Continues Improvement

Are Podiatrists Using Clinical Based Methods in the Treatment of Onychomycosis/Nail InfectionDiaDerm Laboratories, Inc.

35 to 36 million Americans are estimated to have Onychomycosis170% of the population has had fungus recovered from there feet2Only 6.3 million have been diagnosed by a physician with Onychomycosis348% of the people with Onychomycosis have pain38% have some discomfort when wearing shoesThese patients miss 1.8 days of work on average over six month period2Only 2.5 million receive treatment each year3This leaves 33 million untreated Americans3

Onychomycosis Facts and Figures1. Elewski BE. Clin Microbiol Rev. 1998;11:415-429 2. Drake, Scher, Smith: J Am Acad Dermatol;m 1998; 38 702-704 3. Dr. w. Joseph; APMA 2005Presentation 9/16/112

Onychomycosis is 2.8 times more prevalent among people with diabetes than those without1 Thickened fungal nails can develop serious bacterial infections and foot ulcerations2About 82,000 people have diabetes related leg and foot amputations per yearRegular examinations and patient education could prevent up to 85% of these amputations3

Onychomycosis in diabetics

1. Gupta AK Br J Dermatol 1998;139:655-671 2. Rich P J Am Dermatol 1996;35:S10-S12 3. CDC Data 2002Presentation 9/16/113

Nail thickness is 0.5mm for women and in men 0.6mm1Normal fingernail growth varies from less than 1.8mm to 4.5mm/ per month varies between individuals. Average is 3mmToenails grow at to 1/3 the rate of fingernails2Fingernails require 3 to 6 months to regrow completely, and toenails require 12 to 18 months. Actual growth rate is dependent upon age, gender, season, exercise level, diet, and hereditary factors3 Nail growth is proportional to the length of the digit4 Nail growth is faster in the dominate hand, men, during pregnancy, and warm climates5Nail Anatomy facts1. Hamilton JB, J Gerontology 1955 10:401-415 2. Veller OD Am J Clin Nutr 1970; 23:1972-1974 3. Hunter, J. A. Clin Derm 2002; p 173. 4.Dawber R. B J Dermatol 1970; 82:454-457 5. Clark Le G. Br J Dermotol 1938; 50:221-235Men's nails grow faster than women's nails. Toe nails are about twice thicker than finger nails. The fastest growing nail is on the middle finger. The slowest on the thumbnail. When nails are freshly cut, they grow faster than nails that are not cut often. Seasons and weather also affect nail growth. Nails grow faster in warm climates and during daytime, than in cold climates and at night. Nails grow faster on young people than on old people. Also nails grow much faster during pregnancy. Nails grow at different speeds on both hands. Nails reflect your health status. The longest finger nail ever recorded was that of an Indian guy and it was 48 inches long.

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BackgroundOnychomycosis is under diagnosed and undertreated. It is estimated that approximately 10% to15% of the US population has onychomycosis.1 Evidence points to an increasing prevalence as the population ages. Up to 60% of people who are 60 years and older are reported to have onychomycosis. The incidence is also higher in men, smokers, and in those patients with peripheral artery disease.2TreatmentTreatment has had success with obstaclesEfficacy vs. Risk/Reward of Oral MedicationsDifficulty diagnosing condition/causePoor patient compliance due to length of therapyMedical administrator perception of Onychomycosis as merely a cosmetic problem1. Elewski BE. Clin Microbiol Rev. 1998;11:415-429 2.Pierard G.European survey. Dermatology. 2001;202:220-224.Presentation 9/16/115

On average, a podiatrists sees 26 new Onychomycosis patients a monthOnly 4 of these patients are treated with a prescription antifungalScott Levin PDDA 2005/IMS Data viewCurrent Therapies Liberman patient segmentation 2002Presentation 9/16/116

Patient Perception Only 10% of patients with nail fungus know it is called Onychomycosis57% of patients believe OTCs are sufficient to treat75% state that a nail infection is a health problem and not just cosmetic88% of those with diabetes know that medical therapy is necessaryRoper Survey, 2004Perception of Efficacy and RecommendedRx Recommended by Dermatologists 64%Rx Recommended by Primary Care 65%Reason Pain DPMs 69% and Derm/PC 49%

Liberman Research Associates 2004Presentation 9/16/117

38% have some discomfort when wearing shoes. Seventy-five percent of patients have difficulty trimming their toenails, and the disease causes significant embarrassment for patients, such as the inability to wear sandals or to participate in sports.1Patients Attitude About OnychomycosisLieberman Research Associates, 2002 1. Drake, Scher, Smith, J Am Acad Dermatol. 1998;38:702-704.Presentation 9/16/118

Systemic / Oral RxDebridement / AvulsionLaserTopicalTreatment options

Systemic active ingredientsAzole derivativesKetoconazole, fluconazole, itraconazoleAllylaminesTerbinifineGriseofulvinSide effectsContraindications, systemic toxicityEfficacy Mycological/clinical cure Systemic 30 to 60%Presentation 9/16/119

Treatment options contDebridement Alleviates pain and relieves discomfortImproves nail appearanceRecommended to use with TopicalDebridement part of most clinical studies on OnychomycosisNovartis introduced IRON-CLAD (Improving Results in Onychomycosis Lamisil and Debridement Complete cure L=14% LD=39% Clinical cure L=26% LD=54% Mycological neg. culture L=64% LD=63%11. Novartis Oral Terbinafine Analysis of IRON-CLADPresentation 9/16/1110

LaserFDA has approved a Laser therapy for onychomycosis with more approvals expected in the months to comeCost vs. efficacy costs about $1,000, which insurance doesnt cover.Solid evidence of the lasers' effectiveness, is scant. Treatments typically take 30 to 45 minutes for up to 10 toes. Depending on the severity of the problem and the laser used, patients may need one to four treatments.Dr. Warren Joseph, who is a consultant for Nomir and a former consultant for PinPointe, says: "I think it is a really interesting, viable alternative but I want to see published data." His advice to patients: "Ask for the evidenceand not just before-and-after pictures."In clinical practice, results have varied, according to doctors who have used the laser. Dr. Anas Khoury, who has no affiliation with any laser company, says he has been using Nomir's Noveon laser for toenails for about four months and says it works in about 80% of his patients.PinPointe supplied The Wall Street Journal a summary of unpublished data from a study looking at 265 patients over two years. In the summary, 71.4% of the patients experienced continuous improvement over a year after a single session with its laser.Treatment options contPresentation 9/16/1111

Treatment options contNystatinClotrimazoleEconazoleItraconazoleKetoconazoleMiconazoleOxiconazoleSulconazoleSulconazoleAmorolfineButenafine HClNaftifineTerbinafineAmorolfineCiclopirox olamineTolnaftateTea TreeUndecylenate

Topical active ingredientsGeneral published consensus Currently Available topical treatments have limited effectiveness because they cannot penetrate the nail plate sufficiently to transport a therapeutically sufficient quantity of a drug to the target sitePresentation 9/16/1112

Penetration properties PenetrationNail

The human nail is approximately 100 times thicker than the stratum corneumLipid content of the Nail ranges from 0.1 to 1%The nail is hydrophilic membrane ~ water lovingWater content of the nail is 7 to 12%Max water content (@100h) is 25%Stratum Corneum

The stratum corneum is approximately 100 times thinner than the human nail Lipid content of the stratum corneum is approximately 10%The stratum corneum acts as lipophilic (fats, oils, lipids) Water content of the stratum corneum is 25%Max water content (@100h) is 100% to 200%Textbook of Dermatology 3rd Ed. P 57-581. M. Lippold, BC Pharm Pharmacol, 1997; 49:30-40The rate of chemical penetration into/through the nail depends on its water solubility 1

Presentation 9/16/1113

Topical dilemma No delivery system - Any topical product has limited effects Stating a delivery system is not scientificThe word placebo literally means "I will please" in Latin.The first known double-blind placebo-controlled trial was done in 1907.The scientific study of the placebo effect is usually dated to the pioneering paper published in 1955 on "The Powerful Placebo" by the anesthesiologist Henry Beecher concluded that across 26 studies he analyzed, an average of 32% of patients responded to a placebo.All is not lost we have the placebo effectAs noted water content of the nail and stratum corneum is directly related to relative humidityAt high humidity much less water is held by the nail than the stratum corneum1The rate of water diffusion through a nail plate is approximately 10 times great then through the stratum corneum2Considering the stratum corneum is 1/100th of the nail diffusion constant of water through the nail is several times more evident3Finlay AY, BR J Dermatol 1980;103:357-365 2. Spruit D, J Invest Dermatol 1971;56:359-361 3. Baden HP J Invest Dermatol 1970;55:115-117Presentation 9/16/1114

Treatment dilemma The dirty little secret! - Clinical studies show NOT all nail disorder are FUNGUSLost in translation, but very well documented

Evident by:All Rx clinical studies prescreen for a fungal positive culture (KOH/DTM) WHY?

Clinical studies show:Onychomycosis is a progressive fungal infection of the nail, accounting for approximately 40% or all nail disorders150% of nail disorders that appear to be Onychomycosis are not2Onychomycosis is the most common nail disorder in adults, accounting for up to 50% of all nail diseases3DTM culture indicated a dermatophyte in 56% patient specimens4

Supported by MCO/PBM recommendation/requirement for a positive fungal culture prior to prescribing/dispensing a Rx Medication1. Novartis Pharm, Analysis of IRON-CLAD Trial, 2005 2. Scher, et al; Dermatol Nurs 1995; 7:335-47 3. Schleman,BS:;J Foot and Ankle Surg. 1999; 38:290-302 4. Pariser MD; Clin Research Scien, Man Care; Mar 2002Presentation 9/16/1115

Patients often finds their nail infection humiliating and embarrassingYet nail infections once established can be difficult to eradicateTherefore:PREVENTION IS MUCH BETTER THAN CURE

The analysis based on Clinical Studies

Patients are seeking a solution to nail infections

?Approximately 50% of diseased nails tested will have a positive culture for fungus to support the use of an antifungal medicine50%50%Rx Medications are preferred route of therapyAntifungal Topical while using have not shown clinical documentation to support efficacyNow what?

DPMs use debridement

16

Additional costAnother office visitFalse negativeConsBest Option for treatment Recommended for Rx Doctors have an expertise for identifyingProvides a documented testProsIf recommending an antifungal should a KOH be administered?Presentation 9/16/1117

These conditions are met in a formulation containing:Nonionic and amphoteric surfactantsForms surfactant penetrating delivery systemAloe VeraMild keratolyticStimulates cell proliferation and wound healing

Is there a Study on a topical solution with a delivery system?Surfactant, aloe vera and benzalkonium chlorideActive against pathogens that cause infectionFormulated to protect viable skin cellsSurfactants allow rapid penetration through the stratum corneum

These results indicate that an BAC antimicrobial active with a surfactant delivery system in a twice-daily regimen is a clinically-effective therapy for a wide variety of microbial pathogens effecting the health and condition of human nails. In the 10 month study concluded a 32.6% success rate. JAPMA 1999;89:124-130

JAPMA Study on a topical solutionPresentation 9/16/1118

Presentation 9/16/1119Surfactants penetrate the skin

Surfactant, and Benzalkonium Chloride Solution for Onychomycosis Preliminary Results of Treatment with Periodic Debridement

Table 1. Data on the Patients Participating in the Study Abbreviations: APT, area + pain + thickness; DTM, dermatophyte test medium; ID, identification.

Wadhams P J Am Podiatr Med Assoc 89(3): 124-130, 1999) Presentation 9/16/1120

Dystrophic Nail Score Form

Scoring Dystrophic Nails to Chart Therapeutic Results

Score each digit from zero (normal) to a maximum of score of 10 points (totally dystrophic nail) score each digit individually, add individual digit scores to obtain total score maximum patient foot-score is 100 points Patient ID#: ______ Patient: _____________ Visit(1-10): _____

0 - 8 POINTS AREA: The nail area is divided into five regions as shown below.Evaluate each region and score the indicated points if the region appears abnormal (dystrophic).

1 POINT PAIN: Score 1 point if the patient reports pressure pain for that digit.

1 POINT THICKNESS: Score 1 point if the nail plate is thickened. Normal nailplate is less than 0.5 mm thick.

____ ____ ____ ____ ____ "Proximal Zone ____ ____ ____ ____ ____

____ ____ ____ ____ ____ points Nail Score With Pain Thickness ____ ____ ____ ____ ____ points

Total Score __________________ Number of Nails _____________

Date:_________ KOH______________ DTM__________________Dystrophic Nail Score FormPresentation 9/16/1121

Oral great and proven results for those with positive KOH/DTM (fungal pathogen). Generic cost very affordable especially at pulse. High results with combination therapy, i.e. laser, topical Debridement/Avulsion Based on studies is shown to improve the nail and best to support with broad spectrum agent or antifungal.Conclusion Presentation 9/16/1122

Laser New exciting therapy. Best results appear to be a combination approach with oral and broad spectrum topicalTopical Effective provided there is a delivery system to get to the site of infection. Effective with combination therapy i.e. Oral or Laser. Consider the logic in using a broad spectrum topical to address negative KOH/DTM results. Using an antifungal without a positive fungal culture will not workConclusionPresentation 9/16/1123

Presentation 9/16/1124Thank youFrom the Makers of ClearZal BACAntimicrobial Nail Solution

JAPMA Data TableNails InvolvedAverage Nail Score (A.P.T.)Pathogen atFungal CulturePatientAgeLeftRightStart4 month8 month10 monthEnrollmentat Final VisitS.W.61227.310.30.2Aspergillus versicolornegativeW.N.6755103.74.72.6Candida sp.negativeM.A.930110410none recoverednegativeM.F.72559.77.86.96.2DTM positive, no I.D.negativeE.M.44429.55.55.84.3DTM positive, no I.D.negativeM.B.764392.633.9none recoverednegativeC.S.775594.75.76.1none recoverednegativeL.K.50119300hyphae, no I.D.negativeJ.S.7255106.46.46.8GeotrichumnegativeW.A.41147322.8Trichophyton mentagrophytesTrichophyton rubrumJ.R.28445.83.44.84.4Trich. rubrum; Aspergillus sp.negativeC.W.721150.500Candida albicansnegativeW.T795595.144.1Alternaria sp.negativeL.S.71329.42.40.80.4none recoverednegativeG.S.82338.65.74.73.3none recoverednegativeA.M.65119410none recoverednegativeD.W.61226.810.20.2Aspergillus versicolornegativeH.J.79335.8100Epidermophyton floccosumnegativeG.M.48326.43.80.40.6Trichophyton rubrumnegativeA.C.56559.14.33.53.4none recoverednegativeAverage64.73.13.058.33.62.82.5Standard Deviation1.61.92.42.4Standard Error of Mean1.41.52.22.1Chi Squared2.73.64.1Significance (p-value)> 0.10< 0.10< 0.05

&C&BMycocide Study Date