Topical Agent to Treat Onychomycosis

08/21/2014

The FDA approved Valeant Pharmaceuticals North America’s Jublia (efinaconazole topical solution 10%) in June as the first topical triazole indicated for treatment of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes.

Efinaconazole is an azole antifungal. It works by inhibiting fungal lanosterol 14α-demethylase involved in the biosynthesis of ergosterol, a constituent of fungal cell membranes.1

Being a solution, efinaconazole is applied to the nail with a novel bottle that has a built-in flow-through brush applicator. Efinaconazole should be applied to affected toenails once daily for 48 weeks. When applying efinaconazole, ensure the toenail, the toenail folds, toenail bed, hyponychium and the undersurface of the toenail plate are completely covered. The medicine dries quickly and there is no need to remove excess product.1

Onychomycosis is a common and destructive nail infection that is difficult to treat and manage long-term. Currently, over-the-counter or prescription topical treatments provide limited safety and are often administered in conjunction with frequent debridement, or the scraping, cutting or removal the nail. Prescription oral treatments are limited by drug interactions and serious safety concerns, according to the company. For patients who would prefer an efficacious topical onychomycosis treatment, efinaconazole provides an alternative treatment option.2

Onychomycosis is caused predominately by dermatophyte fungi that typically occurs under the toenail, though fingernails may also be affected. Approximately 35 million Americans experience onychomycosis, most of whom are men between 50 and 70 years of age. Currently, 85% of onychomycosis patients are untreated. The fungi that cause onychomycosis live in warm, moist environments and may invade the skin through tiny cuts or small separations between the nail and nail bed.

The condition typically begins as a small white or yellow spot beneath the nail and causes nail discoloration, thickening and/or distortion, pain, detachment of the nail from the nail bed and irregular surface changes. Once onychomycosis begins, it can persist indefinitely if left untreated and may cause permanent nail damage.

The FDA approved efinaconazole based on positive results from 2 pivotal Phase III trials involving 1,655 patients with onychomycosis.1,2

The Dermatologist Product Spotlight provides a summary of the pivotal trials that evaluated the safety and efficacy of efinaconazole for the treatment of onychomycosis of the toenails caused by T rubrum and T mentagrophytes.

 

Phase III Clinical Data

Jublia [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2014.1

Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two Phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68(4):600-608.2

 

Study Objective

To assess the safety and efficacy of efinaconazole for the treatment of distal lateral subungual onychomycosis (DLSO).2

 

Method

The 2 identical, multicenter, randomized, parallel group, double-blind, vehicle-controlled, Phase III studies were conducted at 118 sites including the United States, Canada and Japan. Patients with toenail DSLO onychomycosis (defined as 20%-50% clinical involvement of the target toenail, without dermatophytomas or matrix [lunula] involvement) were randomized 3:1 to receive efinaconazole or vehicle self-applied once daily for 48 weeks without debridement, followed by a treatment-free 4-week follow-up. Treatment was applied to the clean, dry nail plate surface, lateral and proximal nail folds, hyponychium and undersurface of the nail plate. Patients were assessed for efficacy and safety at baseline, 12-week intervals post-baseline (ie, weeks 12, 24, 36 and 38) and final visit at week 52. Studies were conducted from December 2009 to September 2011 and October 2011.2

 

Population

A total of 1,655 patients with DSLO were enrolled. Study 1 included 656 patients randomized to efinaconazole and 214 randomized to vehicle. Study 2 included 583 patients randomized to efinaconazole and 202 patients randomized to vehicle. Inclusion criteria included patients age 18 to 70 years with mild-to-moderate toenail DSLO affecting at least 1 great toenail, target toenail uninfected length of ≥3 mm (from the proximal nail fold), thickness 3 mm or less, evidence of toenail growth, positive potassium hydroxide (KOH) and culture of dermatophyte or mixed dermatophyte/Candida ≤42 days before baseline. Women of childbearing age were required to use birth control.2

At baseline, the patient mean age was 52.3 and 50.6 years (studies 1 and 2, respectively).  A majority of the patients were male and white. The mean area of target toenail involvement was 36.7% and 36.3% (studies 1 and 2, respectively) and the mean number of affected non-target toenails was 2.8 in each study. Overall, 1,436 patients completed the 48-week treatment and 1,420 completed the 4-week follow-up. A total of 235 patients discontinued early because of patient request, lost to follow-up, protocol violation, other worsening condition and pregnancy.2

 

Primary Endpoint

• Complete cure rate defined as 0% clinical involvement of the target toenail plus negative KOH and negative cure at week 52.1,2

 

Secondary Endpoints

• Complete or almost complete cure defined as ≤5% affected target toenail area involved and negative KOH and culture at week 52.1,2

• Mycologic cure defined as negative KOH and negative culture at week 52.1,2

 

Results

The researchers concluded that efinaconazole is an effective treatment for mild-to-moderate onychomycosis. At week 52, complete cure rates with efinaconazole were 17.8% in study 1 and 15.2% in study 2 compared with 3.3% and 5.5%, respectively, of patients treated with vehicle (both P<.001). More patients treated with efinaconazole achieved a complete or almost complete cure in studies 1 and 2 (26.4% and 23.4%, respectively) compared with vehicle (7.0% and 7.5%, respectively; both P<.001). Mycologic cure rates were also significantly better with efinaconazole in studies 1 and 2 (55.2% and 53.4%, respectively) compared with vehicle (16.8% and 16.9%, respectively; both P<.001).1,2

 

Safety Notes

Adverse events that were reported were generally mild and transient and were similar between patients treated with efinaconazole and those treated with vehicle. The most commonly reported adverse events in patients treated with efinaconazole were ingrown toenail (N=28), application site dermatitis (N=27), application site vesicles (N=20) and application site pain (N=13).1 According to the company, there were no concerns for systemic side effects such as drug–drug interactions or acute liver injury. 

 

Additional Resource

Prescribing information for Jublia: http://www.valeant.com/Portals/46/Pdf/PI/Jublia_PI_6June2014_9391901.pdf.