CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203567Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Memorandum
`To:
` NDA 203567
`From:
` Linda S. Pellicore, Ph.D., Pharmacology/Toxicology Reviewer
`Through: Barbara A. Hill, Ph.D., Pharmacology/Toxicology Supervisor
`Re:
`
`Submission date: 12/20/2013, 1/16/2014 and 2/4/2014
`SDN:
`21, 22 and 23
`Submission type: Resubmission Class 2
`Drug:
`JUBLIA (efinaconazole) Topical Solution, 10%
`Drug class:
`Azole antifungal
`Indication:
`Onychomycosis
`Route:
`Topical
`Sponsor:
`Dow Pharmaceutical Sciences
`
`
`
`
`Background:
`
`Efinaconazole is a new molecular entity (NME) and an azole antifungal drug. The
`applicant is seeking an indication for once daily topical treatment of onychomycosis in
`adults with JUBLIA (efinaconazole) topical solution, 10%. The original NDA was
`submitted on July 26, 2012 and this submission received a complete response due to
`Chemistry Manufacturing and Control (CMC) deficiencies on May 13, 2013 (see
`communication in DARRTS).
`
`found
`the original application was
`information submitted with
`The nonclinical
`acceptable, provided the applicant adequately addressed the labeling comments (see
`Primary Nonclinical Review dated March 5, 2013, in DARRTS).
`
`On December 20, 2013 the applicant re-submitted their NDA to address the CMC
`deficiencies. The applicant changed the container closure system. No new nonclinical
`information was submitted.
`
`The sponsor resubmitted draft labeling information to the NDA on January 16, 2014.
`This nonclinical review pertains only to the sponsor’s resubmitted draft labeling.
`
`Review of proposed labeling:
`
`Nonclinical detailed labeling recommendations were provided in the original NDA
`Primary Nonclinical Review (see review dated March 5, 2013 in DARRTS). In this cycle,
`the sponsor’s proprietary name, JUBLIA, was found acceptable (see Proprietary Name
`Review dated March 26, 2014, in DARRTS). Other than adding the proprietary name to
`the sponsor’s proposed label, no additional edits were made to the resubmitted draft
`labeling. Nonclinical labeling edits that are being proposed in this review cycle are
`provided below.
`
`
`
`Reference ID: 3504049
`
`1
`
`

`

`Conclusion:
`
`It is recommended that the underlined wording be inserted into and the strikeout wording
`be deleted from the JUBLIA (efinaconazole) Topical Solution 10% label reproduced
`below. The pharmacologic class designation for efinaconazole for the treatment
`onychomycosis is azole antifungal.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
` indicated for the
`azole antifungal
`JUBLIA
`topical treatment of onychomycosis of the toenails due to Trichophyton mentagrophytes
`and Trichophyton rubrum
` (1)
`
`Pregnancy
`8.1
`Pregnancy Category C
`
`There are no adequate and well-controlled studies with JUBLIA topical solution in
`pregnant women
`. JUBLIA topical solution should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Systemic embryofetal development studies were conducted in rats and rabbits.
`Subcutaneous doses of 2, 10 and 50 mg/kg/day efinaconazole were administered
`during the period of organogenesis (gestational days 6-16) to pregnant female rats. In
`the presence of maternal toxicity, embryofetal toxicity (increased embryofetal deaths,
`decreased number of live fetuses, and placental effects) was noted at 50 mg/kg/day
`[559 times the Maximum Recommended Human Dose (MRHD) based on Area Under
`the Curve (AUC) comparisons]. No embryofetal toxicity was noted at 10 mg/kg/day (112
`times the MRHD based on AUC comparisons). No malformations were observed at 50
`mg/kg/day (559 times the MRHD based on AUC comparisons).
`
`Subcutaneous doses of 1, 5, and 10 mg/kg/day efinaconazole were administered during
`the period of organogenesis (gestational days 6-19) to pregnant female rabbits. In the
`presence of maternal toxicity, there was no embryofetal toxicity or malformations at 10
`mg/kg/day (154 times the MRHD based on AUC comparisons).
`
`In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25
`mg/kg/day efinaconazole were administered from the beginning of organogenesis
`(gestation day 6) through the end of lactation (lactation day 20). In the presence of
`maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live
`litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No
`embryofetal toxicity was noted at 5 mg/kg/day (17 times the MRHD based on AUC
`comparisons). No effects on postnatal development were noted at 25 mg/kg/day (89
`times the MRHD based on AUC comparisons).
`
`
`
`Reference ID: 3504049
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`(b) (4)
`
`12.1 Mechanism of Action
`
`JUBLIA topical solution is an azole antifungal [See Clinical Pharmacology (12.4)].
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`“MA 2 year dermal carcinogenicity study in mice; was conducted with daily topical
`
`administration of 3% 10% and 30% efinaconazole solution. Severe irritation was noted
`
`at the treatment site in all dose groups, which was attributed to the vehicle and
`confounded interpretation of skin effects by efinaconazole. The high dose group was
`terminated at week 34 due to severe skin reactions. No drug—related neoplasms were
`noted at doses up to 10% efinaconazole solution (248 times the MRHD based on AUC
`comparisons)
`m“)
`
`Efinaconazole revealed no evidence of mutagenic or clastogenic potential based on the
`results of two in vitro genotoxiciy tests (Ames assay and Chinese hamster lung cell
`chromosome aberration assay) and one in vivo genotoxicity test (mouse peripheral
`reticulocyte micronucleus assay)
`m“)
`
`(b) (4)
`
`No effects on fertili were observed in male and female rats that were administered
`
`subcutaenous doses up to 25 mg/kg/day efinaconzole (279 times the MRHD based on
`AUC com arisions
`rior to and durin earl
`re nanc .Efinaconazole dela ed the
`
`estrous cycle in females at 25 mg/kg/day but not at 5 mg/kg/day (56 times MRHD based
`on AUC comparisons).
`
`Reference ID: 3504049
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LINDA S PELLICORE
`05/09/2014
`
`BARBARA A HILL
`05/09/2014
`
`Reference ID: 3504049
`
`

`

`Pharmacology/Toxicology Supervisory Memorandum
`
`
`
`
`203567
`NDA number:
`Supporting document: 1
`CDER Stamp Date:
`July 26, 2012
`Type of submission:
`Original NDA
`Applicant:
`Dow Pharmaceutical Sciences
`Supervisor name:
` Barbara Hill
`
`Review Division:
` Dermatology and Dental Products
`Date:
` March 5, 2013
`Product:
`Efinaconazole Topical Solution, 10%
`Pharmacologic class: Azole antifungal
`Indication:
`Onychomycosis
`
`General comments:
`
`I concur with the conclusions contained in Dr. Linda Pellicore’s
`Pharmacology/Toxicology review for this drug product.
`I concur that there are no nonclinical approval issues for this drug product and that
`this NDA is approvable from a Pharmacology/Toxicology perspective.
`I concur that there are no nonclinical Post-Marketing Requirements recommended
`for this NDA.
`I concur with the recommended nonclinical labeling changes proposed by Dr.
`Pellicore for this drug product contained in section 1.3.3 of her review including that
`the appropriate Pregnancy Category is C.
`
`
`
` •
`
`•
`
`•
`
`•
`
`
`
`Reference ID: 3271112
`
`1
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BARBARA A HILL
`03/05/2013
`
`Reference ID: 3271112
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`203567
`Application number:
`SDN 1 and 2
`Supporting document/s:
`July 25, 2012 and August 6, 2012
`Applicant’s letter date:
`July 26, 2012 and August 6, 2012
`CDER stamp date:
`Efinaconazole Topical Solution, 10%
`Product:
`Onychomycosis
`Indication:
`Dow Pharmaceutical Sciences
`Applicant:
`Dermatology and Dental Products
`Review Division:
`Linda Pellicore, Ph.D.
`Reviewer:
`Barbara Hill, Ph.D.
`Supervisor/Team Leader:
`Susan Walker, M.D.
`Division Director:
`Strother Dixon
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203567 are owned by Dow Pharmaceutical Sciences or
`are data for which Dow Pharmaceutical Sciences has obtained a written right of
`reference.
`Any information or data necessary for approval of NDA 203567 that Dow
`Pharmaceutical Sciences does not own or have a written right to reference constitutes
`one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 203567.
`
`Reference ID: 3270887
`
`1
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS............................................................................................ 5
`2 DRUG INFORMATION ............................................................................................ 8
`2.1 DRUG................................................................................................................. 8
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 8
`2.3 DRUG FORMULATION ........................................................................................... 9
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 11
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 11
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 12
`2.7 REGULATORY BACKGROUND .............................................................................. 12
`3 STUDIES SUBMITTED.......................................................................................... 13
`3.1
`STUDIES REVIEWED........................................................................................... 13
`3.2
`STUDIES NOT REVIEWED ................................................................................... 15
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 19
`4 PHARMACOLOGY................................................................................................ 19
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 19
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 20
`4.3
`SAFETY PHARMACOLOGY................................................................................... 20
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 23
`5.1
`PK/ADME........................................................................................................ 23
`5.2
`TOXICOKINETICS ............................................................................................... 30
`6 GENERAL TOXICOLOGY..................................................................................... 30
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 30
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 30
`7 GENETIC TOXICOLOGY ...................................................................................... 55
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 55
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 61
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 65
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................... 69
`8 CARCINOGENICITY ............................................................................................. 69
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 82
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................... 82
`9.2
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 87
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 103
`
`Reference ID: 3270887
`
`2
`
`

`

`NDA # 203567
`
`10
`
`
`
`Linda Pellicore, Ph.D.
`
`SPECIAL TOXICOLOGY STUDIES................................................................. 108
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 110
`
`APPENDIX/ATTACHMENTS........................................................................... 116
`
`11
`
`12
`
`
`Reference ID: 3270887
`
`3
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`Efinaconazole is a new molecular entity. Efinaconazole is a triazole antifungal agent
`that apparently has a low keratin binding affinity. The sponsor believes that
`efinaconazole’s low keratophilicity will provide an important pharmacokinetic advantage
`for topical antifungal treatment of onychomycosis. The sponsor states that binding to
`keratin within the nail and skin is believed to inactivate antifungal agents and may
`explain the poor success of topical therapies. The sponsor expects that the low affinity
`of efinaconazole for keratin and ready release when bound will result in an effective
`topical antifungal treatment.
`1.2 Brief Discussion of Nonclinical Findings
`Repeat-dose systemic rodent toxicity and developmental and reproductive toxicity
`studies were conducted with subcutaneous administration of efinaconazole dissolved
`in propylene glycol. Efinaconazole appeared well tolerated but subcutaneous
`administration of propylene glycol was not well tolerated and resulted in significant
`injection site toxicity.
`
`The primary toxicity noted in the 6 month repeat dose subcutaneous toxicity study in
`rats conducted with doses up to 30 (males) and 40 (females) mg/kg/day efinaconazole
`was injection site toxicity noted in all dose groups including the vehicle (propylene
`glycol) control group.
`
`Efinazonaole solution was evaluated in a 9 month dermal toxicity study in minipigs with
`repeated daily dermal administration of up to 30% efinaconazole solution. The
`efinaconazole solution used in the chronic dermal minipig study was similar to the to-
`be-marketed formulation. The minor differences in a few excipients in the formulation
`were determined to not be of toxicological significance. The vehicle and
`efinaconazole solution produced mild skin irritation. Mild skin irritation (modest
`microscopic hyperkeratosis, acanthosis, and localized inflammation) was noted in all
`dose groups including the vehicle control group. No systemic toxicity was noted at
`topical doses up to 30% efinaconazole solution, which is the maximum feasible
`concentration.
`
`Efinaconazole revealed no evidence of mutagenic or clastogenic potential based on
`the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung
`cell chromosome aberration assay) and one in vivo genotoxicity test (mouse
`peripheral reticulocyte micronucleus assay).
`
` dermal mouse carcinogenicity study was conducted with the to-be-marketed
`efinaconazole solution. Severe skin irritation was noted at the treatment site in all dose
`groups including the vehicle control group. This study was suboptimal due to the mice
`being very sensitive to severe dermal effects elicited by the vehicle. No treatment
`
` A
`
`Reference ID: 3270887
`
`4
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`related increase in the incidence of neoplasms was observed in this study. However, the
`skin effects of the propylene glycol vehicle confounded assessment of any skin effects
`due to efinaconazole.
`
`Reproductive and developmental toxicology studies have been conducted with
`efinaconazole in rats and rabbits.
`
`In a subcutaneous rat fertility study skin thickening at the injection site was noted in all
`efinaconazole treated groups and the vehicle control group. No treatment related
`effects on male or female fertility parameters were noted at doses up to 25 mg/kg/day
`efinaconazole in this study. A tendency to slightly prolong the estrous cycle was noted
`in 25 mg/kg/day treated females but the copulation index was 100% in all dose groups.
`
` A
`
` subcutaneous embryofetal development study in rats was conducted with doses up
`to 50 mg/kg/day efinaconazole. Skin thickening at the treatment site, an 11% decrease
`in maternal body weight gain, complete embryo resorption in two dams and an
`increased incidence of embryofetal death were noted at the 50 mg/kg/day dose.
`Embryofetal resorption and/or embryofetal death may be related to the effects seen in
`the placenta noted at the 50 mg/kg/day dose. However, no drug-related malformations
`were noted at doses up to 50 mg/kg/day efinaconazole in this study.
`
` A
`
` subcutaneous embryofetal development study in rabbits was conducted with doses
`up to 10 mg/kg/day efinaconazole. Injection site reactions were noted in all treatment
`groups including the vehicle control group. A decrease in body weight gain was noted
`in does at 10 mg/kg/day. There were no indications of test article related embryofetal
`toxicity or malformations at doses up to 10 mg/kg/day efinaconazole in this study.
`
` A
`
` subcutaneous pre- and post-natal development study in rats was conducted with
`doses up to 25 mg/kg/day efinaconazole. Injection site swelling and masses were
`noted in all dose groups including the vehicle control group. Prenatal pup mortality was
`increased at 25 mg/kg/day. There were no toxicologically significant effects on duration
`of gestation or the ability of dams to deliver litters. No treatment related effects on
`postnatal development of F1 offspring were noted at doses up to 25 mg/kg/day
`efinaconazole in this study.
`
`Single dermal application of up to 10% efinaconazole solution to rabbits did not elicit
`dermal irritation in intact skin but was a mild irritant to abraded skin. Efinaconazole
`solution, 10%, was a mild ocular irritant in rabbit eyes. Efinaconazole solution did not
`elicit a photoirritation response in guinea pigs.
`
`1.3 Recommendations
`
`1.3.1 Approvability
`Efinaconazole Topical solution, 10%, is approvable from a Pharmacology/Toxicology
`perspective.
`
`Reference ID: 3270887
`
`5
`
`

`

`NDA # 203567
`
`Linda Pellicore, PhD.
`
`1.3.2 Additional Non Clinical Recommendations
`
`None
`
`1.3.3 Labeling
`
`It is recommended that the underlined wording be inserted into and the strikeeut wording
`be deleted from the TRADENAME (efinaconazole) Topical Solution 10% label
`reproduced below. The pharmacologic class designation for efinaconazole for the
`treatment onychomycosis is azole antifungal.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`"’""azole
`Topical Solution is
`“MTRADENAME
`"’m’ indicated for the topical treatment of onychomycosis
`“m
`
`antifungal
`(1)
`
`Pregnancy
`8.1
`Pregnancy Category C
`
`There are no adequate and well-controlled studies with TRADENAME Topical Solution
`in pregnant women
`“m". TRADENAME Topical Solution
`“m" should
`be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`
`Systemic embryofetal development studies were conducted in rats and rabbits.
`Subcutaneous doses of 2I 10 and 50 mg/kg/day efinaconazole were administered
`during the period of organogenesis (gestational days 6-16) to pregnant female rats. In
`the resence of maternal toxici
`emb ofetal toxici
`increased emb ofetal deaths
`
`decreased number of live fetuses and lacental effects was noted at 50 m Ik Ida
`
`[559 times the Maximum Recommended Human Dose (MRHD) based on Area Under
`the Curve AUC com arisons . No emb ofetal toxici was noted at 10 m Ik Ida
`112
`
`times the MRHD based on AUC com arisons . No malformations were observed at 50
`
`mg/kg/day (559 times the MRHD based on AUC comparisons).
`
`Subcutaneous doses of 1, 5, and 10 mg/kg/day efinaconazole were administered during
`the eriod of or ano enesis
`estational da 3 6-19 to re nant female rabbits.
`In the
`
`resence of maternal toxici
`
`there was no emb ofetal toxici
`
`or malformations at 10
`
`mg/kg/day (154 times the MRHD based on AUC comparisons).
`
`In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25
`mg/kg/day efinaconazole were administered from the beginning of organogenesis
`(gestation day 6) through the end of lactation (lactation day 20). In the presence of
`maternal toxici
`emb ofetaltoxici
`increased renatal
`u mortali
`reduced live
`
`litter sizes and increased postnatal pup mortally) was noted at 25 mg/kg/day. No
`emb ofetal toxici was noted at 5 m Ik Ida
`17 times the MRHD based on AUC
`
`com arisons . No effects on ostnatal develo ment were noted at 25 m Ik Ida
`
`89
`
`times the MRHD based on AUC comparisons).
`
`Reference ID: 3270887
`
`

`

`NDA # 203567
`
`Linda Pellicore, PhD.
`
`(0) (4)
`
`12.1 Mechanism of Action
`
`TRADENAME Topical Solution is an azole antifungal
`Clinical Pharmacology (12.421.
`
`(b)(4)
`
`fl
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`"MA 2 year dermal carcinogenicity study in mice was conducted with daily topical
`
`administration of 3% 10% and 30% efinaconazole solution. Severe irritation was noted
`
`at the treatment site in all dose groups, which was attributed to the vehicle and
`confounded interpretation of skin effects by efinaconazole. The high dose group was
`terminated at week 34 due to severe skin reactions. No drug-related neoplasms were
`noted at doses up to 10% efinaconazole solution (248 times the MRHD based on AUC
`comparisons).
`(m4)
`
`Efinaconazole revealed no evidence of mutagenic or clastogenic potential based on the
`results of two in vitro enotoxici
`tests Ames assa and Chinese hamster lun cell
`
`chromosome aberration assa
`and one in vivo enotoxici
`reticulocyte micronucleus assay).
`
`test mouse eri heral
`(”‘4’
`
`No effects on fertili were observed in male and female rats that were administered
`
`subcutanous doses up to 25 mg/kg/day efinaconzole (279 times the MRHD based on
`AUC com arisions
`rior to and durin earl
`re nanc .Efinaconazole dela ed the
`
`Reference ID: 3270887
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`estrous cycle in females at 25 mg/kg/day but not at 5 mg/kg/day (56 times MRHD based
`on AUC comparisons).
`
` Drug Information
`
` 2
`
`2.1 Drug
`CAS Registry Number
`164650-44-6
`
`Generic Name
`Efinaconazole
`
`Code Name
`KP-103; IDP-108
`
`Chemical Name
`(2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-
`yl)butan-2-ol
`
`Molecular Formula/Molecular Weight
`C18H22F2N4O / 348.4
`
`Structure
`
`
`
`
`Pharmacologic Class
`Azole antifungal
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`IND 77732: IDP-108 (KP-103) topical solution for the treatment of onychomycosis.
`Division of Dermatology and Dental Products. Sponsor: Dow Pharmaceutical Sciences,
`Inc.
`
`
`Reference ID: 3270887
`
`8
`
`

`

`NDA # 203567
`
`Linda Pellicore, Ph.D.
`
`DMF 21870: KP-103 as manufactured in Yamagata, Japan. Kaken Pharmaceutical Co
`Ltd. A letter authorizing the Agency to refer to the chemistry information provided in
`DMF 21870. No Phannacology/Toxicology information was contained in DMF 21870.
`
`2.3 Drug Formulation
`
`The sponsor made several changes to the drug formulation during development. Initially
`the active moiety was referred to as KP-103 by Kaken Pharmaceutical. Subsequently
`the active moiety is referred to as IDP-108 b Dow Pharmaceuticals. Earl
`roto
`e
`formulations include
`
`
`
`Reference ID: 3270887
`
`9
`
`

`

`NDA # 203567
`
`Linda Pellicore, PhD.
`
`The quantitative composition of lDP-108 (also referred to as lDP-108A) is provided in
`the table below.
`
`
`
`
`IDP-108
`
`
`"’"" Alcohol, USP
`
`
`C clomethicone (”’WQF
`
`
` Butylated Hydroxytoluene
`
`Diisopropyl Adipate
`
`012-1 5 Alkyl Lactate
`03)“)
`
`
`
`Except for the dermal mouse carcinogenicity study, which was conducted with the to—
`be-marketed drug product, the pivotal GLP toxicity studies were conducted with lDP-
`108.
`
`The difference between lDP-108, the formulation used in the pivotal GLP toxicity studies
`and the to-be-marketed formulation used in the GLP dermal mouse carcinogenicity
`study,
`mm)
`"’m’
`
`The small amount of
`
`is not expected to significantly change the study results from a
`Pharmacology/Toxicology perspective.
`
`The quantitative composition of the to-be-marketed drug product is provided below in
`the sponsor’s table.
`
`Function
`
`Concentration %w/w)
`
`UU3"U _N
`
`Efmaconazole
`
`Z :9
`
`Cyc lomethic one
`
`Diisopropyl Adipate
`
`C' 12-1 5 Alkyl Lactate
`
`Cosmetic
`Cosmetic
`
`Butyla ted
`Hydroxytoluene
`
`Citric Acid. Anhydrous
`
`Edetate Disodiuul
`
`Purified Water
`
`Alcohol
`
`USP
`
`C1:12"U
`
`C}m"U
`
`The dermal mouse carcinogenicity study was conducted with the to-be—marketed
`formulation.
`
`Reference ID: 3270887
`
`1 0
`
`

`

`NDA # 203567
`
`Linda Pellicore, Ph.D.
`
`The Chemistry Manufacturing and Controls (CMC) Reviewer identified some drug
`product container issues (i.e., leaking containers) that may result in a Complete
`Response (CR) for this NDA. However, these containers were not used in any of the
`submitted Pharmacology/1'oxicology studies. Therefore, these CMC issues do not affect
`the integrity of the Pharmacology/Toxicology data package.
`
`2.4 Comments on Novel Excipients
`
`C12-15 alkyl lactate is not listed in the CDER inactive ingredients database. Therefore,
`C12—15 alkyl lactate is a novel excipient. The sponsor provided additional information to
`qualify C12—15 alkyl lactate for use at the 10% level in this topical drug product.
`
`2.5 Comments on Impurities/Degradants of Concern
`
`Two impuritiesH and two degradantsH have been identified in the
`
`e s ruc ures for the impurities egra an s are provided in the table
`
`drug substance.
`below.
`
`"m
`
`Synthesxs
`
`Reference ID: 3270887
`
`1 1
`
`

`

`NDA # 203567
`
`Linda Pellicore, Ph.D.
`
`The sponsor’s proposed specifications for the impurities/degradants in the drug
`substance are provided below.
`
`:2}: NMT "’""% and “m" NMT "’""%; each additional
`"’"" NMT “’""%; "’"" NMT "’""%;
`impurity: NMT "’""% and total impurities: NMT “‘"%. The sponsor's proposed
`specifications for the impurities/degradants in the drug substance are acceptable since
`they are all below the ICH qualification thresholds.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`Efinaconazole, a triazole antifungal agent, is indicated for the topical treatment of
`onychomycosis. Efinaconazole solution, 10%, is a clear solution for topical application.
`Efinaconazole solution should be topically applied once daily using the built—in flow
`through brush applicator provided.
`It is important to ensure that the nail, the nail folds,
`nail bed, and hyponychium are covered.
`
`2.7 Regulatory Background
`
`An End of Phase 2 (EOP2) meeting was conducted on August 4, 2009. The EOP2
`meeting minutes were relayed to the sponsor on August 17, 2009.
`
`A pre-meeting communication for a Pre-NDA meeting was sent to the sponsor on April
`11, 2012. The sponsor canceled the Pre-NDA meeting scheduled for April 17, 2012
`after receipt of the Division’s pre-meeting communication. The Pre-NDA final responses
`were relayed to the sponsor on May 14, 2012.
`
`The dermal mouse carcinogenicity study protocol that was submitted as a SPA and the
`supporting 3 month dermal mouse dose range finding study were discussed during an
`Exec CAC meeting on December 9, 2008. The Executive CAC meeting minutes were
`relayed to the sponsor on December 15, 2008.
`
`The sponsor submitted a request to modify the dermal mouse carcinogenicity study on
`November 11, 2009. Comments concerning appropriate modifications of the dermal
`mouse carcinogenicity study that received Executive CAC concurrence were relayed to
`the sponsor on November 24, 2009. The sponsor submitted a request for early
`termination of the dermal mouse carcinogenicity study on February 18, 2011.
`Comments concerning appropriate criteria for early termination of a particular dose
`group that received Executive CAC concurrence were relayed to the sponsor on
`February 25, 2011. The sponsor submitted a second request for early termination of
`the dermal mouse carcinogenicity study on April 11, 2011. Comments concerning early
`termination of the dermal mouse carcinogenicity study that received Executive CAC
`concurrence were relayed to the sponsor on April 18, 2011.
`
`The sponsor submitted a waiver request for conduct of a systemic carcinogenicity study
`on November 25, 2009. A letter was sent to the sponsor on April 14, 2010 granting the
`waiver request for conduct of a systemic carcinogenicity study.
`
`Reference ID: 3270887
`
`1 2
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`Studies Submitted
`
`
`
`
`
` 3
`
`3.1 Studies Reviewed
`Pharmacology
`Efinaconazole
`1. General pharmacology of KP-103. Study No. KOP001
`2. hERG Block comparator study: Effects of IDP-108 on cloned hERG potassium
`channels expressed in mammalian cells. Study No. DSIN-7001-A6HP-11-08.
`Metabolite H3
`1. Effect of H3 on cloned hERG potassium channels expressed in mammalian cells.
`Study No. DSIN-7001-A6HP-23-09.
`Pharmacokinetics/ADME/Toxicokinetics
`Absorption
`1. Absorption, distribution and excretion studies of KP-103 in rats and dogs. Study
`No. PK9533.
`Distribution
`1. Plasma protein binding of 14C-KP-103 in rats and dogs. Study No. SA950310.
`2. Plasma protein binding of 14C-KP-103 in humans. Study No. SA950311.
`3. Feto-placental transfer and excretion into milk after a single subcutaneous
`administration of 14C-KP-103 to female rats. Study No. P101077.
`Metabolism
`1. In Vitro metabolism study of 14C-KP-103. Study No. SA970103.
`2. Determination of KP-103 metabolites after subcutaneous administration of 14C-
`KP-103 to rats. Study No. SA960307.
`3. Identification of KP-103 metabolites. Study No. SA970108.
`4. Identification of IDP-108 metabolites in the presence of human and minipig
`hepatocytes. Study No. IAS-07-MS-15-DM.
`5. Determination of KP-103 metabolites after subcutaneous administration of 14C-
`KP-103 to dogs. Study No. P101078.
`6. In Vitro metabolism study of 14C-KP-103 by rat, dog, minipig and human
`cryopreserved hepatocytes. Study No. M100202.
`7. In Vitro assessment of reaction phenotyping for human cytochrome P450
`enzymes by IDP-108. Study No. DSIN-7001-A6HP-25-09.
`8. Determination of the potential for IDP-103 to inhibit CYP1A2, CYP2C9,
`CYP2C19, CYP2D6 and CYP3A4 activities in human liver microsomes. Study
`No. DSIN-7001-A6HP-02-06.
`9. Inhibitory effects of KP-103 and its metabolite S-35345 (H3) against nine
`isoforms of cytochrome P450 in human liver microsomes. Study No. M090201.
`10. In Vitro enzyme induction of KP-103 in human hepatocytes. Study No. P101080.
`Excretion
`1. Urinary and fecal excretion studies of KP-103 after percutaneous administration
`of 14C-KP103 to rats. Study No. SA970109.
`General Toxicology
`
`Reference ID: 3270887
`
`13
`
`

`

`NDA # 203567
`
`
`
`
`Linda Pellicore, Ph.D.
`
`Repeat-Dose Toxicity
`1. A 3 month toxicity study of IDP-108 administered by subcutaneous injection to
`rats. Study No. DSIN-7001-A6HP-16-08.
`2. A 6 month toxicity study of IDP-108 administered by subcutaneous injection to
`rats. Study No. DSIN-7001-A6HP-19-08.
`3. A 28 day dermal GLP toxicity study of IDP-108 in Gottingen minipigs. Study No.
`DSIN-7001-A6HP-05-07.
`4. A 9 month dermal GLP toxicity study of