CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`- Cross Discipline Team Leader Review - Melanie Blank, MD. DGIEP - NDA 203284 - Standard review for
`Ravictinl (glycerol phenylbutyrate) liquid for oral administration 0 Class: Nitrogen Binding
`
`Cross—Discipline Team Leader Review
`
`
`Date
`January 22, 2013
`From
`Melanie Blank, M.D.
`m_ Cross-Disci o line Team Leader Review
`NDA/BLA #
`NDA-203284
`
`Su n slement#
`
`Date of Submission
`
`December 23, 2011
`
`23, 2013
`Jan .
`PDUFA Goal Date
`——
`Proprietary Name /
`Ravicti/ Glycerol Phenylbutyrate fl-[PN-IOO)
`Established
`S 1
`
`names
`
`
`
`Dosage forms / Strength
`
`Liquid for oral administration
`1.1 g of glycerol phenylbutyrate (GPB) in 1 ml of Ravicti®
`(equivalent to 1.02 g phenylbutyrate)
`Usual Dose:
`4.5-11.2 mL/mZ/day (so-12.4 g/mZ/day) by mouth divided
`into three e 1 doses with meals
`
`Proposed Indication(s)
`
`Ravicti is indicated as adjunctive therapy for chronic
`management of adult and pediatric patients with urea cycle
`disorders (UCD) 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 (HI-1H) deficiency.
`
`Recommended:
`
`A roval
`
`1. Introduction
`
`Hyperion Therapeutics, Inc. submitted the New Drug Application (NDA) for RAVICTITM
`(glycerol phenylbutyrate; HPN-100) on December 23, 201 l pursuant to Section 505(b)(2) of
`the Federal Food, Drug and Cosmetic Act and in accordance with Title 21, Part 314 of the
`Code of Federal Regulations. Since phenylbutyrate is the active pharmaceutical ingredient, and
`is an approved drug, glycerol phenylbutyrate is not a New Molecular Entity (NIVIE).
`
`After a thorough multidiscipline review, my recommendation, along with the review team’s
`recommendation, is for approval of Ravicti (HPN-100, glycerol phenylbutyrate) as an adjunct
`to dietary management and amino acid supplementation when indicated for the chronic
`management of patients with urea cycle disorders (UCDs) in patients 2 2 years of age when
`dietary management alone is insufficient. Patients with N-acetylglutamate synthase deficiency
`
`Page 1 of 78
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`Reference ID: 3253590
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`

`

`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`(NAGS) were not included in the clinical trials. Carglumic acid (Carbaglu) was approved for
`NAGS deficiency based on the ammonia levels of patients who were treated with and without
`concomitant alternative pathway nitrogen binding agents including sodium phenylbutyrate
`which has the same active moiety as Ravicti. In the carglumic acid label it is stated in the
`Dosing and Administration section that, “concomitant administration of other ammonia
`lowering therapies is recommended.” Therefore, it is prudent to be state in the label under
`limitations of use that, “Safety and efficacy for treatment of N-acetylglutamate synthase
`(NAGS) deficiency has not been established.” Another limitation of use is that RAVICTI is
`not indicated for treatment of acute hyperammonemia in patients with UCDs.
`
`HPN-100 was granted orphan designation for UCDs on May 5, 2006. The review cycle was
`originally a standard 10 month cycle; however this was later amended to a 13 month review
`cycle after the submission of data from Study HPN-100-012 switch over (SO) and Study HPN-
`100-012 safety extension (SE) in children between 2 months and 5 years of age.
`
`It is apparent from the review of the studies and data that were submitted as part of this NDA
`that there is sufficient evidence to conclude that HPN-100 is as effective as Buphenyl, the
`approved standard-of-care for patients with UCDs for controlling serum ammonia AUC0-24.
`The efficacy of HPN-100 was demonstrated in one adequate and well-controlled, non-
`inferiority design study in adults with UCDs (HPN-100-006), using a surrogate endpoint
`(serum ammonia AUC0-24) which was agreed upon in a special protocol assessment (SPA) for
`the pivotal study issued on July 6, 2009. Serum ammonia control has been the endpoint for the
`other ammonia lowering medications (see section titled, “CURRENT TREATMENTS FOR
`UCDS” starting on p. 8). Chronically and intermittently acute serum ammonia levels account
`for the cerebral palsy, psychiatric illness, developmental delays and neurocognitive delays and
`degeneration that occur in UCDs. Occasionally patients develop seizures. Morbidity and
`mortality in these disorders correlate with the duration and severity of hyperammonemic
`episodes.1,2
`
`The neurotoxic effect of ammonia is well recognized; although the manner by which it exerts
`its effects upon the central nervous system is not very well understood. Its acute effects include
`increased blood–brain barrier permeability, depletion of intermediates of cell energy
`metabolism, and disaggregation of microtubules.3 The effects of chronic, mildly elevated
`ammonia may include alterations of axonal development and alterations in brain amino acid
`and neurotransmitter levels.4,5 In models of brain edema, where lethal doses of ammonia are
`
`1 Scaglia, F et al (2004), Clinical Consequences of Urea Cycle Enzyme Deficiencies and Potential Links to
`Arginine and Nitric Oxide Metabolism, Jl of Nutr, 134 (10), 27755-27825
`
`2 Batshaw, M. L., Roan, Y., Jung, A. L., Rosenberg, L. A. & Brusilow, S. W. (1980) Cerebral dysfunction in
`asymptomatic carriers of ornithine transcarbamylase deficiency. N. Engl. J. Med. 302:482-485.
`
`3 Butterworth, R. F. (1998) Effects of hyperammonaemia on brain function. J. Inherit. Metab. Dis. 21(Suppl. 1):6-
`20.
`
`4 Bachmann, C. (2002) Mechanisms of hyperammonemia. Clin. Chem. Lab. Med. 40:653-662.
`
`
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`administered, glial fibrillary acidic protein is reduced6 and glutamine is increased,7 preceded
`by an increase in blood flow8. It is not known whether nitric oxide (NO) production plays a
`role in such an increase. The arginine recycling enzymes are induced in astrocytes by
`ammonium, possibly originating NO via inducible NO synthase or neuronal NO synthesis
`−, which combines with NO to form the
`(nNOS)9. The stimulated nNOS might produce O2
`highly toxic peroxynitrites.10
`For these reasons, serum ammonia control over a 24 hour period was considered to be a
`reasonable primary endpoint. In addition, other drugs for UCDs have been approved on the
`basis of ammonia control: Buphenyl (sodium phenylbutyrate) which has the same active
`moiety as Ravicti, and Carbaglu (carglumic acid).
`There were supportive findings from other uncontrolled studies in children age 2 years to 17
`years and in adults that demonstrated maintenance of ammonia control. HPN-100 was
`successful at preventing hyperammonemic crisis in most UCD patients, a finding that would
`be unexpected in the absence of effective therapy.
`
`There are certain characteristics of HPN-100 and the development program that provide
`support for an approval decision based on a single trial. HPN-100 has the same active moiety
`as sodium phenylbutyrate (NaPBA), Buphenyl®, a drug that has been approved since 1996
`and used for decades for the treatment of UCDs on the basis of its ability to activate an
`alternative pathway for ammonia metabolism. The pivotal study was a multicenter trial (22
`centers, all in U.S. or Canada) where no one center drove the results of the trial. There was
`consistency of results across patients of different ages and underlying enzyme deficiencies,
`and while there was not a statistically persuasive finding since superiority was not achieved,
`the non-inferiority margin was met by a wide margin (point estimate of 1.04 with a 0.85- 1.25
`
`
`
`5 Braissant, O et al, (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine.
`J. Neurosci. 22:9810-9820.
`
`6 Belanger, M et al, (2002) Loss of expression of glial fibrillary acidic protein in acute hyperammonemia.
`Neurochem. Int. 41:155-160.
`
`7 Cooper, A. J. (2001) Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity. Ment.
`Retard. Dev. Disabil. Res. Rev. 7:280-286.
`
`8 Larsen, et al, (2001) Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J.
`Hepatol. 34:548-554.
`
`9 Braissant, O., Gotoh, T., Loup, M., Mori, M. & Bachmann, C. (1999) L-arginine uptake, the citrulline-NO cycle
`and arginase II in the rat brain: an in situ hybridization study. Brain Res. Mol. Brain Res. 70:231-241.
`
`10 Demchenko, I. T., Atochin, D. N., Boso, A. E., Astern, J., Huang, P. L. & Piantadosi, C. A. (2003) Oxygen
`seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthesis.
`Neurosci. Lett. 344:53-56.
`
`
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`Page 3 of 78
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`Reference ID: 3253590
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`- Cross Discipline Team Leader Review - Melanie Blank. MD. DGIEP - NDA 203284 - Standard review for
`Ravictim (glycerol phenylbutyrate) liquid for oral administration 0 Class: Nitrogen Binding
`
`noninferiority/ bioequivalence margin). Also, there was a statistically significant correlation
`between urinary phenylacetylglutamine (U-PAGN)24—hourExcr (which is the nitrogenated active
`metabolite of HPN-100), and NH324—hour AUC observed at steady state which was a key
`secondary endpoint determined through the pre-specified Hochberg’s multiplicity adjustment
`procedure. This relationship would not be expected if HPN-100 was not the reason for
`ammonia control.
`
`There was an adequate safety database: 268 subjects received at least one dose of HPN-lOO;
`The database included 112 UCD patients with deficiencies in carbamyl phosphate synthetase
`(CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS),
`argininosuccinate lyase (ASL), arginase (ARG) or the mitochondrial transporter omithine
`translocase (HI-1H). 68 patients, ages 6 years to 75 years old with UCDs had completed 12
`months of HPN-IOO by the time of the NDA submission. The 120-day safety update included
`patients between 2 months to 5 years of age. The mean exposure for the < 5 year old group at
`the time of the 120-day safety update was 3 1/2 months (maximum 7 months). There were no
`deaths in UCD patients, few withdrawals, few SAEs and multiple mild to moderate nonserious
`AEs that could partly be due to the patients’ underlying diseases. Considering the persuasive
`findings on serum ammonia, the safety profile is acceptable.
`
`The deficiencies of the application, enumerated below, can be handled with labeling and
`PMRs.
`
`1. Lack of information regarding safety and efficacy in patients under two months of age
`
`Recommendation: Contraindicate Ravicti in this population with an explanation
`regarding the immature pancreatic exocrine fimction in patients less than 2 months who
`may or may not have other sources such as salivary lipases or lipases from breast milk
`that would facilitate sufficient absorption of Ravicti. The applicant has agreed to a
`postmarketing requirement (PMR) to study children under 2 months. These children
`should be studied under intensively monitored conditions.
`
`Hmerion-Proposed PMR Language: Hyperion commits to a study to assess safety,
`pharmacokinetics
`(him during Ravicti treatment in pediatric UCD
`patients less than 2 months of age
`(m4)
`
`Information from this study will be submitted annually (in annual reports) with a final
`report submission by the end of 2017. The proposed timetable for this study is as
`follows:
`
`Final Protocol Submission: April 1, 2013
`Study Completion Date: April 1, 2017
`Final Report Submission: December 1, 2017
`
`Page 4 of 78
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`Reference ID: 3253590
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`The review team is going to request a delay for the final protocol submission as it may
`take longer to agree on the details of the protocol.
`We are awaiting agreement from the Safety Review Team, SWAT and Office of Chief
`Counsel.
`
`2. Very few data on patients in the age category of 2 months to 2 years were included in
`the NDA. The numbers of patients in this age range (4) and the timing of assessments
`were insufficient to conduct an adequate exploration of an effective dosing algorithm
`(by mg/kg vs. mg/m2) and the association between adverse events and Ravicti
`metabolite (in particular, PAA) levels. Two of the four patients in this age-range had
`PAA levels ~ 500 μg/mL when on Buphenyl or HPN-100 which may be associated
`with neurotoxicity.
`
`
`
`PAA toxicity, with neurological and gastrointestinal manifestations has been
`demonstrated with IV administration of PAA. The symptoms at PPA levels of ~500
`μg/mL were somnolence, emesis and lethargy in patients with cancer who received IV
`PAA. More severe toxicity (confusion and psychomotor depression) occurred in
`patients with mean peak PAA level of 682 μg/mL11. Overdose of IV PAA in children
`has been reported to cause coma and death.12 Levels of PAA in the children who had
`coma or died were > 1000 μg/mL.
`
`In addition to a neurotoxicity signal, there is also an animal carcinogenicity signal (see
`Pharmacology-Toxicology section). For these reasons, it is important to understand the
`safety and efficacy of HPN-100 in this patient population.
`
`Recommendation: The clinical pharmacology review states that it is not possible from
`data provided in this NDA to provide safe and effective dosing instructions for patients
`< 2 years of age. Therefore, it is advisable to change the indication so that Ravicti is
`approved for patients with UCDs ≥2 years of age. Two PMRs in children between 2
`months and 2 years of age were proposed to Hyperion and accepted. Hyperion agreed
`to commit to this PMR as worded below.
`FDA Proposed PMR Language: Study in pediatric patients aged 2 months to 2 years
`with Urea Cycle Disorders. Patients when they are no longer in the acute
`hyperammonemic phase will be started on Ravicti. Ammonia levels and phenylacetic
`acid (PAA) levels will be checked on a fixed schedule and at the time of adverse
`events.
`The FDA Proposed Language for the second PMR: Conduct pharmacokinetic
`studies in pediatric patients from birth to less than 2 years of age with Urea Cycle
`Disorders. PK of glycerol phenylbutyrate and its metabolites (PBA, PAA and PAGN)
`must be characterized.
`
`11 Thibault A et al, Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer
`1995;75:2932-8.
`12 Parphanphoj et al (2000), Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity
`occurring after the treatment of acute hyperammonemia, J. Inherit. Metab. Dis 23: 129-36.
`
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`The timetable submitted by Hyperion for this study is as follows:
`Final Protocol Submission for both PMRs: April 1, 2013
`Study Completion Date: April 1, 2016 for the overall study and April 1, 2017 for the
`PK study
`Final Report Submission for the overall study: December 1, 2016 and December 1,
`2017 for the PK study.
`The review team is going to request a delay for the final protocol submissions as it may
`take longer to agree on the details of the protocol.
`We are awaiting agreement from the Safety Review Team, SWAT and Office of Chief
`Counsel.
`3. In clinical studies in support of NDA203284 most patients were on an established dose
`of Buphenyl (sodium phenylbutyrate) prior to enrolling in the trial. The dose of Ravicti
`administered to most patients was determined by a formula used to provide equal dose
`of phenylbutyrate (PBA) as they had been receiving from Buphenyl, sodium PBA.
`Therefore there is limited experience with dosing of Ravicti in treatment naïve patients.
`A concerning safety signal was that 2 of the 6 patients who were started on Ravicti
`without first attaining a stable dose of Buphenyl had neurological TEAEs that lead to
`dose reduction and discontinuation. Ravicti has the same active moiety as Buphenyl.
`Therefore, it is considered safe for the purpose of approval to initiate dosing with
`Ravicti. However, the signal of neurotoxicity that was seen in the 2 patients who were
`not already stabilized on Buphenyl raises the concern that treatment naïve patients may
`not tolerate de novo dosing with this product as well as they do with Buphenyl.
`
`
`
`Recommendation: The review team has agreed that dosing instructions in the label
`will have to be divided into several sections as follows:
`
`Important Instructions
`2.1
`RAVICTI should be prescribed by a physician experienced in the management of UCDs.
`Instruct patients to take RAVICTI with food and to administer directly into the mouth via oral
`syringe or dosing cup. See the instructions on the use of RAVICTI by nasogastric tube or g-
`tube [see Dosage and Administration (2.6)].
`The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI
`and patients naïve to phenylbutyric acid are different [see Dosage and Administration (2.2,
`2.3)]. For both subpopulations:
` Give RAVICTI in three equally divided dosages, each rounded up to the nearest 0.5
`mL
` The maximum total daily dosage is 17.5 mL (19 g)
` 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).
`
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`Reference ID: 3253590
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`Switching from Sodium Phenylbutyrate to RAVICTI
`2.2
`Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of
`RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:
`Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.8
`
`Initial Dosage in Phenylbutyrate Naïve Patients
`2.3
`The recommended dosage range, based upon body surface area, in patients naïve to
`phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some
`residual enzyme activity who are not adequately controlled with protein restriction, the
`recommended starting dosage is 4.5 mL/m2/day.
`In determining the starting dosage of RAVICTI in treatment naive patients, consider the
`patient’s residual urea synthetic capacity, dietary protein requirements, and diet adherence.
`Given that approximately 47% of dietary nitrogen is excreted as waste and 70% of an
`administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an
`initial estimated RAVICTI dose for a 24 hour period is 0.6 mL RAVICTI per gram of dietary
`protein in 24 hours.
`
`Dosage Adjustment and Monitoring
`2.4
`Adjustment based on Plasma Ammonia: Adjust the RAVICTI dosage to produce a fasting
`plasma ammonia level that is less than half the upper limit of normal (ULN) (according to
`age).
`Adjustment based on Urinary Phenylacetylglutamine: If available, U-PAGN measurements
`may be used to help guide RAVICTI dose adjustment. Each gram of U-PAGN excreted over
`24 hours covers waste nitrogen generated from 1.4 gram of dietary protein. If U-PAGN
`excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater
`than half the ULN, the RAVICTI dose should be adjusted upward. Consider a patient’s use of
`concomitant medications, such as probenecid, when making dosage adjustment decisions
`based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN [see
`Drug Interactions (7.2)].
`Adjustment based on Plasma Phenylacetate: If available, measurements of the plasma PAA
`levels may be useful to guide dosing if symptoms of vomiting, nausea, headache, somnolence,
`confusion or sleepiness are present in the absence of high ammonia or intercurrent illness.
`Ammonia levels must be monitored closely when changing the dose of RAVICTI [see
`Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
`
`Dosage Modifications in Patients with Hepatic Impairment
`2.5
`For patients with moderate to severe hepatic impairment the recommended starting dosage is
`at the lower end of the range [see Warnings and Precautions (5.1, 5.4) and Clinical
`Pharmacology (12.3)].
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`Page 7 of 78
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`Reference ID: 3253590
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`2.6
`
`Preparation for Nasogastric Tube or Gastrostomy tube
`Administration
`For patients who have a nasogastric tube or gastrostomy tube in place, administer RAVICTI as
`follows:
` Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the
`bottle.
` Place the tip of the syringe into to the tip of the g-tube/nasogastric tube
` Utilizing the plunger of the syringe, administer RAVICTI into the tube.
` Flush once with 30 mL of water and allow the flush to drain.
` Flush a second time with an additional 30 mL of water to clear the tube.
`------------------------------------------------------------------------------------------
`To address the concerns that initial dosing and titration based on the instructions from
`the label may not be safe and effective, a PMR has been stipulated and Hyperion has
`agreed to fulfill it.
`The FDA proposed language for the PMR was as follows: Randomized controlled
`clinical trial to assess the safety and efficacy of initiating and titrating Ravicti in
`treatment naïve patients with UCDs
`The timetable submitted by Hyperion for this study is as follows:
`Final Protocol Submission: December 1, 2013
`Study Completion Date: June 1, 2016
`Final Report Submission: March 30, 2017
`
`
`We are awaiting agreement from the Safety Review Team, SWAT and Office of Chief
`Counsel.
`
`4. Inconclusive Thorough QT (TQT) study
`Recommendation: The IRT-QT recommended that a repeat study should be performed
`because of lack of assay sensitivity in the original study or there should be language in
`the label to explain the lack of assay sensitivity. For there to be assay sensitivity, the
`moxifloxacin effect on QT interval must show an upslope form normal to elevated.
`This upslope was not demonstrated. The QT interval was high from the first ½ hour
`which was the first data point captured in the report. Furthermore, the moxifloxacin
`effect on QT came down from 10 ms to 5 ms very rapidly and stayed there for most of
`the 24 hour test period. This is unusual. The review team agreed with the IRT-QT’s
`recommendation and proposed language to the applicant for use in the QT section of
`the label:
`
`The effect of multiple doses of Ravicti 13.2 g/day and 19.8 g/day (approximately 69%
`and 104% of the maximum recommended daily dosage) on QTc interval was evaluated
`in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`
`
`treatment-arm crossover study in 40 healthy subjects. The upper bound of the one-
`sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc
`based on individual correction method (QTcI) for Ravicti was below 10 ms. However,
`assay sensitivity was not established in this study. Therefore, an increase in mean QTc
`interval of 10 ms cannot be ruled out.
`
`
`The applicant was informed that they will need to repeat a thorough QT study with
`assay sensitivity or they will need to demonstrate that there was an upslope in the
`moxifloxacin arm from a normal length to a prolonged length to have this language
`removed from the label.
`
`5. The risks of treating breast-feeding patients are not known. There is a concern of
`effects on unborn fetuses and neonates because of neurotoxicity findings seen with
`Buphenyl in rat pups given HPN-100 in their food, and carcinogenicity findings in a 2-
`year rat carcinogenicity study which the Cancer Assessment Committee deemed as
`being drug-related. It is unknown if PBA, PAA, or PAGN pass into the breast milk.
`Ravicti is expected to be used by women of reproductive age and data on exposure of
`the drug via breast milk is needed.
`
`Recommendation: Appropriate language will be placed in the label for pregnant and
`breast-feeding patients and encouragement to participate in the Ravicti Urea Cycle
`Disorders registry. We are in the process of having the PMHS team consult to help
`provide the appropriate language in the label. PMHS is also being asked to advise the
`applicant about conducting an appropriately designed post-marketing study to assess
`the quantity of PBA, PAA, or PAGN that passes into breast milk.
`
`6. CYP enzyme interactions. In vitro studies suggested that phenylbutyrate, a metabolite
`of Ravicti, can potentially inhibit the metabolism of concomitant medications that are
`substrates of CYP3A4/5, CYP2D6 and/or CYP2C19.
`Recommendation: Since chronic administration of Ravicti is expected for UCD
`patients, the evaluation of the potential in vivo drug interaction with concomitant
`medications that may compete for CYP enzymes is warranted.
`The FDA proposed language for the PMR: In vivo drug interaction study to evaluate
`the effect of Ravicti on the pharmacokinetics of a drug that is a sensitive substrate of
`CYP3A4/5 (e.g., midazolam).
`
`The timetable submitted by Hyperion for this study is as follows:
`Final Protocol Submission: September 30, 2013
`Study Completion Date: March 31, 2014
`Final Report Submission: July 1, 2014
`
`7. Patients with advanced hepatic disease had elevated phenylacetate (PAA)/
`Phenylacetylglutamine (PAGN) ratios because they do not convert PAA to PAGN as
`quickly as a person without advanced hepatic disease. Patients with advanced hepatic
`impairment are therefore at risk of developing PAA toxicity. There were 5 patients in
`
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`the hepatic impairment studies who died. Their deaths may have been related to their
`underlying disease. PAA toxicity was not evaluated in these patients. 2 were known to
`be on HPN-100, the 3 others were in an ongoing study (HPN-100-008 Part B) that is
`still blinded.
`Recommendation: Labeling in the Dosage and Administration Section (2.4) and in the
`Special Populations Section 8.6 will be placed to advise practitioners to start patients
`with hepatic disease at the lower end of the dosing range (4.5 mL/m2/day). There will
`also be a warning in the Warnings and Precautions in Section 5.5 for patients with
`advanced hepatic disease explaining that they are at increased risk for PAA toxicity.
`
`8. There are unknown benefits and risk of treating patients with renal disease.
`Recommendation: In section 12.3 Pharmacokinetics the following language has been
`proposed to Hyperion:
`Renal Impairment
`The pharmacokinetics of Ravicti in patients with impaired renal function including
`end-stage renal disease (ESRD) or on hemodialysis have not been studied.
`
`2. Background
`
`
`Urea Cycle Disorders
`
`The urea cycle produces arginine by de novo synthesis while also producing urea. Six
`enzymatic reactions comprise the cycle, which occurs in the liver. The first three reactions are
`located intramitochondrially [N-acetylglutamate synthase (NAGS), carbamylphosphate
`synthetase (CPS) and ornithine transcarbamylase (OTC)], and the rest are cytosolic
`[arginosuccinate synthetase (AS), arginosuccinate lyase (AL), and arginase (ARS)]. There is
`also a mitochondrial membrane transporter that can be deficient, ornithine translocase (HHH).
`The enzymatic substrates are ammonia, bicarbonate, and aspartate. There are also cofactors
`necessary for optimal enzyme activity, the most clinically important of which is N-acetyl
`glutamate (NAG). After each turn of the cycle, urea is formed from two atoms of nitrogen (see
`Fig. 1).
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`Phenylacetate then combines with glutamine and is then excreted into the urine as phenylacetylglutamine. Figure from a
`publication by Walters and Brophy13
`
`The prevalence of UCDs is estimated at 1:8,200 in the USA. The overall incidence of defects
`presenting clinically is estimated at approximately 1 in 45,000 live births. Using the US birth
`rate in 2000 of 4.06 million births14 and the incidence rate of 1:8200, it is estimated that
`approximately 495 patients with UCDs are born each year in the US. The prevalence of these
`disorders may exceed the current estimates,15 for all UCDs jointly because of unreliable
`newborn screening and underdiagnosis of fatal cases. From epidemiological studies,16,17 50%
`
`
`13 Walters S, Brophy PD (2009) Inborn errors of metabolism and continuous renal replacement therapy. In: Ronco C, Bellomo R,
`Kellum J (eds) Critical care nephrology, 2nd edn. Elsevier, Oxford, pp 1630–1633
`14 Ventura SJ et al, (2004);Estimated Pregnancy Rates of the United states, 1990-2000: an update, National vital Statistics reports, 52, 23, p.
`1-12
`15 Brusilow SW et al, (1996), Adv Pediatr. 1996;43:127–170.
`16 Bachman C, (2003), Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr; 162(6):410-6.
`
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`COPYRIGHT MATERIAL
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`• Cross Discipline Team Leader Review • Melanie Blank, MD, DGIEP • NDA 203284 • Standard review for
`Ravicti™ (glycerol phenylbutyrate) liquid for oral administration • Class: Nitrogen Binding
`
`of neonatal onset patients die in the neonatal period despite therapy. The National Institute of
`Health- (NIH) funded Urea Cycle Disorders Consortium (UCDC) Longitudinal Study now
`includes 12 major centers in the US as well as sites in Toronto and Zurich, and has enrolled
`only 495 patients over the first 5 years. Of these patients, 400 are prescribed NaPBA. By birth
`incidence, if patients lived a full life span there would be approximately 35,000 patients in the
`U.S. Since many UCD patients die young, and/or have liver transplant, it is not possible to
`estimate the numbers of patients who currently have the disorder in the U.S. A thorough
`literature search did not reveal any reliable prevalence statistics. Clearly, there is a need for
`better natural history studies.
`
`
`The first report resulting from the Longitudinal Study18 describes the patient population. One
`hundred eighty three participants were enrolled into the study at the time this report was
`written. OTC deficiency was the most frequent disorder (55% of total enrolled), followed by
`AL deficiency (16%) and AS deficiency (14%). Intellectual and developmental disabilities
`were reported by 39% of participants, learning disabilities were reported by 35%, and half had
`abnormal neurological examinations (including findings like tone changes, reflex
`abnormalities, and abnormal movements). Sixty-three percent were on a protein restricted diet,
`37% were on sodium phenylbutyrate (Buphenyl) and 5% were on oral sodium benzoate. Forty-
`five percent of OTC deficiency participants were on L-citrulline. Most participants with AS
`deficiency (58%) and AL deficiency (79%) were on L-arginine. Plasma levels of
`branched-chain amin