area of 20% to 65%. Patients with a history of immunosuppression or dermatophytomas, or “spikes” extending to the cuticle, were excluded. Ciclopirox lacquer was applied to the nail plate, nail bed, hyponychium, and 5 millimeters of adjacent skin daily. Patients were instructed not to wash their feet for at least 8 hours after application. In addition, patients were instructed to apply a new coat on top of the old one every day for 7 days prior to removing the lacquer with isopropyl alcohol.
After 48 weeks of treatment, patients were assessed for complete cure, defined as no (0%) nail involvement, negative fungal culture, and negative potassium hydroxide (KOH), and mycologic cure, defined as negative fungal culture and negative KOH regardless of percentage of nail involvement. At week 48, a complete cure was achieved by 5.5% and 8.5% in the ciclopirox groups vs 0.9% and 0.0% in the vehicle placebo groups. Mycologic cure was achieved by 29% and 36% in the ciclopirox group vs 11% and 9% in the vehicle groups.
Importantly, ciclopirox has limited nail penetration that likely results in its limited efficacy. Using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), Pinto et al demonstrated that 24 hours after application on mycosis-infected toenails, ciclopirox demonstrated a highly localized distribution in the uppermost layer of the nail plate compared with other antifungals that exhibited a more homogenous distribution and better penetration.14 There has been recent interest in developing novel formulations of ciclopirox to optimize nail permeation.15 Ultrasound technology is also being studied for enhancing ciclopirox delivery through nails.16
Ciclopirox has not been studied in pediatric populations, nor is it approved for use in children. At this time, ciclopirox is indicated for onychomycosis in patients aged >=12 years.
Tavaborole
Tavaborole 5% solution is the first oxaborole anti-fungal approved by the FDA. It inhibits the enzyme leucyl-transfer RNA synthetase (LeuRS), which is found in the cytoplasm and is critical in fungal protein synthesis.17 While LeuRS is also found in humans as it is a conserved macromolecule used for protein synthesis, tavaborole demonstrates more than 1000-fold greater selectivity for fungal LeuRS.18 Furthermore, given its low molecular weight, tavaborole is able to better penetrate through full-thickness human nail plates than ciclopirox, achieve minimum fungicidal concentration, and retain pharmacologic anti-fungal activity in the presence of keratin.19 Thus, unlike ciclopirox, nail debridement or removal of prior applications is not necessary. Furthermore, it is able to penetrate through nail polish while maintaining anti-fungal activity.20 Tavaborole 5% solution is approved in both adults and children aged >=6 years old.
Elewski et al reported 2 randomized phase 3 trials evaluating the efficacy of tavaborole 5% solution applied once daily for 48 weeks in adults with distal subungual toenail onychomycosis compared with vehicle.17 Subjects aged >=18 years with distal subungual onychomycosis involving 20% to 60% of at least one target great toenail (TGT) and confirmatory laboratory testing with positive KOH wet mount or fungal culture were eligible. Subjects with active tinea pedis, uncontrolled diabetes, dermatophytomas/spikes, or more severe or exclusively lateral disease were excluded. A total of 399 and 396 patients were treated with tavaborole compared with 194 and 205 with vehicle. Complete cure was achieved by 6.5% and 9.1% in the tavaborole treated groups compared with 0.5% and 1.5% in the vehicle treated groups. Mycologic cure was achieved in 31.1% and 35.95% in the tavaborole groups vs 7.2% and 12.2% in the vehicle groups. The most common treatment-related adverse effects were exfoliation, erythema, and dermatitis.
Elewski et al reported 2 randomized phase 3 trials evaluating the efficacy of tavaborole 5% solution applied once daily for 48 weeks in adults with distal subungual toenail onychomycosis compared with vehicle.17 Subjects aged >=18 years with distal subungual onychomycosis involving 20% to 60% of at least one target great toenail (TGT) and confirmatory laboratory testing with positive KOH wet mount or fungal culture were eligible. Subjects with active tinea pedis, uncontrolled diabetes, dermatophytomas/spikes, or more severe or exclusively lateral disease were excluded. A total of 399 and 396 patients were treated with tavaborole compared with 194 and 205 with vehicle. Complete cure was achieved by 6.5% and 9.1% in the tavaborole treated groups compared with 0.5% and 1.5% in the vehicle treated groups. Mycologic cure was achieved in 31.1% and 35.95% in the tavaborole groups vs 7.2% and 12.2% in the vehicle groups. The most common treatment-related adverse effects were exfoliation, erythema, and dermatitis.
Rich et al performed a phase 4 open-label single-arm study of tavaborole 5% solution in pediatric patients with distal subungual onychomycosis of the toenails.21 Inclusion criteria included ages 6 to 17 years and distal subungual onychomycosis affecting >=20% of the target great toenail. Tavaborole was applied once daily to all affected toenails for 48 weeks. At week 52, complete cure and mycologic cure rates were 8.5% and 36.2%, respectively. 14.9% achieved complete/almost complete cure (clear or almost clear nail [<=5% involvement] and negative mycology), and 87.2% had negative fungal culture only. Adverse events were reported by 55.6% of patients, with the most frequently reported being nasopharyngitis, sinusitis, and vomiting in addition to local reactions of erythema and scaling. Local reactions improved with continued applications and time. Notably, tavaborole was systemically absorbed with measurable plasma concentrations.
In addition, a single study by Gupta et al assessed post-treatment follow-up.22 This was a pooled analysis of the phase 3 data noted above for 62 patients that completed treatment at week 48 and were assessed at week 52 and week 60 (8 weeks post-treatment). Tavaborole-treated patients exhibited a complete cure rate of 28.6% vs 7.7% in the vehicle control group. This was an increase from 6.5% and 9.1% complete cure rate in the 2 phase 3 trials, suggesting continued disease severity reduction post-treatment.
Efinaconazole
Efinaconazole is a novel triazole with broad spectrum antifungal activity that is of greater potency than ciclopirox and further exhibits lower keratin binding and quicker release from keratin than ciclopirox.23,24 Formulation of efinaconazole with a vehicle containing alcohol, cyclomethicone, and lipophilic esters further contributes to these “keratin-phobic” properties.25 Its in vitro fungicidal activity is also superior to both ciclopirox and tavaborole in keratin-containing medium with ciclopirox not exhibiting activity and tavaborole being fungistatic.26 In vivo activity of efinaconazole is also superior to ciclopirox and tavaborole in a guinea pig model of onychomycosis.26 Efinaconazole is the first triazole created specifically for the topical treatment of mild-to-moderate toenail onychomycosis and is approved for patients aged 6 and older.
Two phase 3 double-blind, randomized, placebo-controlled trials of efinaconazole 10% solution applied daily for 48 weeks were conducted in 1,420 adults (aged 18-70) with mild-to-moderate toenail onychomycosis leading to the initial FDA approval.27 Unlike ciclopirox, neither debridement of the nail or subsequent removal of the topical medication were performed. Across the 2 studies, complete clinical cure rates at week 52 in the treatment groups were 17.8% and 15.2% compared with 3.3% and 5.5% in the placebo group, respectively. Complete mycologic cure rates were 55.2% and 53.4% compared with 16.8% and 16.9%, respectively. In a subsequent pooled analysis of the 2 trials, 22% of total participants with target nail involvement <40% had a complete cure rate vs 8% in the vehicle group at week 52.28 The treatment effect became statistically significant between efinaconazole and placebo at week 36 onwards.
In a subgroup analysis, efinaconazole complete cure rates were greater in females (27.1%) compared with males (15.8%) at week 52.28 Higher rates were also observed for mild (<33% involvement) onychomycosis compared with moderate (24.2% and 14.5%, respectively). The correlation between cure rates and disease severity was also recapitulated in another post hoc analysis by
