REVIEW
Efinaconazole 10% Nail Solution: A New Topical Treatment with Broad Antifungal Activity for Onychomycosis Monotherapy Aditya K. Gupta and Maryse Paquet Background: Topical therapies for onychomycosis are associated with less adverse events than systemic therapies, but poor nail penetration limits their efficacy. Consequently, an efinaconazole 10% nail solution was developed. Objective: To review the evidence supporting the usefulness of efinaconazole monotherapy in onychomycosis management. Methods: PubMed and clinicaltrials.gov databases and abstracts from the 2013 annual meeting of the American Academy of Dermatology were searched in April 2013 using the terms ‘‘efinaconazole,’’ ‘‘IDP-108,’’ and ‘‘KP-103.’’ Results: In vitro, efinaconazole possesses a broad antifungal activity similar or superior to that of other antifungals. Its low affinity for keratin results in good nail penetration. Efinaconazole 10% nail solution administered daily for 36 or 48 weeks to treat mild to moderate toenail onychomycosis caused by dermatophytes results in complete and mycologic cure rates of 15 to 25% and 53 to 87%, respectively. No serious skin reaction is associated with its use. Conclusion: Efinaconazole 10% nail solution is a promising new treatment for onychomycosis. Contexte: Les traitements topiques de l’onychomycose sont associe´s a` moins d’effets inde´sirables que les traitements a` action ge´ne´rale, mais leur faible capacite´ de pe´ne´tration dans l’ongle en limite l’efficacite´. Aussi une solution d’e´finaconazole a` 10% pour les ongles a-t-elle e´te´ e´labore´e. Objectif: L’e´tude visait a` examiner les donne´es probantes a` l’appui de l’utilite´ de l’e´finaconazole en monothe´rapie dans la prise en charge de l’onychomycose. Me´thode: Une recherche a e´te´ mene´e, en avril 2013, dans les bases de donne´es PubMed et clinicaltrials.gov ainsi que dans les re´sume´s du congre`s annuel de 2013 de l’American Academy of Dermatology, a` l’aide des termes «efinaconazole», «IDP-108», et «KP103». Re´sultats: L’e´finaconazole te´moigne, in vitro, d’une large activite´ antifongique, comparable ou supe´rieure a` celle d’autres antifongiques. Sa faible affinite´ pour la ke´ratine permet une bonne pe´ne´tration dans l’ongle. L’application quotidienne de la solution d’e´finaconazole a` 10% pour les ongles, pendant 36 ou 48 semaines, pour traiter une onychomycose le´ge`re ou mode´re´e des ongles d’orteil, cause´e par des dermatophytes, a permis des taux de gue´rison comple`te et mycologique de 15 a` 25% et de 53 a` 87%, respectivement. Aucune re´action cutane´e n’a e´te´ associe´e a` l’emploi du produit. Conclusion: La solution d’e´finaconazole a` 10% pour les ongles se re´ve`le un nouveau traitement prometteur de l’onychomycose.
NYCHOMYCOSIS is a fungal infection of nails caused by dermatophytes, nondermatophyte molds, and/or yeasts. The two most frequent types of onychomycosis are
O
From the Department of Medicine, University of Toronto, Toronto, ON, and Mediprobe Research Inc., London, ON. Address reprint requests to: Aditya K. Gupta, MD, PhD, FRCPC, FAAD, 645 Windermere Road, London, ON N5X 2P1; e-mail: agupta@ execulink.com.
DOI 10.2310/7750.2013.13095 # 2014 Canadian Dermatology Association
toenail dermatophyte onychomycosis and fingernail Candida onychomycosis.1–12 The incidence of Candida onychomycosis is higher in patients with a defective immune system, such as immunosuppressed or diabetic patients.13 Based on recent species identification studies using molecular techniques, mixed infections can be more common than previously reported.14 Antifungals currently used to treat onychomycosis can be divided into four chemical classes: (1) azoles (itraconazole and fluconazole), (2) allylamines (terbinafine), (3) hydroxypyridinone (ciclopirox), and (4) morpholines (amorolfine). The mechanism of action of these antifungals
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is the inhibition of the synthesis of ergosterol, an important component of the fungal cell membranes required for membrane integrity and fungal growth, with the exception of ciclopirox, which impairs microbial metabolism. The resulting effect is in vitro fungistatic and/or fungicidal activity.15,16 These onychomycosis treatments possess different in vitro antifungal activities against dermatophytes, nondermatophyte molds, and yeasts.17–24 Terbinafine and itraconazole are, respectively, the most potent antifungals against dermatophytes and Candida spp. The antifungals used to treat onychomycosis generally have low antifungal activity against nondermatophyte molds. A new azole, efinaconazole, also known as IDP-108 and KP-103, has been shown to possess antifungal activity similar to that of terbinafine and amorolfine against dermatophytes. Efinaconazole was also more potent than itraconazole against Candida spp. Against nondermatophyte molds, efinaconazole was similar to terbinafine and more potent than amorolfine, ciclopirox, and itraconazole.25 To reduce possible adverse events and drug–drug interactions associated with systemic therapies, efinaconazole was developed as a topical treatment for onychomycosis. The aim of this review is to summarize the available evidence on the usefulness of topical efinaconazole in the treatment of onychomycosis.
Efinaconazole: A Unique Antifungal The lower affinity of efinaconazole for keratin compared to other antifungals, such as amorolfine, ciclopirox, and terbinafine, resulted in less inhibition of its antifungal activity by keratin and better skin and nail penetration.26–28 High levels of efinaconazole (< 5 mg/g) were detected in the toenail after daily treatment with efinaconazole 5 or 10% nail solution for 4 weeks, whereas the plasma concentration stayed relatively low (0.7–2.3 ng/mL).29 This allowed efinaconazole to be the first topical triazole to be developed for monotherapy of onychomycosis. Similar to other azoles, efinaconazole inhibits sterol 14a-demethylase (14-DM) enzyme in the ergosterol biosynthesis pathway.30 In early in vitro pharmacologic studies with 39 isolates of the dermatophyte Trichophyton rubrum and 28 isolates of the dermatophyte Trichophyton mentagrophytes, the minimal fungicidal concentrations and the minimal inhibitory concentrations (MICs) were similar, suggesting fungicidal activity.31 Based on the minimal intracellular phosphate leakage from dermatophytes and Candida albicans treated with efinaconazole, degenerative changes are probably not due to direct damage to the fungal cell membrane and might be secondary to the 152
inhibition of ergosterol biosynthesis.30 With the exception of globular swelling, which was unique to efinaconazole, the morphologic and ultrastructural changes observed were similar to the ones previously observed with itraconazole.30 The development of antifungal resistance can be investigated in vitro by subculturing fungal species for 10 to 12 passages in the presence of the subinhibitory concentration of the antifungal. By using this technique with six T. rubrum strains, a small two- to four fold increase in efinaconazole MIC was observed with only two strains (33%).32 In a similar study using 30 strains of T. rubrum, an increase in MIC was observed with 24 strains (80%, 2- to 64-fold increase) with itraconazole and in 17 strains (56.7%, 2- to 4-fold increase) with fluconazole.33 Overall, the potential for dermatophytes to develop resistance is reduced with efinaconazole compared to other azoles. This finding was confirmed by comparing the MICs of T. rubrum isolates pre- and posttreatment with daily efinaconazole for 48 weeks. These isolates were taken from 10 uncured participants in the phase III trials (see below). Only a minimal increase in MICs was observed for six of the participants.25
Clinical Efficacy One phase II34 and two phase III35 clinical trials investigated the efficacy of efinaconazole for mild to moderate (20–50% of nail surface affected) onychomycosis. Efinaconazole solutions were applied once daily without de´bridement for 36 weeks (phase II) or 48 weeks (phase III). The topical formulations used were slightly different between the phase II and phase III studies (personal communication, Valeant Canada, 2012: development formulation in phase II; commercial formulation in phase III). All studies included participants with toenail distal lateral subungual onychomycosis caused by dermatophytes or mixed infection of dermatophytes with Candida spp. Unfortunately, the number of participants with mixed infection was not reported in the baseline characteristics of the studied population and the efficacy data were not reported separately for the possible mixed infection population. Because toenail onychomycosis due to mixed dermatophyte and Candida infection is probably rare, the efficacy data reported in these studies would be considered relevant for toenail onychomycosis caused by dermatophytes. The phase II clinical trial was a randomized, placebocontrolled, double-blind study performed in Mexico. The mean age of the mestizo Hispanic participants was
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42.8 years, and 45.9% of the participants were male. The mean affected nail surface area of the target toenail was 40.3% at baseline. All efficacy assessments were performed at week 40 and analyzed on an intention-to-treat population (Table 1). Overall, better efficacy was obtained with the efinaconazole 10% nail solution compared to the efinaconazole 5% nail solution, and semiocclusion did not improve the efficacy of the 10% solution. The phase III clinical trials were also randomized, placebo-controlled, double-blind studies, but they were performed in the United States (studies 1 and 2), Canada (studies 1 and 2), and Japan (study 1). The mean age of the participants was 52.3 years in study 1 and 50.6 years in study 2. The participants were mainly white (64.9% in study 1 and 87.8% in study 2). Most of the participants were male (74.4% in study 1 and 80.4% in study 2). Similar mean affected nail surface areas of the target toenail of 36.7 % and 36.3% were obtained for the two studies at baseline. All efficacy assessments were performed at week 52 and analyzed in an intention-to-treat population (Table 2). For all outcomes, efinaconazole 10% nail solution was significantly more effective than placebo against dermatophyte onychomycosis. As shown in Table 1 and Table 2, higher efficacy rates (proportion of participants) were obtained in the phase II study compared to the phase III studies. Several factors might explain these differences. For example, as previously mentioned, the nail solution formulations were slightly different between these studies. The characteristics of the treated populations, such as geographic location, mean age and percentages of male participants, treatment duration, and efficacy end points were also different. Finally, as
efficacy outcomes were secondary outcomes, smaller sample sizes were analyzed for the phase II study.
Safety To prevent lacquer build-up, improve the antifungal nail penetration, and provide better access to the space between the nail plate and the nail bed, an efinaconazole 10% nail solution with low surface tension was developed. This nail solution contains both volatile (alcohol and cyclomethicone) and nonvolatile solvents (esters) and can be easily applied to the top of the nail, its surrounding skin, and the accessible skin of the nail bed.36 Consequently, potential skin reaction has been investigated in depth for the efinaconazole 10% nail solution and its vehicle.37 A contact sensitization study using a series of induction, challenge, and rechallenge phases was conducted in 239 healthy participants, who were mainly women (58.9%) and white (52.2%). No evidence of contact sensitization was found with efinaconazole 10% solution under occlusion, under semiocclusion, or without occlusion. Additionally, a 21-day cumulative skin irritation study was undertaken in 37 healthy participants, who were mainly women (86%) and white (43%). Skin irritation was similar between efinaconazole 10% solution and vehicle and was mild compared to the positive control 0.2% sodium lauryl sulfate. Similar scores for pruritus and burning/stinging were obtained for efinaconazole 10% solution, vehicle, and the negative control deionized water. In addition, 70.5% of the participants treated with efinaconazole 10% solution reported ‘‘no’’ or ‘‘mild’’ erythema. These results were confirmed by the safety data of the clinical trials, where
Table 1. Intention-to-Treat Efficacy of Efinaconazole Nail Solution in a Phase II Study for Treatment of Toenail Onychomycosis Caused by Dermatophytes34 Outcome at Week 40 Complete cure rate (%) Mycologic cure rate (%) Effectiveness rate (%) Clinical efficacy rate (, 20% affected nail surface area) (%) Mean affected nail area (%) Mean healthy nail growth (mm)
10% EFN with Semiocclusion (n 5 36)
10% EFN (n 5 39)
5% EFN (n 5 38)
Placebo (n 5 22)
22.2 83.3 61* 67*
25.6 87.2 64* 69*
15.8 86.8 55* N/A
9.1 N/A 23 32
From 40.3 (baseline) to , 19 4.7*
3.8*
From 40.2 to 35.7 1.8
EFN 5 efinaconazole nail solution; N/A 5 data not reported or available. Complete cure rate: proportion of participants with 0% clinical involvement of the target toenail in addition to a mycologic cure. Mycologic cure rate: proportion of participants with a negative KOH examination and fungal culture of the target toenail sample. Effectiveness rate: proportion of participants with mycologic cure and either an affected target toenail area of 0% or . 3 mm proximal nail growth from baseline in the unaffected target toenail. *p , .05 compared to placebo.
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Table 2. Intention-to-Treat Efficacy of Efinaconazole Nail Solution in Phase III Studies for Treatment of Toenail Onychomycosis Caused by Dermatophytes35 Study 1 Outcome at Week 52 Complete cure rate (%) Mycologic cure rate (%) Complete or almost complete cure rate (%) Clinical efficacy rate (, 10% affected nail surface area) (%) Mean healthy nail growth (mm)
Study 2
10% EFN (n 5 656)
Placebo (n 5 214)
10% EFN (n 5 583)
Placebo (n 5 202)
17.8* 55.2* 26.4* 35.7*
3.3 16.8 7.0 11.7
15.2* 53.4* 23.4* 31.0*
5.5 16.9 7.5 11.9
5.0*
1.6
3.8*
0.9
EFN 5 efinaconazole nail solution. Complete cure rate: proportion of participants with 0% clinical involvement of the target toenail in addition to a mycologic cure. Mycologic cure rate: proportion of participants with negative KOH examination and fungal culture of the target toenail sample. Complete or almost complete cure rate: proportion of participants with mycologic cure and # 5% clinical involvement. *p , .05 compared to placebo.
only rare cases of contact/application site dermatitis and erythema were reported.34,35 Moreover, there were no significant differences in safety between the efinaconazole and vehicle arms in these studies.
Conclusion The lower affinity of efinaconazole for keratin compared to other antifungals, such as amorolfine, ciclopirox, and terbinafine, resulted in less inhibition of its antifungal activity by keratin and better skin and nail penetration. Based on in vitro studies, efinaconazole nail solution can be effective not only for dermatophyte onychomycosis but also for Candida onychomycosis. However, the clinical data available to date only support the efficacy of efinaconazole 10% nail solution for toenail onychomycosis caused by dermatophytes. Future clinical trials are needed for supporting efinaconazole use for onychomycosis caused by yeast or as an adjunct therapy with terbinafine for onychomycosis caused by mixed infection.
Acknowledgment Financial disclosure of authors: Financial support was provided by Valeant Canada. Financial disclosure of reviewers: None reported.
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14. Gupta AK, Nakrieko K-A. Molecular determination of mixed infections of dermatophytes and nondermatophyte moulds in individuals with onychomycosis. J Am Podiatr Med Assoc 2013. [In press] 15. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol 1993;28(5 Pt 1):S28–34, doi:10.1016/S01909622(09)80305-8. 16. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin 2003;21:481–9, doi:10.1016/S07338635(03)00025-1. 17. Torres-Rodrı´guez JM, Madrenys-Brunet N, Siddat M, et al. Aspergillus versicolor as cause of onychomycosis: report of 12 cases and susceptibility testing to antifungal drugs. J Eur Acad Dermatol Venereol 1998;11:25–31, doi:10.1111/j.1468-3083.1998.tb00949.x. 18. Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol 2003;149:296–305, doi:10.1046/ j.1365-2133.2003.05418.x. 19. Gupta AK. In vitro activities of posaconazole, ravuconazole, terbinafine, itraconazole and fluconazole against dermatophyte, yeast and non-dermatophyte species. Med Mycol 2005;43:179–85, doi:10.1080/13693780410001731583. 20. Guilhermetti E, Takahachi G, Shinobu CS, et al. Fusarium spp. as agents of onychomycosis in immunocompetent hosts. Int J Dermatol 2007;46:822–6, doi:10.1111/j.1365-4632.2007.03120.x. 21. Figueiredo VT, de Assis Santos D, Resende MA, et al. Identification and in vitro antifungal susceptibility testing of 200 clinical isolates of Candida spp. responsible for fingernail infections. Mycopathologia 2007;164:27–33, doi:10.1007/s11046-007-9027-6. 22. Bueno JG, Martinez C, Zapata B, et al. In vitro activity of fluconazole, itraconazole, voriconazole and terbinafine against fungi causing onychomycosis. Clin Exp Dermatol 2010;35:658–63, doi:10.1111/j.1365-2230.2009.03698.x. 23. Zalacain A, Obrador C, Martinez JP, et al. Characterization of the antimicrobial susceptibility of fungi responsible for onychomycosis in Spain. Med Mycol 2011;49:495–9. 24. Silva LB, de Oliveira DBC, da Silva BV, et al. Identification and antifungal susceptibility of fungi isolated from dermatomycoses. J Eur Acad Dermatol Venereol 2013 Apr 5, doi:10.1111/jdv.12151. [Epub ahead of print] 25. 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;57: 1610–6, doi:10.1128/AAC.02056-12. 26. Ogura H, Kobayashi H, Nagai K, et al. Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol
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Efinaconazole 10% Nail Solution: A New Topical Treatment with Broad Antifungal Activity for Onychomycosis Monotherapy Aditya K. Gupta and Maryse Paquet Background: Topical therapies for onychomycosis are associated with less adverse events than systemic therapies, but poor nail penetration limits their efficacy. Consequently, an efinaconazole 10% nail solution was developed. Objective: To review the evidence supporting the usefulness of efinaconazole monotherapy in onychomycosis management. Methods: PubMed and clinicaltrials.gov databases and abstracts from the 2013 annual meeting of the American Academy of Dermatology were searched in April 2013 using the terms ‘‘efinaconazole,’’ ‘‘IDP-108,’’ and ‘‘KP-103.’’ Results: In vitro, efinaconazole possesses a broad antifungal activity similar or superior to that of other antifungals. Its low affinity for keratin results in good nail penetration. Efinaconazole 10% nail solution administered daily for 36 or 48 weeks to treat mild to moderate toenail onychomycosis caused by dermatophytes results in complete and mycologic cure rates of 15 to 25% and 53 to 87%, respectively. No serious skin reaction is associated with its use. Conclusion: Efinaconazole 10% nail solution is a promising new treatment for onychomycosis. Contexte: Les traitements topiques de l’onychomycose sont associe´s a` moins d’effets inde´sirables que les traitements a` action ge´ne´rale, mais leur faible capacite´ de pe´ne´tration dans l’ongle en limite l’efficacite´. Aussi une solution d’e´finaconazole a` 10% pour les ongles a-t-elle e´te´ e´labore´e. Objectif: L’e´tude visait a` examiner les donne´es probantes a` l’appui de l’utilite´ de l’e´finaconazole en monothe´rapie dans la prise en charge de l’onychomycose. Me´thode: Une recherche a e´te´ mene´e, en avril 2013, dans les bases de donne´es PubMed et clinicaltrials.gov ainsi que dans les re´sume´s du congre`s annuel de 2013 de l’American Academy of Dermatology, a` l’aide des termes «efinaconazole», «IDP-108», et «KP103». Re´sultats: L’e´finaconazole te´moigne, in vitro, d’une large activite´ antifongique, comparable ou supe´rieure a` celle d’autres antifongiques. Sa faible affinite´ pour la ke´ratine permet une bonne pe´ne´tration dans l’ongle. L’application quotidienne de la solution d’e´finaconazole a` 10% pour les ongles, pendant 36 ou 48 semaines, pour traiter une onychomycose le´ge`re ou mode´re´e des ongles d’orteil, cause´e par des dermatophytes, a permis des taux de gue´rison comple`te et mycologique de 15 a` 25% et de 53 a` 87%, respectivement. Aucune re´action cutane´e n’a e´te´ associe´e a` l’emploi du produit. Conclusion: La solution d’e´finaconazole a` 10% pour les ongles se re´ve`le un nouveau traitement prometteur de l’onychomycose.
NYCHOMYCOSIS is a fungal infection of nails caused by dermatophytes, nondermatophyte molds, and/or yeasts. The two most frequent types of onychomycosis are
O
From the Department of Medicine, University of Toronto, Toronto, ON, and Mediprobe Research Inc., London, ON. Address reprint requests to: Aditya K. Gupta, MD, PhD, FRCPC, FAAD, 645 Windermere Road, London, ON N5X 2P1; e-mail: agupta@ execulink.com.
DOI 10.2310/7750.2013.13095 # 2014 Canadian Dermatology Association
toenail dermatophyte onychomycosis and fingernail Candida onychomycosis.1–12 The incidence of Candida onychomycosis is higher in patients with a defective immune system, such as immunosuppressed or diabetic patients.13 Based on recent species identification studies using molecular techniques, mixed infections can be more common than previously reported.14 Antifungals currently used to treat onychomycosis can be divided into four chemical classes: (1) azoles (itraconazole and fluconazole), (2) allylamines (terbinafine), (3) hydroxypyridinone (ciclopirox), and (4) morpholines (amorolfine). The mechanism of action of these antifungals
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is the inhibition of the synthesis of ergosterol, an important component of the fungal cell membranes required for membrane integrity and fungal growth, with the exception of ciclopirox, which impairs microbial metabolism. The resulting effect is in vitro fungistatic and/or fungicidal activity.15,16 These onychomycosis treatments possess different in vitro antifungal activities against dermatophytes, nondermatophyte molds, and yeasts.17–24 Terbinafine and itraconazole are, respectively, the most potent antifungals against dermatophytes and Candida spp. The antifungals used to treat onychomycosis generally have low antifungal activity against nondermatophyte molds. A new azole, efinaconazole, also known as IDP-108 and KP-103, has been shown to possess antifungal activity similar to that of terbinafine and amorolfine against dermatophytes. Efinaconazole was also more potent than itraconazole against Candida spp. Against nondermatophyte molds, efinaconazole was similar to terbinafine and more potent than amorolfine, ciclopirox, and itraconazole.25 To reduce possible adverse events and drug–drug interactions associated with systemic therapies, efinaconazole was developed as a topical treatment for onychomycosis. The aim of this review is to summarize the available evidence on the usefulness of topical efinaconazole in the treatment of onychomycosis.
Efinaconazole: A Unique Antifungal The lower affinity of efinaconazole for keratin compared to other antifungals, such as amorolfine, ciclopirox, and terbinafine, resulted in less inhibition of its antifungal activity by keratin and better skin and nail penetration.26–28 High levels of efinaconazole (< 5 mg/g) were detected in the toenail after daily treatment with efinaconazole 5 or 10% nail solution for 4 weeks, whereas the plasma concentration stayed relatively low (0.7–2.3 ng/mL).29 This allowed efinaconazole to be the first topical triazole to be developed for monotherapy of onychomycosis. Similar to other azoles, efinaconazole inhibits sterol 14a-demethylase (14-DM) enzyme in the ergosterol biosynthesis pathway.30 In early in vitro pharmacologic studies with 39 isolates of the dermatophyte Trichophyton rubrum and 28 isolates of the dermatophyte Trichophyton mentagrophytes, the minimal fungicidal concentrations and the minimal inhibitory concentrations (MICs) were similar, suggesting fungicidal activity.31 Based on the minimal intracellular phosphate leakage from dermatophytes and Candida albicans treated with efinaconazole, degenerative changes are probably not due to direct damage to the fungal cell membrane and might be secondary to the 152
inhibition of ergosterol biosynthesis.30 With the exception of globular swelling, which was unique to efinaconazole, the morphologic and ultrastructural changes observed were similar to the ones previously observed with itraconazole.30 The development of antifungal resistance can be investigated in vitro by subculturing fungal species for 10 to 12 passages in the presence of the subinhibitory concentration of the antifungal. By using this technique with six T. rubrum strains, a small two- to four fold increase in efinaconazole MIC was observed with only two strains (33%).32 In a similar study using 30 strains of T. rubrum, an increase in MIC was observed with 24 strains (80%, 2- to 64-fold increase) with itraconazole and in 17 strains (56.7%, 2- to 4-fold increase) with fluconazole.33 Overall, the potential for dermatophytes to develop resistance is reduced with efinaconazole compared to other azoles. This finding was confirmed by comparing the MICs of T. rubrum isolates pre- and posttreatment with daily efinaconazole for 48 weeks. These isolates were taken from 10 uncured participants in the phase III trials (see below). Only a minimal increase in MICs was observed for six of the participants.25
Clinical Efficacy One phase II34 and two phase III35 clinical trials investigated the efficacy of efinaconazole for mild to moderate (20–50% of nail surface affected) onychomycosis. Efinaconazole solutions were applied once daily without de´bridement for 36 weeks (phase II) or 48 weeks (phase III). The topical formulations used were slightly different between the phase II and phase III studies (personal communication, Valeant Canada, 2012: development formulation in phase II; commercial formulation in phase III). All studies included participants with toenail distal lateral subungual onychomycosis caused by dermatophytes or mixed infection of dermatophytes with Candida spp. Unfortunately, the number of participants with mixed infection was not reported in the baseline characteristics of the studied population and the efficacy data were not reported separately for the possible mixed infection population. Because toenail onychomycosis due to mixed dermatophyte and Candida infection is probably rare, the efficacy data reported in these studies would be considered relevant for toenail onychomycosis caused by dermatophytes. The phase II clinical trial was a randomized, placebocontrolled, double-blind study performed in Mexico. The mean age of the mestizo Hispanic participants was
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42.8 years, and 45.9% of the participants were male. The mean affected nail surface area of the target toenail was 40.3% at baseline. All efficacy assessments were performed at week 40 and analyzed on an intention-to-treat population (Table 1). Overall, better efficacy was obtained with the efinaconazole 10% nail solution compared to the efinaconazole 5% nail solution, and semiocclusion did not improve the efficacy of the 10% solution. The phase III clinical trials were also randomized, placebo-controlled, double-blind studies, but they were performed in the United States (studies 1 and 2), Canada (studies 1 and 2), and Japan (study 1). The mean age of the participants was 52.3 years in study 1 and 50.6 years in study 2. The participants were mainly white (64.9% in study 1 and 87.8% in study 2). Most of the participants were male (74.4% in study 1 and 80.4% in study 2). Similar mean affected nail surface areas of the target toenail of 36.7 % and 36.3% were obtained for the two studies at baseline. All efficacy assessments were performed at week 52 and analyzed in an intention-to-treat population (Table 2). For all outcomes, efinaconazole 10% nail solution was significantly more effective than placebo against dermatophyte onychomycosis. As shown in Table 1 and Table 2, higher efficacy rates (proportion of participants) were obtained in the phase II study compared to the phase III studies. Several factors might explain these differences. For example, as previously mentioned, the nail solution formulations were slightly different between these studies. The characteristics of the treated populations, such as geographic location, mean age and percentages of male participants, treatment duration, and efficacy end points were also different. Finally, as
efficacy outcomes were secondary outcomes, smaller sample sizes were analyzed for the phase II study.
Safety To prevent lacquer build-up, improve the antifungal nail penetration, and provide better access to the space between the nail plate and the nail bed, an efinaconazole 10% nail solution with low surface tension was developed. This nail solution contains both volatile (alcohol and cyclomethicone) and nonvolatile solvents (esters) and can be easily applied to the top of the nail, its surrounding skin, and the accessible skin of the nail bed.36 Consequently, potential skin reaction has been investigated in depth for the efinaconazole 10% nail solution and its vehicle.37 A contact sensitization study using a series of induction, challenge, and rechallenge phases was conducted in 239 healthy participants, who were mainly women (58.9%) and white (52.2%). No evidence of contact sensitization was found with efinaconazole 10% solution under occlusion, under semiocclusion, or without occlusion. Additionally, a 21-day cumulative skin irritation study was undertaken in 37 healthy participants, who were mainly women (86%) and white (43%). Skin irritation was similar between efinaconazole 10% solution and vehicle and was mild compared to the positive control 0.2% sodium lauryl sulfate. Similar scores for pruritus and burning/stinging were obtained for efinaconazole 10% solution, vehicle, and the negative control deionized water. In addition, 70.5% of the participants treated with efinaconazole 10% solution reported ‘‘no’’ or ‘‘mild’’ erythema. These results were confirmed by the safety data of the clinical trials, where
Table 1. Intention-to-Treat Efficacy of Efinaconazole Nail Solution in a Phase II Study for Treatment of Toenail Onychomycosis Caused by Dermatophytes34 Outcome at Week 40 Complete cure rate (%) Mycologic cure rate (%) Effectiveness rate (%) Clinical efficacy rate (, 20% affected nail surface area) (%) Mean affected nail area (%) Mean healthy nail growth (mm)
10% EFN with Semiocclusion (n 5 36)
10% EFN (n 5 39)
5% EFN (n 5 38)
Placebo (n 5 22)
22.2 83.3 61* 67*
25.6 87.2 64* 69*
15.8 86.8 55* N/A
9.1 N/A 23 32
From 40.3 (baseline) to , 19 4.7*
3.8*
From 40.2 to 35.7 1.8
EFN 5 efinaconazole nail solution; N/A 5 data not reported or available. Complete cure rate: proportion of participants with 0% clinical involvement of the target toenail in addition to a mycologic cure. Mycologic cure rate: proportion of participants with a negative KOH examination and fungal culture of the target toenail sample. Effectiveness rate: proportion of participants with mycologic cure and either an affected target toenail area of 0% or . 3 mm proximal nail growth from baseline in the unaffected target toenail. *p , .05 compared to placebo.
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Table 2. Intention-to-Treat Efficacy of Efinaconazole Nail Solution in Phase III Studies for Treatment of Toenail Onychomycosis Caused by Dermatophytes35 Study 1 Outcome at Week 52 Complete cure rate (%) Mycologic cure rate (%) Complete or almost complete cure rate (%) Clinical efficacy rate (, 10% affected nail surface area) (%) Mean healthy nail growth (mm)
Study 2
10% EFN (n 5 656)
Placebo (n 5 214)
10% EFN (n 5 583)
Placebo (n 5 202)
17.8* 55.2* 26.4* 35.7*
3.3 16.8 7.0 11.7
15.2* 53.4* 23.4* 31.0*
5.5 16.9 7.5 11.9
5.0*
1.6
3.8*
0.9
EFN 5 efinaconazole nail solution. Complete cure rate: proportion of participants with 0% clinical involvement of the target toenail in addition to a mycologic cure. Mycologic cure rate: proportion of participants with negative KOH examination and fungal culture of the target toenail sample. Complete or almost complete cure rate: proportion of participants with mycologic cure and # 5% clinical involvement. *p , .05 compared to placebo.
only rare cases of contact/application site dermatitis and erythema were reported.34,35 Moreover, there were no significant differences in safety between the efinaconazole and vehicle arms in these studies.
Conclusion The lower affinity of efinaconazole for keratin compared to other antifungals, such as amorolfine, ciclopirox, and terbinafine, resulted in less inhibition of its antifungal activity by keratin and better skin and nail penetration. Based on in vitro studies, efinaconazole nail solution can be effective not only for dermatophyte onychomycosis but also for Candida onychomycosis. However, the clinical data available to date only support the efficacy of efinaconazole 10% nail solution for toenail onychomycosis caused by dermatophytes. Future clinical trials are needed for supporting efinaconazole use for onychomycosis caused by yeast or as an adjunct therapy with terbinafine for onychomycosis caused by mixed infection.
Acknowledgment Financial disclosure of authors: Financial support was provided by Valeant Canada. Financial disclosure of reviewers: None reported.
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