CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`2032840rigls000
`
`SUMMARY REVIEW
`
`Par Pharmaceutical, Inc. Ex. 1016
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 1 of 35
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`Division Director Review
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`Summary Review for Regulatory Action
`
`Date
`From
`Subject
`NDA
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`
`Proprietary N arne I
`Established (USAN) Name
`Dosage Forms I Strength
`
`(electronic stamp)
`Donna Griebel, MD
`Division Director Smmmuy Review
`203284
`Hyperion Therapeutics, Inc.
`December 23 , 2011
`Januaty 23, 2013
`Action Date: Februruy 1, 2013
`Ravicti/ glycerol phenylbutyrate
`
`Proposed lndication(s)
`
`Liquid for oral administration
`1.1 g of glycerol phenylbutyrate (GPB) in 1 ml of
`Ravicti® (equivalent to 1.02 g phenylbutyrate)
`Adjunctive therapy for chronic management of adult
`and pediatric patients with urea cycle disorders (UCD)
`involving deficiencies of the following enzymes:
`caTbamyl phosphate synthetase (CPS), ornithine
`transcarbamylase (OTC), aTgininosuccinate synthetase
`(ASS), ru·gininosuccinate lyase (ASL) or arginase
`(ARG) as well as the mitochondrial transpmier
`ornithine translocase (HHH) deficiency.
`Action/Recommended Action for Approval
`NME:
`
`Material Reviewed/Consulted
`Names of discipline reviewers
`OND Action Package, including:
`Nancy Snow, DO/Melanie Blank, MD
`Medical Officer Review
`Behrang Vali, MS/Mike Welch, PhD
`Statistical Review
`Phrumacology Toxicology Review Ke Zhang, PhD/David Joseph, PhD
`Hamid Shafiei, PhD/Moo Jhong Rhee, PhD
`CMC Review
`Insook Kim, PhD/Sue Chih Lee, PhD
`Clinical Phrumacology Review
`DPDP/OPDP
`Kathleen Klemm
`K. Malek, MD/Susan Leibenhaut, MD/Susan
`DSI
`Thompson, MD
`Melanie Blank, MD
`Lubna Merchant, PharmD, MS/Kellie Taylor, PhatmD,
`MPH/Cru·ol Holquist, RPh
`Medication Guide:Latonia Ford, RN, BSN,
`MBAILaShawn Griffiths, MSHS-PH, BSN, RN/ Bru·bru·
`Fuller, RN, MSN, CWOCN
`Proposed REMS : Y asmin Choudhty, MD /Kendra
`
`CDTL Review
`OSE/DMEPA
`
`OSE/DRISK
`
`Page 1 of3 3
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`Reference ID: 3254202
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`Division Director Review
`
`OSE/DPV
`
`PMHS
`
`Pediatric Ethicist/Office of
`Pediatric Therapeutics, OC
`SEALD
`Interdisciplinary Review Team for
`QT Studies
`OND~Office ofNew Drugs
`OPDP~Office of Prescription Drug Promotion
`OC~ Office of the Commissioner
`OSE~ Office of Surveillance and Epidemiology
`DMEPA~Division of Medication Error Prevention and Analysis
`DPDP~Division of Professional Drug Promotion
`DSI~Division of Scientific Investigations
`DRISK~ Division of Risk Management
`CDTL~Cross-Discipline Team Leader
`PMHS~Pediatric and Maternal Health Staff
`
`Worthy, Pharm D./Claudia Manzo, Pharm.D.
`Thang La, PharmD, BCPS/Ann Mackey, RPh,
`MPH/Shewit Bezabeh, MD, MPH/Linda Scarazzini,
`MD,RPh
`Alyson Karesh, MD!Hari Cheryl Sachs, MD/ Jeanine
`Best/Melissa Tassinari, PhD/Lynne Yao, MD
`Michelle Roth-Cline, MD, PhD/Robert Nelson, MD,
`PhD
`Eric Brodsky, MD/Jeanne Delasko/Laurie Burke
`J. Zhang/Q. Dang/D. Marathe/N. Mehrotra/M.
`Fiszman/N. Stockbridge
`
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`Division Director Summary Review
`
`1. Introduction
`
`Hyperion Therapeutics, Inc. submitted the New Drug Application (NDA) for RAVICTI™
`(glycerol phenyl butyrate) on December 23, 2011 pursuant to Section 505(b )(2) of the Federal
`Food, Drug and Cosmetic Act for the proposed indication:
`
`"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 (HHH) deficiency."
`
`Phenylbutyrate, the active pharmaceutical ingredient, is not a new molecular entity (NME).
`Buphenyl (sodium phenylbutyrate) was approved in 1996 and is marketed with the following
`very lengthy indication. I have balded the words that most clearly reflect an actual indication:
`
`"adjunctive therapy in the chronic management of patients with urea cycle
`disorders involving deficiencies of carbamyl phosphate synthetase (CPS), ornithine
`transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). It is indicated
`in all patients with neonatal-onset deficiency (complete enzymatic deficiency,
`presenting within the first 28 days of life). It is also indicated in patients with late(cid:173)
`onset disease (partial enzymatic deficiency, presenting after the first month of life)
`who have a history of hyperammonemic encephalopathy. It is important that the
`diagnosis be made early and treatment initiated immediately to improve survival. Any
`episode of acute hyperammonemia should be treated as a life-threatening emergency.
`BUPHENYL must be combined with dietary protein restriction and, in some cases,
`essential amino acid supplementation. (See Nutritional Supplementation subsection of
`the DOSAGE AND ADMINISTRATION section.) Previously, neonatal-onset disease
`was almost universally fatal within the first year of life, even when treated with
`peritoneal dialysis and essential amino acids or their nitrogen-free analogs. However,
`with hemodialysis, use of alternative waste nitrogen excretion pathways (sodium
`phenyl butyrate, sodium benzoate, and sodium phenyl acetate), dietary protein
`restriction, and, in some cases, essential amino acid supplementation, the survival rate
`in newborns diagnosed after birth but within the first month of life is almost 80%. Most
`deaths have occurred during an episode of acute hyperammonemic encephalopathy.
`Patients with neonatal-onset disease have a high incidence of mental retardation. Those
`who had IQ tests administered had an incidence of mental retardation as follows:
`ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic
`acid synthetase deficiency, 88% (15/17 patients tested); and carbamylphosphate
`synthetase deficiency, 57% ( 4/7 patients tested). Retardation was severe in the majority
`of the retarded patients. In patients diagnosed during gestation and treated prior to any
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`episode ofhyperammonemic encephalopathy, survival is 100%, but even in these
`patients, most subsequently demonstrate cognitive impairment or other neurologic
`deficits. In late-onset deficiency patients, including females heterozygous for ornithine
`transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and
`are then treated chronically with sodium phenylbutyrate and dietary protein restriction,
`the survival rate is 98%. The two deaths in this group of patients occurred during
`episodes ofhyperammonemic encephalopathy. However, compliance with the
`therapeutic regimen has not been adequately documented to allow evaluation of the
`potential for BUPHENYL and dietary protein restriction to prevent mental
`deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered
`to. The majority of these patients tested (30/46 or 65%) have IQ's in the average to low
`average/borderline mentally retarded range. Reversal of pre-existing neurologic
`impairment is not likely to occur with treatment and neurologic deterioration may
`continue in some patients. Even on therapy, acute hyperammonemic encephalopathy
`recurred in the majority of patients for whom the drug is indicated. BUPHENYL may
`be required life-long unless orthotopic liver transplantation is elected."
`
`In keeping with multiple interactions with the Division during the clinical development of
`Ravicti, including a SPA agreement, the safety and efficacy data submitted in support ofthe
`NDA hinge on a trial conducted to establish noninferiority ofRavicti to the approved
`Buphenyl (sodium phenylbutyrate) product in control of venous ammonia level, based on 24-
`hour AUC of ammonia (AUCNH3). This trial (Study 006), which was conducted in adult
`patients with UCD, was essentially designed to demonstrate bioequivalence of the two
`products for the PD marker, AUCNH3, specifically focusing on the upper bound of the
`confidence interval, i.e., the AUCNH3 ratio of the geometric means for Ravicti/Buphenyl must
`not exceed 1.25. Ammonia levels were considered an acceptable endpoint to establish
`efficacy, since high serum ammonia levels are known to cause serious morbidity and mortality
`in patients with urea cycle disorders (UCD). Ammonia was utilized as an endpoint to support
`the 2010 regular approval ofCarbaglu for the UCD, N-acetylglutamate synthase (NAGS)
`deficiency.
`
`Phenylbutyrate has been a key component of the armamentarium for managing UCDs for
`decades. Major review issues identified in this NDA for Ravicti were related to knowledge
`gaps also associated with sodium phenyl butyrate at the time of its approval, which are
`reflected in the Buphenyllabel. Those issues include:
`
`1) There is an absence of a clear methodology for defining a starting dose in an individual
`patient. Buphenyl product labeling states, "The usual total daily dose ofBUPHENYL
`Tablets and Powder for patients with urea cycle disorders is 450 - 600 mg/kg/day in
`patients weighing less than 20 kg, or 9.9 13.0 g/m2/day in larger patients." The key
`efficacy trial submitted in support of the Ravicti NDA (Study 006) evaluated patients who
`were not treatment naive, and were on a stable dose of sodium phenylbutyrate. Patients
`enrolled in other trials submitted to this NDA were also merely converted from their stable
`dose ofBuphenyl, with the exception of only 6 treatment naive patients (two of whom
`developed neurological treatment emergent adverse events that led to dose reduction and
`discontinuation). The relative absence of data on how to initiate Ravicti in treatment
`
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`nai've patients and the lack of specific instructions for initiating therapy in the Buphenyl
`label (beyond providing a range), was a significant review issue that impacted labeling
`decisions. The investigators for the Ravicti trials have stated in a publication in Molecular
`Genetics and Metabolism [Mokhtarani M, et al. 107 (2012) 308-314], "Although sodium
`phenylbutyrate has been used for the treatment ofUCDs since at least 1979, comparatively
`little information is available to guide physicians regarding its optimal dosing."
`
`2) There were limitations to the strength of evidence provided in the NDA to support
`inclusion of information proposed by the applicant in the product label on how to modify
`dose based on various biomarkers, aside from venous ammonia levels.
`
`3) Ravicti is a pre-pro-drug. The drug must be released from the glycerol backbone to enable
`systemic absorption of therapeutic levels of phenyl butyrate (which is subsequently
`converted to the PAA molecule that binds glutamine to clear nitrogen). Because young
`infants, less than 2 months of age, are known to have immature pancreatic function, there
`is a scientifically known reason to have concern that infants less than 2 months of age will
`not absorb therapeutic levels of phenyl butyrate, due to low levels of pancreatic lipases.
`This is not an issue for the currently marketed sodium phenyl butyrate product. Because
`ineffective treatment of blood ammonia levels in a young infant could result in devastating
`outcomes, there was substantial concern that without a contraindication there would be
`substitution errors ofRavicti for Buphenyl in this age group, since both contain
`phenylbutyrate. This concern resulted in a Contraindication for use in this age group.
`
`4) Inadequate data were submitted to establish a safe dose in children between the age of 2
`months and 2 years. There were only 4 children studied in this age range and the data
`collected were inadequate for Clinical Pharmacology reviewers to determine safe dose
`recommendations. The Division had strongly encourage the sponsor during the clinical
`development to obtain adequate clinical data to cover all relevant age groups, recognizing
`that ifRavicti was in fact more palatable, it would be exceedingly important to have
`sufficient data to support labeling a safe and effective dose ofRavicti across all pediatric
`age groups. This gap will be addressed with a PMR under FDAAA, in light of the safety
`issue related toP AA. PREA does not apply since the applicant's product has orphan
`designation for UCDs. The product label will state that the safety and efficacy have not
`been established in this age range (2 months to less than 2 years).
`
`5) The reviewers considered whether a comprehensive list ofUCD subtypes (as proposed by
`the applicant) enrolled in the various trials submitted to the NDA should be included in the
`labeled indication for Ravicti, whether or not the number enrolled with a specific subtype
`was quite small. The Buphenyllabel precedent was considered, which on first glance
`appears relatively limited compared to the applicant's proposal; however, the additional
`text regarding neonatal onset and late onset in that indication seems broad and more
`encompassing. Ultimately, the reviewers considered the variability in the clinical
`presentations of the phenotypes (both among specific UCD subtypes and within specific
`subtypes), how the drug functions biochemically to reduce nitrogen, and how this product
`is clinically used as an adjunct, and determined that more general language was appropriate
`for the Indication section of the label. However, in keeping with the Buphenyl indication,
`
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`the reviewers determined that the Ravicti indication should communicate that the product
`should be reserved for use only in patients who need it to manage serum ammonia. The
`risk of carcinogenesis and the risk of neurotoxicity from P AA cannot be justified if a
`patient's nitrogen can be managed by other standard measures. Patients with UCDs are
`managed by specialists in treatment of these diseases and the reviewers were confident that
`these limitations outlined in the indication would be adhered to without additional
`measures to assure safe use because the specialists who care for these patients are aware of
`these issues and currently practice within guidelines.
`
`6) The reviewers further considered the risk/benefit implications of the nonclinical
`carcinogenicity study results, and how this should be managed in product labeling.
`Ultimately, this (and the neurotoxicity associated with PAA, the active metabolite of
`Ravicti) impacted the Nursing Mothers section of the label and resulted in a PMR to obtain
`levels of the drug and its metabolites in breast milk, since nursing infants (particularly
`those without a diagnosis ofUCD) would not have the same risk/benefit ratio for exposure
`to Ravicti as patients with a UCD.
`
`I will address these issues in the context of this review.
`
`2. Background
`The urea cycle is the final common pathway for the excretion of waste nitrogen in mammals
`and consists of 6 enzymes: (N-acetyl-glutamate synthetase, carbamyl phosphate synthetase
`[CPS], ornithine transcarbamylase [OTC], argininosuccinate synthetase [AS],
`argininosuccinate lyase [AL], and arginase). Each turn of the cycle results in elimination of
`two nitrogens in the form of urea. (See Figure 1 below). Urea cycle disorders result from a
`deficiency of any of the enzymes involved in the urea cycle. These disorders are autosomal
`recessive diseases, with the exception of ornithine transcarbamylase deficiency, which is an X(cid:173)
`linked disorder. As stated in the CDTL review, the prevalence of Urea cycle disorders in the
`US is estimated to be 1:8200, with an overall incidence of approximately 1 in 45,000 live
`births.
`
`UCDs are characterized by hyperammonemia, encephalopathy, and respiratory alkalosis.
`Patients with UCDs are at high risk for neurologic deficits and death secondary to
`hyperammonemia. Patients may present with clinical manifestations across the lifespan,
`including as newborn/infants and in early childhood. The CDTL review provides a discussion
`of the variable phenotypic presentations. Partial enzyme deficiencies may present later in life,
`and depending on the level of function of the enzyme affected and the specific enzyme,
`patients may only require dietary management and nutritional supplements for chronic
`management of their disease.
`
`Current treatments for UCDs include restriction of nitrogen load by a low protein diet, oral
`neomycin to decrease bacterial ammonia production, and the use ofNH3 scavengers. There are
`two nitrogen scavengers approved in the US for treatment of hyperammonemia in patients with
`UCDs: Buphenyl [(oral sodium phenylbutyrate (NaPBA)], Ammonul (intravenous mixture of
`sodium benzoate and sodium phenylacetate (NaPAA). Compounding pharmacies provide
`sodium phenyl acetate and sodium benzoate for oral use. Carbaglu ( carglumic acid), a specific
`
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`treatment for the UCD called NAGS deficiency, is a structural analogue of NAG, which is the
`essential allosteric activator of the enzyme CPS. Carbaglu does not function as a nitrogen
`scavenger, but instead serves to activate the key enzyme "at the top" of the urea cycle (see
`Figure below).
`
`Ravicti contains three molecules of 4-phenylbutyric acid (PBA) bonded via ester linkages to a
`glycerol backbone. It is converted into one glycerol and three phenylbutyrate (PBA) molecules
`either in the gut or during trans-enteric transport, and is converted by B-oxidation into P AA,
`which binds to glutamine. The resulting conjugate, PAGN (phenylacetylglutamine, see Figure
`below), is excreted via kidney. Since glutamine contains two nitrogens, this results in
`elimination of two nitrogens from the body.
`
`Figure 1: Metabolic pathways for nitrogen disposal
`CI'-KcW;l~te
`
`HW,
`
`· Gl~tle ----"----------)o Glutamine Ph n:YiacGtatc
`y
`
`Urine ex-c;l'e:tl'on
`j.l..
`'
`
`' .
`: . '
`' ' ' .
`.
`
`.__c_itru_ n_in_e_.] -•• ••• /
`
`•·-u I
`.
`~ f . .
`. .O.r;slninetw.cx;inatt! J· _./
`
`Ornithine
`
`Supp!lernentl@d •• -· l'"
`A_rgirdll!e
`•• •••
`
`Arginine
`
`Adapted from: http://www.drugs.com/pro/ammonul.html (12-March-2009)
`
`As discussed in the Introduction, one of the major review issues considered during product
`labeling was whether the indication should be limited to only those disorders in which there
`had been adequate characterization of safety and efficacy in the NDA trials. Ultimately,
`considering that the alternative pathway of nitrogen disposal that P AA provides, outside of the
`cycle, the review team determined that a general indication could be justified, as long as the
`indication clearly stated that the product was to be used only as an adjunct to other standard
`
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`interventions, such as diet, and that it should be used only if those other standard interventions
`were inadequate by themselves to manage the patient's nitrogen.
`
`Regulatory background. Key goals for the interactions between FDA and the applicant
`during the clinical development of Ravicti included defming the appropriate endpoint for
`establishing efficacy and assuring that adequate numbers of children were studied to support
`defining a safe and effective dose across the full age range of patients who are affected by
`UCDs. I have summarized content from specific interactions between FDA and the applicant
`that impacted the content and review of the submitted NDA and/or labeling below.
`
`Pre-IND Meeting December 12, 2005:
`1) FDA told IND sponsor that because available phrumacokinetic data did not
`establish that Ravicti was bioequivalent to sodium phenylbutymte, based on
`phenylbutyrate levels P AA and PAGN levels, an efficacy trial would be required
`to suppmt a mru·keting application.
`2) FDA suggested that the primruy efficacy objective for an efficacy trial should
`include AUCNHJ and 24-hour urinruy excretion of glutamine-related compounds.
`
`End of Phase 2 Meeting Januaty 14, 2009:
`1)
`FDA recommended that the primruy efficacy objective for phase 3 trial(s)
`intended to suppmi registration should be a co-primruy of AUCNHJ and AUC
`ofPAGN. FDA recommended that the sponsor consider a bioequivalence
`approach to analyses of the primruy endpoint, and that the definition of success
`should also include that the AUCNHJ does not exceed 100 micromol/L.
`The S_()onsor ro osed
`
`!b1T4!
`
`2)
`
`FDA recommended that the pediatric trial should be completed prior to
`initiating the proposed "pivotal" efficacy trial (Study 006), to infmm
`assumptions used to power the trial. The FDA recommended that if the sponsor
`initiated Study 006 before the completion of Study 005, that children should be
`excluded from Study 006.
`The FDA stated that adult efficacy data might be "extrapolatable" to the
`pediatric population; however, the dose and safety in children is not.
`The FDA stated that the safety database for an NDA should include at least 35-
`40 patients who have been evaluated for at least 12 months on treatment.
`
`3)
`
`4)
`
`The
`
`SPA No Agreement Letter issued to sponsor on April3 , 2009:
`1)
`Sponsor proposed that the primruy efficacy endpoint of Study 006 would be
`!6> (4
`J would be evaluated as a secondruy
`~~--~~------------------------~
`endpoint.
`The FDA did not agree and stated that the p1imruy endpoint should be AUCNHJ.
`AUC of blood PAGN and 24 hour urinruy PAGN excretion should be a
`secondruy endpoints. Other secondruy endpoints of interest were number of
`hyperammonemic crises and severity of hyperammonemic crises.
`
`2)
`
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`Ravicti (glycerol phenylbutyrate) received Otphan Dmg designation for maintenance of
`treatment of patients with deficiencies in enzymes of the urea cycle on April27, 2009.
`
`Meeting to discuss SPA No Agreement Letter on May 7, 2009:
`1) Sponsor agreed to a primruy endpoint of24-hour AUCNH3 .
`2) Sponsor proposed, for the primruy efficacy analysis of ratio of AUCNH3 of
`Ravicti/sodium phenylbutyrate, that the upper bound for the confidence interval to
`defme success would be (bJ<"~l , instead of 1.25.
`3) The FDA disagreed with the proposed upper bound, stating it should be 1.25.
`
`SPA Agreement Letter issued on June 30, 2009:
`1) The trial would only enroll adults.
`2) The primruy endpoint was 24-hour AUC for venous NH3 at the end of treatment
`with each dmg (Days 14 and 28). The primruy efficacy analysis was the ratio of
`the AUCNH3 geomettic means ofRavicti/sodium phenylbutyrate, with an upper
`bound of the confidence interval not exceeding 1.25 (utilizing a 1-sided alpha of
`0.025) constih1ting evidence of efficacy.
`
`(review filed on June 30, 2010):
`(b)l4J
`
`2) The FDA did not agree with the amendment and said that it would result in
`nullification of the SPA. The pediattic data from Study 005 revealed substantive
`differences in PK proftles between pediatric patients and the adults in Study 003
`(adult PK study). Ofpruiicular concern, from a safety standpoint, was the apparent
`higher P AA exposure in children relative to adults. In addition, Study 005 showed
`differences in the PK proftle between Ravicti and sodium phenylbutyrate. The
`table below summarizes the data that were bases for these concerns (reproduced
`from the clinical review in the regulatmy file, dated June 30, 2010):
`
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`PK Pantmctcr
`
`Table 1: PK Compuison of Adult (UP 1204-003) Ys. Pediatrics (HPN-100-005) UCD Subjects
`NaPBA
`HPN-100
`Adults
`UP 1204-003
`(N=lO)
`
`Adults
`UP 1204-003
`(N- 10)
`
`Peds
`HPN-100-005
`(N=II)
`
`Peds
`HPN-100-005
`(N=ll)
`
`PBA in Plasm a
`AUCo.24 (Jlg·h/m L)
`Cmax55 (Jlg/m L)
`Cminss (~tg/mL)
`
`PAA in Plasma
`J\UCo.J4 (JJg·h/mL)
`Cmaxss (11g/mL)
`Cm in 5, (Jlg/rnL)
`PAGN in Plasma
`AUCo.2,1 ( ~tg· h/mL)
`Cmax .. (JJg/mL)
`Cminss (~tg/mL)
`
`739 (49 .2)
`141 (44.3)
`0.588 (255)
`
`236 (105.2)
`37.4 ( 101.6)
`0.366 (171.3)
`
`540 (60.1 )
`70. 1 (64 .7)
`2.87 (265)
`
`63 1 (44.9)
`95.6 (42.0)
`1.50 (99.8)
`
`595 .6 {1 23.9)
`53 .0 (94.7)
`3.56 ( 194 .4)
`
`773 (73 .3)
`75 . 1 (64.4)
`0.674 ( 130.5)
`
`574.6 (168.9)
`40.5 (1 47.6) .,
`i.06 (3 1 0.7)
`
`964 (63.6)
`90.5 (69. 1)
`2 .99 (1 22.1)
`
`I 133 (3 1.1 )
`83 .3 (25.8)
`16.8(86 .. 1)
`
`10 15 (44.7)
`74.8 (37.3)
`4.63 (66.4)
`
`1098 (44.2)
`71.9 (56.0)
`12.1 (134.4)
`
`1378 (40.2)
`I 05 (33 .5)
`13.] (64.9)
`
`Pre-NDA Meeting December 7, 2010:
`1) FDA expressed concern that the sponsor's NDA package, as outlined in the
`meeting backgrounder, would not provide adequate pediatric information,
`specifically information to suppmi dosing in children under the age of 6 years and
`limited characterization of P AA levels in patients 6 years to 17 years of age.
`4
`2) The sponsor proposed
`lbl <
`
`>
`
`The FDA could not agree with this proposal in light of the
`EOP2 recommendation of a safety data base that included 35-40 patients with 12
`months of safety data at the time ofNDA submission.
`
`(b)(4)
`
`3)
`
`Identification of an appropriate
`.--.---.....1
`pediatric dose and evaluation of safety is necessruy in light of the number of
`pediatric UCD patients who would be administered the drug once it is approved.
`
`Written answers issued to questions (submitted by sponsor in a Febmary 2011 meeting
`request) on August 3. 2011:
`1)
`FDA provided comments on the phrumacokinetic model.
`2)
`Sponsor roposed to include a
`
`(b)l4)
`
`Page 10 of33
`
`Reference ID: 3254202
`
`Par Pharmaceutical, Inc. Ex. 1016
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 11 of 35
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`

`

`Division Director Review
`
`(b)(4)
`
`3)
`
`FDA reiterated its recommendation that the sponsor provide data to support
`dosing in children under the age of 6 years of age in the NDA submission,
`stating, "Submission of a Risk Evaluation and Mitigation Strategy (REMS)
`would not satisfy nor replace the need for infmmation in this patient population.
`Again, as stated in the meeting, this population constitutes a significant pmiion
`of the UCD population and would likely use your product, if approved.
`Therefore, we again strongly recommend that you provide this info1mation at
`the time of your NDA submission. It may be acceptable for you to submit the
`PK results from Study HPN-100-012 for review at the time of the NDA
`submission to provide information on dosing in patients younger than 6 years of
`age. However, if these data suggest substantially different exposures compared
`to adults, additional safety data from the 12-month open label extension study
`may also be required."
`
`3. CMC/Device
`I concur with the conclusions reached by the chemistly reviewer this NDA provided
`"sufficient information to assure identity, su·ength, purity, and quality of the dmg product,
`Ravicti liquid for oral adminisu·ation." The manufacturing site inspections were acceptable. I
`concur with the CMC reviewers that the product should be described as an "oral liquid" in the
`product label instead of an "oral solution". The product is not a substance that has been
`dissolved into a solution. There are no outstanding issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`I concur with the conclusions reached by the Pha1macologyfroxicology reviewer that there
`a1·e no outstanding pha1macology/toxicology issues that preclude approval.
`
`I concur that the nonclinical studies suppoti labeling consistent with the requirements for
`Pregnancy Categmy C.
`
`Carcinogenicity. The results of a 2-yeai· cai·cinogenicity study in rats (administered glycerol
`phenylbutyrate) were presented to the CAC on July 17, 2012, and the Committee concluded
`that tumors observed in the study were dmg related. Multiple tumor types were obse1ved,
`a1·ising in the pancreas (acina1· cell adenoma, ca1·cinoma and combined adenomalcai·cinoma) in
`males and females, Zymbal' s gland (ca1·cinoma) in males and females, adrenal coliex
`(combined adenomalca1·cinoma) in females, utems (endomeu·ial su·omal polyp and combined
`polyp/sa1·coma), and thyroid (follicular cell adenoma, ca1·cinoma and combined
`adenomalca1·cinoma) in females. As noted in the Nonclinical Pha1macology review and the
`CDTL review, the doses administered in this ca1·cinogenicity study ranged 3-8 times the
`exposure expected in human patients being u·eated for underlying UCD [range depends on sex
`and age ( adultlpediau·ic)].
`
`Page 11 of33
`
`Reference ID: 3254202
`
`Par Pharmaceutical, Inc. Ex. 1016
`Par v. Horizon, IPR of Patent No. 9,561,197
`Page 12 of 35
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`

`

`Division Director Review
`
`The Pharmacology reviewers concluded that even with the positive carcinogenicity study, the
`risk/benefit ofRavicti favored its approval. The CDTL concurred after considering: 1) an OSE
`consult review, 2) whether carcinogenicity would only be expected with the glycerol
`phenylbutyrate product (and not the currently marketed sodium phenylbutyrate product), and
`3) the benefit associated with phenylbutyrate in managing ammonia levels in patients with
`UCD.
`
`OSE's Division ofPharmacovigilance was consulted to evaluate whether there have been
`spontaneous reports of malignancy associated with Buphenyl (sodium phenyl butyrate). No
`reports were identified in the AERS database and in an NIH PubMed search; however, a signal
`of malignancy would be difficult to detect from these sources. My PubMed search for
`published evidence of increased risk of tumors in patients with UCDs, which had not
`necessarily been linked to their medications, found only limited information. A Japanese
`publication pointed to a case series of 8 cases of hepatocellular carcinoma in 56 adult patients
`with citrullenemia due to argininosuccinate synthetase deficiency (Nakayama M, et al.
`Hepatology, 1990; 11(5):819-23). In addition, Wilson, et al. (Molecular Genetics and
`Metabolism 105, 2012: 263-265) reported a possible association ofUCDs with liver
`dysfunction, which they linked to an increased risk of developing hepatocellular carcinoma.
`The authors examined charts from the Children's Hospital Colorado longitudinal study site for
`the NIH-funded Rare Diseases Clinical Research Center longitudinal study ofUCDs and
`found that more than 50% of patients at that site with symptomatic OTCD had liver
`dysfunction or failure. The authors cited prior publications that had documented acute liver
`dysfunction as a clinical presentation of ornithine transcarbamylase deficiency (OTCD). The
`authors linked these liver dysfunction signals and hepatocellular carcinoma to the underlying
`disease, and not the patients' medications. In addition, the medical history was reported in
`detail in some of the patients, which indicated they had not been exposed to phenylbutyrate.
`
`The Buphenyllabel does not contain carcinogenicity study information, and it appears it was
`approved in the absence of the existence of such information. Buphenyl is sodium
`phenyl butyrate, and while it is unlikely that the carcinogenicity study of sodium
`phenyl butyrate would differ from Ravicti, based on the presence of the glycerol component in
`Ravicti, that possibility cannot be completely excluded without actual data from a sodium
`phenylbutyrate carcinogenicity study. However, the phenylbutyrate is released from the
`glycerol backbone primarily within the gut lumen, so the drug to which both patients and rats
`are primarily systemically exposed is the same between Buphenyl and Ravicti (like UCD
`patients, intact glycerol phenyl butyrate was not detected in blood in rat PK studies). In
`addition, the Clinical Pharmacology review found that intact Ravicti was not detected in
`pharmacokinetic analyses of samples taken from UCD patients. (Although it was detected in
`normal volunteers, the applicant attributed the difference in presence of intact