Infection and Drug Resistance
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`Efinaconazole in the treatment of onychomycosis
`
`Shari R Lipner
`Richard K Scher
`Department of Dermatology, Weill
`Cornell Medical College, New York,
`NY, USA
`
`Correspondence: Shari R Lipner
`Department of Dermatology, Weill
`Cornell Medical College, 1305 York
`Avenue, New York, NY 10021, USA
`Tel +1 646 962 3376
`email shl9032@med.cornell.edu
`
`Abstract: Efinaconazole 10% topical solution is a new triazole recently approved for the
` treatment of onychomycosis. It inhibits fungal lanosterol 14α-demethylase in the ergosterol bio-
`synthesis pathway, has potent antifungal activity against dermatophytes, as well as activity against
`Candida spp. and non-dermatophyte molds, and showed promising results in clinical trials. This
`review summarizes the mechanism of action, in vitro and in vivo data, clinical trials, safety, and
`quality-of-life data of efinaconazole as it applies to the treatment of onychomycosis.
`Keywords: efinaconazole, Jublia, onychomycosis, fungal infection, nail infection
`
`Introduction
`Onychomycosis is a fungal infection of the nail unit caused by dermatophytes, yeasts,
`and non-dermatophyte molds. It is a common disease, with a prevalence of 10%–12%
`in the US.1,2 It may cause both physical and psychological problems, as some patients
`present with pain, difficulty wearing shoes, secondary infection, and problems perform-
`ing everyday functions due to the resulting nail dystrophy or unacceptable cosmetic
`appearance. The treatment objective is to eradicate the fungus and produce a normal
`nail. The therapeutic innovations both in the 1990s and this past year have led to superior
`efficacy, more rapid treatment courses, and fewer drug–drug interactions. However,
`despite these improvements, approximately 20%–25% of patients will not respond to
`treatment,3 and relapse rates are high (10%–53%).4
`There are four approved classes of antifungal drugs for the treatment of
` onychomycosis: the allylamines, azoles, morpholines, and hydroxypyridinones.5 The
`allylamines (eg, terbinafine) inhibit squalene epoxidase, a step in the ergosterol bio-
`synthesis pathway.6 Oral terbinafine (250 mg daily) taken for 6 weeks for fingernails
`and 12 weeks for toenails is considered the current systemic treatment preference in
`onychomycosis therapy7 with a complete cure rate of 38% in 12-week studies, and
`mycological cure rate of 70%.8,9
`The second class of drugs is the azoles, which inhibit lanosterol 14α-demethylase,
`another step in the ergosterol biosynthesis pathway.5 Two members of this class that
`are widely used in treating onychomycosis are oral itraconazole10 and off-label oral
`fluconazole.11 The approved dose of oral itraconazole is 200 mg daily for 3 months
`(or an alternative pulse regimen) with a reported complete cure rate of 14% and
`mycological cure rate of 38%.10 Although fluconazole is not US Food and Drug
`Administration (FDA) approved for the treatment of onychomycosis in the US, it is
`used extensively in other countries and to some extent off-label in the US. In a study
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`Infection and Drug Resistance 2015:8 163–172
`© 2015 Lipner and Scher. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
`License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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`Kaken Exhibit 2055
`Acrux v. Kaken
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`of 362 patients with fingernail onychomycosis treated with
`oral fluconazole, complete cure rates were 48% in patients
`who received 450 mg weekly, 46% in those who received
`300 mg weekly, and 37% in those who received 150 mg
`weekly for up to 9 months.11
`Another class of antifungals is the morpholines including
`topical amorolfine, which is approved for use in Europe but
`not in North America.12 Amorolfine inhibits ∆14-reductase
`and ∆7-∆8-isomerase in the ergosterol biosynthesis pathway,
`thus depleting ergosterol.13 In one randomized controlled
`study, the combination of amorolfine nail lacquer and oral
`terbinafine compared to oral terbinafine alone resulted in a
`higher clinical cure rate (59.2% vs 46%); complete cure rate
`was not reported.12
`Finally, the hydroxypyridinone class includes topical
`ciclopirox, which has a poorly understood mechanism of
`action but may involve iron chelation or oxidative damage.14,15
`The FDA-approved ciclopirox 8% nail lacquer in 1999 for the
`treatment of mild-to-moderate onychomycosis of fingernails
`and toenails without lunula involvement, due to Trichophyton
`rubrum in immunocompetent patients. Complete cure rates are
`5.5%–8.5%, and mycological cure rates are 29%–36% with
`monthly nail debridement and removal of residual lacquer.16
`Until recently, ciclopirox had been the only FDA-approved
`option in the US for patients who had contraindications to oral
`antifungal agents, or preferred a topical treatment to avoid
`blood monitoring and potential for systemic side effects.
`Based on the potential drug–drug interactions and sys-
`temic side effects of oral agents and the poor-efficacy and
`time-consuming treatment courses of topical drugs, it is
`clear that there is a need for alternative and novel therapies.
`There has been a greater emphasis on topical agents due to
`their more favorable side-effect profile and lower risk for
`drug–drug interactions. Efinaconazole, a member of the
`azole class, previously called IDP-108 and KP-103, has
`potent antifungal activity against dermatophytes comparable
`to that of terbinafine and amorolfine, higher activity against
`Candida spp. than itraconazole, and has been comparable to
`terbinafine and more effective than amorolfine, ciclopirox,
`and itraconazole against non-dermatophyte molds.17 Triazoles
`(such as fluconazole and itraconazole) had been used orally
`previously but not topically for the treatment of onychomy-
`cosis. Their appeal derives from their moderate antifungal
`activity but broader spectra than allylamines and morpho-
`lines.18 Efinaconazole is the first azole FDA approved in the
`USA to be used topically in the treatment of onychomycosis.
`This review summarizes the mechanism of action, in vitro
`and in vivo data, clinical trials, safety, and quality-of-life
`
`(QoL) data of efinaconazole as it applies to the treatment of
`onychomycosis.
`
`Mechanism of action
`Fungal cell membranes are composed of the structural
`compound ergosterol, which maintains membrane fluid-
`ity, creates a permeability barrier, and is essential for
`fungal cell viability. It is believed that loss of ergosterol
`affects cell membrane integrity and function and inhibits
`fungal cell growth.19,20
`Using an ergosterol biosynthesis assay, it was shown
`that efinaconazole inhibited ergosterol biosynthesis in both
`Trichophyton mentagrophytes and Candida albicans, and
`was more active than two comparator drugs, itraconazole
`and clotrimazole. T. mentagrophytes hyphal morphology
`exhibited changes that were dependent on the efinaconazole
`concentration (Table 1). The authors concluded that the
`mechanism of action of efinaconazole is through inhibition
`of the ergosterol pathway, likely via 14α-demethylase, with
`secondary degenerative changes.21
`
`Chemistry and formulation
`Efinaconazole was synthesized as an azoleamine derivative
`by Kaken Pharmaceutical Co, and its chemical names are
`1-piperidineethanol, and α-(2,4-difluorophenyl)-β-methyl-
`4-methylene-α-(1H-1,2,4-triazol-1-ylmethyl)-, αR,βR-, or
`(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-
`yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.18 Its molecular for-
`mula is C18H22F2N4O with a molecular weight of 348.39.22 It
`was FDA-approved in the US for the topical treatment of toe-
`nail onychomycosis due to T. rubrum and T. mentagrophytes
`in June 2014, and its trade name is Jublia. The treatment
`course is once daily for 48 weeks, using a flow-through
`brush applicator with application to the affected toenail
`and its undersurface, nail folds, nail bed, and hyponychium.
`Two drops are needed for the great toenails, and one drop
`
`Table 1 Hyphal morphology changes with efinaconazole
`Efinaconazole concentration:
`Efinaconazole concentration:
`0.001–0.01 μg/mL
`0.1–10 μg/mL
`Shortening of interseptal
`Nonuniform widths and flattening
`distance
`of hyphae
`Globular swelling
`Separation of plasma membrane
`from the cell wall
`Accumulation of electron-dense
`granules between the cell wall and
`the plasma membrane
`Discontinuity of the plasma membrane
`Degeneration of organelles
`
`Thickening of the cell
`
`Notes: Data from Tatsumi et al.21
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`Efinaconazole and onychomycosis
`
`is needed for other affected toenails. No debridement is
`necessary. It is formulated as a 10% solution, containing
`100 mg of efinaconazole per gram of a clear, colorless to pale
`yellow solution. Inactive ingredients are alcohol, anhydrous
`citric acid, butylated hydroxytoluene, C12-15 alkyl lactate,
`cyclomethicone, diisopropyl adipate, disodium edetate, and
`purified water.23 It has low surface tension, which aids in
`penetration and spreading, and is sparingly soluble in water.24
`The drug accesses the site of infection by both transungual
`delivery25 and spreading through the subungual space.26 It
`is supplied in 4 mL or 8 mL bottles and should be stored at
`room temperature. While not published by manufacturer,
`judging from patient use, there are approximately 80 drops
`in a 4 mL bottle. Since there have been no studies of the drug
`in pregnant women, it is labeled pregnancy class C, with a
`warning that it “should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus”. With
`repeated subcutaneous administration, efinaconazole was
`found in milk of nursing rats; however, it is unknown if efi-
`naconazole is excreted into human milk. Therefore, the FDA
`states that caution should be exercised when efinaconazole
`is prescribed to women who are breastfeeding.23
`
`In vitro and in vivo studies
`In vitro studies showed that efinaconazole had potent activity
`against C. albicans, Cryptococcus neoformans, Aspergillus
`fumigatus, and T. mentagrophytes, similar to other syn-
`thesized azoleamine agents.18 Since the activities of many
`antifungal drugs are inhibited with keratin binding,27 efina-
`conazole’s activity was tested against T. mentagrophytes in
`the presence of keratin. Efinaconazole demonstrated less
`deactivation than its comparators in the presence of keratin,
`which was attributed to its 4-methylenepiperidino group. In
`addition, it showed the highest efficacy compared to other
`drugs against T. mentagrophytes in a guinea pig model of
`tinea corporis and showed better penetration via both the
`transfollicular and transepidermal routes.18
`Efinaconazole was subsequently shown to have excellent
`in vitro activity against T. rubrum and T. mentagrophytes,
`surpassing that of the reference drugs neticonazole and
`clotrimazole but less so than lanoconazole and butenafine.
`A similar effect was seen for the organisms, Trichophyton
`violaceum, Trichophyton ajelloi, Microsporum canis,
`Microsporum gypseum, and Epidermophyton floccosum.
`Efinaconazole was also more active against C. albicans, other
`Candida spp., and Malassezia furfur than the reference drugs.
`In addition, efinaconazole was the only agent whose activity
`against T. mentagrophytes was unaffected by the presence
`
`of serum or keratin. In vivo, topical efinaconazole achieved
`mycological cure in 80% of guinea pigs with experimental
`cutaneous candidiasis caused by C. albicans, but the refer-
`ence drugs (clotrimazole, neticonazole, and lanoconazole)
`were ineffective in even decreasing the counts of fungi in
`the infected sites. In addition, in a guinea pig model of tinea
`pedis infected with T. mentagrophytes, 10 days of topical
`efinaconazole led to a dose-dependent therapeutic effect,
`which was almost maximal at a drug concentration of 1.0%
`and achieved negative culture results for all infected feet.
`This effect was considerably better than that of neticonazole
`and equal to that of lanoconazole and butenafine. The authors
`concluded that while the antidermatophytic activity of efina-
`conazole was similar to that of neticonazole and inferior to
`butenafine and lanoconazole, the drug might have superior
`efficacy in vivo due to its pharmacokinetics in infected skin
`tissues.28
`Based on these earlier findings, efinaconazole’s efficacy
`was analyzed in guinea pig models of T. mentagrophytes
`interdigital tinea pedis and tinea corporis, as well as its
`ability to prevent relapses following treatment. The 1%
`efinaconazole solution resulted in a dose-dependent thera-
`peutic effect in both infections, with all affected sites being
`culture negative. In the tinea pedis model, 30 days after the
`end of treatment (day 49 postinfection), relapse occurred in
`only 4/20 treated feet, while in the untreated control group,
`the infection continued without spontaneous healing. In the
`tinea corporis model, relapse occurred in only 3/10 animals
`treated with efinaconazole 9 days following treatment (day
`21 postinfection), while the infection continued without
`spontaneous healing in the untreated group. In addition,
`when topical efinaconazole was applied 24–96 hours prior
`to T. mentagrophytes inoculation of skin in the tinea corpo-
`ris model, the number of culture-positive animals 14 days
`postinfection was reduced. While this prophylactic effect was
`observed at all the recorded time points, the maximal effect
`was seen at 24 hours and 48 hours. Furthermore, when the
`binding capacity of efinaconazole was analyzed in an in vitro
`model, it was much lower (60.3%) than either lanoconazole
`(94.9%) or butenafine (99.4%). Finally, efinaconazole was
`released more readily from keratin when washed with saline
`(84.7% released) than lanoconazole (31.3% released) and
`butenafine (5.2% released). The investigators concluded that
`efinaconazole has the potential to achieve mycological cure
`in tinea pedis and tinea corporis infections and to prevent
`relapse.29
`Investigators sought to overcome the problem with
`evaluating the treatment efficacy in animal models due
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`to drug carryover in the treated tissues associated with
`conventional culture techniques. To do this, they developed
`a modified recovery culture method to remove antifungal
`drugs from treated tissue using stepwise dialysis with water,
`trypsin digestion, and phosphate-buffered saline rinses.
`Using this new method, in a guinea pig model of tinea
`pedis in which drug was applied topically for 10 days and
`then evaluated 5 days after the last application, they found
`that 20/20 lanoconazole-treated feet were culture negative
`with the conventional culture method, but only 3/20 were
`culture negative with the newer method. In contrast, culture-
`negative rates were 19/20 and 17/20 in efinaconazole-treated
`feet with conventional and modified methods, respectively.
`Furthermore, using this updated method, they found that on
`posttreatment day 30, 14/20 of the infected feet treated with
`efinaconazole were culture negative, while the two reference
`drugs neticonazole and lanoconazole could not even diminish
`the fungal burden.30
`In another study, it was shown that amorolfine and terbi-
`nafine were tightly bound to keratin and less active against
`dermatophytes in the presence of keratin, while efinaconazole
`is less tightly bound and exhibits better pharmacokinetics
`against fungi. It was also shown that efinaconazole was
`released more readily when bound to keratin than the other
`reference drugs. In addition, in a guinea pig model, while
`amorolfine and terbinafine reduced or eradicated the fungal
`burden in plantar skin tissues, these drugs were unsuccessful
`in reducing fungal burden in nails, likely via inactivation by
`keratin. On the other hand, efinaconazole was effective in
`both reducing the fungal burden in nails and curing infec-
`tions in plantar skins, likely due to its lower affinity for
`keratin.31
`In another report, the authors found that efinaconazole
`had a sevenfold higher free-drug concentration in the pres-
`ence of keratin than both ciclopirox and amorolfine, and that
`this lower affinity for keratin was associated with faster nail
`penetration and fungicidal activity. They also found that
`efinaconazole inhibited growth of T. rubrum in an in vitro
`model of healthy human nails.32
`In another recent study, the investigators characterized the
`in vitro antifungal activity of efinaconazole by analyzing its
`activity against recent clinical isolates recovered from ony-
`chomycosis patients (T. rubrum, T. mentagrophytes, and C.
`albicans isolates) and comparing that activity to that of terbi-
`nafine, ciclopirox, itraconazole, and amorolfine. They showed
`that efinaconazole had potent antifungal activity within a
`narrow concentration range (ie, #0.002–0.06 µg/mL), with
`no geographical differences in susceptibility patterns between
`
`North American (US and Canada) and Japanese isolates.17 It
`should be noted that the efinaconazole minimal inhibitory
`concentrations (MICs) in this study were approximately 13–63
`times lower than previously reported in a study of Japanese
`T. rubrum and T. mentagrophytes clinical isolates.28 The
`authors attribute this difference to different culture techniques
`in the two studies.17 Using the MIC50 and MIC90 data, they
`showed that efinaconazole was at least as effective against T.
`rubrum and T. mentagrophytes (one- to fourfold) as amorolfine
`and terbinafine and higher (eight- to 64-fold) than ciclopirox
`and itraconazole. They also showed that efinaconazole was
`more potent in inhibiting C. albicans growth than terbinafine,
`ciclopirox, itraconazole, and amorolfine. They also studied
`efinaconazole’s antifungal activity in 33 other fungal spe-
`cies and found that the drug was active against all species
`tested, with MIC ranges of #0.002–0.5 µg/mL for dermato-
`phytes, #0.002–0.13 µg/mL for yeasts, and 0.0078–2 µg/mL
`for non-dermatophyte molds. On the whole, efinaconazole
`was more active against molds and yeasts than amorolfine,
`ciclopirox, itraconazole, and terbinafine, and its antifungal
`spectrum was broader than that of the existing drugs.17
`Efinaconazole was tested for its ability to induce resis-
`tance in dermatophytes by continuous exposure of T. rubrum
`strains to the drug in vitro (12 passages) and in a guinea pig
`onychomycosis model (8 weeks).33 Resistance is an important
`feature to consider in treating patients, as topical treatments
`are typically used for a year and recurrences are common.34
`Resistance may be due to a stress reaction in fungi with
`induction of drug efflux pumps.35 Interestingly, there was no
`suggestion of efinaconazole resistance in either the in vitro
`or in vivo experiments.33
`
`Pharmacokinetics
`Pharmacokinetic data were analyzed in healthy volunteers
`(n=10) and patients with severe onychomycosis ($80% sur-
`face area of both great toenails) (n=20) in two single-center
`open-label studies (Phase I). Efinaconazole was applied to the
`healthy volunteers by staff on day 1, and then on days 4–10,
`for a total of eight doses and applied to the onychomycosis
`patients daily for 28 days.36
`The data showed that efinaconazole is absorbed slowly,
`lacks an elimination phase,36 and is metabolized through
`both oxidation and reduction, yielding an H3 metabolite.23
`The concentration of efinaconazole and its metabolite was
`approximately 3.6-fold and 5.8-fold greater on day 10 than on
`day 1 in healthy volunteers and 6.8-fold and 30.5-fold greater
`on day 28 than day 1 in onychomycosis patients, indicating
`that the drug accumulates with successive applications.
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`Efinaconazole and onychomycosis
`
`After five doses (day 8) in healthy volunteers and 14 doses
`(day 14) in onychomycosis patients, the drug and metabolite
`reached steady-state concentrations. The median half-life of
`drug and its metabolite at day 10 in healthy volunteers was
`29.9 hours and 82.4 hours, respectively. In addition, the drug
`and metabolite were detected in plasma 2 weeks after the
`final dose in patients with onychomycosis. Taken together,
`the data suggest that efinaconazole and its metabolite have
`long elimination half-lives. Blood concentrations of efina-
`conazole and its metabolite were very low in both groups of
`patients, signifying that systemic exposure was negligible.
`Specifically, the concentrations of efinaconazole and its H3
`metabolite were 1.47 ng/mL and 7.45 ng/mL, respectively.36
`This is in contrast to daily orally administered itraconazole
`(200 mg) and terbinafine (250 mg) with steady-state plasma
`level greater than 1,000 ng/mL.37,38 The investigators also
`noted that while efinaconazole is a potent inhibitor of several
`cytochrome P450 enzymes, its calculated Cmax/ki is 0.007
`and that of its metabolite is 0.0005, both of which are well
`below the threshold for clinical drug–drug interactions.36
`Protein-binding affinity is 95.8%–96.5%, binding princi-
`pally to albumin, α1-acid glycoprotein, and γ-globulin.23
`The authors suggested that since efinaconazole is highly
`plasma protein bound, the potential for in vivo drug–drug
`interactions is remote.36
`Design and results from clinical
`trials
`Phase II trial
`A multicenter, randomized, parallel-group, double-blind,
`vehicle-controlled study (NCT00777868) was conducted in
`Mexico in 135 patients with mild-to-moderate distal lateral
`subungual onychomycosis (DLSO) of the toenails. Primary
`endpoints were complete and mycological cure. Inclusion
`criteria and exclusion criteria are shown in Table 2. Patients
`who were taking medications that inhibit cytochrome P450
`3A4 were not excluded.
`Patients were randomized to one of four groups (2:2:2:1
`ratio), namely efinaconazole 10% topical solution with
`semiocclusion (n=36), efinaconazole 10% topical solution
`(n=39), efinaconazole 5% topical solution (n=38), or vehicle
`(n=22). The patients applied the medication once daily for
`36 weeks, followed by a treatment-free follow-up period of
`4 weeks. Demographics were similar between groups with
`mean age of 42.8 years and 54.1% female, and all were
`Hispanic/Latino. The mean area of the target toenail was
`40.3%, and the mean number of affected nontarget toenails
`(including great toenails and other affected toenails) was
`
`Table 2 Inclusion and exclusion criteria for efinaconazole Phase II
`clinical trial
`
`Inclusion criteria
`DLSO affecting at least
`one great toenail
`Age 18–65 years
`Clinical involvement 20%–50%
`of the target toenail
`
`Target toenail with uninfected
`length (from the proximal nail
`fold) $3 mm
`Target toenail with
`thickness #3 mm
`Evidence of toenail growth
`
`Exclusion criteria
`Dermatophytoma (fungal abscess)
`
`Matrix (lunula) involvement
`History of immunosuppression
`and/or clinical signs indicative of
`possible immunosuppression
`Known human immunodeficiency
`virus infection
`
`Uncontrolled diabetes mellitus
`
`Presence of toenail infection other
`than dermatophytes and Candida
`Severe moccasin-type tinea pedis
`at the screening or baseline visits
`Any disease/condition that might
`have caused toenail abnormalities
`
`Previous target toenail surgery
`
`Positive potassium hydroxide
`microscopy
`Culture of a dermatophyte or
`mixed dermatophyte/Candida
`#42 days before baseline visit
`Women of childbearing
`potential had to be using
`effective birth control
`Notes: Data from Tschen et al.39
`Abbreviation: DLSO, distal lateral subungual onychomycosis.
`
`4.9. Overall, 117 (86.7%) of subjects completed the study.
`The most frequent reasons for study discontinuation were lost
`to follow-up (n=8, 5.9%), subject request (n=3, 2.2%), and
`adverse events (AEs) (n=3, 2.2%). The data for complete and
`mycological cures at week 36 are shown in Table 3.39
`Based on its greater efficacy in this Phase II trial, efina-
`conazole 10% solution (without semiocclusion) was chosen
`for treatment in the Phase III program. Another parameter that
`was analyzed was mean percent toenail involvement in the
`target toenail. At baseline, subjects had approximately 40%
` involvement. At week 36, percent involvement decreased
`to less than 19% in the efinaconazole-treated groups but
`was 35.7% in the vehicle group at week 36 (P#0.0215).
` Furthermore, the target toenail grew faster (4.7 mm and
`3.8 mm, in the efinaconazole 10% and 5% groups, respec-
`tively) than in the vehicle group (1.8 mm) (P#0.0196) and
`week 36. In terms of safety, adverse effects were generally
`mild (75%–79.7%) and similar between active drug and
`vehicle. Treatment-emergent adverse effects related to the
`study groups were blister, contact dermatitis, erythema, and
`ingrowing nail, none of which caused patients to discontinue
`the study.39
`
`Phase III trials
`Two identical, randomized, double-blind, vehicle-controlled
`Phase III studies (NCT01008033 and NCT01007708) were
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`Table 3 Results from the four treatment arms in efinaconazole Phase II trial
`Efinaconazole 10% solution
`with semiocclusion
`22.2%
`83.3%
`61%
`
`Complete cure (week 36)
`Mycological cure (week 36)
`Mycologic cure and either an affected target toenail area
`of 0% or .3 mm proximal nail growth from baseline
`in the unaffected target toenail (week 36)
`,20% of affected target toenail area (week 36)
`Notes: Data from Tschen et al.39
`Abbreviation: N/A, not available.
`
`Efinaconazole
`10% solution
`25.6%
`87.2%
`64%
`
`Efinaconazole
`5% solution
`15.8%
`86.8%
`55%
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`Dovepress
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`Vehicle
`
`9.1%
`N/A
`23%
`
`32%
`
`67%
`
`69%
`
`N/A
`
`performed in patients with onychomycosis treated with
` efinaconazole 10% solution to assess the primary endpoint of
`complete cure rate at week 52. The four secondary endpoints
`were mycological cure, complete or almost-complete cure
`(defined as less than or equal to 5% clinical involvement
`with mycological cure), treatment success (defined as ,10%
`clinical involvement of the target nail), and unaffected toenail
`growth. Other parameters investigated included change in the
`number of affected nontarget toenails, change in QoL, and
`target toenail growth.40
`Patients qualified for the trial if they were 18–70 years
`old with clinical diagnosis of DLSO affecting 20%–50% of
`at least one great toenail, and had 3 mm of uninfected nail
`measured from the proximal nail fold, nail thickness 3 mm
`or less, and evidence of toenail growth. Potassium hydroxide
`and culture showing a dermatophyte or mixed infection had
`to have been positive within 42 days of starting treatment.
`Those patients with dermatophytomas or matrix (lunula)
`involvement were excluded. Immunosuppressed patients,
`as well as patients with uncontrolled diabetes mellitus,
`non-dermatophyte infection, severe moccasin tinea pedis,
`previous great toenail surgery, or other nail diseases, were
`also excluded.40
`Patients were randomized to receive treatment with efina-
`conazole 10% solution or vehicle (3:1) self-applied to the nail
`plate and undersurface, lateral and proximal nail folds, and
`the hyponychium for 48 weeks. They were evaluated at weeks
`0, 12, 24, 36, and 48 and then at 4 weeks posttreatment.
`One thousand six hundred and fifty-five patients partici-
`pated in the two studies with 118 sites in the US, Canada, and
`
`Table 4 Results from efinaconazole Phase III trials
`Efinaconazole 10% solution
`(n=656) (study 1)
`17.8%
`55.2%
`26.4%
`35.7%
`5.0
`
`Complete cure (primary endpoint)
`Mycological cure
`Complete or almost-complete cure
`Treatment success
`Unaffected toenail growth (mm)
`Notes: Data from Elewski et al.40
`
`Japan. Demographic data were similar for patients treated
`with efinaconazole and with vehicle. For studies 1 and 2,
`respectively, the mean ages were 52.3 years and 50.6 years,
`with the majority of patients being male (74.4% and 80.4%,
`respectively). Most patients were white (64.9% and 87.8%);
`however, in one study, there were a significant number of
`Asian patients (29%), since there were 33 trial sites in Japan.
`Mean target toenail involvement was 36.7% and 36.3%, and
`the mean number of nontarget nails involved was 2.8 in both
`studies. Total of 85.8% of patients completed the studies and
`of the patients who discontinued, reasons in order of frequency
`were patient request, lost to follow-up, adverse effects, proto-
`col violation, other worsening condition, and pregnancy.40
`For the primary endpoint, complete cure, 17.8% and
`15.2% of patients on efinaconazole, in studies 1 and 2,
`respectively, achieved the desired result at week 52, in
`contrast to patients on vehicle (3.3% and 5.5%, P,0.001).
`For the secondary endpoint of mycological cure, 55.2% and
`53.4% of patients on efinaconazole achieved this result as
`compared to vehicle (16.8% and 16.9%, P,0.001). Data for
`primary and secondary endpoints as well as other parameters
`are shown in Table 4.
`The medication was well tolerated, and the AE profile
`was similar between patients treated with efinaconazole
`(66% and 64.5%) and with vehicle (61% and 58.5%). The
`most common AEs were nasopharyngitis, upper respiratory
`tract infection, and sinusitis (Table 5). Note that the numbers
`in Tables 4 and 5 vary due to patients who discontinued the
`trial. Very few patients discontinued the trial due to AEs
`(efinaconazole: 3.2% and 1.9%, vehicle: 0.5% and 0%), and
`
`Vehicle (n=214)
`(study 1)
`3.3%
`16.8%
`7.0%
`11.7%
`1.6
`
`Efinaconazole 10% solution
`(n=583) (study 2)
`15.2%
`53.4%
`23.4%
`31.0%
`3.8
`
`Vehicle (n=202)
`(study 2)
`5.5%
`16.9%
`7.5%
`11.9%
`0.9
`
`168
`
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`Efinaconazole and onychomycosis
`
`Table 5 Most common adverse effects in efinaconazole trials
`Efinaconazole 10% solution
`(n=653) (study 1)
`78 (11.9%)
`38 (5.8%)
`30 (4.6%)
`22 (3.4%)
`15 (2.3%)
`
`Nasopharyngitis
`Upper respiratory tract infection
`Sinusitis
`Eczema
`Headache
`Notes: Data from Elewski et al.40
`
`Vehicle (n=213)
`(study 1)
`25 (11.5%)
`13 (6.1%)
`4 (1.9%)
`7 (3.3%)
`5 (2.3%)
`
`Efinaconazole 10% solution
`(n=574) (study 2)
`63 (11.0%)
`35 (6.1%)
`17 (3.0%)
`–
`25 (4.4%)
`
`Vehicle (n=200)
`(study 2)
`15 (7.5%)
`11 (5.5%)
`5 (2.5%)
`–
`7 (3.5%)
`
`the most common reason was application-site dermatitis and
`vesicles.40
`
`Other safety data
`To address short- and long-term tolerability of efinacon-
`azole, 239 healthy volunteers were enrolled in a study
`evaluating the likelihood of the drug to induce delayed
`contact skin sensitization and its skin irritation potential.
`For the contact sensitization study, there were induction,
`challenge, and rechallenge (if required) phases for both the
`drug and the vehicle. In 99.5% (206/207) of patients tested
`with drug and 99.0% (205/207) with vehicle, there was no
`evidence of contact sensitization. In the three patients who
`were rechallenged, the one patient who received efinacon-
`azole did not have contact sensitization with occlusive,
`semiocclusive, or open applications. However, in the two
`patients who received vehicle upon rechallenge, there was
`likely an allergic reaction. Thirty-seven patients underwent
`a 21-day cumulative irritation study, receiving applications
`of efinaconazole 1%, 5%, and 10% solutions as well as
`the positive control 0.2% sodium lauryl sulfate and the
`negative control deionized water. The calculated mean
`cumulative irritancy indices (based on erythema scores)
`were 1.12, 1.26, and 1.18 for the efinaconazole solutions,
`respectively, 1.04 for the vehicle, and 2.77 and 0.30 for the
`positive and negative controls, respectively. The authors
`concluded from their data that efinaconazole 10% solu-
`tion did not cause contact sensitization and ind