Conflict of interest:
Aditya Gupta has served as consultant, speaker, and investigator for Ortho Dermatologics, a consultant for Moberg Pharma, and a speaker and principal investigator for Bausch Health. Elizabeth Cooper is an employee of Aditya Gupta and has no individual conflicts to declare.

Abstract:
Onychomycosis, a difficult-to-treat fungal nail infection, is more prevalent in the elderly. Efinaconazole 10% topical solution is a firstline therapy for onychomycosis, based on phase III trials of 12-month treatment; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. This is the first efficacy and safety data for a 24-month duration of efinaconazole 10% topical solution treatment for onychomycosis. Enrolled patients (N = 101) with mild to moderate distal lateral subungual onychomycosis applied efinaconazole to all affected toenails once daily for 18-24 months. Efficacy and safety were evaluated at months 6, 12, 18, and 24 (M6, M12, M18, and M24). The study is ongoing; to date, 47 patients have completed to M24. Mycological cure (MC) was 60.0% at M12, increasing to 74.2% at M24; effective cure (MC and ≤10% clinical involvement of the target toenail) was 17.8% at M12, rising to 19.4% at M24. Mild to moderate application site reactions were the only efinaconazole-related adverse events in 8 patients (7.9%). Increased age, increased severity of onychomycosis, and the presence of mixed infections (dermatophyte plus non-dermatophyte moulds) may drive a need for longer treatment durations. Although the data are interim, there is a trend of increasing efficacy beyond M12 use, without increased safety risk, even in patients >70 years of age.

Key Words:
efinaconazole, Jublia, clinical trial, onychomycosis, nail

Introduction

Onychomycosis is a chronic fungal nail infection, occurring at an estimated prevalence of 8-14% in North America.^1-3 Onychomycosis, while mainly asymptomatic, can result in reduced quality of life (cosmetic issues, pain, difficulty walking) and significant health impacts, particularly in diabetic patients and those with poor peripheral circulation (secondary skin infections, ulceration, amputation).^4-16 Traditional treatments for toenail onychomycosis have included oral agents such as terbinafine and itraconazole.¹⁷ Despite good efficacy, oral agents present the potential for a significant number of drug interactions and hepatotoxicity, which are particularly problematic for elderly patients most in need of onychomycosis treatment to maintain health and mobility.

Efinaconazole 10% topical solution (Jublia™) is approved for mild to moderate dermatophyte toenail onychomycosis.^18,19 Efinaconazole inhibits fungal lanosterol 14α-demethylase, with broad spectrum of action against dermatophytes, yeasts and non-dermatophyte moulds (NDMs).²⁰ Efinaconazole 10% solution has low surface tension, with low affinity to keratin in the nail plate,²¹ and accumulates in the nail plate and nail bed to levels well above the minimum inhibitory concentration (MIC) of dermatophytes after continuous application for 28 days.²² In phase III trials that led to the approval of efinaconazole 10% solution, the mycological (MC) and complete cure (CC) rates of 48 weeks of efinaconazole treatment were 53-55% and 15-18%, respectively, comparable to some traditional oral agents.^19,23-26 Efinaconazole has also been shown to be effective in onychomycosis patients with diabetes (CC 13%) and coexisting tinea pedis (CC 29.4%).²⁷

Despite the promising results of efinaconazole in the phase III trials, more than half of the treated patients were left with visual signs of infection in the target toenail.^23,24 It is suspected that the 48-week (12-month) treatment period may be insufficient for complete nail outgrowth, as it is noted that nail growth rates are reduced in onychomycotic compared to healthy nails.^28-31 To investigate this possibility, we present interim results of a study to assess the safety and efficacy of treatment up to 24 months with efinaconazole for mild to moderate toenail distal lateral subungual onychomycosis (DLSO).

Study Design

This phase IV, single-site, Canadian trial included patients aged 18 years or older with mild to moderate DLSO (20-50% of the toenail affected, ≤3 mm thick and ≥1 mm lowest proximal extent of infection) in a great toenail designated as the ‘target’ for evaluation. Diagnosis was confirmed visually and by dermatophyte growth in culture. Study treatment was to be applied topically on all infected toenails as well as the ‘target’ toenail, as per the approved efinaconazole monograph instructions.

The primary variables for efficacy were mycological cure, MC (negative fluorescent potassium hydroxide [KOH] microscopic examination and negative culture) and effective cure EC (MC and ≤10% clinical involvement of the target toenail). Efficacy variables were reviewed at 6, 12, 18 and 24 months.

Results

Fifty-five (55) patients were randomized 1:1 into blinded treatment groups as of April 2018: patients received either oncedaily efinaconazole for 24 months, or once-daily vehicle for 6 months followed by once-daily efinaconazole for 18 months (i.e., 24 months of total study time). From May 2018 onward, the remaining 46 patients enrolled in the study were provided with open-label topical efinaconazole daily for 24 months, for a total of 101 patients entered into the study (Figure 1). The study remains ongoing at this time. Currently, 47 patients have completed 24 months of study and are analyzed here to provide an interim assessment of long-term efficacy. Demographics of the completed patients are shown in Table 1.

Efficacy criteria were evaluated after 6, 12, 18 and 24 months (M6, M12, M18, and M24) of treatment. Good mycological success was found up to M12 (60.0%) and there appears to be an increase in MC from M12 to M24 (74.3%) during prolonged efinaconazole application (Figure 2). Effective cure also increased from M12 (17.8%) to M18 (25.5%), indicating ongoing improvement in target nails beyond the 12-month period with continued efinaconazole 10% solution use (Figures 3 & 4).

Application site reactions (11 events) occurred in 8 of 101 enrolled patients (7.9%), and were graded as mild to moderate only, with symptoms typical of previously reported application site reactions with efinaconazole: erythema, eczema, exfoliation, and pruritus. No systemic reactions occurred in association with efinaconazole. No patients reported reactions during the vehicleuse period. A majority of the reported events occurred within the first 9 months of efinaconazole 10% solution application, i.e. in the ‘labelled’ period of use. For reactions that developed after M12, two patients reported application site trauma not related to study participation, which may have predisposed them to efinaconazole reaction (Table 2 – bottom row, 2 patients). In our ongoing dataset, the long-term use of efinaconazole 10% solution does not appear to increase the risk of an application site reaction.

Discussion

The interim data presented here represents the first assessment of a 24-month efinaconazole 10% solution use period, and demonstrates increased efficacy beyond a 12-month use period, without increased risk of AEs.

In comparison to the controlled phase III populations, our participants had a much older age distribution with one-third of the patients exceeding 70 years old, in contrast to the phase III trials which restricted enrollment to 70 years or less.^23,24 Increased age is a burden for nail clearance, as there may be a decrease in peripheral circulation and slower outgrowth of toenail.^4,32-35 Figures 5 and 6 review efficacy in the elderly subset versus the younger subset; both MC and EC rates are comparable between the age population subsets to M12 (MC: 61.5% <70 years and 57.9% ≥70 years; EC: 19.2% <70 years and 15.8% ≥70 years), and MC is comparable to the phase III trials (53-55%).¹⁹ Our M12 EC data cannot be directly compared to the phase III ‘treatment success’ outcome which did not review area clearance in conjunction with mycology status. At M18, the MC and EC in all patients applying efinaconazole was 72.3% and 25.5%, respectively. It appears that there is an improvement in efficacy with longer treatment durations. Efinaconazole treatment beyond 12 months appears to benefit the <70-year-old subgroup to a greater degree than the ≥70-year-old subgroup; however, interim results at M24 suggest the ≥70-year-old subgroup may be able to achieve similar results to the younger subset when given longer periods of nail outgrowth to reach those levels. This older subset of patients is the population most in need of nonoral antifungal treatment options due to their increased use of systemic pharmaceuticals, and being able to confirm efficacy and safety for these patients is critical. In addition to efficacy, our data shows no increased safety risk from efinaconazole 10% solution application in the elderly subset.

Our population also began treatment with onychomycosis penetrating more proximally into the nail plate of the target toenail, with almost 50% of patients having a lowest proximal extent less than 3 mm at enrollment, versus a minimum of 3 mm for the phase III studies. It is expected that such increase in severity would lead to an overall longer period of outgrowth/ lower cure rate at similar time points relative to less severe populations.

The causative organisms in toenail onychomycosis in North America are generally dermatophytes, specifically Trichophyton rubrum, and to a lesser extent Trichophyton mentagrophytes. Historically, it has been difficult to detect the presence of NDMs in onychomycosis: the addition of cycloheximide to culture media inhibits growth of NDMs in favor of dermatophytes, and high rates of false negative cultures are problematic with any fungal sampling/culturing. With the advent of polymerase chain reaction (PCR) technology, it is now possible to detect NDMs as well as dermatophytes with much greater reliability in fungal samples.^36,37 In fact, studies of PCR detection of NDMs and dermatophytes in onychomycosis suggest that the prevalence of NDMs alone or in mixed infection (dermatophyte plus NDM) may be higher than originally recognized.^36,38-43 It is suspected that the lack of effective NDM removal could be a factor that restricts the efficacy of antifungal nail therapy.^39,44 A small subset of 16 enrolled patients had PCR investigation of target toenail material for the presence of NDMs prior to treatment with efinaconazole 10% solution. All of these patients were culture positive for a dermatophyte at screening; none had mixed infection by culture methods. At screening, dermatophytes were confirmed in 15 of 16 patients by PCR, and 12 of 16 also had at least one NDM found in conjunction with a dermatophyte (75%; unpublished data). Our data suggests the presence of NDMs is high in onychomycosis. Efinaconazole has been shown to be effective in mixed infections (dermatophyte and NDM) since it is fungicidal in nature and has broad spectrum activity.^19,20,45 An extended treatment time in mixed toenail infection (dermatophyte plus NDM) has been described previously, and may be required for effective treatment of mixed infection.³⁹ This long-term study of efinaconazole is well-positioned to provide further evaluation of the role of NDMs in onychomycosis, and potential for treatment with efinaconazole 10% solution. Such review of mixed infection outcomes remains a goal for this study’s future efficacy reporting.

Conclusion

Early clinical trial data indicate the increasing effectiveness and safety of efinaconazole 10% solution use beyond 12 months; application for up to 24 months appears to remain safe even for elderly patients. Review of the final data will provide increased knowledge of both clinical and mycological efficacy with long-term efinaconazole 10% solution use in onychomycosis.

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¹Medical Student, University of Pittsburgh, Pennsylvania, USA
²Board Certified Dermatologist & Clinical Professor, University of Alberta, Alberta, Canada

Introduction

Onychomycosis, also known as tinea unguium, is a progressive fungal infection of the nails resulting in discoloration, nail plate thickening, and onycholysis. This infection is caused by dermatophytes, nondermatophyte molds, and yeasts. It accounts for up to 90% of toenail and 50% of fingernail infections in North America.¹ Onychomycosis afflicts 10% of the general population, 20% of those older than 60 years, and 50% of those older than 70 years. Risk factors include peripheral vascular disease, diabetes mellitus, immunologic disorders, hyperhidrosis, obesity, concurrent fungal infections, and nail trauma.^2,3 As per the Canadian clinical pathway, treatment of onychomycosis needs to start as soon as the infection is diagnosed.^4,5 Especially in diabetic and immunocompromised patients, treatment of onychomycosis is medically indicated, as untreated onychomycosis affects quality of life and often leads to secondary infections as abrasions or ulcerations created by sharp onychomycotic nails allow bacterial and fungal entry.⁶ Efinaconazole is a novel topical azole that has shown promising and superior activity against dermatophytes, non-dermatophytes, and yeasts causing onychomycosis.^7-9

Diagnostic and Clinical Features

• Onychomycosis has several different clinical presentations including distal lateral subungual, proximal subungual, superficial white, and total dystrophic forms.³ Although onychomycosis accounts for about 50% of the nail abnormalities, establishing a differential diagnosis is important to rule out other nail pathologies.¹⁰ Differential diagnoses include other infections (both fungal and bacterial), primary cutaneous dermatoses (such as psoriasis, lichen planus or dermatitis), trauma, and tumors such as melanomas, fibromas, and carcinomas.^3,12
• Accurate diagnosis requires visual identification of physical changes as well as positive laboratory analysis of nail clippings and subungual debris. Laboratory analysis includes microscopy using KOH (potassium hydroxide) and then subsequent culture and/or histological evaluations of negative microscopy results.³ As per product monographs of the approved medications for onychomycosis in Canada, positive laboratory analysis are required prior to starting an oral treatment, though it is not required before starting a topical treatment.

Background on Efinaconazole 10% (w/w) Solution

• Efinaconazole is a topical triazole that has been shown to have superior antifungal potency in vitro and in vivo, when compared to the other commonly used onychomycosis topical therapies such as ciclopirox nail lacquer.^7,8
• The treatment inhibits fungal lanosterol 14α-demethylase in the ergosterol biosynthesis pathway, which is a structural component in fungal cell membranes. The accumulation of 14α-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be responsible for the fungistatic and fungicidal activity of efinaconazole. This activity has been shown to be effective against dermatophytes, non-dermatophytes and yeasts.^8,13
• Efinaconazole 10% w/w topical solution grants easier and more convenient administration, which is important for compliance with its daily application regimen.
  • Its low molecular weight allows it to penetrate easily through the nail plate and even through nail polish.¹⁴
  • Its non-lacquer profile avoids buildup and does not require nail debridement⁷, an added benefit when compared to other topical treatments, e.g. Ciclopirox lacquer.¹⁵
  • It is also easy to administer by patients simply by gently squeezing the bottle in upside-down position to wet the flowthrough applicator brush attached to the bottle and spreading the solution to the affected region.¹⁶ One application on each affected toenail and 2 applications on the big toenail, once daily.
• Its low surface tension and low keratin affinity allows it to permeate through the nail plate more efficiently than Ciclopirox, contributing to higher fungicidal activity underneath and within the nail plate.¹⁷
• The recommended treatment regimen is once daily topical application for 48 weeks to the nail plate surface, lateral and proximal nailfolds, hyponychium, underside of nail plate, and surrounding skin.^7,16 A complete cure may be seen some months after mycological cure is achieved.

Combining Modalities

Several studies have found that combining different modalities of treatment with topical Efinaconazole may provide a synergism that increases fungicidal efficacy and cure rates. Faster visible results and increased efficacy may enhance compliance by inspiring patients to adhere to the combination regimen.

Topical Antifungals

• Fungal infections of the skin surrounding the toenail can often lead to or perpetuate onychomycosis.¹⁸ In a survey of 2761 patient with toenail onychomycosis, 42.8% had some other concomitant fungal infection. Of these, tinea pedis was the most common and accounted for 80% of concomitant infections.¹⁹
• Several studies have documented higher onychomycosis cure rates with the treatment of concomitant tinea pedis. For example, one study found that treatment of concomitant tinea pedis resulted in a complete cure of 29.4% and mycological cure of 56.2% compared to a complete cure of 16.1% and mycological cure of 45.2% in the control of no concomitant tinea pedis treatment.^20,21

Oral/Systemic Antifungals

• Oral therapies have been recorded to have high cure rates for onychomycosis. However, hepatotoxicity, adverse effects, drug interactions and the need for bloodwork monitoring may limit the viable population while also incurring greater burdens on the patient to comply with regular monitoring practices.⁷
• A systematic review of 26 studies found that combined systemic and topical treatment regimens resulted in a higher complete cure rate of 80.8% compared to the 70.8% complete cure rate in systemic treatment alone.²²

Laser Therapy

• Laser treatments for onychomycosis are currently approved by the FDA only as a temporary solution to increase the clear nail surface area. Currently, laser studies primarily provide evidence for aesthetic endpoints rather than medical endpoints.²³
• However, some studies have found that combined use of laser treatments with topical therapy have high cure rates, with clinical efficacy rates ranging from 70% – 90% and mycological cure rates ranging from 57% – 70%.^24-28
• Others have also found that this combined modality has decreased rate of reinfection.²⁸

Managing Patient Expectations

Efinaconazole treatment, given its relatively high efficacy, has been documented to have positive impact on patient satisfaction and quality of life measures. Importantly, this impact was greatest in patients who were considered clinically improved and correlated inversely with percent of nail affected.²⁹ It is important to adequately manage patient expectations in the treatment of onychomycosis, and the following suggestions may help physicians to accomplish this goal:

Laser Therapy

• While Efinaconazole has been shown to be a superior topical treatment, physicians should clearly convey to patients the mycological and complete cure rates so that patients can have realistic expectations for treatment outcome. In two Phase III studies conducted on 1655 patients, at the end of the study at week 52, they found:⁷
  • Mycological cure rates: 55.2% and 53.4%
  • Complete cure rates: 17.8% and 15.2%

Explain Prognostic Factors

• Physicians should educate patients on factors that affect response
  to treatment and prognosis.¹³ These include:
  • Patient demographics:
    • Gender³⁰, advancing age, and history of nail trauma
  • Comorbidities:
    • Diabetes mellitus, liver or kidney transplantation, immunosuppression, cancer, neutrophil defects, chronic steroid therapy, and peripheral vascular disease
  • Nail characteristics and disease severity:
    • Distal lateral subungual onychomycosis, proximal subungual onychomycosis, total dystrophic onychomycosis, dermatophytoma, severe onycholysis, two feet-one hand syndrome, slow nail growth, and lengthy disease duration
  • Co-infection with other pathogenic organisms:
    • Mixed bacterial and fungal infections, yeasts, and nondermatophytes

Detail Recurrence Rates

Physicians should also educate patients on the recalcitrant nature of the disease and high rates of recurrence. Indeed, recurrence rates vary from 20% to 25%.^31,32

Preparation for Appropriate Therapy Duration

• Physicians should also explain the long duration of treatment for the topical solution, i.e. at least 48 weeks. It may work well to justify this lengthier treatment by explaining the limitations of oral treatments. That is, although generally efficacious, systemic medications are limited by drug interactions and potential hepatotoxicity which may require regular monitoring.⁷
• The rate of nail clearance is dependent on slow toenail regrowth in healthy subjects. With a growth rate of 1 to 2 mm per month, it may take up to 4-6 months for fingernail clearance and 12-18 months for toenail clearance. Slower growth occurs in patients with comorbidities and older patients.³³

Encouraging Compliance

Patient compliance is essential to positive treatment outcomes and is consistently a struggle with a variety of therapies. It has been shown that up to 80% of patients are non-adherent to drug treatments independent of diagnosis or prognosis.³⁴ One study found that up to 95% of dermatology patients underdose on topical treatments.³⁵ Nonadherence is particularly concerning with onychomycosis treatment. The following suggestions may assist physicians to improve compliance in their onychomycosis patients:

Remind Patients of the Consequences of Noncompliance

• Issues with medical adherence such as early termination, incorrect or irregular dosing, and missed dosing are serious risk factors in poor response to treatment.³
• Afflicted nails, if left unattended, can become increasingly discolored, thickened, flaky, separated from the nail bed, and painful. Severe onychomycosis can also hinder mobility and thus occupational functions, as well as lead to cellulitis in older adults and foot ulcers in diabetics.^3,36 Moreover, serious cases might require surgery.³⁷

Use Visual Aids to Demonstrate the Potential for Treatment Success

• Visual aids can significantly increase comprehension of treatment schedules and improve patient compliance.³⁸ Physicians should consider using a “before-and-after” set of pictures taken at intermittent intervals in the treatment process (e.g. baseline, 6 months and 1 year) (see Figure 1). This discussion can be paired with charts showing Efinaconazole cure rates and nail clearance over time (see Figures 2 & 3). Showing patients pictures of positive results, while still managing expectations, can help them visualize potential success with compliance to proper treatment.
• Additionally, physicians can utilize visual aids to help patients better understand the pathology of onychomycosis (see Figure 4), which has similarly been shown to increase compliance.³⁸
• A patient toolkit may be beneficial in packaging together a comprehensive and encouraging onychomycosis treatment plan, with explanations and visualizations of disease pathology, treatment mechanism, and treatment regimen and trajectories.

Conclusions

• Efinaconazole 10% solution is an effective and convenient topical antifungal treatment for onychomycosis, with toenail mycological cure rates between 53.4% and 55.2% and complete cure rates between 15.2% and 17.8%.
• Treatment may be more effective when combining Efinaconazole with other modalities such as topical antifungals for the management of tinea pedis on adjacent skin, oral antifungals, and laser treatment.
• Patient adherence is the cornerstone of treatment success. It is crucial that patients adhere to daily application of efinaconazole throughout the treatment course. Compliance should be encouraged by emphasizing the consequences of nonadherence, using visual guides to aid in understanding of disease pathology and treatment mechanisms, and inspiring a motivated outlook on treatment trajectory.

Introduction

Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, or non-dermatophyte molds. Results from a large international study show that onychomycosis affects up to 23% of the population.¹ The rates of onychomycosis in people older than 40 is even higher, and has been reported to be greater than 50%.¹ Risk factors for onychomycosis include increasing age, atopy, sports, diabetes, obesity, peripheral arterial disease, immunosuppression, and pre-existing nail disease.¹

Diagnostic Features

• The clinical diagnosis of onychomycosis can be challenging given that inflammatory disorders of the nails can mimic onychomycosis.
  • The differential diagnosis of onychomycosis includes psoriasis of the nails, idiopathic onychodystrophy, traumatic onychodystrophy, lichen planus, and alopecia areata.
  • Onychomycosis accounts for approximately 50% of nail disorders.²
• In patients with mycologically proven onychomycosis the most common clinical findings are:
  • Discoloration of the nail (85%), hyperkeratosis (80%) and onycholysis (43%).
  • The rates of damaged nail (13%) and paronychia (7%) were lower.¹
• To confirm a diagnosis of onychomycosis, clippings can be obtained from the distal nail, curettings can be obtained from below the nail plate with a 1mm curette, or a scalpel can be used to pare down the overlying normal nail plate to get to the debris beneath the nail for KOH and/or culture.³
• Curetting beneath the nail plate increases the sensitivity of KOH and culture when done in conjunction with either clipping or paring alone.³

Treatment Rationale

• • Onychomycosis impacts patients’ psychosocial functioning.
  • In a survey on how adults with onychomycosis are perceived by others, survey respondents said they would:⁴
    • Perceive those with onychomycosis as less likely to be able to form good relationships.
    • Be more likely to exclude those with onychomycosis from social activities.
    • Feel uncomfortable sitting or standing beside an infected person.
  • Many patients with onychomycosis have associated pain, which can be underestimated by physicians.⁵
  • Onychomycosis in diabetic patients may be associated with serious consequences.
    • Diabetic patients with onychomycosis have higher rates of infections and of foot ulcers⁶ compared to diabetic patients without onychomycosis.
    • The presence of onychomycosis in a patient increases the risk of diabetic foot complications from moderate to high risk.⁷

Treatment/Management Options

Systemic Therapies

• • • Terbinafine
      • Terbinafine is currently the most efficacious systemic agent for treating onychomycosis.
        • Mycological cure – 74%
        • Complete cure – 38%
        • Assessed at week 48, after a 12 week treatment course.⁸
        • Mycological cure is defined as a negative KOH and negative fungal culture.
      • Complete cure is defined as mycological cure with 0% clinical nail involvement. There is a Health Canada Black box warning stating “Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine tablets; Treatment with terbinafine tablets should be discontinued if biochemical or clinical evidence of liver injury develops.” The actual rates of idiosyncratic hepatobiliary dysfunction have been reported to range between 1 : 45 000 to 1 : 120 000.^9,10
      • The typical dosing for toenail onychomycosis is 250mg once daily for 12 weeks.
  • • Azoles
      • Ketoconazole
        • In 2013, the FDA issued a safety announcement that oral ketoconazole tablets should not be a first-line treatment for any fungal infection due to hepatotoxicity, adrenal insufficiency and drug interactions. The US label for ketoconazole now carries an FDA black box warning that systemic ketoconazole should only be used when other effective antifungals are not available or tolerated, due to hepatotoxicity and drug interactions leading to QT prolongation.¹¹
      • Itraconazole
        • Mycological cure – 54%
        • Complete cure – 14%
        • Black box warning: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.¹²
        • 200mg once daily for 3 months or pulse dosing: 3 pulses of 200mg bid for 7 days, with 3 week drug free intervals between pulses.

Topical Therapies

• • • Ciclopirox 8% nail solution¹³
      • The cure rates for ciclopirox in two double blinded Phase III trials were:
        • Mycological cure – 29-35%
        • Complete cure – 6%-9%
      • The treatment protocol for Ciclopirox 8% nail solution involves once daily application, with removal of the ciclopirox solution every 7 days with isopropyl alcohol, with removal of the unattached, infected nail as frequently as monthly for up to 48 weeks.
    • Efinaconazole 10% solution
      • Mycological cure – 55.2% and 53.4%
      • Complete cure – 17.8% and 15.2%
      • 48 weeks of treatment

Efinaconazole 10% Solution

Background

• • • Efinaconazole is a topical azole antifungal that inhibits ergosterol, a structural component of fungal cell membranes, leading to the loss of cell membrane integrity.^14,15
    • In vitro efinaconazole has been found to be active against dermatophytes, non-dermatophytes, and yeasts.16
    • It has low keratin affinity which allows enhanced penetration through the nail compared to ciclopirox, this presumably allows the topical to better treat fungus within and under the nail plate.¹⁷
    • Efinaconazole 10% solution has been shown to penetrate through nail polish, so that patients do not need to remove their nail polish to treat on a daily basis.¹⁸
    • The treatment course for efinaconazole 10% solution is once daily for 48 weeks, applied to the affected toenail, underside of the nail plate, and to the surrounding skin. Debridement or removal of previously applied efinaconazole 10% solution is not necessary as there is no buildup from daily application.¹⁹

Efficacy

• • • The efficacy of topical 10% efinaconazole was demonstrated in two Phase III studies with 1655 patients.
    • The cure rates at 52 weeks, 4 weeks after the completion of treatment, in the two Phase III studies were:
      • Mycological cure – 55.2% and 53.4%
      • Complete cure – 17.8% and 15.2%

Factors Affecting the Efficacy of Topical Efinaconazole 10% Solution

• • • Females had higher complete clearance rates than males (27.1% versus 15.8%, p=0.001).²⁰
    • Concomitant tinea pedis²¹
      • Treatment of concomitant tinea pedis – complete cure 29.4% and mycological cure 56.2%.
      • Without treatment of concomitant tinea pedis – complete cure 16.1% and mycological cure 45.2%.
    • Diabetes²²
      • Patients with controlled diabetes (n=69) were compared to non-diabetic patients (n=993).
      • Complete cure rates were 13% and 18.8% respectively, the difference was not statistically significant.
    • Duration of disease – There is a trend that patients with onychomycosis for less than 1 year had higher complete cure rates than those with a longer duration of disease.²³
      • < 1 year – 42.6% complete cure versus 16.7% for vehicle – not statistically significantly different from vehicle.
      • 1-5 years – 17.1% complete cure versus 4.4% for vehicle.
      • > 5 years – 16.2% complete cure versus 2.5% for vehicle.
    • Disease severity – Patients with less nail involvement had higher cure rates.²⁴
      • ≤ 25% nail involvement – complete cure rate 25.8%; mycological cure 58.2%.
      • >25% nail involvement – complete cure rate 15.9%; mycological cure 55.5%.

Clinical Pathway

• • In 2015 a group of Canadian dermatologists developed a clinical pathway for managing toenail onychomycosis (figure 1),²⁵ based on the available data.
  • The clinical pathway provides a guide toward a patient-centred treatment strategy, focusing on prevention, management, and minimizing re-infection of onychomycosis.
  • Treatment stragies are based on severity of disease:
    • >60% of toenail affected: oral terbinafine
    • 20-60% of toenail affected: topical efinaconazole +/- oral terbinafine
    • <20% of toenail affected: topical efinaconazole

Summary

• • • When making a diagnosis of onychomycosis, curetting beneath the nail plate with a 1mm curette combined with clipping the nail, can increase the sensitivity of clipping the nail alone.
    • Topical therapy appears most effective for patients with early disease and smaller amounts of nail involvement.
    • When treating topically, concurrently treating the concomitant tinea pedis appears to increase the complete cure rate.
    • Treatment with efinaconazole involves once daily application of the 10% solution to the nail plate, under the nail plate, and to the surrounding skin for 48 weeks with penetration through the nail plate, without removing nail polish; there is also no need to remove the solution from the nail plate on a weekly basis.
    • The complete cure rate with efinaconazole 10% solution is between 15.2% and 17.8%.
    • In terms of systemic therapy, terbinafine has a complete cure rate of 35%; ketoconazole has an FDA black box warning against using it first-line for any fungal infections.

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  15. Parks LW, et al. Lipids. 1995 Mar;30(3):227-30.
  16. Jo Siu WJ, et al. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
  17. Sugiura K, et al. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
  18. Zeichner JA, et al. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
  19. Valeant Pharmaceuticals. Jublia (efinaconazole) topical solution, 10%. 2014.
  20. Gupta AK, et al. J Drugs Dermatol. 2014 Jul;13(7):815-20.
  21. Markinson B, Caldwell B. J Am Podiatr Med Assoc. 2015 Sep;105(5):407-11
  22. Vlahovic TC, Joseph WS. J Drugs Dermatol. 2014 Oct;13(10):1186-90.
  23. Rich P. J Drugs Dermatol. 2015 Jan;14(1):58-62.
  24. Rodriguez DA. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-29.
  25. Gupta AK, et al. J Cutan Med Surg. 2015 Sep-Oct;19(5):440-9.

Introduction

Onychomycosis in diabetic patients increases the risk for other foot disorders and limb amputation and is included in diabetic foot ulcer guidelines as one of the risk factors for serious complications that should be screened for. Even though foot examination in diabetes patients is common practice, onychomycosis either goes unnoticed or is left untreated and remains unresolved. Early treatment and intervention including diabetic foot care and education is advisable owing to the progressive nature of fungal infections and the high-risk diabetic foot. Treatment with transungual efinaconazole 10% solution is an effective and safe option for many of these patients. A recently published clinical pathway for toe onychomycosis¹ is used as the basis for the management strategy presented here, and follows a pathway reflective of the therapeutic options available in Canada.

Background

• Onychomycosis accounts for about half of all nail abnormalities and comprises a third of fungal skin infections.²
• The prevalence of onychomycosis becomes more common as people age and conditions such as diabetes, peripheral vascular disease, psoriasis and immunosuppression (HIV infection or immunosuppressive therapy) increase in our populations.
• Fungal nail disease can coexist with other nail disorders.^2,3,6
• The prevalence of onychomycosis in patients with diabetes has been reported to be 26%.^3-5
• Diabetics appear almost three times as likely to have onychomycosis as non-diabetic individuals.^3-5
• Although there are no studies addressing the relationship between onychomycosis and diabetic foot ulcers, it is possible that one could predispose to the other.⁴
• Other factors enhancing the risk for onychomycosis are smoking; avid sports participation; the use of commercial swimming pools; wearing occlusive, tight footwear; use of common, hot, humid climates; and frequent travel to endemic areas.²
• This common nail infection often results in nail plate damage, deformity and toenail dystrophy that can interfere with walking.²
• It is also associated with detrimental psychosocial effects.⁷

Toe Onychomycosis

• Onychomycosis is most frequently caused by dermatophytes (approximately 90% of toenail infections) and non-dermatophyte molds (approximately 6%) that mainly affect toenails (Figure 1).^8,9
• Onychomycosis may present with four patterns of involvement.¹ Most common is a distal subungal pattern, where proximal subungal presentation is rare and often indicates immunodeficiency.¹ Yeast infections may present as a superficial white pattern and can be treated topically.¹ In advanced disease the whole nail plate may be involved, making the condition less responsive to therapy.¹
• Onychomycosis is a serious condition in people with diabetes and increases their risk for other foot disorders and limb amputation (Figure 2).^{11,12,15,16,20}
• Onychomycosis will often result in thickened and dystrophic nails that are difficult to manage for many patients because often they can’t reach, see, feel or have the strength or dexterity to cut their nails.¹² The result is that the nails go unmanaged and provide a significant and often overlooked area of risk for lower extremity infection and limb loss.^11,12
• Many diabetic patients have loss of protective sensation that will result in their inability to feel any of the warning signs of infection in their feet.
• Advanced peripheral neuropathy will also lead to motor neuropathy resulting in an imbalance of the stabilizing muscles of the foot causing deformity such as digital overlap and hammertoes, as significant precursors to fungal infections and ulcerations.^12,15,16
• A simple ingrown nail or a lesser toe deformity that causes the nail to rub into the adjacent toe can easily and too often cause cellulitis or osteomyelitis of the underlying bone.¹²
• Broken skin provides a portal for bacteria and often will start the cascade of diabetic foot complications.¹²
• Early treatment and intervention including diabetic prophylactic foot care education is advisable owing to the progressive nature of fungal infections and the high risk diabetic foot.^12,15,16
• The long course of treatment for onychomycosis, together with the existing polypharmacy in diabetic patients may lead to monetary challenges and potential side effects.

Assessment

• Diagnosis of onychomycosis is based on clinical presentation and test results.¹ As there are many disorders that cause nail changes, objective assessment may help clarify the aetiology.
• A practical approach may be to treat topically before testing or while waiting for test results.¹ In clinical practice, treatment is often begun without confirmation of test results. A positive potassium hydroxide microscopic or culture for fungus should be performed before considering using systemic antifungal therapy.^1,8-9,14
• Fungal infection may also exist with other disorders (e.g. psoriasis / pincer nails) and successful treatment of the fungus will not clear the co-existing disorder.¹

The following¹ may be reviewed when a patient presents with onychomycosis:

• Investigate patient history and what treatment has been utilized.
• Check if there is an incidental finding of onychomycosis.
• Establish the patient’s past medical history including age (is the patient elderly), comorbidities such as diabetes, cancer and renal disease.
• Check if the patient is immuno-suppressed or has an inflammatory skin disease such as psoriasis.
• Establish if there is a history of fungus elsewhere, e.g. Tinea pedis
• Discuss the recreational habits of the patient including their hygiene, environment and athletic wear.
• Establish the patient’s foot care maintenance including spa’s, self-debridement or pedicures.
• Patient psychological welfare is another important area for assessment, with concerns around how the disease impacts their lifestyle. Ask patients if they are embarrassed about their condition, if the visit to the clinic was their own initiative, and if they are engaged and informed in their health care choices.
• Before considering treatment, it is important to discuss patient expectations of treatment outcomes.¹ The physician must be able to discuss all options and roadblocks that are common with onychomycosis treatment.

Treatment for Toe Onychomycosis

• A recently published clinical pathway for the prevention and treatment of toe onychomycosis¹ was modified for use by podiatrists and chiropodists and addresses the following steps: aetiology and differential diagnosis, prevention, treatment, evaluation and maintenance strategies (Figure 3).
• Before initiating treatment, patients should be informed about steps they can take to contain the infection and prevent recurrence, such as. foot hygiene, use of shower sandals and regular medical pedicures.¹
• Often patients present with a long history of trying a myriad of home remedies. When recommending treatment, pros and cons of various available options may be discussed.¹
• Patients may have searched the Internet for information and often have concerns regarding treatments they have read about, such as oral antifungal and hepatic involvement, and various drug-interactions.
• Patients may have heard about laser treatments and may be concerned about cost, side effects, efficacy and the possibility of infection reoccurrence.
• If the patient does not respond to treatment, microscopic or culture confirmation is needed before proceeding to oral therapy.^1,8-9,14

Systemic Treatment

• Oral treatment is the gold standard for toe onychomycosis with more than 60% nail plate involvement.^8,13 The two options available are Itraconazole (Sporanox (itraconazole), Janssen Pharmaceuticals Inc, Titusville, NJ) and terbinafine (Lamisil (terbinafine HCl), Novartis Pharmaceuticals Corporation, East Hanover, NJ).
• There are issues to be considered when prescribing systemic treatment, such as drug interactions, hepatotoxicity, safety concerns and the need for monitoring.⁸
• Studies of oral treatment that evaluated mycologic cure at week 48, defined as negative KOH and negative culture,⁸ showed terbinafine HCl to be more effective, with a 70% healing rate versus 54% with itraconazole. For complete cure rates, terbinafine was equally more effective, with 38% complete cure versus 14% for itraconazole.⁸

Topical Treatment

• Topical nail preparations are indicated for distal subungal and superficial white patterns of nail onychomycosis.^1,10
• Some topical antifungal agents act as a lacquer applied to the nail surface (e.g. Penlac lacquer with the antifungal ciclopirox).^8,19 This specific topical treatment should be combined with selective debridement of the nail, to enable penetration.¹⁹
• Newer topical or transungal agents have the ability to penetrate nail keratin.¹⁰
• The non-laquer transungal treatment containing efinaconazole 10% solution has demonstrated clinical effectiveness when applied as monotherapy in patients with mild-to-moderate toe onychomycosis.¹⁰ The primary efficacy endpoints (complete clinical cure and mycologic cure) were significantly greater than vehicle at week 52 (p<0.001) and clinical improvement continued after treatment was stopped (week 48).¹⁰

Laser Treatment

• Laser may be used for the treatment of onychomycosis with an emphasis on clinical improvement of the nail.^17,18
• Protocols include debridement of the nail, followed by laser therapy 5-7 times, with more passes (not increasing joules) to disrupt fungus sepsis.^17,18
• Treatment with laser may take 3-4 months or more. ^17,18
• The efficacy of laser therapy is a subject of debate and currently research has not demonstrated sustained efficacy.¹⁸
• It has become common practice to adopt a universal foot care approach for the utilization of laser therapy, which includes addressing concomitant Tinea pedis infections, hygiene, shoe gear and sock changes, and habit changes including awareness of environmental factors such as gym or locker room floor contamination.
• The patient must be educated about foot caredue to the high chance of recurrence and must not rely solely on one treatment modality.

Conclusion

• A large population of onychomycosis patients are seen in podiatrist and chiropodists offices,^1,15 and the incidence is increasing particularly among young, elderly and diabetic patients.^2,4
• Diabetic foot ulcer guidelines identify onychomycosis as a high-risk factor for complications, even amputation.¹² Early diabetic foot examination should include screening for onychomycosis.
• A diabetic foot exam will include a dermatological evaluation, vascular assessment, neurological evaluation and biomechanical review^11,12,15,16 to identify the associated risk factors and enable accurate categorization of the patient’s condition (e.g. low, medium or high-risk status).¹²
• Even though foot examination in diabetic patients is common practice, onychomycosis either goes unnoticed or is left untreated and remains unresolved in many patients. It is imperative that patients be engaged in diabetic foot education.
• The information obtained enables the physician to develop an effective plan for prevention and treatment.
• The goal of management is to educate the patient, assess risk factors and manage those risks in a prophylactic manner.^12,15
• Health care providers must be aware of patient barriers regarding treatment and foot care. To that end, it is quite common to include the family or caregivers in conversations concerning risk factors and foot care for in patients with diabetes.
• Efinaconazole solution is effective in patients that have mild to moderate onychomycosis¹ where the nail is less than 60% involved and less than 3 nails in total are involved. Moreover, it is a good option when systemic onychomycosis treatment is contraindicated.¹
• Transungual onychomycosis treatment has benefits over systemic treatment as both patients and clinicians prefer to avoid systemic side effects and the need for monitoring.¹⁷
• When using a topical agent, the properties of nail plate – thickness and the relative compact structure of the nail- must be addressed.
• A limitation associated with using topical lacquer treatments is the necessity of frequent nail debridement to enable treatment penetration.¹⁹
• Efinaconazole 10% solution is a non-lacquer alcohol-based formulation that has a low molecular weight and binds with keratin.¹⁰ The product is easy to administer, with a plastic squeeze bottle with a flow-through brush used for application.^1,10
• Although the transungual efinaconazole 10% solution does not require debridement to be effective in individuals with onychomycosis, high-risk diabetic foot patients do require assessment, daily observation and possibly nail debridement.¹²
• Treatment that can be topically applied should be offered.^12,15
• When onychomycosis is treated early with efinaconazole solution, complications may be avoided, including the serious and costly outcome of limb salvage.^10,12
• It is imperative that prevention measures be taken to reduce the risk of recurrence. These measures include, but are not limited to lifestyle modifications (avoid being barefoot in high areas of contagion), sanitization of shoes and socks, regular follow up and periodic foot exams, treat tinea pedis and treat toenails previously infected or reinfected with topical medication.

References

1. Gupta AK, Sibbald RG, Andriessen A, Belley R, Boroditsky A, Botros M, Chelin R, Gulliver W, Keast D, Raman M. Toenail Onychomycosis-A Canadian Approach With a New Transungual Treatment: Development of a Clinical Pathway. J Cutan Med Surg. Sep-Oct; 19(5): 440-9, 2015.
2. Gupta AK, Gupta MA, Summerbell RC, Cooper EA, Konnikov N, Albreski D. The epidemiology of onychomycosis: possible roles of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol 1: 466-469, 2000
3. Vender RB, Lynde CW, Poulin Y. Prevalence and epidemiology of onychomycosis. Cutan Med Surg 10 (Supp 2): 528-33, 2006.
4. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists’ offices in Ontario, Canada—a multicenter survey of 2001 patients. Int J Dermatol 36 (10): 783-7, 1997.
5. Rich P: Onychomycosis and tinea pedis in patients with diabetes. J Am Acad Dermatol 43: S130-4, 2000.
6. Baran et al., 33% of oncychomycosis patients also have tinea pedis and this has implications on recurrence rates. Arch derm 142: 1279-84, 2006.
7. Reich A, Szepietowski JC. Health-related quality of life in patients with nail disorders. Am J Clin Dermatol. 12: 313-320, 2011.
8. Lecha M, Effendy I, Feuilhade de Chauvin M, Di Chiacchio N, Baran R. Treatment options-development of consensus guidelines. J Eur Acad Dermatol Venereol. 19 (Suppl): 25-33, 2005.
9. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis-risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 19 (Suppl): 13-16, 2005.
10. Elewski B, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, Ieda C, Smith K, Pillai R, Ramakrishna T, Olin JT. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol 68 (4): 600-8, 2013.
11. Joseph W., Onychomycosis in the Patient with Diabetes, Diabetic Microvascular Complications today. 25-27, 2005.
12. Botros M, et al. Best practice recommendations for the prevention, diagnosis and treatment of diabetic foot ulcers: Update 2010. Wound Care Canada 8 (4): 6-40, 2010.
13. Ginter-Hanselmayer G, Weger W, Smoile J. Onychomycosis: a new emerging infectious disease in childhood and adolescents. Report on treatment experience with terbinafine and itraconazole in 36 patients. J Eur Acad Dermatol Venerol 22 (4): 470-475, 2008.
14. Shemer A, Davidovici B, Grunwalkd MH, Trau H, Amichal B. New criteria for the laboratory diagnosis of nondermatophythe moulds in onychomycosis. Br J Dermatol 160 (1): 37-39, 2009.
15. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and management. Am J Clin Dermatol 10 (4): 211-220, 2009.
16. Bristow IR, Spruce MC. Fungal foot infection, cellulitis and diabetes: a review. Diabet Med 26 (5): 548-51, 2009.
17. Harris DM, McDowell B, Strisower J. Laser treatment for toenail fungus. Proc SPIE 7161A: 1-7, 2009.
18. Bornstein E. A review of current research in light-based technologies for the treatment of podiatric infectious disease states. JAPMA 99 (4): 348-352, 2009.
19. Shemer A, Nathansohn N, Trau H, et al. Ciclopirox nail lacquer for the treatment of onychomycosis: an open non-comparative study. J Dermatol 37(2): 137-139, 2010.
20. Joseph W. Onychomycosis in the Patient with Diabetes, Diabetic Microvascular Complications today, 25-27, 2005.

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.

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.

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.

^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.

References

1. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013 Jun;32(2 Suppl 1):S2-4.
2. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):244-8.
3. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br J Dermatol. 2003 Sep;149 Suppl 65:1-4.
4. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol. 1997 Oct;36(10):754-6.
5. Lubeck DP, Gause D, Schein JR, et al. A health-related quality of life measure for use in patients with onychomycosis: a validation study. Qual Life Res. 1999 8(1-2):121-9.
6. LaSenna CE, Tosti A. Patient considerations in the management of toe onychomycosis – role of efinaconazole. Patient Prefer Adherence. 2015 9:887-91.
7. Tabara K, Szewczyk AE, Bienias W, et al. Amorolfine vs. ciclopirox – lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol. 2015 Feb;32(1):40-5.
8. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005 Sep;19(Suppl 1):13-6.
9. Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol. 1998 Dec;134(12):1551-4.
10. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
11. Markham A. Tavaborole: first global approval. Drugs. 2014 Sep;74(13):1555-8.
12. LamisilÆ (terbinafine hydrochloride) tablets [Prescribing information]; revised
    August 2016. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Available
    at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/
    files/Lamisil_tablets.pdf. Accessed September 26, 2016.
13. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013 Sep-Oct;31(5):544-54.
14. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013 Apr;68(4):600-8.
15. Jo 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.
16. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
17. Gupta AK, Pillai R. The presence of an air gap between the nail plate and nail bed in onychomycosis patients: treatment implications for topical therapy. J Drugs Dermatol. 2015 Aug;14(8):859-63.
18. Gupta AK, Simpson FC. Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis. J Dermatolog Treat. 2016 27(1):2-4.
19. Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
20. Rodriguez RJ, Low C, Bottema CD, et al. Multiple functions for sterols in Saccharomyces cerevisiae. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
21. Parks LW, Smith SJ, Crowley JH. Biochemical and physiological effects of sterol alterations in yeast–a review. Lipids. 1995 Mar;30(3):227-30.
22. Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014 Jul;13(7):815-20.
23. JUBLIA® (efinaconazole) topical solution, 10% [Prescribing information]; revised July 2014. Valeant Pharmaceuticals North America LLC, Bridgewater, NJ. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf. Accessed September 26, 2016.
24. Lipner SR, Scher RK. Efinaconazole in the treatment of onychomycosis. Infect
    Drug Resist. 2015 8:163-72.
25. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of
    toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014
    Oct;13(10):1186-90.
26. Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea
    pedis. J Drugs Dermatol. 2015 May;14(5):492-4.
27. Rich P. Efinaconazole topical solution, 10%: the benefits of treating
    onychomycosis early. J Drugs Dermatol. 2015 Jan;14(1):58-62.
28. Rodriguez DA. Efinaconazole topical solution, 10%, for the treatment of mild and
    moderate toenail onychomycosis. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-9.
29. Szepietowski JC, Reich A, Garlowska E, et al, Onychomycosis Epidemiology Study
    Group. Factors influencing coexistence of toenail onychomycosis with tinea
    pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol. 2006
    Oct;142(10):1279-84.
30. Markinson B, Caldwell B. Efinaconazole topical solution, 10% efficacy in patients
    with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015
    Sep;105(5):407-11.
31. Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004 21(2):101-12.
32. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000 Jul-Aug;10(5):379-84.
33. Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 2013 Dec;148(6):603-8.
34. Lipner SR, Scher RK. Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail. Expert Rev Clin Pharmacol. 2015 8(6):719-31.
35. Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails. J Drugs Dermatol. 2014 Nov;13(11):1388-92.

Introduction

Hand dermatitis (HD) can have a significant impact on quality of life of those affected. It may interfere with activities both at work and in the home and can be associated with social and psychological distress.^1,2 The chronic form, chronic hand dermatitis (CHD) affects up to 10% of the population, which can have a considerable societal impact.² Canadian Guidelines for the management of chronic hand dermatitis have been published to help guide management of this burdensome condition.³ This article provides helpful practical guidance for the general practitioner in the management of patients with HD.

Abbreviations: CHD – chronic hand dermatitis; ENT – ear, nose, and throat; HD – hand dermatitis; KOH – potassium hydroxide; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroid(s)

Diagnosing HD – Important points to cover:

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposure to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum as needed.

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

Figure 2.
Establish diagnosis of acute hand dermatitis and chronic hand dermatitis (CHD). HD – hand dermatitis

• It is important to first differentiate between acute and chronic forms of HD, as the treatment options may vary.
• Acute HD lasts less than 3 months or occurs only once in a calendar year.
• CHD lasts for at least 3 months and/or patients experience at least 2 relapses in a calendar year.

TIP: Could This Be Tinea?

• Check the feet for signs of tinea pedis and onychomycosis.
• Look for an active border suggestive of tinea.
• Take a skin scraping for KOH microscopy and culture.

TIP: Could This Be Psoriasis?

• Check the feet, scalp, elbows, knees, gluteal cleft and umbilicus for signs of psoriasis.
• Check the nails for signs of psoriasis: pitting, onycholysis, subungual hyperkeratosis, splinter hemorrhages, salmon patches (oil drops).

Prevention, Avoidance and Patient Education

• Every patient with HD, whether acute or chronic, should protect their hands and avoid irritants and exacerbating factors.
• Avoid wet work, frequent hand washing and alcohol-based hand sanitizers.
• Gloves should be worn to protect the hands: cotton gloves at home, or during the night; gel padded gloves for friction and protective gloves for wet work and irritant exposure.
• The following tips are provided for patients on what to use, what to avoid and helpful common practices.

Assessing and Encouraging Patient Adherence

• Ask patients to bring products and prescriptions to follow up appointments to assess usage.
• More frequent patient follow up visits improve adherence.
• Provide education on the disease, treatment options and potential side effects of therapy.
• Choose treatment in agreement with the patient.
• Suggest joining a support group or organization, such as the Eczema society of Canada ( https://eczemahelp.ca/).

Emollient Therapy

• All patients with HD should use a bland, rich emollient to help restore the skin barrier, and apply frequently throughout the day.
• Regular application may prevent itching and reduce the number of flares.
• For hyperkeratotic eczema, patients should use an emollient with keratolytic agent (salicylic acid 10-20% or urea 5-10%).
• Unscented petroleum jelly is inexpensive and helpful for many patients.

Management of Acute HD

• It is important to make a diagnosis of acute HD so that treatment can be started as quickly as possible to maximize the outcome and prevent chronic involvement.
• Patients with HD should be adequately counselled on prevention and avoidance strategies.
• Avoidance of irritants, potential allergens and regular use of emollients is essential.
• Early treatment includes control of flares with a potent or super-potent topical corticosteroid (TCS) applied twice daily. For example, clobetasol propionate 0.05% ointment applied twice daily is generally effective in acute flares.
• For less severe flares, consider betamethasone valerate 0.1% ointment applied twice daily until controlled.
• In more severe cases, systemic steroids (prednisone, intramuscular triamcinolone) should be considered. Prednisone starting at 40-50 mg orally once a day and tapering over three weeks is an effective treatment course.
• Avoid short courses of prednisone as the condition may flare again, so a tapering dose is advised.
• Look for signs of infection and treat concomitantly.
• Try to identify any allergen exposures and recommend avoidance. If allergy is suspected, the patient should be referred for patch testing.
• Once controlled, consider maintenance therapy with topical calcineurin inhibitors (TCIs), such as tacrolimus 0.1% ointment twice daily when necessary, or twice weekly as maintenance therapy.

Figure 3.
Severity-based treatment algorithm for the management of hand dermatitis (HD). CS – corticosteroid; TCS – topical corticosteroid

QoL Consideration

• Patients with mild or moderate CHD who have a significant impact on QoL should be managed as severe CHD.

Did You Know?

• Hydrocortisone topical agents should not be recommended for most cases of HD because it is rarely effective and patients may become sensitized.
• Hydrocortisone is responsible for the majority of allergies to topical steroid products.

Management of Chronic HD

• The treatment plan for CHD depends on whether it is mild, moderate or severe.

Management of Mild CHD

• Patients with mild CHD should be educated on proper prevention and avoidance strategies as outlined earlier.
• Regular emollient therapy should be used to restore and maintain the skin barrier.
• TCS therapy should be initiated with betamethasone valerate 0.1% ointment twice daily for 4-8 weeks.
• If not responding, adherence to the treatment plan should be assessed. Ask the patient to bring medication to follow up appointment to assess amount of product actually used.
• The patient can then be counselled on proper use of the product and provide support for ongoing management.
• If not responding with an adequate trial, a higher potency TCS, such as clobetasol priopionate 0.05% ointment should be prescribed as next line therapy. Reassess after 2 weeks. If not responding to an adequate trial of a potent or super potent TCS, the patient should be considered to have moderate CHD.

Figure 4.
Treatment algorithm for the management of mild chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

TIP: Always assess adherence, reconsider the diagnosis and rule out contact allergens, concomitant infection or colonization when patients do not respond to therapy.

Management of Moderate CHD

• In addition to regular use of emollients, patients with a diagnosis of moderate CHD should be given a 4-8 week trial of a moderate TCS, such as betamethasone valerate 0.1% ointment, or a super potent TCS, clobetasol propionate 0.05% ointment for a 2-week trial. If improved, the patient can continue this as necessary, for control of the condition.
• Another option is maintenance with a TCI, such as tacrolimus 0.1% ointment twice a day as needed, or twice weekly for maintenance. If not improved, reconsider the diagnosis and assess the patient for adherence.
• If a diagnosis of moderate CHD is confirmed, consider treating the patient with a course of phototherapy, if accessible. If unavailable or the patient does not respond, consider treating as severe CHD.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 5.
Treatment algorithm for the management of moderate chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Safety Tip

When patients show signs of adverse effects to TCS, including
atrophy or telangiectasias or they cannot tolerate topical steroid
use, consider TCI (tacrolimus ointment 0.1%) as a non-steroid
topical therapy option for treatment and maintenance.

When to Refer

• Patients with CHD should be referred to a dermatologist when:
  • They may require patch testing
  • They are not responding to therapy
  • Condition is worsening instead of improving
  • Require phototherapy

Management of Severe CHD

• Patients who are diagnosed with severe CHD, patients with mild to moderate CHD who have failed an adequate trial on therapy, or patients who have a significant impact on the QoL, should be treated as having severe CHD.
• Treatment should be initiated with a potent or super-potent TCS, such as clobetasol propionate 0.05% ointment twice a day for 4-8 weeks (2 weeks on dorsal hands if super potent). If improved, patients may continue to use on an as needed basis, or switch to a TCI for ongoing maintenance therapy.
• Patients should be reassessed at 4-8 weeks. If they are not responding to therapy, consider adherence and review proper care.
• A course of phototherapy may also be considered if available.
• Treatment with oral alitretinoin (30 mg orally, once a day) is the next line of therapy based on best available evidence.⁴ Alitretinoin should be prescribed by those who are comfortable with prescribing retinoids.
• As with all retinoids, caution should be used in females of child bearing potential due to teratogenic potential. Monitoring of therapy with regular blood tests for hepatotoxicity and alterations in lipid profile is also recommended.
• If the patient responds to therapy, it should be continued for 3-6 months and reassessed at that time. Patients may discontinue therapy at this point, and continue with ongoing maintenance with topical therapy. If, in the future, they experience a flare, they can be retreated with alitretinoin.⁵
• If a patient does not respond to 12 weeks of alitretinoin, they should be referred for confirmation of diagnosis and other treatment options, which would include treatment with immunosuppressive therapy such as cyclosporine, methotrexate, mycophenolate mofetil or azathioprine.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 6.
Treatment algorithm for the management of severe chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Conclusion

HD can have a significant burden on the patient with an impact on
QoL. Early diagnosis of acute or chronic HD is important for optimal
management. Other conditions such as tinea manuum and psoriasis
need to be ruled out and managed appropriately. Once a diagnosis of
HD is confirmed, treatment depends on the severity of the disease.
A treatment algorithm has been developed to assist the general
practitioner to make a diagnosis and either refer or treat accordingly.
Whichever treatment option is prescribed, all patients should be
educated on emollient therapy, hand protection and avoidance of
irritants or allergens, which may be contributing to their disease.

References

1. Diepgen TL, Agner T, Aberer W, et al. Management of chronic hand eczema. Contact Dermatitis 2007;57:203-10, doi:10.1111/j.1600- 0536.2007.01179.x.
2. Agner T. Hand eczema. In: Johansen JD, Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. 5th ed. Berlin: Springer-Verlag; 2011. p. 395-406
3. Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, Agner T, Barber K, Bissonnette R, Ho V, Shear NH, and Toole J. Canadian Hand Dermatitis Management Guidelines. J Cut Med Surg 2010; 14(6): 267-284
4. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008;158:808-17, doi:10.1111/j.1365- 2133.2008.08487.x.
5. Bissonnette R, Worm M, Gerlach B, et al. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol 2009;162:420-6, doi:10.1111/j.1365-2133.2009.09572.x.
6. Veien NK, Larsen P, Thestrup-Pedersen K, and Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate British Journal of Dermatology Volume 140( 5): 882-886, May 1999
7. Krejci-Manwaring J, McCarty MA, Camacho F, Manuel J, Hartle J, Fleischer A Jr and Feldman SR: Topical tacrolimus 0.1% improves symptoms of hand dermatitis in patients treated with a prednisone taper. J Drugs Dermatol. 7:643-646. 2008. PubMed/NCBI
8. Thestrup-Pedersen K, Andersen KE, Menne T, and Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo controlled study. Acta Derm Venereol 2001; 81: 353-355
9. Granlund H, Erkko P , Eriksson E , and Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Dermato-venereologica [1996, 76(5):371-376]

¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto, Toronto, ON, Canada

Conflicts of interest:
Gita Gupta has no conflicts of interest. Aditya Gupta has been a clinical trials investigator, advisory board member, consultant, and speaker for Valeant. Aditya Gupta was involved in preclinical studies of tavaborole for Anacor Pharmaceuticals Inc. and has consulted for Anacor. Kelly Foley is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.

ABSTRACT
Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection.

Key Words:
clinical efficacy, dermatophyte, fungal infection, nail penetrance, nondermatophyte, onychomycosis, tavaborole, topical treatment

Introduction

Onychomycosis is a persistent fungal infection of the nails and nail bed, predominantly caused by the dermatophytes Trichophyton
rubrum or Trichophyton mentagrophytes.¹ The prevalence of onychomycosis in Europe and North America ranges from 3.22- 8.9%,^2,3 with recurrence and reinfection occurring in up to 25%⁴. Distal lateral subungual onychomycosis (DLSO) is the most common clinical presentation, invading the nail plate, nail bed, and hyponychium from the distal edge and lateral nail folds.¹

Treatment for onychomycosis consists of systemic (oral) and topical medications, with or without mechanical/chemical debridement. Systemic therapy is generally more successful
than topical therapy with clinical cure rates ranging from 40-80%.⁵ The advantage to systemic therapy is that medication can directly reach the site of infection in the nail bed.⁶ However, systemic therapy may not be feasible for those who are immunocompromised or at risk for drug-drug interactions (e.g., the elderly and/or diabetics).⁷ Alternatively, other patients are uncomfortable with long-term use of oral medications. Oral antifungal medications have been associated with asymptomatic increases in liver enzymes and there is a small risk of hepatotoxic injury.^8,9 Thus, topical therapies have an important role in onychomycosis management.

The efficacy of topical therapy for onychomycosis ranges from 5.5-17.8% for complete cure and 29-55% for mycological cure.¹⁰ The lower efficacy of topical treatments as compared to systemic therapy can be attributed to their limited ability to reach the site of infection.¹¹ In order for topical treatments to be effective, they need to penetrate the nail plate and down into the nail bed, and mechanical or chemical nail debridement of nails may facilitate this. The major advantage to topical therapy is that long-term use is safe, with minimal side effects.¹¹ Additionally, topical treatments used in combination with systemic treatment may increase clinical efficacy. Furthermore, fungal resistance to azole medications has become a concern in recent years.¹² Therefore, there is a need for new topical therapies for onychomycosis.

Tavaborole: A Novel Topical Antifungal

Tavaborole 5% solution (Kerydin^®) was approved by the US FDA for treatment of onychomycosis in July 2014. Tavaborole is the first in a new class of boron atom-containing drugs, the oxaboroles. Tavaborole’s mechanism of action is unique from current antifungals. Other antifungal agents act by blocking ergosterol synthesis (triazoles and terbinafine),⁶ or interfering with microbial metabolism (ciclopirox).¹³ Tavaborole inhibits protein synthesis, and thus fungal cell growth, by binding to leucyl-tRNA synthetase (LeuRS), an aminoacyl-tRNA synthetase (AARS).¹⁴ AARSs are critical for correct DNA translation and contain proofreading editing sites. Tavaborole binds to the editing site of LeuRS, trapping tRNA and preventing further DNA translation and protein synthesis.¹⁴ In vitro studies have shown that tavaborole can inhibit a wide range of fungal species, with minimum inhibitory concentrations (MIC) against dermatophytes, nondermatophyte molds, and yeasts (Table 1)¹⁵ allowing for potential treatment of mixed dermatophyte-nondermatophyte/mold infections. Of note is the potential for tavaborole to act against Fusarium and Malassezia species.¹⁵ Additionally, tavaborole’s low molecular weight compared to other available topical antifungal agents appears to allow for increased nail penetrance, with increased penetrance demonstrated compared to both amorolfine and ciclopirox.^16,17 Tavaborole’s broad spectrum of antifungal activity, coupled with its ability to penetrate the nail plate, suggested that it may be an effective topical treatment for toenail onychomycosis and led to its investigation in Phase I-III clinical trials.

Clinical Efficacy

Phase I
A Phase I study assessed the efficacy of once daily tavaborole 7.5% solution for 28 days in 15 otherwise healthy patients with severe onychomycosis of both great toenails (at least 80% involvement).¹⁸ Additionally, at least one great toenail was potassium hydroxide (KOH) positive, each great toenail had a combined thickness of the nail plate and nail bed of >3 mm, and at least six other toenails were diagnosed with onychomycosis. After 14 and 28 days of treatment, negative culture was reported for 88% (21/24) and 100% (24/24) of toenails, respectively. Clinical improvement was also observed 2-4 months following treatment, with an average clear nail growth of 1.2 mm.¹⁸

Phase II
Three Phase II studies have been conducted to evaluate the efficacy of a range of doses for tavaborole.¹⁹ All of these studies enrolled adult patients (18-65 years of age) with mild to moderate onychomycosis of at least one great toenail (20-60% nail involvement) and did not allow debridement of the nails during treatment. Study 200/200A (N=187) was a double-blind, randomized, vehicle-controlled trial evaluating 2.5%, 5%, and 7.5% tavaborole solution applied to affected toenails once daily for 3 months, followed by three times weekly for 3 months.¹⁹ The primary efficacy endpoint at 6 months was treatment success of the target toenail, defined as an Investigator Static Global Assessment (ISGA) of clear or almost clear plus negative culture or ≥2 mm of new clear nail growth plus negative culture. The rates of treatment success for all tavaborole treatments were significantly greater than vehicle control (P=0.030). While the number of patients that achieved negative culture was higher in tavaborole groups than vehicle, the differences were not statistically significant (Table 2).¹⁹

Studies 201 (N=89) and 203 (N=60) were open-label trials with the same primary efficacy endpoint as Study 200/200A, treatment success.¹⁹ Patients in Study 201 applied tavaborole 5% solution (Cohort 1) or tavaborole 7.5% solution (Cohort 2) to all affected toenails once daily for 6 months. Cohort 3 applied tavaborole 5% solution once daily for 12 months. Patients in Study 203 applied tavaborole 1% once daily for 6 months or tavaborole 5% once daily for 30 days, followed by three times weekly for 5 months. Efficacy outcomes are listed in Table 2.¹⁹ Overall, treatment with tavaborole was very promising and well tolerated, prompting larger-scale Phase III trials to be conducted. The 5% concentration of tavaborole was selected for Phase III testing.

Phase III

Two identical multi-center, randomized, double-blind, vehiclecontrolled clinical trials were conducted (Study 301, N=593 and Study 302, N=601).^20,21 Patients aged 18 years and older with mycologically confirmed (positive KOH and culture) onychomycosis involving 20-60% of the great toenail applied either tavaborole 5% solution or vehicle solution once daily for 48 weeks. At Week 52, complete cure (completely clear nail and mycological cure) and mycological cure (negative KOH and negative culture) were assessed (Table 3). ^20,21 Treatment with tavaborole 5% solution led to a significantly greater complete cure and mycological cure rates than vehicle treatment in both clinical trials (Ps≤0.001). Additionally, the outcome of completely or almost completely clear nail (≤10% nail involvement) plus negative mycology was significantly greater with tavaborole 5% solution compared to vehicle (Study 301: 15.3% vs. 1.5%; Study 302: 17.9% vs. 3.9%, P≤0.001).^20,21

Adverse Events

For all three Phase II studies combined, treatment-emergent adverse events (TEAEs) occurred in 177 of 366 patients.¹⁹ There were 13 reports of serious adverse events (AEs), unrelated to treatment. A reduction in dosing frequency and/or treatment discontinuation resolved any mild to moderate application site reactions. Specifically, in Study 200/200A, four patients in the tavaborole 7.5% solution group required ‘drug holidays’ (discontinued treatment until persistent grade 2 stinging/burning, pruritus, or grade ≥3 irritation was resolved, then treatment resumed with reduced frequency), while no patients in the tavaborole 5% solution group required a break from treatment. Other TEAEs reported included influenza (9.0%), pharyngitis (3.8%), upper respiratory tract infection (3.6%), tinea pedis (3.8%), headache (3.6%), contact dermatitis (2.5%), onychomadesis (1.4%), and tooth extraction (0.8%).¹⁹

Safety data was available for 1186 participants in the Phase III clinical trials.²⁰ No serious AEs were considered treatment related. In both trials, discontinuation due to treatment was comparable for tavaborole 5% solution and vehicle groups. TEAEs in ≥1% of participants treated with tavaborole were limited to application site reactions (exfoliation 2.7%, erythema 1.6%, and dermatitis 1.3%), and there were few reports of TEAE’s due to vehicle (exfoliation 0.3%, erythema and dermatitis 0%).20,21 Taken together, these results demonstrate that tavaborole 5% solution is both safe and more effective than vehicle in treating toenail onychomycosis.

Discussion

Tavaborole 5% solution was approved by the US FDA in July 2014 for use as a topical treatment for onychomycosis. Phase III clinical trials demonstrated that once daily use of tavaborole 5% solution for 48 weeks produced significantly higher rates of mycological and complete cure than vehicle.^20,21 Adverse events reported from Phase II and III trials indicate that the 5% formulation of tavaborole provides optimum efficacy and safety, producing mild application site reactions in a small number of patients.^19-21 As with all topical treatments for toenail onychomycosis, treatment outcomes are, in part, reliant on patient compliance and commitment to therapy, as toenails generally require at least 10-12 months to regrow.

Formulating an agent capable of penetrating the nail plate is one of the major challenges in developing topical treatments for onychomycosis. Tavaborole’s low molecular weight and high solubility allow for greater nail penetration and subsequent delivery of medication to the nail bed. The ability of tavaborole to effectively penetrate the nail plate prevents the need for mechanical debridement that may be required with other topical treatments. Additionally, tavaborole 5% solution’s broad-spectrum antifungal activity against dermatophytes, nondermatophytes, and yeasts make it a potential treatment for mixed infections. This is a relevant concern as little is known about the efficacy of current treatments for mixed infections, which may also contribute to the high recurrence rates observed in onychomycosis.

The availability of tavaborole 5% solution for the topical management of toenail onychomycosis may represent the promising start of a new line of treatments with increased nail penetrance and a novel mechanism of action against pathogenic fungi.

References

1. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
2. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1039-44.
3. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014 Nov;28(11):1480-91.
4. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
5. de Sa DC, Lamas AP, Tosti A. Oral therapy for onychomycosis: an evidencebased review. Am J Clin Dermatol. 2014 Feb;15(1):17-36.
6. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993 May;28(5 Pt 1):S28-S34.
7. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat. 2008 19(3):168-75.
8. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999 Dec;48(6):847-52.
9. Kao WY, Su CW, Huang YS, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014 Jan;77(1):180-9.
10. Gupta AK, Daigle D, Foley KA. Topical therapy for toenail onychomycosis: an evidence-based review. Am J Clin Dermatol. 2014 Dec;15(6):489-502.
11. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008 Nov;5(11):1267-82.
12. . Parker JE, Warrilow AG, Price CL, et al. Resistance to antifungals that target CYP51. J Chem Biol. 2014 Oct;7(4):143-61.
13. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin. 2003 Jul;21(3):481-9
14. Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007 Jun 22;316(5832):1759-61.
15. Sanders V, Baker SJ, Alley MRK, et al. Microbiological activity of AN2690, a new antifungal agent in development for the topical treatment of onychomycosis. [Poster P1608]. Presented at the 64th Annual Meeting of the American Academy of Dermatology; March 3-7, 2006; San Francisco, CA.
16. Elewski BE, Tosti A. Tavaborole for the treatment of onychomycosis. Expert Opin Pharmacother. 2014 Jul;15(10):1439-48.
17. Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007 Oct;96(10):2622-31.
18. Beutner KR, Sanders V, Hold K, et al. An open-label, multi-dose study of the absorption and systemic pharmacokinetics of AN2690 applied as a 7.5% solution to all toenails of adult patients with moderate to severe onychomycosis. [Poster 1823]. Presented at the 65th Annual Meeting of the American Academy of Dermatology; February 2-6, 2007; Washington, DC.
19. Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, et al. The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis. J Drugs Dermatol. 2014 Sep;13(9):1124-32.
20. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015 Jul;73(1):62-9.
21. Kerydin^™ (tavaborole) topical solution, 5% [Full prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; revised July 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf. Accessed September 20, 2015.
22. Jo 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.

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

Introduction

Onychomycosis is a common nail disorder for which successful treatment can be clinically challenging. The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also increase the risk of co-morbid onychomycosis infection including diabetes, peripheral vascular disease, HIV, immunosupression, obesity, smoking, and increased age.^1-5 Onychomycosis has traditionally been treated by oral and topical antifungals that often yield low to moderate efficacy.⁶ Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^7-8 Efinaconazole, a sterol 14α-demethylase inhibitor, is an emerging antifungal therapy for the topical treatment of onychomycosis, which has shown greater efficacy in vitro than terbinafine, itraconazole, ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds.⁹ Further, it may be a useful adjunct to oral and device-based therapies, during the main course of treatment, and as a subsequent maintenance therapy to prevent reinfection.

Background

• Onychomycosis is a fungal infection of the nail apparatus.¹⁰ It is primarily caused by dermatophytes, yeasts and non-dermatophyte molds.
• Keratinolytic dermatophytes infect and colonize the nail plate, bed, and matrix.¹¹ This may cause symptoms such as onycholysis, discoloration, and thickening of the nail plate.¹¹
• Onychomycosis needs to be treated 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 like diabetics and the immunosuppressed.^2,12
• 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.¹³
• Problematically, all of the oral drugs suffer from a potential for systemic adverse events and drug interactions.¹⁴
• 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, these individuals are the most susceptible to health complications if left untreated.
• Existing topical antifungals are not associated with adverse events to the same extent as oral therapy, as they rarely penetrate the systemic circulation and gain a significant concentration in the body.
• The topical antifungals available in the past were less widely used because their poor penetrance into the nail plate results in correspondingly poor mycological and complete cure rates.¹⁵
• The ideal topical antifungal would have a higher nail plate penetrance than existing drugs but maintain the advantage of minimal systemic uptake.^15,16

Diagnosis of Onychomycosis Caused by Dermatophytes

• • Diagnosing onychomycosis on clinical grounds alone is challenging; therefore, correlation with mycological evidence remains critical for an accurate diagnosis.¹⁷
  • Definitive laboratory criteria include positive microscopic evidence of septate hyphae and/or arthroconidia (KOH preparation, Calcofluor white, Sigma-Aldrich, St Louis, Mo), periodic acid Schiff, and/or biopsy, and positive fungal culture findings for dermatophytes (Trichophyton, Epidermophyton, or Microsporum species) or certain nondermatophyte nail pathogens (eg, Scytalidium dimidiatum and S hyalinum).¹⁷
  • The primary criteria for clinical diagnosis are:¹⁷
    • White/yellow or orange/brown patches or streaks
  • Secondary criteria are*
    • Onycholysis
    • Subungual hyperkeratosis/debris
    • Nail-plate thickening

* Tinea pedis often occurs concomitantly with pedal onychomycosis, and tinea manuum with infected fingernails.

• Laboratory diagnostic criteria are:¹⁷
  • Positive microscopic evidence
  • Positive culture of dermatophyte
• If onychomycosis is suggested based on clinical observation, diagnostic laboratory tests should be performed. If these produce negative findings, they should be repeated.

Treatment

• The primary aim of treatment is to eradicate the organism as evidenced on microscopy and culture.¹⁸

Oral Therapies Approved in Canada

• There are two oral therapies currently approved for use in Canada:
  1. Terbinafine 250mg/day for 12 weeks
  2. Itraconazole pulse therapy: for dermatophyte onychomycosis
     • 1 pulse = 200mg twice daily for 1 week on, 3 weeks off.
     • 3 pulses are standard for toenail onychomycosis.
• Oral therapies provide access to the nail bed and matrix of all toes; both terbinafine and itraconazole may persist in nails for long periods after treatment.
• Oral therapy can also treat concomitant skin infections such as tinea pedis.
• Current prescribing information should be consulted for contraindications and monitoring requirements.
• Liver function testing should be done prior to therapy, and periodically during therapy.

Topical Therapies Approved in Canada

• Ciclopirox nail lacquer 8%, once daily for 48 weeks.¹⁰
• Adverse events are few, with mild localized reactions at the application site.
• It may not provide adequate penetration where nails are thick or severe onycholysis is present.
• Efinaconazole 10% topical triazole antifungal was approved by Health Canada in October 2013.

Efinaconazole, A New Topic Antifungal

• Efinaconazole is a topical triazole antifungal developed specifically for the topical treatment of distal and lateral subungual onychomycosis (DLSO).¹⁹
• Efinaconazole expands on the success of the existing triazole antifungals, while being intentionally formulated to more effectively penetrate the nail plate.²⁰
• Additionally, because it is a solution, there is no product build-up and removal time.

In Vitro Efficacy

• Efinaconazole is an inhibitor of sterol 14α-demethylase (14-DM).²¹
• In broth dilution tests in vitro against reference strains, efinaconazole was more potent than terbinafine, ciclopirox, itraconazole and amorolfine.⁹
• The efficacy of efinaconazole was comparable in clinical isolates of T. mentagrophytes and T. rubrum from Canada, the USA and Japan.
• The high in vitro efficacy of efinaconazole against the reference strains suggests that the agent would be effective in onychomycosis should the formulation provide sufficient nail penetrance.

Clinical Efficacy

• A randomized, parallel-group, double-blind, vehicle-controlled, Phase II clinical trial of efinaconazole was conducted at 11 sites in Mexico.²² This initial trial compared the use of 10% solution, 5% solution and 10% solution with semi-occlusion in a 2:2:2:1 ratio with placebo. The treatment period was 36 weeks with a 4 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 1). Efinaconazole 10% solution without semi-occlusion was the most effective treatment for all outcomes measured.
• Recently, two parallel, double-blind, randomized, controlled, Phase III trials of efinaconazole 10% nail solution (ENS) were completed.¹⁹ Trial participants applied ENS daily for 48 weeks followed by a 4-week wash-out period. Trial outcome measures were evaluated at week 52. Results demonstrated that ENS was superior to vehicle for all outcome measures. The primary outcome measure, complete cure for efinaconazole, was 17.8% and 15.2% respectively in the two parallel studies.
• The mycological cure rates were 55.2% and 53.4% respectively. Table 1 shows a comparison of the mycological cure rates for efinaconazole, itraconazole, terbinafine and ciclopirox.^22-24 The mycological and complete cure rates for efinaconazole were comparable to oral itraconazole.

Safety and Adverse Events

• In Phase II, 76.9% of the ENS group experienced treatment associated adverse events (TEAEs) compared with 63.6% of vehicle.²²
• The main TEAEs associated with efinaconazole were blisters, contact dermatitis, erythema and ingrown nail, none of which resulted in study discontinuation.
• In the duplicate Phase III studies, the reporting rates for a single adverse event during treatment with efinaconazole were comparable to vehicle (S1: 66.0% vs. 61.0%; S2: 64.5% vs. 58.5%).²⁰
• The reported primary TEAEs 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 and vehicle groups respectively.
• Overall, efinaconazole showed low rates of treatment emergent adverse events.

Other Therapies

• Mechanical or chemical debridement lessens the burden of infection and may benefit any degree of onychomycosis; it can be performed in office, or by other healthcare professionals.

Combination Therapy

• Dual therapies: oral/topical, oral/debridement, or topical/ debridement.²⁶
• Triple therapies: oral/topical/debridement: Oral therapy combined with topical therapy can provide penetration of the nail plate from inside and out, which may increase the overall amount of antifungal medication reaching the infection, particularly where the nail is thickened, shows extensive onycholysis, has lateral or matrix involvement, or is a dermatophytoma.²⁶
• Debridement may increase access to the infection by topical medications.

Clinical Variables Affecting Treatment and Outcomes

Nail Disease Variables

• Number of nails affected
• Percentage of affected nail plate area
• Is it DLSO or another presentation?
• Infection confirmed as dermatophyte? (i.e., Trichophyton sp., Microsporum sp., or Epidermophyton sp.)
• Thickness of nails
• Is matrix (proximal nail fold) area involved in infection?
• Are lateral streaks or central spikes (dermatophytoma) present?

Patient Variables

• Presence of peripheral vascular disease
• Diabetes
• Age of patient
• Obesity
• Other co-morbid conditions, e.g., liver disease
• Oral drugs patient is using
• Compliance
• Drug insurance status
• Patient preference

Criteria for Onychomycosis Mycological and Complete Cures

• Criteria for a mycological cure are eradication of the fungus as confirmed by negative fungal culture and negative KOH examination.²⁷
• Criteria for a complete cure are mycological cure plus complete clearance.²⁸

Factors Affecting Treatment Failure and Recurrence29

• Poor adherence
• Poor absorption
• Immunosuppression
• Dermatophyte resistance
• Zero nail growth
• Concomitant disease
• Age >60 years
• Trauma/faulty biomechanics
• Moisture exposure
• Poor patient hygiene/footwear

Recurrence

• Patient education on recurrence is recommended, specifically:³⁰
  • One course of treatment may not produce the optimum results.
  • May require multiple courses of antifungals.
• Recurrence of onychomycosis is very common.
• If the patient experiences any signs of onychomycosis recurrence or tinea pedis, they should be treated immediately.
• Proper foot care may minimize the chance of recurrence.
• Due to the high rate of recurrence and relapse, even in completely cured individuals, long-term topical therapy is often recommended concurrently or following oral therapy.^7,8,31

Foot Care & Maintenance³²

• Wear footwear and cotton socks that minimize humidity.
• Replace or sanitize shoes and socks as they can be contaminated with the microorganism.
• Dry feet and interdigital spaces thoroughly after washing.
• Use footwear to avoid fungal transmission from shared public spaces such as swimming pools.
• Keep nails clean and cut short.
• Avoid sharing nail clippers or footwear.
• Bring their own nail clippers, files, and emery boards to the salon.
• Prevent further trauma to toenails (nonrestrictive footwear or orthotics).
• Wear rubber gloves with cotton liners to protect the fingernails in those persons who have hands immersed in water for long periods of time.
• Apply emollients on cracked skin to reduce further entry points for fungus.
• Control chronic health conditions such as diabetes mellitus or peripheral vascular disease.

Table 2: Simple treatment algorithm for dermatophyte toenail onychomycosis

Conclusion

Efinaconazole 10% solution is a significant advancement in the efficacy of topical therapy for onychomycosis. It has demonstrated good tolerability and as such, the increase in efficacy is not met with the increase in complications observed with oral drugs. The safety profile for participants treated with efinaconazole is good, with minimal and transient TEAEs that ceased upon conclusion of treatment and minimal contact sensitization. Used either as monotherapy or in addition to device-based or oral therapy, it offers a promising addition to the clinical management of onychomycosis.

References

1. Gupta AK, Gupta MA, Summerbell RC, et al. J Eur Acad Dermatol Venereol. 2000;
   14:466-469.
2. Gupta AK, Taborda P, Taborda V, et al. Int J Dermatol. 2000;39:746-753.
3. Gulec AT, Demirbilek M, Seckin D, et al. J Am Acad Dermatol. 2003;49:187-192.
4. Baran R. Clin Dermatol. 2011;29:54-60.
5. Döner N, Yasar S, Ekmekçi TR. Turk Derm. 2011;45:146-151.
6. Gupta AK, Uro M, Cooper EA. J Drug Dermatol. 2010;9:1109-1113.
7. Scher RK, Baran R. Br. J. Dermatol. 2003;149 Suppl 65:5- 9.
8. Tosti A, Piraccini BM, Stinchi C, et al. Dermatology (Basel). 1998;197:162-166.
9. Jo Siu WJ, Tatsumi Y, Senda H, et al. Antimicrob. Agents Chemother. 2013;[Epub ahead of print].
10. Zaias N. Onychomycosis. Arch Dermatol. 1972;105:263-274.
11. Welsh O, Vera-Cabrera L, Welsh E. Clin. Dermatol. 2010;28:151-159.
12. Gupta AK, Humke S. Eur J Dermatol. 2000;10:379-384.
13. Gupta AK, Paquet M, Simpson F, et al. Journal of the European Academy of Dermatology and Venereology: JEADV. 2013;27:267-272.
14. Shear N, Drake L, Gupta AK, et al. Dermatology. 2000;201:196-203.
15. Murdan S. Expert Opin Drug Deliv. 2007;4:453-455.
16. Murdan S. Expert Opin Drug Deliv. 2008;5:1267-1282.
17. Scher RK, Tavakkol A, Sigurgeirsson B, et al. J Am Acad Dermatol 2007;56:939-944.
18. Roberts DT, Taylor WD, Boyle J. Brit J. Dermatol, 2003; 148: 402-410
19. Elewski BE, Rich P, Pollak R, et al. J Am Acad Dermatol. 2012;[Epub ahead of print].
20. Suguira K, Sugimoto N, Hosaka S, et al. Antimicrob Agents Chemother. 2014;58: 3837-3842
21. Tatsumi Y, Nagashima M, Shibanushi T, et al. Antimicrob. Agents Chemother. 2013; 57:2405.
22. Tschen EH, Bucko AD, Oizumi N, et al. J Drugs Dermatol. 2013;12:186-192.
23. Janssen Pharma. SPORANOX® (itraconazole) Capsules. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf.
24. Novartis. LAMISIL (terbinafine hydrochloride) Tablets, 250 mg. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf. Accessed March 15, 2013.
25. Valeant. Penlac® Nail Lacquer (ciclopirox) Topical Solution, 8%. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21022s004lbl.pdf. Accessed March 15, 2013.
26. Gupta AK, Lynch LE. Cutis. 2004;74(1 Suppl):5-9.
27. Gupta MA. Gupta AK. Intl J of Derm. 2003;4:833-842
28. CRC Press. Onychomycosis: The Current Approach to Diagnosis and Therapy: Baran R, Hay R, Haneke E, Tosti A. 1999. 0000415385792: 405.
29. Westerberg DP, Voyack MJ. Am Fam Physician. 2013;88:771-772.
30. Pariser D, Scher RK, Elewski B, et al. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S13-14
31. Arrese JE, Piérard GE. Dermatology. 2003;207:255-260.
32. Miller P. Skin Disorders: Fungal Nail Infections. Available at: https://www.etherapeutics.ca/ Accessed June 10 2014.

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.

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.

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.

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. Jo 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.
12. 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.
13. Sporanox® (itraconazole) capsules [package insert]. Revised April 2012. Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ.
14. Lamisil® (terbinafine hydrochloride) tablets, 250 mg [package insert]. March 2011. Novartis Pharmaceuticals Corporation, East Hanover, NJ.
15. Penlac® nail lacquer (ciclopirox) topical solution, 8% [package insert]. July 2006. Dermik Laboratories/ sanofi-aventis U.S. LLC, Bridgewater, NJ. Available at: http://products.sanofi.us/penlac/Penlac.pdf. Accessed November 24, 2013.
16. 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.
17. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
18. 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.
19. Arrese JE, Pierard GE. Treatment failures and relapses in onychomycosis: a stubborn clinical problem. Dermatology. 2003;207(3):255-60.

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

ABSTRACT

Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals, reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies.

Key Words:
antifungal, iontophoresis, laser devices, nails, onychomycosis, photodynamic therapy, ultrasound

Introduction

Onychomycosis is a common nail disorder that faces significant barriers to successful treatment. Etiologically, fungal pathogens such dermatophyte fungi, yeasts, and non-dermatophyte molds invade and colonize the nail plate, bed, and matrix creating an entrenched infection.^1-10 The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also confer an increased risk of co-morbid onychomycosis infection including diabetes,¹¹ peripheral vascular disease,¹¹ HIV,¹² immunosupression,^13,14 obesity,¹⁵ smoking,¹¹ and increased age.¹⁴ Many individuals have sustained infections persisting for months or years and, hence, they may not be motivated to initiate or complete therapy due to a perception that their condition is untreatable.

Onychomycosis has traditionally been treated by oral and topical antifungals¹⁶ that often yield low to moderate efficacy. Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^17,18 Successful treatment for onychomycosis requires antifungal drugs to penetrate the nail plate and nail bed, but incomplete dissemination to the lesion is a problem for both oral and topical agents. Antifungal drugs may be associated with adverse events that can cause patients to discontinue treatment and therapy may be complicated with the presence of a co-morbid condition.^19,20 Additionally, the extended course of treatment may discourage patient compliance, which poses a significant detriment to effective therapy. Thus, these factors can contribute to the suboptimal delivery of conventional therapy for onychomycosis.

Device-based therapies are promising solutions for the treatment of onychomycosis because they can mitigate some of the negative factors that contribute to treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis and ultrasound. Each of these techniques is a noninvasive procedure conducted by a medical professional, which reduces the need for long-term patient compliance. Photodynamic therapy, iontophoresis and ultrasound are used in combination with local pharmacological agents, thereby avoiding adverse effects associated with systemic antifungal therapy.

Laser Therapy

Laser treatment of onychomycosis infections uses the principle of selective photothermolysis.^21,22 Laser therapy is intended to exploit the differences in laser energy absorption and thermal conductivity between the fungal infection and the surrounding tissue. The absorption of light energy by the fungi results in the conversion of the energy into heat or mechanical energy.^21,22 Fungi are heat sensitive above 55°C, so absorption of laser energy that results in sustained photothermal heating of the mycelium (10+ minutes) is likely to result in fungicidal effects.^23,24 However, heating dermal tissue to temperatures above 40°C results in pain and necrosis; therefore, the laser energy format must either be pulsed to allow the dissipation of heat by the tissue through its superior thermal conduction or delivered at a moderate energetic level to prevent tissue damage. The exact mechanism of laser therapy is still under investigation, but it may combine direct fungicidal effects of the laser with induced modifications in the immune system or changes in the local microenvironment.

Laser therapy for onychomycosis is currently being studied in vitro and in vivo. In addition, at the time of this writing, the following lasers have been granted FDA marketing approval for the treatment of onychomycosis: PinPointe™ FootLaser™ (PinPointe USA, Inc.),²⁵ Cutera GenesisPlus™ (Cutera, Inc.),²⁶ Q-Clear™ (Light Age, Inc.),²⁷ CoolTouch VARIA™ (CoolTouch, Inc.),²⁸ and JOULE ClearSense™ (Sciton, Inc.).²⁹ The parameters of lasers that have been FDA cleared or tested and supported by publications for onychomycosis are summarized in Table 1. It is important to note that regulatory clearance of device systems are made on the basis of “substantial equivalence” to the technical specifications of pre-existing devices approved for marketing for onychomycosis, not on the basis of clinical trials data, so these systems cannot be directly compared to pharmacologic therapies.

Solid State Lasers

Solid state lasers use a solid crystal rod and they include many of the common commercial lasers such as the neodymium-doped yttrium aluminum garnet (Nd:YAG) and titanium sapphire (Ti:Sapphire) lasers. Solid state lasers may be built for use as continuous lasers or as pulsed lasers with pulse durations in the millisecond, microsecond, nanosecond, or femtosecond ranges. The maximum pulse energy increases as the pulse length decreases, so different pulse formats may result in greater nonspecific heating of the nail plate, or require longer treatment lengths to produce a fungicidal effect. The lasers that have been approved for the treatment of onychomycosis in North America have all been Nd:YAG lasers.

Long Pulse Laser Systems

Long pulse Nd:YAG lasers have received CE Marking in Europe (the mandatory conformity designation for marketed products in the European Economic Area), but they have not yet been approved to treat onychomycosis in North America.³⁰ The pulse duration for these lasers is in the millisecond range. These lasers can cause a high degree of non-specific heating and may need to be operated in the presence of a dedicated cooling system. The largest study of millisecond Nd:YAG lasers was conducted using the Fotona Dualis SP™ laser on 162 participants in Serbia.^31,32 Fungal infections in both fingernails and toenails were identified by potassium hydroxide (KOH) microscopy.³¹ Participants were treated with a 30-40 J/cm² energy fluence with a spot size of 4 mm and a pulse duration of 35 ms in the presence of cold air cooling.³¹ The nail plate was treated in a spiral pattern. A 2 minute wait period was observed before repeating the laser treatment.³¹ Participants received 4 treatments at 1 week intervals and they were followed after therapy from 12-30+ months. A completely clear nail plate was achieved by 93.5% of participants.³² The Fotona Dynamis™ family of laser systems has the same technical parameters as the laser used in the studies described above and has received marketing clearance in Europe.

Short Pulse Laser Systems

The first two lasers that were sanctioned by the FDA for the treatment of onychomycosis (PinPointe™ FootLaser™ and Cutera GenesisPlus™) are both flashlamp pumped short pulse Nd:YAG 1064 nm lasers.^25,26 The CoolTouch VARIA™ laser is the most recent addition to this class of devices.²⁸ These lasers emit 100-3000 µs pulses with an energy fluence of 25.5 J/cm² for a 1 mm spot size.^25,26,28 The PinPointe™ FootLaser™ was used in an initial phase I/II clinical trial.³³ Seventeen participants demonstrating great toenails afflicted with onychomycosis were enrolled and randomized into treated (n=11) or untreated (n=6) groups. Participants received a single treatment and were followed-up at 3 and 6 months. At the 6 month time period, 11 of 14 treated toes showed improvement in clear linear nail growth. Clinicaltrials.gov reports that a phase III clinical trial for the PinPointe™ laser (NCT00935649) was completed on November 29, 2010, but the data from this study remains unpublished.³⁴ Cutera has released a white paper on the GenesisPlus™ laser³⁵ that reported a 70% improvement rate in the 7 participants treated with 2 sessions of laser therapy. The JOULE ClearSense™ laser was tested in an initial trial of 21 patients.³⁶ Onychomycosis was confirmed by culture and periodic-acid schiff (PAS) microscopy. Patients were treated 4 times, at 1 week intervals with a pulse length of 0.3 ms, an energy fluence of 13 J/cm², and a repetition rate of 6 Hz. Follow-up mycological culture was negative in 95% of patients.³⁶ Clinical trials data for the CoolTouch™ laser has not yet been released.

An additional clinical study was published by Hochman et al. using a short pulse Nd:YAG laser system that has not been FDA cleared for onychomycosis.³⁷ This study confirmed active fungal infections in toenails and fingernails by culture or PAS stain. Participants were treated with a 223 J/cm² energy fluence with a 2 mm spot size for ≤45 seconds. Each subject received 2-3 treatments spaced at least 3 weeks apart. Antifungal cream was used daily where anatomically possible during this study. The efficacy of treatment was followed for between 4-6 months after therapy. Treatment resulted in negative mycological culture in 7 of 8 participants.

CoolTouch, Inc. is also conducting a clinical trial with a 1320 nm Nd:YAG laser (NCT01498393).³⁸ The CoolTouch CT3 Plus™ with the CoolBreeze Zoom handpiece can be operated in short pulse (450 µs) or continuous mode.³⁹ The handpiece has a pre-set temperature threshold that employs a cryogen cooling system.⁴⁰ Duration of the trial is 6 months and the inclusion criteria require patients to have a fungal infection on both great toenails.

Q-switched Laser Systems

Q-switched lasers have a pulse duration in the nanosecond range and they emit the highest peak power per pulse of all the Nd:YAG lasers. In vitro, an energy fluence of 4 J/cm² optimally inhibited Trichophyton rubrum (T. rubrum) colony growth.⁴¹ The Light Age Q-Clear™ is a FDA-cleared Q-switched Nd:YAG 1064 nm laser.²⁷ The FDA 510(k) summary for this laser device states that “Light Age, Inc.’s study of 100 randomized subjects of both genders,including Caucasian, Asian, African American, and Latino, has demonstrated substantially effective clearance of dystrophic toenails having a clinically apparent diagnosis of onychomycosis. Statistical analysis of results indicates significant apparent clearing in 95% of the subjects with an average clearance of affected areas of 56 ± 7% at 98% level of confidence.”²⁷

Modelocked Laser Systems

A modelocked femtosecond pulsed Ti:Sapphire laser tuned to 800 nm was used in an in vitro study on T. rubrum.⁴² Nail clippings were obtained from participants with onychomycosis and the fungal infection was confirmed by culture (n=99). The cultures were irradiated with a Ti:Sapphire laser that was pumped by a solid-state laser, which emitted 200 fs pulses at a frequency of 76 MHz through a variety of numerical apertures from 0.12 to 0.45. Treatment with energy above 7×10³¹ photons m^-2 s^-1 resulted in a 100% fungicidal effect.

Near Infrared Diode Lasers

Diode lasers use semiconductors for the optical gain medium as an alternative to solid crystals. The diode lasers that are currently under investigation for onychomycosis operate at near infrared wavelengths. The Noveon® laser (Nomir Medical Technologies) is an 870 nm and 930 nm dual wavelength diode laser.⁴³ In vitro studies have shown that 870 nm and 930 nm wavelengths photoinactivate T. rubrum and Candida albicans, and have a minimal negative effect on cultured fibroblasts.⁴⁴ Preliminary trials for the Noveon® laser have been conducted.⁴² Distal and lateral subungual onychomycosis was confirmed by culture or PAS stain and each participant received 4 treatments on days 1, 14, 42 and 120. Each treatment comprised 4 minutes of dual wavelength therapy, followed by 2 minutes of 930 nm treatment. At 180 days, the participants showed an 85% improvement of infection in 26 toes treated.⁴³ The status of the phase II and II/III trials for the Noveon® laser in onychomycosis (NCT00771732 and NCT00776464) remains unknown.^45,46

ConBio Inc. has registered a single assignment, open label clinical trial (NCT01452490) for a near infrared diode laser.⁴⁷ The V-Raser® laser is a 980 nm near infrared diode laser that has previously been marketed for the removal of vascular lesions. The study aims to enroll 50 participants at two podiatric practices in the United States. Participants will receive 4 laser treatments at 6 week intervals.⁴⁷

Photodynamic Therapy

Photodynamic therapy (PDT) uses visible spectrum light to activate a topically applied photosensitizing agent, which generates reactive oxygen species that initiate apoptosis. Photodynamic therapy was originally optimized for actinic keratosis, but photosensitizers can also be absorbed by fungi.^48,49 The effects of various photosensitizing agents have been studied in vitro and in vivo. These include 5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), and 5,10,15-tris (4-methylpyridiuium)-20-phenyl-[21H,23H]-porphine trichloride (Sylsens B).

Heme Biosynthesis Intermediates – ALA and MAL

ALA and its methyl ester MAL are heme precursors. They cause a build-up of protoporphyrin IX (PpIX), which is a photodynamically active molecule. In the presence of the correct spectrum of light, PpIX generates reactive oxygen species that initiate apoptosis.⁵⁰ Both of these drugs are commercially available for the treatment of actinic keratosis. Several studies have tested these formulations in small studies on participants with onychomycosis (Table 2).^51-54 These studies are heterogeneous, preventing any form of direct comparison; however, these investigations have shown promising initial results, but their small sample sizes (n>30) limit our ability to draw conclusions on the efficacy of this mode of therapy. The protocols developed for these studies indicate that the nail plate should be pre-treated with urea ointment to soften the nail plate prior to application of the photosensitizer.

Non-Heme Porphyrins – Sylsens B

Sylsens B is a non-heme porphyrin that has been used for in vitro studies on T. rubrum. PDT with Sylsens B is fungicidal in T. rubrum suspensions of both hyphae and microconidia at concentrations above 10 µM.^49,55,56 PDT with Sylsens B is also fungicidal when T. rubrum is adhered to keratinized structures.⁵⁷ In vitro experiments determined that ultraviolet-A (UVA-1) light is fungicidal in commercial strains and clinical isolates of T. rubrum, so it was an ideal excitatory light source for PDT.⁵⁸ The clinically isolated strain required a higher dose of Syslens B (9 µM) than the commercial strain (1 µM) using a UVA-1 energy fluence of 18 J/cm².⁵⁸ Sylsens B has not yet been tested in vivo.

Iontophoresis

Iontophoresis is a technique that uses a low level electrical current to increase the transport of drugs across semi-permeable barriers. The limitation of many topical treatments for onychomycosis is their inability to fully penetrate the nail plate.⁵⁹ This technique may be more successful in incorporating the drug into the nail plate and passing it through the plate to ensure that it penetrates the nail bed and matrix. Iontophoresis is currently being optimized for terbinafine, because it has the highest antifungal effect on dermatophytes in vitro.⁶⁰ There are two iontophoresis devices currently in clinical trials.

Iontophoresis increases the amount of terbinafine accumulated in the nail plate over the uptake from a passive source.^61-67 The nail plate then acts as a reservoir of terbinafine that is then released into the nail bed and matrix over 60-70 days.^62-65,67 The drug uptake during iontophoresis can be enhanced after removal of the dorsal layer of the nail plate, or in the presence of keratolysis.⁶⁴ The devices by NB Therapeutics were effective at targeting the nail plate exclusively and both the nail plate and surrounding skin.⁶³ The iontophretic device (Electrokinetic Transungual System) by Transport Pharmaceuticals was registered in a phase I clinical trial (NCT00768768) that has since been completed, but the data remains unpublished.⁶⁸ A phase II clinical trial is also ongoing in North America (NCT01484145).⁶⁹

The Power Paper iontophoretic patch device was used in a single preliminary trial of 38 participants.⁶¹ Infections were confirmed by both KOH examination and mycological culture. The participants were randomized into two groups for the treatment of a single great toenail. The first group received terbinafine iontophoresis with a current density of 100 µA/cm². The second was treated with the terbinafine gel patch without iontophoresis. The participants wore the patch overnight, every day for 4 weeks. After the initial visit, two further iontophoresis treatments were conducted. Follow-up occurred at 8 weeks and 12 weeks. At the final follow-up, 84% of participants demonstrated a mycological cure confirmed by KOH microscopy.

Ultrasound Drug Delivery System

The most recent development in device-based treatments for onychomycosis is an ultrasound mediated nail drug delivery system.⁷⁰ This system has been tested in a canine nail model. The intent was to determine which period of 1.5 W/cm² ultrasound treatment increased the nail uptake of a blue dye. Findings showed that the 120 second period was the most effective, increasing dye permeability by 1.5 fold. Further studies will be required to determine if this technique is suitable for existing antifungal drugs.

Conclusion

Device-based therapies for onychomycosis show promise in initial clinical studies involving lasers, photodynamic therapy, iontophoresis, and ultrasound-based therapy. Device-based treatments may be advantageous because they are conducted in the clinic and only require short-term patient compliance. These modalities also have the potential to reduce adverse events caused by antifungal drugs, as they are highly localized treatments. Devices may also be alternatives for patients whose susceptibility to onychomycosis infection arises from a co-morbidity, as these therapies do not interact with the drugs involved in the management of such conditions.^{65, 66} In order to substantiate the efficacy of device-based therapies for onychomycosis, randomized controlled trials with mycological evaluation and long-term follow-up are required. We believe this therapeutic area will continue to expand and hope that broader clinical investigations will result in new options for practitioners.

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