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

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation, Labeling Review
`
`NDA 203567
`Date Review Completed: 17 May 2014
`
`Page 1 of 5
`Clinical Microbiology Review
`
`Date Original NDA Received by CDER: 26 July 2012
`Date Assigned: 17 August 2012
`Date Review Completed: 17 May 2014
`Reviewer: Kerry Snow MS, MT(ASCP)
`
`APPLICANT
`
`Dow Pharmaceutical Sciences, Inc.
`1330 Redwood Way
`Petaluma, CA 94954-7121
`Barry M. Calvarese, MS
`Vice President
`Regulatory and Clinical Affairs
`
`DRUG PRODUCT NAME
`
`Proprietary name: JUBLIA™
`Established name: Efinaconazole Solution, 10%
`Non-proprietary name: IDP-108 Topical Solution or KP-103 Topical Solution
`Chemical name: C18H22F2N4O
`Molecular formula: (2R,3R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-
`(1H-1,2,4-triazol-1-yl)butan-2-ol
`Molecular weight: 348.39
`Chemical structure:
`
`PROPOSED INDICATION
`
`Treatment of mild to moderate onychomycosis of the toenails
`
`PROPOSED DOSAGE FORM, STRENGTH, ROUTE OF ADMINISTRATION
`
`Form: liquid
`Strength: 10%
`Route of Administration: topical
`
`Reference ID: 3508609
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation, Labeling Review
`
`NDA 203567
`Date Review Completed: 17 May 2014
`
`Page 2 of 5
`Clinical Microbiology Review
`
`DISPENSED
`
`Rx
`
`RELATED DOCUNIENTS
`
`none
`
`REMARKS
`
`The Applicant filed a New Drug Application for Efmaconazole Solution 10% for the once
`daily treatment of onychomycosis (tinea unguium) on 26 July 2012. The Division of
`Dermatology and Dental Products consulted the Division of Anti-Infective Products to
`review clinical microbiological information and conclusions, included in that submission.
`The consultation was completed and filed on 4 March 2013. The Application was deemed
`approvable, from a clinical microbiology perspective, provided that the Applicant address
`proposed changes to the product labeling (see Clinical Microbiology review dated 4 March
`2013).
`
`The Applicant re-submitted NDA 203567 on 20 December 2013 to address deficiencies
`noted in the CMC review of the original Application. No new clinical microbiology
`information was included in that resubmission.
`
`CONCLUSIONS
`
`From a clinical microbiology perspective, the Application is approvable, provided that
`changes are made to the proposed product labeling, as described below.
`
`PROPOSED LABEL
`
`The Agency recommends the following changes to the proposed labeling:
`1. Change
`M4)” to “an azole antifungal” (preference
`stated by DDDP).
`2. Strike discussion of
`
`(mm from the Mechanism of Action section.
`(b) (4)
`
`Studies performed to evaluate the
`were inconclusive
`
`mm)
`
`and no
`
`clinical relevance of this finding has been established.
`3. Strike discussion of
`
`M“) from the
`
`Mechanism of Action section. The terms are very broad and may be
`misleading.
`(m4)
`Finally, the
`
`clinical relevance of such descriptions is Imclear.
`4. Change “ (b)(4)%” to “290%” in the Activity In Vitro and In Vivo section.
`
`Reference ID: 3508609
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation, Labeling Review
`
`NDA 203567
`Date Review Completed: 17 May 2014
`
`Page 3 of 5
`Clinical Microbiology Review
`
`5. Delete
`
`
`
`
`7. sm* from the Resistance
`
`6. Delete
`informative or
`
`e
`
`oses 0
`
`r0
`
`section. This information is non-
`ct labelin .
`
`section. This statement is speculative, not well supported by data included in
`the NDA submission, and ma be misleading, clinically.
`8. Delete
`” section. The section is non-
`
`informative.
`
`The changes to the proposed labeling (Section 12.4) are presented below (bold font
`indicates additions, double-strikethrough font indicates deletions).
`
`12.4
`
`NIicrobiology
`
`Mechanism of Action
`
`Efinaconazole is_ Efinaconazole inhibits fungal lanosterol 14a-
`dememylase involvedin—
`
`Activity In Vitro and In Vivo
`
`Efinaconazole has been shown to be active against isolates of the following
`
`microorganisms, both in vitro and in clinical infections. Efinaconazole exhibits in vitro
`minimum inhibitory concentrations (MICs) of 0.06 ng/mL or less against most-
`(Z90%) of isolates of the following microorganisms:
`
`Trichophyton mentagrophytes
`
`Trichophyton rubrum
`
`
`
`Reference ID: 3508609
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation, Labeling Review
`
`NDA 203567
`Date Review Completed: 17 May 2014
`
`Page 4 of 5
`Clinical Microbiology Review
`
`Efinaconazole drug resistance development was studied in vitro against T. mentagrophytes,
`T. rubrum and C. albicans. Serial passage of fungal cultures in the presence of sub-growth
`inhibitory concentrations of efinaconazole increased the MIC by up to 4-fold,
`
`. The clinical significance of these in vitro results is
`
`unknown.
`
`Reference ID: 3508609
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation, Labeling Review
`
`NDA 203567
`Date Review Completed: 17 May 2014
`
`Page 5 of 5
`Clinical Microbiology Review
`
`
`
`Reference ID: 3508609
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KERRY SNOW
`05/17/2014
`
`Reference ID: 3508609
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`FROM:
`
`THROUGH:
`
`cc:
`
`SUBJECT:
`
`10 January 2014
`
`NDA 203567
`
`Bryan S. Riley, Ph.D.
`Team Leader (Acting)
`OPS/New Drug Microbiology Staff
`
`Stephen E. Langille, Ph.D.
`Master Review Microbiologist
`OPS/New Drug Microbiology Staff
`
`Strother D. Dixon
`Regulatory Project Manager
`OND/DDDP
`
`Product Quality Microbiology assessment of Microbial Limits for
`Efinaconazole Topical Solution, 10% [Submission Date: 20 December
`2013]
`
`The Microbial Limits specification for Efinaconazole Topical Solution, 10% is acceptable
`from a Product Quality Microbiology perspective. Therefore, this submission
`is
`recommended for approval from the standpoint of product quality microbiology.
`
`Efinaconazole Topical Solution, 10% is for administration directly to the nail, to the skin folds
`surrounding the nail, and to any accessible skin of the nail bed for the treatment of onychomycosis.
`
`The drug product is tested for Microbial Limits at release using a method consistent with USP
`Chapter <61> (Microbiological Examination of Non-sterile Products: Microbial Enumeration
`Tests) and <62> (Microbiological Examination of Non-sterile Products: Tests for Specified
`Microorganisms). The Microbial Limits acceptance criteria are consistent with USP Chapter
`<1111> (Microbiological Examination of Non-sterile Products: Acceptance Criteria for
`Pharmaceutical Preparations and Substances for Pharmaceutical Use).
`
`Reference ID: 3435606
`
`

`

`M E M O R A N D U M
`
`Table 1 – Microbial Limits Specifications
`Test
`Total Aerobic Microbial Count (USP <61>)
`Total Yeast and Mold Count (USP <61>)
`S. aureus (USP <62>)
`P. aeruginosa (USP<62>)
`
`Acceptance Criteria
`NMT
`CFU/g
`NMT
`CFU/g
`Absent
`Absent
`
`The Microbial Limits test methods were verified to be appropriate for use with the drug product
`following procedures consistent with those in USP Chapter <61> and <62>.
`
`The drug product will not be tested for Microbial Limits as part of the post-approval stability
`protocol. The drug product contains
` Ethanol and
` water and is therefore unlikely to
`support microbial growth. The drug product was also tested for antimicrobial effectiveness
`according to USP <51> and met the acceptance criteria for a topical drug product.
`
`ADEQUATE
`
`Reviewer Comments – The microbiological quality of the drug product is controlled via a
`suitable testing protocol and the drug product formulation is appropriate for a multiple dose
`topical drug product.
`
`END
`
`Reference ID: 3435606
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRYAN S RILEY
`01/13/2014
`
`STEPHEN E LANGILLE
`01/13/2014
`
`Reference ID: 3435606
`
`

`

`Page 1 of 33
`Clinical Microbiology Review
`
`
`
`
`
`
`
`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Date Received by CDER: 26 July 2012
`Date Assigned: 17 August 2012
`Date Review Completed: 28 February 2013
`Reviewer: Kerry Snow MS, MT(ASCP)
`
`APPLICANT
`
`Dow Pharmaceutical Sciences, Inc.
`1330 Redwood Way
`Petaluma, CA 94954-7121
`Barry M. Calvarese, MS
`Vice President
`Regulatory and Clinical Affairs
`
`DRUG PRODUCT NAME
`
`
`Proprietary name:
`Established name: Efinaconazole Solution, 10%
`Non-proprietary name: IDP-108 Topical Solution or KP-103 Topical Solution
`Chemical name: C18H22F2N4O
`Molecular formula: (2R,3R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-
`(1H-1,2,4-triazol-1-yl)butan-2-ol
`Molecular weight: 348.39
`Chemical structure:
`
`
`
`
` onychomycosis of the toenails
`
`
`PROPOSED INDICATION
`
`Treatment of
`
`PROPOSED DOSAGE FORM, STRENGTH, ROUTE OF ADMINISTRATION
`
`Form: liquid
`Strength: 10%
`Route of Administration: topical
`
`
`
`Reference ID: 3270426
`
`(b) (4)
`
`(b) (4)
`
`

`

`Division of Anti—Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Page 2 of 33
`Clinical Microbiology Review
`
`DISPENSED
`
`Rx
`
`RELATED DOCUNIENTS
`
`none
`
`REMARKS
`
`m“) (efinaconazole)
`The Applicant has submitted a New Drug Application for
`Solution 10% for the once daily treatment of onychomycosis (tinea 1mguium).
`
`CONCLUSIONS
`
`From a clinical microbiology perspective, the Application is approvable, provided that
`changes are made to the proposed product labeling, as described below.
`
`PROPOSED LABEL
`
`The Agency recommends the following changes to the proposed label:
`1. Strike discussion of
`mm from the Mechanism of Action section.
`Studies performed to evaluate
`(mm
`were inconclusive
`
`(m4)
`
`clinical relevance of this finding has been established.
`2. Delete
`
`and no
`
`M“)
`
`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`Page 3 of 33
`Clinical Microbiology Review
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`12.4 Microbiology
`Mechanism of Action
`
`Efinaconazole is
`demethylase involved
`
`. Efinaconazole inhibits fungal lanosterol 14α-
`
`
`
`
`
`
`
`Activity In Vitro and In Vivo
`
`Efinaconazole has been shown to be active against isolates of the following
`microorganisms, both in vitro and in clinical infections. Efinaconazole exhibits in vitro
`minimum inhibitory concentrations (MICs) of 0.06 μg/mL or less against most
`
`isolates of the following microorganisms:
`
`Trichophyton mentagrophytes
`
`Trichophyton rubrum
`
`Reference ID: 3270426
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`Page 4 of 33
`Clinical Microbiology Review
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`
`
`
`
`
`Efinaconazole drug resistance development was studied in vitro against T. mentagrophytes,
`T. rubrum and C. albicans. Serial passage of fungal cultures in the presence of sub-growth
`inhibitory concentrations of efinaconazole increased the MIC by up to 4-fold,
`
` The clinical significance of these in vitro results is
`
`unknown.
`
`
`
`
`
`
`
`
`Reference ID: 3270426
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 5 of 33
`Clinical Microbiology Review
`
`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`INTRODUCTION
`
`Onychomycosis is a common fungal infection, most frequently caused by two genera of
`filamentous fungi (Trichophyton sp and Epidermophyton sp). Candida species are
`occasionally associated with nail infections in patients with chronic mucocutaneous
`candidiasis [Gorbach 2004]. Other filamentous fungi (non-dermatophytes) are isolated in
`rare instances, as the etiologic agents of nail disease [Murray 2003]. There are three types
`of true dermatophyte infection: 1) distal subungual onychomycosis, 2) proximal subungual
`onychomycosis, and 3) superficial white onychomycosis. Distal subungal onychomycosis
`(fungal infection originating from the distal portion of the nail and/or nail bed) is the most
`commonly diagnosed form of the disease.
`
`Onychomycosis is diagnosed by physical examination, in combination with laboratory
`findings. Recent guidelines suggest that microscopic examination and culture of subungual
`debris increase the sensitivity and specificity of diagnosis, and that laboratory results are
`particularly important when systemic therapy is considered [Drake 1996].
`
`Up to 25% of patients with onychomycosis can be categorized as poor responders or non-
`responders to topical and/or systemic treatment [Scher 2003]. Although most
`dermatophyte infections are restricted to the keratinized tissues that are derived from the
`skin (skin, hair, and nails), significant morbidity is associated with the infection, spread to
`surrounding tissues is frequent [Szepietowski 2006], and rare invasive disease (deep
`dermatophyte infection) may occur. Currently available topical therapy is usually
`inadequate for the successful treatment of nail infections. Oral treatment options for
`onychomycosis include griseofulvin, terbinafine, itraconazole, and fluconazole [Mandell
`2005]. Systemic antifungal therapy, however, is associated with a variety of adverse
`effects (e.g. hepatotoxicity, congestive heart failure) and the extended time of treatment
`presents a compliance problem for some patients. Recent evidence suggests a 25 to 30%
`relapse rate for onychomycosis of the toenail, when treated with either oral terbinafine or
`oral itraconazole [de Berker 2009].
`
`
` (Efinaconazole Solution, 10%) is a novel triazole antifungal developed as a
`topical treatment for onychomycosis. Investigations have demonstrated a lower affinity of
`IDP-108 for keratin than currently marketed triazole antifungals. This property purportedly
`allows for greater mobility across the nail plate, and provides the principle rationale for
`development of the drug.
`
`MECHANISM OF ACTION
`
`The azole-based antimycotic agents appear to target the fungal heme proteins that
`cocatalyze 14α-demethylase, a P450 enzyme necessary for the conversion of lanosterol to
`ergosterol [Ghannoum 1999]. The inhibition of 14α-demethylase results in the depletion of
`the ergosterols that are required for the maintenance of fungal cell wall integrity, and in the
`buildup of ergosterol precursors. Evidence suggests that this depletion results in increased
`
`Reference ID: 3270426
`
`(b) (4)
`
`

`

`Page 6 of 33
`Clinical Microbiology Review
`
`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`cell permeability, with leakage of cell contents. Azoles may affect mammalian cholesterol
`biosynthesis, but this has only been demonstrated at very high dosages [Balkis 2002].
`
`The Applicant has submitted a study report (Study P090302) from a recent investigation of
`the mechanism of antifungal action of efinaconazole (KP-103). In this study, researchers
`measured the effect of efinaconazole on ergosterol synthesis in isolates of
`T. mentagrophytes, by comparing the concentration of [1,2-14C]-sodium acetate in sterol
`fractions. Results indicated that both efinaconazole and control (itraconazole) decreased
`the labeled sterols in ergosterol fractions (with concomitant increases in labeled sterol in
`the lanosterol fraction), in a concentration-dependent manner, when tested at sub-inhibitory
`concentrations against isolates of T. mentagrophytes. These results suggest a mechanism of
`action in common with that proposed for azole antifungals (described above).
`
`REVIEWER COMMENTS
`The Applicant has submitted a study report that supports a mechanism of action similar to
`other agents described in the azole class of antifungal agents, by correlation of increased
`antifungal activity in isolates of T. mentagrophytes with an efinaconazole-concentration-
`dependent decrease in ergosterol concentration in the fungal cell membrane sterol fractions.
`
`
`ANTIMICROBIAL SPECTRUM OF ACTIVITY
`
`The in vitro antifungal activity of efinaconazole has been investigated in several studies.
`Study 07-42 was performed at the
` in 2010.
`Minimum inhibitory concentrations (MICs) were determined using methods approved by
`CLSI (M38A2). The investigators tested 118 clinical isolates, including 69 isolates of
`T. rubrum (25 collected in the U.S.) and 49 isolates of T. mentagrophytes (25 collected in
`the U.S.). Table 1 summarizes the data for this study. Efinaconazole MIC values were
`lower against all both species than the MIC values of the comparator (itraconazole), and
`the highest MIC noted was 0.12 mcg/mL, observed in 3 isolates of T. mentagrophytes (1
`collected in the U.S. and 2 collected in Japan).
`
`Table 1: Antifungal activity against T. rubrum and T. mentagrophytes
`
`Reference ID: 3270426
`
`
`
`(b) (4)
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Source: This submission, Module 2.7.2.4, page 32
`
`Page 7 of 33
`Clinical Microbiology Review
`
`Study DSIN—7001—A6HP-27-ll was performed at the
`
`"’""
`in 2012.
`
`Investigators compared the in vitro activity of efinaconazole, itraconazole, ciclopirox,
`amorolfine, and terbinafine against clinical isolates of T. rubrum (n=130) and
`T. mentagropllvtes (n=129), using susceptibility testing methods approved by CLSI (M38-
`A2). The results of the study are summarized in Tables 2 and 3. Efinaconazole, in this
`study, was more active, in vitro, against all tested isolates of T. rubrum, as determined by
`the calculated MICgo. In Vitro efficacy against isolates of T. mentagrophytes was equal to
`or better than all comparators.
`
`
`Table 2: Trichophyton mbrum minimal inhibitory concentration MC) data summary
`Source
`\nr
`EFIV
`TERB
`(1c
`ITRA
`.mo
`(uglmL)
`
`North
`(ii—10.31
`
`0001-0015 0001006 0013006 0001-001.3
`
`
`\ucgD
`0008
`Geometric
`0.00.3
`mean
`
`
`
`
`Range
`
`0001-0015 0.0040015 0.03-0.25
`
`0015-0125 0004-0015
`
`Geometric
`mean
`
`0.001
`
`0.008
`
`0.079
`
`0.038
`
`0.008
`
`.-\11(n—130) Range
`\11(50
`
`Geometric
`H 11:11“
`
`0001-0013 0.001006
`0.002
`0008
`0.008
`0.01.3
`
`0003
`
`0009
`
`00.3-0 .3
`0 12.3
`
`0013-0 12.3 000-1-0 01.3
`0. 03
`0008
`
`EHN e elimlcun:Izole llRA ilucumzole; A310 7 :uncwllme; (K e cidopiwx. IERB lelbinalme
`Source: Snulv DSTN-TOOl-AOHP-lel
`Source: This submission Module 2.7.2.4, page 33
`
`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 3: Trichophyton mentagrophytes minimal inhibitory concentration (MIC) data
`summary
`
`Page 8 of 33
`Clinical Microbiology Review
`
`
`
`Source: This submission, Module 2.7.2.4, page 34
`
`The Applicant has reported results from a study conducted in Japan (Study P080101),
`where 27 clinical isolates of T. mentagrophytes, collected in Japan, were tested against
`efinaconazole and comparators (clotrimazole, neticonazole, lanoconazole, butenafine,
`terbinafine, ciclopirox, itraconazole, and amorolfine). Investigators employed
`susceptibility test methods approved by CLSI (M38-A). The calculated MIC90 of
`efinaconazole against the tested isolates was 0.13 mcg/mL (slightly more active than all
`comparators except for lanoconazole, butenafine, and terbinafine). The results of the study
`are summarized in Table 4.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 4: MIC values of KP-103 (efinaconazole) and commercially available antifungal
`agents for 27 T. mentagrophytes clinical isolates
`
`Page 9 of 33
`Clinical Microbiology Review
`
`
`
`Source: Table 1; Study P080101 study report
`
`In two identically designed studies, researchers in Japan investigated the minimum
`inhibitory concentration and minimum fungicidal concentration (MIC/MFC) of
`efinaconazole against 39 isolates of T. rubrum (Study KP950631) and 28 isolates of
`T. mentagrophytes (Study KP950630). The studies, conducted in 1996 at Kaken
`Pharmaceutical Co, Ltd (Japan), did not employ methods approved by CLSI, but complete
`study reports including details of methodology have been provided. Susceptibility testing
`was performed by the micro-dilution method, using 96-well plates, which were incubated
`at 30oC for 7 days following inoculation. Following determination of the MIC (“…the
`minimum concentration of the test compound at which the growth of the microorganisms
`was grossly inhibited…”), aliquots were removed from the well corresponding to the MIC
`and the next 3 2-fold dilutions, and were plated to determine the fungicidal concentration
`(“…concentration at which more than 98% of the inoculated microorganisms are killed.”).
`In these studies, the efinaconazole MIC90 and MFC90 were both 0.5 mcg/mL for
`T. mentagrophytes. For isolates of T. rubrum, the efinaconazole MIC90 was 0.25 mcg/mL
`and the MFC90 was 0.50 mcg/mL. The study results suggest that efinaconazole
`demonstrates fungicidal activity against these commonly isolated dermatophytes.
`
`In Study DSIN-7001-A6HP-31-11, conducted the
` in 2012, researchers investigated the in vitro antifungal activity of
`efinaconazole against 105 clinical isolates of Candida albicans. The laboratory employed
`yeast susceptibility testing methods approved by CLSI (M27-A3). The results of the study
`are summarized in Table 5. The efinaconazole MIC90 value was lower than those of all
`comparators (terbinafine, ciclopirox, amorolfine, and itraconazole)
`
`
`
`
`
`
`
`Reference ID: 3270426
`
`(b) (4)
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 5: Candida albicans minimal inhibitory concentration (MIC) data summary
`
`Page 10 of 33
`Clinical Microbiology Review
`
`
`
`
`The Applicant has included a table summarizing the in vitro antifungal activity of
`efinaconazole against a variety of “other causative pathogens of onychomycosis in
`humans” (Table 6). The data included in the table was culled from two similarly-designed
`studies (Study P100301 and Study P100303), performed at Kaken Pharmaceutical Co.
`(Japan) in 2010. In these studies, researchers employed methods approved by CLSI (M38-
`A2), testing small numbers of each species by broth microdilution techniques. For the
`purposes of this submission, no single species (i.e. those species listed in Table 6) was
`tested in numbers sufficient to permit meaningful microbiologic analysis. In addition, no
`rationale was provided to support the contention that any single species listed in Table 6 is
`a significant pathogen typically associated with onychomycosis.
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`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 6: “Efinaconazole antifungal activity in onychomycosis causative pathogens”
`
`Page 11 of 33
`Clinical Microbiology Review
`
`
`
`Source: Module 2.7.2; Table 17, this submission
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`Reference ID: 3270426
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`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Page 12 of 33
`Clinical Microbiology Review
`
`In Study P110302, conducted at Kaken Pharmaceuticals (Japan) in 2011, investigators
`conducted in vitro susceptibility tests against isolates of T. mentagrophvtes, T. mbrum, and
`C. albicans, using three efinaconazole stereoisomers, five metabolites, two impurities, and
`three degradation products, all identified as efmaconazole-related compounds. The
`susceptibility testing was performed according to methods approved by CLSI (M38—A2 and
`M27—A3). The results of the study are summarized in Table 7. In vitro activity of the
`tested compmmds varied widely and all displayed activity significantly lower than that of
`efmaconazole. The Applicant concluded, based on the result of this study, that “. . .these
`compounds may not contribute to the therapeutic effects of KP-103.”
`
`Table 7: MICs of KP—103, its metabolites, stereoisomers, impurities, degradation products,
`and reference compounds (itraconazole and ciclopirox olamine)
`MK (11:91:11)
`
`2
`
`a.
`
`K
`
`Ill”!3
`KD—ll III
`K130112000?!
`[ED-K;
`0.00-0
`
`"
`
`M
`64
`64
`
`tumu— .Jmman Dun-auntl15.33~ 1211.l!) l’6. 3m
`
`
`1s
`( ~11
`40
`0..C
`
`0.1.)
`
`0.50
`10
`
`1016
`9.016
`
`
`
`0'3e
`
`
`mu—--m
`KD—KJ
`O.0039
`1.0
`0.13
`C.0075
`
`[CD 101
`(ram: am.)
`
`
`
`mu—-m
`—mn——--—m
`"mum
`
`mun
`(0mm mu! .m
`
`Source: Study P110302, Appendix Table
`
`(law)in 2012, investigators tested
`In a study performed by
`efmaconazole (identified in the study report as S-32282) at various concentrations in an in
`vitro T. rubrum-infected nail model. In this model, human nail sections are infected on the
`underside with actively growmg cultures of the dermatophyte, placed on specially designed
`cells (ChubTur®), and incubated at 25°C for 14 days. The nails were then treated “on the
`dorsal surface with a single 1 uL of efmaconazole formulated in IDP-108 vehicle at 2.5%,
`5%, or 10% w/w (n= 8 cells per treatment) and incubated for another 14 days.” In this
`assay, ATP is measured in the tested nail samples to determine the extend of fimgal
`infection. Baseline ATP levels are defined as those measured in the uninfected nail
`
`sample. In addition to this control, an untreated nail was included in the assay. The results
`of the study are summarized in Table 8. Compared to the infected control, all doses of
`efmaconazole resulted in greater reduction in ATP levels (without apparent relationship of
`dose to eradication effect).
`
`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 8: “IDP-108 antifungal activity (ATP levels) in an in vitro onychomycosis model
`
`Page 13 of 33
`Clinical Microbiology Review
`
`
`
`
`REVIEWER COMMENTS
`The Applicant has submitted study reports that support a claim for in vitro antifungal
`activity of efinaconazole against isolates of T. rubrum and T. mentagrophytes (the fungal
`pathogens included in the proposed indications for this drug). Data from these studies
`suggest an MIC90 against isolates of T. rubrum ranging from 0.0015 – 0.06 mcg/mL, and
`for an MIC90 against isolates of T. mentagrophytes ranging from 0.004 – 0.13 mcg/mL.
`The highest MIC observed for efinaconazole against any isolate of the two significant
`species tested (T. rubrum and T. mentagrophytes) was 0.13 mcg/mL.
`
`
`RESISTANCE STUDIES
`
`The Applicant has submitted two reports from studies designed to investigate the
`development of resistance in dermatophytes to efinaconazole.
`
`Study P100304, “Resistance-acquiring test of Trichophyton rubrum to KP-103” was
`performed in 2011 by Kaken Pharmaceutical Co., Ltd (Kyoto, Japan). The investigation
`was designed as a serial passage study, where 6 isolates of T. rubrum were cultured in the
`presence of sub-inhibitory concentrations of efinaconazole (KP-103) or itraconazole for 12
`passages, with MIC values obtained at each step. Susceptibility testing was performed
`using a “modified CLSI M38-A2 method” (using Sabouraud dextrose broth instead of
`RPMI 1640 media). Tested drug ranges were 0.0038 – 0.13 mcg/mL for efinaconazole and
`0.002 – 1.0 mcg/mL for itraconazole. In this study, investigators noted only two isolates in
`the efinaconazole group with a MIC increase of 2-fold or higher (with a maximum of a 4-
`fold increase, from 0.0020 mcg/mL to 0.0078 mcg/mL). The highest efinaconazole MIC
`observed was 0.031 mcg/mL.
`
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`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 9: Changes in MIC of KP-103 and ITCZ for T. rubrum
`
`Page 14 of 33
`Clinical Microbiology Review
`
`
`
`Source: Study P100304, study report
`
`Study KP960608, “In vitro resistance-acquiring test of T. mentagrophytes to KP-103 or
`clotrimazole”, was performed at the Kaken Pharmaceutical Co. Ltd. (Japan) in 1996. The
`investigators employed a study design similar to the one described above, but tested only
`one isolate of T. mentagrophytes (“KD-04”), over 10 passages. The susceptibility test
`method employed in the study was not adequately described in the study report. The
`investigators reported that the MIC of the tested isolates “increased two-fold after 10
`passages” (from a baseline of 0.5 mcg/mL) (data not shown).
`
`In Study KP960217, “In vitro resistance-acquiring tests of C. albicans to KP-103 or
`clotrimazole” (Kaken Pharmaceutical Co, Ltd., Japan), investigators studied the
`development of resistance in an isolate of C. albicans using serial passage studies in sub-
`inhibitory concentrations of efinaconazole or control (clotrimazole). Over 10 passages, the
`MIC of the test isolate increased only two-fold (data not shown), indicating no significant
`development of resistance in this pathogen.
`
`REVIEWER COMMENTS
`The Applicant has submitted reports from three studies that demonstrate a low potential for
`the development of resistance in specific fungal pathogens (T. rubrum, T. mentagrophytes,
`and C. albicans) to efinaconazole. In investigations of T. rubrum, one isolate demonstrated
`a 4-fold MIC increase in serial passage studies (comparable to the comparator,
`itraconazole), but overall, the increase in MIC values over 10 passages, for the three tested
`pathogens, was 2-fold or less.
`
`
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`
`
`Reference ID: 3270426
`
`

`

`Page 15 of 33
`Clinical Microbiology Review
`
`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`MISCELLANEOUS STUDIES
`
`Keratin Binding
`
`The Applicant has submitted study reports from a series of experiments designed to
`investigate the keratin-binding properties of efinaconazole and comparators (Studies
`M100102 and KP960211), and to describe the effect of such binding on the in vitro
`antifungal activity of the tested antifungals against a strain of T. mentagrophytes (Study
`KP990205). In Study M100102, the investigators demonstrated that efinaconazole
`absorption to keratin was less than that seen in the various comparators (e.g. 85.7%
`absorption for efinaconazole compared to 99.5% absorption for itraconazole), and that the
`cumulative release of the drug after 5 washes was greater than that observed in the
`comparators (Figure 1). The results of Study KP960211 (where keratin binding of
`efinaconazole was compared to that of lanoconazole and butenafine) demonstrated similar
`absorption properties of the study drug.
`
`Figure 1: Cumulative drug release from animal keratin
`
`
`
`Source: Module 2.7.2; Figure 9, this submission
`
`In an investigation of the effect of keratin binding on the in vitro antifungal activity of
`efinaconazole, the minimum inhibitory concentration of efinaconazole was less effected by
`the presence of keratin than either of the tested comparators (amorolfine and terbinafine),
`although the MICs of all tested drugs were identical against the test isolate. The results of
`the study are summarized in Table 10.
`
`
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`
`
`
`Reference ID: 3270426
`
`

`

`Division of Anti-Infective and Ophthalmology Products
`Clinical Microbiology Consultation
`
`
`
`NDA 203567
`Date Review Completed: 28 February 2013
`
`Table 10: MICs of KP-103 (efinaconazo