SUPPORTED BY AN EDUCATIONAL GRANT FROM
`DERMIK LABORATORIES
`
`Ciclopirox nail lacquer topical solution 8%
`in the treatment of toenail onychomycosis
`
`Aditya K. Gupta, MD, FRCP(C),• Philip Fleckman, MD,b and Robert Baran, MD'
`Toronto, Ontario, Canada, Seattle, Washington, and Cannes, France
`
`Background: Onychornycosis is a relatively common condition affecting toenails more than fingernails. It
`is caused predominantly by dermatophytes. Onychomycosis can cause pain and discomfort and has the
`P<?tential to be a source of n1orbidity.
`
`Objective: We evaluated the efficacy and safety of ciclopirox nail lacquer solution 8% used to treat
`onychomycosis of the toe in the United States and in centers worldwide.
`
`Methods: Two identically designed, double-blind, vehicle controlled, parallel group multicenter studies
`were performed in the United States to evaluate che u.se of ciclopirox nail lacquer to treat mild to moderate
`toe onychomyco.si.s caused by dermatophyte.s. In the first study, 223 patients were randomized to treatment
`(ciclopirox group: 112, vehicle group: 111), and in the .second stUdy, 237 subjects were randomized
`(ciclopirox group: 119, vehicle group: 118). Before randc)mization, patients were to have clinical features of
`onychomycosis in at least one great toe with positive light microscopic examination and a positive
`dermatophyte culture. The te.st material was applied daily for a period of 48 weeks to all toenails and
`affected fingernails, covering the entire nail plate and approximately 5 mm of surrounding skin. At baseline,
`.subjects had between 20% to 65% area of target nail involved. Physician's assessments were carried out
`every 4 weeks, and 1nycologic evaluation and photographic planimetry using standardized photographs
`were performed eve1y 12 weeks during the 48 weeks of treatment. In studies conducted outside the United
`States, patients were also to have clinical, microscopic, and culture evidence of onychornycosis. However,
`these studies included some patients infected with nondermatophyte organisms (eg, Candida species),
`and the area of nail involvement was generally greater than observed in the US studies. Treatment regimens
`_also v:;i.riec;I i0 the non-US studies with lc1cquer applications that wet:e sometii;nes less frequent than the once
`daily treatment used in the US studies (eg, alternate clay or twice weekly). In addition, the typical duration
`of treatment was 6 months in the non-US studies as compared with 48 weeks in the United States. Outcome
`measures were similar to those used in rhe US trials, although a non-photographic planimetric method was
`used to quantify disease extent.
`
`Results: Data from the pivotal US trials have demonstrated that ciclopirox nail lacquer 8% topical solution
`is significantly more effective than placebo in the treatment of onychomycosis caused by Trichophyton
`ruhrum, and of mild to moderate toe onychomycosis without lunula involvement. At the end of the 48-
`week treatment period, the mycologic cure rate (negative culture and negative light microscopy) in study
`I was 29% vs 11% in the ciclopirox and vehicle groups, respectively. Similarly, the mycologic cure rate for
`study II was 36% vs 9%, respectively. In the non-US studies, the rnycologic cure rates ranged from 46.7% to
`85.7%. In addition, ciclopirox nail lacquer has den1onstrated a broad spectrum of activity with efficacy
`against Candida species and some nondermacophytes in non-US studies. Ciclopirox nail lacquer is
`considered extremely safe regarding causally related treatment emergent adverse-effects (TEAEs), with
`most TEAEs tr.1nsient and localized to the site of action (eg, erythema and application site reaction). In the
`US studies, TEAEs were generally nlild .and cleared while the patient continued to use the nail lacquer.
`
`Conclusions: Studies conducted worldwide demonstrate the efficacy of ciclopirox nail lacquer for the
`treatment of finger and roe onycho1nycosis. Both controlled and open-label studies confirm the excellent
`
`From the Division of Dermatology, Department of Medicine,
`Sunnybrook and Women's College Health Sciences Center
`(Sunnybrook site), and the University of Toronto, a the Division of
`Dermatology, Department of Medicine, University of Washington,
`Seattle,b and the Nail Research Center,Cannes5
`This article is part of a supplement sponsored by Aventis.
`Dr Baran and Dr Fleckman have been consultants for Aventis.
`
`Dr Gupta has been a consultant for Aventis, Janssen, Novartis, and
`Pfizer.
`Reprint requests: Aditya K. Gupta, MD, FRCP(C), 490 Wonderland Road
`South, Ste 6, London, Ontario Canada N6K 1 L6.
`Copyright© 2000 by the American Academy of Dermatology, Inc.
`~--"!I·----~
`0190-9622/2000/$ 12.00 + 0 16/0/109071
`do;,10.1067/mjd.2000.109071
`
`Chi aniw
`
`S70
`
`EXHIBIT NO.±.
`
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`

`
`J AM ACAD DERMATOL
`VOLUME 43. NUMllER 4
`
`Gupta, F/eckman, and Baran S 71
`
`safety profile of this topical therapy. Thus, the nail lacquer provides a treatment choice with a favorable
`benefit-to-risk ratio. With its novel mechanism of action and its topical route of administration, ciclopirox
`nail lacquer offers an innovative approach(() the treatment of this often difficult-to-manage disease. a Arn
`Acad Dermatol 2000;43:570-80.)
`
`C iclopirox and its salt ciclopirox ola1nine
`
`are hydroxypyridone derivatives that differ
`chemically and mechanistically from other
`marketed antifungal agents such as the azoles and
`the allylamines. 1.5 Unlike most antifungals currently
`available, ciclopirox does not affect sterol biosynthe(cid:173)
`sis. Ciclopirox is glucuronidated and is not metabo(cid:173)
`lized via the cytochrome P 450 pathway. The novel
`antifungal action of ciclopirox involves chelation of
`polyvalent cations (such as fe3+) with inhibition of
`metal-dependent enzymes responsible for the degra(cid:173)
`dation of toxic peroxi4es in the fungal celL6
`Ciclopirox is a broad spectrum antifungal agent
`chat is effective against the major human fungal
`pathogens responsible for onychomycosis.7·11 In
`fact, ciclopirox is fungicidal in vitro to strains of
`Trichophyton rubrum, T mentagrophytes, and
`Epidermophyton jloccosum, the fungal species typi(cid:173)
`cally irnplicated as the causative organisms in ony(cid:173)
`chomycosis.' In vitro, ciclopirox is also effective
`against Candida sp and nondermatophyte molds,
`for example, Scopulariopsis brevicaulis, Aspergillus
`sp, and Scytalidium f?yalinum. 9,10
`Ciciopirox olaffiine wa.S first introduced to the
`market in April 1975, and is now marketed in more
`than 70 countries worldwide. Ciclopirox olamine has
`been marketed as a 1 % cream and lotion in the
`United States for 15 years and worldwide for 24
`years. It was recently approved as the 0. 77% gel in
`the United States. Ciclopirox nail lacquer topical
`solution 8% (also referred to in this article as
`ciclopirox nail lacquer) was first approved for use in
`France in 1991. Since then, the product has been
`approved for use in over 40 countries and has most
`recently been approved in the United States in
`December 1999 for the topical treatment of mild to
`moderate onychomycosis of fingernails and toenails
`without lunula involvement in immunocompetent
`individuals infected by T rubrum.
`Onychomycosis is a common condition; some esti(cid:173)
`mates suggest that it affects approximately 6% to 13%
`of the North American population.12,13 Onycho(cid:173)
`mycosis is present predominantly in toenails rather
`than fingernails, in males, and in the elderly, and is
`most commonly caused by T rubrum. Invasive nail
`disease caused by molds is less common in North
`American series. Candida sp are more likely to cause
`invasive nail disease in fingernails than toenails in
`
`immunocompetent individuals. Onychomycosis may
`have medical significance especially in some disease
`states such as diabetes and others where the individ(cid:173)
`ual is immunocompromised.14 Also, onychomycosis
`can have a substantial effect on the activities of daily
`living, such as ambulation.IS
`In the United States, griseofulvin and ketocona(cid:173)
`zole were the only available treatments approved
`for onychomycosis until oral itraconazole became
`available for this indication in October 1995,16,17
`Subsequently, oral terbinafine was approved for
`the treatment of tinea unguium in May 1996. Oral
`fluconazole is not approved in the United States
`for this indication. Ciclopirox nail lacquer is the
`first non-oral agent approved in the United States
`for the management of onychomycosis. This arti(cid:173)
`cle focuses on the 2 pivotal studies conducted in
`the United States that confirmed the efficacy and
`safety of ciclopirox nail lacquer for the treatment
`of mild to 1noderate toenail onychomycosis. In
`addition, results from non-US studies are also
`summarized.
`Two idenUcally designed, double-blind, vehicle(cid:173)
`controlled, paratler group," multicenter s·rudies were
`performed to evaluate the use of ciclopirox nail lac(cid:173)
`quer in individuals with a diagnosis of mild to mod(cid:173)
`erate distal subungual tinea unguium of at least one
`great toenail. These two pivotal trials were conduct(cid:173)
`ed in the United States to meet the regulatory
`requirements necessary for confirming the efficacy
`and safety of an investigational drug.
`
`MATERIALS AND METHODS FOR THE
`UNITED STATES STUDIES
`Study design
`Baseline evaluation included recording informa(cid:173)
`tion such as demographic data, medical history,
`duration of onychomycosis, and the presence or
`absence of chronic tinea pedis. A physical examina(cid:173)
`tion was conducted; clinical laboratory and mycolog(cid:173)
`ic sampling was carried out, ensuring that the eligi(cid:173)
`bility criteria were met. Each eligible subject was
`randomly assigned to receive either the active treat(cid:173)
`ment or matching vehicle for 48 weeks. Subjects
`reported to the clinic for evaluations by the physi(cid:173)
`cian every 4 weeks. If a subject had a clinically and
`mycologically cured target nail (treatment cure) at
`the conclusion of the 48 week treatment period, the
`
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`S 72 Gupta, Fleckman, and Baran
`
`J AM ACAD DERMATOL
`0CTOl~ER 2000
`
`patient was eligible for post-treatment follow-up
`evaluations for a 12 to 24 week period.
`Inclusion criteria included individuals age 18 to 70
`years with distal subungual tinea unguiuin of at least
`one great toenail (target nail). Before randomization,
`patients were to have clinical evidence of ony(cid:173)
`chornycosis with positive potassiu1n hydroxide
`(KOH) preparation and positive clermatophyte cul(cid:173)
`ture. Subjects had between 20% to 65% area of target
`nail involved (confirn1ed by co1nputerizecl planime(cid:173)
`try of standardized photographs). Subjects were
`excluded if either white superficial or proxin1al sub(cid:173)
`ungual onychomycosis \Vas present. Also excluded
`were subjects with abnonnalities of the target nail
`that could have prevented obtaining a normal
`appearing nail if complete cure of the tinea unguium
`was achieved. Similarly, individuals with a structural
`deformity of the target nail or foot that could inter(cid:173)
`fere with photography or planilnetric analysis were
`excluded. An individual with a "spike" of onychomy(cid:173)
`cosis extending to the cuticle of the target nail could
`not enter the study. A patient with a history of
`immunosuppression or clinical signs indicative of
`possible immunosuppression was not allowed to
`enroll in the study.
`Subjects were not allowed to use systemic anti(cid:173)
`fungal therapy within 24 weeks before the screening
`visit; however, local treaonent of vaginal candidiasis
`and the use of ciclopirox olamine cream 1% for treat(cid:173)
`ing flares of tinea pedis \Vere allowe~I. Patients <.;:ould
`not use topical antifungal therapy within 14 days of
`the screening visit; ho\vever, no washout period was
`required for ciclopirox olamine cream l %.
`
`Treatment procedures
`The test material was applied daily, approximate(cid:173)
`ly 24 hours apart, with the lacquer brushed on all
`toenails and any affected fingernails. Subjects were
`instructed to apply the material to all toenails
`regardless of involvement. The areas covered with
`the lacquer were the entire nail plate and approxi(cid:173)
`mately 5 mm of adjacent skin. If possible, tfie mate(cid:173)
`rial was applied to the nail bed, the hyponychium,
`and the ventral surface of the nail plate where it was
`free of the nail bed. Patients were to wait at least 8
`hours after application of the lacquer before wash(cid:173)
`ing the feet.
`The nail lacquer was not removed on a daily basis;
`rather daily applications were applied over the previ(cid:173)
`ous coat. Every 7 days subjects were instructed to
`completely remove the lacquer with isopropyl alco·
`ho! swabs, file away any loose nail 1naterial, and trin1
`the nails as necessary.
`Norn1al hygiene and foot care practices were per(cid:173)
`n1itted. No occlusive dressings were allowed. At each
`
`visit the target nail was trimmed to at least the distal
`groove or an onycholytic nail was trimmed to the
`point of attachment. Any excess horny material was
`filed from the nail surface before treatment applica(cid:173)
`tion. Excessive debridement or drilling of nails was
`not permitted. As per protocol, fungal infections
`besides onychomycosis (eg, tinea peclis or tinea
`cruris) were treated with ciclopirox olamine crean1
`1%. Subjects were not allowed to apply any product
`other than the nail lacquer on the treated nails.
`
`Method of assessment
`The efficacy variables pertained to the target nail
`and included the KOH exa1nination and fungal cul(cid:173)
`ture of material obtained from the nail, planimetric
`measurement of the involved area, and a physician's
`global evaluation. The global evaluations were per(cid:173)
`formed at each 4 week clinic visit, whereas the myco(cid:173)
`Iogic evaluations and photographic planimetry n1ea(cid:173)
`surements were performed every 12 weeks during
`the 48 week treatment.
`
`Planimetry
`Computerized planimetric 1neasurements of the
`involved area of the target nail were 1nade from stan(cid:173)
`dardized photographs and analyzed at a central lab(cid:173)
`oratory in a blinded fashion. Using a fine point felt
`tip pen, the investigator outlined the portion of tar(cid:173)
`get nail that was clinically involved and the boundary
`of the hyponychium or nail gi;:oove .. Tbe pho(cid:173)
`tographs were scanned into a computer and a plani(cid:173)
`metric measurement of the area of target nail
`involved was performed. The affected area (which
`included visually involved nail plus any area of miss(cid:173)
`ing nail because of trimming back from the distal
`groove) as a percentage of the whole nail area was
`used for the analysis. Computerized photoplanime(cid:173)
`try is reproducible; however, because areas are delin(cid:173)
`eated by ink lines with a finite thickness, and
`because the final length of the healthy nail can only
`be presumptive, loss of precision is inevitable as a
`treatment cure is approached. Thus, planimeuy can(cid:173)
`not be used to distinguish minimal residual disease
`fron1 cure. Hence, the establishment of cure
`re1nained a ciinical decision.
`
`Global evaluation score
`The global evaluation score (GES) of the target
`nail was ao;sessed visually by comparing subsequent
`evaluations to the Day 1 (baseline) evaluation. The 5-
`point grading scale was, 0 = cleared (100% clearance
`of clinical signs of disease corroborated by an
`absence of investigator markings on the photo(cid:173)
`graph), l = excellent improvement (~ 75% but
`< 100% clearance of clinical signs of disease), 2 =
`
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`

`
`J AM ACAD DERMATOL
`VOLUME 43. NUMBER 4
`
`Gupta, Fleckman, and Baran S73
`
`Table I. Demographic and background characteristics (intention to treat, ITT population)
`
`Total number of subjects treated (ITT population)
`Sex
`Male
`Female
`Age (years)
`Mean (±SD)
`Range
`Area of target nail involved (%)
`Mean (±SD)
`Range
`Duration of onychomycosis at the target nail (years)
`Mean
`Range
`Causative organism (n [o/o])
`Trubrum
`T mentagrophytes
`Efloccosum
`Other
`
`Study I (Study 312)
`
`Study II (Study 313)
`
`Ciclopirox
`
`Vehicle
`
`Ciclopirox
`
`Vehicle
`
`112
`
`111
`
`119
`
`118
`
`85 (76%)
`27 (24%)
`
`90(81%)
`21 (19%)
`
`94(79%)
`25 (21%)
`
`89 (75%)
`29 (25%)
`
`50.4 (±12.3)
`20-70
`
`48.6 (±13.2)
`18-70
`
`49.6 (±11.9)
`19-70
`
`50.1 (±12.2)
`23-70
`
`39.6 (±10.0)
`20-63
`
`40.3 (±9.6)
`20-63
`
`37.7 (±10.8)
`20-65
`
`38.3 (±8.6)
`21-62
`
`11.8
`0.6-44
`
`108 (96%)
`4(4%)
`0(0%)
`0(0%)
`
`11. 1
`0.3-50
`
`108 (97%)
`3 (3%)
`0(0%)
`0(0%)
`
`10.8
`0.5-51
`
`114(96%)
`5(4%)
`0(0%)
`0(0%)
`
`11.6
`0.5-50
`
`112 (95%)
`5(5%)
`1 (0.9%)
`0(0%)
`
`moderate improvement P-: 50% to < 75% clearance
`of clinical signs of disease), 3 = slight improvement
`( <50% clearance of clinical signs of disease), 4 = no
`change (no detectable improvement from baseline
`evaluation), and 5 = exacerbation (flare of area
`being studied or increase in area of invoh'.'~~en.t).
`
`Efficacy criteria
`The efficacy criteria pertained to the target toenail
`and were based on the following: fungal culture,
`light microscopic examination (KOH exam), physi(cid:173)
`cian's GES, and affected area as a percentage of the
`whole nail plate area (planimetry). The primary effi(cid:173)
`cacy variable was treatment success (defined as
`simultaneous negative KOH and culture, and :s:; 10%
`area involvement of the target nail plate as deter(cid:173)
`mined by planimetry). Other secondary variables
`included: treatment cure (defined as simultaneous
`negative KOH and culture, and a GES of cleared),
`mycologic cure (defined as simultaneous negative
`KOH and culture), and negative mycologic culture.
`
`Safety criteria
`Adverse events (AEs) were recorded during the
`study, and were defined as any signs, symptoms, ill(cid:173)
`nesses, or diagnoses that appeared or worsened. For
`example, flares of tinea pedis, skin irritation adjacent
`to the treated nails, or nail bed irritation were report(cid:173)
`ed as AEs. All AEs that occurred at any time during
`the study, whether believed by the investigacor to be
`related or unrelated to the test material, were report·
`
`eel as an AE. For the safety analysis, only treatment(cid:173)
`emergent AEs (TEAEs) were considered. This includ(cid:173)
`ed any AE occurring during treatment that was not
`present before treatment or was present before
`treaunent but became more intense (that is,
`increased in severity or frequency) during the treat(cid:173)
`n1en·t pefiod. In addition to continuous AE moni'tot:(cid:173)
`ing, clinical laboratory evaluations (complete blood
`count, serum chen1istry including liver function tests
`and electrolytes, and urinalysis) were performed
`every 12 weeks during the 48 week study. At select(cid:173)
`ed study sites blood sa1nples were collected before,
`during, and after treatment for measurement of
`serun1 levels of ciclopirox and its glucuronide
`n1etabolite.
`
`Statistical analysis
`Descriptive statistics were used to summarize the
`patients' demographic characteristics (age, gender,
`race) and the background characteristics (percent
`area of involve1nent of the target great toenail, dura(cid:173)
`tion of onychon1ycosis, causative organism, pres(cid:173)
`ence/absence of tinea peclis). Area of involvement at
`baseline (less than or greater than 40% of nail sur(cid:173)
`face) was also used as a stratification variable in the
`efficacy analyses. The age of the subject, percentage
`involvement of nail plate at the baseline visit, and the
`duration of onycho1nycosis were considered as con(cid:173)
`tinuous variables and compared by means of the
`analysis of variance (Al'\JOVA) between the 2 treat-
`1nents without any acljustn1ents. The other variables
`
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`
`S 7 4 Gupta, Fleckman, and Baran
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`J AM ACAO 0ERMATOL
`0CTOllER 2000
`
`Table II. Efficacy results for week 48 (last observation carried forward*; ITT population)
`
`Study I
`
`Study II
`
`Efficacy parameter
`
`Ciclopirox
`
`Vehicle
`
`CMH Pvaluet
`
`Ciclopirox
`
`Vehicle
`
`CMH P valuet
`
`Mycologic cure*
`Treatment successll
`Treatment cure'
`Negative culture
`
`30/105 (29%)
`7/107 (6.5%)
`6/110 (5.5%)
`94/112 (84%)
`
`12/106(11%)
`1/108 (0.9%)
`1/109 (0.9%)
`41/111 (37%)
`
`.002•
`.Q31§
`.059
`<.001•
`
`41 /115 (36%)
`14/116 (12%)
`10/118 (8.5%)
`100/119 (84%)
`
`10/114 (9%)
`1/115 (0.9%)
`0/117 (0%)
`52/118 (44%)
`
`<.001 §
`.001•
`.001•
`<.001•
`
`*Last available follow-up measurement for each subject.
`tp value for treatment difference from Cochran-Mantel-Haenszel test adjusting for center.
`*Mycologic cure: negative KOH and negative culture.
`§Statistically significant.
`llTreatment success: S:10% target nail plate involvement and negative KOH and negative culture.
`'Treatment cure: negative culture and negative KOH, global evaluation score= cleared.
`
`Table III. Treatment emergent adverse events (TEAEs) reported by more than 1 patient and considered by the
`investigator to be possibly related to test material
`
`Study I
`
`Study II
`
`Ciclopirox
`
`Vehicle
`
`Ciclopirox
`
`Vehicle
`
`112
`10(9%)
`3(3%)
`2(2%)
`4 (4%)
`
`111
`7(6%)
`2(2%)
`1 (1%)
`1 (1%)
`
`119
`16 (13%)
`0
`3(3%)
`12 (10%)
`
`118
`9(8%)
`1 (1%)
`4(3%)
`2(2%)
`
`Total number of subjects treated
`Number with related TEAEs
`Application site reaction*
`Nail disordert
`Rash*
`
`*eg, tingling sensation, pain, or intermittent burning.
`teg, changes in nail shape or color.
`*eg, localized erythema.
`
`were considered as categorical and the Cochran(cid:173)
`Mantel-Haenszel test adjusted for the investigator
`site was used. All subjects who had received at least
`one dose of the randomized study nleclication were
`included in the intent-to-treat (ITl) population. The
`primary time point of interest was end of treatn1ent
`(typically week 48), although interim time points
`were also analyzed. This conservative approach
`(known as a Last Observation Carried Forward
`method of analysis) assun1ed that a subject would
`not have achieved treaunent success or treatn1ent
`cure if he or she remained in the study.
`
`RESULTS OF US STUDIES
`Study patients
`In the first study (Study 312), a total of 223 indi(cid:173)
`viduals were randomized to treatment and were
`included in the ITT analysis (ciclopirox group: 112,
`vehicle group: 111). Of the patients randomized to
`treatment, 89 (79.5%) and 84 (75.7%) completed the
`study for the active and vehicle group, respectively.
`Similarly, 237 subjects were randomized to trearn1ent
`in study II (Study 313) and were included in the ITT
`
`analysis (ciclopirox: 119 subjects, vehicle: 118). Of
`the patients randomized to treatment in this study,
`96 (80.7%) and 94 (79.7%) completed the study,
`respectively. None of the 231 patients receiving the
`ciclopirox treatment in either study discontinued the
`study prematurely because of an AE. The primary
`reasons for being withdrawn from the study for both
`the ciclopirox and vehicle groups included: with(cid:173)
`drawal of consent, unreliability, violation of protocol
`criteria, lost to follow-up, and lack of efficacy.
`Demographic and baseline characteristics for
`study I and study II are presented in Table I.
`Population characteristics were homogenous
`between the two treatment groups (P > .05) and
`consistent across studies. The studied population
`was predominantly male (approxilnately 80%), with
`a 111ean age of approximately 49 years. In addition,
`the mean area of involvement for the target toenail
`was approximately 40%, and the predominant
`causative pathogen was T rubrum.
`The most frequently used non-study medication
`was ciclopirox olamine crean1 1%, for the trearn1ent
`of any tinea pedis flares that 1nay have occurred dur-
`
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`J AM ACAD 0ERMATOL
`VOLUME 43. NUMl\ER 4
`
`Gupta, Fleckman, and Baran S75
`
`ing the 48 week study. Approximately 61 % to 75% of
`the patients used this concomitant treatment at one
`tirne or another during the conduct of the studies.
`The use of this therapy was relatively high because it
`was a therapy provided per protocol to treat the
`tinea pedis infections that commonly accompany
`onychomycosis.
`
`Efficacy
`The incidence of mycologic cure, treatment suc(cid:173)
`cess, treatment cure, and negative mycology cultures
`at the end of treatment through 48 weeks is pre(cid:173)
`sented in Table II. These data indicate that ciclopirox
`nail lacquer is an effective treatment of mild to mod(cid:173)
`erate onychomycosis of the toenail. Although the
`data presented focus on the week 48 endpoint, sig(cid:173)
`nificant improvements were realized as early as week
`12 for the mycologic cure and negative mycologic
`culture responses (f! < .001; ciclopirox nail lacquer
`vs vehi~le). These significant improvements were
`maintained throughout the entire 48 week treat(cid:173)
`ment period. Outcomes for patients with greater
`(40% to 65% nail surface area involved) and lesser
`(20% to <40% nail area) severity of disease were also
`analyzed and showed results similar to the popula(cid:173)
`tion as a whole. Of the 17 patients who were eligible
`for follow-up after treatment (ie, those meeting the
`stringent "treatment cure" criteria), many had
`incomplete data to adequately assess the relapse
`rate. However, 7 of the 12 patients with complete
`data remained "Cufed" at i2 weeks· after treatment.
`Alternately, 4of12 patients did not maintain negative
`mycology (ie, negative KOH and culture) at 12 weeks
`after treatment. One patient had negative mycology
`and was recorded to have "almost clear" toenails.
`
`Safety
`The TEAEs reported by more than one patient
`and considered by the investigator to be possibly
`related to the test material are presented in Table III.
`Typically the "rashes" reported as TEAEs consisted of
`erythema in the skin adjacent to the nail plate. Most
`of the reported erythema cases (coded as rash) were
`mild in severity and generally cleared by the end of
`the study. Application site reactions were occasional(cid:173)
`ly recorded for both the ciclopirox and vehicle, and
`were mild in intensity. These local reactions general(cid:173)
`ly consisted of a tingling sensation, pain, or intermit(cid:173)
`tent burning, and were transient and cleared during
`therapy without requiring specific treatment. Nail
`disorders were infrequently reported for both
`the ciclopirox and vehicle groups, and typically con(cid:173)
`sisted of changes in nail shape or color without
`requiring any specific treatment. These were mild in
`intensity and cleared during the course of the study
`
`without necessitating treatment or discontinuation
`from the protocol.
`In both studies, there were no serious AEs con(cid:173)
`sidered causally related to the ciclopirox nail lacquer,
`and none of the subjects in the ciclopirox group in
`either study discontinued therapy because of TEAEs.
`There were no suggestive trends or important differ(cid:173)
`ences between treatments for any clinical laboratory
`evaluation.
`Ciclopirox nail lacquer is considered extremely
`safe as den1onstrated by the pivotal US studies. AEs
`that have been observed are generally localized and
`consist pri1narily of erythema, and even less fre(cid:173)
`quently, burning/tingling sensation or swelling at the
`application site. Jn most instances these are mild in
`intensity and clear with continued application of the
`lacquer.
`
`NON-US TRIALS CONDUCTED TO
`DETERMINE THE EFFICACY AND SAFETY
`OF CICLOPIROX NAIL LACQUER
`Thirteen trials that have been conducted outside
`of the United States using ciclopirox nail lacquer to
`treat onychomycosis of fingers and toes are summa(cid:173)
`rized in Table IY. The majority of patients had toe ony(cid:173)
`chomycosis caused by dermatophytes. The countries
`in which these trials were conducted included
`Europe (Germany, France, Finland, and Austria), A'iia
`(Korea), North America (Mexico), and South America
`(Argentina and Brazil). The 13 non-US studies used a
`variety of trial designs. 'Altli.ough most were open
`label, they were frequently multicenter studies with
`standardized techniques for efficacy evaluations. In
`addition, safety was assessed by adverse experiences
`captured in the studies. Qualified study patients gen(cid:173)
`erally were to have clinical, microscopic, and culture
`evidence of onychomycosis. This usually meant that
`patients were to have culture evidence for clennato(cid:173)
`phytes, although son1e patients having nondermato(cid:173)
`phyte organisms (eg, Candida sp) or negative fungal
`cultures were included. Although a specified surface
`area involven1ent was not a requiren1ent, the majori(cid:173)
`ty of patients had evidence of extensive nail involve·
`ment (>2/3 of nail surface) at baseline. Treatment
`regimens in the non-US studies varied, with some
`studies using a less frequent regimen than the once
`daily 48-week treatment studied in the US. In addi(cid:173)
`tion, the typical treatment duration was usually 6
`months for the non-US studies. Outco1ne measures
`(physician and patient assessments, and mycology)
`were similar to those used in the US trials, although a
`nonphotographic planimetric method was used to
`quantify disease extent.
`Results of the non-US studies demonstrated the
`efficacy of ciclopirox nail lacquer across a range of
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1079- Page 6 of 12
`
`

`
`S76 Gupta, Fleckman, and Baran
`
`J AM ACAD 0ERMATOL
`Ocro11ER 2000
`
`Table Iv. Summary of some non-US studies where ciclopirox nail lacquer has been used to treat onychomycosis
`
`Study location
`
`Type of study
`
`Treatment regimen
`
`Toenails/fingernails
`
`Causative organisms
`
`FN
`
`Trubrum: 8
`T mentagrophyres: 7
`
`TN: (82.7%); FN: (17.3%); Oermatophytes: 76o/o
`60% of patients with
`Yeast: 13.5°/o
`>50o/o nail surface
`Molds/fungi: 5.So/o
`Multiple organisms: 5%
`involvement
`TN
`Trubrum: 54
`T mentagrophytes: 17
`T vio(aceum: 1
`C albicans: 3
`
`Finland
`
`Germany
`
`Randomized
`double-blind
`
`Every 2nd day application
`x 3-6 months. Follow-up:
`2-4 months after stopping
`therapy
`Open, multicenter Once daily up to 6 months;
`1 month follow-up
`
`Germany
`and Finland
`
`Germany
`
`Germany
`
`Open, multicenter Once daily application.
`Active treatment: 3 to 6
`months. After 2 successive
`negative KOH examinations
`treatment was stopped
`with final evaluation 8
`weeks later
`Open, multicenter Three times a week
`application. Active treatment
`up to 7.5 months (average
`5.7 months)
`Open, multicenter Once daily application. Up to
`12 months, median 6
`months. Follow-up: 1 month
`after stopping therapy
`
`Germany
`
`Open
`
`Once daily up to 6 months.
`Follow-up: another 6 months
`after stopping therapy
`
`Germany
`
`Open, multicenter Once daily, up to 6 months
`
`Brazil
`
`Open, multicenter Alternate day application for
`(1 O centers)
`1 month, twice a week in
`2nd month, once weekly
`during months 3-6,
`follow-up at month 7
`
`TN:41/43 FN:2/43
`
`TN:FN4.2:1
`
`DLSO: 54/58 (93.1 %)
`P50 2/58 (3.4%)
`W50 2/58 (3.4%)
`TN:FN =6.1:1
`TN:FN 5.8:1
`
`Tl~:FN = 84:16
`DLSO: 95% W50: 5%
`
`Trubrum:26
`T mentagrophytes: 4
`C albicans: 1 Others: 17
`
`Trubrum: 71
`T mentagrophytes: 7
`T verrucosum: 1
`C albicans: 2 Others: 3
`
`Trubrum: 27
`T mentagrophytes: 6
`T rubrum +others: 15
`S brevicaulis: 4 Others: 6
`Trubrum: 20
`T mentagrophytes: 3
`Others:2 ·
`Trubrum: 61
`Tmentagrophytes: 31
`Trichophyton sp: 4
`E floccosum: 2
`C a/bicans: 3
`Candida sp: 15
`T rubrum: 53.2%
`Tmentagrophytes: 19.1%
`E floccosum: 3.5o/o
`Other dermatophytes: 7.0°/o
`C albicans: 11.3%
`Other Candida sp: 2.1 o/o
`Aspergillus sp: 1.4%
`Mixed infections: 2. 1 %
`Dermatophytes: 76.7%
`Yeasts: 23.3%
`
`Dermatophytes: 78%
`Yeasts:22%
`
`Dermatophytes (59 patients)
`Trubrum: 53
`Tmentagrophytes: 4
`T beigefii: 1 Yeasts: 38
`Other: 1
`N/A
`
`Mexico
`
`Open, multicenter Once daily, up to 6 months
`
`TN: 94.3% FN: 5.7%
`
`Argentina
`
`Korea
`
`Korea
`
`Open, randomized Once daily (n = 30) or twice
`weekly (n = 30), up to
`6 months
`Once daily, up to 6 months
`
`Open
`
`TN
`
`TN/FN
`
`Open, multicenter Once daily for 1 month, then
`twice weekly for 5 months
`
`TN: 98 patients
`FN: 9 patients
`
`Austria
`
`Open
`
`2.5 times per week on
`average, up to 6 months
`
`TN: 79% FN: 17%
`
`AE, Adverse event; DLSO, distal lateral subungual onychomycosis; FN, fingernail; ITT, intent-to-treat population; KOH, potassium hydroxide; NIA,
`not available; PSO, proximal subungual onychomycosis; QD, once daily; TN, toenail; WSO, white superficial onychomycosis; 2x/wk, twice per wee