8/1/2017
`
`www.medscape.com/viewarticle/SZ1083_print
`
`www.medscape.com
`
`Efinaconazole: A New Topical Treatment for
`Onychomycosis
`
`Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC; Fiona C. Simpson, HBSc
`
`Skin Therapy Letter. 2014;19(1)
`
`Abstract and Introduction
`Abstract
`
`Efinaconazole is an emerging antifungal therapy for the topical treatment of onychomycosis. Efinaconazole
`is an inhibitor of sterol 14u-demethylase and is more effective in vitro than terbinafine, itraconazole,
`ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds. Phase II studies
`indicate that efinaconazole 10% nail solution is more effective than either the 5% strength or 10% solution
`with semi-occlusion. In duplicate Phase III clinical trials, complete cure rates of 17.8% and 15.2% were
`demonstrated. The mean mycological cure rate for efinaconazole is similar to the oral antifungal
`itraconazole and exceeds the efficacy of topical ciclopirox. Efinaconazole showed minimal localized
`adverse events, which ceased upon stopping treatment. Overall, efinaconazole 10% nail solution is an
`effective topical monotherapy for distal and lateral subungual onychomycosis (<65% nail involvement,
`excluding the matrix) that shows further potential use as an adjunct to oral and device-based therapies.
`
`Introduction
`
`Onychomycosis is a fungal infection of the nail apparatusm caused primarily by dermatophytes, yeasts,
`and non-dermatophyte molds. Keratinolytic dermatophytes infect and colonize the nail plate, bed, and
`matrix,[2] resulting in symptoms such as onycholysis, discoloration, and thickening of the nail plate.[2]
`Onychomycosis warrants treatment for both cosmetic and medical purposes. Left untreated, the infection
`can spread to other nails and potentially cause further complications, especially in at—risk populations such
`as diabetic and immunosuppressed patients.[3'4]
`
`The treatment of onychomycosis poses a number of challenges due to the nail plate‘s lack of intrinsic
`immune function and the poor accessibility of drugs into the nail plate. The current gold standard therapy
`for onychomycosis is oral antifungals because their systemic distribution allows them to penetrate the nail
`apparatus and, to a certain extent, the nail plate via the circulatory system.[51 Problematically, all of the oral
`drugs suffer from potential systemic adverse events and drug interactionsle] This potential for negative side
`effects and drug interactions is often higher in the very populations who are at the greatest risk for
`onychomycosis, such as diabetics and the immunosuppressed; however, if left untreated, these individuals
`are the most susceptible to health complications. The existing topical antifungals are not associated with
`dangerous adverse events, as they rarely penetrate the systemic circulation and gain a significant
`concentration in the body. Topicals are less widely used for onychomycosis because their poor penetrance
`into the nail plate results in correspondingly poor mycological and complete cure ratesm Hence, the ideal
`scenario would be to develop topicals that have a higher nail plate penetrance compared with existing
`drugs, but maintain the advantage of minimal systemic uptake.[7'8]
`
`A Novel Topical Triazole Antifungal
`
`Efinaconazole is a triazole antifungal that has been developed specifically for the topical treatment of distal
`and lateral subungual onychomycosis (DLSO).[9] Efinaconazole expands on the success of existing triazole
`antifungals, itraconazole and fluconazole, and is specifically formulated to more effectively penetrate the
`nail plate. In addition, the solution formulation avoids product build-up and removal time associated with the
`use of lacquers.
`
`http://www.medscape.com/viewarticle/821083_print
`
`1/5
`
`Page 1 of 5
`
`Kaken Exhibit 2085
`
`Acrux V. Kaken
`
`IPR2017-00190
`
`

`

`8/1/2017
`
`www.medscape.com/viewarticle/821083J)rint
`
`In Vitro Efficacy
`
`Efinaconazole is an inhibitor of sterol 14a-demethylase (14-DM).[1°] In broth dilution tests in vitro against
`reference strains, it was more potent than terbinafine, ciclopirox, itraconazole, and amorolfine.[11] The
`efficacy of efinaconazole was comparable in clinical isolates of Trichophyton mentagrophytes (T.
`mentagrophytes) and Trichophyton rubrum (T. rubrum) from Canada, the US, and Japan 0. The high in
`vitro efficacy of efinaconazole against the reference strains suggests that the agent would be effective in
`onychomycosis, providing the formulation renders sufficient nail penetrance.
`
`Table 1. Minimal inhibitory concentration (MIC) geometric mean values (ngmL) for reference strains of
`common causative agents of onychomycosis1
`
`m T
`
`richophyton rubrum
`Trichophyton mentagrophytes
`Candida albicans (24 hours)
`
`0.003
`
`0.0029
`
`
`
`0.009 m 0.037
`0.094
`0.063
`0.151
`0.014
`
`1.409
`
`0.008
`0.009
`0.0079
`
`mm
`
`_
`Clinical Efficacy
`
`The randomized, parallel-group, double-blind, vehicle-controlled Phase II clinical trial of efinaconazole was
`conducted at 11 sites in Mexico.[12] This initial trial compared the use of 10% solution, 5% solution, 10%
`solution with semi-occlusion, and placebo in a 2:2:2:1 ratio. The treatment period was 36 weeks with a four
`week wash-out period prior to the evaluation of the outcome measures. The efficacy variables reported
`were mycological cure, complete cure, clinical efficacy, and effective treatment 0. Efinaconazole 10%
`solution without semi-occlusion was the most effective treatment for all outcomes measured.
`
`Table 2. Phase II efficacy outcomes at 40 weeks: intent-to-treat population12 (-) = not reported
`
`
`
`Clinical
`
`Efficacy
`67%
`
`Effective
`
`Treatment
`61%
`
`Complete Mycological
`
`222%
`
`25.6%
`15.8%
`
`83.3%
`
`87.2%
`86.8%
`
`.
`.
`0
`Efinaconazole 10 A) With semi
`occlusron (n—36)
`
`Efinaconazole 10% (n=39)
`Efinaconazole 5% (n=38)
`
`Efinaconazole 10% nail solution (ENS) has recently completed two parallel, double-blind, randomized,
`controlled, Phase III trials.[9] Trial participants applied ENS daily for 48 weeks followed by a four week
`wash-out period. The trial outcome measures were evaluated at week 52 and results from these
`evaluations demonstrated that ENS was superior to vehicle for all outcome measures 0. The primary
`outcome measure, complete cure, was 17.8% and 15.2% for efinaconazole. The mycological cure rate was
`55.2% and 53.4%. shows a comparison of the mycological cure rates for efinaconazole, itraconazole,
`terbinafine, and ciclopirox.[13‘15 The mycological cure rate for 48 weeks of topical efinaconazole was
`comparable to 12 weeks of oral itraconazole.
`
`Table 3. Efinaconazole 10% nail solution Phase III trial outcome measures at 52 weeks: intent-to-treat
`population9
`
`I
`
`l
`
`Completel Mycological lComplete Treatment Success: % Nail l Unaffected
`
`http://www.medscape.com/viewartic|e/821083Jarint
`
`2/5
`
`Page 2 of 5
`
`

`

`8/1/2017
`
`www.medscape.com/viewarticle/821083_print
`
`Cure
`
`Cure
`
`
`Plate Involvement
`or
`Almost —
`
`Complete 0% 55%
`<10% 510%
`
`ftUdy Einggg‘am'e 17.80%
`55.20%
`26.40% 45% 35.70% 35% 21%
`
`
`17% 11.70% 11% 6%
`7.00%
`16.80%
`3.30%
`Ve_hi°'e
`
`(n—214)
`
`StUdy aingggnam'e 15.20%
`X19333)
`5.50%
`
`53.40%
`16.90%
`
`‘23.40% 40% 31.00% 29% 18%
`|7.50%
`
`Table 4. Comparison of Phase III trial outcomes between efinaconazole and comparator drugs '
`not reported
`
`‘ H =
`
`
`
`
`
` 15% 11.90% 11% 7%
`
`
`
`
`
`
`
`
`
`
`
`Efinaconazole ltraconazole Terbinafine Ciclopirox
`
`lTreatment duration
`48 weeks
`[12 weeks
`[12 weeks
`48 weeks
`
`Assessment timepoint 52 weeks
`48 weeks
`60 weeks
`
`Mycological cure rate
`
`54%
`
`Complete cure rate
`Safety and Adverse Events
`
`17%
`
`54%
`
`14%
`
`70%
`
`38%
`
`33%
`
`7%
`
`In a Phase II trial, 76.9% of participants in the efinaconazole 10% group experienced treatment associated
`adverse events (TEAEs) compared with 63.6% of vehicle.[12] The main TEAEs associated with
`efinaconazole were blisters, contact dermatitis, erythema and ingrown nail, none of which resulted in study
`discontinuation. In two identical Phase III studies, the reported rates for a single adverse event during
`treatment with efinaconazole were comparable to vehicle (study 1: 66% vs. 61%; study 2: 64.5% vs.
`58.5%).[9] The primary TEAEs reported were application site dermatitis and vesicles; however, the rates for
`localized skin reactions were comparable to vehicle. Discontinuation as a result of TEAEs was low, with
`3.2% and 1.9% vs. 0.5% and 0% of participants in the efinaconazole groups vs. the vehicle groups,
`respectively. Overall, efinaconazole showed low rates of treatment emergent adverse events.
`
`An additional study was conducted to determine if efinaconazole was associated with contact sensitization.
`[16] Healthy participants (n=239) were treated nine times each with efinaconazole 10% solution or its
`vehicle in occlusive patches over a three week period. A subsequent 48—hour challenge to a naive site
`occurred three weeks later. Participants who showed signs of contact sensitization were then re-challenged
`and evaluated at 48, 72, and 96 hours after patch application. An additional re-challenge was evaluated on
`the forearm in addition to the back. These evaluations resulted in mild irritation scores of 0 or 0.5 in 67.8%
`and 91.6%, respectively, in efinaconazole exposures. Vehicle produced a similar result with 71% scoring 0
`and 95% scoring 0.5. The highest reported score, indicating bright-red erythema with or without edema,
`petechiae, or papules, was observed in two efinaconazole and four vehicle treated participants. An
`additional 21-day cumulative irritation test was conducted in 37 individuals. Each individual was exposed to
`efinaconazole and vehicle solutions for three weeks. The cumulative irritation scores were comparable to
`the vehicle solution.
`
`Discussion
`
`Efinaconazole 10% solution represents a significant advancement in improving the efficacy of topical
`therapy for onychomycosis. In assessing the Phase III results for existing oral therapeutics, efinaconazole
`exhibits a similar mycological and complete cure rate compared to oral ltraconazole. Efinaconazole shows
`significantly improved cure rates over topical ciclopirox and does not require additional nail debridement.
`Furthermore, all three studies reported efinaconazole therapy was well-tolerated, therefore, demonstrating
`
`http://www.medscape.com/viewarticle/821083_print
`
`3/5
`
`Page 3 of 5
`
`

`

`8/1/2017
`
`www.medscape.com/viewarticle/821083J)rint
`
`that the improved efficacy is not necessarily accompanied by an increase in complications, as is associated
`with oral drugs. A Phase II investigation of the 10% solution reported a treatment completion rate of 86.7%,
`and rates of 87.7% and 85.4% in Phase III studies.[9'12] These exceed the completion rates for vehicle,
`which were 81%, 87.4%, and 79.2%, respectively.[9’12] The safety profile for participants treated with
`efinaconazole was favorable, with minimal or transient TEAEs (e.g., contact sensitization) that resolved
`upon cessation of treatment.
`
`Although efinaconazole may primarily be intended for monotherapy, it could also serve as an excellent
`adjunct for oral or device-based therapies. Due to the high rate of recurrence and relapse in DLSO, even
`for completely cured individuals, long-term topical therapy is often recommended concurrently or following
`oral therapy.[ 7‘19]Adjunctive treatment may also be desirable with newer therapeutic modalities such as
`lasers, in order to promote sustained cure. Thus, the addition of efinaconazole may be ideal for these
`situations as it demonstrates the potential for prolonged efficacy and tolerability, as well as safety for long-
`term use.
`
`Efinaconazole 10% nail solution is an effective and safe emerging topical treatment of DLSO. It shows
`promise in comparison to the currently available topical prescription and over-the-counter options. The first
`regulatory approval of efinaconazole (Jublia®) as a topical monotherapy was recently granted by Health
`Canada in October 2013 and marketing authorization is pending in several other countries. In addition to its
`usefulness as a single agent therapy, efinaconazole may be a useful adjunct to oral and device-based
`therapies, both during the main course of treatment and as subsequent maintenance therapy to prevent
`reinfection.
`
`References
`
`1. Zaias N. Onychomycosis. Arch Dermatol. 1972 Feb;105(2):263—74.
`
`2. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151—9.
`
`3. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J
`Dermatol. 2000 Jul-Aug;10(5):379—84.
`
`4. Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-
`positive individuals. Int J Dermatol. 2000 Oct; 39(10):746—53.
`
`5. Gupta AK, Paquet M, Simpson F, et al. Terbinafine in the treatment of dermatophyte toenail
`onychomycosis: a meta-analysis of efficacy for continuous and intermittent regimens. J Eur Acad
`Dermatol Venereol. 2013 Mar;27(3):267—72.
`
`6. Shear N, Drake L, Gupta AK, et al. The implications and management of drug interactions with
`itraconazole, fluconazole and terbinafine. Dermatology. 2000;201(3):196—203.
`
`7. Murdan S. 1st meeting on topical drug delivery to the nail. Expert Opin Drug Deliv. 2007
`Jul;4(4):453—5.
`
`8. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008
`Nov;5(11):1267—82.
`
`9. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail
`onychomycosis: Two phase III multicenter, randomized, doubleblind studies. J Am Acad Dermatol.
`2013 Apr;68(4):600—8.
`
`10. Tatsumi Y, Nagashima M, Shibanushi T, et al. Mechanism of action of efinaconazole, a novel triazole
`antifungal agent. Antimicrob Agents Chemother. 2013 May;57(5):2405—9.
`
`11. J0 Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole
`and currently available antifungal agents against a variety of pathogenic fungi associated with
`onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610—6.
`
`http://www.medscape.com/viewartic|e/821083Jarint
`
`4/5
`
`Page 4 of 5
`
`

`

`8/1/2017
`
`www.medscape.com/viewarticle/821083_print
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail
`onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013
`Feb;12(2):186—92.
`
`Sporanox® (itraconazole) capsules [package insert]. Revised April 2012. Ortho-McNeil-Janssen
`Pharmaceuticals, Inc., Titusville, NJ. Available at:
`http://www.accessdata.fda.gov/drugsatfda_docs/Iabel/2012/020083s0483049s050lbl.pdf. Accessed
`November 24, 2013.
`
`Lamisil® (terbinafine hydrochloride) tablets, 250 mg [package insert]. March 2011. Novartis
`Pharmaceuticals Corporation, East Hanover, NJ. Available at:
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/0205395021|b|.pdf. Accessed November
`24, 2013.
`
`Penlac® nail lacquer (ciclopirox) topical solution, 8% [package insert]. July 2006. Dermik
`Laboratories/sanofi-aventis US. LLC, Bridgewater, NJ. Available at:
`http://products.sanofi.us/penlac/Penlac.pdf. Accessed November 24, 2013.
`
`Del Rosso JQ, Reece B, Smith K, et al. Efinaconazole 10% solution: a new topical treatment for
`onychomycosis: contact sensitization and skin irritation potential. J Clin Aesthet Dermatol. 2013
`Mar;6(3):20—4.
`
`Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J
`Dermatol. 2003 Sep;149 Suppl 65:5—9.
`
`Tosti A, Piraccini BM, Stinchi C, et al. Relapses of onychomycosis after successful treatment with
`systemic antifungals: a three-year follow-up. Dermatology. 1998;197(2):162—6.
`
`Arrese JE, Pierard GE. Treatment failures and relapses in onychomycosis: a stubborn clinical
`problem. Dermatology. 2003;207(3):255—60.
`
`Skin Therapy Letter. 2014;19(1) © 2014 SkinCareGuide.com
`
`This website uses cookies to deliver its services as described in our Cookie Policy. By using this website, you
`agree to the use of cookies.
`close
`
`http://www.medscape.com/viewarticle/821083_print
`
`5/5
`
`Page 5 of 5
`
`