.
`
`_
`
`5mm... I:_— am
`~
`ems
`0.60. 0.90. 1.20. 1.50.
`
`In- 0051000.
`"051003;“,
`
`.
`Mice
`
`Repea‘ed d°5°
`
`0.65. 0.90. 1.2, 2.0
`M: 0.60. 0.90. 1.20
`
`F: 0.90. 1.50. 2.00
`
`0.55. 0.90. 1.2
`
`Monkeys
`
`0.75. 1.25. 1.75
`0.7. 1.1. 1.5
`
`GenotoxmiryGPB:
`
`.
`.
`S. aphzmunum
`
`_.
`
`‘,
`10—5000 11g, plate
`
`Chromosomal
`
`.
`.
`Human
`.‘
`7
`.
`W W...
`——m- 0.5.1.0. 2.0
`
`Carcinogenicity
`‘
`
`Repmchlction and
`femhty
`
`Developmental
`
`CD(SD) rats n F: 01‘ 0‘3. 0'9
`
`M: 0.07. 0.21 0.65
`‘
`
`Om]
`
`,,
`0‘61 0‘9' 1'”
`0.65. 0.9. 1.2. 1.5"
`0.3.0.65. 0.9
`b
`
`0.2. 0.4. 0.6
`
`“Wt—510007
`
`"
`
`671001
`
`"40510010
`”M67100:
`
`7602-100
`
`7-
`760-
`
`MR)
`
`671007
`
`_
`MQYUWU
`MQY00007
`MQY00008
`
`MQY00009
`
`May
`
`7
`
`-4 months
`
`.
`
`a
`
`GD 7—17
`GD 7-17
`
`GD 7-19
`
`
`
`0.15. 0,25. 0.35
`——m- 03.06.09
`
`GD 7—19
`MQYOOOIO
`cm—wzo movooou
`
`Reference ID: 3222607
`
`1 2
`
`

`

`NDA 203,284
`
`Ke Zhang
`
`Table 2.4-3: Toxicology Studies Conducted with GPB (Continued)
`
`.
`
`_
`
`GPB Doses
`
`Dosing
`
`,
`
`.
`
`.
`
`PND-’ —15:
`
`and
`PND-73—4
`
`QBL'00006
`
`PND 3—50:
`and PND Z—
`127139 (M):
`or PND Z—GD
`20 (F)
`GPB—- 31Vcerol phenylbutyrate: GD= gestation day; LD—- lactation daV'; NA: not applicable: PND: postnatal day.
`S" ' Male: 28 daVs prior to mating through sacnfrce; Female: 15 day5 prior to mating through gestation day. 7
`b Dose range—finding study
`
`065. 0.9. 1.2
`
`QBU00007
`
`Neonatal Juvenile
`
`
`Table 2.4-4: Toxic