CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Management Review
`
`Date:
`
`December 13, 2012
`
`
`
`Reviewer(s):
`
`
`
`
`
`Division Director:
`
`Drug Name(s):
`
`Indication(s):
`
`Yasmin Choudhry, M.D., Medical Officer, Division of Risk
`Management (DRISK)
`
`Kendra Worthy, Pharm. D., Team Leader, DRISK
`
`Claudia Manzo, Pharm. D., DRISK
`
`Ravicti (glycerol phenylbutyrate)
`
`
`
`
`
`
`
`As adjunctive therapy for chronic management of adult and
`pediatric patients ≥
` of age with Urea Cycle
`Disorders
`Liquid for oral administration
`Formulation and Route:
`Application Type/Number: NDA 203284
`Applicant/sponsor:
`Hyperion Therapeutics
`OSE RCM #:
`2012-72
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3230292
`
` 1
`
`(b) (4)
`
`

`

`1 INTRODUCTION
`This is a review of Hyperion Therapeutics’ proposed Risk Evaluation and Mitigation
`Strategy (REMS) submitted with NDA 203284 to the Division of Gastroenterology and
`Inborn Errors (DGIEP) for Ravicti (glycerol phenylbutyrate) on December 23, 2011.
`2 BACKGROUND
`Ravicti (glycerol phenylbutyrate) is a triglyceride containing three molecules of
`phenylbutyrate (PBA) joined via ester linkage to a glycerol backbone. It is a prodrug of
`PBA and a pre-prodrug of phenyl acetic acid (PAA), the active moiety of the compound.
`The proposed indication is adjunctive therapy for chronic management of Urea Cycle
`Disorders (UCD) in adult and pediatric patients of ≥
` of age.
`The Ravicti NDA 203284 was submitted as 505b(1) with reference listed drug Buphenyl
`(sodium phenylbutyrate). Buphenyl oral tablet and powder formulation was approved in
`1996 as adjunctive therapy in the chronic management of UCD in adult and pediatric
`patients of all ages and is the only approved nitrogen scavenging drug for chronic
`management of UCD.
`At the time of NDA submission, data on pediatric patients less than 6 years of age were
`not available. In order to limit access to Ravicti only to patients 6 years of age and older,
`DGIEP requested the Applicant submit a proposed REMS (Information Request letter
`dated September 13, 2011). The pediatric data were subsequently submitted in April 2012
`(with 120-day safety and efficacy update).
`
`2.1 Materials Reviewed
`• Proposed REMS for Ravicti NDA 203284 submitted on December 23, 2011
`• Buphenyl label
`• Clinical review Ravicti NDA 203284 by Nancy F. Snow MD dated November 27,
`2012
`2.2 Overview of Clinical Program
`
`Ravicti was studied in a total of 180 patients in short-term and open-label safety
`extension studies. The key studies that demonstrated non-inferiority to Buphenyl are:
`
` Study HPN-100-006, a Phase 3, randomized, double-blind, cross-over active-
`controlled study in adult patients (n=44) with UCD.
`
` •
`
` •
`
` Study HPN-100-012, a Phase 2, switch-over, open-label study was completed in April
`2012. A total of 15 pediatric patients (with UCD) ≥ 29 days were studied. This study
`provided efficacy and safety data in pediatric patients for Ravicti that had previously
`been missing.
`
`
`See Dr. Nancy Snow’s clinical review for details of the clinical development for Ravicti.
`
`
`Reference ID: 3230292
`
` 2
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`(b) (4)
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`

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`Common adverse events seen in the Ravicti clinical trials included gastrointestinal
`disorders, dizziness and headache. Serious adverse events included acute gastroenteritis,
`hyperammonemia, aggression, abdominal pain, dizziness, lobar pneumonia, lung
`infiltration, peripheral neuropathy, psychotic disorder, and pelvic pain. No serious
`adverse events were noted in the pediatric study HPN-100-012. These adverse events can
`be addressed by the label.
`
`No deaths were reported in UCD patients during the Ravicti clinical trials. The safety
`issues raised by the clinical reviewer for Ravicti include the following:
`• A 2-year carcinogenicity study in rats showed an increased incidence of
`tumors of the pancreas, thyroid, adrenal cortex, uterus, Zymbal’s glands, and
`cervix. Because Buphenyl and Ravicti share the same active moiety these
`findings would pertain to Buphenyl as well. No carcinogenicity studies were
`submitted in support of the Buphenyl application and a search by the Division
`of Pharmacovigilance for reports in the adverse events reporting system, or
`literature reports of neoplasms in UCD patients taking Buphenyl did not yield
`any cases. The postmarketing requirements and commitments are still under
`review by DGIEP.
`• A potential risk for Ravicti is toxicity of the active metabolite PAA. According
`to the clinical reviewer, this is based on toxicity seen in non-UCD population
`at the range of 499-1285 mcg/mL. PAA toxicity may present as nausea,
`headache, emesis, fatigue, weakness, lethargy, somnolence, dizziness, slurred
`speech, memory loss, confusion, and disorientation. Adverse events suggestive
`of PAA toxicity were not seen in clinical trials with Ravicti. In adult UCD
`patients PAA levels were lower with Ravicti than Buphenyl however, in
`pediatric patients PAA levels were higher compared to adults.
`
`The clinical reviewer stated that based on the data available there was no correlation
`between PAA levels and adverse events in UCD patients and recommended that the PAA
`levels should be measured in UCD patients, particularly in the context of neurological
`adverse effects at >476 mcg/ml PAA levels. These concerns will be addressed in the
`postmarketing requirement/commitment (under review).
`2.3 Risk Management Proposed by Applicant
`
`The proposed REMS for Ravicti submitted with the original application in response to
`the September 13, 2011 IR consisted of:
`
`Reference ID: 3230292
`
` 3
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`(b) (4)
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`

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`The proposed goal was to support informed dosing and treatment decisions, including
`key PK differences between adults and children and limit access to patients ≤ 6 years of
`age.
`
`The additional pediatric data (Study HPN-100-012) submitted as 120-day Safety in April
`2012 was considered adequate by DGIEP for approval of Ravicti as adjunctive therapy
`for chronic management of UCD in pediatric patients ≥
`. A decision was made by
`DRISK in conjunction with DGIEP and the REMS Oversight Committee (ROC) (email
`communication dated September 26, 2012) that a REMS for Ravicti is not necessary at
`this time.
`
`3 DISCUSSION
`Urea Cycle Disorders are rare disorders comprising a group of inherited deficiencies of
`one of the enzymes or transporters involved in the urea cycle, which converts ammonia to
`urea. Clinical manifestations of UCD are due to hyperammonemia and management is
`largely aimed at controlling ammonia levels and preventing seizures, cerebral edema,
`hyperventilation, posturing and coma1.
`
`Ravicti (glycerol phenylbutyrate) liquid formulation was found non-inferior to Buphenyl
`(sodium phenylbutyrate). The number of pediatric patients studied, even though small,
`was acceptable for this rare disease that has a prevalence of < 2000 patients in US.
`Compared to Buphenyl, Ravicti liquid formulation has an advantage of being neutral in
`taste/odor, the pill burden and volume of liquid with drug administration is less, and is
`sodium free (high sodium load of Buphenyl is undesirable in a subtype of UCD patients
`who are prone to hypertension).
`
`DGIEP requested the Applicant submit a proposed REMS to limit use of the drug to only
`patients greater than 6 years of age because data below this age was not available at the
`time of submission. The Applicant has subsequently submitted data in pediatric patients
`down to 29 days. The overall adverse event profile of Ravicti is similar to that of
`Buphenyl, and the clinical trials showed that the adverse events tended to diminish over
`time. Since Ravicti is broken down into the active metabolite PAA and PAA toxicity can
`occur at high levels, the clinical reviewer believes that pediatric patients who develop
`neurological symptoms be monitored for PAA levels (even though no specific adverse
`events have been identified with PAA. As noted above, the PAA toxicity and the signal
`
`
`1 Clinical review Ravicti NDA 203284 by Nancy F. Snow MD dated November 27, 2012
`
`
`Reference ID: 3230292
`
` 4
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`(b) (4)
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`(b) (4)
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`

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`for carcinogenicity will be closely followed in the postmarketing period (the
`postmarketing requirements and/or commitments are still under review).
`
`DRISK concurs with DGIEP that the risks associated with treatment of Ravicti can be
`managed at this time through labeling and routine pharmacovigilance and that a REMS
`for Ravicti is not necessary to ensure the benefits outweigh the risks.
`
`4 CONCLUSION
`DGIEP and DRISK are in agreement2 that the Study HPN-100-012 provides the pediatric
`efficacy and safety data for Ravicti NDA 203284 that had previously been missing, and
`obviates the need for a REMS. DRISK believes that labeling and routine
`pharmacovigilance measures are sufficient to manage the risks associated with Ravicti at
`this time. DGIEP should consult DRISK if additional safety information is identified that
`warrants risk mitigation measures.
`
`
`
`2 Additional concurrence was obtained from the REMS Oversight Committee (ROC) via email on
`September 26, 2012.
`
`Reference ID: 3230292
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` 5
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YASMIN A CHOUDHRY
`12/13/2012
`
`CLAUDIA B MANZO
`12/13/2012
`concur
`
`Reference ID: 3230292
`
`