¹Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest:
Joseph Lam has served as an advisory board member for Bausch Health, Leo Pharma, Pfizer Canada and Sanofi-Genzyme.
He is on the speaker’s bureau for Pfizer Canada. He has received a research grant from the Eczema Society of Canada. Aryan Riahi has no conflicts to declare.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory condition marked by pruritus and traditionally treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole 2% ointment (a topical phosphodiesterase-4 inhibitor) is a newer topical agent for the treatment of AD. Crisaborole is indicated for treating mild-to-moderate AD and evidence from phase 3 and phase 4 trials show that crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age. The most common side effects are pain and paresthesia at the application site. Treatments with tolerable safety profiles such as crisaborole may provide an alternative to patients with TCS phobia. The role of crisaborole in AD therapy may become clearer as multiple phase 4 trials are currently underway and their results are poised to answer more questions, including its safety profile for patients as young as 3 months of age, potential use as a steroid-sparing agent, and direct comparisons to TCS and TCI, which are the current mainstay treatments of mild-to-moderate AD.

Key Words:
crisaborole, Eucrisa, atopic dermatitis, eczema, topical treatment, phosphodiesterase-4 inhibitor, corticosteroids

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, and inflammatory condition affecting the skin. Clinical features include xerosis, oozing, crusting, and erythema. Pruritus is a hallmark manifestation of AD that can cause frequent scratching, leading to skin infections and lichenification.¹ The face, scalp and extensor surfaces are commonly involved in infancy, while there is prominent flexural involvement in older children and adults.² While some patients experience resolution by adolescence, others have symptoms that persist into adulthood.³ AD has been estimated to affect 15-30% of children and 10% of adults in industrialized nations.⁴ The economic burden of AD has been estimated to be $3.8 billion per year.⁵ Due to the chronic nature of AD and limitations of current available topical agents, especially for pediatric use, there remains an unmet need for novel AD therapies to address long-standing treatment gaps. Crisaborole 2% ointment (Eucrisa™) is a Health Canada and US FDA-approved topical phosphodiesterase-4 (PDE4) inhibitor for treating mild-to-moderate AD. Evidence from phase 3 and 4 trials demonstrate crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age.⁶

Overview: Diagnosis and Pathogenesis

The diagnosis of AD is clinical. Skin biopsy and laboratory testing such as serum immunoglobulin E (IgE) levels are not routinely performed in the evaluation of suspected AD, but may be useful in ruling out other skin conditions.⁷ Adverse impacts from AD are wide ranging and include impairments to general health, quality of life, and mental health, with the financial cost of disease management posing a significant concern for patients and their families. Scratching may expose patients to secondary infections, which can exacerbate the severity of AD.⁸ The differential diagnosis for AD includes irritant or allergic contact dermatitis, serborrheic dermatitis, psoriasis, and scabies. Intractable, chronic itch is a hallmark of AD. Scratching may expose patients to secondary infections, which can exacerbate the disease severity.⁶

The pathogenesis of AD is determined by numerous factors including abnormalities in the skin barrier, a skewed T helper type 2 (Th2) immune response, impaired innate immunity, and changes in the resident microbial flora of the skin.⁹ The epidermis of patients with AD is prone to increased transepidermal water loss.¹⁰ The filaggrin (FLG) protein, which is produced by keratinocytes and encoded by the FLG gene, serves a critical role in skin barrier formation.¹¹ Patients with AD have lower levels of expression of skin barrier-related proteins including FLG-2, corneodesmosin, and enzymes necessary for skin hydration and water retention at the stratum corneum.¹² In addition to a barrier defect, the underlying immune system is also dysregulated in patients with AD. The innate immune response depends on toll-like receptors, which are stimulated by tissue damage and microorganisms, and enhance the strength of tight junctions to prevent allergen and microorganism penetration.¹³ Grouping patients with AD into one endotype may be overly simplistic. AD has a variety of endotypes depending on age groups, ethnicities, FLG mutations, and IgE levels.¹⁴ These include Asian versus European American, adults versus children, and presence or absence of family history of FLG mutations.¹⁴ Since increased Th2 cell levels are common across the spectrum of AD, targeting this factor should theoretically be therapeutic for all phenotypes of AD. However, phase 3 trials of dupilumab, an interleukin (IL)-4 and IL-13 blocker targeting the Th2-mediated pathway, was only able to reduce the Investigator’s Global Assessment score of patients down to 1 or 0 in 36-38% of cases.¹⁵ This suggests that other immune mediators outside of Th2 cells may be involved in the pathogenesis and treatment of AD.

Treatment Options for Atopic Dermatitis

The goals of treatment for AD are to achieve symptom reduction and prevent exacerbations. This approach is balanced with minimizing the risks of therapy. The mainstay therapy of AD is topical corticosteroids (TCS).¹⁶ An alternative to TCS is topical calcineurin inhibitors (TCI). Both treatments elicit potential side effects if used improperly. The face and skin folds are areas at high risk for atrophy with inappropriate use of TCS. High potency TCS also pose the risk of systemic toxicity, such as adrenal suppression in pediatric populations, especially if used under occlusion, e.g., diapered area.^17,18 TCI medications such as topical tacrolimus ointment and pimecrolimus cream do not carry the risk of skin atrophy, but may burn and sting on application. Patient education is needed as topical tacrolimus and pimecrolimus come with an FDA black box warning for increased risk of malignancies such as lymphoma.^19,20 Since the regulatory manadate to include the black box warning was institued in 2005, there has been mounting evidence to support the safe use of TCIs and the increased risk of malignancy remains theoretical. Prior to topical crisaborole, no new topical molecules have been approved to treat AD over the last 15 years.

Severe AD may warrant the use of ultraviolet-B (UVB) phototherapy or systemic immunosuppressant therapy such as cyclosporine, methotrexate, or mycophenolate mofetil when the patient is refractory to topical treatments.²¹ In 2019, both the FDA and Health Canada approved dupilumab for treating patients with AD >12 years of age who suffer from moderate-to-severe AD when topical therapies are ineffective or not advised.^22-24 Dupilumab is a fully human monoclonal antibody that binds to the IL-4 receptor and inhibits signaling of IL-4 and IL-13.²⁵

Crisaborole 2% is a topical PDE4 inhibitor indicated for the treatment of mild-to-moderate AD. Studies have shown that crisaborole 2% ointment improves AD signs such as exudation, excoriation, lichenification, and especially pruritus. Unlike TCS and TCI therapies, systemic exposure to crisaborole is limited.²⁶ The most common side effects are pain and paresthesia at the application site.²⁷

Crisaborole‘s Mechanism of Action

Crisaborole inhibits the action of PDE4. Pharmaceutical interest in phosphodiesterase enzymes, including crisaborole, was sparked by their role in nucleotide signaling pathways, leading to the development of specific novel inhibitors.²⁸ Elevated PDE4 enzyme levels have been associated with a chronic inflammatory state.²⁹ Since PDE4 is expressed by immune cells and keratinocytes, inhibition of PDE4 increases intracellular levels of cyclic adenosine monophosphate (cAMP) which inhibits the nuclear factor kappa B (NF-kB) pathway and the release of tumor necrosis factor (TNF)-alpha and pro-inflammatory cytokines that have a causal role in AD and psoriasis.²⁹

Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively.³⁰ Systemic exposure and risk of adverse effects from crisaborole is generally avoided due to the molecule’s rapid metabolism to inactive metabolites that do not affect cytokine release or the activity of PDE4.²⁹

Completed and Ongoing Studies of Crisaborole

Crisaborole’s safety profile and efficacy has been evaluated through 2 double-blind vehicle-controlled controlled phase 3 clinical trials. These studies assigned patients aged 2 years and older with mild or moderate AD as per Investigator’s Static Global Assessment (ISGA) scoring for treatment with either 2% crisaborole ointment or vehicle for 28 days. Results collected on day 29 demonstrated that 51.7% of patients receiving crisaborole had an ISGA of clear (0) compared to 40.6% of vehicle-treated patients (P = 0.05) and 48.5% of patients had ISGA of almost clear (1) compared to 29.7% of those treated with vehicle (P < 0.001).⁷

Two randomized, double-blind, vehicle controlled phase 3 studies with 759 and 763 participants demonstrated that crisaborole improves pruritus compared with vehicle (56.6% vs. 39.5%; P < 0.001) as early as day 2 of therapy (34.3% vs. 27.3%; P = 0.013).³¹

TCS are routinely used as therapy for flare-ups in AD.³² However, only short-term TCS use is recommended to minimize local and systemic adverse effects such as striae, telangiectasia, cutaneous atrophy, and acne.³³ As for TCI, both Health Canada and FDA initially advised against the use of long-term TCI therapy due to the unclear risk of malignancy.^19,20 Health Canada has subsequently removed the black box label for primecrolimus.³⁴ However, patients may continue to be apprehensive about using TCIs given their previous black box labeling. More research, including investigations on long-term maintenance, is needed to determine optimal topical treatment options for AD with favorable safety profiles. There is a phase 3 randomized, double-blind, vehicle-controlled study being conducted with 700 patients with mild-to-moderate AD.³⁵ Patients will receive crisaborole twice a day for a maximum of 8 weeks to identify responders, defined as ISGA score of 0 or 1 with 2-grade improvement from baseline or 50% improvement from baseline based on Eczema Area and Severity Index (EASI50) scoring. Non-responders will be discontinued after the 8-week run-in period. Maintenance treatment consists of once daily administration of crisaborole QD. Flares defined as ISGA ≥2 will be treated with twice daily crisaborole for up to 12 weeks. Completion of the trial is anticipated by July 2022.³⁵

The efficacy and safety profile of crisaborole is currently being investigated in phase 4 trials. A randomized, double-blind, vehicle-controlled study is evaluating the efficacy and safety of 3 different application rates of crisaborole ointment 2% in adults with mild-to-moderate AD.³⁶ Each patient will have 4 application areas and receive 1 of 4 treatments ranging from vehicle to 3 different application rates of crisaborole. Patients will be randomly assigned to treatment with topical crisaborole (application rates A, B, or C) or vehicle, once daily, for 2 weeks. The results of this study, with a projected completion of June 2020, may demonstrate whether the efficacy and safety of crisaborole is dose dependent. The results may be compared and contrasted with TCS use, which has a well-known dose dependent effect (e.g., anti-inflammatory effects at lower doses, immunosuppressive activity at higher doses) as well as dose dependent adverse effects (e.g., ecchymosis, parchment-like skin, and sleep disturbances).³⁶

Long-term topical treatment is often required for the management of a chronic inflammatory skin conditions like AD. Crisaborole’s long-term safety was evaluated in an open-label extension study of 517 patients with mild-to-moderate AD who used crisaborole for 48 additional weeks after the 28-day phase 3 study. The most frequently reported treatment related adverse effect (AE) were AD (3.1%), pain at the site of application (2.3%), and localized infection (1.2%).²⁷

The treatment options for patients under 2 years of age with AD are sparse. Pimecrolimus has recently been approved for infants as young as 3 months.³⁷ However, having a wider array of therapeutic strategies would be ideal for this demographic. A phase 4 multicenter, open-label, single arm investigation called the CrisADe CARE 1 study evaluated the safety, efficacy, and pharmacokinetics of crisaborole 2% ointment applied twice daily on 125 pediatric patients between 3-24 months of age.³⁸ These patients had extensive AD involving at least 5% of body surface area (BSA) except for the scalp. A total of 29.93% of patients reported non-serious AEs. The most common side effect was pyrexia (9.49%). The study found a total of 1 (0.73%) serious AE involving a febrile convulsion. The study did not comment on whether this AE was related to the use of crisaborole. No deaths occurred. This study is the first to evaluate the safety profile of crisaborole in children less than 24 months of age.

Crisaborole may have the potential of decreasing steroid use in patients with AD. Side effects of TCS can range from cutaneous atrophy to suppression of the hypothalamic-pituitary-axis.³⁹ Misunderstandings and steroid phobia can interfere with patient compliance, which in turn negatively affect disease control.⁴⁰ Currently, a proof-of-concept phase 4 clinical trial with 60 children between 2-18 years with mild-moderate AD is underway to determine whether crisaborole is an effective steroid reducing agent. The trial will be completed by November 2020.⁴¹ Similarly, a single-center observational prospective cohort study aimed to evaluate the efficacy and safety profile of crisaborole ointment 2% and a TCI versus crisaborole alone over 8 weeks. The study included participants aged 2-79 with mild-tomoderate AD and the projected completion was March 2020.⁴²

While high-quality phase 3 studies have demonstrated the efficacy of crisaborole compared to vehicle, head-to-head studies comparing crisaborole with TCS or TCI are needed to better define its role in the management of AD. A phase 4 multicenter, randomized, vehicle versus active (TCS and TCI) controlled study is being conducted on 600 patients with mild-to-moderate AD over 4 weeks to evaluate the safety and efficacy of crisaborole 2% ointment, crisaborole vehicle, TCS, and TCI applied BID in patients over 2 years of age.⁴³ Inclusion criteria include patients with AD involving at least 5% of BSA except for the scalp. The primary efficacy endpoint is change from the patient’s baseline in the EASI score by Day 29. The study will be completed by March 2021. This will be the first study to directly compare crisaborole to the current mainstay treatments of mild-to-moderate AD.

Conclusion

Crisaborole provides a novel and safe treatment option for mild-to-moderate AD. Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively but is inactivated and metabolized rapidly.³⁰ Crisaborole therapy has been shown to decrease pruritus, which disrupts the itch-scratch cycle that exacerbates signs of AD, improve quality of life, and decrease the risk of infection and scarring.⁴⁴ Adverse events related to crisaborole 2% are overall infrequent and range from mild-to-moderate in severity. Studies are currently underway to determine whether crisaborole can be used as long-term maintenance therapy for patients who respond to treatment. Furthermore, while crisaborole’s side effect profile is generally well tolerated, new head-to-head studies comparing crisaborole with TCS or TCI are underway to better define its role in the management of AD.

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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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Articles are indexed by drug names, trade names and disease terms. Bold entries refer to major references.

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