CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203567Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review
`
`
`
`Date:
`
`Reviewer(s):
`
`
`
`Team Leader:
`
`Division Director:
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`Indication(s):
`
`May 23, 2014
`
`Nyedra W. Booker, Pharm.D., M.P.H., Risk Management
`Analyst, Division of Risk Management (DRISK)
`
`Reema Mehta, Pharm.D., M.P.H., DRISK
`
`Claudia Manzo, Pharm.D., DRISK
`
`Jublia (efinaconazole) topical solution, 10%
`
`azole anti-fungal
`
`Topical Solution (10%), applied to affected toenails
`
`Onychomycosis of the toenail due to Trichophyton
`mentagrophytes or Trichophyton rubrum
`
`
`Application Type/Number: NDA 203-567
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`
`Dow Pharmaceutical Sciences, Inc.
`
`2014-935
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3512094
`
`

`

`1
`INTRODUCTION
`This review documents the Division of Risk Management (DRISK) evaluation of the
`NDA 203-567 for Jublia (efinaconazole) topical solution (10%) to assess the need for a
`Risk Evaluation and Mitigation Strategy. A 505(b)(1) application for Jublia was received
`by the Division of Dermatology and Dental Products (DDDP) from Dow Pharmaceutical
`Sciences, Inc. on December 20, 2013,1 to treat onychomycosis
` The
`Sponsor did not propose a REMS for Jublia.
`
`1.1 PRODUCT BACKGROUND
`Jublia (efinaconazole) is an azole antifungal developed for the topical treatment of
`onychomycosis. Pharmacologic activity is achieved through the inhibition of fungal
`lanosterol 14α-demethylase involved in ergosterol biosynthesis, making Jublia first in a
`new pharmacologic class of topical azole antifungals.
`Jublia is a topical solution developed to provide sufficient penetration to the diseased
`portion of the nail and nail bed without the need for debridement to deliver the active
`ingredient, in patients with onychomycosis of the toenails due to the dermatophytes
`Trichophyton rubrum or Trichophyton mentagrophytes.
`Recommended dosage and administration of Jublia is as follows:
` Apply Jublia to affected toenails once daily for 48 weeks using the integrated
`brush applicator.
` When applying Jublia, ensure the toenail, the toenail folds, toenail bed,
`hyponychium, and the undersurface of the toenail plate are completely covered.
`Jublia is for topical use only and not for oral, ophthalmic, or intravaginal use.
`
`1.2 DISEASE BACKGROUND
`Onychomycosis2 is a common fungal nail infection with a reported incidence of 2-13% in
`North America. While most cases are caused by dermatophytes and limited to toenail
`involvement, infection may also occur in the fingernails. Dermatophytic onychomycosis
`can be categorized as “distal subungual”, “proximal subungual”, and “white superficial.”
`Distal and proximal subungual onychomycosis most often result from Trichophyton
`rubrum, while white superficial onychomycosis is usually caused by Trichophyton
`mentagrophytes.3 Older age, tinea pedis, and immunodeficiency are some of the risk
`factors for acquiring onychomycosis.
`
`
`1 NDA 203-567 received a Complete Response on May 13, 2013, based on the following: 1) Inadequate manufacturing
`process and control information of the filling/capping
` operation, 2) Inadequate specification for the drug
`product, and 3) Inadequate integrity of the container closure system.
`2
`
`.
`
`3 (2013). Chapter 193. Onychomycosis. In Usatine R.P., Smith M.A., Chumley H.S., Mayeaux E.J., Jr. (Eds), The
`Color Atlas of Family Medicine, 2e. Retrieved March 13, 2014 from
`http://accessmedicine.mhmedical.com/content.aspx?bookid=685&Sectionid=45361264.
`
`Reference ID: 3512094
`
` 1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`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 pain and other toenail
`discomfort when walking. Social embarrassment may also develop.
`Treating onychomycosis can be challenging, as topical creams and lotions are often
`unable to sufficiently penetrate the nail plate, and oral agents may be associated with
`numerous potential drug interactions and severe systemic adverse effects.4 Currently
`approved treatment options for onychomycosis include topical ciclopirox, oral
`griseofulvin, oral itraconazole, or oral terbinafine. Of the approved treatment options,
`none are marketed under a REMS program.
`
`1.3 REGULATORY HISTORY
`July 26, 2012: Dow Pharmaceutical Sciences, Inc. submitted 505(b)(1) NDA 203-567 for
`Jublia topical solution, 10%
`May 13, 2013: Dow Pharmaceutical Sciences, Inc. received a Complete Response based
`on Chemistry, Manufacturing, and Controls (CMC) finished product quality issues
`April 16, 2013: Cross-Discipline Team Leader (CDTL) review concludes that Jublia
`would not require any risk management beyond product labeling and a REMS would not
`need to be considered for the application upon eventual approval
`December 20, 2013: Dow Pharmaceutical Sciences, Inc. re-submitted 505(b)(1) NDA for
`Jublia topical solution, 10%
`
`2 MATERIALS REVIEWED
`The following are a list of materials used to inform the review:
` Division of Anti-Infective Products (DAIP), Clinical Microbiology Review (K.
`Snow), dated May 17, 2014
` DDDP Clinical Review Resubmission (G. Chiang), dated May 16, 2014
` Draft Labeling for Jublia, dated May 15, 2014
` Dow Pharmaceutical Sciences, Inc. Clinical Overview for Jublia (NDA 203-567),
`dated July 26, 2013
` Dow Pharmaceutical Sciences, Inc. Summary of Clinical Safety for Jublia (NDA
`203-567), dated July 26, 2013
` Dow Pharmaceutical Sciences, Inc. Summary of Clinical Efficacy for Jublia
`(NDA 203-567), dated July 26, 2013
` DDDP Cross-Discipline Team Leader Review (D. Kettl), dated April 16, 2013
` DDDP Clinical Review (G. Chiang), dated April 15, 2013
`
`
`4 Botek, G. (2003). Fungal nail infection: Assessing the new treatment options. Cleveland Clinic Journal of Medicine,
`110-118.
`
`Reference ID: 3512094
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`3 OVERVIEW OF CLINICAL PROGRAM
` The clinical development program for Jublia included 9 clinical studies [four Phase 1
`studies, one Phase 2 study5, two Phase 3 studies, and two additional studies providing
`supplemental safety data not conducted under the Investigational New Drug (IND)
`application]. The following pivotal Phase 3 studies formed the basis of safety and
`efficacy analyses:
`
`
`Study Design
`Inclusion Criteria
`
`Treatment arms,
`sample size and
`study location
`
`Studies P3-01 and P3-02
`Multi-center, randomized (3:1 ratio), double-blind, vehicle-controlled studies
`Adults with a clinical diagnosis of mild to moderate distal lateral subungual
`onychomycosis affecting at least one great toenail. Disease severity defined as clinical
`involvement of 20%-50% of the area of the target great toenail, without
`dermatophytomas or lunula (matrix) involvement. The target toenail must have had an
`uninfected length ≥ 3 mm (measured from the lunula), a thickness no greater than 3
`mm, evidence of toenail growth, positive microscopic examination with KOH and
`positive fungal culture within 42 days prior to baseline visit.
`Treatment protocol Apply once daily at bedtime to all affected nails for 48-weeks.
`“Complete Cure” defined as 0% involvement of the target great toenail, negative KOH
`Primary endpoint
`examination and negative fungal culture of the target toenail, at Week 52 (four-week
`post-treatment follow-up visit).
`P3-01; 74 investigational centers-US (34 centers), Japan (33 centers), and Canada (7
`centers)
`
`Jublia (N=656); Vehicle (N=214)
`P3-02; 44 investigational centers-US (36 centers) and Canada (8 centers)
`
`Jublia (N=580); Vehicle (N=201)
`
`3.1 EFFICACY
`The primary efficacy endpoint (percentage of patients in each treatment group achieving
`a “Complete Cure” at Week 52) was met in both pivotal studies. Jublia solution (10%)
`was statistically and clinically more effective than the vehicle in providing a “Complete
`Cure” at Week 52, with cure rates of 17.8% in subjects treated with Jublia in P3-01 and
`15.2% in Jublia-treated subjects in P3-02. Complete Cure for vehicle-treated subjects was
`3.3% and 5.5% for P3-01 and P3-02 respectively.
`
`Efficacy of Jublia versus vehicle was also demonstrated in both trials, for all three
`secondary endpoints (p<0.001) as presented in Table 1.
`
`Table 1: Secondary Efficacy Endpoints Analysis
`
`Secondary Endpoints6
`Trial
`P3-01
`Complete or almost complete cure
`Mycologic cure
`Unaffected new nail growth in mm
`(change from baseline in healthy
`target nail measurement)
`Complete or almost complete cure
`P3-02
`
`5 The Phase 2 study was a dose-ranging study conducted with the original efinaconazole formulation, NOT the to-be-
`marketed Jublia formulation.
`6 The secondary endpoint “Complete or almost complete” cure was defined by ≤5% affected toenail and mycological
`cure (negative KOH and culture).
`
`Jublia 10%
`173/656 (26%)
`362/656 (55%)
`5.0 (0.2)
`
`Vehicle
`17/214 (7%)
`36/214 (17%)
`1.6 (0.4)
`
`136/580 (23%)
`
`15/201 (7%)
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`Reference ID: 3512094
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`
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`Mycologic cure
`Unaffected new nail growth in mm
`(change from baseline in healthy
`target nail measurement)
`
`310/580 (53%)
`3.8 (0.2)
`
`34/201 (17%)
`0.9 (0.4)
`
`DDDP Clinical Reviewer Comment: The secondary endpoints were supportive to
`the primary efficacy of this drug product. In the opinion of this reviewer, the
`supportive secondary measures are not clinically relevant
`.
`
`
`
`3.2 SAFETY
`The Phase 3 safety population consisted of 1655 subjects randomized to receive topical
`treatment with Jublia (1239 subjects) or vehicle (416 subjects) once daily for 48 weeks. A
`total of 1227 subjects applied the active study drug at least once, and of the 1655 enrolled
`subjects, 86.8% completed the 48-week treatment period and 85.8% completed the entire
`52-week study.
`The safety evaluation consisted of the following: reported adverse events, laboratory
`tests, and electrocardiogram (ECG) data.
`The most common treatment-related adverse events (AEs) occurring in >1% of subjects
`receiving Jublia (and at greater frequency than observed with vehicle) included
`application site dermatitis and application site vesicles7. Systemic exposure to Jublia was
`low, and no systemic toxicities were identified. There were also no clinically meaningful
`trends observed related to laboratory values and ECG findings.
`There were 65 serious adverse events (SAEs) reported during Phase 3 studies; none were
`deemed treatment-related.
`DDDP Clinical Reviewer Comment: The SAEs experienced by the subjects in the
`combined Phase 3 clinical trials are unlikely related to study drug. None are
`recommended for labeling by this reviewer.
`A total of 33 subjects (all but one receiving Jublia) discontinued the study due to an
`adverse event. Most of these events were associated with application site reactions. Two
`deaths were reported during Phase 3 studies; both deaths were determined to be unlikely
`related to Jublia treatment.
`DDDP Clinical Reviewer Comment: The majority of AEs related to
`investigational drug product are application site reactions, some of which caused
`discontinuation of study drug or study. The two deaths involved in the Phase 3
`clinical trials are unlikely related to investigational drug. The first subject died of
`reported suicide. It is unlikely that a topical antifungal with low systemic
`absorption would cause the psychological effects enabling a suicide attempt. In
`the second case of squamous cell carcinoma, the advance stage of the disease and
`metastasis tells this reviewer that the patient likely had undiagnosed lung cancer
`prior to the start of the onychomycosis trial. It is unlikely that this drug product
`increased the likelihood of metastasis or caused the squamous cell lung cancer.
`
`7 Application site vesicle is a small bubble that can form within the cell at the application site of a drug.
`
`Reference ID: 3512094
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`(b) (4)
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`

`

`4 DISCUSSION
`Jublia has the ability to penetrate the nail plate to the bed of infected nails, with low
`systemic absorption following topical application. If approved, Jublia would represent the
`first in a new class of topical azole antifungals. According to the DDDP clinical reviewer,
`Jublia may be a reasonable option for patients with onychomycosis who do not wish to
`undergo more comprehensive topical treatment required8 with Penlac®, currently the only
`approved topical product in the U.S. to treat toenail onychomycosis. Penlac® Nail
`Lacquer (ciclopirox) Topical Solution, 8%, does not have REMS program requirements.
`Jublia has demonstrated clinical benefit in the treatment of onychomycosis due to the
`dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Treatment
`related AEs consisted of application site reactions and local skin reactions, which is
`expected for topical products. Systemic exposure with Jublia is low. The safety profile
`of Jublia is similar to that of other topical azole antifungal medications. There are no
`serious risks identified at this time to warrant a REMS. The professional labeling for
`Jublia will include ingrown toenails, application site dermatitis, application site vesicles,
`and application site pain as ADVERSE REACTIONS.
`
`5 CONCLUSION
`In conclusion, risk mitigation measures beyond professional labeling are not warranted
`for Jublia (efinaconazole) topical solution (10%). Jublia has demonstrated efficacy in the
`treatment of onychomycosis. There were no serious risks of concern identified during the
`review of the application that required mitigation beyond labeling. Thus, the benefit-risk
`profile for Jublia is acceptable and the risks, like with other topical azole antifungals, can
`be mitigated through professional labeling.
`Should DDDP have any concerns or questions, or feel that a REMS may be warranted for
`this product, please send a consult to DRISK.
`
`
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`8 Penlac® requires up to 48 weeks of daily applications. Professional removal of the unattached, infected nail, as
`frequently as monthly, is considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or
`less residual nail involvement).
`
`Reference ID: 3512094
`
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`

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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/
`----------------------------------------------------
`
`NYEDRA W BOOKER
`05/23/2014
`
`CLAUDIA B MANZO
`05/23/2014
`concur
`
`Reference ID: 3512094
`
`