Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC1,2 and Fiona C. Simpson, HBSc2


1Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada

Conflict of interest: Dr. Gupta has served as a clinical trials investigator for Valeant Pharmaceuticals Inc.
ABSTRACT

Efinaconazole is an emerging antifungal therapy for the topical treatment of onychomycosis. Efinaconazole is an inhibitor of sterol 14α-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.

Key Words:
antifungal agent, efinaconazole, fungal nail infection, onychomycosis, topical triazole

Introduction

Onychomycosis is a fungal infection of the nail apparatus1 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.5 Problematically, all of the oral drugs suffer from potential systemic adverse events and drug interactions.6 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 rates.7 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.

In Vitro Efficacy

Efinaconazole is an inhibitor of sterol 14α-demethylase (14-DM).10 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 (Table 1). 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.

Species Efinaconazole Terbinafine Ciclopirox Itraconazole Amorolfine
Trichophyton rubrum 0.003 0.009 0.101 0.037 0.008
Trichophyton mentagrophytes 0.005 0.010 0.094 0.063 0.009
Candida albicans (24 hours) 0.0029 1.409 0.151 0.014 0.0079
Epidermophyton floccosum ≤0.005 0.039 0.31 0.08 0.16
Microsporum canis 0.18 0.13 0.25 0.35 >4
Fusarium oxysporum 1 2.5 1 >4 >4
Table 1. Minimal inhibitory concentration (MIC) geometric mean values (μg/mL) for reference strains of common causative agents of onychomycosis11

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 (Table 2). Efinaconazole 10% solution without semi-occlusion was the most effective treatment for all outcomes measured.

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 (Table 3). The primary outcome measure, complete cure, was 17.8% and 15.2% for efinaconazole. The mycological cure rate was 55.2% and 53.4%. Table 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.

Treatment Complete Cure Mycological Cure Clinical Efficacy Effective Treatment
Efinaconazole 10% with semi occlusion (n=36) 22.2% 83.3% 67% 61%
Efinaconazole 10% (n=39) 25.6% 87.2% 69% 64%
Efinaconazole 5% (n=38) 15.8% 86.8% – 55%
Vehicle (n=22) 9.1% – 32% 23%
Table 2. Phase II efficacy outcomes at 40 weeks: intent-to-treat population12 (-) = not reported
Complete Cure Mycological Cure Complete or Almost Complete Cure Treatment Success: % Nail Plate Involvement Unaffected Nail Growth
0% ≤5% <10% ≤10%
Study 1 Efinaconazole (n=656) 17.80% 55.20% 26.40% 45% 35.70% 35% 21% 5.0 mm
Vehicle (n=214) 3.30% 16.80% 7.00% 17% 11.70% 11% 6% 1.6 mm
Study 2 Efinaconazole (n=583) 15.20% 53.40% 23.40% 40% 31.00% 29% 18% 3.8 mm
Vehicle (n=202) 5.50% 16.90% 7.50% 15% 11.90% 11% 7% 0.9 mm
Table 3. Efinaconazole 10% nail solution Phase III trial outcome measures at 52 weeks: intent-to-treat population9
Efinaconazole Itraconazole Terbinafine Ciclopirox
Treatment duration 48 weeks 12 weeks 12 weeks 48 weeks
Assessment timepoint 52 weeks – 48 weeks 60 weeks
Mycological cure rate 54% 54% 70% 33%
Complete cure rate 17% 14% 38% 7%
Table 4. Comparison of Phase III trial outcomes between efinaconazole and comparator drugs9,13-15 (-) = not reported

Safety and Adverse Events

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 naïve 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 itraconazole. 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 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.17-19 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.

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