Journal of clinical and aesthetic dermatology.
`v. 7, no. 7 (July 2014)
`General Collection
`W1 JO585V\/X
`2014-08-28 11:47:27
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`ISSUE 7
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`Dermatology
`
`EDITOR-IN-CHIEF, CLINICAL DERMATOLOGY
`James Q. Del Rosso, DO, FAOCD
`D07m0.zol()gy Resicimzcy D7‘/rector
`Valley Ifuspilal Med'ic0,l Came?"
`Las Vegas, Nevada
`
`EDITOR-IN-CHIEF, AESTHETIC DERMATOLOGY
`W. Philip VVersch1er, MD, FAAD, FAACS
`Ass/mam Clz'm'cal Professor of
`Mecimme/I)er*rrLaLology
`U2'Li'U07‘si/,g/ of IVcLs/zmgéon b'ch,00l o_f'A/Ied'icz”ne
`Seattle, Was/7/mgxrm,
`
`PnEs|DEN1'
`Robert Dougherty
`(484) 965-0709
`rdoughe7ty@matr'i.z‘medco7n. com
`‘
`v
`PARTNER
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`Patnck D. Scullm
`(484) 266-0702
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`This materiafl was mpied
`atthe NW! and mavtre
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2164 - 2/12
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`

`
`Vol. 7, No. 7 July 2014
`
`Editorial Message ............................................................................................................................ ..7
`
`Journal Watch ............................................................................................................................. ..
`
`8
`
`LITERATURE REVIEW
`
`The Role of Topical Antifungal Therapy for Onychomycosis and the Emergence
`of Newer Agents ......................................................................................................................... .. 10
`-James Q. Del Rosso, DO, FAOCD
`'
`
`ORIGINAL RESEARCH
`Racial Differences in Clinical Characteristics, Perceptions and Behaviors,
`and Psychosocial Impact of Adult Female Acne ..................................................................... .. 19
`Valerie D. CCY,llC’l’ldC"7‘, MD; /l’I’l(/l7'6’LU F. Alexis, MD, MPH;
`"
`Selena R. Damels, Plan/r*rrzD, MS; Amtme K. Ka'z.ua,(;a, PhD;
`CCL7"Oli’i’L6 T. Bur/c, P/LLUWID, MS; Teresct K I/I/ilcox, P/21); Susan C. Ta.yl0'r; MD
`
`ORIGINAL RESEARCH
`Retapamulin 1% Ointment and Clobetasol Propionate 0.05% Foam is More
`Efficacious than Vehicle Ointment and Clobetasol 0.05% Propionate Foam
`in the Treatment of Hand/Foot Dermatitis .......
`.......... .:.......................................................... ..32
`Mc1.(lel(L72m2 [Jadcl'lca'n, MD; Rita V. L'm/mev", MD; Gzselle Smger, BS;
`Slzclbl C. Jim ()rz., MD; Mall/zew G(lQl'lOlli, BA; Gary Gol(l(ml)eVg, MD
`
`LITERATURE REVIEW
`Beta Blockers: An Innovation in the Treatment of Infantile Ilemangiomas ........................ ..37
`S/'l(,’/ll(Lz‘ld1Tl(l’}’l’l, MD; Slap/Lame Feldste/in, BA; Errzeslo M Gonzalez, MD, MBA;
`.S‘Iw’ilcL [<'allo'rL ["'rledlcmcle7", MD
`
`.
`LITERATURE REVIEW
`Diet and Dermatology: The Role of Dietary Intervention in Skin Disease........................... _.46
`I€aj(.1m:i Kn,lIa,, MD; Samir P. Desai, MD
`
`®
`PRO
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`Clinical..Aesthetic
`D°"'"'°'°57
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`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`[LITERATURE REVIEW]
`
`ll'he litole of iiopieal Ahlliliungal Therapy for
`Dinyehomycosis and the Emergence of itleuueir Agents
`
`JAMES 0. DEL R0830, D0, FAOCD
`Clinical Professor (Dermatology), Adjunct Faculty, Touro University College of Osteopathic Medicine, Henderson, Nevada and Private Practice,
`Dermatology and Cutaneous Surgery/Mohs Micregraphic Surgery and Las Vegas Skin & Cancer Clinic/West Dermatology Group,
`Henderson and Las Vegas, Nevada
`
`ABSTRACT
`Onychomycosis is a common infection of the nail unit that is usually caused by a dennatopliyte (Linea unguium) and most
`frequently affects toenails in adults. In most cases, onychomycosis is associated with limited treatment options that are
`effective in achieving complete clearance in many cases. In addition, recurrence rates are high in the subset of treated patients
`who have been effectively cleared, usually with an oral antifungal agent. There has been a conspicuous absence of medical
`therapies approved in the United States since the introduction of topical ciclopirox (8% nail lacquer), with no new effective
`agents introduced for more than 10 years. Fortunately, newer agents and formulations have been under formal development.
`While patients might prefer a topical therapy, efficacy with ciclopirox 8% nail lacquer, the only available agent until the very
`recent approval of efinaconazolc 10% solution, has been disappointing. The poor therapeutic outcomes achieved with
`ciclopirox 8% nail lacquer were not unexpected as the cure rates achieved in the clinical trials were unimpressive, despite
`concomitant nail debridement, which was an integral part of the pivotal trials with ciclopirox 8% nail lacquer. Efinaconazole
`10% solution and tavaborole 5% solution are new topical anti fungals specifically developed for the treatment of derrnatophyte
`onychomycosis. In Phase 3 clinical trials, both newer agents were a19}911eCl 01106 daily for 48 weeks without concomitant nail
`debridement. Mycologic cure rates with efinaconazole 10% solution are markedly superior to what was achieved with
`ciclopirox 8% nail lacquer. To add, they appear to be nearly comparable to those achieved with oral itraconazole in pivotal
`clinical trials. However, it is important to remember that direct comparisons between different studies are not conclusive, are
`not generally considered to be scientifically sound, and may not be entirely accurate due to differences in study design and
`other factors. Well-designed and properly powered head—to-head studies are needed in order to draw definitive conclusions
`about efficacy comparisons between therapies, at least based on academic and regulatory standards. Although tavabei-ole 5%
`solution is in an earlier phase of development for onychomycosis, treatment success rates reported thus far for both
`eiinaconazole 10% solution and tavaborole 5% solution are superior to ciclopirox 8% nail lacquer. As a result, a new era of
`onychomycosis appears to be upon us that incorporates topical therapy more effectively than in the past. Not only may these
`newer topical agents provide viable monotherapy alternatives to oral therapy for onychomycosis,
`topical
`therapy for
`onychornycosis that is effective, well tolerated, and easy to 1130 may 3150 find kl role i11 cornbinat.ion therapy, and/or as
`confirmed therapy after initial clearance to reduce recurrence or re-infection. (J Cl'mAest/wt Dermatol. 20l4;7(7):l0—l8.)
`
`QriycliornycosisistheInostcommonfungalinfectionof
`
`the nail bed, matrix, and/or plate, representing up to
`50 percent of all nail disorders seen in dermatology
`practice? Overall prevalence, noted to be approximately 14
`percent, appears to be increasing, with onychomycosis
`reported to affect half the population by the time they reach
`70 years of age.“ Left untreated, it can lead to progressive
`destruction and deformity of the toenails and fingerriails.”
`Onychomycosis, especially cases caused by dermatophytes,
`may serve as a nidus for more widespread cutaneous
`
`involvement, spreading to other digits, body areas, and even
`to other predisposed family members? It can be very
`distressing for many patients psychosocially and/or
`pliysically."’i*"“'
`Causes of onychomycosis. The vast majority of cases of
`onychomycosis are caused by dcrrnatophyte fungi. In 80 to
`98 percent of affected individuals, T7vIch0p}I.ylon ntbrum or
`7’m'cltop/Lymrr
`/)7/Z/(1)7?/£61/‘(J1/l()]jf’IV7jz(‘l)6‘ are identified as
`the
`causative pathogen."‘“ Adults are most commonly affected
`with toenails being affected much more corn_monly than
`
`NOTE: Tavaborole 5% topical solution was approved by the FDA for treatment of dermatophyte onychomycosis on July 7, 2014.
`DISGLOSURE: Dr. Del Rosso has served as a consultant/advisory speaker‘, and/or researcher‘ for Allergan-r’, Anacor‘, Bayer HealthCare*",
`Dermiran Eisai-, Galderma”, lnnocutisr, LeoPnarma", Merz“, Onset Dermatologicsr“, PharmaDerm (Fougera)*', Promius“, Puracapr,
`Ranbaxy", Taro”, Unilever: Valeant (Medicls Division; Consumer Division)“, and Warner-Chilcot". No compensation was provided for his
`development, writing, and handling of the submission of this article.
`ADDRESS COHRESPONDENGE T0: James 0 Del Rosso, DO; E-mail: jqdelrosso@yahoo.com
`1»: mmtal
`This material was copied
`v3f;i‘ilfiiNLt~’rEdr<riiatritiE«~.- 7]
`Subject US Cexpyright Laws
`
`CIinical..Aesthetic
`Dermatology
`
`[July 291.1 -
`
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`
`fuigerriails."‘*’*““‘ Fingernail onychomycosis is frequently
`concomitant with toenail onychomycosis, especially when a
`dermatophyte is causative, and most of these patients exhibit
`concurrent unilateral or bilateral dry plantar (moccasin)
`tinea pedis and sometimes also tinea irianus. Both fingernail
`and toenail onychomycosis can occasionally be caused by
`nondermatophyte
`fungi,
`such
`as
`Scopulam'0ps'is
`bree'icaulz's, Aspergillus
`spp, Fu.sariu'm spp,
`and
`sometimes Ccmdrida spp (i.e., C. albiccms), with the latter
`noted to be rare in toenails.“ Increasing prevalence of
`riondermatophyte onychomycosis has been observed in some
`reports, either due to improved diagnostic techniques and/or
`increased awareness; however, differentiation of a laboratory
`contaminant from a true nail pathogen may at times be
`overlooked arid/or prolilernaticf‘-"" In addition, mixed
`infections have been reported, although their significance is
`less clear.” Idcntificat.ion of the fungal pathogen by culture is
`highly dependent on the method used to obtain the
`specimen, the anatomic location within the nail iuiit that the
`specimen is obtained f'rom, and the medium used.
`Patterns of nail invasion/clinical presentations of
`onychomycosis. Toenail onychomycosis frequently involves
`several nails, and as noted above, dry plantar tinea pedis is
`almost always present concurrently.“-W“ Indeed, tinea pedis
`is believed to be the predominant source of deimatophyte
`onychomycosis. This occurs in most cases as 7”m',cIz()p/iyton
`spp (usually '1‘. mtbrrtm) migrates from distal pedal skin into
`nail bed by violating the liyporiychium. As a result, distal
`lateral suburigual onychomycosis (DLSO) is by far the most
`common form of the ciisease."““”-“‘” Here the causative
`fungus, usually T. 7"rtb'mm, invades the nail bed at the distal
`and lateral edges, leading to distal onycliolysis, subungual
`hypeikeratosis, and both nail bed and nail plate thickening.“
`This subungual process of nail
`invasion by the fungal
`pathogen is the most common, with direct nail plate
`(endonychial) invasion much less common, especially with
`derrnatophyte furigi.="""“"“ In DLSO, the undersurface of the
`nail plate is oi'ten affected by fungal penetration as it is
`directly
`contiguous with
`the
`invaded
`nail
`bed.
`Oriychomycosis involving the surface of the nail plate
`(superficial onychomycosis)
`is also usually caused by
`’1"mZ(:/'z.op/Lg/ton spp, is much less corrmion, and sits on the
`surface of the plate as a powdery film that can be scraped
`away from that surface with a surgical blade or lightly with a
`curet. Superficial dermatophyte onychomycosis is amenable
`to topical therapy as the fungal pathogen is easily accessible
`to the applied antifungal ageiit.""“*““" Proximal subllllgtlai
`onychomycosis is also less common than DLSO and occurs
`when the dermatophyte organism (usually Tm'c/top/'2,yto'i'2,
`spp) migrates from pedal skin under the proximal nail fold
`and cuticle and extends under the nail plate and into the nail
`l)ed."v““ '
`
`Challenges in treating onychomycosis. Successful
`treatment of onychomycosis is fraught with difficulty due to
`several factors, especially with toenail involvement. These
`include slow growth; the physical presence of the nail plate
`interfering with nail bed access after application of a topical
`antifiuigal agent; difficulty in finding compounds with the
`
`pharmacologic/pliarmacokinetic profile to allow adequate
`nail unit penetration; challenges in achieving therapeutic
`substaritivity of drug levels
`after
`topical
`or
`oral
`administration; development of optimal vehicles for topical
`use that allow delivery of effective drug levels to the site(s)
`of nail infection (primarily nail bed); the anatomic nature of
`the nail imit and its vascular access, which allows for higher
`drug levels in nail bed/plate centrally as compared to laterally
`after oral antifungal administratioii; the high incidence of
`recurrence after clearance with therapy; widespread
`environmental exposure to deriiiatophytes and other fungal
`organisms; and the genetic predisposition of many
`individuals to pedal colonization and infection with T.
`7”Z(.b’)“u?’rL, which eventually leads to invasion of the nail imit
`with
`reinfection
`with
`onychomycosis
`(tinea
`urigLiiuiii).‘-"W3“‘v"'-3”” Toenails may take up to 78 weeks to
`grow out completely, depending on the age and general
`health of
`the patier1t.“'”“ In addition, certain clinical
`presentations of onycliomyeosis are more difficult to clear
`and often represent cases that are not included in many
`clinical studies, incli.iding some pivotal trials. These include
`marked nail plate thickening, extensive onycholysis,
`completely affected nail plate with marked involvement of
`the nail matrix, dcrmatophytomas, band-like lateral
`involvement, extensive subungual debris/thickening, lack of
`nail growtli of chronically traumatized toenails (i.e., 5th, 2nd
`longest toe), and iiriniuriocompromised patients. Such
`cases often involve physical debrideinent combined with
`medical
`therapy, and may warrant repeated courses of
`treatment and/or more prolonged therapy than what is stated
`in product labeling.‘-3‘
`“
`Poor nail unit penetration limits the use of current topical
`antifungal agents in the treatment of onychomycosis and
`directly relates to the iuiique physical and kinetic properties
`of the nail unit,
`its thickness, and relatively compact
`structure.” 3" Due to the high potential for persistence of
`some organisms within the nail unit even after visible
`clearance and/or dermatophyte presence on pedal skin,
`relapse and re~infection of onychomycosis are common and
`can occur in at least 20 to 25 percent of patients.‘~“‘“-W’
`"7
`Oral treatment considerations. Current treatment of
`deimatophyte onychomycosis includes both oral and topical
`antifungal agents, adjimctive physical modalities (chemical
`debridemerit, mechanical debridement, nail avulsion), £1ll(l
`approaches to minimize the risk of recurrence or re-infection
`(i.e.,
`topical
`therapy to suppress pedal colonization or
`infection [tinea pedis]).'-'“ Oral antifungal therapy, such as with
`agents approved by the United States (US) Food and Drug
`Administration (FDA) for derinatopliyte onychomycosis (i.e.,
`terbiiiafine, itraconazole), is preferred because of their ability
`to penetrate the nail bed and nail plate and sustain
`therapeutic levels that correlate with iuarkedly superior
`efficacy as compared to oral giiscofulviii. This latter oral agent
`was the first to become FDA~approved for derinatopliyte
`infections, including onychomycosis, despite a very low cure
`rate for tinea unguium even with several months of daily
`the 'apy (especially toeiiails).‘*"" Nevertheless, oral antifungal
`inonotherapy for toenail dermatophyte onychomycosis is still
`This material was to-pied
`
`[§E?i‘Fi‘E'-«ii’l15i”“5l-“l\5‘!{i7’fii...-
`Eubject US—-Ca-pgrright: Laws
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`7
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`- Nu Miller 7} mc“fifiicaLAes-the-tic ®
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`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2164 - 5/12
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`
`not capable of clearing many cases due to the reasons explained
`above.
`In
`addition,
`there
`are
`safety concerns
`(i.e.,
`hepatotoxicity) that warrant monitoring and a risk of clinically
`sigiiificant drug interactions, especially with itraeonazole. 'l‘liese
`factors can be of greater concern in elderly patients with
`onychoinycosis where polypharmacy is common. In many cases,
`both patient. and physician preference for an effective t.opical
`solution exists. in some cases, the clinician may wish to combine
`oral and topical therapy.
`Approved topical agents for onycliomycosis. There
`have been a number of failed topical therapies in development
`over the last 10 t.o 15 years. Until June 6, 2014, only one topical
`agent, ciclopirox 8% nail
`lacquer, was FDA approved and
`available in the United States for treatment of oriyclioiiiycosis.
`Efficacy has been disappointing, resulting in topical eiclopirox
`usually being used for the Inildest cases; only for palliative
`benefit at best; or when oral therapy cannot be tolerated, is best
`avoided, or is coiitraindicated.”" This review highlights the data
`with “standard" regimens of oral therapy and provides an
`overall comparison of their efficacy and safety profiles with
`existing and newer topical agents in development. There are a
`number of important aspects to consider in reviewing efficacy
`data from onychomyeosis studies. First, myeologic cure (i.e.,
`the eradication of
`the causative organism)
`is
`the only
`consistently defined efficacy parameter applied to toenail
`oriychomycosis clinical trials that is objective,“ and it is widely
`accepted that mycologic cure is the main treatment goal.“
`Clinical cure (completely normal-appearing nail at study
`endpoint) is also a very important goal, but is fraught with the
`complication of prc-existing nail changes unrelated to
`onycliomycosis (i.e., trauma-related). Secondly, the duration of
`treatment in clinical trials can suggest lower efficacy rates than
`would be the case with continued treatment when elected by a
`clinician in “real-worlc” clinical practice. In many cases of
`toenail onychomycosis, prolonged or repeated therapy is
`needed to achieve resolution of the disease, given the slow
`growth of the toenail mentioned earlier, and also the propensity
`for continued re-exposure to the fungal pathogen over time,
`especially in those with pedal colonization by T. mbmm.
`Jontinued improvement has been reported with longer—terin
`studies, although data are somewhat li'mited."”’l‘liird1y, the use
`of an adjiinctive physical modality such as debridement may be
`needed in combination with medical therapy to augment the
`therapeutic response based on the clinical presentation of
`onychomycosis. Finally, while most studies have defined
`disease severity based on the percent
`involvement of the
`affected target toenail,
`there is no consistency in defining
`severity of a condition where a number of other factors (i.e.,
`proximity of infection to the matrix, degree of subungual
`hyperkeratosis, presence of dermatophytoma, extent of
`oiiycliolysis, multiple nail involvement, associated tinea pedis)
`are important in assessing severity and selecting thera.py."”
`
`ORAL ANTTFUNGAL THERAPY FOR TOENAIL
`ONYGHOMYGOSIS
`
`is not suggested that oral griseofulviii be used for
`It
`deriiiatopliyte oiiycliomycosis in adults due to poor efficacy,
`
`and oral kctoconazole is also not suggested for oiiycliomycosi
`treatment due to poor efficacy and safety concerns. Oral?
`terbinafine (250mg daily for 12 weeks) and itraconazole “pulse"
`therapy (200mg given twice daily for 1 week per month) have ‘
`been shown to be
`the most effective dermatophyte
`onyclioinycosis regimens, althoiigh the latter regimen is not
`FDA—appi'oved for toenail onycliomycosis. Itraconazole (FDA ‘
`approval 1995) and terbinafine (FDA approval 1996) offer
`myeologic cure rates of 54 and 70 percent,
`respectively,
`following continuous therapy as reported in their approved»
`product labe1irig.““"“.
`Few comparative studies have evaliiated the relative efficacy 3
`of these two regimens ‘*8; however,
`the literature suggests,
`superiority of terbinaline or comparable efficacy.“ Studies:
`suggest that at least 20 to 30 percent of patients with toenail?
`dermatophyte onychomycosis may not respond adequately to ,
`initial
`therapy with terbinafine or pulsed itracoriazolesl“ A
`comprehensive meta—analysis compared the efficacy of ‘
`continuous and pulsed itraconazole with terbinafine and
`reported niycologic cure rates of 71.1150, 6:3.5:5.l, and
`77.2:4.0 percent, respectively?“ A more recent cumulative
`meta-analysis of randomized clinical trials from the same group ‘
`reported myeologic cure rates of 63:7 percent with
`itraconazole pulse, 76:3 percent with terbinafine, and 48:5
`percent with iliiconazolefl" Fluconazole has been shown to be
`effective for dennatopliyte onychomycosis, but is not FDA~
`approved for any type of onychomycosis.
`Standard courses of itraconazole and terbinafine have been
`shown to achieve a disease—free nail in approximately 2-5 to 40
`percent and 35 to 50 percent of patients, respectively.“ Nail
`infections are difficult to cure, with rates of recurrence of 38.7
`and 11.9 percent being reported for
`itraconazole and
`terbinafine, respectively, after long-term follow—up.'‘3 After five
`years, 46 percent of patients treated with terbinafine remained
`disease—free compared with just 13 percent of patients treated
`with itracoiiazole.“‘
`Although most studies with oral terbinafine and itraconazole
`have been for treatment of dermatophyte infections, efficacy
`against nondermatophyte infections, reported to affect 1.5 to 22
`percent of patients,
`is an important coiisideratioii when
`selecting treatment
`for onychomycosis."“"‘“ In many cases,
`itracoiiazole appears to be more effective overall
`for
`nondemiatophytc nail [)31.llOgeIlS.'"’“” Treatment of C, (Llb’iC(L’flS
`oriychoiiiycosis, which almost always involves fingernails as
`opposed to toenails, suffers lower efficacy when treated with
`oral i;erl)iriafi1ie."“‘i“"
`
`TOPICAL ANTTFUNGAL THERAPY FOR TOENAIL
`DERMATOPHYTE ONYGHOMYOOSIS
`Prior to the development of topical efinaconazole and
`tavaborole for onycliomycosis, available topical agents have ‘
`exhibited limited nail unit penetration and very poor efficacy.
`Cure rates, alone or in combination with physical modalities,
`such as debridenient or aviilsion, have been modest at best?“
`The daily application of eiclopirox 8% nail lacquer used in
`combination with nail plate debridemeiit may be effective in
`some patients with milder severity of disease if treatmerlt
`
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`Dcnmllology
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`
`the nail plate grows out completely.“
`continues until
`However, ciclopirox 8% nail lacquer with nail debridement
`has only rarely been effective with a reported rnycologic cure
`rate (negative culture and negative potassium hydroxide
`preparation [I{OH])
`range of 29 to 36 pe1‘ceIit.“”“ This
`iuycologic cure rate range is out of step with complete cure
`rates
`(mycologic cure and normaleappearing toenail)
`reported to range from 5.5 to 8.5 percent.“" There is a definite
`need for an effective and safe topical product that can
`adequately penetrate the toenail plate and nail bed and
`inhibit the growth of fungi that cause onychomycosis.
`
`NEW TOPICAL SOLUTIONS FOR THE TREATMENT
`OF TOENAIL ONYGHOMYCOSIS
`failed development
`There have been a number of
`programs over the last IO to 15 years as researchers attempt
`to l'ormulate antifungals that show M m'L'r'o activity against
`the common pathogens that cause onychomycosis and to
`penetrate the nail unit with adequate access to the site of
`infection. The logical place to start is with the oral antifungal
`agents already being used to effectively treat dermatophyte
`onychomycosis. A topical
`formulation of
`terbinafine
`demonstrated mycological and clinical efficacy in wire and
`was superior to topical ciclopirox in a Phase 2 stt1dy.“-3“
`However, Phase 3 studies failed to demonstrate superior
`efficacy in mild—to—moderate DLSO compared to vehicle in
`terms of complete cure?“ In two vehicle-controlled studies,
`mycologic cure rates Mth terbinaline were 13 and 19 percent
`(P=0.014 and P<0.0001, respectively, compared to vehicle)
`after 24 and 48 weeks of treatment. Complete cure rates
`were only 1.2 and 2.2 percent after 24 and 48 weeks of
`treatment with terbinafine solution and not significantly
`different
`than vehicle. The third study was an active-
`comparator controlled study with amorolfmc 5% nail lacquer
`with both treatments administered over 48 weeks. Mycologic
`cure rates were 16 percent
`in both study groups and
`complete cure rates were very low in both the terbinafine
`study arm and amorolfine study arm (1.2 and 0.96%,
`respectively).““ Although the results reported for amorolfine
`are lower than those reported in earlier studies, there are
`important methodological differences, including less strictly
`defined endpoints and lack of control groups in previous
`sti1clies.""'”“" One concern expressed by some investigators is
`the short duration of studies using topical treatments given
`the slow growth rate of toenails, suggesting that a treatment
`duration of 18 months is required to achieve both clinically
`meaningful and demonstrable bcncl"1t.“" Studies with oral
`antifungal agents have demonstrated higher cure rates and
`greater clinical benefit
`following long-term (72 weeks)
`treatment.“ Improvement in cure rates with longer follow-up
`periods as compared to the usually reported durations (ie, 4
`weeks) has been observed with topical
`therapy.
`In one
`mult.icenter study, the complete cure at Week 52 following 48
`weeks of therapy with ciclopirox 8% nail lacquer in Inild—to—
`moderate DLSO was 3.2 percent and at Week 60 had
`increased to 5.8 percent (Figure 1).“ Interestingly in this
`study, which stated a primary objective to see if formulation
`
`the secondary
`improvements can enhance efficacy rates,
`endpoint of “responder rate,” defined as a decrease in
`diseased nail to $10 percent of total, did not increase over a
`more prolonged follow-up period. The “responder rate" was
`17 .13 percent at both followup points.“
`The development of new topical antifungal agents for the
`treatment of onychomycosis has focused on formulation
`enhancements and also the discovery of new chemical
`entities that exhibit a broad spectrtun of activity against
`multiple relevant ftuigal pathogens and that exhibit
`the
`pharmacological characteristics that are needed for effective
`treatment of toenail onychomycosis. This review focuses
`primarily on efinaconazole 10% topical solution, which has
`been evaluated in mandatory studies and clinical
`trials
`required for submission to the FDA, and was recently FDA
`approved in June
`2014
`for
`toenail dcrmatophyte
`onychomycosis."7 Topical tavaborole is also under evaluation
`by the FDA for treatment of toenail onychomycosis although
`data from clinical trials was not available at the time this
`article was written and accepted for publication.
`Efinaconazole. Efmaconazole 10% solution has shown
`efficacy based on mycologic and complete cure that appear
`based on an overall assessment to be relatively comparable to
`rates reported with oral itraeonazole in some studies for mild-
`to-moderate DLSO and greater than those reported with
`ciclopirox 8% nail lacquer combined with tiebritleiI1er1t.”"-"’
`Physicochemical properties, antifungal activity, and the
`nature of the vehicle formulation are components that are
`believed to contribute to favorable therapeutic outcomes in
`onychomycosis pa.tie1its."*‘v""’
`Elinaconazole has a broad spectrum of 2'11 mire activity
`against dermatophytes, nondermatophytes, and yeasts.
`Against the most common pathogens,
`'1'. mbrmrz. and T.
`?'rL(3?’t£CLg1”0])/Lylfes
`(MIC90: 0.008—0.()15 pg/mL) and C.
`a,ll)'zIccms (MIC50: 0.004 pg/rnL),
`it was more potent than
`currently marketed antifungal agents used to treat
`onychomycosis."" Efinaconazole 10% solution was also
`significantly superior to amorolfine (P<0.001) and ciclopirox
`(l’<0.0l)
`lacquers
`in
`decreasing
`the
`number
`ol'
`dermatophytes in an in moo guinea pig model of
`onychomycosis."“'
`The physicochcinical properties of a topical antilungal
`need to be favorable for its penetration through the dense
`kera.tinized nail plate to its deeper layers, into nail bed and
`into nail matrix. Many antifungal agents are known to possess
`a high binding affinity to keratin that can have a
`counteractive effect on their efficacy by reducing the
`availal‘>ility of free (i1‘t1g.“""“Botl1 keratin binding and the rate
`of drug release from keratin are important considerations in
`allowing the antifungal agent to become freely accessible to
`exert its activity against causative fungal organisms.
`Efinaconazole 10% solution has considerably lower
`binding to keratin, and keratin—bound drug was released at a.
`faster rate following repeated washings (85.7% bound; 46%
`released) when compared to amorolfine (98.1% bound, (5.9%
`released) and ciclopirox (09.3% bound, 2.4% released)."‘"
`Efinaconazole 10% solution is a clear solution containing
`
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`ProportionofSubjects
`
`‘zero percent clinical
`lIW0lVL‘mt)l\! of the
`target nail (nail is totally
`clear) in addition to
`mycoiegic cum.
`
`Followup
`Study Week
`um from Ban» :1. ram‘ A, Hartman: i, el nl. An mnovalwe watrmnlublc biaualyvvu.-I xmpmvu emmy oludooivon nail Iatquer in the managemrnl at onychamymnx. /lurnmd
`cumm: vmmai zoom): m—m.
`
`Figure 1. Ciclopirox 8% nail lacquer primary efficacy endpoint. Complete cure* in toenail onychomy-
`cosis (N=i18). Outcomes with longer-term fo||ow—up Weeks 12 to 60 (results reported based on last
`observation carried forward)
`
`Study 2
`Mycologic Cure ‘
`
`study 2'
`Study 1’
`Treatment Success 2
`
`*‘*
`sdmy
`Complete Cure
`
`1
`
`3
`
`‘negative KOH
`(potassium
`hydroxide)
`examination and
`negative {ungal
`(ulture oflhc large!
`nnll specimen.
`’<=]ll%aflei:tcd
`large! nail arc.)
`30‘/‘scliniral
`lnvolvemnntohhe
`target nail (nail Is
`totally clear) in
`addition to
`mycologic cure.
`
`i
`
`2.’L)
`.2.0:3
`U)..
`.91:oD.
`20.
`
`oC
`
`Data hem Ilewxll BE. Ridn P. Pollak R, cl al.Ef1namnaxole um soiulton In the lveatmem 01 toenail onychomvcoslsz two phase 3 mulrlccnlev, randomized,
`double-blind undies, lam Amd Dermotol 2013,6l.5D0r60B.
`
`Figure 2. Efinaconazole 10% solution in toenail onychomycosis. Secondary efficacy
`endpoints—Week 52 (LOCF)
`
`
`lipophilic esters, and cyclolnethicone. These
`alcohol,
`ingredients help to create a low surface tensio