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

`

`CLINICAL REVIEW
`Application Type NDA
`Application Number(s) 203284
`Priority or Standard S
`
`Submit Date(s) 12-23-11
`Received Date(s) 12-23-11
`PDUFA Goal Date 01-23-13
`Division / Office DGIEP
`
`Reviewer Name(s) Nancy F. Snow
`Review Completion
`11-27-12
`Date
`
`Established Name Glycerol Phenylbutyrate
`(Proposed) Trade Name Ravicti
`
`Therapeutic Class Not established
`Applicant Hyperion Therapeutics
`
`Formulation(s) Liquid
`Dosing Regimen TID with meals
`Indication(s) Adjunctive therapy for chronic
`management of patients with
`Urea Cycle Disorders
`Intended Population(s) Pediatric and adult patients
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3224463
`
`

`

`Clinical Review
`{NDA203284}
`Ravicti (glycerol phenylburyrate)
`
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ........................................ 7
`1.1 Recommendation on Regulatory Action ............................................................ 7
`1.2 Risk Benefit Assessment ................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 8
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information ......................................................................................... 11
`2.2 Tables of Currently Available Treatments for Proposed Indication .................. 13
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 13
`2.4
`Important Safety Issues with Consideration to Related Drugs ......................... 13
`2.5 Summary of Pre-submission Regulatory Activity Related to Submission ......... 14
`2.6 Other Relevant Background Information ......................................................... 15
`3 ETHICS AND GOOD CLINICAL PRACTICES ...................................................... 16
`3.1 Submission Quality and Integrity ..................................................................... 16
`3.2 Compliance with Good Clinical Practices ........................................................ 17
`3.3 Financial Disclosures ...................................................................................... 17
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................ 18
`4.1 Chemistry Manufacturing and Controls ........................................................... 18
`4.2 Clinical Microbiology ....................................................................................... 18
`4.3 Preclinical Pharmacology/Toxicology .............................................................. 18
`4.4 Clinical Pharmacology ..................................................................................... 19
`4.4.1 Mechanism of Action ................................................................................. 19
`4.4.2 Pharmacodynamics .................................................................................. 20
`4.4.3 Pharmacokinetics ..................................................................................... 21
`5 SOURCES OF CLINICAL DATA .......................................................................... 24
`5.1 Tables of Studies/Clinical Trials ...................................................................... 25
`5.2 Review Strategy .............................................................................................. 25
`5.3 Discussion of Individual Studies/Clinical Trials ................................................ 25
`6 REVIEW OF EFFICACY ........................................................................................ 33
`6.1
`Indication......................................................................................................... 33
`6.1.1 Methods .................................................................................................... 33
`6.1.2 Demographics ........................................................................................... 33
`6.1.3 Subject Disposition ................................................................................... 35
`6.1.4 Analysis of Primary Endpoint(s) ................................................................ 36
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 38
`6.1.6 Other Endpoints ........................................................................................ 42
`6.1.7 Subpopulations ......................................................................................... 43
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`Clinical Review
`{NDA203284}
`Ravicti (glycerol phenylburyrate)
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`
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 43
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ................ 45
`7 REVIEW OF SAFETY ........................................................................................... 49
`7.1 Methods .......................................................................................................... 49
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 49
`7.1.2 Categorization of Adverse Events ............................................................. 49
`7.1.3 Pooling of Data across Studies/Clinical Trials to Estimate and Compare
`Incidence .................................................................................................. 49
`7.2 Adequacy of Safety Assessments ................................................................... 49
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations .................................................................................... 50
`7.2.2 Explorations for Dose Response ............................................................... 50
`7.2.3 Special Animal and/or In Vitro Testing ...................................................... 50
`7.2.4 Routine Clinical Testing ............................................................................ 51
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 51
`7.3 Major Safety Results ....................................................................................... 51
`7.3.1 Deaths ...................................................................................................... 51
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 52
`7.3.3 Dropouts and/or Discontinuations ............................................................. 53
`7.3.4 Significant Adverse Events ....................................................................... 58
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 58
`7.4 Supportive Safety Results ............................................................................... 67
`7.4.1 Common Adverse Events ......................................................................... 67
`7.4.3 Vital Signs ................................................................................................. 73
`7.4.4 Electrocardiograms (ECGs) ...................................................................... 73
`7.4.5 Special Safety Studies/Clinical Trials ........................................................ 73
`7.4.6
`Immunogenicity ......................................................................................... 74
`7.5 Other Safety Explorations ............................................................................... 74
`7.5.1 Dose Dependency for Adverse Events...................................................... 74
`7.5.2 Time Dependency for Adverse Events ...................................................... 74
`7.5.3 Drug-Demographic Interactions ................................................................ 74
`7.5.4 Drug-Disease Interactions......................................................................... 75
`7.5.5 Drug-Drug Interactions .............................................................................. 75
`7.6 Additional Safety Evaluations .......................................................................... 75
`7.6.1 Human Carcinogenicity ............................................................................. 75
`7.6.2 Human Reproduction and Pregnancy Data ............................................... 75
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 75
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ..................... 76
`7.7 Additional Submissions / Safety Issues ........................................................... 76
`8 POSTMARKET EXPERIENCE .............................................................................. 76
`9 APPENDICES ....................................................................................................... 77
`9.1 Literature Review/References ......................................................................... 77
`9.2 Labeling Recommendations ............................................................................ 77
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`Clinical Review
`{NDA203284}
`Ravicti (glycerol phenylburyrate)
`
`
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`
`9.3 Advisory Committee Meeting........................................................................... 77
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`Clinical Review
`{NDA203284}
`Ravicti (glycerol phenylburyrate)
`
`
`Table of Tables
`Table 1 Currently Available Treatment for Proposed Indication .................................... 13
`Table 2 PK Parameters (steady-state) NaPBA vs. HPN-100 ........................................ 21
`Table 3 Tables of Clinical Trials ................................................................................... 25
`Table 4 Treatment Arms .............................................................................................. 26
`Table 5 HPN-100-006 Schedule of Study Assessments .............................................. 27
`Table 6 HPN-100-012 Schedule of Assessments ........................................................ 31
`Table 7 Baseline Characteristics UCD Population Receiving Ravicti ........................... 34
`Table 8 Additional Baseline Characteristics ................................................................. 35
`Table 9 Patient Disposition, Pooled Analysis ............................................................... 36
`Table 10 Non-Inferiority Analysis Study 006 ................................................................ 37
`Table 11 Non-Inferiority Analysis of Blood Ammonia AUC0-24 across Studies ............ 38
`Table 12 Mean Blood Ammonia AUC0-24 and Cmax .................................................. 39
`Table 13 Ammonia Values above Upper Limit Normal ................................................. 40
`Table 14 Pooled Analysis: Mean Blood Ammonia ........................................................ 40
`Table 15 Hyperammonemic Crisis Long-Term Studies HPN-100 ................................. 41
`Table 16 Correlation Total Dose with Blood Ammonia and Metabolites ....................... 42
`Table 17 PK parameters at Steady State – HPN-100 vs. NaPBA (ITT) ........................ 42
`Table 18 HPN-100 Proposed Starting Dose ................................................................. 44
`Table 19 HPN-100-005SE Mean (SD) and Maximum Ammonia Levels Over Time ...... 46
`Table 20 HPN-100-007 On-study Hyperammonemic Crises ........................................ 48
`Table 21 HPN-100-007 Hyperammonemia .................................................................. 48
`Table 22 HPN-100-011 Serious Adverse Events as of 01 March 2012 ........................ 53
`Table 23 Percentage of Patients with Neurologic Adverse Events ............................... 56
`Table 24 PK of HPN-100 and NaPBA in Adult and Pediatric UCD Patients ................. 59
`Table 25 PK Parameters of PAA at Steady State for NaPBA and HPN-100 ................. 60
`Table 26 Adverse Events HPN-100-012 Switch-Over .................................................. 61
`Table 27 AEs subject 05-1209. .................................................................................... 62
`Table 28 TEAE in Short and Long Term Studies .......................................................... 63
`Table 29 Toxicities Reported to be Associated with PAA Reported during NDA2-3284
`Short-Term Trials .......................................................................................... 63
`Table 30 Toxicities Reported to be Associated with PAA Reported during NDA203284
`Long-Term Studies ....................................................................................... 64
`Table 31 TEAE in ≥ 2 patient HPN-100-006 ................................................................. 68
`Table 32 Common TEAS in UCD patients short and long term studies ........................ 69
`Table 33 Change from Baseline and Shifts in Liver Function Tests in Long-Term Open-
`Label Studies HPN-100 ................................................................................ 70
`Table 34 Summary of Changes from Baseline and Shifts in Hematology Parameters
`HPN-100 Open-Label Studies ...................................................................... 71
`Table 35 Shift Tables Chemistry HPN-100 Long-Term Studies .................................... 72
`Table 36 Shifts from baseline Coagulation Parameters Long-Term ............................. 73
`Table 37 TEAE & TESAE Short-Term Trials ................................................................ 75
`
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`Clinical Review
`{NDA203284}
`Ravicti (glycerol phenylburyrate)
`
`
`Table of Figures
`Figure 1 Alternate Pathway for Nitrogen Disposal ........................................................ 10
`Figure 2 Structural Formula ......................................................................................... 12
`Figure 3 Metabolic Pathway of HPN-100 ..................................................................... 13
`Figure 4 Approaches to Hyperammonemia ................................................................. 16
`Figure 5 Alternative Pathway for Nitrogen Disposal ..................................................... 20
`Figure 6 Mean Plasma PAA Concentration-Time Profile .............................................. 22
`Figure 7 Mean U-PAGN excreted during Steady-State Dosing .................................... 23
`Figure 8 Analysis of Blood Ammonia AUC across subpopulations ............................... 43
`Figure 9 HPN-100-007 Mean Ammonia Levels over Time ........................................... 47
`Figure 10 Cmax of PAA in Subject with and Without TEAE of Nervous System ........... 56
`Figure 11 PAA levels and dose tQT study .................................................................... 57
`Figure 12 PAA levels and nervous system disorders UCD patients ............................. 57
`Figure 13 Adult with Highest PAA value and TEAEs during short and long term
`treatment ...................................................................................................... 65
`Figure 14 Adult UCD patient with highest PAA during Short and Long-term treatment
`with HPN-100 ............................................................................................... 66
`Figure 15 Pediatric UCD patients with highest PAA with Ammonia and TEAEs ........... 66
`Figure 16 Pediatric UCD Patient with PAA, Ammonia and TEAEs ............................... 67
`
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`
`1 Recommendations/Risk Benefit Assessment
`1.1 Recommendation on Regulatory Action
`
`Approval of this application is recommended. The population studied in the Ravicti
`clinical development program, patients with Urea Cycle Disorders (UCD) aged 29 days
`and older, requires life-long treatment for this rare and life-threatening condition. Since
`1996 treatment has been available for chronic management in the form of sodium
`phenylbutyrate (Buphenyl®). Ravicti was found to be non-inferior to Buphenyl in a
`single Phase 3 study of UCD patients with deficiencies of carbamyl phosphate
`synthetase (CPS), ornithine transcarbamylase deficiency (OTC), or argininosuccinate
`(ASS). In a small cross-over study fifteen pediatric patients age 29 days to 6 years
`were switched from Buphenyl to Ravicti and followed for ten days.
`
`1.2 Risk Benefit Assessment
`
`The risk-benefit assessment supports approval of Ravicti based on the following
`considerations:
`
`Risks - A 2-year study to assess the carcinogenic potential of HPN-100 was conducted
`in male and female Sprague-Dawley rats. The rat carcinogenicity study showed an
`increased incidence of tumors of the pancreas, thyroid, adrenal cortex, uterus, Zymbal’s
`glands, and cervix. Because Buphenyl and Ravicti share the same active moiety these
`findings would pertain to Buphenyl as well. No carcinogenicity studies were submitted
`with the Buphenyl application. A search by the FDA Division of Pharmacovigilance for
`reports in the adverse events reporting system (AERS), or literature reports of
`neoplasms in UCD patients taking Buphenyl did not yield any cases.
`
` second potential risk of Ravicti is toxicity of the active metabolite phenylacetic acid
`(PAA). PAA toxicity has been reported in UCD and non-UCD patients receiving
`intravenous sodium benzoate and sodium phenylacetate. In studies conducted for the
`Ravicti application adverse events in UCD patients suggestive of PAA toxicity were not
`seen. However in some studies PAA levels were not obtained, either because blood
`samples could not be drawn or because obtaining PAA levels was not part of the study
`protocol. In adult UCD patients PAA levels were lower with Ravicti than NaPBA. PAA
`levels were higher in pediatric patients than adults for both Ravicti and Buphenyl.
`
`Dosing of Ravicti was based on the dose of Buphenyl the patient was receiving at
`baseline, and in cross-over studies doses were not titrated. Although patients in the
`Phase 3 safety and efficacy trial had similar outcomes whether receiving Ravicti or
`Buphenyl, this trial did not enroll pediatric patients. In a small pediatric study of UCD
`patients under the age of 6, only four patients were less than two years of age, and one
`less than 12 months. Overall, there is a paucity of data available in pediatric patients
`
` A
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`upon which to base dosing to control ammonia levels while also maintaining safe levels
`of the metabolite phenylacetic acid.
`
`Benefits – If approved, Ravicti will be the second nitrogen scavenging drug to be
`available, in conjunction with diet, for chronic management of UCDs. In the clinical
`studies in UCD patients there were no deaths. The overall adverse event (AE) profile
`was similar to that of NaPBA, and AEs tended to diminish over time. Ravicti was able to
`control ammonia levels as well as NaPBA, and also reduce glutamine levels.
`
`Ravicti has further benefits with respect to formulation palatability and sodium load. For
`patients of the ASL subtype, who are genetically prone to hypertension, the high sodium
`content of Buphenyl is problematic. In contrast, Ravicti is sodium free. In addition the
`taste and odor of Ravicti is more neutral, and the pill burden and volume of liquid
`associated with drug administration is less.
`
`In the final analysis, UCDs are rare diseases, and patients require life-long treatment for
`their condition. Although Ravicti is not risk-free, the risks that have been identified with
`Ravicti would pertain to Buphenyl as well. The benefits and ease of use outweigh the
`risks associated with this drug.
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`This reviewer does not recommend that a postmarket risk evaluation and mitigation
`strategy (REMS) be implemented. At the time of the NDA submission data on pediatric
`patients less than six years of age were not available. In order to limit access to Ravicti
`only to patients six years of age and older the company submitted a REMS. In April
`2012 the sponsor completed study HPN-100-012, which studied pediatric patients down
`to ≥ 29 days. As is discussed later in this review, fifteen patients aged >29 days to six
`years were successfully switched from Buphenyl to Ravicti. Although the number of
`patients is small, it is acceptable for this rare disease, whose prevalence is <2000
`patients. Ravicti was found to work as well as Buphenyl in controlling serum ammonia
`levels in this patient population, with few adverse events reported. Study HPN-100-012
`provided efficacy and safety data for Ravicti that had previously been missing, and
`obviates the need for REMS.
`
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`Two postmarketing studies are recommended:
`
`
`• A PK and safety study in pediatric patients under the age of two years to better
`inform dosing in this age group.
`• A repeat thorough QT (tQT) study to assess the cardiovascular safety of Ravicti
`in which assay sensitivity is demonstrated.
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`2 Introduction and Regulatory Background
`Urea Cycle Disorders
`Urea Cycle Disorders (UCDs) are rare genetic disorders resulting from deficiencies of
`the following enzymes or transporters: N-acetylglutamate synthase (NAGS), carbamyl
`phosphate synthetase (CPS), ornithine transcarbamylase 1 (OTC 1), argininosuccinate
`synthetase (AS or ASS), argininosuccinate lyase (AL or ASL), arginase (ARG). These
`disorders prevent the normal conversion of waste nitrogen into urea, and result in the
`accumulation of toxic levels of ammonia in the blood and brain of affected patients.
`
`The clinical manifestations of UCDs are due to hyperammonemia, and management is
`based on controlling ammonia levels and avoiding a hyperammonemic crisis. Some
`patients have a total or near total absence of activity of the first four enzymes of the
`urea cycle (CPS, OTC, AS, AL) and accumulate ammonia and other precursor
`metabolites during the first few days of life. Other patients may have a milder form of the
`disease. In the second group hyperammonemia is less severe, and symptoms more
`subtle than in patients with early-onset disease.1
`
`Treatments are aimed at reducing ureagenesis through dietary protein restriction,
`arginine or citrulline supplementation (which can enhance waste nitrogen excretion in
`patients with ASS and ASL subtypes), and administration of nitrogen-scavenging drugs.
`Currently approved nitrogen scavenging drugs include sodium phenylbutyrate
`(BUPHENYL®) tablets or powder for chronic management of UCDs, and intravenous
`sodium phenylacetate with sodium benzoate (AMMONUL®) for acute management of
`hyperammonemia.
`
`The following Figure 1depicts the alternative pathway for nitrogen disposal in lieu of the
`urea cycle. The large circle at the center shows the site at which each enzyme functions
`in patients without urea cycle disorders. The pathway on the right bypasses the urea
`cycle, and provides patients lacking in critical UCD enzymes an alternate pathway by
`which to dispose of nitrogen.
`
`
`
`1 Summar ML, Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders
`from a 21-year, multicenter study of acute hyperammonaemic episodes. Acta Paediatrica 2008; 97:1420.
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`Figure 1 Alternate Pathway for Nitrogen Disposal
`
`
`
`
`[Ref: HPN-100-007 Clinical Study Report, Figure 1, p.17]
`
`Glycerol phenylbutyrate (Ravicti) is a pre prodrug that contains 3 moles of phenylbutyric
`acid (PBA) joined to glycerol in an ester linkage. In the small intestine it is hydrolyzed by
`pancreatic lipases to PBA, and then follows the same chemical pathway as Buphenyl.
`Results of an in vitro study of pancreatic lipase activity against HPN-100 conducted
`during Ravicti development showed that pancreatic triglyceride lipase (PTL), carboxyl
`ester lipase (CEL) and pancreatic lipase related protein 2 (PLRP2) all hydrolyzed HPN-
`100. This is important because even though PTL is absent in the early neonatal period,
`PLRP2 and CEL may contribute to digestion of HPN-100 until the appearance of PTL.
`[Ref: Digestive Lipases Activity on HPN-100]
`
`The rationale for developing HPN-100 (Ravicti) is that it lacks the high pill burden, odor,
`bad taste, and high sodium content (~2300 mg/d for patients taking 20 g Buphenyl)
`associated with Buphenyl. Removing these impediments may increase compliance, and
`decrease hyperammonemic episodes.
`
`Reviewer’s Comment:
`
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`Clinical Review
`
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`In the NDA review the names Ravicti, HPN-100, and glycerol phenylbutyrate are used
`interchangeably. All are the to-be-marketed drug product. Likewise the currently
`approved drug Buphenyl is also referred to as NaPBA, or sodium phenylbutyrate.
`
`2. 1
`
`Product Information
`
`Established name: Glycerol Phenylbutyrate
`
`Proposed Trade Name: Ravicti
`
`Chemical Class: Ester
`
`Pharmacological class:
`Ravicti is a triglyceride with three molecules of phenylbutyrate (PBA) joined via an ester
`linkage to a glycerol backbone. It is a predrug of PBA and a pre-prodrug of
`phenylacetate (PAA), the active moiety of the compound. The pharmacotherapeutic
`group is expected to be alimentary tract and metabolism product.
`
`Proposed Indications:
`The proposed indication for Ravicti is adjunctive therapy for chronic management of
`adult and pediatric patients
`m" with urea cycle disorders involving deficiencies of
`the following enzymes: carbamyl phosphate synthetase (CPS), ornithine
`transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate Iyase
`(ASL) or arginase (ARG) as well as the mitochondrial transporter ornithine translocase
`(hyperornithinemia—hyperammonemia—homocitrulIinuria [HH H] syndrome, also referred
`to as ornithine translocase deficiency).
`
`Dosing Regimen:
`The sponsor’s recommended starting dose is based on body surface area (BSA). For
`patients with a BSA
`"””
`
`‘”"" adult UCD patients is 4.5
`The recommended dosing range for
`mUm lday to 11.2 mL/mzlday [5.0 glmzlday to 12.4 glm Iday); with the total daily dose
`not to exceed 17.5 mL [199]).
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`Clinical Review
`
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`Figure 2 Structural Formula
`
`Structural formula:
`
`0 o
`o\)\,o o
`
`m
`
`Molecular formula:
`
`C33H3x05
`
`Relative Molecular Mass:
`
`530.67
`
`The drug product is composed 01
`colorless to pale yellow liquid, filled into glass bottles. There are
`
`“m a clear
`
`“m"
`
`After oral administration glycerol phenylbutyrate is hydrolyzed to phenylbutyrate (PBA)
`in the gastrointestinal tract by intestinal lipases. Intact HPN-100 is not detected in the
`circulation. Phenylbutyrate undergoes Ill-oxidation to the active metabolite,
`phenylacetate (PAA). PAA is conjugated with glutamine via acetylation in the liver and
`kidney to form phenylacetylglutamine, and excreted in the urine as U-PAGN. Glutamine
`levels correlate with plasma ammonia; elevated levels of glutamine can result in
`accumulation of glutamine in glial cells, and cause cerebral edema. The nitrogen
`content of PAGN per mole is identical to urea (both contain 2 moles of nitrogen). The
`metabolic pathway for HPN-100 is shown below in Figure 3.
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
` Figure 3 Metabolic Pathway of HPN-100
`
`[Ref: Clinical Overview, Figure 2.5-1, p.13]
`
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indication
`Urea Cycle Disorders are managed chronically and acutely. Ravicti is proposed for
`chronic use. Buphenyl is the only drug currently marketed in the US for the same
`chronic indication. Buphenyl comes in a tablet or powder form. Once broken down
`chemically, Buphenyl and Ravicti have the same active moiety, phenyl acetic acid.
`Table 1 Currently Available Treatment for Proposed Indication
`Drug
`Formulation
`Indication
`Dosage
`NaPBA (Buphenyl®)
`tablet
`chronic
`<20 kg - 450-600 mg/kg/day
`>20 kg – 9.9-13g/m2/day
`NDA20572
`(500mg)
`management
`NaPBA (Buphenyl®)
`powder
`chronic
`<20 kg - 450-600 mg/kg/day
`>20 kg – 9.9-13g/m2/day
`NDA20573
`
`management
`[Ref: Buphenyl prescribing information]
`
`
`Ammonul is another nitrogen scavenging drug, but its indication differs from that of
`Buphenyl and Ravicti in that it is used as an intravenous formulation for acute
`management of hyperammonemia.
`
`Reviewer’s Comment:
`The Buphenyl label offers a dosing range based on weight in kilograms. Much discretion
`is left to the prescribing physician.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`The proposed active ingredient glycerol phenylbutyrate is not available in the United
`States since it is not yet approved.
`
`Important Safety Issues with Consideration to Related Drugs
`2.4
`Buphenyl was approved in 1996 by the Division of Metabolism and Endocrine Drug
`Products. Approval was based on a review of clinical data from Dr. Saul Brusilow in
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`Clinical Review
`{NDA203284
`Ravicti (glycerol phenylburyrate)
`
`pediatric patients in whom serum ammonia was managed with NaPBA and diet. The
`study was non-randomized and uncontrolled, and no formal PK study was done in
`pediatric patients. No animal safety data were provided, and pre-clinical carcinogenicity
`and pharmacokinetic studies were not performed. The Annual Periodic Safety reports
`for Buphenyl covering the period May 1, 2009 to April 30, 2010, and May 1, 2010 to
`April 30, 2011 did not reveal any new safety signals or reports of neurologic adverse
`events.
`
`However, as will be discussed further in this review, there have been literature reports
`from the 1980’s and 1990’s of possible safety issues associated with the active
`metabolite phenylacetic acid (PAA). Phenylacetate has been associated with nausea,
`headache, emesis, fatigue, weakness, lethargy, somnolence, dizziness, slurred speech,
`memory loss, confusion, and disorientation at PAA levels ranging from 499-1285
`µg/mL2. These adverse events resolved with discontinuation of the drug. Cases have
`also been reported of toxicity from intravenous sodium benzoate and sodium
`phenylacetate when administered for the treatment of acute hyperammonemia.3 The
`clinical manifestations of PAA toxicity (headache and vomiting) may mimic those of
`hyperammonemia. In UCD patients in studies conducted for this NDA PAA levels were
`not associated with neurologic adverse events.
`
`Reviewer’s Comment:
`In both references patients were receiving intravenous treatment. PAA levels should be
`monitored, particularly when ammonia levels decrease but neurologic symptoms do not.
`
`2.5 Summary of Pre-submission Regulatory Activity Related to
`Submission
`Orphan Drug Designation was given for this indication on 5-May-2006 (#05-2035). The
`sponsor was granted fast-track designation 4-Oct-2010. The sponsor and the Agency
`reached agreement on a Special Protocol Assessment for Phase 3 protocol HPN-100-
`006 on 6-July-09. Below is a brief discussion of meetings with FDA.
`
`PIND73480 meeting 12-Dec-05
`At this meeting it was agreed that GT4P (later changed to HPN-100) was not a new
`molecular entity. Because PK studies showed that GT4P is not bioequivalent (plasma
`and urinary excretion lower) to Buphenyl a clinical trial is needed. Pre-clinical data
`showed the potential to prolong the QT interval, so a tQT study was required.
`
`
`
`2 Thibault A, et al. A Phase 1 and Pharmacokinetic Study of Intravenous Phenylacetate in Patients with
`Cancer. Cancer Research 54: 1690-1694, 1994.
`3 Praphanphoj, V. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity
`occurring in the treatment of acute hyperammonaemia. J. Inherit. Metab. Dis 23:129-135.
`
`Reference ID: 3224463
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`14
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`

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`Clinical Review
`{NDA203284
`Ravicti (glyc