CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208030Orig1s000
`
`SUMMARY REVIEW
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`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`Date
`
`From
`
`Sub'ect
`
`electronic stam
`
`
`Edvardas Kaminskas, MD.
`Summ Review
`
`208030
`NDA #
`
`Supplement #
`A licant Name
`
`AtoPhanna, Inc.
`
`Date of Submrssron
`November 17, 2014
`
`PDUFA Goal Date
`September 17, 2015
`Ferriprox
`Proprietary Name /
`Name
`Established
`S ‘
`Deferi nrone
`
`Oral Solution 50 g/500 mL (100 mg/mL)
`Dosage Forms / Strength
`For treatment of patients with transfusional iron
`Proposed Indications
`overload due to thalassemia syndromes when current
`chelation thera is inade u uate
`
`Andrew DmE'uk, M.D./Kathy Robie-Suh, Ph.D., M.D.
`
`Clinical Pharmacology Review
`
`OMP/DMPP
`Morgan Walker, Pharm.D., M.B.A./LaShawn Griffiths,
`
`MSHS-PH, BSN/Sharon Mills, B.S.N
`
`
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`Statistical Review
`
`Pharmacology Toxicology Review
`Brenda J. Gehrke, Ph.D., Christopher M. Sheth, Ph.D.
`CMC Review
`Katherine Windsor, Ph.D.lDonghao Lu, Ph.D./Lin Qi,
`Ph.D.IDenise Miller, Ph.D.thong Li, PhD.
`Sriram Subramaniam, Ph.D./Bahru Habtemariam,
`PhannD.
`
`Michelle Rutledge, Pharm.D./Yelena Maslov, PharmD.
`James Dvorsky, Pharm.D.
`John Kadavil, Ph.D./Charles R. Bonapace, Pharm.D.
`
`OSE/OMEPRM/DMEPA
`OPDP
`Division of New Drug
`Bioequivalence Evaluation/OSIS
`CDTL Review
`OND=0mce ofNew Drugs
`OMP=0flice ofMedical Policy
`OSE= Ofiice of Surveillance and Epidemiology
`0PDP=Ofice of Prescription Drug Promotion
`0MEPRM=0flioc ofMedication Error Prevention and Risk Management
`DMPP=Division ofMedical Policy Programs
`DMEPA=Division ofMedication Error Prevention and Analysis
`OSIS=0flice of Study Integrity and Surveillance
`CDTIFCross-Discipline Ton- Leader
`
`Janice Brown, M.S.
`
`
`
`Referenoe ID: 381 6298
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`Signatory Authority Review Template
`
`1. Introduction
`
`Deferiprone is a small molecule iron chelator that was approved in 500 mg tablet form on
`Octeober 14, 2011 “for the treatment of patients with transfusional iron overload due to
`thalassemia syndromes when current chelation therapy is inadequate” (NDA 21825). The
`current application is for Ferriprox (deferiprone) oral solution, submitted as a 505(b)(1) NDA
`with no change in the indication.
`2. Background
`
`Available treatments of patients with transfusional iron overload due to thalassemia syndromes
`are:
`
`• Deferoxamine (Desferal®, Novartis Pharmaceuticals) powder for Injection Solution
`(NDA 16267) approved on April 1, 1968
`• Deferasirox (Exjade®, Novartis Pharmaceuticals) tablets (NDA 21882) approved on
`November 2, 2005
`• Deferiprone (Ferriprox®, ApoPharma) film-coated tablets (NDA 21825) approved on
`October 14, 2011
`• Deferasirox (Jadenu®, Novartis Pharmaceuticals) film-coated tablets (NDA 206910)
`approved on March 30, 2015.
`Since treatment of patients may start as early as 2 years of age (as in the indications for both
`formulations of deferasirox) and compliance with the drug regimens have been problematic for
`all of the above products, there is a need for a more acceptable formulation than the available
`tablets. This new formulation of Ferriprox, a 100 mg/mL oral solution was developed for
`patients who have difficulty taking the tablets.
`
`The application contains CMC information for the oral solution and demonstration of
`bioequivalence of Ferriprox 100 mg/mL oral solution with the 500 mg tablet. A new NDA is
`submitted instead of a sNDA, since this is a new dosage form of deferiprone.
`
`3. CMC/Device
`
`. It was
`The applicant cross-referenced the CMC information for deferiprone to DMF
`reviewed and was found to be adequate to support NDA 208030. Stability data of drug
`substance supports a retest period of
` months.
`
`2
`
`Reference ID: 3816298
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`Ferriprox oral solution contains deferiprone (100 mg/mL), hydroxyethyl cellulose, glycerin,
`purified water, HCl, artificial cherry flavor, peppermint oil, and FD&C Yellow No. 6. The
`commercial
`roduction batch size is
`Ferri rox oral solution is manufactured b
`
`into 500 mL amber polyethylene terephthalate round bottle and closed with a white
`polypropylene child-resistant cap with a foam liner. The nominal fill volume is -mL. An
`expiration dating period of 18 months is granted for Ferriprox oral solution when stored at 20°
`to 25°C, protected from light. No product quality issues which preclude approval were found
`and the product quality review recommended approval of the NDA. No microbiology issues
`that preclude approval were found and the Microbiology Review recommended approval of
`the NDA. No facility issues that preclude approval were found and the facility review
`recommended approval of the NDA.
`
`I concur with the conclusions reached by the chemistry reviewers regarding the acceptability
`ofthe manufacturing ofthe drugproduct and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of18 months. There are no outstanding
`issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`No new nonclinical information was submitted for this NDA submission. ApoPharma Inc.
`cross—referenced NDA 21825 for the pharmacology/toxicology studies for deferiprone. The
`nonclinical studies reviewed under NDA 21825 to support the initial approval of Feniprox
`(deferiprone) provide sufficient information to support the use of Ferriprox (deferiprone)
`100/mL oral solution for the same indication.
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstandingphamtacologv/toxicologv issues thatpreclude approval
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The Sponsor submitted the results of relative bioavailability study of deferiprone oral solution
`and deferiprone 500 mg tablets. In study LAZI-BA, the bioavailability of 3 x 500 mg tablets of
`Ferriprox relative to that of 1500 mg deferiprone administered as the oral solution (15 mL, 100
`mg/mL) was determined under fasting conditions in 41 healthy adult volunteers (28 males and
`13 females).
`
`Study LA21-BE demonstrated that the relative bioavailability of ApoPharma’s to-be-marketed
`deferiprone oral solution is comparable to the currently marketed Feniprox 500 mg tablet, in
`that the primary PK parameters Cmax, AUC(0—t), and AUC(O-oo) for the test product
`demonstrated bioequivalence 03E) against the Feuiprox tablet (see Table 1 below).
`
`Reference ID: 381 6298
`
`

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`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`Table 1: Summary Bioequivalence Statistics, Study LA21-BE (n=41)
`
`I' arameter (unit)
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`I east Squares Geometric Mean
`I erri rox Soln I erri rox®
`
`
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`I' tin of Test/ 0% Confidence
`| ' eference
`I nterval of Ratio
`
`A graphical representation of deferiprone concentrations is shown below in Figure 1 below.
`
`The clinical pharmacology reviewers concluded that the BE study demonstrated the
`bioequivalence of ApoPhann’s deferiprone oral solution and Feniprox® tablet.
`
`Reference ID: 381 6298
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`I concur with the conclusions reached by the clinical pharmacology/biopharmaceutics
`reviewers that there are no outstanding clinical pharmacology issues that preclude approval.
`
`5
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`Reference ID: 3816298
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`
`
`6. Clinical Microbiology
`
`
`N/A.
`7. Clinical/Statistical-Efficacy
`
`No new clinical information was submitted, besides the Bioequivalence study. The Clinical
`Reviewer concluded that no clinical issues that preclude approval were found and
`recommended accelerated approval for the same indications as the currently approved product
`Ferriprox tablets.
`
`I concur with the conclusions reached by the clinical reviewers that there are no outstanding
`clinical issues that preclude approval.
`
`8. Safety
`
`The Clinical review for deferiprone oral solution evaluated the safety information from study
`LA21-BE. The review concluded “Review of safety in study LA21-BE …does not raise new
`or additional safety concerns for deferiprone oral solution formulation compared to the
`marketed deferiprone tablet product formulation. The safety labeling described in the
`deferiprone tablet product label is the same as the safety labeling for the proposed deferiprone
`oral solution product label.”
`9. Advisory Committee Meeting
`This application was not presented at an Advisory Committee meeting.
`10.
`Pediatrics
`
`There is no Pediatric and Maternal Health Staff review for this NDA.
`
`11.
`
`Other Relevant Regulatory Issues
`
`• Application Integrity Policy (AIP): N/A/
`• Exclusivity or patent issues of concern: None.
`• Debarment certification: Debarment certification was submitted by the Applicant and
`the US Agent in module 1.3.
`
`6
`
`Reference ID: 3816298
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`• Financial disclosures: ApoPharma certified that they have not entered into any
`financial arrangement with the listed clinical investigator, Gaetano Morelli, M.D.
`Financial disclosure was submitted by the Applicant in module 1.3.
`• Other GCP issues: None.
`• DSI audits: No inspection was performed.
`
`There are no other unresolved relevant regulatory issues.
`
`12.
`
`Labeling
`
`• Proprietary name: The proprietary name, Ferriprox, was previously found acceptable
`during the review of NDA 21825 for Ferriprox (deferiprone) tablets
`• Physician labeling, Medication Guide and Instructions for Use were reviewed by the
`clinical, non-clinical, clinical pharmacology, and product quality review teams, as well
`as by the reviewers from Office of Prescription Drug Promotion and the Division of
`Medication Error Prevention and Analysis. The review teams recommended changes to
`all sections of the applicant’s proposed labeling, the Medication Guide and Instructions
`for Use. The applicant accepted the Agency’s revisions.
`• Carton and immediate container labels were reviewed by reviewers from the Division
`of Medication Error and Analysis. The Applicant accepted all suggested changes.
`
`Decision/Action/Risk Benefit Assessment
`• Regulatory Action: Accelerated Approval with no change in the indication.
`
`• Risk Benefit Assessment: The clinical team continues to finds favorable
`benefit-risk profile for Ferriprox oral solution for the stated indication. This
`recommendation is based on the efficacy and safety of the marketed deferiprone
`tablet (Ferriprox) product and the available deferiprone supportive safety
`information from the bioavailability/bioequivalence study LA21-BE.
`
`• Recommendation for Postmarketing Risk Management Activities: None.
`
`• Recommendation for other Postmarketing Study Commitments: Postmarketing
`Requirements and Postmarketing Commitments which were issued during the
`accelerated approval of deferiprone tablets on October 14, 2011 also apply to
`deferiprone oral solution. In an August 20, 2015 submission, ApoPharma
`acknowledged the postmarketing requirements and commitments for Ferriprox
`(deferiprone) oral solution and agrees to the following milestone dates:
`
`• 1
`
`3.
`
`Accelerated Approval
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`7
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`Reference ID: 3816298
`
`

`

`Deputy Division Director Summary Review for Regulatory Action
`NDA 2080301
`
`PMR 1828-1: Conduct a trial to determine the efficacy and safety of the use of deferiprone to
`treat iron overload in patients with sickle cell disease and transfusional
`hemosiderosis who have not been adequately treated with available chelating
`agents. Submit the protocol for review and concurrence prior to commencing.
`The trial will enroll a sufficient number of patients with sickle cell disease as
`described above, to provide sufficient evidence to assess the efficacy and safety
`described above, to provide sufficient evidence to assess the efficacy and safety
`in the sickle cell disease population described. The trial may enroll patients
`with other conditions who have developed transfusional iron overload. The trial
`will stratify for hematologic diagnosis for the randomization. The primary and
`secondary endpoints will measure changes in cardiac iron concentration and
`liver iron concentration.
`
`Final Protocol Submission: Completed.
`Trial Completion:
`02/2017
`Final Report Submission:
`07/2017
`
`Postmarketing Requirements under 505(o)
`
`PMR 1828-2: Establish a registry in order to perform an enhanced pharmacovigilance study
`of agranulocytosis. Submit a protocol to establish the registry and describe
`procedures for this enhanced pharmacovigilance prior to commencing the
`study. Procedures should include: Creation of marketing materials to inform
`and encourage clinicians to report agranulocytosis events to the sponsor;
`monitoring of all reported cases and active follow-up to characterize the
`demographics, recent prior blood counts, concomitant medications, co-existing
`conditions, duration of drug exposure prior to onset, outcomes of the event, and
`other factors that may help to characterize the agranulocytosis event. Sponsor
`also will institute procedures to obtain blood samples from patients with
`reported cases of agranulocytosis to store for later analysis of possible genetic
`underlying factors that may predict the risk of agranulocytosis. Submit interim
`reports annually describing the above results.
`
`Final Protocol Submission: Completed
`Annual Interim Report #1
`04/2016
`Annual Interim Report #2
`04/2017
`Annual Interim Report #3
`04/2018
`Study Completion:
`10/2018
`Final Report Submission:
`04/2019
`
`• Recommended Comments to Applicant: None.
`
`8
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`Reference ID: 3816298
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`EDVARDAS KAMINSKAS
`09/07/2015
`
`Reference ID: 3816298
`
`