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 ( 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

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 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

Of all patients (1655) from Phase III trials, 1526 were categorized
based on disease duration: 5 years (770 patients).27 Complete cure rates of
42.6%, 17.1%, and 16.2% were observed in efinaconazole-treated
patients with 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 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 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 5 years (Figure 3). All secondary endpoints are identical to those
defined above.

Figure 1.Summary of cure rates for patients with baseline disease duration of 27

While cure rates are numerically higher for all efficacy outcomes, efinaconazole cure rates were not significantly greater than vehicle.

Figure 2.Summary of cure rates for patients with baseline disease duration of 1-5 years with efinaconazole.27

*

Figure 3.Summary of cure rates for patients with baseline disease duration of >5 years with efinaconazole.27

*P

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 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

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.

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
(27 who receive concurrent
treatment for tinea pedis (if present),26,30 are female,22 and weigh
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.

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