A CME/CE CERTIFIED SUPPLEMENT TO
`
`SUPPLEMENT 3
`VOL. 35, NO. 3S
`MARCH 2016
`
`EDITORS
`Kenneth A. Arndt, MD
`Philip E. LeBoit, MD
`Bruce U. Wintroub, MD
`
`Onychomycosis:
`Diagnosis, Treatment, and
`Prevention Strategies
`
`GUEST EDITORS
`Linda F. Stein Gold, MD
`Theodore Rosen, MD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Introduction S47
`
`Understanding Onychomycosis:
`Resolving Diagnostic Dilemmas S48
`
`Antifungal Drugs for Onychomycosis:
`Efficacy, Safety, and Mechanisms of Action S51
`
`Concepts in Onychomycosis Treatment
`and Recurrence Prevention: An Update S56
`
`Using Topical Antifungal Medications:
`Instructions for Patients S60
`
`Post-Test and Evaluation Form S61
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2062 - 1/8
`
`Page 1 of 8
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1522
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`Onychomycosis:
`Diagnosis, Treatment, and Prevention Strategies
`
`Original Release Date: March 2016
`Most Recent Review Date: March 2016
`Expiration Date: February 28, 2018
`Estimated Time to Complete Activity: 2.5 hours
`Participants should read the activity information, review the activity in its
`entirety, and complete the online post-test and evaluation. Upon completing
`this activity as designed and achieving a passing score on the post-test, you
`will be directed to a Web page that will allow you to receive your certificate of
`credit via e-mail or you may print it out at that time. The online post-test and
`evaluation can be accessed at http://tinyurl.com/onychosuppl16.
`Inquiries about CME accreditation may be directed to the University of Louisville
`CME & PD at cmepd@louisville.edu or (502)852-5329.
`Accreditation Statements
`Physicians: This activity has been planned and implemented in accordance with
`the Essential Areas and Policies of the Accreditation Council for Continuing Medical
`Education (ACCME) through the joint providership of The University of Louisville and
`Global Academy for Medical Education, LLC. The University of Louisville is accred-
`ited by the ACCME to provide continuing medical education for physicians.
`The University of Louisville Office of Continuing Medical Education &
`Professional Development designates this enduring material for a maximum
`of 2.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit
`commensurate with the extent of their participation in the activity.
`Nurses: This program has been approved by the Kentucky Board of Nursing
`for 3.0 contact hours through the University of Louisville Hospital, provider
`number 4-0068-7-16-895. The Kentucky Board of Nursing approval of an indi-
`vidual nursing education provider does not constitute endorsement of program
`content. Participants must complete the entire session, provide their license
`number, and complete the evaluation to receive contact hours.
`Target Audience
`This journal supplement is intended for dermatologists, family practitioners,
`internists, nurse practitioners, physician assistants, and other clinicians who
`treat patients with onychomycosis.
`Educational Needs
`For many years, the treatment of onychomycosis was frustrating for clinicians
`and patients alike, and the perceived futility of addressing fungal nail infec-
`tions meant that many patients failed to seek treatment, and many others with
`suspected infections were neither definitively diagnosed nor treated. With the
`introduction of oral terbinafine in 1996 and the approval of the first topical agent
`in 1999, more effective control—if not cure—became possible, and clinicians
`showed increased interest in diagnosing and treating the condition. The intro-
`duction of two new topical agents in 2014 broadened the therapeutic options.
`The optimum results with these agents requires the correct diagnosis, which
`cannot be made reliably on visual inspection alone. To use antifungals most
`effectively, clinicians must test to confirm the presence of infecting organ-
`isms and, in appropriate cases, identify the species involved so that the most
`appropriate antifungal can be prescribed. Patient selection also is important:
`for example, the potential for drug-drug interactions with systemic antifungals
`must be considered, the presence of certain comorbid conditions may affect
`the choice of antifungal employed, and the patient’s ability to adhere to the
`long treatment regimens required must be addressed.
`Clinicians must remain up-to-date on these issues, and must be able to effec-
`tively and safely use the available antifungal, evaluate the emerging data on
`medications and devices now being investigated, and educate patients to
`improve adherence.
`Learning Objectives
`After reading and studying this journal supplement, participants will be better
`able to:
`• Establish or improve practice protocols for identifying patients with
`onychomycosis, particularly in special populations (eg, the elderly, pediatric
`patients, immunocompromised patients, patients with psoriasis, and those
`with diabetes mellitus).
`• Discuss techniques, including obtaining good culture specimens, that
`
`permit more accurate diagnosis of the infecting organisms and the most
`appropriate choice of therapy.
`• Explain the drug classes and mechanisms of action for the currently
`available therapeutic options, including differences in formulation and
`associated efficacy.
`• More effectively use currently available oral and topical medications to
`treat various patient populations.
`• Review and, if necessary, improve patient education materials designed
`to enhance patient adherence with the treatment regimen and to change
`habits that increase the chances of good long-term management of
`onychomycosis.
`• Determine and help each patient recognize the realistic expectations for
`improvement in his or her individual case.
`• Evaluate the results of clinical studies on new and emerging and available
`treatments for onychomycosis based on an understanding of possible
`differences in testing protocols (eg, inclusion or exclusion of patients with
`psoriasis or diabetes mellitus).
`Disclosure Declarations
`As a provider accredited by the ACCME, the Office of CME & PD, School of
`Medicine, University of Louisville must ensure balance, independence, objec-
`tivity, and scientific rigor in all its sponsored educational activities. All planners,
`faculty, reviewers, and other persons that affected the content of this CME
`activity were required to submit a financial disclosure form from which rele-
`vant conflicts of interest were determined. The persons below disclosed the
`following:
`Linda F. Stein Gold, MD, Consultant: Anacor Pharmaceuticals Inc., Eli Lilly
`and Company, Galderma Laboratories, L.P., LEO Pharma
`Inc., Novartis
`Pharmaceuticals Corporation, Pfizer
`Inc., Sandoz, Taro Pharmaceutical
`Industries Ltd., and Valeant Pharmaceuticals North America LLC. Speaker:
`Galderma, LEO, Novartis, and Valeant. Grant Research/Support: Anacor,
`Galderma, GlaxoSmithKline, LEO, Novartis, Pfizer Inc., Sandoz, Taro, and Valeant.
`Theodore Rosen, MD, Consultant: Anacor Pharmaceuticals and Valeant
`Pharmaceuticals North America LLC.
`CME Reviewer: Cindy England Owen, MD, Assistant Professor, Division of
`Dermatology, University of Louisville School of Medicine, has no relevant finan-
`cial relationships to disclose.
`The CME & PD Staff and Advisory Board have nothing to disclose with the
`exception of Douglas Coldwell, MD, Speaker: Sirtex, Inc.; Consultant: DFine, Inc.
`Global Academy for Medical Education Staff: Sylvia H. Reitman, MBA, DipEd;
`Shirley V. Jones, MBA; Jenny Campano; and Joanne Still have no relevant
`financial relationships to disclose.
`Off-Label/Investigational Use Disclosure
`This CME/CE activity discusses the off-label use of fluconazole for the treatment
`of onychomycosis. Also discussed are off-label, alternative dosing sched-
`ules for itraconazole, as well as the use in pediatric patients of medications
`approved for the treatment of onychomycosis in adults; currently, no medica-
`tion is approved for the treatment of onychomycosis in pediatric patients.
`
`This continuing education supplement was developed from a satellite
`symposium held at Skin Disease Education Foundation (SDEF)‘s 16th Annual
`Las Vegas Dermatology Seminar, which took place Friday, November 6, 2015,
`in Las Vegas, Nevada. The Guest Editors acknowledge the editorial assistance of
`Global Academy for Medical Education and Joanne Still, medical writer, in the
`development of this supplement. The manuscript was reviewed and approved by
`the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and
`Surgery. The ideas and opinions expressed in this supplement are those of the
`Guest Editors and do not necessarily reflect the views of the supporters, Global
`Academy for Medical Education, the University of Louisville, or the Publisher.
`
`Jointly provided by
`
`and
`
`Supported by an educational grant from
`PharmaDerm, a Fougera Pharmaceuticals company
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2062 - 2/8
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`Page 2 of 8
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`

`

`STATEMENT OF PURPOSE
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`well-rounded and authoritative discussions of important
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`the specialty. Each issue, under the direction of the Editors
`and Guest Editors selected because of their expertise in the
`subject area, includes the most current information on the
`diagnosis and management of specific disorders of the skin,
`as well as the application of the latest scientific findings to
`patient care.
`
`Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is
`published quarterly by Frontline Medical Communications Inc., 7 Century
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`Copyright © 2016 by Frontline Medical Communications Inc. No part of
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`Publication of an advertisement in Seminars in Cutaneous Medicine and
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`
`The ideas and opinions expressed in Seminars in Cutaneous Medicine
`and Surgery do not necessarily reflect those of the Editors or Publisher.
`Publication of an advertisement or other product mention in Seminars in
`Cutaneous Medicine and Surgery should not be construed as an endorsement
`of the product or the manufacturer’s claims. Readers are encouraged to
`contact the manufacturer with any questions about the features or limitations
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`for any injury and/or damage to persons or property arising out of or related
`to any use of the material contained in this periodical. The reader is advised
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`currently provided by the manufacturer of each drug to be administered
`to verify the dosage, the method and duration of administration, or
`contraindications. It is the responsibility of the treating physician or other
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`of the patient, to determine drug dosages and the best treatment for
`the patient.
`
`Seminars in Cutaneous Medicine and Surgery is indexed in Index
`Medicus/MEDLINE
`
` EDITORS
`
`Kenneth A. Arndt, MD
`Clinical Professor of Dermatology,
` Emeritus
`Harvard Medical School
`Adjunct Professor of Surgery
`Dartmouth Medical School
`Hanover, New Hampshire
`Adjunct Professor of Dermatology
`Brown Medical School
`Providence, Rhode Island
`
`Philip E. LeBoit, MD
`Professor of
` Clinical Dermatology
`University of California,
` San Francisco
`San Francisco, California
`
`Bruce U. Wintroub, MD
`Associate Dean
`Professor and Chair
` of Dermatology
`School of Medicine
`University of California,
` San Francisco
`San Francisco, California
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2062 - 3/8
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`Page 3 of 8
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`

`

`Antifungal Drugs for Onychomycosis: Efficacy,
`Safety, and Mechanisms of Action
`
`Theodore Rosen, MD*, and Linda F. Stein Gold, MD†
`
`n Abstract
`In 1996, oral terbinafine joined itraconazole and flucon-
`azole on the short list of systemic medications that could
`be used to treat onychomycosis (although fluconazole
`was not approved for this indication by the US Food and
`Drug Administration [FDA], it was commonly used for this
`purpose). In 1999, ciclopirox was the first topical treatment
`to be FDA approved. The addition of the topical antifungal
`agents efinaconazole and tavaborole in 2014 expanded
`the roster of medications available to more effectively
`manage onychomycosis in a wide range of patients,
`including those for whom comorbid conditions, concomi-
`tant medications, or patient preference limited the use of
`systemic antifungals.
`Keywords
`Candidiasis; ciclopirox; efinaconazole; dermatophytosis;
`fluconazole; itraconazole; onychomycosis; tavaborole;
`terbinafine
`Semin Cutan Med Surg 35(supp3):S53-S57
`© 2016 Frontline Medical Communications
`
`In selecting an antifungal agent to treat onychomycosis, clini-
`
`cians must consider several factors: efficacy, side effect profile,
`drug-drug interactions, and the presence of comorbid diseases
`and conditions. This article focuses on the efficacy, safety, and
`drug-drug interactions associated with the systemic and topical
`medications used in the treatment of onychomycosis. [The third
`article in this supplement, “Concepts in Onychomycosis Treatment
`
`* Professor of Dermatology, Baylor College of Medicine, Houston, Texas.
`† Director of Dermatology Research, Henry Ford Health System, Detroit,
`Michigan.
`Publication of this CME/CE article was jointly provided by the University
`of Louisville, and Global Academy for Medical Education, LLC with Skin
`Disease Education Foundation (SDEF) and is supported by an educational
`grant from PharmaDerm, a Fougera Pharmaceuticals company.
`Dr Rosen and Dr Stein Gold have received an honorarium for their
`participation in this activity. They acknowledge the editorial assistance of
`Joanne Still, medical writer, and Global Academy for Medical Education in the
`development of this continuing medical education journal supplement.
`Linda F. Stein Gold, MD, Consultant: Anacor Pharmaceuticals Inc., Eli Lilly
`and Company, Galderma Laboratories, L.P., LEO Pharma Inc., Novartis
`Pharmaceuticals Corporation, Pfizer Inc., Sandoz, Taro Pharmaceutical
`Industries Ltd., and Valeant Pharmaceuticals North America LLC. Speaker:
`Galderma, LEO, Novartis, and Valeant. Grant Research/Support: Anacor,
`Galderma, GlaxoSmithKline, LEO, Novartis, Pfizer Inc., Sandoz, Taro, and
`Valeant.
`Theodore Rosen, MD, Consultant: Anacor Pharmaceuticals and Valeant
`Pharmaceuticals North America LLC.
`Address reprint requests to: Theodore Rosen, MD, 2815 Plumb, Houston, TX
`77005; vampireted@aol.com.
`
`and Recurrence Prevention: An Update,” on pages S59-S61, ad-
`dresses the topic of onychomycosis comorbidities in detail.]
`
`Systemic Therapy: Efficacy Rates
`Clinical trials have established the efficacy of terbinafine, itracon-
`azole, and fluconazole in dermatophyte infections, using the FDA
`standard of complete cure—ie, negative mycology (both direct mi-
`croscopy of a potassium hydroxide [KOH] wet-mount preparation)
`and normal nail plate appearance as the end point (Table 1).
`Terbinafine has been the drug of choice since its introduction in
`1996. The initial clinical trials comparing terbinafine with itracon-
`azole showed that terbinafine was more effective. Those studies
`demonstrated a 38% complete cure rate using what became the
`FDA-approved dosage regimen for oral terbinafine—250 mg/day
`for 12 weeks.1,2 Subsequently, Evans and colleagues3 investigated
`the use of pulsed dosing of terbinafine, using either three or four
`pulses of 250 mg/day (ie, 1 week of daily treatment followed by 3
`weeks off, repeated either once or twice). The reported cure rates
`were 49% for the three-pulse regimen and 54% for the four-pulse
`regimen. Pulsed dosing of terbinafine is not approved by the FDA.
`Itraconazole, at a dosing schedule of 200 mg/day for 12 weeks,
`has been reported to yield a cure rate of 14%.4 The results of clini-
`cal trials of pulsed dosing of itraconazole in patients with finger-
`nail onychomycosis—a complete cure in 47% of patients—led to
`FDA approval of a regimen of two pulses of 400 mg/day for this
`indication (ie, 1 week of treatment followed by 3 weeks off, re-
`peated once).3 Studies of pulsed dosing of itraconazole in patients
`with toenail onychomycosis yielded efficacy rates of 23% for three
`pulses and 26% for four pulses.3 Although not approved by the
`FDA for this indication, pulsed dosing of itraconazole frequently
`is used to treat toenail onychomycosis.
`Fluconazole is not FDA approved for onychomycosis, but it is
`used quite commonly to treat both fingernail and toenail fungal
`infections. The typical regimen is a single weekly dose of 150 to
`450 mg, for at least 6 months. Scher and colleagues5 reported ef-
`ficacy rates of 37% with 150 mg/week, 46% with 300 mg/week,
`and 48% with 450 mg/week.
`In addition, Gupta and colleagues6 reviewed other clinical trials
`that examined the efficacy of these medications with some smaller
`or noncontrolled trials yielding higher efficacy rates than those
`seen in the phase III trials. Although none of these medications
`is FDA approved for onychomycosis caused by Candida species,
`clinical studies have demonstrated that these oral antifungals do
`have some efficacy.6
`
`Systemic Therapy: Safety
`Oral antifungal agents generally are considered safe, but the pre-
`scribing information for each medication should be considered
`with respect to individual patient characteristics, and careful atten-
`
`1085-5629/13$-see front matter © 2016 Frontline Medical Communications
`DOI: 10.12788/j.sder.2016.009
`
`Vol. 35, No. 3S, March 2016, Seminars in Cutaneous Medicine and Surgery S51
`
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`Page 4 of 8
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`n TABLE 1. Systemic Antifungals: Efficacy in Phase III Pivotal Trials
`
`Medication/Regimen
`
`Complete Cure Rates
`
`Comments
`
`Terbinafine
`250 mg/day x 12 weeks1
`250 mg/day x 1 week/month2
` Repeated for 3 pulses
` Repeated for 4 pulses
`
`Itraconazole
`200 mg/day x 12 weeks3
`
`400 mg/day x 1 week/month2
` Repeated for 3 pulses
` Repeated for 4 pulses
`Fluconazole4
`150 mg/week
`300 mg/week
`450 mg/week
`
`38%
`
`49%
`54%
`
`14%
`
`23%
`26%
`
`37%
`46%
`48%
`
`Pulsed dosing of terbinafine is not FDA approved.
`
`Approved regimen for toenail onychomycosis, with/without
`fingernail involvement.
`This regimen is not approved for either toenail or fingernail
`onychomycosis.
`
`Fluconazole is not FDA approved for use in onychomycosis.
`
`tion should be paid to recommendations for baseline and follow-up
`testing and clinical monitoring.
`For example, terbinafine has been associated with hepatic failure,
`and the prescribing information recommends that liver function tests
`be performed both at baseline and periodically during treatment.
`Other adverse events previously reported with the use of terbinafine
`include taste and smell disturbances that may become permanent,
`depression, severe neutropenia, and skin diseases such as Stevens-
`Johnson syndrome, drug reaction with eosinophilia and systemic
`symptoms (DRESS), and lupus erythematosus–like illness.1
`The prescribing information for itraconazole contains cautions
`about heart failure, other cardiac effects, including life-threatening
`arrhythmias, and sudden death (especially when itraconazole is
`used concomitantly with certain cytochrome P450 inhibitors—see
`“Drug-Drug Interactions,” below). Hearing loss has been reported
`with the use of this medication, and hepatotoxicity rarely has been
`reported to occur as early as the first week of treatment.4 Moreover,
`in vitro drug resistance has been demonstrated with this and the
`other azole drug, fluconazole.4,7
`In addition to in vitro drug resistance, fluconazole use has been
`associated with hepatotoxicity, significant skin diseases, and pro-
`longation of the QT interval on electrocardiogram. Fluconazole
`also has been associated with congenital defects, and its use should
`be avoided during the first trimester of pregnancy.7
`
`Drug-Drug Interactions
`No drug interactions have been reported with the use of any of the top-
`ical antifungal agents approved for the treatment of onychomycosis.
`A number of drug-drug interactions—many of which are theo-
`retical—are listed for each of the systemic antifungal medications
`(Table 2). The prescribing information for each of these medica-
`tions should be consulted before choosing an oral antifungal. A
`detailed description of the mechanisms by which these interactions
`
`may occur is beyond the scope of this article, so one or two illustra-
`tive examples have been chosen for terbinafine, itraconazole, and
`fluconazole.
`Terbinafine, which is metabolized by the cytochrome p450
`(CYP450) enzyme 2D6 (CYP2D6), may interact in particular with
`drugs that are also metabolized by CYP2D6.1 Although the class of
`beta-blockers is listed in the prescribing information, not all beta-
`blockers may interact to the same degree. Metoprolol—the most
`commonly prescribed beta-blocking agent in the United States—is
`the most likely drug in this class to interact with terbinafine. Terbi-
`nafine may inhibit the metabolism of metoprolol, resulting in ex-
`cess systemic levels of metoprolol and a risk for bradycardia, low
`blood pressure, and, possibly, cardiogenic shock.8
`Itraconazole is metabolized by the CYP3A4 enzyme, a charac-
`teristic it shares with several other medications.4 One interaction of
`note is itraconazole’s inhibition of metabolism of statin drugs, par-
`ticularly simvastatin and lovastatin; this action can result in rhab-
`domyolysis. In addition, a potentially fatal interaction can occur
`when itraconazole is given concomitantly with opioids, particular-
`ly methadone; the combination is associated with a high likelihood
`of a fatal arrhythmia.9
`Fluconazole has been widely studied and demonstrated to be
`effective against onychomycosis, and, although it is not FDA
`approved for this indication, it is widely used for treating this
`infection. Potential interactions include antiarrhythmic drugs, an-
`tipsychotics, and antihistamines7 (although the most problematic
`among these, terfenadine, is no longer marketed).
`However, not on the list derived from the fluconazole prescrib-
`ing information is an interaction that has been demonstrated re-
`cently with tofacitinib—a medication currently approved for
`rheumatoid arthritis, well studied and likely to be approved for
`psoriasis and psoriatic arthritis, and being used investigationally in
`alopecia areata. Fluconazole inhibits tofacitinib’s metabolism and,
`
`S52 Seminars in Cutaneous Medicine and Surgery, Vol. 35, No. 3S, March 2016
`
`n n n Antifungal Drugs for Onychomycosis: Efficacy, Safety, and Mechanisms of Action
`
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`Page 5 of 8
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`

`

`therefore, may lead to gastrointestinal disturbances, such as severe
`diarrhea. Furthermore, inhibition of tofacitinib’s metabolism may
`potentiate tofacitinib-related infections, particularly pharyngitis,
`sinusitis, and bacterial infections; some of these infections may
`be severe.10
`
`Topical Agents: Efficacy and Safety
`Currently, three topical agents are approved for the treatment of
`onychomycosis: ciclopirox 8% solution, efinaconazole 10%, and
`tavaborole 10%. No systemic adverse events have been reported
`with these topical agents, and the incidence of serious local reac-
`tions generally is quite low. Because the pivotal studies of these
`agents were not conducted using standardized protocols, each
`medication must be considered on its own merits in determining
`which topical agent to choose for an individual patient. The ef-
`ficacy rates from the pivotal trials of these three agents are listed
`in Table 3.
`
`Ciclopirox
`Ciclopirox has antifungal, antibacterial, and anti-inflammatory ef-
`fects. The lacquer is painted on the nail plates of the affected nails
`daily for 48 weeks. It has demonstrated good fungicidal activity in
`vitro against the dermatophytes Trichophyton rubrum, T. mentag-
`rophytes, and Epidermophyton floccosum; Candida spp; and the
`nondermatophyte molds Scopulariopsis brevicaulis, Aspergillus
`spp, and Scytalidium hyalinum.6
`The phase III pivotal trial protocol included patients between
`the ages of 18 and 70, with distal subungual onychomycosis of
`at least one great toenail (target nail) and positive KOH examina-
`tion and culture for dermatophytic onychomycosis. Involvement
`of the target nail was no less than 20% and no greater than 65%.
`The lacquer was painted once daily on the entire nail plate of the
`target nail(s), along with approximately 5 mm of adjacent skin, the
`hyponychium, and the accessible ventral surface of the nail plate.
`The lacquer was removed once weekly with an alcohol wipe. In
`addition, subjects were required to report each month for profes-
`sional trimming and debridement of the nails.11 The guidelines for
`use specified in the prescribing information for ciclopirox include
`weekly removal of the lacquer and regular visits to a health care
`professional for debridement.12
`In the two phase III pivotal trials, the complete cure rates re-
`ported were 5.5% and 8.5%.12
`
`Efinaconazole
`Efinaconazole is an azole drug with good potency against T. ru-
`brum, T. mentagrophytes, and C. albicans. The formulation has
`a low surface tension, causing a “wicking” action that draws the
`medication around the nail. Studies of in vivo penetration showed
`that daily application of 10% and 5% solutions to all 10 toenails
`for 28 days demonstrated high levels of nail deposition and low
`systemic exposure to efinaconazole and its metabolite.13
`In two parallel, 52-week, phase III, multicenter trials of efinac-
`onazole,14 a total of 1,655 subjects were randomized, in a 3:1 ratio,
`to receive either efinaconazole or placebo. Included were subjects
`between 18 and 70 years of age with mild to moderate onychomy-
`cosis affecting 20% to 50% of at least one great toenail, with at
`least 3 mm of uninfected nail as measured from the proximal nail
`fold, and a nail plate thickness no greater than 3 mm. Nail trim-
`
`n TABLE 2. Systemic Antifungals: Potential
`Drug-Drug Interactions
`
`Terbinafine1
`• Beta-blockers
`• Antiarrhythmics
`• Tricyclic antidepressants
`• Selective serotonin reuptake inhibitors (SSRIs)
`• Monoamine oxidase inhibitors (MAOIs)
`Itraconazole4
`• Antiarrhythmics
`• Statins
`• Antihypertensives
`• Benzodiazepines
`• Opioids
`• Antipsychotics
`• Vasoconstrictors (ie, migraine therapy)
`Fluconazole7
`• Antiarrhythmics
`• Antipsychotics
`• Antihistamines
`• Tofacitinib10 (fluconazole inhibits tofacitinib’s metabolism)
`
`ming, to any extent, was permitted but not required.
`The cure rates in the efinaconazole pivotal trials were 15% and
`18%.14,15
`
`Tavaborole
`Tavaborole represents a new class of antifungal agent, a boron-
`based therapy. Boron is a low-molecular-weight, highly reactive
`molecule that targets protein synthesis.16 In preclinical studies,
`tavaborole demonstrated excellent and rapid penetration through
`the nail plate and into the nail bed.17
`The inclusion criteria for the two parallel, phase III pivotal trials
`of tavaborole had several of the same or similar inclusion criteria
`as the pivotal trials of the other two topical antifungals: laborato-
`ry-confirmed onychomycosis of at least one great toenail; nail in-
`volvement of between 20% and 60%; at least 3 mm of uninvolved
`nail, as measured from the proximal nail fold; and nail thickness
`of 3 mm or less.18
`However, these tavaborole studies differed from the ciclopirox
`
`n TABLE 3. Topical Antifungals:
`Efficacy in Phase III Pivotal Trials
`
`Medication
`
`Complete Cure Rates*
`
`Ciclopirox 8%12
`
`Efinaconazole 10%15
`
`5.5% and 8.5%
`
`15% and 18%
`
`7% and 9%
`Tavaborole 10%16
`Regimens: All of these medications are approved for daily
`application for 48 weeks.
`
`*Results of two phase III trials, respectively.
`
`Vol. 35, No. 3S, March 2016, Seminars in Cutaneous Medicine and Surgery S53
`
`Theodore Rosen, MD, and Linda F. Stein Gold, MD
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2062 - 6/8
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`Page 6 of 8
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`

`

`and efinaconazole trials in three important respects, which should
`be considered when comparing cure rates. First, in the tavaborole
`studies, no upper age limit was established (whereas the upper age
`limit in the other two studies was 70). Second, in the tavaborole
`studies, the medication was to be applied without debridement.
`Third, the final nail trimming prior to the final assessment allowed
`no less than 1 mm of growth at the distal edge of the target nail(s);
`in the other studies, the nail could be trimmed to the distal edge of
`the nail, which could affect the grading results.
`The complete cure rates in the tavaborole pivotal trials were
`9.5% and 6.5%.16,18
`
`Mechanisms of Action
`The antifungal activities of the medications used to treat onycho-
`mycosis vary by class (Figure). The systemic agents itraconazole
`and fluconazole and the topical agent efinaconazole are in the
`azole class—specifically, in the triazole category. Triazoles work
`by inhibiting 14α-demethylase of the P450 enzyme, blocking con-
`version of lanosterol to ergosterol in fungal cells; ergosterol is es-
`sential to fungal cell growth.4,7,15
`Terbinafine, in the allylamine class, also inhibits ergosterol bio-
`synthesis, but at a different point in the pathway. Rather than af-
`fecting P450 and lanosterol-converting enzymes, the allylamines
`
`inhibit squalene oxidase, resulting in lethal fungal cell membrane
`changes.1
`Ciclopirox is a synthetic antifungal agent. Its mechanism of
`action has not been clearly established but seems to involve both
`the inhibition of the metal-dependent enzymes responsible for the
`degradation of peroxides within the fungal cell as well as upregu-
`lation of fungicidal reactive oxygen formation within the fungal
`cytoplasm.19,20
`Tavaborole’s mechanism of action also is not completely un-
`derstood, but it is thought to most likely involve inhibition of the
`enzyme leucine aminoacyl-transfer ribonucleic acid synthetase.
`Tavaborole is active against most strains of T. rubrum and T. men-
`tagrophytes, the two species most commonly found in onychomy-
`cosis. No resistance to tavaborole has been observed.16
`Efinaconazole shows in vitro activity against T. rubrum and T.
`mentagrophytes. No clinically significant evidence of drug resis-
`tance to efinaconazole has been reported.
`
`Conclusion
`In the pivotal trials for antifungal therapy for onychomycosis, the
`FDA-mandated criterion for efficacy is “complete cure.” This is
`defined as negative results on both direct microscopic examination
`of samples prepared with 10% to 20% KOH and on mycologic
`
`Allylamines, including
`terbinafine
`
`Azoles, including
`itraconazole, fluconazole,
`and efinaconazole
`
`Tavaborole
`
`Leucyl-tRNA
`synthetase
`
`Ciclopirox
`
`Chelate Fe3+ and Al3+
`
`Peroxidases
`
`Ergosterol Biosynthesis
`
`Squalene
`
`Squalene 2,3,-oxide
`
`Lanosterol
`
`14α-dimethyl-lanosterol
`
`4,4-dimethylergosta-8,14,24,(28)-dien-3ß-ol
`
`4,4-dimethylergosta-8,24,(28)-dien-3ß-ol
`
`Fecosterol
`
`Episterol
`
`Ergosterol
`
`n FIGURE. Antifungal Medicatio