Tavaborole 5% Solution: A Novel Topical Treatment for Toenail Onychomycosis

Gita Gupta MD^1,2; Kelly A. Foley PhD²; Aditya K. Gupta MD, PhD, FRCP(C)^2,3

¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto, Toronto, ON, Canada

Conflicts of interest:
Gita Gupta has no conflicts of interest. Aditya Gupta has been a clinical trials investigator, advisory board member, consultant, and speaker for Valeant. Aditya Gupta was involved in preclinical studies of tavaborole for Anacor Pharmaceuticals Inc. and has consulted for Anacor. Kelly Foley is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.

ABSTRACT
Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection.

Key Words:
clinical efficacy, dermatophyte, fungal infection, nail penetrance, nondermatophyte, onychomycosis, tavaborole, topical treatment

Introduction

Onychomycosis is a persistent fungal infection of the nails and nail bed, predominantly caused by the dermatophytes Trichophyton
rubrum or Trichophyton mentagrophytes.¹ The prevalence of onychomycosis in Europe and North America ranges from 3.22- 8.9%,^2,3 with recurrence and reinfection occurring in up to 25%⁴. Distal lateral subungual onychomycosis (DLSO) is the most common clinical presentation, invading the nail plate, nail bed, and hyponychium from the distal edge and lateral nail folds.¹

Treatment for onychomycosis consists of systemic (oral) and topical medications, with or without mechanical/chemical debridement. Systemic therapy is generally more successful
than topical therapy with clinical cure rates ranging from 40-80%.⁵ The advantage to systemic therapy is that medication can directly reach the site of infection in the nail bed.⁶ However, systemic therapy may not be feasible for those who are immunocompromised or at risk for drug-drug interactions (e.g., the elderly and/or diabetics).⁷ Alternatively, other patients are uncomfortable with long-term use of oral medications. Oral antifungal medications have been associated with asymptomatic increases in liver enzymes and there is a small risk of hepatotoxic injury.^8,9 Thus, topical therapies have an important role in onychomycosis management.

The efficacy of topical therapy for onychomycosis ranges from 5.5-17.8% for complete cure and 29-55% for mycological cure.¹⁰ The lower efficacy of topical treatments as compared to systemic therapy can be attributed to their limited ability to reach the site of infection.¹¹ In order for topical treatments to be effective, they need to penetrate the nail plate and down into the nail bed, and mechanical or chemical nail debridement of nails may facilitate this. The major advantage to topical therapy is that long-term use is safe, with minimal side effects.¹¹ Additionally, topical treatments used in combination with systemic treatment may increase clinical efficacy. Furthermore, fungal resistance to azole medications has become a concern in recent years.¹² Therefore, there is a need for new topical therapies for onychomycosis.

Tavaborole: A Novel Topical Antifungal

Tavaborole 5% solution (Kerydin^®) was approved by the US FDA for treatment of onychomycosis in July 2014. Tavaborole is the first in a new class of boron atom-containing drugs, the oxaboroles. Tavaborole’s mechanism of action is unique from current antifungals. Other antifungal agents act by blocking ergosterol synthesis (triazoles and terbinafine),⁶ or interfering with microbial metabolism (ciclopirox).¹³ Tavaborole inhibits protein synthesis, and thus fungal cell growth, by binding to leucyl-tRNA synthetase (LeuRS), an aminoacyl-tRNA synthetase (AARS).¹⁴ AARSs are critical for correct DNA translation and contain proofreading editing sites. Tavaborole binds to the editing site of LeuRS, trapping tRNA and preventing further DNA translation and protein synthesis.¹⁴ In vitro studies have shown that tavaborole can inhibit a wide range of fungal species, with minimum inhibitory concentrations (MIC) against dermatophytes, nondermatophyte molds, and yeasts (Table 1)¹⁵ allowing for potential treatment of mixed dermatophyte-nondermatophyte/mold infections. Of note is the potential for tavaborole to act against Fusarium and Malassezia species.¹⁵ Additionally, tavaborole’s low molecular weight compared to other available topical antifungal agents appears to allow for increased nail penetrance, with increased penetrance demonstrated compared to both amorolfine and ciclopirox.^16,17 Tavaborole’s broad spectrum of antifungal activity, coupled with its ability to penetrate the nail plate, suggested that it may be an effective topical treatment for toenail onychomycosis and led to its investigation in Phase I-III clinical trials.

Clinical Efficacy

Phase I
A Phase I study assessed the efficacy of once daily tavaborole 7.5% solution for 28 days in 15 otherwise healthy patients with severe onychomycosis of both great toenails (at least 80% involvement).¹⁸ Additionally, at least one great toenail was potassium hydroxide (KOH) positive, each great toenail had a combined thickness of the nail plate and nail bed of >3 mm, and at least six other toenails were diagnosed with onychomycosis. After 14 and 28 days of treatment, negative culture was reported for 88% (21/24) and 100% (24/24) of toenails, respectively. Clinical improvement was also observed 2-4 months following treatment, with an average clear nail growth of 1.2 mm.¹⁸

Phase II
Three Phase II studies have been conducted to evaluate the efficacy of a range of doses for tavaborole.¹⁹ All of these studies enrolled adult patients (18-65 years of age) with mild to moderate onychomycosis of at least one great toenail (20-60% nail involvement) and did not allow debridement of the nails during treatment. Study 200/200A (N=187) was a double-blind, randomized, vehicle-controlled trial evaluating 2.5%, 5%, and 7.5% tavaborole solution applied to affected toenails once daily for 3 months, followed by three times weekly for 3 months.¹⁹ The primary efficacy endpoint at 6 months was treatment success of the target toenail, defined as an Investigator Static Global Assessment (ISGA) of clear or almost clear plus negative culture or ≥2 mm of new clear nail growth plus negative culture. The rates of treatment success for all tavaborole treatments were significantly greater than vehicle control (P=0.030). While the number of patients that achieved negative culture was higher in tavaborole groups than vehicle, the differences were not statistically significant (Table 2).¹⁹

Studies 201 (N=89) and 203 (N=60) were open-label trials with the same primary efficacy endpoint as Study 200/200A, treatment success.¹⁹ Patients in Study 201 applied tavaborole 5% solution (Cohort 1) or tavaborole 7.5% solution (Cohort 2) to all affected toenails once daily for 6 months. Cohort 3 applied tavaborole 5% solution once daily for 12 months. Patients in Study 203 applied tavaborole 1% once daily for 6 months or tavaborole 5% once daily for 30 days, followed by three times weekly for 5 months. Efficacy outcomes are listed in Table 2.¹⁹ Overall, treatment with tavaborole was very promising and well tolerated, prompting larger-scale Phase III trials to be conducted. The 5% concentration of tavaborole was selected for Phase III testing.

Phase III

Two identical multi-center, randomized, double-blind, vehiclecontrolled clinical trials were conducted (Study 301, N=593 and Study 302, N=601).^20,21 Patients aged 18 years and older with mycologically confirmed (positive KOH and culture) onychomycosis involving 20-60% of the great toenail applied either tavaborole 5% solution or vehicle solution once daily for 48 weeks. At Week 52, complete cure (completely clear nail and mycological cure) and mycological cure (negative KOH and negative culture) were assessed (Table 3). ^20,21 Treatment with tavaborole 5% solution led to a significantly greater complete cure and mycological cure rates than vehicle treatment in both clinical trials (Ps≤0.001). Additionally, the outcome of completely or almost completely clear nail (≤10% nail involvement) plus negative mycology was significantly greater with tavaborole 5% solution compared to vehicle (Study 301: 15.3% vs. 1.5%; Study 302: 17.9% vs. 3.9%, P≤0.001).^20,21

Adverse Events

For all three Phase II studies combined, treatment-emergent adverse events (TEAEs) occurred in 177 of 366 patients.¹⁹ There were 13 reports of serious adverse events (AEs), unrelated to treatment. A reduction in dosing frequency and/or treatment discontinuation resolved any mild to moderate application site reactions. Specifically, in Study 200/200A, four patients in the tavaborole 7.5% solution group required ‘drug holidays’ (discontinued treatment until persistent grade 2 stinging/burning, pruritus, or grade ≥3 irritation was resolved, then treatment resumed with reduced frequency), while no patients in the tavaborole 5% solution group required a break from treatment. Other TEAEs reported included influenza (9.0%), pharyngitis (3.8%), upper respiratory tract infection (3.6%), tinea pedis (3.8%), headache (3.6%), contact dermatitis (2.5%), onychomadesis (1.4%), and tooth extraction (0.8%).¹⁹

Safety data was available for 1186 participants in the Phase III clinical trials.²⁰ No serious AEs were considered treatment related. In both trials, discontinuation due to treatment was comparable for tavaborole 5% solution and vehicle groups. TEAEs in ≥1% of participants treated with tavaborole were limited to application site reactions (exfoliation 2.7%, erythema 1.6%, and dermatitis 1.3%), and there were few reports of TEAE’s due to vehicle (exfoliation 0.3%, erythema and dermatitis 0%).20,21 Taken together, these results demonstrate that tavaborole 5% solution is both safe and more effective than vehicle in treating toenail onychomycosis.

Discussion

Tavaborole 5% solution was approved by the US FDA in July 2014 for use as a topical treatment for onychomycosis. Phase III clinical trials demonstrated that once daily use of tavaborole 5% solution for 48 weeks produced significantly higher rates of mycological and complete cure than vehicle.^20,21 Adverse events reported from Phase II and III trials indicate that the 5% formulation of tavaborole provides optimum efficacy and safety, producing mild application site reactions in a small number of patients.^19-21 As with all topical treatments for toenail onychomycosis, treatment outcomes are, in part, reliant on patient compliance and commitment to therapy, as toenails generally require at least 10-12 months to regrow.

Formulating an agent capable of penetrating the nail plate is one of the major challenges in developing topical treatments for onychomycosis. Tavaborole’s low molecular weight and high solubility allow for greater nail penetration and subsequent delivery of medication to the nail bed. The ability of tavaborole to effectively penetrate the nail plate prevents the need for mechanical debridement that may be required with other topical treatments. Additionally, tavaborole 5% solution’s broad-spectrum antifungal activity against dermatophytes, nondermatophytes, and yeasts make it a potential treatment for mixed infections. This is a relevant concern as little is known about the efficacy of current treatments for mixed infections, which may also contribute to the high recurrence rates observed in onychomycosis.

The availability of tavaborole 5% solution for the topical management of toenail onychomycosis may represent the promising start of a new line of treatments with increased nail penetrance and a novel mechanism of action against pathogenic fungi.

References

1. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
2. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1039-44.
3. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014 Nov;28(11):1480-91.
4. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
5. de Sa DC, Lamas AP, Tosti A. Oral therapy for onychomycosis: an evidencebased review. Am J Clin Dermatol. 2014 Feb;15(1):17-36.
6. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993 May;28(5 Pt 1):S28-S34.
7. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat. 2008 19(3):168-75.
8. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999 Dec;48(6):847-52.
9. Kao WY, Su CW, Huang YS, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014 Jan;77(1):180-9.
10. Gupta AK, Daigle D, Foley KA. Topical therapy for toenail onychomycosis: an evidence-based review. Am J Clin Dermatol. 2014 Dec;15(6):489-502.
11. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008 Nov;5(11):1267-82.
12. . Parker JE, Warrilow AG, Price CL, et al. Resistance to antifungals that target CYP51. J Chem Biol. 2014 Oct;7(4):143-61.
13. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin. 2003 Jul;21(3):481-9
14. Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007 Jun 22;316(5832):1759-61.
15. Sanders V, Baker SJ, Alley MRK, et al. Microbiological activity of AN2690, a new antifungal agent in development for the topical treatment of onychomycosis. [Poster P1608]. Presented at the 64th Annual Meeting of the American Academy of Dermatology; March 3-7, 2006; San Francisco, CA.
16. Elewski BE, Tosti A. Tavaborole for the treatment of onychomycosis. Expert Opin Pharmacother. 2014 Jul;15(10):1439-48.
17. Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007 Oct;96(10):2622-31.
18. Beutner KR, Sanders V, Hold K, et al. An open-label, multi-dose study of the absorption and systemic pharmacokinetics of AN2690 applied as a 7.5% solution to all toenails of adult patients with moderate to severe onychomycosis. [Poster 1823]. Presented at the 65th Annual Meeting of the American Academy of Dermatology; February 2-6, 2007; Washington, DC.
19. Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, et al. The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis. J Drugs Dermatol. 2014 Sep;13(9):1124-32.
20. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015 Jul;73(1):62-9.
21. Kerydin^™ (tavaborole) topical solution, 5% [Full prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; revised July 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf. Accessed September 20, 2015.
22. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.