Drug Design, Development and Therapy
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`Spotlight on tavaborole for the treatment
`of onychomycosis
`
`Sphoorthi Jinna
`Justin Finch
`Department of Dermatology,
`University of Connecticut School
`of Medicine, Farmington, CT, USA
`
`Correspondence: Justin Finch
`Department of Dermatology,
`University of Connecticut School of
`Medicine, 21 South Road, Farmington,
`CT 06032, USA
`Tel +1 860 679 4600
`Fax +1 860 679 4759
`email finch@uchc.edu
`
`Abstract: Onychomycosis is a fungal nail plate infection that has been increasing in preva-
`lence. A variety of oral and topical anti-fungal agents are currently available but their use is
`limited by their adverse effect profile, drug–drug interactions, and limited efficacy. Therefore,
`there is a great need for newer anti-fungal agents. Tavaborole is one of these newer agents and
`was approved by the US Food and Drug Administration in July 2014 for the topical treatment
`of mild to moderate toenail onychomycosis. Tavaborole is a novel, boron-based anti-fungal
`agent with greater nail plate penetration than its predecessors, due to its smaller molecular
`weight. It has proven through several Phase II and III trials that it can be a safe and effective
`topical agent for the treatment of mild to moderate toenail onychomycosis without the need
`for debridement. In this paper, we review the landscape of topical and systemic treatment
`of onychomycosis, with particular attention to the pharmacokinetics, safety, and efficacy of
`topical tavaborole.
`Keywords: tavaborole, boron-based antifungals, oxaboroles, onychomycosis
`
`Introduction
`Onychomycosis is a fungal nail plate infection affecting between 10% and 30% of
`the global population1,2 and accounting for approximately one-half of all nail disor-
`ders seen in dermatology practices.3 Prevalence of the disease continues to increase,
`partly due to the growing elderly population,4 the increasing number of patients with
`diabetes mellitus,5,6 and the increase in peripheral vascular disease.7 If left untreated,
`it can spread to adjacent nails, to additional body sites, or to other individuals.8 Goals
`of onychomycosis therapy therefore include mycological cure (negative potassium
`hydroxide [KOH] or fungal culture) and a normal appearing nail. Currently, a variety
`of anti-fungal options, both topical and oral, are available.9 While oral medications
`are the gold standard of onychomycosis therapy, the side effect profile and drug–drug
`interactions are limiting to many patients.10 Therefore, effective topical remedies are
`heavily sought after by both patients and providers. Successful treatment, however,
`is often hindered by the topical agents’ limited ability to penetrate the nail.11 This can
`lead to a high incidence of relapse, often making onychomycosis a chronic condition
`for patients.12,13
`Current antifungal agents
`Before discussing the novel mechanism of the new class of boron-containing anti-
`fungals ushered in by tavaborole, it is worthwhile to review the existing antifungal
`landscape. Currently, there are several approved classes of antifungal drugs for the
`treatment of onychomycosis: allylamines, azoles, morpholines, and hydroxypyridi-
`nones, most of which target fungal cell membrane synthesis.14
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`Drugs of the allylamine class, including naftifine,
`butenafine, and terbinafine, inhibit squalene epoxidase, thereby
`blocking fungal ergosterol synthesis.15 Ergosterol is a sterol
`integral to fungal cell membrane synthesis, and without it many
`fungi cannot survive. Terbinafine (250 mg) taken orally for 12
`weeks is considered the current gold standard in onychomycosis
`therapy.16–18 Terbinafine’s superior efficacy may be due to the
`fact that it is strongly lipophilic and therefore distributes well
`into skin, fat, and nails.16 While this therapy is the gold stan-
`dard, mycologic cure rates with terbinafine are 73%–81%, with
`complete cute rates merely 23%–38%, indicating that current
`gold standards are still far from ideal. Also, periodic monitoring
`of liver function tests is recommended with terbinafine due to
`potential hepatotoxicity associated with this drug.16
`The azole drug class also inhibits ergosterol biosynthesis,
`but does so via inhibition of lanosterol 14α-demethylase.15
`This class can be subdivided into imidazoles and triazoles
`based on the drugs’ molecular structures.15 Currently,
`US Food and Drug Administration (FDA)-approved oral
`itraconazole19 and off-label oral fluconazole20 are used in
`the treatment of onychomycosis and are considered second
`and third line therapies, respectively. In June 2014, topical
`efinaconazole 10% nail solution was FDA approved for
`onychomycosis.21 Phase III trials indicated 15%–18%
`complete cure and 53%–56% mycologic cure with this
`topical regimen. This efinaconazole formulation represents
`an important advance in topical treatment of onychomycosis,
`but detailed discussion is beyond the scope of this paper.
`The morpholine drug class includes topical amorolfine,
`which is approved in Europe but not in the US.22 Amorolfine
`works to deplete ergosterol as well, through inhibition of
`D14 reductase and D7–D8 isomerase.23 Ciclopirox is a
`hydroxypyridinone drug with a poorly understood mecha-
`nism of action that may involve iron chelation or oxidative
`damage.24,25
`Finally, griseofulvin deserves mention as it was the
`first oral antifungal agent specifically approved for ony-
`chomycosis treatment in the US.26 A meta-analysis of three
`randomized trials using griseofulvin found a mycologic cure
`rate of approximately 60% with complete cure rates as low
`as 2%. Compared with the other systemic agents, griseofulvin
`has little role in current anti-fungal therapy given these low
`efficacy rates, high relapse rates, long treatment durations
`(12–18 months), and drug interactions as a potent CYP3A4
`inhibitor.26
`
`Topical antifungal therapy
`There has been a recent emergence of topical anti-fungal
`agents with improved nail permeation and efficacy.
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`Drug penetration through the nail plate is mostly predicted by
`low molecular weight in addition to the hydrophilic proper-
`ties of the drug.27 Varying the molecular targets of these new
`therapies can be invaluable as well, especially considering the
`high proportion of incomplete onychomycosis treatment lead-
`ing to antifungal resistance.28 Until June 2014, ciclopirox 8%
`nail lacquer was the only topical agent approved for onycho-
`mycosis in North America.29,30 Two double-blind, vehicle-
`controlled studies demonstrated complete cure (defined as
`clear nail and negative mycology by negative KOH and
`culture) in 5.5% and 8.5% of participants using ciclopirox
`solution. Negative mycology was noted in 29% and 36% of
`individuals.31
`
`Tavaborole
`The newest class of topical antifungal therapies is a novel drug
`class of boron-containing compounds called oxaboroles.32
`Boron has uniquely been found to bind functional groups at
`target sites of particular enzymes, thereby rendering them
`inaccessible and impairing their function. The first molecule
`in this class of drugs to achieve FDA approval in July 2014
`is tavaborole (formerly AN2690), which is formulated as a
`5% topical solution for the treatment of toenail onychomy-
`cosis (Table 1).33
`
`Nail penetration
`Tavaborole’s low molecular weight (approximately half of
`most antifungals, such as terbinafine and efinaconazole) per-
`mits optimal nail plate penetration, superior to that of existing
`topical antifungal medications.34 In a head-to-head study with
`ciclopirox, the amount of tavaborole 5% solution penetrating
`an ex vivo cadaver fingernail plate was 250-fold higher than
`ciclopirox 8% solution after 14 days of daily application
`(524.7 µg/cm2 vs 13.0 µg/cm2, respectively).32,35 In vitro
`nail penetration studies also show that tavaborole is better
`
`Table 1 Tavaborole at a glance
`Structure
`
`(cid:50)(cid:43)
`(cid:37)
`
`(cid:50)
`
`Mechanism of action
`
`(cid:41)
`5-fluoro-1,3-dihydro-1-hydroxy-2,1-
`benzoxaborole
`inhibits cytoplasmic leucyl-transfer RNA
`synthetase, interfering with fungal protein
`synthesis
`5% topical solution
`Commercial availability
`Apply daily ×48 weeks
`FDA-approved use
`Abbreviation: FDA, US Food and Drug Administration.
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`Tavaborole for onychomycosis treatment
`
`able to penetrate human nails compared with ciclopirox 8%
`and amorolfine 5% nail lacquers.35,36
`
`Mechanism of action
`Tavaborole possesses a unique mechanism of action making
`it highly specific against pathogenic fungi.37 Unlike existing
`antifungals that inhibit ergosterol synthesis (terbinafine,
`itraconazole, fluconazole, amorolfine, and efinaconazole) or
`microbial metabolism (ciclopirox), tavaborole interferes with
`protein synthesis in fungal cells by acting on cytoplasmic
`aminoacyl-transfer RNA (tRNA) synthetases.34 Tavaborole
`specifically binds with leucyl-tRNA synthetase in the editing
`site, thus preventing the synthesis of leucine-charged tRNAs
`and ultimately suppressing fungal cell activity.34 Tavaborole
`has a greater than 1,000-fold higher affinity for fungal leucyl-
`tRNA synthetase compared with the human version.34,38,39
`Therefore, human exposure is very low, providing a wide
`margin of safety.40
`
`Antifungal activity
`Tavaborole’s unique mechanism of action is shown
`to be effective across a wide range of fungal organ-
`isms. In in vitro studies, tavaborole shows minimal
`inhibitory concentrations (MICs) of 1–8 µg/mL against
`the dermatophytes Trichophyton mentagrophytes and
`Trichophyton rubrum (the primary causative agents of
`onychomycosis) and of #0.5–4 µg/mL against the dermato-
`phytes Trichophyton tonsurans (2–4 µg/mL), Epidermo-
`phyton floccosum (#0.5 µg/mL), Microsporum audouinii
`(2 µg/mL), Microsporum canis (2 µg/mL), and Microspo-
`rum gypseum (2 µg/mL).41 Specifically, both T. rubrum and
`T. mentagrophytes indicated an MIC50 of 4 µg/mL and an
`MIC90 of 8 µg/mL.41 The presence of 5% powdered keratin
`has no effect on the microbiological activity of the drug
`against T. rubrum (MIC 2 µg/mL).37,41 The drug is also active
`against the far less common nondermatophytic molds, such
`as Aspergillus fumigatus (MIC 0.25 µg/mL) and Fusarium
`solani (MIC #0.5 µg/mL), and yeast such as Candida albi-
`cans (MIC 1 µg/mL).41 Two weeks after the completion of
`28 days of treatment with tavaborole 7.5%, nail plate concen-
`trations above these MIC ranges are maintained; furthermore,
`therapeutic levels remain in the nail up to 3 months after
`treatment cessation, with drug levels corresponding to 161
`times the MIC90 for T. rubrum.30
`
`Phase ii trials
`Three Phase II clinical trials were conducted for tavaborole;
`two as open-label trials and one as a double-blind, dose-
`ranging, placebo-controlled trial.42 They all evaluated the
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`Drug Design, Development and Therapy 2015:9
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`treatment of distal and lateral subungual onychomycosis
`(DLSO; the most common form of onychomycosis) of at least
`one great toenail with 20%–60% nail plate involvement.42
`The Phase II portion of a Phase I/II open-label study
`examined the efficacy of tavaborole 7.5% in 15 adults
`aged 18–65 years.30 Participants had mycologically (KOH)
`confirmed onychomycosis of at least one great toenail, a
`clinical diagnosis of onychomycosis in at least six additional
`toenails, $80% involvement of both great toenails, and a
`combined great toenail plate thickness of .3 mm. Participants
`applied tavaborole 7.5% to all ten toenails and surrounding
`skin once daily for 28 days. Twenty-five great toenails were
`evaluated for efficacy by fungal culture or KOH. After only
`2 weeks of treatment, 88% (22/25) of toenails treated with
`tavaborole demonstrated conversion from positive to nega-
`tive culture. After 4 weeks of treatment, 100% mycologic
`clearance was noted.30
`A second, double-blind, vehicle-controlled, dose-ranging
`Phase II study was performed to investigate three concen-
`trations of tavaborole compared with vehicle.30 A total of
`187 patients with KOH- and culture-confirmed DLSO of
`the great toenail and 20%–60% involvement of the target
`nail were enrolled in the study. Participants applied vehicle
`(n=63), tavaborole 2.5% (n=33), tavaborole 5% (n=31), or
`tavaborole 7.5% (n=60) daily for 3 months and then three
`times per week for the subsequent 3 months. The primary
`efficacy endpoint was negative culture and either $2 mm of
`clear nail growth or an Investigator Static Global Assessment
`(ISGA) of clear or almost clear growth at 6 months. All con-
`centrations of tavaborole demonstrated a significantly greater
`therapeutic effect compared with vehicle after 6 months
`of treatment (clearance rates: 14% for vehicle, 27% for
`2.5% tavaborole, 26% for 5% tavaborole, and 32% for 7.5%
`tavaborole).30
`Another Phase II trial was composed of 89 individuals
`with KOH- and culture-confirmed DLSO of one great toenail
`and 20%–60% involvement of the target nail.30 Cohort 1
`(n=30) was treated with tavaborole 5% daily for 6 months,
`cohort 2 (n=30) was treated with a 7.5% concentration daily
`for 6 months, and cohort 3 (n=29) was treated with a 5%
`concentration daily for 12 months. The primary efficacy
`endpoint was a negative culture and either $2 mm of clear
`nail growth or an ISGA of clear or almost clear growth at
`6 months for cohorts 1 and 2, and at 12 months for cohort 3.
`After 6 months of treatment, efficacy rates were 43% and
`53% for cohorts 1 and 2, respectively. Following 12 months
`of treatment, the efficacy rate was 14% in cohort 3.30
`A final Phase II trial investigated 1% and 5% concentra-
`tions in 60 participants with mycologically confirmed DLSO
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`of the great toenail and 20%–60% involvement of the target
`nail.30 One group (n=30) applied tavaborole 1% daily for
`6 months and the other group (n=30) applied tavaborole 5%
`daily for the first 30 days and then three times per week for the
`following 5 months. The primary efficacy endpoint was nega-
`tive culture and either $2 mm of clear nail growth or an ISGA
`of clear or almost clear growth at 6 months. After 6 months of
`treatment with tavaborole, 30% and 50% efficacy rates were
`achieved with 1% and 5% concentrations, respectively.30
`
`Phase iii trials
`Two duplicate, multicenter, double-blind, randomized,
`vehicle-controlled Phase III trials were conducted for
`tavaborole 5% nail solution (trial 1, n=601; trial 2, n=593).
`Adults 18 years and older with DLSO of at least one great
`toenail with 20%–60% nail plate involvement without der-
`matophytoma or lunula involvement were enrolled. Subjects
`were randomized 2:1 to applying either tavaborole 5%
`solution or vehicle once daily for 48 weeks. The primary
`efficacy endpoint was complete cure of the target great toe-
`nail defined as negative mycology (KOH and culture) and
`completely clear nail at week 52. The complete cure rates
`for tavaborole were 6.5% and 9.1% (P=0.001 and ,0.0001,
`respectively), statistically superior to vehicle. Mycological
`cure rates were also significantly higher at 31.1% and 35.9%
`(P,0.001). Overall, once daily application of tavaborole 5%
`is significantly more effective than vehicle in the treatment
`of toenail onychomycosis.43 Comparison to other antifun-
`gal agents makes it an attractive therapeutic option as well
`(Table 2).26,44
`
`Safety
`Boron-containing compounds have been known for many
`years to exhibit high toxicity in insects, enabling their use
`as pesticides.45 But, in general, toxicity in mammals has not
`
`Table 2 Tavaborole compared to other oral and topical antifungal
`agents for the treatment of toenail onychomycosis
`
`Mycologic cure
`rate
`
`Clinical cure
`rate
`
`Complete
`cure rate
`
`Oral
`Griseofulvin
`Terbinafine
`itraconazole
`
`60%
`76%
`59% (continuous)
`63% (pulse)
`48%
`
`Fluconazole
`Topical
`Efinaconazole 10% 53%–56%
`Ciclopirox 8%
`29%–36%
`Tavaborole 5%
`30%–36%
`
`66%
`70% (continuous)
`70% (pulse)
`
`26%–28%
`
`15%–36%
`
`15%–18%
`5%–9%
`6%–10%
`
`been established. (In fact, boron itself may be an essential
`mineral in humans.46) That said, isolated reports have shown
`developmental or postnatal damage due to boron-containing
`compounds in rodents.47,48 Tavaborole, however, appears to
`have an excellent safety profile.
`In preclinical safety studies, a concentration of 10 µM
`of tavaborole did not inhibit the cytochrome P450 isoforms
`CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.30
`Plasma levels of tavaborole were below the limits of quan-
`titation after topical application of 0.25 mL of 7.5% solu-
`tion of tavaborole once daily for 28 days to the toenails
`of 15 subjects with onychomycosis.30 Another study of
`24 subjects found that only a small fraction of the topically
`applied dose of tavaborole is absorbed systemically and that
`the drug does not accumulate after repeated application.37
`Therefore, the risk for drug interactions with tavaborole is
`low.30 Further studies are needed, however, to confirm this
`finding in long-term use. In all, Phase II and III studies, none of
`the serious adverse events that occurred were deemed related
`to tavaborole, whereas the frequency of treatment-related
`adverse events were comparable to vehicle. The most com-
`mon adverse events were application site exfoliation (2.7% vs
`0.3% in the vehicle group), application site erythema (1.6%
`vs 0%), and dermatitis (1.3% vs 0%).30 They were generally
`mild to moderate and transient. Treatment discontinuation
`rates were low (2.5% and 0.8% in the two Phase III trials).37
`The carcinogenic potential of tavaborole was investigated
`in a traditional 2-year carcinogenicity study in mice and rats.43
`In mice, tavaborole was applied topically at concentrations of
`0%, 5% (clinically relevant concentration), 10%, and 15%.
`It was also administered orally to the rat at 0, 12.5, 25, and
`50 mg/kg/day. There were no tavaborole-related neoplastic
`findings in either species. This study provides evidence that
`tavaborole is not carcinogenic in rodents and is therefore suit-
`able for long-term use in humans.49 In a broader study, genetic
`toxicology studies were completed with four benzoxaboroles
`and one boronic acid ester and none of them demonstrated
`genetic toxicology liabilities, thus supporting the favorable
`safety profiles of tavaborole.50
`
`Conclusion
`Onychomycosis is a fungal infection that is steadily growing
`in prevalence and is in desperate need for highly effective
`and safe treatment options. Oral agents, while effective,
`come with a significant side effect profile and concern about
`drug–drug interactions. Therefore, good topical agents that
`can penetrate the nail plate while being safe and effective
`are paramount. Topical agents have historically had limited
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`Tavaborole for onychomycosis treatment
`
`efficacy given the low penetration through the nail plate.
`This leads to frustration, noncompliance, and recurrence in
`onychomycosis patients.
`The emergence of a new class of boron-containing drugs
`is exciting. The boron-containing molecule tavaborole offers
`a unique mechanism of action among antifungal agents,
`inhibiting leucyl-tRNA synthetase. Other boron-containing
`drugs under development for dermatologic disease inhibit
`phosphodiesterase-4, with potential applications for psoriasis
`and atopic dermatitis.33
`Tavaborole has been shown to effectively treat mild to
`moderate onychomycosis caused by dermatophytes without
`the need for debridement. It effectively penetrates the nail
`plate given its significantly lower molecular weight compared
`to other agents. While its mycologic cure rate (30%–36%)
`is lower than oral antifungal agents (50%–76%), it offers
`an important alternative to available topical antifungal
`therapies.
`Long-term studies need to be performed to assess both the
`full potential of the drug by providing more time for healthy
`regrowth of the nail and to assess recurrence rates. Head-to-
`head comparison studies of the efficacy of tavaborole vs efi-
`naconazole and ciclopirox for the treatment of onychomycosis
`would be of value. Given tavaborole’s unique mechanism of
`action, studies evaluating its use in combination with systemic
`antifungal therapy – for example, in preventing recurrence
`after systemic treatment – would be of interest as well.
`
`Disclosure
`The authors report no conflicts of interest in this work.
`
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