Table of Contents  
MOLECULES OF THE MILLENNIUM
Year : 2015  |  Volume : 6  |  Issue : 4  |  Page : 236-239  

An upcoming drug for onychomycosis: Tavaborole


1 Department of Pharmacology, NIMS Medical College, Jaipur, Rajasthan, India
2 Department of General Surgery, Jawaharlal Nehru Medical College, Ajmer, Rajasthan, India

Date of Submission03-Feb-2015
Date of Decision14-Jan-2015
Date of Acceptance12-Jun-2015
Date of Web Publication15-Dec-2015

Correspondence Address:
Neha Sharma
Department of Pharmacology, NIMS Medical College, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-500X.171870

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   Abstract 

Fungal infection of the nail as well as nail bed is termed as 'onychomycosis'. It is caused by dermatophytes, non-dermatophytic fungal species and yeasts like Candida albicans. It is traditionally treated by topical antifungals, systemic agents like ketoconazole, griseofulvin, itraconazole, fluconazole, etc. Chemical avulsion or surgical removal of nail can also be tried to treat this disease. In spite of all these treatment options available, podiatrists were always in search of an ideal drug molecule with lesser side effects and which may improve the patient compliance. This exhaustive search led to the discovery of a better antifungal agent, known as “Tavaborole.” A systematic literature search was carried out using databases such as PubMed, Cochrane Reviews, Google Scholar, etc. Detailed information about onychomycosis and tavaborole was gathered. Tavaborole is the first oxaborole antifungal agent approved by FDA in July 2014. It is marketed under the trade name “Kerydin.” It acts by inhibiting protein synthesis in the fungus. It inhibits an enzyme known as cytosolic leucyl-transfer RNA synthetase, or LeuRS, which plays a key role in fungal essential protein synthesis. Dermatitis at the site of topical application, erythema, exfoliation and ingrowing toe nail has been reported in 1% of subjects. Tavaborole may offer a promising role in the treatment of onychomycosis and may compell podiatrists to offer its use in onychomycosis. The present study describes about chemical nature, mechanism of action and two completed phase 3 clinical trial findings of Tavaborole.

Keywords: Clinical trial, onychomycosis, tavaborole


How to cite this article:
Sharma N, Sharma D. An upcoming drug for onychomycosis: Tavaborole. J Pharmacol Pharmacother 2015;6:236-9

How to cite this URL:
Sharma N, Sharma D. An upcoming drug for onychomycosis: Tavaborole. J Pharmacol Pharmacother [serial online] 2015 [cited 2019 Dec 9];6:236-9. Available from: http://www.jpharmacol.com/text.asp?2015/6/4/236/171870


   Introduction Top


A non-dermatophytic infection of the nail which was traditionally termed as “onychomycosis” has now become a general term to denote any fungal nail infection.[1] Onychomycosis is mainly caused by the dematophytes, specially Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. Non- dermatophytes species of fungus and yeasts also possess potential to infect nail.[1],[2]

It affects patients' emotional, social, and occupational functioning and imposes financial burden to them. But, in immunocompromised patients, it can result in serious life-threatening conditions.[2] Onychomycosis accounts for about 20–40% of onychopathies and about 30% of all mycotic cutaneous infections. Overall it affects 5% of world population. Most of the patients are treated by topical antifungal agents. Systemic antifungal drugs and chemicals as well as surgical debridement are the other treatment options available.[3]

But, unfortunately none of these proved to be satisfactory by the podiatrists in treating onychomycosis and most of the patients remained untreated. In spite of all these treatment options available, podiatrists were always in search of an ideal drug molecule with lesser side effects, which may improve the patient's compliance. This exhaustive search led to the discovery of a better antifungal agent, known as “Tavaborole.” A systematic literature search was carried out using databases such as PubMed, Cochrane Reviews, Google Scholar, etc. Detailed information about onychomycosis and tavaborole was gathered.

What is tavaborole?

Tavaborole is the first oxaborole antifungal agent approved by FDA in July 2014. It is marketed under the trade name “Kerydin” and is used to treat a fungal infection of the nail as well as nail bed that is termed as onychomycosis of the toe nail. Tavaborole with the molecular formula C7H6 BFO2 has a molecular weight of 151.930743 g/mol.[4],[5]

Chemical structure of tavaborole has been depicted in [Figure 1].
Figure 1: Chemical structure of tavaborole containing 1 boron atom

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Mechanism of action of tavaborole

It acts by inhibiting protein synthesis in the fungus. It inhibits an enzyme known as cytosolic leucyl-transfer RNA synthetase, or LeuRS, which plays a key role in fungal essential protein synthesis. Termination of protein synthesis leads to inhibition of fungal cell growth which ultimately leads to death of fungus.[6]

Efficacy of tavaborole in treating onychomycosis

The efficacy and safety was based on two randomized, double-blind, vehicle-controlled, multi-centere trials to evaluate the efficacy and safety of AN2690 topical solution 5%, versus solution vehicle in the treatment of onychomycosis of the toenail in adults. It has completed phase 3 clinical trial that was sponsored by Anacor Pharmaceuticals. In this study the study drug AN2690 topical solution, 5% was applied once daily for 48 weeks among the clinically diagnosed cases of distal subungual onychomycosis (DSO) affecting at least one great toenail with 20% to 60% clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement and who were KOH positive at the time of screening.[7]

A total of 1194 subjects (795 Kerydin, 399 Vehicle), 18 to 88 years of age, participated in these two trials. Out of 1194 patients, 795 patients were treated with Kerydin (Tavaborole) while 399 patients received vehicle.[5],[7] It has been shown in [Figure 2].
Figure 2: Recruited 1194 patients in two clinical trials

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Primary efficacy endpoints

The primary efficacy endpoint was taken as “Completely Clear Nail” that means 0% clinical involvement of the target toenail plus “Mycological Cure” which indicates negative KOH wet mount and negative fungal culture. The primary efficacy endpoint of trials 1 and 2 has been depicted in [Figure 3].
Figure 3: The primary efficacy endpoint of trials 1 and 2

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Secondary efficacy endpoints

Secondary endpoints has been depicted in [Figure 4] and [Figure 5] and included “Complete or Almost Complete Cure” (≤10% affected target toenail area involved plus “Mycological Cure") and “Mycological Cure."
Figure 4: Complete or almost complete cure as the secondary efficacy endpoint of trials 1 and 2

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Figure 5: Mycological cure as the secondary efficacy endpoint of trials 1 and 2

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Side effects

Dermatitis at the site of topical application, erythema, exfoliation and ingrowing toe nail has been reported in 1% of subjects.[4],[6],[8]

Existing treatment options available for onychomycosis

Treatment of onychomycosis is very difficult because of high recurrence rates with limited treatment options available. Other factors are slow growth of toenail and anatomic nature of nail plate that hinders the nail bed access of topical antifungal agents.[9]

Systemic antifungal agents

Terbinafine (250 mg daily for 12 weeks) and itraconazole “pulse” therapy (200 mg given twice daily for 1 week per month) are the most effective oral drugs available for treating onychomycosis. Griseofulvin and ketoconazole are not used nowadays due to safety concerns. Hepatotoxicity and drug interactions are the two most common limiting features of oral drug therapy.[9] Oral drugs are more effective but patients usually prefer topical agents because of adverse effects and long duration of therapy of oral agents.[10]

Topical antifungal agents

Ciclopirox olamine 8% lacquer is the most commonly used topical agent for toenail onychomycosis. Ciclopirox is a synthetic hydroxypyridone antifungal agent which is metabolized by glucuronidation which leads to lesser chances of drug interactions.[11],[12],[13] In a study, treatment with ciclopirox olamine 8% lacquer has resulted in clinical improvement in 63.4% of patients with mycologic cure in 54.3% of patients.[14] Amorolfine 5% nail lacquer (unavailable in North America) is another agent for topical application.[15] Efinaconazole 10% solution was approved on June 9, 2014 by FDA for the treatment of onychomycosis. It has shown complete and mycologic cure rates of 15% to 25% and 53% to 87%, respectively.[16]

Comparison of complete cure and mycological cure rates of efinaconazole and tavaborole has been elaborated in [Table 1]. More studies on the comparison of efficacy of these two newly approved topical agents are suggested.
Table 1: Comparison of mycological and complete cure of efinaconazole and tavaborole

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Current status

The new drug candidate tavaborole has been approved by US FDA in July 2014. It has been marketed under the trade name Kerydin by Anacor Pharmaceuticals. It is not available in India. The present study describes about chemical nature, mechanism of action and two completed phase 3 clinical trial findings of tavaborole.

The advantage of tavaborole over other older drugs is that it can be used topically so lesser chances of systemic side effects. Debridement of the affected toenail is not required with this drug. Tavaborole has shown negligible inhibition of cytochrome P450 enzyme so there are least chances of drug–drug interactions. In addition to that, its safety and efficacy is comparable to other available topical antifungal agents.[15]

Ongoing trials

After the convincing results of two clinical trials that has been documented by Ancor Pharmaceuticals, results of several other multicentric similar arms trials are also eagerly awaited. These clinical trials have additional benefits of evaluation of systemic doses, different doses apart from topical application. Some of them have completed phases I and II.[5]

A transfersome formulation containing 1.5% of the antifungal terbinafine (TDT-067) and newer laser therapies are also under trial for targeted drug delivery of an antifungal drug.[15] Luliconazole 10% nail solutions and another topical antifungal agent of benzoxaborole derivative, AN7718, are also under testing.[15]


   Conclusion Top


Tavaborole may offer a promising role in the treatment of onychomycosis. The presence of a very small element of Boron in its structure is conferring a strong antifungal action to this drug. It may result in improved patient compliance because of its topical application with minimized side effects. More exhaustive studies are required to establish the efficacy of this boron-containing new topical antifungal candidate against other topical agents available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Elewski BE. Onychomycosis: Pathogenesis, diagnosis, and management. Clin Microbiol Rev 1998;11:415-29.  Back to cited text no. 1
    
2.
Scher RK. Onychomycosis: A significant medical disorder. J Am Acad Dermatol 1996;35:S2-5.  Back to cited text no. 2
    
3.
Kaur R, Kashyap B, Bhalla P. Onychomycosis-epidemiology, diagnosis and management. Indian J Med Microbiol 2008;26:108-16.  Back to cited text no. 3
[PUBMED]  Medknow Journal  
4.
Fda.gov. FDA Approves Kerydin (tavaborole) Topical Solution for Onychomycosis of the Toenails. Available from: http://www.drugs.com/nda/tavaborole_131003.html. [Last accessed on 2015 Jan 11].  Back to cited text no. 4
    
5.
Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, et al. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1- hydroxy-2,1-benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem 2006;49:4447-50.  Back to cited text no. 5
    
6.
ClinicalTrials.gov. Efficacy and Safety of AN2690 Topical Solution to Treat Onychomycosis of the Toenail. Available from: https://clinicaltrials.gov/tavaborole. [Last accessed on 2015 Jan 11].  Back to cited text no. 6
    
7.
Tavaborole. Kerydin™ (tavaborole) topical solution, 5% has received FDA approval. Available from: http://www.investor.anacor.com/releasedetail.cfm?ReleaseID=858211. [Last accessed on 2015 Jan 12].  Back to cited text no. 7
    
8.
Fda.gov. Tavaborole. Available from: http://www.fda.gov/. [Last accessed on 2015 Jan 11].  Back to cited text no. 8
    
9.
Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the emergence of newer agents. J Clin Aesthet Dermatol 2014;7:10-8.  Back to cited text no. 9
    
10.
Gupta AK, Gover MD, Lynde CW. Pulse itraconazole vs. continuous terbinafine for the treatment of dermatophyte toenail onychomycosis in patients with diabetes mellitus. J Eur Acad Dermatol Venereol 2006;20:1188-93.  Back to cited text no. 10
    
11.
Matricciani L, Talbot K, Jones S. Safety and efficacy of tinea pedis and onychomycosis treatment in people with diabetes: A systematic review. J Foot Ankle Res 2011;4:26.  Back to cited text no. 11
    
12.
Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol 2000;43:S57-69.  Back to cited text no. 12
    
13.
Brenner MA, Harkless LB, Mendicino RW, Page JC. Ciclopirox 8% nail lacquer topical solution for the treatment of onychomycosis in patients with diabetes: A multicenter, open-label study. J Am Podiatr Med Assoc 2007;97:195-202.  Back to cited text no. 13
    
14.
Shemer A, Nathansohn N, Trau H, Amichai B, Grunwald MH. Ciclopirox nail lacquer for the treatment of onychomycosis: An open non-comparative study. J Dermatol 2010;37:137-9.  Back to cited text no. 14
    
15.
Gupta AK, Daigle D. Potential role of Tavaborole for the treatment of onychomycosis. Future Microbiol 2014;9:1243-50.  Back to cited text no. 15
    
16.
Gupta AK, Paquet M. Efinaconazole 10% nail solution: A new topical treatment with broad antifungal activity for onychomycosis monotherapy. J Cutan Med Surg 2014;18:151-5.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1]


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