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

`

`Clinical Pharmacology Review
`203567
`December 20, 2013
`JUBLIA
`Efinaconazole solution, 10%
`Solution
`10%
`Chinmay Shukla, Ph.D.
`Doanh Tran, Ph.D.
`Capt. E. Dennis Bashaw, Pharm.D.
`Division of Clinical Pharmacology 3
`Division of Dermatology and Dental Products
`Dow Pharmaceutical Sciences, Inc.
`077,732
`Resubmission
`Topical treatment of onychomycosis in adults
`
`NDA #:
`Submission Date:
`Brand Name:
`Generic Name:
`Dosage Form:
`Dosage Strength:
`Reviewer:
`Team Leader:
`Division Director:
`OCP Division:
`OND Division:
`Applicant:
`Relevant IND(s):
`Submission Type:
`Indication:
`
`Background and regulatory history: Efinaconazole is a new molecular entity (NME)
`and belongs to triazole antifungal drug class. The applicant is seeking an indication for
`once daily topical treatment of onychomycosis in adults with 10% solution formulation of
`efinaconazole. 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). The Clinical
`Pharmacology program submitted with the original application was found acceptable,
`provided the applicant adequately addressed the labeling comments (see Clinical
`Pharmacology review dated March 07, 2013, in DARRTS).
`
`On December 20, 2013 the applicant re-submitted their NDA to address the CMC
`deficiencies. The applicant has changed the container closure system. No new Clinical
`Pharmacology or Clinical trials were conducted. In the opinion of the medical officer Dr.
`Gary Chiang, the steps adopted by the applicant to address the CMC issues do not
`warrant any new Clinical trials. Based on this assessment, additional Clinical
`Pharmacology trials will not to be needed to support an indication in adults.
`
`Pediatric assessment: With the original NDA application, the applicant
`
` With this re-submission, the applicant has requested for a waiver in
`pediatric subjects from 0 - 11 years old and has provided the reason of low prevalence of
`onychomycosis in this age group. The applicant has requested a deferral to conduct
`pediatric assessment in subjects aged 12 to 17 years, post approval of this NDA in adults.
`Along with this submission, the applicant has submitted a synopsis of the proposed
`protocol (DPSI-IDP-108-P3-03), a vehicle controlled safety and efficacy trial of IDP-108
`topical solution in pediatric subjects with mild to moderate onychomycosis of the
`toenails. The applicant has not proposed any pharmacokinetic (PK) assessment in this
`trial.
`
`Reference ID: 3501156
`
`1
`
`(b) (4)
`
`

`

`Reviewer comments: To support an indication in pediatrics, the applicant will need to
`evaluate the PK of IDP-108 under maximal use conditions in the target pediatric
`population.
`
`This NDA was presented to the Pediatric Review Committee (PeRC) on April 30, 2014.
`PeRC recommended a waiver of <2 year of age group for reason that studies are
`impossible or highly impractical and a deferral for ≥2 years of age. This
`recommendation is similar to what PeRC has recommended previously for tavaborole
`(down to 6 years of age) and terbinafine (down to 2 years of age). The PeRC
`recommends opening up enrollment to younger ages to see whether subjects could be
`enrolled. In the tavaborole and terbinafine cases, DDDP had decided to move forward
`with waiver for <12 years and a decision along similar lines would likely be taken by
`DDDP for this NDA. PeRC agreed with Clinical Pharmacology recommendation to add
`PK assessment under maximal use conditions in a subset of pediatric subjects.
`
`Summary of important Clinical Pharmacology findings: No new Clinical
`Pharmacology trials were conducted. The original submission contained 2 PK trials, Trial
`DPSI-IDP-108-P1-03 was a maximal use PK trial in adult subjects with severe
`onychomycosis and Trial DPSI-IDP-108-P1-02 was conducted in healthy adult subjects.
`The original NDA also contained information about drug metabolism and drug
`interaction assessment. These data were reviewed with the original application (for
`further information, see Clinical Pharmacology review dated March 07, 2013, in
`DARRTS).
`
`Labeling recommendations: The Clinical Pharmacology detailed labeling
`recommendations were provided in the original NDA Clinical Pharmacology review (see
`review dated March 07, 2013 in DARRTS). Additional labeling edits that are being
`proposed in this review cycle are provided below.
`
`With the original NDA application review, it was suggested to delete Section 7 – Drug
`Interactions. In this cycle, to be consistent with other recent labels, the review team
`decided to add this section and following is the addition shown as bold and underlined
`text.
`
`7
`
`Drug Interactions
`
`No formal drug-drug interaction studies have been conducted with JUBLIA. In
`vitro studies have shown that JUBLIA, at therapeutic concentrations, neither
`inhibits nor induces cytochrome P450 (CYP450) enzymes.
`
`Reviewer comments: Other than adding Section 7 to the label, no additional edits were
`made in Section 12.2 – Pharmacodynamics and Section 12.3 – Pharmacokinetics, in this
`review cycle.
`
`Recommendation: From a Clinical Pharmacology standpoint, this application is
`acceptable provided the labeling comments are adequately addressed by the applicant.
`
`Reference ID: 3501156
`
`2
`
`

`

`Post-marketing requirements: Pharmacokinetic assessment of IDP-108 under maximal
`use conditions in sufficient number of subjects aged 12 to 17 years with moderate to
`severe onychomycosis of the toenails.
`
`Clinical Pharmacology briefing: An official briefing was not conducted for this NDA
`resubmission.
`
`Reference ID: 3501156
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHINMAY SHUKLA
`05/05/2014
`
`DOANH C TRAN
`05/05/2014
`
`EDWARD D BASHAW
`05/06/2014
`
`Reference ID: 3501156
`
`

`

`
`NDA #:
`Submission Date:
`Brand Name:
`Generic Name:
`Dosage Form:
`Dosage Strength:
`Reviewer:
`
`Team Leader:
`Division Director:
`OCP Division:
`OND Division:
`Sponsor:
`
`Relevant IND(s):
`Submission Type:
`Indication:
`
`
`Table of Contents
`
`* 1
`*
`*
`*
`*
`*
`*
`*
`1. Executive Summary
`* 2
`*
`*
`*
`*
`*
`*
`*
`1.1 Recommendation *
`* 2
`*
`*
`*
`*
`1.2 Post-Marketing Requirements/Commitments
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings* 2
`2. Question Based Review
`*
`*
`*
`*
`*
`*
`*
`* 3
`2.1 General Attributes of the Drug *
`*
`*
`*
`*
`*
`* 3
`2.2 General Clinical Pharmacology *
`*
`*
`*
`*
`*
`* 6
`2.3 Intrinsic Factors *
`*
`*
`*
`*
`*
`*
`*
`* 11
`2.4 Extrinsic Factors *
`*
`*
`*
`*
`*
`*
`*
`* 12
`2.5 General Biopharmaceutics
`*
`*
`*
`*
`*
`*
`* 13
`2.6 Analytical Section
`*
`*
`*
`*
`*
`*
`*
`* 13
`3. Detailed Labeling Recommendations
`*
`*
`*
`*
`*
`* 16
`4. Individual Study Review *
`*
`*
`*
`*
`*
`*
`* 19
`
`1. Executive Summary
`
`Efinaconazole is a new molecular entity (NME) and belongs to triazole antifungal drug
`class. The Sponsor has submitted this NDA via 505(b)(1) regulatory pathway and is
`seeking an indication for once daily topical treatment of onychomycosis in adults with
`10% solution formulation of efinaconazole. The clinical program consists of four Phase 1
`trials which include a maximal use pharmacokinetic (PK) trial in subjects with severe
`onychomycosis and a PK trial in healthy subjects, one Phase 2 safety and efficacy trial
`and two Phase 3 safety and efficacy trials in subjects with mild to moderate
`onychomycosis. The Sponsor has also submitted reports of two additional Phase 1
`Japanese trials that were not conducted under their investigational IND 77732. The
`Sponsor’s reason for including the non-IND trials was to provide supplemental safety
`data.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Clinical Pharmacology Review
`203567
`July 26, 2012
`Pending
`Efinaconazole solution, 10%
`Solution
`10%
`Chinmay Shukla, Ph.D.
`Doanh Tran, Ph.D.
`Capt. E. Dennis Bashaw, Pharm.D.
`DCP-3
`Division of Dermatology and Dental Products
`Dow Pharmaceutical Sciences, Inc.
`077,732
`New-submission
`Topical treatment of onychomycosis in adults
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3271034
`
`1
`
`

`

`
`1.1 Recommendation
`
`From a Clinical Pharmacology standpoint, this application is acceptable provided the
`labeling comments are adequately addressed by the Sponsor. The package integrity issues
`causing leakage of the product did not affect the maximal use pharmacokinetic trial as
`none of the products used in this trial leaked. The effect of package integrity on the safety
`and efficacy data produced in the Phase 3 trials is deferred to Clinical.
`
`1.2 Post-Marketing Requirements/ Commitments
`
`None.
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`To support this NDA the Sponsor has completed 2 PK trials. Trial DPSI-IDP-108-P1-03
`was a maximal use PK trial in adult subjects with severe onychomycosis and Trial DPSI-
`IDP-108-P1-02 was conducted in healthy adult subjects. In addition to the above, the
`Sponsor has also provided a summary of systemic PK results from the 2 non-IND
`Japanese trials, Trial KP-103-03 which evaluated concentrations in effected versus
`normal toenails and Trial KP-103-02 which was skin irritation and photosensitization
`trial in healthy subjects.
`
`The maximal use PK trial (DPSI-IDP-108-P1-03) was conducted in 20 adult male and
`female subjects (18 completed) with severe onychomycosis with at least 80% of the area
`of both great toenails and at least 4 other toenails with onychomycosis infection. The
`study drug was applied once daily for 28 days to all 10 toe nails and 0.5cm of adjacent
`surrounding skin. Serial PK blood samples were collected at pre-dose and post dose on
`Day 1, Day 14 and Day 28, and a single sample was obtained any time during the 2
`weeks post treatment follow up visit. PK of the parent drug (IDP-108) and 2 metabolites
`[H3 and H4] were assessed. Plasma concentrations of the parent drug were quantifiable in
`15 out of 18 subjects on Day 1 and in all subjects on Day 14 and Day 28. The ratio of
`mean AUC and Mean Cmin on Day 14 versus Day 28 was ≤ 1.18 for the parent drug (IDP-
`108) suggesting concentrations in-vivo were near steady state by Day 14. The mean ± SD
`values of AUC(0-t) and Cmax on Day 28 for the parent drug were 12.15 ± 6.91 ng*h/mL
`and 0.67 ± 0.37 ng/mL, respectively. The concentration profile for the parent drug at
`steady state on Day 28 was relatively flat over the 24 hour dosing interval.
`
`The Sponsor has also provided information on drug metabolism and addressed the
`potential for drug-drug interaction. In-vivo, H3 was the major metabolite in human
`plasma but it is inactive. In-vitro, H4 was the major metabolite and it is active. In-vivo
`H4 was quantifiable only in 4 subjects and in those subjects it was present < 25% of the
`parent compound based on the ratio of the AUCs (Mean ratio = 0.14). All other
`metabolites were formed in very low levels in-vivo, and did not warrant further
`investigation. Multiple CYP enzymes were involved in efinaconazole metabolism with
`CYP2C19 and CYP3A4 identified as the primary isozymes.
`
`
`
`Reference ID: 3271034
`
`2
`
`

`

`Efmaconazole reversibly inhibited CYP2C8, CYP2C9, CYP2C 19 and CYP3A4 and there
`was minimal inhibition of CYP1A2, CYP2A6, CYP2E1 and CYP2D6 activity. The major
`metabolite H3, had much less CYP activity. Efmaconazole was not an inducer of
`CYP1A2 or CYP3A4 in human hepatocytes in-Vitro. The mean plasma levels of
`efmaconazole following administration to subjects with onychomycosis under maximal
`use conditions were low (< 2 nM) and the risk of CYP mediated drug-drug interaction
`appears to be low.
`
`Pediatric assessment: The Sponsor
`
`(m4)
`
`(m4)
`. The Pediatric Review Committee (PeRC) did not agree
`and the Division of Dermatology and Dental Products GDDDP) is considerin
`(mm. In case DDDP decides
`on )
`
`then evaluation of PK under maximal use conditions in pediatric subjects
`would be recommended.
`
`Clinical Pharmacology Briefing: An optional inter-division level Clinical Pharmacology
`briefing was conducted on February 26, 2013 with the following in attendance: Hae-
`Young Ahn, E. Dennis Bashaw, Gary Chiang, Bogdan Klutyka, An—Chi Lu, Balimane
`Praveen, Doanh Tran and Chinmay Shukla.
`
`2. Question Based Review
`
`2.1 General Attributes of the Drug
`
`2.1.1 What are the highlights ofthe chemistry andphysical-chemicalproperties ofthe
`drug substance and theformulation?
`
`Drug substance and Formulation: The chemical name of efinaconazole is (2R,3R)—2-(2,4—
`difluorophenyl)-3-(4-methylenepiperidin—1-yl)-1-(1H—1,2,4—triazol-l-yl) butan-2-ol and
`its molecular weight is 348.39. It is represented by C 1,;sz F2N4O, and has the chemical
`structure is shown in Figure l. Efmaconazole has 2 asymmetric centers at carbons 2 and 3
`(Figure 1) and the compound has an absolute configuration of (2R, 3R).
`
`
`
`Figure 1: Structure ofEfinaconazole
`
`The drug product contains 10% w/V of active ingredient efinaconazole (IDP-108) in a
`solution dosage form for topical application. It is a clear, colorless to pale yellow solution
`with an alcohol content of approximately M“) w/w. The qualitative and quantitative
`composition of the drug product is shown in Table 1 below.
`
`Reference ID: 3271034
`
`

`

`The drug product is packaged in a 10 mL white bottle with a brush applicator and
`(um) cap. The amount of solution in the to-be-marketed container is 83m, and
`in physician sample is 8 mL. The same container is used for both presentations.
`
`
`Table 1: Qualitative and quantitative composition of efinaconazole solution, 10%
`Ingredient
`Function
`(‘nncvnlralinn (°/ow/“)
`l‘l‘lnucun/nlc
`( '_\’ClUl1ls:llllCUl]U
`( 'nsinctic
`l)ii‘upln'-pyl Adipmc
`
`( ‘ I 2- l S /\lk\'l Lactate ( ‘oxlnclic
`Bulylulcd
`N1-
`Hydruxylulucnc
`(‘ilnc .'\-;i\|. {\nhydruus
`l‘Llclzllu l)i\(lllillli)
`Purified \V'ulcr
`
`Alcohol
`
`Efinaconazole isomerism: Efmaconazole is the RR stereoisomer form. Efinaconazole
`
`and the 8,8; SR, and RS stereoisomers were quantitated in a subset of plasma samples
`from Trial DPSI-IDP-108-Pl-02 conducted in healthy subjects by applying IDP-108
`topically to back skin. According to the Sponsor, with the use of a chiral bioanalytical
`method, no stereo-isomers other than the RR form were detected in plasma. Furthermore,
`efmaconazole did not interconvert to other stereoisomers.
`
`2.1.2 What will be the impact of issues with the container/closure system on product
`
`quality and clinical trials?
`
`For the two Phase 3 trials, two batches of the formulation were used:
`0 Batch DP1444: Manufactured on
`M")
`0 Batch DP1453F1: Manufactured on
`PK trial DPSI—IDP-108-Pl—03)
`
`(m4) (Also used in maximal use
`
`Product leakage issue: For Batch DP1444, product leaking was observed which showed
`up as more than 50% of the bottles being smudged and smeared, when samples arrived at
`Dow Pharmaceutical Sciences, Inc Manufacturing was done by
`mm
`. Following initial investigation, the Sponsor decided to:
`
`(ma)
`
`As per CMC reviewer’s assessment, both leaky and non-leaky bottles from batch DP1444
`were used in the Phase 3 trials (for additional information see CMC review dated
`02/08/2013 by Dr. Bogdan Kurtyka in DARRTS). However, it is not clear if the sponsor
`excluded bottles that weighed less than a certain specified limits nor is it clear what those
`limits were.
`
`To address the issue of product leaking, Dr. Kurtyka’s review further states that the
`Sponsor implemented some improvements in the manufactluing process such as
`
`(hm)
`5
`
`Reference ID: 3271034
`
`

`

`. But, it is not clear if all the improvements were
`implemented in the manufacture of the second clinical batch DP1453F1 (also used in the
`maximal use PK trial). Further, leaking was observed in 15.7% of bottles from Batch
`DP1453 but, as per Report 129, the leaking bottles were stored for further
`
`evaluations. The Sponsor has not provided any information on the
` evaluations.
`
`Reviewer comments: From CMC review by Dr. Bogdan Kurtyka, it appears that the
`Sponsor used some criteria
` before
`relabeling and releasing Batch DP1444 to be used in the Phase 3 clinical trials, but it is
`not clear what were the weight limits used to reject bottle suspected of leakage. For
`Batch DP1453F1, none of the bottles that leaked were used in the maximal use PK trial.
`However, this is not clear for the Phase 3 clinical trials (although the Sponsor has
`reported that the leaking incidence from the Phase 3 trials is 0.2%, it is not clear that the
`bottles that leaked belonged to which Batch). It should be noted that the formulation
`contains
` alcohol, there is a potential for the strength of the product to be altered
`due to excessive evaporation in bottles that were leaky (in the non leaking bottle, changes
`in the strength due to evaporation were within the specified limits). The acceptability of
`the efficacy and safety data obtained from the Phase 3 trials is deferred to Clinical.
`
`Impact of leaking on the results of maximal use PK trial (DPSI-IDP-108-P1-03): The
`maximal use PK trial was conducted using products from Batch DP1453F1. The issue of
`product leakage was clarified from the Sponsor via an information request (IR) sent on
`December 21, 2012 (see communication in DARRTS). The Sponsor responded to this IR
`on January 09, 2013 and stated that “No bottles with leakage were reported during study
`DPSI-IDP-108-P1-03”. Furthermore, As per CMC review Dr. Bogdan Kurtyka, it seems
`none of the leaking bottles from Batch DP1453F1 were used in the maximal use PK trial
`(for additional information see CMC review dated 02/08/2013 in DARRTS). Based on
`this information, the product used in the maximal use PK trial is acceptable.
`
`2.1.3 What are the proposed mechanism of action and the therapeutic indications?
`
`Mechanism of action: Efinaconazole is a triazole antifungal agent and it inhibits fungal
`lanosterol 14α-demethylase involved in ergosterol biosynthesis. The accumulation of
`14α-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be
`responsible for the fungistatic and fungicidal activity of efinaconazole.
`
`Therapeutic indication: With this application, the Sponsor is seeking an indication of
`topical treatment of onychomycosis (tinea unguium) in adults.
`
`2.1.4 What is the proposed route of administration and dosage?
`
`Proposed route of administration: Topical.
`
`Proposed dosage: Efinaconazole solution, 10% should be topically applied once daily
`using the built-in flow-through brush applicator provided. When applying the drug
`product ensure the nail, the nail folds, nail bed, hyponychium, and as much of the
`
`
`
`Reference ID: 3271034
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`undersurface of the nail plate, are completely covered. No debridement is necessary when
`treating onychomycosis. A complete cure may be seen some months after mycological
`cure is achieved. This is related to time required for outgrowth of healthy nail.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What were the clinical trials conducted to support this NDA?
`
`Table 2 shows a list of all clinical trials provided to support this application.
`
`Table 2: List of all clinical trials
`Trial number
`
`Objective
`
`Treatment
`duration
`
`No. of subjects
`
`Phase 1
`
`55 (healthy)
`21 days
`DPSI-IDP-108-P1-01 Dermal Irritation
`10 (healthy)
`28 days
`DPSI-IDP-108-P1-02 PK in Healthy subjects
`20 (severe disease)
`28 days
`DPSI-IDP-108-P1-03 Maximal use PK trial
`239 (healthy)
`8 weeks
`DPSI-IDP-108-P1-04 Contact sensitization
`Phase 2 (The to-be-marketed formulation was not used in this trial)
`DPSI-IDP-108-P2-01
`Safety and Efficacy
`40 weeks
`135 (mild to moderate)
`Conducted in Mexico
`
`Phase 3
`870 (mild to moderate)
`DPSI-IDP-108-P3-01 Safety and Efficacy
`781 (mild to moderate)
`DPSI-IDP-108-P3-02 Safety and Efficacy
`Non-IND Phase 1 studies (included to provide supplemental safety data)
`KP-103-02
`Skin irritation and
`28 days
`56 (healthy)
`Conducted in Japan
`Photosensitization
`
`KP-103-03
`To investigate efinaconazole
`40 (diseased)
`Conducted in Japan
`concentrations in effected vs.
`normal toenails
`
`52 weeks
`
`7 days
`
`
`2.2.2 What are the design features of the clinical pharmacology and the clinical trials
`used to support dosing or claims?
`
`Design features of maximal use PK trial (DPSI-IDP-108-P1-03): Topical drug
`bioavailability is a complex interaction of drug substance, formulation and the effect of
`disease itself on the barrier function of the skin. In order to adequately assess systemic
`safety, it is necessary to design trials to maximize the potential for drug absorption with
`the aim of capturing the worst case scenario. Hence, the Sponsor has conducted a
`maximal use PK trial in adult subjects with severe onychomycosis of toenails with at
`least 80% of the area of both great toenails and at least four other toenails with infection.
`The goal of this trial was to assess safety and systemic exposure of IDP-108
`(investigational product). Study drug (IDP-108) (total volume of 0.42 mL = 42 mg dose)
`was applied to all 10 toe nails and 0.5 cm of adjacent skin by a trained nurse or a study
`technician (there was no self administration of the study drug in this trial). PK plasma
`samples for the determination of drug (IDP-108) and metabolite (H3 and H4) levels were
`
`
`
`Reference ID: 3271034
`
`6
`
`

`

`collected at baseline (pre-treatment) and serial samples up to 24 hours were obtained post
`treatment on Days 1, 14 and 28. Additionally a single sample was obtained at any time
`during the 2 week follow up period. Steady state was achieved by Day 14.
`
`Design features of Phase 3 clinical trials (DPSI-IDP-108-P3-01 & DPSI-IDP-108-P3-02):
`The Phase 3 trials were similar in design and both the trials were multicenter,
`randomized, double-blind, vehicle controlled, parallel design to evaluate the safety and
`efficacy of once daily topical application of IDP-108 relative to vehicle in the treatment
`of mild to moderate onychomycosis of the toenails. In these trials, subjects were
`randomized (3:1) to apply either IDP-108 or vehicle once daily at bedtime to all affected
`toenails for 48 weeks. In both the trials, the primary efficacy endpoint consisted of a
`comparison between percentage of subjects in each treatment group who achieved
`complete cure (defined as 0% clinical involvement of the target toenail) at Week 52 (the
`4 week post-treatment follow-up visit).
`
`2.2.3 In which trials were PK assessed and what were the results?
`
`The list of clinical trials which included PK assessment of the parent drug (IDP-108)
`and/or metabolites (H3 and H4) is shown below. Table 3 (a to c) provided PK summary
`for the first 3 trials listed below [the calculated values excluded concentrations that were
`below the limit of quantification (BLQ)]. For the 2 supportive trials in Japanese, the
`systemic concentrations of the parent drug were within the range seen for other 3 trials
`and a detail review was not conducted.
`• DPSI-IDP-108-P1-03: Maximal use PK trial
`• DPSI-IDP-108-P1-02: Healthy subject PK
`• DPSI-IDP-108-P2-01: Phase 2 safety and efficacy trial*
`• KP-103-02: Skin irritation and photosensitization trial (Japanese)
`• KP-103-03: Assessment of concentrations in the infected and non infected nail
`(Japanese)
`* All trials except the Phase 2 trial (DPSI-IDP-108-P2-01) used the to-be-marketed
`formulation. Hence results of drug exposure from the Phase 2 trial will be discussed only
`with the aim of assessing any systemic safety signals with respect to drug levels.
`
`Table 3a: Cmax and AUC (mean ± SD) in Trial DPSI-IDP-108-P1-03 (Maximal use PK
`trial)
`Mean PK Parameters
`
`Days 14-15
`
`Days 28-29
`
`12.15±6.91 (n=18)
`0.67±0.37 (n=18)
`
`AUC(0-t) (ng*h/mL)
`Cmax (ng/mL)
`
`AUC(0-t) (ng*h/mL)
`Cmax (ng/mL)
`
`Days 1-2
`IDP-108
`1.79±2.04 (n=15)
`10.29±5.90 (n=18)
`0.23±0.18 (n=18)
`0.62±0.30(n=18)
`H3
`1.50±1.13 (n=6)
`0.01±0.14 (n=18)
`H4*
`
`40.03±34.02(n=18) 45.80±31.58(n=18)
`2.20±1.73 (n=18)
`2.36±1.64 (n=18)
`
`BLQ
`AUC(0-t) (ng*h/mL)
`BLQ
`Cmax (ng/mL)
`* In most subjects H4 concentrations were BLQ
`
`1.41 ± 1.34 (n=4)
`0.03 ± 0.06 (n=5)
`
`2.30 ± 0.11 (n=4)
`0.05 ± 0.08 (n=5)
`
`
`
`Reference ID: 3271034
`
`7
`
`

`

`
`Table 3b: Cmax and AUC (mean ± SD) in Trial DPSI-IDP-108-P1-02 (Healthy subject
`PK trial)
`Mean PK
`Parameters
`
`Back
`Single dose Multiple dose#
`
`AUC(0-24) (ng*h/mL)
`Cmax (ng/mL)
`
`2.64 ± 2.85
`0.38 ± 0.39
`
`Toenails
`Single dose Multiple dose#
`IDP-108
`9.48 ± 3.86
`0.54 ± 0.22
`H3
`32.52 ± 14.70
`1.63 ± 0.80
`
`23.56 ± 14.30
`1.91 ± 1.76
`
`54.45 ± 36.99
`3.53 ± 3.06
`
`18.86 ± 8.37
`1.61 ± 0.77
`
`117.22 ± 57.96
`5.46 ± 2.81
`
`5.65 ± 5.30
`AUC(0-24) (ng*h/mL)
`0.44 ± 0.36
`Cmax (ng/mL)
`# Multiple dose - 7 daily application
`
`Table 3c: Pre-treatment drug concentrations (mean ± SD) in Trial DPSI-IDP-108-P2-
`01 (Phase 2 Safety and efficacy trial. To-be-marketed formulation not used)
`Treatment
`Mean pretreatment concentration (ng/mL)
`Week 4 Week 8 Week 12 Week 24 Week 36 Follow-up
`30 days#
`
`0.02±0.1
`
`0
`0.12±0.3
`
`0.21±0.1
`
`0.11±0.1
`0.25±0.5
`
`
`IDP-108, 10%
`semi-occlusion
`IDP-108, 10%
`IDP-108, 5%
`
`IDP-108, 10%
`semi-occlusion
`1.53±1.0
`IDP-108, 10%
`1.08±0.6
`IDP-108, 5%
`# 30 days after the last dose
`
`Reviewer comments: Trial DPSI-IDP-108-P2-01 was conducted using a different
`formulation which was not the to-be-marketed formulation. The Sponsor obtained only a
`single pretreatment sample at each noted visit. The baseline value (pre-treatment
`concentration on Day 1) is not included in Table 3c because there was no drug and
`metabolite concentration in the sample. The purpose of including this data is to provide
`additional support for systemic safety because the maximum mean parent drug
`concentration (week 8 under semi-occlusion) is approximately 1.73 fold higher than
`those observed under maximal use conditions (Day 28).
`
`Based on the available PK data (Table 3a, 3b and 3c), highest drug exposure for IDP-108
`and metabolite H3 was seen in the healthy subject PK trial (DPSI-IDP-108-P1-02)
`following multiple applications to the back. The results showed that the mean Cmax and
`AUC for IDP-108 on Day 10 following multiple administrations to the back were
`approximately 5.3 fold and 4.5 fold respectively, higher than the Cmax and AUC on Day
`28 in the maximal use PK trial (DPSI-IDP-108-P1-03).
`
`
`0.48±0.4
`
`1.16±2.4
`
`0.68±0.8
`0.40±0.2
`
`0.74±0.7
`0.50±0.6
`
`1.18±0.6
`
`0.84±0.5
`
`Parent drug
`0.62±0.5
`0.70±0.7 0.73±0.5
`
`0.70±0.5 0.75±0.7
`0.63±0.5
`0.89±0.8 0.41±0.4
`0.57±0.8
`H3 Metabolite
`1.70±1.6
`1.91±1.7 1.77±1.3
`
`1.57±1.7
`1.42±1.3
`
`1.67±0.8
`1.20±1.1
`
`1.80±1.3 1.29±0.9
`1.60±1.0 0.88±0.6
`
`
`
`Reference ID: 3271034
`
`8
`
`

`

`Reviewer comments: Refer to section 4 for further details on the trial designs and PK
`results. The Phase 2 Safety and Efficacy trial DPSI-IDP-108-P2-01 is not described in
`detail in this review because it did not use the to-be-marketed formulation.
`
`2.2.4 What information is known about drug metabolism?
`
`Efinaconazole is metabolized via oxidation (H4 and H5) and cleavage (H1, H2 and H3)
`and most metabolites are further glucuronidated (H2, H3, H4 and H5). Following
`metabolite chemical structures were determined with LC-MS/MS:
`•
`(H1): 2,3-hydroxyl 2-difluorinated phenyl triazole
`•
`(H2): 2-hydroxyl 2-difluorinated phenyl triazole
`•
`(H3): piperidine diol
`•
`(H4): monohydroxylated piperidine
`•
`(H5): 2-carbonyl 2-difluorinated phenyl triazole
`• Carboxylated piperidine
`• 2R,3R amine
`
`
`In-vivo, H3 was the major metabolite in human plasma and it is inactive. This was the
`only metabolite that was higher or equal to efinaconazole levels. In-vitro, H4 was the
`major metabolite and it is active. In-vivo H4 was quantifiable only in 4 subjects and in
`those subjects it was present < 25% of the parent compound based on the ratio of the
`AUCs (Mean ratio = 0.14). All other metabolites had some activity but were formed in
`very low levels, in-vivo. This did not warrant further investigation. The maximal use PK
`trial evaluated both the parent drug and H3 and H4 metabolite levels.
`
`2.2.5 What is the systemic safety margin of the drug exposure under maximal use
`conditions based on animal toxicity data?
`
`The mean exposure (AUC) for the max use PK trial (DPSI-IDP-108-P1-03) for the parent
`drug (IDP-108) was 12.15 ng*h/mL (Range: 1.46 – 25.25). Based on the highest
`observed exposure (25.25 ng*h/mL), the safety margin based on animal toxicity data is
`17 fold. Please see Pharmacology-Toxicology review by Dr. Linda Pellicore in DARRTS
`for further details.
`
`2.2.6 What is the safety profile of efinaconazole?
`
`According to the Sponsor, overall, no safety signals or trends were observed based on a
`review of adverse events (AEs) reported among subjects (both healthy volunteers and
`subjects with onychomycosis) who were exposed to IDP-108 (with efinaconazole
`concentrations of 1%, 5% and 10%) when applied to the toenails and via patches to skin
`on the back for up to 28 days.
`
`There were no deaths in the Phase 1 or 2 trials. However, 2 subjects, one in each of the
`Phase 3 trials, died and the events were assessed by the investigators as not related to the
`study drug. Specifically, in Phase 3 trial DPSI-IDP-108-P3-01, one subject committed
`suicide after being lost to follow-up and in the second Phase 3 trial DPSI-IDP-108-P3-02
`
`
`
`Reference ID: 3271034
`
`9
`
`

`

`one subject died due to lung squamous cell carcinoma. Both the deaths were determined
`by as unrelated to the study drug (IDP-108) the investigator.
`
`In the two Phase 3 trials combined, 1640 subjects reported 2763 AEs. According to the
`Sponsor most of the events occurred in a relatively few number of subjects (less than 1%
`of the subjects in each treatment group). In general, similar percentages of subjects in
`each treatment group experienced similar types of AEs. The most commonly reported
`treatment-related AEs (experienced by 1% or more of the subjects in either study drug
`group regardless of seriousness or severity) included application site dermatitis and
`application site vesicles. The Sponsor also claims that none of the 65 SAEs were
`treatment-related and most occurred in only one subject. Overall, 33 subjects, all but one
`of whom was in the IDP-108 group, discontinued either the study drug or the trial
`because of an AE. Most of the events were associated with application site reactions, and
`many of these were assessed as treatment-related. Finally the Sponsor concluded that no
`safety signals or unexpected trends associated with the use of IDP-108 were observed in
`the Phase 3 trials.
`
`Reviewer comments: For further information on drug safety, please see Clinical review
`by the medical officer Dr. Gary Chiang.
`
` 2.2.7 Has the potential for QT prolongation adequately addressed?
`
`In response to the Sponsor’s request for TQT assessment waiver, the Division of
`Dermatology and Dental Products (DDDP) granted the waiver request on 04/14/2010
`(see communication in DARRTS under IND 077732).
`
`Summary of DDDP review of TQT waiver request: The waiver request was reviewed by
`the medical office Dr. Brenda Vaughan (see review in DARRTS dated 03/18/2010 under
`IND 077732). According to Dr. Vaughan, CDER’s DCRP QT Interdisciplinary Review
`Team was consulted who took into consideration the PK results from Study DPSI-IDP-
`108-P1-02, that was conducted in 10 healthy subjects by applying the drug to healthy
`nails or back. Additionally, no potential for IDP-108 to delay cardiac repolorization
`(based on hERG inhibition, tissue distribution, cardiovascular safety pharmacology and
`ECG analysis in chronic studies) were identified. Although results from Study DPSI-IDP-
`108-P1-02 were considered inconclusive, the QT Interdisciplinary Review Team
`recommended a waiver of TQT study based on the fact that the bioavailability of IDP-
`108 and H3 metabolite were low. The team however recommended that periodic ECGs
`should be collected in all Phase 3 trials.
`
`Reviewer comments: The molecular weight of IDP-108 is 348.39. Therefore 1 nM
`concentration will be 348.39 ng/L or 0.34839 ng/mL. The mean Cmax of IDP-108 in the
`maxi