An Update On Current And Emerging Topical Antifungals

With the development of new topical agents for onychomycosis, the author takes a closer look at the research on these modalities, explores the possibility of subungual and transungual delivery of topical agents, and reviews options for treating the frequently concomitant tinea pedis.

Until recently, topical treatments for onychomycosis have employed lacquer formulations (e.g., ciclopirox). These are organic solutions of film-forming polymers. Upon application to the surface of the nail, the solvent evaporates, leaving a water resistant polymer film on the nail plate. This occlusive film acts as a drug reservoir that facilitates the release and penetration of the drug into and through the nail. One must then remove the film either mechanically or with organic solvents, and apply fresh lacquer to replenish the drug reservoir, which can render the nail more prone to infection.^1,2

Efficacy in treating onychomycosis with these nail lacquers has been disappointing as reported complete cure rates with ciclopirox nail lacquer range between 5.5 to 8.5 percent.³ Various authors have suggested that poor nail penetration is the main factor limiting the use of topical antifungal agents in the treatment of onychomycosis, directly relating to the nail plate’s unique properties, its thickness and relatively compact structure, the physicochemical properties of the antifungal agent and its formulation.^4-10

Most cases of onychomycosis are characterized by thickening of the nail, discoloration (ranging from white to black) and onycholysis. Chronic nail plate infection reportedly increases nail thickness, confirming observations that physicians have seen in clinical studies and practice.^11,12 Other authors have noted that chronic nail plate infection significantly reduces nail density and tensile strength, suggesting a more porous structure of the nail and erosion of the intracellular matrix that renders the tissue more permeable to topically applied agents when clinicians use an aqueous vehicle formulation.¹³

A Closer Look At The Recent Research On The Newer Topical Antifungals
Newer topical agents for onychomycosis have emerged with efinaconazole (Jublia, Valeant Pharmaceuticals) and tavaborole (Kerydin, PharmaDerm). The cure rates of tavaborole solution are 6.5 to 9.1 percent while the cure rate results with efinaconazole solution are 15.2 to 17.8 percent.^14-16 However, there were different protocols and inclusion criteria for the studies of the products.

Both efinaconazole and tavaborole solutions have been studied in large phase 3 clinical programs. Elewski and colleagues assessed the efficacy, safety and tolerability of efinaconazole in two double-blind, randomized, vehicle-controlled, multicenter studies in 1,655 patients with mild to moderate onychomycosis (ranging between 20 to 50 percent affected target toenail involvement).¹⁶ In addition to the aforementioned cure rates, researchers noted significantly greater mycologic cure rates (55.2 and 53.4 percent) in efinaconazole-treated patients in comparison to the vehicle control.

Elewski and co-workers studied tavaborole in two similarly designed studies of 1,197 patients with mild to moderate onychomycosis (ranging between 20 to 60 percent affected target toenail involvement) with slight differences in enrollment criteria.^14,15 (See “Studies Cite Benefits Of Tavaborole For Onychomycosis” at https://www.podiatrytoday.com/studies-cite-benefits-tavaborole-onychomycosis .) In the two studies, 26.1 and 27.5 percent of patients treated with tavaborole achieved a completely or almost clear nail at 52 weeks in comparison to 9.3 and 14.6 percent in the vehicle groups. The study authors also noted that the rates of negative mycology in the tavaborole groups were 31.1 and 35.9 percent in comparison to 7.2 and 12.2 percent in the vehicle groups.

In all of the aforementioned studies, patients applied the topical antifungal or vehicle once daily for 48 weeks with a four-week follow-up. Unlike studies with ciclopirox and tavaborole, researchers applied efinaconazole by brushing the solution on the skin surrounding the nail as well as the nail plate. Other studies that have had a broader inclusion range in terms of target nail involvement for patient enrollment have reported similar mean percent involvement to that clinicians reported from the pivotal efinaconazole trials.³ Most importantly, given that clinicians previously reserved topical monotherapy for mild cases of onychomycosis without matrix involvement, which only affects the distal half of the nail units, three quarters of the patients in the efinaconazole studies had moderate disease. Comparative data for tavaborole have not yet been released as this issue went to press.  

Another possible difference between the studies for efinaconazole and tavaborole could be the age of patients enrolled. The two efinaconazole studies enrolled patients 18 to 70 years of age whereas there was no upper age limit for the tavaborole studies.^14-16 Just over 13 percent (13.2 percent) of the patients in the efinaconazole studies were 65 years of age or older. The number of elderly patients in the tavaborole studies was greater and patients up to the age of 88 were enrolled. Interestingly, in a post-hoc analysis of the pooled data, researchers saw no significant difference in the efficacy of efinaconazole with respect to age although there was a trend to greater efficacy in patients under 40 years of age.¹⁶ This data is still pending regarding the tavaborole trial.

Could Subungual And Transungual Delivery Reinvent Nail Penetration?
Much has been written about topical onychomycosis treatments and the challenge of effective nail penetration following their application to the nail plate with the dorsal layer acting as the major barrier to penetration.^18,19 Researchers have emphasized the need for the active ingredient to pass through the nail to reach the site of infection and have suggested a number of physicochemical factors (such as molecular size, hydrophilic or lipophilic nature of the agent, pH, ionic strength and nature of the vehicle formulation) as important factors in influencing permeability.¹⁸ Studies have reported variable nail permeability for all the available topical preparations available in the United States and work continues to find agents and formulation approaches to enhance nail penetration.^20-23

There are different morphological types of onychomycosis with the most common being distal lateral subungual onychomycosis, which usually arises from dermatophyte infection. Distal lateral subungual onychomycosis begins in the distal or lateral part of the nail plate and spreads proximally under the nail to involve the nail bed and subsequently the nail plate. It might be logical to consider an approach to treatment that follows this infection path.

Efinaconazole is an alcohol-based solution that provides low surface tension and good wetting properties.²⁴ In a study of 11 patients with onychomycosis, Elewski and coworkers found that applying efinaconazole vehicle solution solely to the hyponychium spread the topical into the subungual space between the nail plate and nail bed, reaching the site of infection.²⁵ It is possible that the unique properties of the vehicle formulation and this additional route to the infection site may be contributing to the efficacy researchers have seen with efinaconazole.

Tavaborole is an alcohol-based solution that provides low surface tension but also boasts a low molecular weight active ingredient that penetrates well through the human nail plate.¹⁶ In a human cadaver nail study, tavaborole penetrated the nail plate 40 times greater than topical ciclopirox.²⁶

Further studies are underway to assess the relative merits of subungual and transungual delivery of new topical antifungal agents to determine optimal development strategies, notwithstanding the importance of the active agents’ relative potency and spectrum of antifungal activity.

Understanding The Link Between Tinea Pedis And Onychomycosis
Onychomycosis is a very common fungal infection of the toenails, represents approximately half of all nail diseases and affects up to 20 percent of adults, particularly the elderly.^27,28 Tinea pedis is inexorably linked to onychomycosis. The need to evaluate and treat both diseases is critical for successful long-term management of onychomycosis, and reduced risk of recurrence or re-infection. (See “What The Studies Reveal About Imidazole Antifungals For Interdigital Tinea Pedis” at right.)

However, there is limited data on the management of the two fungal infections when they coexist. Onychomycosis is significantly more likely to be diagnosed in the context of tinea pedis and a history of tinea pedis more than doubles the risk of onychomycosis.^33,34 A post-hoc analysis showed that prevalence rates of tinea pedis at baseline in the efinaconazole studies (21.3 percent) were similar to those recorded in previous surveys.³⁵ For the patients who were treated for coexisting tinea pedis (with the physician’s preferred treatment), cure rates almost doubled those of the onychomycosis patients that did not receive treatment for coexisting tinea pedis, providing clinical evidence for the first time to support a management strategy ingrained in podiatry practice.³⁶

What You Should Know About Diabetes And Onychomycosis
Diabetes is a very important comorbidity in patients with onychomycosis. Almost a third of patients with diabetes suffer with onychomycosis and it can be a significant limb-threatening infection if left untreated.^37,38 Despite the importance of this association, few studies have looked at the treatment of onychomycosis in a diabetic population.³⁹

Although authors have suggested that people with diabetes may be more resistant to treatment due to hyperglycemia or poor foot hygiene, the patients in the efinaconazole studies who had coexisting diabetes experienced similar levels of efficacy to those that did not have coexisting diabetes.^40,41 Although the number of patients with coexisting disease was relatively small, it was still the largest cohort of diabetic patients with onychomycosis reported to date and supports earlier studies that had suggested similar efficacy in both cohorts.³⁹

Could Photodynamic Therapy Have An Impact For Onychomycosis In The Future?
In addition to the topical antifungals recently approved, preliminary studies in the use of light therapy for the treatment of onychomycosis are being investigated outside of the United States.⁴² Photodynamic therapy describes the interaction of light, photosensitive materials and oxygen to have an effect on destruction of bacteria, fungi and viruses on tissue. Light activates a photosensitizing agent that patients topically apply to the nail, which generates a reactive oxygen species that can ultimately cause programmed cell death. The photosensitizing agents can also be absorbed by dermatophytes, which make the use of this therapy for nails compelling for those who do not want to take a systemic agent.

At this time, there are no FDA-approved photodynamic therapy devices for nail management even though photodynamic therapy describes the interaction of light, photosensitive materials widely used in dermatology for the treatment of various cancerous and pre-cancerous lesions.

In Conclusion
Despite the ongoing development of new treatments, onychomycosis is still an extremely recalcitrant disease with high rates of relapse and reinfection. New topical therapies that provide better efficacy would be welcomed. In many cases of toenail onychomycosis, prolonged or repeated therapy is needed to achieve resolution of the disease. The aforementioned clinical data suggests that clinicians might achieve higher efficacy rates with continued treatment when warranted. Maintenance therapy with topical agents also warrants further study.

The increased interest we see for clinical studies in onychomycosis also provides us with important insights into treatment practice as well as identifying areas for further work. Looking out for and treating coexisting tinea pedis come as second nature to podiatrists. Now we have compelling evidence to support the broader communication of this important practice. We all recognize the importance of treating onychomycosis in patients with diabetes and having topical agents that are effective in this group of patients is important as they tend to be on multiple treatment regimens with potential contraindications.
One area of research that we are likely to hear more of in the future is the potential of other penetration routes for topical therapy. The benefits of subungual delivery are clear and a dual approach of transungual delivery and application under the hyponychium could provide greater efficacy. Subungual delivery may also be an important consideration for those patients who ether want to continue to use nail polish or wish to start using nail polish once they see improvement in the toenail.

Onychomycosis will remain a common nail disease that one should treat effectively and early to prevent progression into a more severe, debilitating and painful condition. In addition, prevalence will likely continue to increase as the population ages and more patients seek treatment due to resurgence of media interest. Product development will focus on physicochemical properties suited to treating onychomycosis and advances in formulation research to ensure sufficient product reaches the site of infection in the nail bed. It is likely that other routes to the infection (not just permeability through the nail plate) will become important.

With more new topical products entering the market, we are likely to see increased patient awareness and expectation. Education of our patients in terms of disease management, how long it takes for the nail to become normal and what they can do to prevent disease spreading or reinfection will be critical.

Dr. Vlahovic is an Associate Professor and J. Stanley and Pearl Landau Fellow at the Temple University School of Podiatric Medicine. She writes a monthly blog for Podiatry Today. Readers can access Dr. Vlahovic’s blog at www.podiatrytoday.com/blogs/556 .

Dr. Vlahovic has disclosed that she was a principal investigator in the pivotal trials with efinaconazole topical solution, 10%. She is on the Valeant Pharmaceuticals Speaker’s Bureau and has been on the Advisory Board for PharmaDerm. Dr. Vlahovic acknowledges Brian Bulley, MSc, of Inergy Limited for medical writing support. Valeant Pharmaceuticals North America LLC funded Inergy’s activities pertaining to this article.

References

1.     Murdan S. The nail: anatomy, physiology, diseases and treatment. In: Murthy SN and Maibach HI (eds): Topical Nail Products and Ungual Drug Delivery, Taylor and Francis Group, CRC Press, Boca Raton, FL, 2013, pp. 1–36.
2.     Sparavigna A, Setaro M, Frisenda L. Physical and microbiological properties of a new nail protective medical device. J Plastic Dermatol. 2008;4(1):5-12.
3.     Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the treatment of onychomycosis of the toenails in the United States. J Am Podiatr Med Assoc. 2000; 90(10):495–501.
4.     Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol. 2005;19(1): 21–29.
5.     Lecha M, Effendy I, Feuilhade de Chauvin M, Di Chiacchio N, Baran R. Treatment options—development of consensus guidelines. J Eur Acad Dermatol Venereol. 2005;19 suppl 1:25–33.
6.     Murdan S. Drug delivery to the nail following topical application. Int J Pharm. 2002;236(1-2):1-26.
7.     Baker SJ, Hui X, Maibach HI. Progress on new therapeutics for fungal nail infections. Ann Rep Med Chem. 2005;40:323-334.
8.     Mertin D, Lippold BC. In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum flux. J Pharm Pharmacol. 1997;49(1):30-4.
9.     Kobayashi Y, Komatsu T, Sumi M, Numajiri S. et al. In vitro permeation of several drugs through the human nail plate: relationship between physicochemical properties and nail permeability of drugs. Eur J Pharm Sci. 2004;21(4):471-477.
10.     Tatsumi Y, Yokoo M, Senda H, Kakehi K. Therapeutic efficacy of topically applied KP-103 against experimental tinea unguium in guinea pigs in comparison with amorolfine and terbinafine. Antimicrob Agents Chemother. 2002;46(12):3797-3801.
11.     Baraldi A, Jones SA, Guesne S, et al. Human nail plate modifications induced by onychomycosis: implications for topical therapy. Pharm Res. 2015;32(5):1626-1633.
12.     Tosti A, Daniel R, Piraccini BM, Iorizzo M. Color Atlas of Nails. Springer, Berlin, 2010. p. 15-22.
13.     Hamilton JB, Terada H, Mestler GE. Studies of growth throughout the lifespan in Japanese: growth and size of nails and their relationship to age, sex, heredity, and other factors. J Geront. 1955;10(4):401–415.
14.     Elewski BE, Rich P, Wiltz H, et al. Effectiveness and safety of tavaborole, a novel boron-based molecule for the treatment of onychomycosis: results from two phase 3 studies. Poster presented at Winter Clinical Meeting 2014.
15.     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 onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015 May 5. S0190-9622(15)01512-1. doi: 10.1016/j.jaad.2015.04.010. [Epub ahead of print].
16.     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.
17.     Gupta AK, Elewski BE, Sugarman JL, et al. Efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014;13(7):815-820.
18.     Thatai P, Sapra B. Transungual delivery: deliberations and creeds. Int J Cosmet Sci. 2014;36(5):398-411.
19.     Kobayashi Y, Miyamoto M, Sugibayashi, K, et al. Drug permeation through the three layers of the human nail plate. J Pharm Pharmacol. 1999;51(3):271–278.
20.     Monti D, Tampucci S, Chetoni P, et al. Ciclopirox vs amorolfine: in vitro penetration through human health nails of commercial nail lacquers. J Drugs Dermatol. 2014;13(2):143-147.
21.     Monti D, Saccomani L, Chetoni P, et al. Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation. Br J Dermatol. 2011;165(1):99-105.
22.     Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN 2690) into the human nail plate. J Pharm Sci. 2007;96(10):2622-2631.
23.     Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vivo fungicidal activity in the human nails. J Drugs Dermatol. 2014;13(11):1338-1392.
24.     Bhatt V, Pillai R. Efinaconazole topical solution, 10%: formulation development program of a new topical treatment of toenail onychomycosis. J Pharm Sci. 2015; May 4. doi: 10.1002/jps.24459. [Epub ahead of print]
25.     Elewski BE, Pollak RA, Pillai R, et al. Access of efinaconazole topical solution 10% to the infection site by spreading through the subungual space. J Drugs Dermatol. 2014;13(11):1394-1398.
26.     Elewski BE, Tosti A. Tavaborole for the treatment of onychomycosis. Expert Opin Pharmacother. 2014; 15(10):1439-1448.  
27.     Gupta AK, Ricci MJ. Diagnosing onychomycosis. Dermatol Clin. 2006;24(3):365-369.
28.     De Berker D. Clinical practice. Fungal nail disease. N Engl J Med. 2009;360(20):2108-2116.
29.     Khanna D, Bharti S. Luliconazole for the treatment of fungal infections: an evidence-based review. Core Evid. 2014; 9:113-24.
30.     Jarratt M, Jones T, Kempers S, et al. Luliconazole for the treatment of interdigital tinea pedis: a double-blind, vehicle-controlled study. Cutis. 2013; 91(4):203-210.
31.     Draelos ZD, Vlahovic TC, Gold MH, et al. A randomized, double-blind, vehicle-controlled trial of luliconazole cream 1% in the treatment of interdigital tinea pedis. J Clin Aesthet Dermatol. 2014; 7(10):20-27.
32.     Elewski BE, Vlahovic TC. Econazole nitrate foam 1% for the treatment of tinea pedis: results from two double-blind, vehicle-controlled, phase 3 clinical trials. J Drugs Dermatol. 2014; 13(7):803-8.
33.     Walling HW, Sniezek PJ. Distribution of toenail dystrophy predicts histologic diagnosis of onychomycosis. J Am Acad Dermatol. 2007;56(6):945-948.
34.     Sigurgeirsson B, Steingrimsson O. Risk factors associated with onychomycosis. J Eur Acad Derm Venereol. 2004;18(1):48-51.
35.     Szepietowski JC, Reich A, Garlowska E, et al. Factors influencing coexistence of toenail onychomycosis with tinea pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol. 2006;142(10):1279-1284.
36.     Markinson BC, Caldwell BD. Efinaconazole topical solution, 10%: efficacy in patients with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015; Apr 13 (Epub ahead of print).
37.     Gupta A, Konnikov N, MacDonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicenter study. Br J Dermatol. 1998;139(4):665-671.
38.     Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 2013; 148(6):603-608.
39.     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.
40.     Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004; 21(2):101-112.
41.     Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13(10):1186-1190.
42.     Silva AP, Chiandrone DJ, Tinta JW, Kurachi C, Inada NM, Bagnato VS. Development and comparison of two devices for treatment of onychomycosis by photodynamic therapy. J Biomed Opt. 2015;20(6):61109.

Editor’s note: For related articles, see “Current Concepts In Treating Onychomycosis In Patients With Diabetes” in the March 2015 issue of Podiatry Today and “Keys To Managing Severe Onychomycosis” in the May 2013 issue.