Two New Topical Antifungals for Onychomycosis

Nga Lam, PharmD Candidate; Marcus Campbell, PharmD, BC-ADM

Onychomycosis is a fungal infection of the toenails or fingernails. It is characterized by thickening of the nail, discoloring, shaping distortion, and detaching of nail plate from the nail bed. Onychomycosis is relatively common and accounts for approximately 35 million cases inthe United States.¹ The major cause of onychomycosis is a dermatophyte, mostly Trichophyton rubrum. Other causes could be due to yeasts and non-dermatophyte molds.²Onychomycosis poses challenges in treatment due to a high rate of recurrence and the difficulty of achieving adequate drug penetration to affected sites. Without treatment, onychomycosis can lead to pain and discomfort while walking or wearing shoes, and it can spread to other regions of the body including feet, hands, and groin. Available treatment for onychomycosis are topical ciclopirox, oral griseofulvin, oral itraconazole and oral terbinafine. Oral antifungals are a mainstay of treatment due to the ability to penetrate the nail bed and the nail plate. However, some disadvantages that limit the use of oral therapy in patients include drug interactions and risk of liver injury.³

In 2014, the United States Food and Drug Administration (FDA) approved two new topical antifungal drugs, Jublia® (efinaconazole 10%) and Kerydin® (tavaborole 5%), for the treatment of nail fungus caused by Trichophyton rubrum and Trichophyton mentagrophytes. Efinaconazole is the first approved topical triazole, and tavaborole is the first approved oxobarole antifungals for this indication. However, they have two different mechanisms of action in treating nail fungus. Efinaconazole inhibits fungal lanosterol 14-alpha-demethylase involved in the biosynthesis of ergosterol.⁴ Tavaborole inhibits protein synthesis by inhibition of  aminoacyl-transfer ribonucleic acid (tRNA) synthetase.⁵   Neither treatment  requires nail debridement for drug penetration. Patient cost should be considered; a single 4ml vial of efinaconazole and 10 ml vial of tavaborole cost about $463 and $1240 respectively.^6,7

Efinaconazole and tavaborole were both evaluated in clinical trials utilizing “complete cure” as the primary endpoint. Complete cure was defined as no clinical onychomycosis plus as negative results on both fungal culture and potassium hydroxide (KOH) test. The efficacy and safety of efinaconazole was studied in two multi-center, randomized, and double blinded trials, which included a total of 1651 patients. Trial 1 had 870 patients and trial 2 had 781 patients. Included, patients were aged 18 to 70 years with 20-50% clinical involvement of toenail distal subungual onychomycosis (DLSO). Patients were randomly assigned to self-apply either efinaconazole or placebo once daily for 48 weeks. The primary endpoint was assessed at week 52, 4 weeks after completing the course of treatment. In trial 1, 17.8% of patients receiving efinaconazole and 3.3% of patients receiving the placebo achieved complete cure (P< 0.001). In trial 2, patient treated with efinaconazole achieved a higher cure rate of 15.2% versus 5.5% in placebo (P <0.001).  Efinaconazole was well tolerated, with the most common side effects including ingrown toe nail, application site vesicles, pain and dermatitis. ³

The effectiveness of tavaborole was also evaluated in two multi-center, double blinded, randomized, and placebo-controlled trials. A total of 1195 patients aged 18 to 88 years with 20% to 60% clinical involvement of the target toenail fungus were recruited in the studies. Patients were randomly assigned to self-apply either tavaborole or placebo once daily for 48 weeks. The results were evaluated at week 52. For the patients treated with tavaborole, 6.5% in trial 1 and 9.1% in trial 2 reached primary endpoints comparing with 0.5% and 1.5%, respectively, for patients treated with the placebo.  Tavaborole had mild side effects, such as ingrown toe nail, skin peeling, redness, itching, and swelling at the treated site.⁵

References:

1. Jublia [Internet]. If you’ve got toenail fungus, you’re not alone; [cited 2015 Feb 17]; Available from: http://www.jubliarx.com/about-toenail-fungus
2. Bpacnz. Management of fungal nail infections. Best Practice Journal. 2009 Feb [cited 2015 Feb 19]. Available from:http://www.bpac.org.nz/BPJ/2009/february/nailfungas.aspx
3. 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;68:600-608.
4. Jublia Prescribing Information [Internet]; 2014 Jun [cited 2015 Feb 17]; Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf
5. Kerydin Prescribing Information[Internet]. Anacor Pharmaceuticals, Inc., Palo Alto, CA. July, 2014. Available from : http://www.anacor.com/pdf/Kerydin%20labeling.pdf