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Update on Efinaconazole 10% Topical Solution for the Treatment of Onychomycosis

Aditya K Gupta, MD, PhD, FRCPC1,2; Catherine Studholme, PhD2
1School of Medicine
2Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA


Conflict of interest disclosure: None reported.

ABSTRACT

Efinaconazole 10% nail solution is a novel topical antifungal drug for the treatment of onychomycosis. Two Phase III trials were completed using efinaconazole 10% nail solution, where 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4% achieved mycological cure. Several post hoc analyses were carried out using data from Phase III trials to determine the efficacy of efinaconazole with respect to disease duration, disease progression, and comorbidities of diabetes or tinea pedis with onychomycosis. Efinaconazole produced higher efficacy rates with patients presenting onychomycosis in a small portion of the toenail (≤25%) for a shorter duration of time (<1 year and 1-5 years). When patients presenting with both onychomycosis and tinea pedis underwent concurrent treatment, efficacy of efinaconazole increased from 16.1% to 29.4%, suggesting combination therapy improved results. Most interestingly, there was no difference in efinaconazole efficacy between diabetic and non-diabetic groups, indicating efinaconazole could be a safe and effective form of treatment for diabetics. Overall, efinaconazole 10% nail solution shows potential as an antifungal therapy for the treatment of onychomycosis.

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

Introduction

Onychomycosis is a fungal infection of the nail unit caused by dermatophytes, yeasts, and nondermatophyte molds.1 Onychomycosis affects toenails more frequently than fingernails and accounts for 50% of nail disease.2,3 Although this infection can be perceived as merely a cosmetic issue of thickening and discoloration of the nail plate, onychomycosis can result in numerous side effects that can impede the use of shoes and make walking difficult in general, leading to decreased quality of life.4,5 Additional risks include bacterial infections, foot ulcers, and gangrene.6 As a commonly occurring disease, it affects 2-13% of the general population, with prevalence of up to 50% in patients aged 70 years or higher.7 Along with advanced age, there are several other risk factors including diabetes, peripheral arterial disease, immunosuppression, and other pre-existing nail diseases like psoriasis.8 Due to an increased chance of comorbidity with onychomycosis, most recent investigational interests have focused on topical antifungals, which have a lower risk of adverse effects and drug-drug interactions.

The goal of onychomycosis treatment is restoring the nail to a normal appearance and complete eradication of fungus. This can be difficult to achieve as the nail plate acts as a barrier for topical treatments, and poor circulation in the elderly can prevent systemic treatments from reaching their target. Although some therapies can result in complete clinical and mycological cure, the rates are low (35-50%), and risk of relapse is high (10-53%).9 Currently, there are five classes of drugs approved for the treatment of onychomycosis: allylamines, azoles, morpholines, hydroxypyridinones, and benzoxaboroles.10,11 Historically, systemic therapies have been the most effective, with the oral allylamine terbinafine being the current gold standard with a complete cure rate of 38% and mycological cure rate of 74%.12,13 The recommended dose of terbinafine for toenail onychomycosis is 250 mg daily for 12 weeks. Patients who are high risk for adverse effects from oral antifungals are prescribed topical agents. In the US there are three topical therapies approved for the treatment of onychomycosis: ciclopirox 8% nail solution, tavaborole 5% solution, and efinaconazole 10% solution. Given the challenges of transungual delivery, there is a need for novel topical antifungals that can increase penetrance, are potent, and carry minimal side effects.

Efinaconazole 10% solution is a novel topical antifungal of the azole class that was US FDA approved for the treatment of toenail onychomycosis in June 2014.14 Efinaconazole has demonstrated a broad spectrum of activity against dermatophytes and yeasts in vitro,15 and has uniquely low keratin affinity, allowing drug release from keratin and enhanced penetration through the nail plate compared to ciclopirox and amorolfine.16 Due to the unique formulation of efinaconazole, both transungual and subungual routes of delivery are achieved as the drug penetrates through the nail plate into the underlying nail bed, as well as via spreading around and under the nail plate through the air gap to reach the fungal infection.17,18 Recently, a human cadaver nail study demonstrated that efinaconazole is able to penetrate the nail even in the presence of nail polish,19 which may be a potential advantage for patients concerned with hiding nail abnormalities while at the same time using a topical treatment. Efinaconazole works by inhibiting the synthesis of ergosterol, an essential structural component of fungal cell membranes.20,21 Its inhibition results in a loss of cell membrane integrity, thus preventing fungal cell growth.20,21

Previously, two identical, randomized, double-blind, vehiclecontrolled Phase III studies were performed using 1655 patients with mild to moderate toenail onychomycosis.22 The treatment course was once daily application of efinaconazole 10% nail solution to the affected toenail and underside, as well as surrounding skin, for 48 weeks followed by a 4 week washout period.23 At week 52, 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4% achieved mycological cure.24 Interestingly, female patients demonstrated higher efficacies than males (27.1% vs 15.8%, respectively, P=0.001), where the only notable difference between genders were mean weight (73.3 kg and 90.2 kg).22 Further subgroup analyses were completed using Phase III data to elucidate the differences in treatment efficacy in patients with concurrent tinea pedis or diabetes, as well as duration and severity of disease.25-28

Clinical Efficacy

Consistent with previous findings,29 21.3% (352/1655) of patients from Phase III clinical trials reported onychomycosis with concurrent tinea pedis, and 61.1% (215/352) underwent concomitant treatment for tinea pedis with an investigatorapproved topical antifungal.26,30 Butenafine, luliconazole, and ketoconazole were the most commonly used topical antifungal agents for tinea pedis treatment; used by 64, 52, and 23 patients, respectively.30 With concomitant treatment of onychomycosis (efinaconazole) and tinea pedis, complete and mycological cure rates were 29.4% and 56.2%, respectively (7.8% and 26.6% vehicle, P=0.003 and P<0.001, respectively). When tinea pedis was left untreated, complete and mycological cure rates were 16.1% and 45.2% (0% and 12.5% vehicle, P=0.045 and P=0.007, respectively). Efinaconazole treatment was superior to all vehicle outcomes, and concurrent treatment for tinea pedis was superior to untreated tinea pedis measures. Moreover, patients treated with efinaconazole achieved a higher complete or almost complete cure and higher treatment success, compared with vehicle (data summarized in Table 1). Complete or almost complete cure was defined as ≤5% clinical involvement of the target toenail plus mycologic cure. Treatment success was defined as ≤10% clinical involvement of the target toenail.

Tinea pedis reported and treated Tinea pedis reported but not treated Patients without tinea pedis
Efinaconazole Vehicle Efinaconazole Vehicle Efinaconazole Vehicle
Complete cure 40/136 (29.4%)b 5/64 (7.8%) 15/93 (16.1%)a 0/24 (0%) 141/833 (16.9%)c 11/255 (4.3%)
Mycological cure 77/137 (56.2%)c 17/64 (26.6%) 42/93 (45.2%)b 3/24 (12.5%) 480/834 (57.6%)c 37/255 (14.5%)
Complete/almost complete cure 51/136 (37.5%)b 9/64 (14.1%) 22/93 (23.7%)a 0/24 (0%)
Treatment success 80/136 (58.8%)c 17/64 (26.6%) 41/94 (43.6%)c 1/24 (4.2%) 385/842 (45.7%)c 45/258 (17.4%)
Table 1:Efficacy of efinaconazole in patients with concurrent tinea pedis, with or without concomitant treatment (Phase III studies).26,30

a P<0.05; b P<0.001; c P<0.001 efinaconazole significantly different from vehicle

For Tables 1 to 3 and Figures 1 to 3:
  • Complete cure is defined as 0% clinical involvement of the target toenail plus negative potassium hydroxide (KOH) preparation and negative fungal culture.
  • Mycological cure is defined as negative KOH preparation and negative fungal culture.
  • Complete/almost complete cure is defined as ≤5% clinical involvement of the target toenail and mycologic cure.
  • Treatment success is defined as ≤10% clinical involvement of the target toenail.

Of the 1655 patients from Phase III clinical trials, 112 patients had coexistent onychomycosis and diabetes.25 Only patients whose diabetes was under control (N=96) were included in the study. Diabetic (N=69) and non-diabetic (N=993) patients had similar efficacies when treated with efinaconazole, with complete cure rates of 13% and 18.8%, respectively and mycological cure rates of 56.5% and 56.3%, respectively. These values were significantly higher than vehicle (N=27) for complete cure (3.7% and 4.7%, P<0.001 for both) and mycological cure (14.8%, P=0.016, and approximately 17.4%, P<0.001) for diabetic and non-diabetic patients, respectively. Moreover, patients receiving efinaconazole treatment had greater success achieving complete or almost complete cures as well as treatment success at week 52 (data summarized in Table 2). All secondary endpoints were identical to those defined above.

Diabetic patients Non-diabetic patients
Efinaconazole Vehicle Efinaconazole Vehicle
Complete cure 9/69 (13.0%)b 1/27 (3.7%) 187/993 (18.8%)b 15/316 (4.7%)
Mycological cure 39/69 (56.5%)a 4/27 (14.8%) 560/995 (56.3%)b Approx. 55/316 (17.4%)
Complete/almost complete cure 17/69 (24.6%) 2/27 (7.4%) 277/993 (27.9%) -
Treatment success 29/71 (40.8%) 5/27 (18.5%) 477/1001 (47.7%)b 58/319 (18.2%)
Table 2:Efficacy of efinaconazole in diabetic vs non-diabetic patients (Phase III studies).25

a P<0.05; b P<0.001 efinaconazole significantly different from vehicle

Of all patients (1655) from Phase III trials, 1526 were categorized based on disease duration: <1 year (74 patients), 1-5 years (682 patients), and >5 years (770 patients).27 Complete cure rates of 42.6%, 17.1%, and 16.2% were observed in efinaconazole-treated patients with <1 year, 1-5 years, and >5 years disease duration, respectively. Complete cure rates with efinaconazole treatment were significantly improved over vehicle for patients with baseline disease durations of 1-5 years (17.1% vs. 4.4%, P<0.001) and >5 years (16.2% vs. 2.5%, P<0.001), however, this was not the case for patients presenting with onychomycosis for <1 year (42.6% vs. 16.7%, not significant). It is possible that non-significance may be due to the small sample size (N=33 efinaconazole). Furthermore, 66.0%, 59.0%, and 53.8% of patients achieved mycological cure with disease duration of <1 year, 1-5 years, and >5 years, respectively. Similar to complete cure, the latter two durations were significantly different from vehicle (P <0.001). Lastly, while not significant for any duration, patients receiving efinaconazole treatment did show numerically higher complete or almost complete cure rates, as well as treatment success, for disease durations of <1 year (Figure 1), 1-5 years (Figure 2), or >5 years (Figure 3). All secondary endpoints are identical to those defined above.

Figure 1

Figure 1.Summary of cure rates for patients with baseline disease duration of <1 year with efinaconazole.27
While cure rates are numerically higher for all efficacy outcomes, efinaconazole cure rates were not significantly greater than vehicle.

Figure 2

Figure 2.Summary of cure rates for patients with baseline disease duration of 1-5 years with efinaconazole.27
*<0.001 compared to vehicle

Figure 3

Figure 3.Summary of cure rates for patients with baseline disease duration of >5 years with efinaconazole.27
*P<0.001 compared to vehicle

Finally, effectiveness of efinaconazole based on disease severity was measured using 414 patients with mild onychomycosis (≤25% nail involvement), and 1237 patients with moderately severe onychomycosis (>25% nail involvement).28 Patients presenting with mild onychomycosis had complete and mycological cure rates of 25.8% and 58.2%, respectively, which are significantly higher than vehicle cure rates of 11.3% (P=0.006) and 25.0% (P<0.001), respectively. Patients with moderately severe onychomycosis had complete and mycological cure rates of 15.9% and 55.6%, respectively, again demonstrating significant improvement over vehicle cure rates of 2.7% and 14.1% (P<0.001 for both), respectively. Moreover, all patients with efinaconazole treatment had significantly higher complete or almost complete cure rates and treatment success compare to vehicle (summarized in Table 3, P<0.001 for all). All secondary endpoints were identical to those defined above.

Mild onychomycosis (≤25% toenail involvement) Moderately severe onychomycosis (≥25% toenail involvement)
Efinaconazole Vehicle Efinaconazole Vehicle
Complete cure 80/311 (25.8%)a 12/103 (11.3%) 147/925 (15.9%)b 8/312 (2.7%)
Mycological cure 181/311 (58.2%)b 26/103 (25.0%) 514/925 (55.6%)b 44/312 (14.1%)
Complete/almost complete cure 117/311 (37.5%)b 18/103 (17.5%) 225/925 (24.3%)b 15/312 (4.9%)
Treatment success 204/311 (65.7%)b 39/103 (37.8%) 376/925 (40.7%)b 38/312 (12.1%)
Table 3:Efficacy of efinaconazole in patients with varying severity of disease (Phase III studies).28

a P<0.01; b P<0.001 efinaconazole significantly different from vehicle

Discussion

The data from two Phase III clinical trials have been analyzed and the efficacy of efinaconazole with respect to concurrent treatment for tinea pedis, diabetic patients, disease duration, and severity of disease shows promise. Efficacies were highest among patients with less severe (≤25% nail involvement) and shorter disease duration (<1 year and 1-5 years) compared to vehicle.

Efinaconazole treatment was more effective than vehicle for the treatment of onychomycosis with or without concurrent treatment of tinea pedis. Since one-third of onychomycosis patients also have tinea pedis, it is recommended that patients are examined for concomitant dermatomycoses, and treatment for both fungal infections (if present) be sought, as pathogens that cause tinea pedis can also lead to onychomycosis.29,30 Although concurrent treatment for tinea pedis and onychomycosis (efinaconazole) improved complete cure rates from 16.1% to 29.4%, there was no information about the severity of tinea pedis, or the success of tinea pedis treatment. Therefore, further testing would need to be completed to confirm whether combination therapy could increase treatment efficacy of both fungal infections.

Onychomycosis in diabetic patients is extremely difficult to treat with traditional antifungals due to hyperglycemia and problematic foot hygiene.31 Moreover, onychomycosis left untreated poses a significant risk for further complications that can potentially lead to loss of limb.32,33 The findings that the efficacy of efinaconazole was comparable between diabetic and non-diabetic patients and cure rates for both groups were significantly higher than respective vehicle groups, indicate that diabetics can now receive safe and effective treatment for onychomycosis.

In summary, good responders to efinaconazole treatment are more likely to be patients with mild (≤25% clinical toenail involvement) onychomycosis and have a low number of nontarget nail involvement,28 with early or baseline onychomycosis (<1 year or 1-5 years, respectively),27 who receive concurrent treatment for tinea pedis (if present),26,30 are female,22 and weigh <84.4 kg.22 Most interestingly, whether patients were diabetic or non-diabetic had no effect on the efficacy of efinaconazole treatment.

Efinaconazole 10% topical solution is an effective topical treatment for onychomycosis with favorable clinical and mycological efficacies, low risk of drug-drug interactions, and a minimal side effect profile.34 With complete cure rates of 17.8% and 15.2%,22,34 and a favorable safety profile, efinaconazole also looks promising for use in children and in combination therapy. Moreover, since levels of efinaconazole reach a steady state in the nail after 2 weeks of daily application, and remain at high concentrations well above the minimum inhibitory concentration for dermatophytes for at least 2 weeks off therapy,35 it is possible that efinaconazole may be used twice weekly as a maintenance regime. This strategy may be considered after the completion of the 48 week treatment period in order to prevent relapse; however, maintenance studies have yet to be conducted. Taken together, efinaconazole 10% topical solution is an easy to use, safe, and effective therapy for the treatment of onychomycosis.

References

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In this issue:

  1. A Review of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, for Moderate-to-Severe Plaque Psoriasis
  2. Update on Efinaconazole 10% Topical Solution for the Treatment of Onychomycosis
  3. Update on Drugs and Drug News - November-December 2016