` July 2015
`
`Journal oflhe American Academy of Dermatolog
`Volume 73 - Numbert
`
`
`v. 73, no. 1 (July 2015)
`
`General Collection
`W1 J0907WL
`2015-09-18 06:25:02
`
`
`
`
`
`www.jaad.org
`—_-—-_—__
`
`New psoriasis treatments
`
`Enhancing wound healing in
`dystrophic epidermolysis bullosa
`
`A new topical agent for onychomycosis
`
`Cellulitis in hospitalized patients
`
`Combination treatment of segmental
`vitiligo
`
`Sunscreen use among US adults
`
`Risk factors for failure of topical
`treatrmant for BBC
`
`@ Patient safety in dermatologic surgery
`
` Journal of the American Academy of Dermatology
`Vismodegib for operable BCC Timothy J. Hansen, MD, Margarita Lolis. MD, Scott W. Dunbar, MD,
`
`David .J. Goldberg, MD, JD, and Deborah F. MacFarIane, MD, MPH
`Amos, lows; New York, New York;
`Hackensaok and Newark, New Jersey," and Houston, Texas
`
`Melanoma in Sweden
`
`I
`DermOSCODY 0f blaCk Skln
`
`PROPERTY 0" THE
`NATIONAL
`LIBRARY OF
`.
`.. MEDICINE
`
`
`
`High-risk SCC
`
`Care of low-risk BCC at the end of life
`
`NEW FEATURE: Be 0nd JAAD
`3’
`JAAD Online: Clinical,therapeutic,
`and surgical pearls
`
`LELsavren }
`
`Page 1 of 16
`
`Kaken Exhibit 2073
`
`Acrux V. Kaken
`
`IPR2017-00190
`
`

`

`Journai of the
`3
`American
`8.
`a.
`Academy of
`
`(9 Dermatology “in. no“
`
`a»: “0,,
`
`www_jaad,arg
`
`Juiy2015 / VolumeTB / Numberi
`
`CONTENTS
`
`continuing @ 1
`Medical
`Ed
`t_
`"03 Ion
`
`Patient safety in detmatologic surgery
`Part I. Safety related to surgical procedures
`Timothy J. l'iatisen, MD, Mitigaiira Lolis, MD,
`David], Goldberg, MD, fl), and Deborah E MacFariune, MD, MPH,-
`Ames, Iowa; New York, New York; Hachensaclz and Newark, New jersey;
`and Houston, Texas
`
`13
`
`CME examination
`
`14
`
`Answers to CME examination (Identification No._]A0715),
`july 2015 issue ofthejoumal of the American Academy of
`Dermatology
`
`® 15
`
`Patient safety in prOCedural dermatology
`Part 11, Safety related to cosmetic procedures
`Margarita Lolis, MD, Scott W Dunbar, MD, David j. Goldberg, MDJD,
`Timothy j. Hansen, MD, and Deborah F. MacFarlaiie, MD, MPH;
`New York, New York; l'iaclterisacla and Newark, Newjersey; Ames,
`Iowa: and Houston, Texas
`
`25
`
`CME examination
`
`26
`
`Answers to CME examination (Identification No. JBOTIS),
`july 2015 issue of the journal of the American Academy of
`Dermatology
`
`
`
`Original Articles
`
`27
`
`Secukinumab retreatrnent-as-needed versus fixed-interval
`maintenance regimen for moderate to severe plaque psoriasis:
`A randomized, doublesblind, noninferiority trial (SCULPTURE)
`Ulrich Mrowietz, MD, Craig L Leonardi, MD, Gian‘lplero Girolomoiti, MD,
`Darryl Toih, MD, FRCPC, Akimiciii Morita, MD, Shyamal A. Baiki, FCPS,
`jacela C. Szepieiowsiti, MD, Pascalinechnauli, PhD,
`Helen Thurston, MSc, and Charis Papavassiiis, MD, for iiie SCULPTURE
`Study Group; Kiel, Germany; 51 Louis, Missouri; Verona, lialy,‘ Windsoi;
`Ontario, Canada; Nagoyohlapan; Nagpur india; Wroclaw: Poland;
`and Basel, Switzerland
`
`Continued on page A6
`mm
`
`90W” © 2915 by the Ameiican Academy at Derma-‘ology. 111:, Journal arrhe American Academy of Dormafoiogy 0330': 0100-0022),
`Harrier inc. 300 Park Avenue South. New York, NY 10010-1710. Pericdicais posilge paid at New York. NY and additional mating oliioes.
`POSTMASTER: Send address changes 10 Journal of the Armt'can Acaden'y of Dermatology. Eisevio Health Sciences Division. Sulisoipti0n Cuslanor Service.
`3251 RNBiDDi’i Lane. Maryiand Heights. MO 630213.
`
`is maimed moniiiy by
`
`_[ AM Amt) DERMATOL
`
`jour 2015
`
`A5
`
`This material was copied
`nooLnIIIII—nd —-..L...
`
`Page 2 of 16
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`

`

`Contents continued
`
`_(_AJM_.,M
`
`37
`
`50
`
`56
`
`62
`
`70
`
`76
`
`Apremilast, an oral phosphodiesterase 4 (PDE‘i) inhibitor, in
`patients Willi moderate to severe plaque psoriasis: Results of a
`phase III, randomized, controlled trial (EfficaCy and Safety Trial
`Evaluating the Eflects oi Apremilast in Psoriasis [ESTEEMl 1)
`Kim l’app, MD, PhD, Kristian Reich, MD, PhD, Craig L. USUI’iLII'Lll, MD,
`Leon Kirciie, MD, Sergio Clnmcnii, MD, Richard G. B. Langley, MD)
`ChiaClii Hit, Eth, MS, Randall M, Stevens, MD, Robert M, Day, PhD,
`Kenneth E, Gordon, MD, Neill. Korman, MD, PhD, and
`Clirlsiopilt’l‘ E. M. Grifliths, MD, FMcclSci; Waterloo, Ontario, and Halifax,
`Nova Scotia, Canada; Hamburg, Germany; Saint Louis, Missouri; Louisville,
`Kentucky; New York, New York; Rome, Italy; Summit, New Jersey; Chicago,
`lllinois; Cleveland, Ohio,- ancl Manchester, United Kingdom
`
`Coexistence of autoimmune bullous diseases (AlBDs) and
`psoriasis: A series of 145 cases
`Chiba Ohata, MD, Norito lsltii, MD, Hiraslti. Koga. MD, PhD,
`Shunpei Fuhuda, MD, PhD, Cliiliaru Tateislti, MD, PhD,
`Daisulce Tsttrtttti, MD, PhD, MllICiG Fttramtti'a, MD, PhD, and
`Taltasl'ii Hashimoto, MD: Ful'aialea and Osaka, japan
`
`Systemic granulocyte colony-stimulating factor (G—CSF)
`enhances wound healing in dystrophic epidermolysis bullosa
`(DEB): Results of a pilot trial
`'
`Iii-David Fine, MD, MPH, FRCP,’ Becky Manes, RN, and
`Hayclar Frangotil, MD; Nashville, Tennessee
`
`Efficacy and safety of tavaborole topical solution, 5%, a novel
`boron-based antifungal agent, for the treatment of toenail
`onychoniycosis: Results from 2 randomized phasealll studies
`Bani E, Eiewsiti, MD, Raza Aly, PhD, Sheryl L. Baldwin, RN,
`llcmtgio E Gonzalez Soto, MD, Phoebe Rich, MD, Max Weisfclcl, DPM,
`Hector Wiltz, MD, CPL Lee I. Zane, MD, and Richard Pollalz, DPM, M5;
`Birmingham, Alabama; San Francisco and Palo Alto, California; Monterrey,
`Mexico; Portland, Oregon; Baltimore, Maryland; Miami, Florida;
`and San Antonio, Texas
`
`Inpatient dermatology consultation aids diagUOSis of cellulitis
`among hospitalized patients: A multi-institutional analysis
`Lauren Strazznla, MD, jonathan Coiliar, MD, Lindy P. Fox, MD,
`Lauren Httglit’y, MD, Kanadc Shinhai, MD, Sarah N. Gee, MD, and
`Daniela Krosliinshy, MD, MPH; Boston, Massachusetts; Chicago, lllinois;
`San Francisco and Los Angelcs, California; and Birmingham, Alabama
`
`Combination therapy with BOB-rim excimer laser, topical
`tacrolimus, and short—term systemic corticosteroids for
`segmental vitiligo: A retrospective study of 159 patients
`fling Min Bat, MD, llyanja You, MD, liyuli Kim, MDJE Hoe Lee, MD, and
`Gyong Moon Kim, MD, PhD; Sill-V011 and Seoul, Korea
`
`See related letter on page 170
`
`A6
`
`JULY 2015
`
`1-“, ,-.-.:_I .. s, ,-..:....:
`
`Con tintiecl on page A10
`
`J AM Acan DERMATDL
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`Page 3 of 16
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`

`

`
`
`Contents continued o a 1958
`
`
`
`
`
`83
`
`93
`
`99
`
`106
`
`Patterns of sunscreen use on the face and other exposed skin
`among US adults
`Dawn M, Holman, MPH, Zahara Bcrhowitz, MSc, MSPH,
`Gary R Guy, jr, PhD, MPH, Nikki A. Hawkins, PhD,
`Mona Saraiya, MD, MPH, and Meg Watson, MPH; Atlanta, Georgia
`
`Tumor thickness and aclnexal extension of superficial basal cell
`carcinoma {SBCQ as determinants of treatment failure for
`methylaminolevulinate (MAD—pilotedynamic therapy (PDT).
`imiquimod, and S-fluorouracil (FU)
`I
`Marlene H. Roozeboom, MD, Lotte van Kleef, MD,
`Aimee H. M. M. Arits. MD, PhD, Klara Mostercl, MD, PhD.
`Veronique], L Winnepenninckx, MD, PhD,
`Arienne M, W van Marion, MD, PhD, Patty j. Nelemans, MD, PhD, Md
`Nicole W. 1. Kellenersafimeets, MD, PhD; Maastricht and Venlo, The Netherlands
`
`A phase II, multicenter, open-label, 3-cohort trial evaluating the
`efficacy and safety of vismodegib in operable basal cell carcinoma
`Howard Sofen, MD, Kenneth G. Gross, MD, Leonard H, Goldberg, MD, FRCB
`Harry Sharata, MD, PhD, Tiffani K. Hamilton, MD, Barbara Egbert, MD,
`Benjamin Lyons, PhD, jeannt'e Hon, MD, and Ivor Caro, MD; [as Angeles,
`San Diego, Palo Alto, and South San Francisco, California; Houston, Texas;
`Madison, Wisconsin; and Atlanta, Georgia
`
`Cutaneous malignant melanoma in the Swedish organ
`transplantation cohort: A study of clinicopathological
`.
`characteristics and mortality
`Britta Krynitz, MD, Barbra Lundh Rozell, MD, PhD, johan Lytli, MS, PhD,
`Karin E. Smedby, MD, PhD, and Berni Lindeléf. MD, PhD; Stockholm and
`Linhtiping, Sweden
`
`114
`
`Dermoscopy of black skin: A cross-sectional study of clinical and
`dermoscopic features of melanocytic lesions in individuals with
`type VNI skin compared to those with type l/IE skin
`Erana Toma, MD, Sergio Yamada, MD, Alvaro Nagib Atallah, PhD,
`Fernanda Mcndes Araajo, EDS, and Sergio Henrique Hiram, PhD; sac Paulo
`and Londrina, Brazil
`
`
`Dermatologic
`Surgery
`
`120
`
`Squamous cell carcinoma with aggressive subclinical extension;
`5-year retrospective review of diagnostic predictors
`Alina Goldenberg, MAS, Arisa Ortiz, MD, Silvia S. Kim, MD, and
`5. Brian jiang. MD; Lajolla, California, and Salem, Massachusetts
`
`See related works on pages l2? and 165
`
`
`Reviews
`
`1 27
`
`High—risk cutaneous squamous cell carcinoma and the emerging
`role of sentinel lymph node biopsy: A literature review
`Cristian Navarrete-Declient, MD, Michael ]. lvimess, MD,
`Nicolas Droppelmann, MD, and Pablo Uribe, MD, PhD: Santiago, Chile,
`and Sydney, Australia
`
`See related works on pages 120 and 165
`
`A10
`
`JULY 2015
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`This material was copied
`
`Continued on page A14
`
`_] AM Acno Dunnaror.
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`Page 4 of 16
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`

`

`
`
`Contents continued a,” no»
`
`138
`
`Assessment of rosacea severity: A review of evaluation methods
`used in clinical trials
`Dennis Hopkinson, BA, Sara Momdi ‘tiichayi, MD, MPH, HosseinAlirtia, MD, and
`Steven R Feldntan, MD, PhD; Winston-Salem, North Carolina
`
`144
`
`Angiogenesis and lymphangiogenesis in inflammatory skin
`disorders
`
`Gilda Varricchi, MD, PhD, Prancescopaoln Granata, MD, PhD,
`Stefania Loflretlo, PhD, Arturo Gennvesc, MD, and Gianni Maronc, MD;
`Naples, italy
`
`Dermatoethics
`Consultation
`
`Should self-destructive behavior affect a patient’s access to scarce
`medical resources?
`Catherine S. Yang, MD, George Kroumpouzos, MD, and
`Lionel Bcrcovitch. MD; Providence, Rhode island
`
`154
`
`Point/Counterpoint
`
`158
`
`Point: Care of potential lowerisk basal cell carcinomas (BCCs) at
`the end of life
`The key role of the dermatologist
`Eleni Lines, MD, DrPl-i, Timothy Berger, MD, and
`Mary-Margaret Chren, MD; San Francisco, California
`
`Counterpoint: Limited life expectancy, basal cell carcinoma,
`health care today, and unintended consequences
`Scott W. Foslzo, MD; Saint Louis, Missouri
`WM
`
`162
`
`Letters: Research
`LattGI'S
`
`165
`
`Overall and progression-free survival of stage 4 cutaneous
`I
`.
`squamous cell carcinoma at a Single large referral center
`Golgi Alex Zita, BS, and Anne Lynn 5a Chang, MD; chlthOtl City, California
`
`166
`
`188
`
`170
`
`See related works on pages 127 and 120
`
`Facial basal cell carcinomas treated with hypo-fractionated
`radiotherapy: A retrospective analysis in 117 elderly patients
`Antonio Pelisscro, MD, Elvis G. Russi, MD, Antonella Malaria, MD,
`Claudia Fillini, MD, Riccardo Vigna—Taglianti, MD, Nicola Settinen', PhD,
`Francesco Lucio, MR Giampiero Girolomoni, MD, and Stefano Pergolizzi, MD;
`Caner), Mcssina, and Verona, Italy
`
`Digital dermoscopy monitoring in patients with multiple nevi:
`How many lesions should we monitor per patient?
`Elvin; Moscarclla. MD, Riccardo Pampt’no, MD, Athanassios Kyrgitlis, MD,
`tsoiina Tion, MD, Caterina longo, MD, Aimilios toilets, MD, and
`Giuseppe Argcnziano, MD; Reggio Emilia, Polo Pontiac, Sasswi, and Naples, ttaly
`
`Autologous cell suspension transplantation using a cell
`extraction device in segmental vitiligo and piebaldism patients:
`A randomized controlled pilot study
`Lisa Konlt’n, MD. Charlotte Vrijman, MD, Esther E M, Tjin, PhD,
`Gabrielle Krehbers, Merino A. do Rie, MD, PhD, Rosalie M. Luitcn, PhD,
`]. l? Wictze‘ van tier Vern, MD, PhD, and Albert Wallecrstorfei', MD, PhD;
`Amsterdam and Den Haag, the Netherlands
`
`See related article on page 76
`
`This materialwascnpied
`atthe HLM and mayr be
`Subiec‘t US Copyrigflt laws
`
`Continued on page A16
`
`j AM Acno DERMATOL
`
`’A14
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`JULY 2015
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`Page 5 of 16
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`

`

`533
`Contents continued ‘4‘. i, new“
`
`vnNa.
`u
`r.
`'v
`it
`.w‘
`5*
`1
`.
`G
`«-
`
`‘o
`.5.
`7.
`J.
`.
`a.
`o
`
`
`
`1 72
`
`The applicability and prognostic value of the TNM classification
`system for primary cutaneous lymphomas other than mycosis
`fungoides and Sézary syndrome in primary cutaneous NK/Pcell
`lymphoma patients
`Woojin Lee, MD. Yi'Jiri Lee, MD, Chang Hytm Wrm, MD, PhD,
`Sung Eim Chang, MD, PhD, jar Ha Chat, MD, PhD, and
`Mt Woo Lee, MD, PhD; Seoul, South Korea
`
`Intravenous immunoglobulin for treatment of
`dermatomyositis-assoeiated dystrophic calcinosis
`Fabrizio Galimbcrti. PhD. Yumcng Li, BS, and
`Anthony P. Fernandez. MD, PhD; Cleveland, Ohio
`
`
`174
`
`Beyond JMD
`
`'BeyondJAAD july 2015: Articles of interest from the
`nondermatologic literature
`Andrew Brant”, MD. and Robert Phelps, MD; New Haven. Connecticut,
`and New Yorla, New York
`
`
`177
`
`Retraction Notice
`
`1 80
`
`Pap}: K, Gottlieb AB. Naldi L, et 211. Experience with ustekinurnab
`in patients with psoriasis enrolled in a large, multicenter,
`prospective, disease—based registty (Psoriasis Longitudinal
`Assessment and Registry [PSOLARD ] Am Acad Dermatol. clot:
`10. 1016/].jaad2014. 10.025. Published online januai‘y 9, 2015.
`
`
`
`Images in
`Dermatology
`
`Available at http://www.jaad.org
`
`ET
`
`83
`
`Crusted dusky red papules in a newborn
`jenm‘fer L. Brooks, ES, Morgan W Thalzorc, MD, and Loretta S. Davis, MD;
`Lexington, Kentucky and Augusta, Georgia
`
`Nontender preauricular nodule and papules
`Katherine l3. Abcil, BS, and jammy D. jackson. MD; Jackson, Mississippi
`
`Arcuate, scaly plaques on the face and scalp
`M. David Meyer, MD, and Kalman L. Walsliy, MD; New Haven, Commit”;
`
`
`e5
`
`Dermoscopy Cases
`of the Month
`
`Available at http://www.jaad.org
`
`e7
`
`Derm05copy ol elastosis perforans serpiginosa: A useful tool to
`distinguish it from granuloma annular-e
`Cristian Ncwarrete-Dechent, MD, Constanza dei Puerto, MD, Silirm Bajqj, BA
`Ashfaq A. Marglioob, MD, Sergio Gonzalez, MD, and Alejmulrajaque, MD;
`Santiago, Chile, and llaappattgc. New York
`
`A16
`
`JULY 2015
`
`This material was copied
`at the NLM and may be
`
`Continued on page AIS
`
`J AM ACAD DERMATDL
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`

`
`
`Contents continued an»... 51°"
`
`911
`
`e15
`
`A case of dyskeratosis congenita with demoscopic and
`reflectance confocal microscopic features
`Stile Gungo'r, MD, fish Vefa Erclemit; MD, Emcle Kocaitirlt Goncti, PhD,
`Mehmet Salih Gtircl, PhD, and Server Ozelzinci, PhD; Istanbul, Turkey
`
`Dcrmoscopy and confocal microscopy for in vivo detection and
`characterization of Dcrmanyssus gallinac mite
`Elisa Cinotti, MD, Bruno lat-cilia, MD, Charloitr: Bernigaurl, MD,
`Pang Fang, DVM, Christellc Chol, MD, ch6' Chermctic, D‘VM,
`jacques Guilloi, DVM, PhD, Frédc'rir.‘ Cambazarcl, PhD, anti
`jean-Lu: Pcrrot, MD; Saint-Etienne, Cre‘teil, and Maisons—Alfort, France
`
`e1 7
`
`Using dermoscopy to assess diagnostic criteria of
`neurofibromatosis
`Elisabeth Gomez Moyano, MD, PhD, Leandra Martinez Film; MD,
`Marina Rodriguez Cairo a’c Mora, MD, PhD,
`Maria Virginia Herrera Garcia, MD, Anionic Francia, MD,
`Daniel jeais Carley Diaz, MD, and Angel Vera Casafio, MD; Mailaga, Spain
`
`
`Clinical Pearls
`
`Available at http://www.jaad.org
`
`919
`
`A novel technique of digital photography for oral lesions
`Deep Surcshjosliipura, M3135, MD, and
`Sttresltjasltipura, MD, FRCP, PltD, FAAD, DVD; Bhttj and Rjkot, lnclia
`
`Titanium dioxide induces eyelid dermatitis in patients
`allergic to gold
`Melissa Daneslt, BS, and jenny E. Mamie. MD; San Francisco and
`Mountain View, Cali ornia
`
`
`821
`
`Therapeutic Pearl
`
`Available at http:l/www.jaad.org
`
`623
`
`Iatralesional cidolovir for the treatment of a plantar wart
`Elizabeth Moore, 13A, and Carrie Kovarilz, MD; Philadelphia, Pennsylvania
`
`Surgical Pearls
`
`Available at http://www.jaad.org
`
`e25
`
`e27
`
`The dog—ear tacking suture technique
`janalltan Kantor, M D, MSCE, MA; Philadelphia, Pennsylvania, and
`Sainl Augustine, Honda
`
`Use of the diagonal mattress suture to prevent dog-ear formation
`Maulilz M. Ditancllta, MD, Tripurari Mishra, MD, and David H. Whimsy, MD;
`Saint Louis, Missouri; and Chicago and Evanston, lllinois
`
`A18
`
`1111.? 2015
`
`This material was copied
`atthe NLM and may be
`
`Continued on page A20
`
`] AM ACAD DERMATOL
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`Page 7 of 16
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`

`

`Contents continued
`
`JAAD Online
`
`Available at http://www.jaad.org
`
`829
`
`931
`
`833
`
`e35
`
`e37
`
`939
`
`Vernurafenib as first line therapy in BRAF—mutated Langerhans
`cell histiocytosis
`fuller: Huroclie, MD, PhD, Fleur Cohen-Aubert, MD, PHD,
`jean-Francois Emile, MD, PhD, jean Donadicn, MD, and
`ZahirAmottra, MD, MSC; Paris and Boulogne, France
`
`Access to molecular guided therapy for Langerhans cell
`histiocytosis patients
`julie Charles. MD, PhD,}ean-Claude Beani, MD,
`Mathilde Tardien, MD, and Benoit Busscr. PharmD, PhD; Grenoble, France
`
`Skirt moisturization for xerosis related to targeted anticancer
`therapies
`Paolo Gisondi, MD, and Giarnpiero Gtrolomoni, MD; Verona, Italy
`
`Reply to: “Skin moisturization for xerosis related to targeted
`anticancer therapies"
`johonnal'i Valentine, MD, Viswanath Raddy Bolton, MD,
`juanita Duran, MD, Kathryn Ciccoltni, RN, BSN, Katja Schindler, MD,
`Shcnlmng Wu, MD, PhD, and Mario E. Locoutnre, MD; San Diego,
`California; New York, Stony Brook, and Northport, New York;
`Bogota. Colombia; and Vienna, Austria
`
`Familial frontal fibrosing alopecia
`Christos Tziotzios, MA, MBBChir (Cantab), MRCP (UK), FHEA,
`David A. Fenian, MBE, FRCP, Catherine M Stefanato, MD, FRCPaih, and
`john A. McGratlt, MD, FRCP, FMetlSEi; London, United Kingdom
`
`HLA-DRI in familial frontal fibrosing alopecia
`Derek ll Chart, MD, PhD, joseph Flynn, DO, MPH,
`Rebecca Ziegler, MD, and Henry K. Wong, MD. PhD; Columbus, Ohio
`
`lotaderma #257
`Robert I. Rudolph, MD, FACP
`
`
`641
`
`Announcements
`
`14
`
`American Board of Dermatology examination dates
`
`26
`Change of address
`
`
`Reader Services
`
`A25
`
`A31
`
`Information for readers
`
`jAAD Case Reports article list
`
`A36
`
`Journal based CME instructions and information
`
`A39
`
`A40
`
`Dermatology calendar
`
`Statement on advertising in the journal
`
`A20
`
`JULY 2015
`
`This material was copied
`
`Continued on page A24
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`] AM ACAD DERMATOL
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`Page 8 of 16
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`

`_———I_———_
`
`Efficacy and safety of tavaborole topical solution,
`5%, a novel boron-based antifungal agent,
`for the treatment of toenail onychomycosis:
`Results from 2 randomized phase-III studies
`
`Boni E. Elewski, MD,” 12:1er My. PhD." Sheryl 1.. Baldwin. RN.“ Remigio r. Gonzalez sum, Mo,"
`Phoebe Rich, MD,C Max Weisfeid, DPM," Hector Wiltz, MD, CPI,“
`Lee T. Zane, MD," anti Richard l‘ollak, DPM, MS"
`Br‘r'rm‘rrgbam, Alcrbmmr; San Francisco and Palo Alto, California; Monierrcy, Mexico;
`Portico-rd, Gregor-t; Baltimore, Maryland; Mt'mm', Narnia; cmr! Sm: Antonio, fiestas
`
`Background: Onychomycosis, a fungal nail infection, can impact quality of life.
`
`Objective: We sought to evaluate tlte efficacy and safety of tavalaorole topical solution, 5% for treatment of
`toenail onycltomycosis.
`
`Methods: in 2 phaseslll trials, adults with distal subungual onycltotnycosis allectirtg 20% to 60% of a target
`great toenail were randomized 2:1 to tavahorole or vehicle once daily for 48 weeks. The primary end point
`was complete cure of the target great toenail (completely clear nail with negative mycology) at week 52.
`Secondary end points included completely or almost clear nail, negative mycology, completely or almost
`Clear nail plus negative mycology, and safety.
`
`Results: Rates of negative mycology (31.I%-55.9% vs 7296-12235) and complete cum (65% and 9_1% v5
`0.5% and 15%) significantly favored tavahorole versus vehicle (P S .001). Completely or almost clear nail
`rates also significantly favored lavalirole versus vehicle (26.1%-27.S% vs 9_3%14,6%; ,v < 301; 11;,ch of
`completely or almost clear nail plus negative mycology (15.3%—17.9% vs two—3.9%} were significantly
`greater for tavaborole versus vehicle (P < .001). Applicatiomsite reactions with tavalaorole included
`exfoliation (2.7%), erythemzt (1.6%), and dermatitis (1.3%).
`
`Limitations: Duration of follow—up is a limitation.
`
`From the Department of Dermatology, University of Alabama at
`Birmingham"; Department of Dermatology, University of
`California, San Francisco“: Anacor Pharmaceuticals, Inc, Palo
`Alto“: Centro de Dermatologla tie Monterrey“,- Oregon Health
`and Science Universitye; Hamilton Foot Care, Baltimore': FXM
`Research Corp, Miami“; and Endeavor Clinical Trials, San
`Antonio.I1
`Writing and editorial assistance was provided by Callie Grimes of
`Peloton Advantage, LLC, Parsippany, NJ, and was supported by
`Anacor Pharmaceuticals,
`Inc. Diane Nelson
`of Anacor
`Pharmaceuticals,
`inc, provided critical review and revision of
`the manuscript.
`Disclosure: Ms Baldwin and Dr Zane are employees of Anacor
`Pharmaceuticals,
`Inc. Dr Elowskl has received honoraria and
`grants while serving as a consultant and investigator with the
`following companies: Anacor Pharmaceuticals,
`Inc; Valeant
`Pharmaceuticals International
`Inc, Bridgewater, NJ; and Meiji
`Seika Pharma Co. Ltd, Tokyo, Japan. Dr Aly was consultant and
`investigator for Anacor Pharmaceuticals, Inc. Dr Gonzélez Soto
`was an investigator
`for
`the following companies: Anacor
`Pharmaceuticals,
`Inc; Pfizer. New York, NY; and Eli Lilly,
`Indianapolis,
`IN. Dr Rich was the principal
`investigator for
`onychomycosis studies with the following companies: Anacor
`
`Pharmaceuticals, inc; Topica Pharmaceuticals, Los Altos. CA;
`Vaieant Pharmaceuticals
`International
`Inc;
`and Viamet
`Pharmaceuticals Inc, Durham, NC. Dr Pollak has received grants
`‘and honoraria While serving as advisory board member,
`investigator, and speaker for the following companies: Anacor
`Pharmaceuticals. Int; Valeant Pharmaceuticals International inc;
`and Topica Pharmaceuticals. Drs Weisfeld and Wiltz were
`principal
`investigators fer Anacor Pharmaceuticals,
`Inc. The
`authors were full);r
`responsible {or
`the content, editorial
`decisions, and opinions expressed in the current article. No
`author received an honorarium related to the development of
`this manuseript.
`Accepted for publication April 5. 2015.
`Reprint reguests: Boni E. Elewski, MD, Department of Dermatology,
`UniverSIIy of Alabama at Birmingham, EFH 414, 1530 3rd Ave 5.
`Birmingham. AL 35294-0009. E—mail: beelewski@aol.com.
`Published online May 5. 2015.
`Di 90—9622
`
`© 2015 by the American Academy of Dermatology. Inc. Published
`by Elsevler, Inc. This is an open access article under the CC
`BYANCrND license (httpaicreativecommon5.orgfiicensr25fby—nc-
`mil/4.0!).
`http:Ud><.doi.org!10.‘l 01 6rj.jaad.20i 5.04.010
`
`62
`
`Page 9 of 16
`
`This material was copied
`
`

`

`] AM ACAD DEILMATOL
`VOLUME 73. Newest
`
`Hierasei e! a! 63
`
`Conclusion: ’I'avaborole demonstrates a favorable benefit-risk profile in treatment of toenail onychomy-
`cosis. (J Am Acad Dermatol 2015;73:62-9.)
`
`Key words: antifungal agents; arthrodermaIaCCae; nails; onychomycosis: randomized controlled trial;
`tava borole.
`
`solu—
`'I'avaborole topical
`tion, 5% (Anacor Pharmaceu—
`ticals, inc, Palo Aito. CA) is :1
`novel, boron—based pharma-
`ceutical approved by the Food
`and
`Drug Administration
`(FDA)
`in
`july
`2014
`for
`the
`treatment
`of
`toenail
`
`by
`caused
`onychomycosis
`Tricbopbyton mbmtn and ’1'
`iirettrcigr'opf‘iyies.l
`'l‘avaborole
`represents a new class of phar-
`maceutical antifungal agents
`with a novel chemical structure
`and mechanism of action
`
`CAPSULE SUMMARY
`
`- Tavaborole topical solution, 5% is
`approved for treatment of toenail
`onychomycosis.
`
`METHODS
`
`Study treatment and
`patients
`inciti—
`Study treatments
`ded tavaborole and vehicle,
`which were applied topically
`to the affected nails once
`
`- Tavaborole was significantiy more
`effective than vehicle in treating toenail
`onychomycosis in 2 phase-Ill trials:
`incidence of treatment-related
`
`application-site reactions was low.
`
`- The favorable benefit-risk profile makes
`tavaborole a reasonable therapeutic
`option for toenail onychomycosis.
`
`daily for 48 weeks by the
`patient. Patients were in-
`structed to apply a sufficient
`amount of study treatment
`on,
`under,
`and
`around
`the
`infected
`target
`great
`toenail
`('l‘G'I') and infected
`nontarget
`toenails with a
`thin, even layer.
`Patiean 18 years of age or
`older with distal subungual toenail onychomycosis
`involving 20% to 60% of at least 1 TG’l‘ were eligible if
`they had a positive potassium hydroxide (Koo) wet
`mount and positive culture for dermatophytes,
`greater than or equal to 3—mm clear nail measured
`from the proximal nail fold to the most proximal
`visible mycolic border, and distal TGT thickness
`3 mm or less. Patients were excluded if
`they
`had proximal
`subunguai or
`superficial white
`onychomycosis, severe disease, dermatophytoma,
`exclusively lateral disease, yellow/brown spikes,
`coinfection with nontlermatophyte fungi, anatomic
`abnormalities of the toes or toenails, active tinea
`pedis (involving the sides or back of the foot,
`interdigital, or plantar) requiring treatment, history
`of chronic moccasin—type tinea pedis (involving the
`sides or back ofthe foot), history ofother significant
`chronic fungal disease, psoriasis,
`lichen planus,
`known immuuodeficiency,
`significant peripheral
`vascular disease, known structural heart disease, or
`uncontrolled diabetes
`(hemoglobin A'lC 28%}.
`Patients who used topical antifungnls on tile toenails
`within =3 weeks or systemic antifungals within
`2.4 weeks were also excluded. Recent use of other
`
`(Fig 112$ 'l'aval)orole targets
`fungal
`cytoplasmic
`leucyl—
`transfer ribonucleic acid (IRNA) synthetase, a member
`of a family of aminoacyl—tRNA synthetase enzymes
`essential for protein synthesisSThese enzymes maintain
`and tntnsiate genetic code witl'iin DNA, and possess a
`proofreading mechanism that Corrects emphatic
`mistakes that occur on a separate, active editing site.
`Tavahorole binds to the editing site via its boron atom to
`trap leucyl
`tRNA, preventing its catalytic turnover
`and inhibiting protein synthesis. Tavaborole demon-
`strates broad-spectrum antifungal activity and more
`than lOOO—fold greater
`selectivity for
`the fungal
`leucyl—tRNA synthase titan the mammalian leucyl-tRNA
`synthetasefi; T mbmm and 7' tirerricrgrrgohyies isolates
`collected
`from clinical
`trial
`patients
`have
`not
`demonstrated resistance after repeated exposure to
`avaborole.1
`The low molecular weight of tavaborole allows a
`high amount of penetration through full-thickness
`human nail plates7 Ex vivo permeation studies have
`demonstrated
`tavaborole
`penetration
`through
`multiple layers of nail polish (data on file, Anacor
`I’ltarmaceuticals, Inc; TIER-00244, ANA-GUS, 2015).
`Phase—l
`trials shoWed favorable safety and low
`systemic
`exposure
`in
`patients with
`toenail
`onycllomycosis,H and
`phase-II
`trials
`provided
`evidence of
`improved clear nail growth and
`negative fungal cultures.9 The objective of the 2
`phase-iii
`trials described herein was to evaluate
`the
`efficacy and safety of
`tavaborole versus
`valliClC in adults with distal subungual
`toenail
`onychomycosis.
`
`Page 10 of 16
`
`toenails, systetllie
`topical agents on the toe or
`corticosteroids, or immunomtxlulatory agents was
`not permitted.
`
`Study design
`Two phase—Iii, multicenter, randomized, double
`blind, vehicle~controlled, parallel-group trials of
`
`

`

`64 Elerashr‘ er a!
`
`] AM ACAU Dr: RMATOL
`]ULY 2015
`
`
`
`Abbreviations used:
`AE:
`adverse event
`FDA:
`Food and Drug Administration
`KOII:
`potassium hydroxide
`TEAE:
`treat ment‘ernergent adverse event
`TGT:
`target great toenail
`tRNA:
`
`transfer ribonucleic acid
`
`identical design were conducted: '1 at 27 sites in the
`United States and Mexico from December 2010 to
`
`November 2012 (study 1; NCT01270971) and the
`other at 52 sites in the United States and Canada from
`
`2;
`(study
`2015
`january
`to
`2011
`February
`NC’l‘UlSOZiW). Both studies were conducted in
`accordance with ethical principles originating in
`the Declaration of Helsinki and in compliance with
`the principles of Good Clinical Practice and all
`applicable
`regulatory requirements. The
`study
`protocol was approved by an institutional review
`board/independent ethics committee at each site,
`and all patients provided written informed consent.
`Patients were screened 11
`to 10 weeks before
`
`andomization. Eligible patients were randomized
`2:1 to receive tavaborole or vehicle, and applied
`study treatment to the TGT and all other affected
`toenails once daily for 48 weeks. Nail debridement
`was not permitted.
`Disease involvement was assessed at screening,
`baseline ( day '1), week 2, Week 6, and every 6 weeks
`thereafter. At
`these visits, nail
`trimming of the
`'I‘G'I‘ was limited to within 1 mm distal
`to the
`
`hyponychium or distal groove if needed. Patients
`were encouraged not to trim the 'I‘GT. All other
`toenails were also evaluated for
`the presence
`of onyclrolysis
`anti
`subungual hyperkeratosis.
`Subungual samples were obtained from the TG’t' at
`screening and every '12 weeks during treatment and
`sent to a central mycology laboratory for KOH wet
`mount examination with calcofluor white stain and
`
`fungal culture to identify pathogenic fungi including
`dermatophyte
`species. After
`study
`treatment
`was completed at week 48,
`follow-up efficacy
`assessments were made at Week 52.
`
`Efficacy
`The primary efficacy end point was complete cure
`of [he TG'l' defined as completely clear nail and
`negative mycology at week 52. Secondary end points
`included completely or almost clear nail of the TGT,
`negative mycology of the TG’I‘, and completely or
`almost clear nail plus negative rnycology, each
`determined at week 52. Completely clear nail was
`defined as no clinical evidence of onyclromycosis
`based on a normal toenail plate, no onycholysis, and
`
`Page 11 of16
`
`Tavaborole
`Fig 1. Tavaborole chemical structure. Tavaborole is a
`novel, boron—based pharmaceutical approved for
`the
`treatment oftoenail onychomycos‘ts caused by ii‘r‘cbopby—
`tor-r rtibr‘rrm and T meniagrophyfes.' Tavaborole inhibits
`|cucyl-tltNA-syntlretase, resulting in inhibition oi" fungal
`protein synthesis and termination of Fungal cell growth.i
`
`no subungual l'iyperltenttosis. Aimost clear naii was
`defined as no more than minimai evidence of
`
`onychomycosis based on a toenail plate that was
`dystrophic or discolored on 10% or less of the distal
`aspect, with minimally evident onycholysis and
`subungual hypetkeratosis. Negative rnycology was
`defined as negative KOII wet mount and negative
`fungal culture.
`
`Safety
`Safety assessments were conducted at each
`visit,
`as was a physical examination evaluating
`the
`frequency and severity of application-site
`r-‘actions:
`burning/stinging,
`induration/edema,
`OOZiDg/Cl‘LlStlng, pruritus, elythema, and scaling,
`Adverse
`events
`CARS"),
`treatnitent—emergent AEs
`(TEAEs), serious AEs, vital signs, laboratory parame-
`ters,
`and electrocartliographic parameters were
`monitored throughout the study.
`
`Statistics
`
`the
`evaluated in
`Efficacy parameters were
`all
`intent—to—treat population, which
`included
`randomized patients who received study treatment.
`Safety pa ratrretcrs were evaluated in all randomized
`patients who received at
`least
`1 dose of study
`treatr‘nent and had at least 1 postbaseline assessment.
`Comparisoas between treatment groups for
`the
`primary and secondary efficacy end points were
`made
`using
`the CoclrraniMantel—iriaenszel
`test
`stratified by analysis. A last~obsewation-catried—
`forward approach was used to impure missing
`efficacy data.
`’I'woisided hypothesis testing was
`conducted using a significance level of .05. Am
`were classified using the Malice! Dictionary fer
`
`

`

`] AM ACAD DERMATDL
`VOLUME 73. NUMBEItl
`
`Eiewsiei er a! 65
`
`Study 1
`
`Screened
`
`
`(n=2482)
`
`Screening failures
`
`
`(n=1388]
`
`
`Study 2
`Screened
`
`[n=2593)
`
`Screening failures
`
`
`lln=1989)
`
`Randomized
`
`(n=504)
`
`Tavahorole
`Tavaboroie
`
`
`(11:399)
`(“3400)
`
`
`
`
`Discontinued
`Discontinued
`Discontinued
`Discontinued
`
`
`
`
`
`(n=50]
`ln=281
`ln=231
`{n=52)
`
`
`
`
`0 Patient request (11)
`I Patient request {20]
`- Patient request {24]
`- Patient request (303
`
`
`
`- lost to follow-up [10)
`- Lost to foilow-up (4)
`
`I lost to follow-up (5]
`- Lost to follow-up (18)
`
`
`
`
`- Noncompiiance {4)
`I Noncompliance [2]
`- Noneompliance [21
`I Noncompllance [2]
`
`
`
`c Adverse event (2)
`- Adverse event (1)
`- Adverse event {2)
`
`- Adverse event (1)
`
`
`
`- Other (1)
`0 Other [3}
`- Other {4]
`
`o Other {‘3'}
`
`
`
`
`Compieted study
`
`(n=349) Completed study(n=177i
`Completed study
` Completed study
`
`
`(n=343}
`
`
`
`
`[11' population (n=194)
`l'i‘l' population (n: 205]
`i'l'l' population (n=396)c
`I'l'l' population (n=399}'
`
`
`
`
`Safety population ($193)"
`Safety population (n=395)““1
`Safety population ($202)"
`Safety population in=396}"’
`
`
`
`
`
`
`
`Randomized
`[n=594]
`
`
`
`
`
`
`
`llime patient exduded because study treatment not dispensed
`I’Five patients excluded because no post-baseline assessment In=3
`and 1, respectively) and no study treatment dispensed tn=1}
`
`‘Three patients excluded because study treatment not dispensed
`*Seven patients excluded because no post-baseline assessment (n=1
`and 3, respectively] and no study treatment dispensed [n=3)
`
`Fig 2. Toenail onyclromycosis. Patient disposition. HT, Intent—to-trczrt.
`
`(Version 15.1, http:/ www.
`Regulatory Aciz‘w‘iies
`nrcddmorg). All safety parameters were summarized
`dcscriptivcly by treatment group.
`
`RESULTS
`Patients
`
`The disposition of patients (study 1, N = 594; study
`2, N = 604)
`is depicted in Fig 2. Demographic
`and clinical characteristics of the intent-to-trcat
`
`p