DISTAL LATERAL SUBUNGUAL ONYCHOMYCOSIS

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1 Boni E. Elewski, MD James Elder Professor of Dermatology University of Alabama RESEARCH GRANTS -TO UNIVERSITY Dusa, Meiji, Valeant, Viamet Amgen, Abbvie, Boehringer Ingelheim, Celgene, Lilly, Merck, Novartis, Pfizer CONSULTANT- HONORARIUM Anacor, Celgene, Lilly, Pfizer, Valeant Diagnosis of Onychomycosis Bedside and laboratory diagnosis Differential diagnosis New Topical Antifungal Agents Efinaconazole and tavaborole solutions More common in toenails than fingernails Fingernails only seldom occurs Caused by dermatophytes, non-dermatophyte molds, and Candida Tinea unguium- dermatophytes only Four subtypes that are named by the method of fungal invasion DLSO most common and indication for treatment with topical and oral drugs ONYCHOLYSIS GENERALLY PRESENT LOOK FOR: Distal onycholysis with subungual debris in toenails IGNORE: Thick nail plate -not diagnostic! OBSERVE: Fingernails, presence of tinea pedis or dermatophytoma ASK ABOUT Present or past history of tinea pedis in patient and family members and risk factorspedicures, gymnasiums, military history DISTAL LATERAL SUBUNGUAL ONYCHOMYCOSIS 1

T I P LOOK FOR EVIDENCE OF TINEA PEDIS Mocassin Tinea Pedis 221 asympomatic

rubrum TINEA PEDIS CAN BE HIDDEN! TINEA PEDIS MAY NOT BE OBVIOUS!

Rubrum Tinea Pedis Sakka N et al Int J Derm 2015;54:146-149 IF YOU THINK THERE IS

2 T I P LOOK FOR EVIDENCE OF TINEA PEDIS Mocassin Tinea Pedis 221 asympomatic subjects with normal feet 14% were culture positive T. rubrum TINEA PEDIS CAN BE HIDDEN! TINEA PEDIS MAY NOT BE OBVIOUS! Onychomycosis presence was a predictive factor Look for Collarettes of Scale in T. Rubrum Tinea Pedis Sakka N et al Int J Derm 2015;54: IF YOU THINK THERE IS ONYCHOMYCOSIS Collarettes of Scale Seen in T. rubrum Infection LOOK HARDER Look for Collarettes of Scale to Confirm in Tinea Pedis 2

3 DERMATOPHYTOMA STREAKS AND PATCHES ARE FUNGAL ABSCESSES YELLOW TO ORANGE STREAKS OR PATCHES Presence or absence of fungal elements KOH/ calcofluor PAS stain Fungal identification Fungal culture PCR analysis PAS STAIN FOR HYPHAE ABNORMAL FINGERNAILS WITH NORMAL TOENAILS UNLIKELY ONYCHOMYCOSIS PAS STAIN POSITIVE 3

4 T. rubrum MOST COMMON CAUSE OF ONYCHOMYCOSIS Empiric treatment with terbinafine for patients with suspected onychomycosis is more cost effective than confirmatory testing with minimal effect on safety Confirmatory testing before efinaconazole will reduce costs across a range of disease prevalence Empiric oral terbinafine Mikailov A et al JAMA Derm 2015 online Dec 23 HALF OF ABNORMAL NAILS HAVE FUNGUS THE OTHER HALF DO NOT! LICHEN PLANUS TUMOR:ONYCHOMATRICOMA TRACHYONYCHIA ONYCHOGRYPHOSIS PSORIASIS YELLOW NAIL SYNDROME 4

SOLUTIONS: Efinaconazole10% Tavaborole Non-lacquer alcohol based therapies can be delivered on,

laboratory monitoring Topical formulations can be applied direct to infection- lacquers and

not new therapies Triazole antifungal New molecule Broad spectrum antifungal with activity

(2R,3R)-2-(2,4-difluorophenyl)-3- (4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-

Phase Study P3-01 Study P3-02 Follow-up Phase Follow-up Phase Proportion of Subjects Proportion

5 SOLUTIONS: Efinaconazole10% Tavaborole Non-lacquer alcohol based therapies can be delivered on, under and around the nail bed Preferred by many patients NO systemic side effects No need for laboratory monitoring Topical formulations can be applied direct to infection- lacquers and solutions Efinaconazole 10% and Tavaborole are both solutions Lacquers- ciclopirox and amorolfine not new therapies Triazole antifungal New molecule Broad spectrum antifungal with activity against yeasts, molds and dermatophytes Proportion of Subjects Study P3-01 Study P3-02 (2R,3R)-2-(2,4-difluorophenyl)-3- (4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol Mycologic cure mimics clinical experience Active Treatment Phase Active Treatment Phase Study P3-01 Study P3-02 Follow-up Phase Follow-up Phase Proportion of Subjects Proportion of Subjects Week 48 Week 48 Week 48 Source: package insert terbinafine and itraconazole 52 Treatment Period (Weeks) Treatment Period (Weeks) 52 5

20-50% in efinaconazole Elewski BE et al. Efficacy and safety of tavaborole topical solution. JAAD 73:62 69,2015 Elewski BE et al.

6 Week 52 Week 24 Baseline 40% 50% 4 1 0% 0% 8% 0% BORON IS FOUND IN FOODS: FRUITS, VEGETABLES AND NUTS e Similar to efinaconazole study designapplied once daily for 48 weeks in mild to moderate disease Differences in studies: No upper age limit in tavaborole study Nails were 20-60% involved in tavaborole vs % in efinaconazole Elewski BE et al. Efficacy and safety of tavaborole topical solution. JAAD 73:62 69,2015 Elewski BE et al. Efficacy and safety of tavaborole topical solution. JAAD 73:62 69,2015 COMPLETE CURE LAGS BEHIND MYCOLOGICAL CURE Baseline Day mm 9.6mm Day 240 Day mm 9.9mm p<0.001 p<

Baseline Day 180 3.7mm 8.2mm TREATMENT FAILURE?

Culture -) 37 Elewski Elewski BE BE et et al. Presented al.

20 22, of 2013; tavaborole Phoenix, AZ. topical solution.

Week 52 Week 24 Baseline 40% 50% 4 20% 20% 10% 3% 3% Psoriasis High

tumors and structural abnormalities Onychomatricoma Pincer nails Yellow

7 Baseline Day mm 8.2mm TREATMENT FAILURE?? Before Treatment (KOH +, Culture +) Week 52 (KOH -, Culture -) Day 240 Day mm 14.1mm Before Treatment (KOH +, Culture +) Complete Cure Week 52 (KOH -, Culture -) 37 Elewski Elewski BE BE et et al. Presented al. Efficacy at: Desert Foot and 2013; safety Nov , of 2013; tavaborole Phoenix, AZ. topical solution. JAAD 73:62 69, Week 52 Week 24 Baseline 40% 50% 4 20% 20% 10% Week 52 Week 24 Baseline 40% 50% 4 20% 20% 10% 3% 3% Psoriasis High prevalence (about 30%) of onychomycosis with psoriatic toe nails Nail tumors and structural abnormalities Onychomatricoma Pincer nails Yellow nail syndrome Prior nail trauma Onychogryphosis Bedside diagnosis Presence of tinea pedis dermatophytoma Half of abnormal nails caused by fungi Topical tavaborole and efinaconazole solutions effective treatments 7

MANAGEMENT OF ONYCHOMYCOSIS Beyond Topical Monotherapy JAMES Q.

Dermatology Research Center Las Vegas, Nevada Allergan +# Anacor Aqua/Almirall + Bayer Dermatology +# BioPharmX Celgene + Cutanea #

+# Unilever + Viamet Consultant/ Speaker + / Researcher # (Updated as of 9-29-16) Develop a Rational Strategy Designed to Achieve Optimize

and palliative measures Debridement ~ physical, chemical Avulsion Removal of dermatophytoma THINK BEYOND THE CLINICAL TRIALS, STUDY-

Assess patient-related factors Age / Gender Pathogen Severity ~ surface area, thickness, onycholysis, dermatophytoma Number of nails

Immunologic status Effects of chronic trauma Concomitant medications Potential drug interactions, immunologic effects When to Use Oral

Rational choice for moderate to severe involvement Nail plate thickness >4mm >50% nail plate area involved (distal to proximal) May be

8 MANAGEMENT OF ONYCHOMYCOSIS Beyond Topical Monotherapy JAMES Q. DEL ROSSO, DO, FAOCD, FAAD Adjunct Clinical Professor (Dermatology) Touro University Nevada Henderson, Nevada Lakes Dermatology Del Rosso Dermatology Research Center Las Vegas, Nevada Allergan +# Anacor Aqua/Almirall + Bayer Dermatology +# BioPharmX Celgene + Cutanea # Dermira Ferndale Galderma +# Genentech + Disclosures LeoPharma +# Novartis + Novan # Valeant +# Pharmaderm + Promius + Sebacia # SunPharma +# Unilever + Viamet Consultant/ Speaker + / Researcher # (Updated as of ) Develop a Rational Strategy Designed to Achieve Optimize Management of Onychomycosis Confirm diagnosis Clinical examination Putting together the pieces of the puzzle Diagnosis ~ proper specimen collection! Potassium hydroxide preparation (KOH) Fungal Culture Nail plate biopsy + Periodic Acid-Schiff (PAS) stain Physical modalities Adjunctive and palliative measures Debridement ~ physical, chemical Avulsion Removal of dermatophytoma THINK BEYOND THE CLINICAL TRIALS, STUDY- MANDATED ENDPOINTS, AND PACKAGE INSERTS Develop a Rational Strategy Designed to Achieve Optimize Management of Toenail Onychomycosis Assess patient-related factors Age / Gender Pathogen Severity ~ surface area, thickness, onycholysis, dermatophytoma Number of nails involved ~ toenails, fingernails Nail growth rate Concurrent disease states Tinea pedis/manus, diabetes, peripheral vascular disease Immunologic status Effects of chronic trauma Concomitant medications Potential drug interactions, immunologic effects When to Use Oral Therapy for ONYCHOMYCOSIS Good General Rule: When the patient has onychomycosis! Rational choice for moderate to severe involvement Nail plate thickness >4mm >50% nail plate area involved (distal to proximal) May be used for milder cases based on discussion with patient May be used after discussion and review of potential adverse effects May be used after exclusion of drug-drug interactions Duration of therapy may need to be extended Repeated courses or intermittent oral therapy may be warranted Frequent integration of COMBINATION THERAPY Debridement / Removal of dermatophytomas Oral + topical antifungal therapy Oral + topical nail barrier therapy 8

Oral Therapy Options for ONYCHOMYCOSIS GRISEOFULVIN not recommended for treatment especially in adults KETOCONAZOLE not recommended / risk >>> benefit TERBINAFINE

and history Low risk of symptomatic hepatotoxicity Short list of potentially significant drug-drug interactions (CYP2D6) ITRACONAZOLE Very good broad-spectrum

cardiotoxicity (CHF) Long list of potentially significant drug-drug interactions (CYP3A4) Oral Therapy Options for ONYCHOMYCOSIS FLUCONAZOLE Very good

drug interactions with once weekly dosing ORAL THERAPY MAY BE USED IN COMBINATION WITH TOPICAL THERAPY AND/OR PHYSICAL MODALITIES Methods to Expedite Therapeutic

DISEASE PROXIMAL DISEASE EXTENSIVE ONYCHOLYSIS TINEA PEDIS Pre-Debridement Poly ureaurethane 16% Topical Solution Photograph Courtesy of Tracey Vlahovic DPM

Onychomycosis Laboratory monitoring Oral Agents Terbinafine Itraconazole Fluconazole Think Outside the Box Prolong the duration of therapy Intermittent therapy

The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S2-4. Rosen T, Friedlander SF, Kircik L, et al.

Onychomycosis: an overview. J Drugs Dermatol. 2013;12(7):s96-s103. Sigurgeirsson B. Prognostic factors for cure following treatment of onychomycosis.

Onychomycosis: epidemiology, diagnosis, and treatment in a changing landscape. J Drugs Dermatol. 2015;14(3):223-233. Gupta AK. Systemic antifungal agents.

9 Oral Therapy Options for ONYCHOMYCOSIS GRISEOFULVIN not recommended for treatment especially in adults KETOCONAZOLE not recommended / risk >>> benefit TERBINAFINE Highly active against dermatophytes Continuous therapy once daily: toenails x 12 weeks; fingernails x 6 weeks Laboratory monitoring based on patient-related factors and history Low risk of symptomatic hepatotoxicity Short list of potentially significant drug-drug interactions (CYP2D6) ITRACONAZOLE Very good broad-spectrum antifungal activity Continuous or pulse therapy regimens Laboratory monitoring based on patient-related factors and history Low risk of symptomatic hepatotoxicity / cardiotoxicity (CHF) Long list of potentially significant drug-drug interactions (CYP3A4) Oral Therapy Options for ONYCHOMYCOSIS FLUCONAZOLE Very good broad-spectrum antifungal activity Studies confirming efficacy and safety with intermittent (once weekly) dosing Highly favorable safety profile Negligible risk of drug interactions with once weekly dosing ORAL THERAPY MAY BE USED IN COMBINATION WITH TOPICAL THERAPY AND/OR PHYSICAL MODALITIES Methods to Expedite Therapeutic Outcomes with Oral Therapy for Onychomycosis Methods to Expedite Therapeutic Outcomes with Oral Therapy for Onychomycosis DERMATOPHYTOMA PANUNGUAL THICKNESS LATERAL DISEASE PROXIMAL DISEASE EXTENSIVE ONYCHOLYSIS TINEA PEDIS Pre-Debridement Poly ureaurethane 16% Topical Solution Photograph Courtesy of Tracey Vlahovic DPM Immediate Post-Debridement + Topical Barrier Repair SEM Cross Section Protective Barrier Develop a Rational Strategy Designed to Achieve Optimize Management of Onychomycosis Laboratory monitoring Oral Agents Terbinafine Itraconazole Fluconazole Think Outside the Box Prolong the duration of therapy Intermittent therapy Sustain efficacy Prevent relapse or recurrence Patient wants to use nail polish References Scher RK, Rich P, Pariser D, Elewski B. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S2-4. Rosen T, Friedlander SF, Kircik L, et al. Onychomycosis: epidemiology, diagnosis, and treatment in a changing landscape. J Drugs Dermatol. 2015;14(3): Elewski BE, Rich P, Tosti A. Onychomycosis: an overview. J Drugs Dermatol. 2013;12(7):s96-s103. Sigurgeirsson B. Prognostic factors for cure following treatment of onychomycosis. J Eur Acad Dermatol Venereol. 2010;24: Rosen T, Friedlander SF, Kircik L, et al. Onychomycosis: epidemiology, diagnosis, and treatment in a changing landscape. J Drugs Dermatol. 2015;14(3): Gupta AK. Systemic antifungal agents. In: Comprehensive Dermatologic Drug Therapy, 3rd Edition, Wolverton SE, Ed., Saunders-Elsevier, New York, New York, USA, 2013: Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea pedis. J Drugs Dermatol. 2015;14(5): Gupta A, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000;10:

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