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

`

`CLINICAL PHARMACOLOGY REVIEW ADDENDUM
`
`
`
`NDA
`
`203-284
`
`Submission Date(s)
`
`December 23, 2011, February
`22, March 13, March 27,
`April 20, June 29, July 03,
`July 05, August 23, 2012
`
`Ravicti®
`Glycerol phenylbutyrate
`Insook Kim, Ph.D.
`Sue-Chih Lee, Ph.D.
`Capt. Edward D. Bashaw, Pharm.D.
`Division of Clinical Pharmacology 3
`Division of Gastroenterology and Inborn Errors Products
`Hyperion
`Original
`
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`Division Director
`OCP Division
`OND Division
`Sponsor
`Submission Type;
`
`
`
`Executive Summary
`
`This is an addendum to the original clinical pharmacology review of NDA 203-284 dated
`1/2/13 to discuss two post-marketing studies. We require a pharmacokinetic study in
`pediatric patients < 2 years old and recommend an in vivo drug interaction study with a
`sensitive CYP3A4 substrate as a post-marketing commitment as below.
`
`
`Post-Marketing Requirement
`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 and the exposure-response relationship should be
`evaluated for safety and efficacy.
`
`Rationale
`In the NDA, Ravicti was not studied in patients younger than 2 month old and very few
`data on patients in the age category of 2 months to 2 years were included. Because of no
`or insufficient data in patients younger than 2 years old, additional clinical studies will be
`required in these two age groups i.e. < 2 months old and 2 months to 2 years old.
`
`In the age category of 2 months to 2 years, two of the four patients had PAA levels ~ 500
`μg/mL when on buphenyl or HPN-100. Therefore we recommend PK blood samples be
`collected to characterize PK of Ravicti and its metabolites, PBA, PAA and PAGN.
`
`toxicity with neurological and gastrointestinal manifestations has been
`PAA
`demonstrated with IV administration of PAA. In cancer patients, the symptoms at PAA
`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)
`
`Reference ID: 3248057
`
`

`

`occurred in patients with mean peak PAA level of 682 μg/mL1. In patients with acute
`hyperammonemia, overdose of IV PAA in children has been reported to cause death and
`coma.2 Levels of PAA in these children were > 1000 μg/mL.
`
`
`Post-Marketing Commitment
`In vivo drug interaction study to evaluate the effect of Ravicti on a concomitant drug that
`is metabolized by CYP3A4.
`
`The highest proposed dose of Ravicti should be used to maximize the potential of in vivo
`drug interaction while the dose for individual patients may vary.
`
`Rationale: Based on the in vitro studies suggested drug interaction potential with
`substrates of three CYP enzymes, we are requesting one in vivo study with CYP3A.
`
`The [I]/Ki of PBA was the highest for CYP2C9 i.e. 0.451 and it was 0.393 for CYP2D6
`and [I]/IC50 for CYP3A4 was 0.325. Although the [I]/Ki was higher for CYP2C9 than for
`CYP3A4, we recommend that in vivo drug interaction study with a sensitive substrate of
`CYP3A4/5 based on following:
`1) The wider range of drugs that are metabolized by CYP3A4
`2) The significant contribution of CYP3A4 to the metabolism in the intestine
`because phenylbutyrate, a metabolite of glycerol phenylbutyrate is presumably
`generated in the intestine.
`3) Phenylacetate (PAA), which is converted from phenylbutyrate, showed an
`inhibitory effect on CYP3A4 and CYP2C9 at a concentration higher than the
`observed plasma concentrations. While the possibility of in vivo drug interaction
`with CYP2C9 substrate is unlikely based on the [I]/Ki of PAA for CYP2C9
`determined in an additional study, the [I]/Ki of PAA for CYP3A4 was not
`determined. Therefore, potential effects PAA on CYP3A4 can not be ruled out.
`
`
`
`
`
`
`1 Thibault A et al, Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer
`1995;75:2932-8.
`2 Parphanphoj et al (2000), Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity
`occurring the treatment of acute hyperammonemia, J. Inherit. Metab. Dis 23: 129-36.
`
`
`Reference ID: 3248057
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`INSOOK KIM
`01/18/2013
`
`SUE CHIH H LEE
`01/23/2013
`
`EDWARD D BASHAW
`01/23/2013
`
`Reference ID: 3248057
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`
`
`NDA
`
`203-284
`
`Submission Date(s)
`
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`PM Reviewer
`PM Team Leader
`OCP Division
`OND Division
`Sponsor
`Submission Type;
`Formulation;
`Strengths; Regimen
`
` Indication
`
`December 23, 2011, February
`22, March 13, March 27, April
`20, June 29, July 03, July 05,
`August 23, 2012
`
`Ravicti®
`Glycerol phenylbutyrate
`Insook Kim, Ph.D.
`Sue-Chih Lee, Ph.D.
`Kevin Krudys, Ph.D.
`Nitin Mehrotra, Ph.D.
`Division of Clinical Pharmacology 3
`Division of Gastroenterology and Inborn Errors Products
`Hyperion
`Original
`Liquid for oral administration
`1.1 g of glycerol phenylbutyrate (GPB) in 1 ml of Ravicti®
`(equivalent to 1.02 g phenylbutyric acid)
`• Recommended starting total daily dose is as below
`
`505(b)(1)
`
`• Dose range: 4.5-11.2 ml/m2 (5-12.4 g/m2)
`• Not to exceed 17.5 ml (19 g) total
`• Total daily dose should be administered in three divided doses
`with meals
`Adjunctive therapy for chronic management of adult and
`pediatric patients with urea cycle disorders
`involving
`deficiencies of the following enzymes: Carbamyl phsphate
`synthetase
`(CPS), Ornithine
`transcarbamylase
`(OTC),
`Argininosuccinate synthetase (ASS), Argininosuccinate lyase
`(ASL), Arginase (ARG), Mitochondrial transporter ornithine
`translocase (HHH deficiency)
`
`
`Table of Contents
`1
`Executive Summary.....................................................................................................2
`1.1
`Recommendations............................................................................................... 3
`1.2
`Phase IV Commitments ...................................................................................... 3
`1.3
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ............... 3
`2 Question-Based Review...............................................................................................8
`2.1
`General Attributes of the drug ............................................................................ 8
`2.2
`General Clinical Pharmacology ........................................................................ 12
`
`Reference ID: 3236181
`
`(b) (4)
`
`

`

`Intrinsic Factors ................................................................................................ 34
`2.3
`Extrinsic Factors ............................................................................................... 40
`2.4
`General Biopharmaceutics................................................................................ 44
`2.5
`Analytical Section............................................................................................. 46
`2.6
`3 Major Labeling Recommendations............................................................................54
`4 Appendices.................................................................................................................59
`4.1
`Pharmacometric Reviews.................................................................................. 59
`4.2
`Demographic and individual PAA systemic exposure in pediatric patients. …76
`4.3
`OCP Filing Form............................................................................................... 79
`
`
`
` 1
`
`
`
`Executive Summary
`
`
`This original submission is to support the approval of glycerol phenylbutyrate (GPB; HPN-100,
`proposed tradename:Ravicti®), as an adjunctive therapy for chronic management of adult and
`pediatric patients ≥ 6 years of age 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
`(also called Hyperornithinemia-
`Hyperammonemia-Homocitrullinuria; HHH deficiency).
`
`Glycerol phenylbutyrate is a prodrug of phenylbutyrate which is a nitrogen scavenger.
`Phenylbutyrate in a sodium salt form was approved in 1996 for use in patients ≥ 6 years of age
`with UCD involving deficiencies of the following enzymes: CPS, OTC, and ASS (Buphenyl®
`Tablets (NDA 20-572) and Powder (NDA 20-573)). In addition to the enzyme deficiencies that
`Buphenyl® is indicated for, use of Ravicti is proposed for other enzyme deficiencies i.e. ASL,
`ARG and a transporter deficiency i.e. HHH related to urea cycle disorders.
`
`In support of this application, the sponsor conducted clinical trials in UCD patients > 6 years old.
`The primary efficacy endpoint was blood ammonia level at steady-state of treatment during the
`switch-over period. The efficacy of Ravicti to Buphenyl was based on the non-inferiority of
`Ravicti in maintenance of blood ammonia level in UCD patients. The control of blood ammonia
`level was evaluated based on the area under the curve of ammonia concentration over 24 hours.
`
`Because of the concern of neurotoxicity associated with phenylacetate (PAA) reported in cancer
`patients and in animals, the evaluation of systemic exposure to PAA in UCD patients < 6 years
`old in comparison to that after Buphenyl was requested. The results of PK study in patients < 6
`years old was submitted in April, 2012 after filing of the NDA as agreed upon prior to the NDA
`submission. In the initial submission, the sponsor did not seek the indication in patients < 6
`years old.
`
`
`
`
`Reference ID: 3236181
`
`2
`
`

`

`1.1 Recommendations
`The Division of Clinical Pharmacology 3 and the Division of Pharmacometrics reviewed the
`submission and found acceptable provided a mutual agreement on the labeling languages can be
`reached.
`
`
`1.2 Post-Marketing Studies
`A potential post-marketing study(ies) is currently under discussion. An addendum will
`be followed if a study(ies) is deemed necessary.
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings
`Throughout this review Ravicti was also referred as glycerol phenylbutyrate and by its code
`name HPN-100.
`
`
`Exposure (Dose)-Response Relationship
`(cid:131) Efficacy
`The Sponsor performed an analysis to explore the relationship between blood ammonia and
`exposure. Blood ammonia was represented as AUC0-24 or change in ammonia from time 0 to
`Cmax. No consistent or strong relationship between exposure and blood ammonia was observed.
`The sponsor notes that the lack of a relationship is most likely due to the fact that the patients
`enrolled in these studies were already dosed to effect so that their ammonia levels were already
`within the normal range. Also, other factors contribute to ammonia levels, including residual
`urea synthetic capacity and dietary nitrogen intake. One way to understand the dose-response
`relationship would be to study patients as they are titrated to a dose of BUPHENYL or HPN-100.
`
` (cid:131)
`
` Safety:
`In healthy subjects
`In healthy subjects, a positive relationship between plasma peak PAA level and the incidence of
`nervous system AEs was observed. The incidence of a nervous system adverse event is elevated
`when the PAA Cmax exceeds 80 µg/mL (90%) compared to when PAA levels are lower than 80
`µg/mL (32%). Please see the Pharmacometrics review in the appendix by Dr. Krudys for more
`details.
`
`In UCD patients
`No clear relationship between PAA Cmax and the incidence of nervous system adverse event was
`observed in UCD patients. The discrepancy may be because UCD patients were well-controlled
`on a stable dose of BUPHENYL upon entering the trial. Presumably, this dose was titrated based
`on safety as well as ammonia levels. Therefore, for each individual patient, the PAA levels were
`tolerable. This is supported by the relatively lower overall incidence of nervous system adverse
`events in UCD patients compared to healthy volunteers. On the other hand, Healthy subjects
`more sensitive or responsive to nervous system side effects of PAA.
`
`
`In addition, UCD patients may be more tolerant to nervous system side effects because some of
`the manifestations of hyperammonemia are similar to those that can be expected at high levels of
`
`
`
`Reference ID: 3236181
`
`3
`
`

`

`PAA. These patients, therefore, may have become more tolerant to these adverse reactions over
`the course of their disease.
`
`Effects of Ravicti on the QT interval
`The review of the thorough QT study by the IRT-QT team (dated 5/30/2012) noted that there
`was no QTc prolongation effect of HPN-100 based on the double delta analysis. The largest
`upper bounds of the 2-sided 90% CI for the mean difference between HPN-100 (13.2 g/day and
`19.8 g/day) and placebo were below 10 ms. However the study was considered inconclusive
`because the moxifloxacin time profile was not consistent with the expected moxifloxacin time
`course. IRT-QT team review noted that it was unexpected to see moxifloxacin peaks at 0.5 h
`post-dose after a single oral dose of 400 mg was administered. Therefore, IRT-QT team
`recommended a further evaluation of effects of Ravicti on the QT prolongation. The necessity of
`an additional study is under discussion.
`
`The rationale for the proposed daily dose range
`The ammonia scavenger therapy should be individualized due to various factors that contribute
`to the management of ammonia such as the patients’ residual urea formation capacity, the age-
`dependent nutritional need, and intrinsic capacity elimination of PAA via conjugation with
`glutamine. The wide range of observed maintenance dose for sodium phenylbutyrate implicates
`that the starting dose should also be individualized. Nevertheless, this development program was
`not designed to address the starting dose for Ravicti nor the dose titration strategy. In this
`development program, all patients except six patients were on Buphenyl prior to the switch to
`Ravicti. The removal of Buphenyl was considered unethical due to a risk of hyperammonemia.
`The dose of Ravicti was determined based on the molar equivalent dose of phenylbutyrate to
`Buphenyl.
`
`The proposed dose range i.e. 4.5-11.2 ml/m2(5-12.4 g/m2) is based on the dose range of observed
`doses for Buphenyl. The proposed lower end of the dose corresponds to the observed Buphenyl
`dose at 25% quartile and the proposed upper end of the dose is equivalent to the upper end of the
`Buphenyl dose (Table 1).
`
`Table 1. The proposed daily starting dose and the dose range in UCD patients
`BSA
`Starting dose
`Dose range
`4.5-11.2 ml/m2; (5-12.4 g/m2); not to
`exceed 17.5 ml total (19 g)
`
`
`Approved dose range for sodium phenylbutyrate
`9.9 g—13 g/m2
`> 20 kg
`No starting dose
`< 20 kg
`No starting dose
`450-600 mg/kg
`
`
`The proposed dose range is reasonably acceptable in UCD patients > 2 months of age.
`
`
`
`UCD patients > 2 years of age
`• The maintenance of blood ammonia during the switch-over period was comparable.
`• The dosing range is based on the observed range of effective individual doses.
`
`
`
`Reference ID: 3236181
`
`4
`
`(b) (4)
`
`

`

`• The observed and simulated systemic exposure to PAA was comparable between Ravicti
`and Buphenyl treatments.
`• The simulated mean Cmax for PAA patients > 2 years old at the high end of the proposed
`dose was below 200 µg/ml and lower than the concentrations reported to be associated
`with neurotoxicity in cancer patients e.g. ~400-500 mcg/ml.
`
`
`UCD patients < 2 years of age
`•
`In patients younger than 2 years old, PK data is insufficient due to the limited number of
`patients (n=4), and sparse PK samplings. Therefore, modeling and simulation of PK was
`not reliable in this age group.
`• Because there are two patients who experienced PAA concentrations higher than 400
`µg/ml after Ravicti as well as Buphenyl, further PK and safety information is desired to
`better define the upper limit of the dose range. In the meantime, the proposed dose range
`is applicable to this age group based on the high end of the dose range similar to that of
`Buphenyl for this age group.
`
`
`
`UCD patients < 2 months of age
`Because Ravicti was not studied in newborns younger than 2 months old and the concern of
`inefficient hydrolysis of Ravicti due to lower lipase activity in this age group, we do not
`recommend that the use of Ravicti in neonates <2 months old until further information
`becomes available.
`
`
`Starting dose
`The starting dose should also be individualized based on the individual patient’s needs at the
`time of initiation of Ravicti treatment e.g. dietary needs changes by the developmental stage.
`Therefore, the proposed starting dose in patients > 6 years old may not be the optimal starting
`dose for all patients. The initiation of treatment for individual patients should follow an
`established clinical treatment guideline as available. Nevertheless, it seems to be a reasonable
`starting point to avoid excessive under- or overdosing for majority of patients in the absence of
`the treatment guideline. In addition, the dose is expected to be further titrated based on the
`patients’ response. Therefore, the median observed dose should be provided in the label but
`should not be recommended as a starting dose. Comments on the treatment initiation strategy are
`deferred to the clinical reviewers.
`
`Patients who were not on Buphenyl
`In the open-label extension period, there were a limited number of patients (n=6), were not on
`Buphenyl. For those patients, the starting dose of HPN-100 was to be equivalent to the lower
`end of the approved dose range for BUPHENYL® at the investigator’s discretion. According to
`the comments from the six investigators who initiated HPN-100 on patients who were not on
`Buphenyl, the starting dose was determined taking several factors into considerations such as the
`prescribed dietary protein, the recommended Buphenyl dose range, UCD subtype, and
`supplementary amino acid intake. Among these patients, two patients who received 17.4 ml or
`18 ml of HPN-100 (the proposed upper limit is 17.5 ml) discontinued after dose reduction for
`toxicity at 1 week or 2 months after the initiation of the treatment.
`
`Ammonia assay in Phase 3 trial
`
`
`
`Reference ID: 3236181
`
`5
`
`

`

`Total eleven ammonia assay kits were used for the assay for blood ammonia in the pivotal phase
`3 study. Because the cross-assay validation was not performed, the comparison of blood
`ammonia level between patients across study sites is not considered reliable. Nevertheless, it
`was concluded that the lack of the cross-assay validation did not invalidate the comparison of
`ammonia control during the switch-over period because blood ammonia for the each patient was
`measured at the same laboratory using the same assay kit and each patient served as his or her
`own control.
`
`Pharmacokinetic/ Biopharmaceutics Properties
`The evaluation of pharmacokinetics of Ravicti was in comparison to that after Buphenyl in all
`UCD patients. Upon oral administration Ravicti is hydrolyzed by lipases to release
`phenylbutyrate. Phenylbutyric acid (PBA) is further converted to phenylacetic acid (PAA) which
`is conjugated with glutamine to form phenylacetylglutamine (PAGN). Urinary excretion of one
`molecule of PAGN is equivalent to the elimination of two nitrogen molecules.
`
`The systemic exposure to PBA and its active moiety, PAA was about 3-4 fold lower after Ravicti
`than that after Buphenyl in healthy subjects. On the other hand, in adult UCD patients, the mean
`systemic exposure to PBA and to PAA was 15-25% lower after Ravicti than Buphenyl while the
`mean blood ammonia level tended to be lower after Ravicti than Buphenyl.
`
`PK of glycerol phenylbutyrate, HPN-100
`After multiple doses, UCD patients aged 6-17 year, intact HPN-100 was not detectable in plasma
`samples. The evaluation of PK in UCD patients was performed only at steady-state. Intact
`HPN-100 was not measured in the pivotal Study HPN-100-006.
`
`In healthy subjects intact HPN-100 was detected in plasma. However, the detectable HPN-100
`in healthy subjects was attributed to the contaminated plasma samples at the study site. While
`there was no direct evidence to support the assertion, it makes the HPN-100 results unreliable in
`healthy subjects. Therefore a firm conclusion can not be drawn and the incomplete hydrolysis of
`HPN-100 can not be ruled out.
`
`PK of metabolites of glycerol phenylbutyrate
`In healthy subjects, after single dose administration, Tmax for PBA, PAA, and PAGN was 1 h, 4
`h, and 4 h, respectively. Mean terminal half-life for PBA, PAA and PAGN was 1.9, 1.4 and 5.9
`hours, respectively. The ratio of mean AUCi of PAA and PAGN to PBA is 0.58 and 2.1,
`respectively. In comparison to Buphenyl, the systemic exposure (AUC) to PBA and PAA of
`Ravicti was 75% and 73% lower, respectively. The AUC and urinary excretion of PAGN over
`24 hours was also 18% and 17% lower after Ravicti. Multiple dose PK under the proposed three
`times daily dosing frequency was not studied in healthy subjects. After multiple doses (BID for
`7 days), AUC of PBA, PAA, and PAGN was 1.4, 2.9, and 1.6 fold higher than after single dose.
`
`In UCD patients > 2 years old, the modeling and simulation of PK suggests that the systemic
`exposure to PAA is similar between Ravicti and Buphenyl at the high end of the dose range and
`the mean peak plasma concentration is predicted to be lower than 500 µg/ml. In pediatric UCD
`patients, a higher variability and higher concentrations of PAA than in adult patients is predicted
`after administration of Buphenyl and Ravicti. The modeling and simulation was not reliable in
`
`
`
`Reference ID: 3236181
`
`6
`
`

`

`UCD patients < 2 years old due to the limited number of patients and sample numbers. There is
`no PK data available for patients < 2 months old of age.
`
`PK in patients with hepatic impairment
`In patients with hepatic impairment, mean AUC of PAA was higher than in healthy subjects and
`mean AUC increased as the degree of hepatic impairment increased. Of note the effects of
`hepatic impairment on the systemic exposure to PAA was studied under a different dosing
`frequency i.e. BID. Mean AUC of PAA in patients with moderate and severe hepatic
`impairment was 1.53-- and 1.94--fold higher than in healthy subjects. For patients with hepatic
`impairment Child-Pugh B and C, the dosing should be initiated at the lower end of the range. If
`possible, measurement of PAA concentration and the PAA/PAGN ratio at steady-state will be
`useful to guide further dose increase.
`
`In vitro drug interaction studies
`In vivo drug interaction via induction of CYP3A4 and CYP1A2 is not expected based on a lack
`of induction of CYP3A4 and CYP1A2 in in vitro studies.
`
`In vitro PBA inhibited CYP2C9, CYP2D6, and CYP3A4/5 and potential in vivo drug interaction
`was suggested by the [I]/Ki > 0.1 for CYP2C9 and CYP2D6 and [I]/IC50 >0.1 for CYP3A4.
`Mean plasma peak concentration of PBA was used as [I]. Of note the likelihood of in vivo drug
`interaction may vary among patients depending on the dose because of the wide range of
`individual dose and the systemic exposure.
`
`Plasma PAA/PAGN ratio as a biomarker to the probability of exceed 400 µg/ml PAA
`concentration
`To mitigate a risk of exposing patients to high PAA concentration, the sponsor proposed plasma
`PAA/PAGN ratio as a biomarker for the lower conversion of PAA to PAGN. A high PAA to
`PAGN ratio could indicate inefficient conversion of PAA to PAGN in a given patient. The mean
`ratio of AUC of PAA to PAGN was about 0.5 in adult UCD patients and the ratio of plasma
`PAA to PAGN was mostly lower than 1 at any given PK sampling time point in UCD patients as
`well as in healthy subjects. On the other hand, in patients with hepatic impairment (Child-Pugh B
`and C classes), the ratio greater than 2 was common and mostly associated with peak PAA
`concentration higher than 100 µg/ml.
`The sponsor proposes to measure PAA level when symptoms of vomiting, nausea, headache with
`somnolence, confusion or sleepiness are present in the absence of high ammonia. The sponsor
`also proposes that the Ravicti dose should be reduced if the plasma PAA level is ≥ 500 μg/mL
`and/or the ratio of plasma PAA to PAGN (both in μg/mL) is greater than
`
`While it is reasonable to use PAA to PAGN ratio as an inherent measure of conversion efficiency,
`it alone should be not used as a dose reduction criteria and the dose reduction should be done
`based on the patient response. The ratio of PAA to PAGN may be informative to modify UCD
`management strategy such that when the ratio is high and the PAA level is high, modification of
`other aspects of management should be considered rather than an increase in dose because
`further increase in dose may not necessarily increase the efficiency of ammonia elimination as
`the conjugation of PAA with glutamine could be saturated.
`
`However, there are no commercially available assays for PAA and PAGN.
`
`
`
`Reference ID: 3236181
`
`7
`
`(b) (4)
`
`

`

`2 Question-Based Review
`2.1 General Attributes of the drug
`
`2.1.1 What pertinent regulatory background or history contributes to the current
`assessment of the clinical pharmacology and biopharmaceutics of this drug?
`
`In this original submission, the sponsor seeks a marketing approval of glycerol phenylbutyrate
`(GPB; HPN-100, Ravicti®), a prodrug of phenylbutyrate as an adjunctive therapy in the chronic
`management of patients with urea cycle disorders. Phenylbutyrate (Buphenyl® Tablets and
`Powder (NDA 20-572, NDA 20-573)) is approved for the same indication. Because most of
`patients were likely already on Buphenyl®, the evidence of efficacy of HPN-100 was agreed to
`be primarily based on a comparable maintenance of blood ammonia level during the switch-over
`between Buphenyl® and HPN-100.
`
`In addition to the enzyme deficiencies indicated for Buphenyl®, i.e. OTC, CPS, and ASS, the
`sponsor proposes to expand the indication to additional enzyme deficiencies including
`argininosuccinate lyase (ASL), arginase (ARG), and mitochondrial transporter ornithine
`translocase (HHH deficiency).
`
`The approved product, Buphenyl® is indicated for children weighing more than 20 kg and for
`adults. Although Buphenyl® is not indicated for children weighing < 20 kg; dosing information
`is provided in the current label. The sponsor stated that HPN-100 was developed to reduce pill
`burden, sodium load, and to improve palatability of sodium phenylbutyrate.
`
`The sponsor is not seeking the indication in patients younger than 6 years of age in this
`submission, however to address the concern of the neutrotoxicity associated with high plasma
`concentration of phenylacetic acid (PAA) reported in cancer patients 1 2 , a PK study was
`conducted in patients with UCD < 6 years old. A priori agreement was made to provide PK data
`in patients younger than 6 years old after the NDA filling. The PK in patients younger than 6
`years of age was submitted in an amendment dated April 23, 2012.
`
`Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300
`mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominately
`somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia,
`hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy.
`These adverse events were mainly mild in severity. The reversible toxicities as reported by
`Thibault were reported to be temporally associated with PAA levels ranging from 499–1285
`µg/mL. The acute onset and reversibility when the phenylacetate infusion was discontinued
`suggest a drug effect.
`
`
`1 Thibault et al. (1995) Phase I study of phenylacetate administered twice daily to patients with cancer, Cancer
`75(12); 2932
`2 Thibult et al. (1994) Phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer,
`Cancer Res. 54, 1690
`
`
`
`Reference ID: 3236181
`
`8
`
`

`

`Based on the reported association between plasma PAA level and neurotoxicity and PAA
`being an active moiety, the systemic exposure to PAA was used for the exposure-response
`relationship analysis for safety.
`
`2.1.2 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance, and the formulation of the drug product as they relate to clinical pharmacology
`and biopharmaceutics review?
`
`Glycerol phenylbutyrate is a triglyceride containing 3 molecules of PBA linked to 3 glycerol
`backbone via
`mm and its molecular weight is 530.67 (Figure 16). Glycerol phenylbutyrate
`is insoluble in water and most organic solvents, and it is soluble in dimethylsulfoxide (DMSO)
`and > 65% acetonitrile. Upon administration, the active moiety phenylacetate (PAA) should be
`released following hydrolysis of phenylbutyrate (PBA) from glycerol phenylbutyrate (GPB).
`
`Figure 1. Structure of glycerol phenylbutyrate and its metabolites (a) PBA; (b) PAA
`
`Ravicti® is
`
`M (4)
`
`-
`in liquid form containing
`
`M“)
`
`One glycerol contains three molecule of phenylbutyrate which will be converted to phenylacetate.
`Each mL of liquid contains 1.1 grams of glycerol phenylbutyrate and delivers 1.02 grams of
`phenylbutyrate G’BA).
`
`In clinical trials to compare the proposed Ravicti® and Buphenyl®, the dose for Ravicti was
`determined based on the molar content of PBA equivalent to Buphenyl.
` -__ x 0.95 11.1 = Total dailv HPN-100 dose mL
`Each I-IPN-100 dose may have been rounded up to the nearest 0.2 mL. Disposable syringes and
`medication cups were provided by the sponsor.
`
`Reference ID: 32361 81
`
`

`

`2.1.3 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`“The urea cycle disorders (UCD) result from defects in the metabolism of waste nitrogen from
`the breakdown of protein and other nitrogen-containing molecules3. Severe deficiency or total
`absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in the urea cycle or
`the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor
`metabolites during the first few days of life (Figure 2). Infants with a severe urea cycle disorder
`are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia,
`hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. In milder (or
`partial) deficiencies of these enzymes and in arginase (ARG) deficiency, ammonia accumulation
`may be triggered by illness or stress at almost any time of life. In these disorders the elevations
`of plasma ammonia concentration and symptoms are often subtle and the first recognized clinical
`episode may not occur for months or decades.”
`
`Figure 2. Urea Cycle
`
`
`
`
`Glycerol phenylbutyrate is a nitrogen scavenger. Upon administration, glycerol phenylbutyrate
`will be mainly eliminated as phenylacetic glutamine (PAGN) following the conjugation of the
`active moiety PAA with glutamine. Phenylacetic glutamine will be further excreted in the urine
`eliminating two nitrogen molecules (Figure 3).
`
`
`3 GeneReviews™. Pagon RA, Bird TD, Dolan CR, et al., editors. Seattle (WA): University of
`Washington, Seattle; 1993- (http://www.ncbi.nlm.nih.gov/books/NBK1217/)
`
`
`
`
`Reference ID: 3236181
`
`10
`
`

`

`NH“
`
`Glycerol Phenylbutyrate
`
`u-Kotoglutaraw
`
`gummy
`Pitt-air Um
`
`Glutamate
`
`Phonylbutyrlc Acld
`
`NH" “I
`l [macaw
`GlutamineTPhenylacelate
`
`Phenylacetylglutamlne
`
`l
`
`U rine Exc retion
`
`Figure 3: Mechanism of Action of Phenylbutyric acid
`
`The proposed indication is an adjunctive therapy for chronic management of adult and pediatric
`patients 2 6 years of age with urea cycle disorders (UCD) involving deficiencies of the following
`enzymes:
`carba