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1 June VOLUME 16 ISSUE 6 Copyright 2017 ORIGINAL ARTICLE Journal of Drugs in Dermatology The Efficacy and Safety of Azelaic Acid 15% Foam in the Treatment of Truncal Acne Vulgaris Lauren K. Hoffman BS, a James Q. Del Rosso DO, b and Leon H. Kircik MD c a Albert Einstein College of Medicine, Bronx NY b JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV; Touro University Nevada, Henderson, NV c Indiana University School of Medicine, Indianapolis, IN; Physicians Skin Care, PLLC, Louisville, KY; Icahn School of Medicine at Mount Sinai, New York, NY ABSTRACT INTRODUCTION: Truncal acne is often associated with facial acne, but there are fewer options for an effective topical treatment on the trunk. Given the advent of foam formulations with enhanced percutaneous absorption and convenient application due to easy spreadability on skin, the previously held idea that effective treatment of truncal acne requires oral treatment is challenged. Azelaic acid cream has been previously approved for acne vulgaris, thus azelaic acid foam may be a viable treatment option for truncal acne. STUDY DESIGN: A single-center, open label pilot study was conducted to investigate the efficacy and safety of azelaic acid 15% foam as a treatment modality for moderate truncal acne. Use for facial acne was also allowed and monitored during the study. RESULTS: Twice-daily application of azelaic acid 15% foam to affected areas resulted in a 1-grade reduction in truncal investigator global assessment (IGA) scores in nearly all patients (16/18). Eight out of 18 patients (44%) were rated as Clear or Almost Clear in the trunk by the end of the study. There were also improvements in facial IGA scores; 9 of 18 patients (50%) exhibited a 1-grade improvement in IGA scores and 11 of 18 were Clear or Almost Clear by the end of the study. A significant reduction in lesion counts was found throughout the study and the medication was well tolerated. CONCUSION: Azelaic acid 15% foam was effective in treating moderate truncal acne and facial acne in this pilot study. Given the efficacy and convenience of the foam vehicle, azelaic acid may be considered as a viable option for treatment of acne vulgaris, including on the trunk. Further studies are suggested in a larger population of patients, including adult females with acne. J Drugs Dermatol. 2017;16(6): INTRODUCTION JDD While truncal acne vulgaris is estimated to occur in about 50-60% of patients who also suffer from facial acne vulgaris, often times it is undertreated. 1-2 When confronted about treatment, the majority of patients with truncal acne are in fact interested in receiving therapy. 2 However, the use of topical treatment alone is difficult to implement when using traditional vehicles due to the difficulty of covering large body surface areas. This leaves clinicians to rely on oral therapies over topical interventions because it is assumed that oral medications are more effective. While this line of reasoning may hold up with the use of standard creams and gels, it is challenged with the advent of foam formulations. Foam vehicles have been reported to be associated with enhanced ease of use, better adherence, and consequently improved therapeutic results. 2-5 Azelaic acid (AzA) is available in several different topical formulations. AzA 20% cream was the initial formulation approved by the Food and Drug Administration (FDA) for treatment of inflammatory acne vulgaris.

2 Due to improvements in percutaneous delivery, azelaic acid was reformulated into a 15% gel. Previous investigations have shown the percutaneous penetration of AzA to be approximately 8-fold greater after application of AzA 15% gel compared with AzA 20% cream. 6 It is thought that the new formulation of AzA foam will improve pharmacologic activity due to its rapid dispersal upon application and enhanced percutaneous absorption compared to other vehicle types. 7 Azelaic acid 15% foam (Finacea Foam) is FDA approved for the treatment of papulopustular roasacea in individuals that are 18 years of age or older. The current pilot study focuses on the investigation of the efficacy and safety of azelaic acid 15% foam in the treatment of truncal acne. METHODS Study Design A single, center open label pilot study was conducted to investigate the efficacy and safety of azelaic acid 15% foam as a treatment for moderate truncal acne. Male or female subjects of any race, 12 years of age or older, with truncal acne were potentially eligible for the study. To be enrolled in the study, subjects had to have a truncal acne Investigator Global Assessment (IGA) score of 3 or more (Table 1). Patients were required to be capable of providing informed consent and complying with study instructions. Ke y exclusion criteria included pregnancy, allergy or sensitivity to any component of the test medication, recent use of investigational drugs, and presence of a concurrent medical condition determined by the investigator to potentially interfere with study outcomes or patient assessments. Concomitant medications were allowed

3 at the discretion of the investigator. The use of the following medications were prohibited during the trial and were washed out for an appropriate standardized time period prior to starting treatment: topical retinoids, antibiotics, benzyl peroxide, dapsone, and bleaching agents, oral antibiotics for acne and oral retinoids, cryotherapy, chemical peels, microdermabrasion, and laser resurfacing. Female subjects of childbearing potential had to have a negative urine pregnancy test at baseline and practice a reliable form of birth control during the trial period. If on oral contraceptives, female patients had to be on a stable dose of the same agent for at least 3 months. Informed consent was obtained from all study participants and the study was performed in accordance with Good Clinical Practices, including guidelines outlined by the International Conference on Harmonisation. Treatment was provided in an open label fashion at Baseline. Subjects were instructed to sparingly apply to the affected areas on the trunk twice a day for sixteen consecutive weeks. If facial acne was present, this could also be treated if the patient agreed to this. Subject compliance was assessed at each visit by questioning patients about any missed doses of medication since the previous visit. Efficacy Assessments The primary endpoint of this study was the percent of patients who achieved a one-grade improvement in IGA scores for truncal acne. IGA scores were determined at Baseline and follow-up visits at week 4, week 8, week 12, and week 16. The IGA assessed the current disease severity on the basis of the appearance of the disease at the time of assessment (static assessment) on a five-point scale from 0-clear to 5- very severe disease (Table 1). The percent of patients who achieved clear or almost clear IGA scores for truncal acne was a secondary endpoint. Facial acne vulgaris was also assessed using IGA scores. Other secondary endpoints included inflammatory, non-inflammatory (comedonal) and total lesion counts. Tolerability assessments were also captured. Investigators graded the severity of erythema, dryness, peeling, and oiliness at the time of examination on a four-point scale from 0-absent symptoms to 4-very severe symptoms (Table 2). Subjects were interviewed by the investigator to determine the severity of pruritus and burning at the time of examination on a ve-point scale from 0 normal/ no discomfort to 5 - severe disease (Table 3). These assessments were conducted at all study visits including baseline, week 4, week 8, week 12, and w e e k 1 6. At the final study visit (week 16), patients were given a Patient Preference Questionnaire to compare different skin medications previously used (gel, lotion, cream, ointment, and spray). The questionnaire also asked subjects to rate different qualities of the study medicine (ie, ability to moisturize, lack of residue, greasiness, absorption, ease of

4 application, fragrance, spreadability, and lack of stickiness) and to compare different qualities of the study foam to other skin medications used in the past. Any adverse events (AEs), including those spontaneously reported and those suspected by investigators, were noted at each study visit. Statistical Analysis As this is a pilot study, no formal justification for the sample size of 20 subjects is provided. Statistical analyses were conducted on an intent-to-treat basis, which corresponded to 18 of the 20 study subjects enrolled, as 2 patients withdrew consent from the study prior to the week 16 endpoint. All statistical tests were two-sided and interpreted at a 5% significance level. Descriptive statistics were calculated for all continuous variables and frequencies for all categorical variables collected in this study. Comparisons between efficacy end points and baseline were performed using the Wilcoxon signed-rank test. All statistical analyses were performed using SAS. RESULTS Patient Demographics A total of 20 subjects were enrolled in the study, 9 males and 11 females. Two subjects withdrew consent to participate and four subjects were lost to follow up. A total of 14 subjects completed the 16-week trial. The four subjects lost to follow-up were imputed with the last observation carried forward (LOCF) method. Subjects were enrolled for over four and one-half months, and the last study visit was on 12/12/2016. The mean subject age was 22 years (age range, years). Ten subjects were white, 6 Black, 2 Hispanic, 1 Asian, and 1 mixed race (Table 4). Efficacy Investigator Global Assessment (IGA) Reductions in truncal IGA from Baseline were observed (Table 5). At baseline, 17 subjects had a truncal IGA score of 3 and 1 had a truncal IGA score of 4. Nearly all subjects (16/18) experienced a 1-grade reduction in truncal IGA from Baseline. The two subjects that did not experience a 1-grade improvement were lost to follow up. Eight out of 18 subjects (44%) were Clear or Almost Clear on the trunk by the end of the study. There were also improvements in facial IGA (Table 6). Nine of 18 subjects (50%) experienced a 1-grade improvement from Baseline by week 16 and 61% (11 of 18) were Clear or Almost Clear by week 16. Lesion Counts There were significant reductions in lesion counts within the first 4 weeks, and these reductions further improved through-out the remainder of the treatment. All subjects experienced reductions in inflammatory, non-inflammatory, and total lesion counts by the week 16 visit. Figure 1 details the progression of changes in acne lesion counts. Tolerability, Pruritus, and Burning The medication was well tolerated. There were 7 reports of erythema rated as trace or mild, 1 report of dryness reported as trace, 2 reports of oiliness reported as trace to mild, 3 reports of pruritus rated as trace to mild, and 2 reports of burning rated as mild. In most cases (10 of 15), issues with tolerability, pruritus or burning were resolved by week 8 or 12. There was 1 non-serious adverse event reported; a subject reported headaches of mild intensity at week 10, which were unlikely to be related to the study medication. No serious adverse reactions occurred during the trial.

5 Patient Preference Questionnaire There was roughly equal preference among the different types of delivery methods (gel, lotion, cream, ointment, and spray), although sprays appeared to be preferred somewhat more than the other methods. The study medication compared well to past medicines used by study subjects, with average responses ranging from About the same to Better. Additionally, the individual qualities of the cream were rated on average as Fair to Good. DISCUSSION Nearly all patients (16 of 18) experienced a 1-grade reduction in truncal IGA scores and nearly half of the patients truncal IGA scores were rated as Clear or Almost Clear by study completion. There were also improvements in facial IGA, but not to the same magnitude as the truncal scores. There were significant reductions in lesion counts within the first 4 weeks of treatment and these reductions were further improved throughout the remainder of the treatment. The medication was well tolerated, with minimal reports of erythema, dryness, peeling, oiliness, pruritus, and burning. Results from this pilot study suggest that use of azelaic acid 15% foam is bene cial in the treatment of truncal acne, and also facial acne. Use of foam allows for treatment of an extensive body surface area, which is a critical limitation when treating truncal acne with traditional topical methods. Moreover, foams are a sensible topical treatment due to their ease of spreadability, rapid cutaneous penetration, effective drug delivery, and lack of residue. 3 A long term benefit of using azelaic acid 15% foam for treating truncal acne is to gain effective control of the disease in order to prevent troublesome sequelae such as dyschromia and scarring. DISCLOSURES Lauren Hoffman has no conflicts of interest to disclose. Dr. Del Rosso was one of the investigators on the study presented in this article. He is a researcher, consultant, and speaker for Bayer Dermatology. He also is a researcher, consultant, and/ or speaker for several companies who market and/or develop FIGURE 1 acne products including Allergan, Aqua/Almirall, BiopharmX, Cutanea, Dermira, Galderma, Novan, Promius, Sebacia, SunPharma, and Valeant. Dr Kircik has served either as a consultant, an advisor or a speaker for Bayer, Galderma, Aqua/Almirall, La Roche Posay, Dermira, Allergan, Novan, Valeant, SunPharma, and Promius. This study has been funded by Bayer as an investigator initiated study. REFERENCES 1. Tan, J.K., et al. Prevalence and severity of facial and truncal acne in a referral cohort. J Drugs Dermatol, (6): Del Rosso, J.Q., et al. A closer look at truncal acne vulgaris: prevalence, severity, and clinical significance. J Drugs Dermatol (6): Del Rosso, J.Q., Truncal acne vulgaris: the relative roles of topical and systemic antibiotic therapy. J Drugs Dermatol (2): Del Rosso, J.Q., Management of truncal acne vulgaris: current perspectives on treatment. Cutis (5): Savage, L.J. and A.M. Layton, Treating acne vulgaris: systemic, local and combination therapy. Expert Rev Clin Pharmacol (4): Draelos, Z.D., The rationale for advancing the formulation of azelaic acid vehicles. Cutis (2 Suppl): Del Rosso, J.Q. Using a foam vehicle for dermatologic applications. The Dermatologist. 2002;10. AUTHOR CORRESPONDENCE Lauren Hoffman BS

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