There have been many recent additions to the armamentarium— from new dosing protocols to new drugs—for treating onychomycosis and other fungal infections. And there are other potential new therapies on the way. Here, we'll review the latest research.
Luliconazole Cream 1%. In 2013, the FDA approved Luzu (luliconazole, Valeant) Cream, 1% for the topical treatment of inter-digital tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older. It is the first topical azole antifungal agent approved to treat tinea cruris and tinea corporis with a one-week, once-daily treatment regimen. All other approved treatments require two weeks of treatment. Interdigital tinea pedis is approved with a two-week, once-daily treatment.
In a Phase II study of luliconazole for the treatment of interdigital tinea pedis, complete clearance was achieved in 26.8 percent and 45.7 percent of subjects in the two-week and four-week treatment groups at two weeks post-treatment, respectively.1 The study found that the antifungal effect persisted several weeks post-treatment, resulting in increased rates of mycologic and clincal cure. Four weeks post-treatment complete clearance rates were 53.7 percent and 62.9 percent for the two-week and four-week treatment groups, respectively.
When comparing in vitro and in vivo antidermatophyte activities, luliconazole exhibited strong antifungal activity against Trichophyton spp— its minimum inhibitory concentration (MIC) was one to four times lower than that of lanoconazole or terbinafine.2 Seven-day topical therapy with 0.5% solution luliconazole was shown to be more effective than lanoconazole or terbinafine (0.5%). Only luliconazole achieved complete mycologic cure.
Naftifine Gel 2%. Last year, the FDA approved Naftin (naftifine HCl, Merz North America) Gel 2% for the treatment of interdigital-type tinea pedis. Naftin Gel 2% improves on the current formulation of Naftin Gel 1% by delivering the efficacy of naftifine hydochloride with a once-daily application treatment regimen. In clinical studies, Naftin Gel 2% demonstrated continuous improvement in post-treatment efficacy rates for up to four weeks after treatment regimen had ended.
Efinaconazole. Although the FDA rejected Valeant Pharmaceuticals' New Drug Application for efinaconazole for the treatment of onychomycosis in 2013, the questions raised by the FDA that precluded the approval pertained only to Chemistry, Manufacturing and Controls areas of the container closure apparatus. No efficacy or safety issues were raised by the FDA. Efinaconazole, a novel triazole antifungal agent, inhibits fungal lanosterol 14α-demethylase involved in ergosterol biosynthesis at concentrations below minimum inhibitory concentrations.3
Efinaconazole has been found to be 4.8 times more potent than itraconazole in inhibiting ergosterol biosynthesis in T. mentagrophytes and 7.3 times more potent than clotrimazole in C. albicans.
In a multicenter, randomized, double-blind, vehicle-controlled Phase II study investigating the efficacy and safety efinaconazole in distal lateral subungual onychomycosis (DLSO), 135 subjects were randomized in a 2:2:2:1 ratio to receive efinaconazole 10% solution (with or without semiocclusion), efinaconazole 5% solution, or vehicle, once daily for 36 weeks, with one four-week post-treatment follow-up. Efficacy assessments included complete cure, mycologic cure, clinical efficacy, and other At follow-up, complete cure was numerically higher in all active groups (16 percent to 26 percent) compared with vehicle (nine percent). Mycologic cure rates with efinaconazole 10% semiocclusion, efinaconazole 10%, and efinaconazole 5% were 83 percent, 87 percent, and 87 percent, respectively. Efinaconazole 10% (with or without semiocclusion) demonstrated significantly greater clinical efficacy and treatment effectiveness when compared with vehicle (P=.0088 and .0064; .0056 and .0085, respectively, for both efinaconazole 10% groups).4 It has also been shown that efinaconazole has a higher percentage of drug unbound to keratin resulting in greater cumulative nail permeation compared to ciclopirox.5
Tavaborole. Anacor Pharmaceuticals' NDA for tavaborole, a novel boron-based molecule for the topical treatment of onychomycosis, was accepted by the FDA in October 2013. The Prescription Drug User Fee Act (PDUFA) V goal date is July 29, 2014. The company announced that in two Phase III trials, tavaborole demonstrated better efficacy than ciclopirox lacquer, the only approved topical treatment for onychomycosis. Tavaborole achieved statistically significant and clinically meaningful results on all primary and secondary endpoints in both Phase III pivotal studies of tavaborole to treat onychomycosis topically without concomitant debridement (Table 1). Ciclopirox is currently approved to treat for onychomycosis with concomitant nail debridement.
Tavaborole represents a new class of antifungals. Tavaborole inhibits an essential fungal enzyme, leucyl transfer RNA synthetase, or LeuRS required for protein synthesis, which leads to termination of cell growth and cell death, eliminating the fungal infection. The inhibitory activity of tavaborole requires the presence of boron within the compound. Boron has an empty P-orbital and can form a new bond under specific conditions. The new bond forms a tetrahedral structure. Exploitation of P-Orbital expands drug design possibilities.
Econazole 1% Foam. Econazole foam 1% (Ecoza) is an antifungal for the treatment of interdigital tinea pedis. Econazole 1% Foam was found to be superior to vehicle foam in mycologic cure and treatment efficacy (Figure 1).
Ketoconazole. Ketoconazole Gel 2% (Xolegel) has the same side effect precautions as oral ketoconzole on the label, but it is doubtful that the side effects are the same. The FDA limited the use of ketoconazole oral tablets last year, warning that the oral tablets can cause severe liver injuries and adrenal gland problems and advising that it can lead to harmful drug interactions with other medications. The FDA approved label changes and added a new Medication Guide to address these safety issues. In some markets, the authors note, the Xolegel Brand is cheaper than generic.
Itraconazole. Itraconazole (Onmel) 200mg-dose tablets use Metrex technology to offer a convenient dose with enhanced bioavailability. The 200mg dose has the same active drug and the same warnings at the 100mg tablets. There is no A/B-rated generic substitute for Onmel. Studies of itraconazole 200mg found statistically significant efficacy across all endpoints compared to vehicle at Week 52 (40 weeks after the end of 12-week treatment). It is also noninferior to itraconazole capsules on complete cure of onychomycosis. Safety of itraconazole 200mg is comparable to two 100mg itraconazole capsules.6
This article is based on part of presentation on new drugs presented at the 2014 Winter Clinical Dermatology Conference, which took place January 17-22, 2014 in Hawaii.
Neal Bhatia, MD, FAAD is in private practice in San Diego, CA. Dr. Bhatia has affiliations with Affiliations with Bayer, Dusa, Ferndale, Galderma, Genentech, Leo, Onset, PharmaDerm, Promius, Quinnova, and Valeant Pharmaceuitcals.
Ted Rosen, MD is a Professor of Dermatology, Chief of Dermatology Service at Michael E. DeBakey Veterans Affairs Medical Center at Baylor College of Medicine in Houston, TX. Dr. Rosen has affiliations with Anacor, Galderma, Genentech, Merz, Pharmaderm, and Valeant Pharmaceuitcals.
- Jarratt M, Jones T, Kempers S, et al. Luliconazole for the treatment of interdigital tinea pedis: a double blind vehiclecontrolled study. Cutis 2013;91:203-210.
- Niwano Y, et al Antimicrob Agents Chemother 1998;42(4):967-970.
- Tatsumi Y, Nagashima M, Shibanushi T, Iwata A, Kangawa Y, Inui F, Jo Siu WJ, Pillai R, Nishiyama Y. Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother. 2013;57(5):2405-2409
- Tschen EH, Bucko AD, Oizumi N, H Kawabata, JT Olin, R Pillai. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2 multicenter, randomized, double-blind study. J Drugs Dermatol 2013;12(2):186-192.
- Unique properties of efinaconazole 10% solution, a new topical treatment for onychomycosis. Sugiura K et al American Academy of Dermatology 71st Annual Meeting Miami March 2013.
- ONMEL® (itraconazole) 200-mg Tablets Prescribing Information. Merz Pharmaceuticals, LLC. 2012; Rev 11/12.