CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`204427Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Deputy Division Director for Safety Review
`
`Summary Review for Regulatory Action
`
`electronic stamp)
`atiana Oussova, M.D., M.P.H.
`From
`
`Subject
`Deputy Division Director for Safety Summary Review
`NDA/BLA #
`NDA 204427
`Su lement #
`
`Anacor Pharmaceuticals, Inc.
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established
`S .
`
`July 29, 2013
`July 29, 2014
`Kerydin (tavaborole)
`
`Name
`
`
`
`-—_
`Dosa _e Forms / Stren_ h
`Proposed Indication(s)
`
`Topical solution 5%
`Treatment of onychomycosis of the toenail due to
`Trichophyton rubrum or Trichophyton mentagrophvtes
`
`Action/Recommended Action for Approval
`
`Material Reviewed/Consulted
`0ND Action Package, including:
`Medical Officer Review
`
`Names of discipline reviewers
`
`Milena Lolic, M.D.
`
`Statistical Review
`Pharmacolo 3 Toxicolo; Review
`CMC Review/OBP Review
`
`Kathy Fritsch, PhD.
`Barbara Hill, Ph.D.
`Gene W. Holbert, Ph.D.
`
`Microbiolo 3 Review
`
`Kerian Grande Roche, PhD.
`
`——
`
`OSE/DDRE —
`OSE/DRISK
`Nyedra W. Booker, Pharm.D., M.P.H.
`CDTL Review
`David Kettl, M.D.
`0ND=0fiice ofNew Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`05B: 05C: of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OSI=Omce of Scientific Investigations
`DDRE= Drvision of Drug Risk Evaluation
`DRISK=Division ofRisk Management
`CD'IIFCross—Discipline Team Leader
`
`Page 1 of 8
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`Reference ID: 3527853
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`

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`Deputy Division Director for Safety Review
`
`Signatory Authority Review Template
`
`1. Introduction
`
`This is a 505 (b)(1) new drug application for a new molecular entity (NlVlE), tavaborole,
`submitted by Anacor Pharmaceuticals, Inc. for the proposed indication: “ the treatment of
`onychomycosis
`m (4) However, the data submitted support
`m ‘0
`indication: “ the treatment of toenail onychomycosis caused by Trichophyton mbrum or
`Trichophyton mentagroplrvtes ”. This application has been reviewed under the PDUFA V
`Program.
`Tavaborole is an oxaborole, the first in a new class of antifungal agents. It is a topical solution
`for an application to an affected toenail.
`There was a recent approval (June 2014) of another topical antifungal product Jublia
`(eficonazole) for a similar indication. However, prior to that the last approval of a topical
`product for the treatment of onychomycosis of a toenail was issued to Penlac (ciclopirox) in
`1999.
`
`Tavaborole has not been approved in any other countries.
`The Applicant proposed proprietary name KERYDIN was found acceptable.
`
`There are no outstanding clinical or regulatory concerns. All discipline reviews have been
`completed and approval is recommended. There were no disagreements within the review
`team. There were a few disagreements between the Applicant and the review team on labeling
`issues that have been resolved. This review will provide more details on those issues and will
`briefly summarize the review team conclusions and my conc1urence with the approval
`recommendation.
`
`2. Background
`
`The Applicant opened an IND for tavaborole in 2005 with a pharmacokinetic study. Since
`then, the Agency had multiple interactions with the Applicant, including EOP2 meeting in
`2009, Guidance Meeting in 2012 and pre-NDA meeting in May of 2013.
`
`Request for a special protocol assessment (SPA) was received on August 4, 2010 and the
`Agreement Letter was sent to the Applicant on September 13, 2010. Pivotal clinical studies
`were conducted according to the agreement.
`
`Onychomycosis is a chronic fungal infection of toenails and/or fingernails. It is estimated that
`15-20% of persons in United States between 40 and 60 years old have onychomycosis. It is
`more prevalent in adults than in children (prevalence rate 0.2% to 2.6%). The most common
`site of infection is the toenail. The most common type of toenail onychomycosis is distal
`subungual onychomycosis and the most common dermatophytes causing distal subungual
`onychomycosis are Trichoplivton rubrum and Trichophyton mentagrophytes. Fingernail
`onychomycosis is more likely to be caused by yeasts, most commonly Candida albicans.
`
`Page 2 of 8
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`Reference ID: 3527853
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`Deputy Division Director for Safety Review
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`The clinical manifestations of onychomycosis include separation of the nail plate from
`the nail bed (onycholysis), subungual hyperkeratosis, and changes in the nail plate that make it
`thicker, brittle, and discolored. Symptoms include toenail discomfort when walking, pain and
`social embarrassment.
`Without treatment, the disease can cause progressive damage to the nail unit, and can spread to
`infect other nails, the skin, or potentially predispose to secondary bacterial infections (in
`immunocompromised populations). The criteria for diagnosis of onychomycosis include
`clinical evaluation, potassium hydroxide (KOH) microscopic evaluation, and fungal culture.
`
`The mechanism of action of tavaborole is inhibition of fungal protein synthesis. Tavaborole
`inhibits protein synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA)
`synthetase (AARS). Tavaborole has been shown to be active against most strains of
`Trichophyton mentagrophytes and Trichophyton rubrum.
`
`Tavaborole should be applied to the entire nail surface and under the tip of each nail being
`treated once daily for 48 weeks.
`
`3. CMC/Device
`
`KERYDIN topical solution, 5% is an alcohol/propylene glycol based clear, colorless solution
`containing 5% tavaborole (w/w).
`dropper assembly, which is used to apply the product
`The product is packaged with a
`to the affected nail. The dropper assembly consists of a clear glass straight-tip pipette fitted
`with a rubber squeeze bulb and a black
` closure.
`The proposed drug product specification includes tests and acceptance criteria for the
`following attributes: description, identity, tavaborole assay, impurities, EDTA assay,
`packaging integrity, weight loss, minimum fill, and microbiological testing.
`
`I concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. The stability data support the proposed expiration dating period
`of 24 months for tavaborole solution when stored at 20-25 ºC (68-77 ºF).
`
`The product is flammable and it is reflected in the label.
`
`There are no outstanding issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The non-clinical pharmacology/toxicology data for this application was reviewed by Barbara
`Hill, Ph.D. Dr. Hill concluded that “the toxicity profile of tavaborole solution has been well
`characterized by the nonclinical studies conducted by the sponsor. There is no significant
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`Page 3 of 8
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`Reference ID: 3527853
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`(b) (4)
`
`(b) (4)
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`

`

`Deputy Division Director for Safety Review
`
`safety concern for tavaborole solution at the proposed clinical dose”. The most notable adverse
`effect was dose-dependent dermal irritation at the application site.
`Dr. Hill recommended approval for this application.
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding phann/tox issues that preclude approval
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The clinical pharmacology data was reviewed by An Chi Lu, PhD. PK data was assessed in
`maximal use study of 24 subjects with toenail onychomycosis. Tavaborole undergoes
`extensive metabolism and renal excretion is the major route of elimination. No formal drug-
`drug interaction studies were conducted. In vitro studies and induction studies indicated that
`tavaborole is not likely to induce the activity of CYP450 enzymes.
`
`(m4)
`The Applicant proposed
`
`Section 12.1 Mechanism of Action. Both Clinical and PK teams disagree with this proposal.
`In clinical trials the product was applied onto entire nail surface including lmder the tip of the
`nail therefore the clinical effect is due to penetration of the drug through different structure‘sb;(4)
`
`. The Applicant has agreed to this rationale.
`
`The Applicant did not conduct PK studies in pediatric population therefore the PREA PIVIR
`will be issued with the approval letter requiring the Applicant to conduct maximal use study in
`pediatric patients ages 12 to 17 year 11 months with onychomycosis of toenails.
`Dr. Lu recommended approval for this application.
`
`I concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer
`that there are no outstanding clinical pharmacology issues that preclude approval.
`
`6. Clinical Microbiology
`
`Clinical microbiology review was conducted by Kerian Grande Rochel Ph.D.
`mm) for
`This review was critical for this application as the Applicant proposed a
`the treatment_of onychomycosis
`(mu Mycological testing (fungal culture and
`KOH wet mount) was performed in five Phase 2 and two Phase 3 studies of subjects with
`onychomycosis.
`The microbiology studies included examination of the spectra of activity of tavaborole and
`characterization of the mycology and susceptibility of strains of Trichophyton rubrum and
`Trichophyton mentagrophvtes, obtained from clinical isolates of subjects treated with
`tavaborole topical solution, 5% for 48 weeks. Tavaborole has been shown to be active against
`most strains of Trichophylon mentagrophytes and Trichophvton rubrmn, both in vitro and in
`clinical infections. Given that clinical development program only evaluated subjects with
`toenail onychomycosis plus supporting data from microbiology testing, only data for toenail
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`Deputy Division Director for Safety Review
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`onychomycosis due to Trichophyton mbrum and T. mentagrophvtes were included in labeling.
`(m4)
`
`I concur with the conclusions reached by the clinical microbiology reviewer that there are no
`outstanding clinical microbiology or sterility issues that preclude approval.
`
`7. ClinicalIStatistical-Efiicacy
`
`Tavaborole solution was evaluated in a double-blind dose—ranging Phase 2 study, two open
`label cohort Phase 2 studies, where one dosing regimen cohort is fully enrolled before the next
`cohort is enrolled, and two identical vehicle-controlled Phase 3 studies. The Phase 2 studies
`
`evaluated dose levels of 1%, 2.5%, 5%, and 7.5% and various treatment regimens from once
`daily for 30 days followed by three times weekly for 150 days to once daily treatment for 360
`days.
`The Phase 3 studies evaluated tavaborole solution 5% with a dosing regimen of once
`daily treatment with for 48 weeks. Study 301 randomized 400 tavaborole and 194 vehicle
`subjects. Study 302 randomized 399 tavaborole and 205 vehicle subjects. Both studies enrolled
`subjects age 18 and older with 20-60% involvement of the target toenail, positive culture, and
`
`positive KOH. Subjects applied treatment once daily for 48 weeks. The primary efficacy
`endpoint was complete cure at Week 52 (0% clinical involvement of target toenail plus
`negative KOH and negative culture). The secondary efficacy endpoints were: (1) completely
`clear or ahnost clear target nail at Week 52 (510% involvement of the nail), (2)
`treatment success (completely clear or almost clear target nail and negative mycology) at
`Week 52, and (3) negative mycology (negative KOH and negative culture). Secondary
`endpoints were analyzed in sequential order.
`
`Tavaborole solution 5% was superior to vehicle in the treatment of onychomycosis in both
`studies. The complete cure rate for tavaborole vs. vehicle was 6.5% vs. 0.5% in Study 301 and
`9.1% vs. 1.5% in Study 302. The secondary efficacy endpoints defined in the protocol were
`supportive of the primary endpoint. The primary and secondary efficacy endpoints were all
`statistically significant (p 5 0.001).
`Table 1 shows the Applicant proposed efficacy endpoints for labeling.
`
`Table 1. Pro u osed Prima
`and Seconda Efficac End a oints at Week 52
`———
`Tavaborole Vehicle
`p—value
`Tavaborole Vehicle
`p—value
`N=399 N=l94
`N=396
`N=205
`
`(I!) (4)
`
`(b) (4)
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`Reference ID: 3527853
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`Deputy Division Director for Safety Review
`
`The Applicant proposed to include
`Review team disagreed and proposed that
`at Week 52 be included instead. The Applicant has
`
`accepted review team proposal.
`
`(I!) (4)
`.(m4)
`
`Table 2 shows the final table with primary and secondary efficacy endpoints for labeling
`inclusion.
`
`.oint at Week 52
`
`Efficacy Variable
`
`Complete Cure'
`Complete or Almost Complete Cure”
`
`n
`
`n
`
`n
`
`11
`
`26 (6.5%)
`61 (15.3%)
`
`1 (0.5%)
`3 (1.5%)
`
`36 (9.1%)
`71 (17.9%)
`
`3 (1.5%)
`8 (3.9%)
`
`25 (12.2%)
`
`
`
`142 (35.9%)
`14 (7.2%)
`124 (31.1%)
`Mycologic Curec
`a. Complete cure defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture.
`
`1). Complete 01 almost complete cure defined as 510% afiected target toenail area involved and negative KOH and culture.
`
`c. Mycologic cure defined as negative KOH and negative culture.
`
`8. Safety
`
`The Applicant presented an adequate safety database consisting of 12 clinical trials in which a
`total of 1500 subjects received at least one dose of tavaborole. The safety evaluation consisted
`of reported adverse events, local tolerability assessments, vital signs, laboratory tests, and
`EKG data. Approximately 58-64% of tavaborole and 54-70% of vehicle subjects experienced
`at least one adverse event, and approximately 2-3% of tavaborole and 1-4% of vehicle subjects
`experienced a serious adverse event. Approximately 1-3% of tavaborole subjects and 0.5-2%
`of vehicle subjects discontinued treatment due to adverse events.
`Common adverse reactions occurring in 21% in subjects treated with KERYDIN included
`application site exfoliation, ingrown toenail, application site erythema, and application site
`dermatitis.
`
`Subjects on the tavaborole arm had a higher rate of application site adverse reactions than
`subjects on the vehicle arm, including application site exfoliation (2.7% vs. 0.3%), application
`site erythema (1.6% vs. 0%), application site dermatitis (1.3% vs. 0%), and application site
`pain (1.0% vs. 0.3%). Systemic exposure of tavaborole solution 5% is low and no systemic
`toxicities have been identified. QTc related effects were not noted in the development program
`for this NME. There were no clinically meaningful changes observed in vital signs, laboratory
`values, or EKGs compared to vehicle.
`
`Kerydin safety profile is similar to that of recently approved Jublia.
`
`I concur with the review team recommendation that risk mitigation measures beyond
`professional labeling are not warranted for Kerydin (tavabarole) topical solution, 5%.
`
`Page 6 of 8
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`Reference ID: 3527853
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`Deputy Division Director for Safety Review
`
`9. Advisory Committee Meeting
`
`Tavaborole, a new oxaborole antifungal, though an NME, presented no novel or complex
`regulatory issues that required the input of an advisory committee.
`
`10.
`
`Pediatrics
`
`Safety and efficacy of Kerydin in pediatric subjects under the age of 18 years have not been
`studied as required under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c).
`The Applicant has requested a partial waiver to study Kerydin in pediatric age group <12 years
`of age. This request for partial waiver was granted because based on literature review, the
`prevalence of onychomycosis in subjects 12 years of age and younger is low and studies in this
`patient population would be impossible or highly impractical.
`
`The applicant has requested a deferral of studies in pediatric subjects ages 12 to 17 years 11
`months. A deferral was granted, as the adult studies are ready for approval and the pediatric
`study has not been completed.
`The Applicant proposed the following timelines for the required maximal use PK trial:
`Final Protocol Submission:
`12/2014
`Study Completion:
`12/2018
`Final Report Submission:
`06/2019
`The agency found these timelines acceptable. PREA PMR will be issued with the approval
`letter.
`
`11.
`
`Other Relevant Regulatory Issues
`
`There are no other unresolved relevant regulatory issues
`
`12.
`
`Labeling
`
`There are no unresolved labeling issues.
`Efficacy results for both pivotal trials are provided in Section 8, Efficacy.
`Information that tavaborole topical solution is flammable is included in How Supplied/Storage
`and Handling Section of the labeling, Patient Counseling Information, and Patient Information.
`Carton and immediate container labels were found to be acceptable.
`13.
`Decision/Action/Risk Benefit Assessment
`
`Recommended regulatory action: Approval
`
`Page 7 of 8
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`Reference ID: 3527853
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`Deputy Division Director for Safety Review
`
`I concur with the review team conclusion that NDA 204427 for Kerydin (tavaborole) topical
`solution 5% be approved for the treatment of onychomycosis of the toenails due to
`Trichophyton rubrum or Trichophyton mentagrophyte.
`
`There is sufficient evidence of safety and efficacy to support use of Kerydin (tavaborole)
`topical solution, 5% as described in approved labeling.
`
`No REMS or other risk management programs are recommended for this application.
`
`This application is subject to PREA and will have a required pediatric assessment as described
`above under PEDIATRICS.
`
`Page 8 of 8
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`Reference ID: 3527853
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TATIANA OUSSOVA
`06/19/2014
`
`Reference ID: 3527853
`
`