New Topical Therapeutic Options in the Management of Superficial Fungal Infections

nail.²⁶ Efinaconazole is thought to reach the site of infection beneath the nail by 2 pathways: both transungual delivery²⁷ as well as spread through the subungual air space.²⁸ Finally, a study using cadaveric nails showed that nail polish did not interfere with penetration of efinaconazole 10% solution through the nail.²⁹

Two identical 52-week multi-center, randomized, double-blind, vehicle- controlled studies were performed to evaluate the safety and efficacy of efinaconazole 10% solution for the treatment of onychomycosis. In total, 1,655 patients were enrolled across the U.S., Canada, and Japan.30

Eligible patients were aged 18 to 70 years, and had mild to moderate distal lateral subungual onychomycosis of the great toenail, defined as 20% to 50% clinical involvement. The affected part of the nail had to be at least 3 mm from the proximal nailfold. In addition, nail thickness could be no more than 3 mm. Subjects were randomized 3:1 to receive either active drug or vehicle. Baseline demographic characteristics were evenly matched in the active vs vehicle arms. The mean patient age was 52.3 and 50.6 years in each study. The majority of enrolled patients were Caucasian males, and the mean area of the affected target toenail was 36.7% and 36.3% in the 2 studies.²⁹

The study protocol required participants to apply the study medication once daily for 48 weeks. They were then followed up in the study center for another 4 weeks, for a total of 52 weeks. No nail debridement was performed at any time point in the study. The study drug was brushed on to a clean, dry nail, covering the nail plate itself, along with the lateral and proximal nailfolds, hyponychium, and underside of the nail plate.²⁹

Efinaconazole 10% solution met all of the primary and secondary efficacy endpoints in the study. The primary efficacy variable was the complete cure at week 52, defined as a clinical cure of the target toenail (aka, 0% clinical involvement) in addition to a mycologic cure, defined as a negative KOH and negative fungal culture. At week 52, 17.8% of patients in the first study and 15.2% of patients in the second study achieved a complete cure on active drug, compared with only 3.3% and 5.5% of subjects using the vehicle (P<.001).²⁹

Secondary efficacy endpoints included the mycologic cure, complete or almost complete cure, and clinical efficacy at week 52. The mycologic cure was defined as a negative KOH and fungal culture, independent of clinical appearance. 55.2% and 53.4% of patients in studies 1 and 2 using efinaconazole achieved a mycologic cure compared with 16.8% and 16.9% of subjects on vehicle (P<.001). A complete or almost complete cure was defined as clinical involvement less than or equal to 5% of the nail in addition to a mycologic cure. 26.4% of patients in study 1 and 23.4% of patients in study 2 on efinaconazole achieved a complete or almost complete cure at week 52, vs only 7% and 7.5% of vehicle-treated patients (P<.001).²⁹

Efinaconazole was safe and well-tolerated throughout both studies. Adverse reactions that occurred during the 48 weeks of active treatment were generally mild to moderately severe, predominantly not related to study medication, and resolved without long-term effects. The discontinuation rate in the study was low. Only 2.6% and 0.2% of patients in the efinaconazole and vehicle groups, respectively, discontinued the study for any reason, the most common reason being an application site reaction to the drug.

Since the conclusion of the phase 3 clinical trials, several post-hoc analyses have been performed re-analyzing data from the original enrolled subjects under different parameters. Onychomycosis is frequently found in the setting of concurrent tinea pedis, and both conditions should be treated at the same time to minimize the risk of a cyclical re-infection.³¹ The presence and treatment of tinea pedis were not exclusion criteria from the phase 3 study program; thus, the onychomycosis patients with concurrent tinea pedis could treat the tinea pedis with topical antifungal agents during the study. When the tinea pedis was treated, the efficacy of the efinaconazole on the nails was actually found to be enhanced.³² In addition, when comparing short vs long-term nail disease, better improvements were seen when onychomycosis was treated early.³³ This should encourage practitioners to treat nail infections when they see them, rather than brushing them off as a cosmetic issue.

In looking at diabetic vs non-diabetic patients, no differences were observed in terms of the efficacy or safety of efinaconazole.³⁴ Moreover, no differences in safety or efficacy were observed between subjects over and below 65 years.²³ Finally, use of efinaconazole solution in the phase 3 studies provided significant improvement in all aspects of QOL. The most significant QOL improvements were observed in patients who had improvement in the clinical appearance of the nail, with the greatest QOL improvements reported by those who had improvement in the largest percentage of their nail.³⁵

Tavaborole topical solution 5% is a novel anti-fungal drug based on boron-based chemistry. This hydrophilic, small molecule is highly specific in targeting fungal cytoplasmic leucyl-transfer ribonucleic acid (tRNA) synthetase. This enzyme is important in fungal cellular