Aditya K. Gupta, MD, PhD1,2 and Elizabeth A. Cooper, BESc, HBSc2
1University of Toronto Department of Medicine, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada

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.

flow chart of schematic profile of study disposition
Figure 1: Schematic profile of study disposition
Efinaconazole 10% solution 18-month useEfinaconazole 10% solution 24-month useTotal number of Patients
Average age, years (Min, Max) <70 yo; ≥70 yo61 years (46, 77)
N = 13; 3		69 years (48, 82)
N = 14; 17		66 years (46, 82)
N = 27; 20
Average # of TN infected (Total number of TN affected)5.9 (94)4.6 (144)5.1 (238)
# of patients with FN involvement112/47 (4.3%)
Average area involved, %43%44%44%
Average LPE of infection, mm (Min, Max)2.6 mm (1, 8)3.1 mm (1, 7)2.9 mm (1, 8)
Avg nail thickness, mm (Max 3 mm)1.50 mm1.53 mm1.52 mm
Dermatophyte detectedTr: 15
Tm: 1		Tr: 26
Tm: 4
Tt: 1		Tr: 41
Tm: 5
Tt: 1
At least 1 TN cleared by M24
Total number of TN cleared
(% of affected TN cured)		14/16 (87.5%) 42/94 (44.7%)24/31 (77.4%) 54/144 (37.5%)38/47 (80.8%) 96/238 (40.3%)
Table 1: Demographics summary for patients completing to M24
M24 = month 24 of study; LPE = lowest proximal extent; TN = toenail; FN = fingernail; yo = years old; Tr = Trichophyton rubrum;
Tm = Trichophyton mentagrophytes; Tt = Trichophyton tonsurans

 

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).

Graph of mycological cure rates
Figure 2: Mycological cure rates
(negative KOH and negative culture)
Mycological cure rate, analyzed via KOH microscopy and fungal culture, of target great toenail subjected to once daily efinaconazole 10% topical solution (blue circle) or vehicle (orange triangle) at baseline and months 6, 12, and 18 for all patients. Month 24 data is from 31 patients to date who completed 24 months of treatment (striped circle).
Graph of effective cure rates of efinaconazole 10% topical solution use.
Figure 3: Effective cure rates
(≤10% clinical involvement of the target great toenail and MC)
Effective cure rate, determined via KOH microscopy, fungal culture, and visual analysis, of target great toenail subjected to once daily efinaconazole 10% topical solution (blue circle) or vehicle (orange triangle) at baseline and months 6, 12, and 18 for all patients. Month 24 data is from 31 patients to date who completed 24 months of treatment (striped circle).
Set of photos from 4 patients, showing the progress of toenail treatment
Figure 4: Subject efficacy photos Photos of target great toenail from four patients (rows 1-4) at baseline (column 1), month 12 (M12, column 2), and month 24 (M24, column 3).

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.

Serious Adverse Events (N = 9, in 8 patients)
Completed study:Myocardial infarction: 3
Bilateral pulmonary emboli: 1		Possible bradyarrhythmia: 1
Surgical repair of umbilical hernia: 1
Early termination:Lung cancer – terminal stage: 1 subject
Lost to follow-up:Blood clot in heart; accidental lorazepam overdose (2 events; 1 subject)
Possible efinaconazole 10% solution reactions – 8 patients with application site reactions

  • Mild to moderate grading of all reactions; typical symptoms – erythema, eczema, exfoliation and pruritus
3 patients, reactions starting from
M3/M6/M9 of active treatment:
mild-moderate		Efinaconazole 10% solution permanently withdrawn (ET-2 patients, 43 and 55 yo); 1 subject remaining in long-term safety FU only, (84 yo); resolution of symptoms after stopping efinaconazole 10% solution.
1 subject with mild toe web reaction,
M6, 48 yo		Attributed to poor application technique; efinaconazole 10% solution continued with more attention to application. Adverse event resolved. Efinaconazole 10% solution restarted daily.

  • Same subject developed application site reaction at M16 period; temporary interruption for healing; able to resume efinaconazole 10% solution daily use.
2 patients, reaction starting M0-M3 of
efinaconazole 10% solution treatment,
55 and 69 yo		Temporary interruption of efinaconazole 10% solution for healing; efinaconazole 10% solution restart with a return of symptoms and signs; intermittent use adopted to control symptoms, allow application to continue.

  • 1 of the patients (69 yo) also developed a similar FN application site reaction at M9; resolved upon stopping efinaconazole 10% solution. Efinaconazole 10% solution permanently discontinued from application to FNs.
2 patients, reactions after application site
trauma events1 – insect bite-M20, 74 yo;1 – hiking boot damage-M16, 57 yo		Symptoms resolved with efinaconazole 10% solution interruption;

  • Patient with insect bite had ‘cured’ nail prior to event, and remained ‘cured’, bite/reaction resolved; patient opted to stop efinaconazole 10% solution permanently;
  • Hiking trauma/reaction resolved, but efinaconazole 10% solution reaction returned upon restarting application – efinaconazole 10% solution permanently withdrawn.
Table 2: Safety events with long-term efinaconazole 10% solution use
M0/3/6/9/12/16 = month 0/3/6/9/12/16; yo = years old; ET = early termination; FU = follow-up; FN = fingernail

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.

graph of age vs. mycological cure of once daily efinaconazole 10% topical solution
Figure 5: Age vs. mycological cure
(negative KOH and negative culture)
Mycological cure rate, analyzed via KOH microscopy and fungal culture, of target great toenail subjected to once daily efinaconazole 10% topical solution by patients aged <70 years (closed circles) or ≥70 years (open squares) at baseline and months 6, 12, and 18 for all patients. Month 24 data is from 31 patients who completed 24 months of treatment, 14 patients <70 years old (striped circle) and 17 patients ≥70 years old (striped square).

 

Graph of Age vs. effective cure f target great toenail subjected to once daily efinaconazole 10% topical solution
Figure 6: Age vs. effective cure
(≤10% clinical involvement of the target great toenail and MC)
Effective cure rate, determined via KOH microscopy, fungal culture, and visual analysis, of target great toenail subjected to once daily efinaconazole 10% topical solution by patients aged <70 years (closed circles) or ≥70 years (open squares) at baseline and months 6, 12, and 18 for all patients. Month 24 data is from 31 patients who completed 24 months of treatment, 14 patients <70 years old (striped circle) and 17 patients ≥70 years old (striped square).

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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