RESULTS. TABLE 1 FOOT, TOE, AND TOENAIL EXAMINATION CONDITION (Number of patients with)

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1 Over the several decades that I have been in practice I have been struggling to provide my patients with onychomycosis an effective treatment for this pervasive and embarrassing disease. I have had several patients break down and cry in my office from embarrassment. Early on I used oral meds such as Griseofulvin and Gris-Peg with total nail evulsion. I would have them apply topical antifungal cream twice daily until the nail grew out. My success rate was always less than 50% and by success I mean that the nail looked noticeably better. I could seldom achieve 100% clear nail, but only in mildly infected nails. In the 1980 s we tried a technique with the CO 2 laser. The idea was to use the laser to punch a bunch of holes through the nail plate to facilitate delivery of a topical antifungal to the underlying nail bed. This didn t work at all. The nail lacquer, Penlac (Ciclopirox), is only effective in less than 10% of my patients. For a while I would prescribe Sporanox (Intraconazole) and Lamisil (Terbinafine) but stopped because of serious drug interactions and I was afraid of placing my patients at risk for dangerous and unpleasant side effects. In 2007 a patient showed me an ad in the Sacramento paper where they were recruiting patients for a pilot study at the practice of my colleague, Brian McDowell, DPM. I tracked down the company nearby in Chico, CA and, although I couldn t participate in the research study, I did become their first commercial provider. Since then we have treated over 1400 patients in my practice. At the time of this study 2 the practice had almost two hundred patients who had been treated with the PinPointe FootLaser between July 2008 and February 2009 with at least a 6 months follow-up visit, so we decided to evaluate, retrospectively, the treatment at the 6-month time point. Some patients also had 3-month photos, which were included in the analysis. The aim of this study was to evaluate in a private practice the effectiveness of a single treatment with the PinPointe FootLaser for onychomycosis. METHODS. An independent consultant came into the office and selected patients based on only two criteria: (1) all those having had the FootLaser treatment and (2) the availability of legible pre-treatment and 6-month post-treatment great toe photographs. No other criteria were used and we had no say in the selection process, so this sample was totally independent of treatment outcome. Patients were contacted and their consent was obtained to use their photos and records in the study. In all, 71 patients with 139 infected great toes were recruited for analysis. Demographics, history, baseline, treatment, and outcome data were extracted from the patients records and entered onto standardized case report forms. Digitized photographs pre and post treatment were collected for measurement. Toe images were blinded by coding them to a five digit random number, so that the patient identification and evaluation period were masked. Three expert, blinded independent raters, two podiatrists and one dermatologist, examined hard copy prints of the toes and outlined the affected area. Marked photographs were digitized and a research technician used computer software (planimetry) to measure the nail plate area and the clear nail area in order to calculate clear nail area on a percentage basis. STATISTICAL ANALYSIS. Demographic, history, baseline, and treatment data were summarized using descriptive statistics. Rater evaluations of the photos were compared using Friedman nonparametric tests. For the area calculations, correlation coefficients between pairs of raters were computed to assess the degree of agreement. To further address consistency, repeated measures analysis of variance on the calculated areas with the factors of time and rater were performed to test whether changes over time were consistent among raters.

2 The primary measure of efficacy was the median of the area calculations across the three raters, so that outliers would not affect the results as much as a mean. Since not every toe had both three month and six month photos evaluated, analyses were performed for baseline versus three months and baseline versus six months areas separately. Results are presented descriptively by rater, but only the median value was compared statistically using Wilcoxon signed rank tests. Values given are in percent of the toenail with clear nail and improvement is calculated as the difference in these percents between baseline and follow-up. Efficacy is defined as the percent of toes with an increase in clear nail area. RESULTS. Seventy one patients were included in the study. There were 30 males and 41 females with an average age of 58 years (range 21-84). 62 were white, five were Hispanic, two were black, one was Asian, and one ethnicity was not recorded. Table 1 summarizes foot, toe, and toenail examinations. Most patients had hypertrophic nails, discolored toenails, crumbling toenails, and fungal spikes/streaks on both feet. Three right feet and two left feet had ankle edema. Seven feet had abnormalities of touch sensation, four had abnormal pedal pulses, seven had abnormal hallux alignment, and one had abnormal lesser digits alignment. Other abnormalities were noted for eight right and eleven left feet. TABLE 1 FOOT, TOE, AND TOENAIL EXAMINATION CONDITION N=69 N=70 (Number of patients with) RIGHT FOOT LEFT FOOT HYPERTROPHIC TOENAILS DISCOLORED TOENAILS CRUMBLING TOENAILS FUNGAL SPIKES/STREAKS PSORIATIC NAILS 0 0 ANKLE EDEMA 3 2 ANKLE VARICOSITIES 0 0 TOE TISSUE TURGOR (ABNORMAL) 0 0 TOE TISSUE TEXTURE (ABNORMAL) 0 0 TOE TISSUE COLOR (ABNORMAL) 0 0 TOE TEMPERATURE (ABNORMAL) 0 0 TOUCH SENSATION (ABNORMAL) 3 4 PLANTAR RESPONSE (ABNORMAL) 0 0 PEDUAL PULSES (ABNORMAL) 2 2 SUBPAPILLARY VENOUS PLEXUS FILLING TIME (ABNORMAL) 0 0 HALLUX ALIGNMENT (ABNORMAL) 4 3 LESSER DIGITS ALIGNMENT (ABNORMAL) 0 1 OTHER ABNORMALITIES 8 11 Most of the patients had great toe involvement, while about two thirds had involvement of each of the other four toes. Pre treatment debridement was done for most feet (Right N=65; Left N=67), pretreatment photographs were taken for all feet, and mycological testing was only done for 4 right feet and 5 left feet. All FootLaser treatments occurred between July 2008 and February Treatments on or before September 14 used one laser pass (17 patients) and those treated after that date received two passes (54 patients). Five different devices were used and all used the same standard spot size, energy output and pulse train timing. Sixty-nine right great toes and 70 left great toes were treated, with the number of

3 other toes treated ranging from 61 to 65. Three patients had one foot treated and 68 had two feet treated, for a total of 139 feet. Laser treatment is done within the context of proper medical management of the patient. Post-treatment the patients are given antifungal spray and cream and given instructions to obtain and apply topical antifungals, shoe sterilization instructions, 2-3 week post treatment instructions, and instructions on how to trim and clean nails. They are strongly counseled that they are always at risk for reinfection and need to continue vigilant foot hygiene, forever. SAFETY There were two mild adverse events recorded. One patient had onychogryphosis (claw-like thickening of nail) on the left foot starting 82 days post treatment. Debridement was performed and the condition resolved following debridement. This was rated as unrelated to treatment. One patient had onychocryptosis (ingrown toenail) on the right foot occurring 228 days post treatment which was continuing at the time of data recording. It was rated as related to the procedure. Debridement was also performed. Both of these patients had two laser passes. EFFICACY AS MEASURED BY AFFECTED AREA DETERMINATIONS. Planimetry evaluations were available for 71 patients and 130 of the 139 feet. Photo raters differed somewhat on the rating of photo quality and whether the photos were useable, so not all raters marked every photo. Photos were obtained at baseline, three months, six months, and later. Due to small numbers, the later photos were not statistically analyzed. Photos were given a random code blinding the rater and subsequent planimetry technician to patient identification and time of evaluation. Although raters initially differed with respect to rating the quality of each photo, most were able to mark the extent of the affected area so that the area could be calculated. To compare raters, correlation coefficients were made for the 394 photo areas. Pairwise correlation coefficients between raters ranged from to Another way to assess consistency of raters was to perform a repeated measures analysis of variance on the calculated areas with the factors of time and rater. While there were overall rater differences (higher or lower values for a particular rater), no time by rater interactions were seen, confirming that the raters were noting similar treatment differences over time. It should also be noted, that although there were differences among raters, statistical significance could still be achieved if results from each rater are tested separately. This analysis focuses on photos evaluated by the three raters, with marking of affected areas and subsequent calculation of affected areas using automated planimetry techniques. The median of the area calculations for the three raters was used as the primary outcome variable for analysis. Values given are in percent of the toenail that is clear nail and improvement is calculated as the difference in these percents between baseline and follow-up. Table 2 presents summary data from the study. At the three month evaluation median improvement over raters was 4.8 percent (p=0.011). At six months median improvement was 9.6 percent (p<0.001). Efficacy, the percent of toes that improved, was 64/116 or 55% at three months and 84/130 or 65% at six months.

4 TABLE 2 SUMMARY STATISTICS FOR PERCENT CLEAR NAIL AREA Baseline 3-month Change Baseline 6-month Change N MEAN SD MIN MAX WILCOXON SIGNED RANK P-VALUE: <0.001 Since the number of laser passes changed from one to two during the study period, data were broken out by number of passes. These data are shown in Tables 3 and 4. There is an obvious dose response relationship: not much improvement with one pass compared to greater improvement with two passes. Median improvement at three months increased from -3.9% to 7.1% and at six months from 4.4% to11.2%. With two passes efficacy increased from 32% to 62% of patients improved at three months and from 52% to 68% improved at six months. For patients who improved, the average improvement was 18% at three months and 20% at six months. TABLE 3 PERCENT CLEAR NAIL AREA: 1-PASS Baseline 3-month Change Baseline 6-month Change N MEAN SD MIN MAX WILCOXON SIGNED RANK P-VALUE: TABLE 4 PERCENT CLEAR NAIL AREA: 2-PASSES Baseline 3-month Change Baseline 6-month Change N MEAN SD MIN MAX WILCOXON SIGNED RANK P-VALUE: <0.001 This strong dose/response effect is important. Since all other factors remained constant it proves that it was the laser light dose alone that caused the improved treatment effect. Another way to present the entire data set is as a frequency distribution. In Figure 1 are plotted the number of toes (percent of sample) that had a certain response (percent change in clear nail). Data from the 1-pass group are blue and the 2-pass data are red. The improvement from 1-pass to 2-passes is seen. It is also evident from this graph that a average improvement of 11% in the 2-pass group

5 means that half of the patients actually did better than 11%. Figure 1. Distribution of responses of 130 fungal toes to a single FootLaser treatment by Dr Uro July 2008 to February 209. Twenty-nine toes were treated with a single pass and 101 toes were treated with 2-passes. Notice that there are no rapidly progressing infections (-40 to -60) such as are often seen without treatment. Figure 2 illustrates what percentage of toes had different amounts of improvement. Nearly 70% of the toes treated in the practice experienced an increase in clear nail. Shown here are the proportion of toes that improved by the amount of improvement. There is a broad range of positive improvement (up to 68% new clear nail at 6 months) that can be achieved with this technology. For example, 1/3 of the toes had a 20% or greater amount of improvement. Figure 2. Percent of toes that improved at six months for those toes that improved

6 TABLE 5 INCREASE IN CLEAR NAIL AREA BY SEVERITY: 2-PASSES 3-months 6-months Baseline clear nail Number treated Mean change Number / % improved Number treated Mean change Number improved ANY /62% /68% 0%-75% /64% /71% 0%-50% /64% /73% 0%-30% /70% /80% Another determinant of outcome was investigated for patients with two passes. Results were broken down by the extent of affected area at baseline. As expected, with greater affected areas at baseline, more improvement can be seen (Table 5). For patients with 30% or less clear nail at baseline, the improvement at three months averaged 11.1 percent (70% of patients improved) and at six months average improvement was 15.9%. (80% of patients improved). SUMMARY OF ANALYSIS Treatment of toenail fungus with the PinPointe FootLaser showed statistically significant improvement at three months and six months. Dose response was demonstrated as two passes outperformed one pass. The magnitude of the outcome was also dependent on the baseline area. CASE REPORT 1 White 47 year old female. Right toe was 64% infected at baseline with a proximal nail plate distortion. Distortion grew out and lesion area decreased by 48% by 6 months post treatment (2-passes). Pre-treatment U MONTHS 6-MONTHS

7 CASE REPORT 2 Patient was a white 34 year old female. Discolored left toe was debrided along the medial fold. Right toe has a roughened surface with superficial onychomycosis that was smoothed and thinned with a dremmel prior to treatment with 2-passes. All ten toes responded well to treatment. Patient admitted to following a vigilant program of post-op hygiene including regular application of topical antifungal cream. Pre-treatment U MONTHS 6-MONTHS

8 CASE REPORT 3 White 54 year old female. This is an unusual case as the lesion has cleared distal to proximal Pre-treatment U-060R 3-MONTHS 6-MONTHS CASE REPORT 4 White 45 year old female. Right toe was 49% infected at baseline with 100% clear and normal nail morphology obtained at 6-months. Pre-treatment U-042R 3-MONTHS 6-MONTHS

9 POSTSCRIPT I am very pleased with the results from the FootLaser. I can finally offer my patients a safe and effective option. The overall efficacy of 65% is better than I have achieved with any of the drugs and, importantly, there have been no side effects or toxicity to worry about. As an added bonus numerous patients have volunteered that symptoms associated with fungal nails such as subungual itching and pain from tight shoes have been dramatically reduced. This has also been a boon to my practice as a cash modality that offsets continued reductions in managed care reimbursement. Sincerely, Michael Uro, DPM References 1. Harris DM, J Strisower, B McDowell (2009). Pulsed laser treatment for toenail fungus. SPIE Proceedings 7161A Uro M, Gupta A (2010). Retrospective 6 month study of new laser modality demonstrates improved effectiveness in treating onychomycosis. 20th Fédération Internationale des Podologues (FIP) World Congress of Podiatry 2010, Amsterdam, The Netherlands