Darrell Rigel MD, MS1; Mark Lebwohl MD1; Todd Schlesinger MD2; April Armstrong MD3; Brian Berman MD, PhD4; Neal Bhatia MD5; James Del Rosso DO6; Leon Kircik MD1; Vishal A. Patel MD7; Siva Narayanan PhD8; Volker Koscielny MD9; Ismail Kasujee PhD9 1Mount Sinai Icahn School of Medicine, New York, NY, USA; 2Clinical Research Center of the Carolinas, Charleston, SC, USA; 3Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 4University of Miami Miller School of Medicine, Miami, FL, USA; 5Therapeutics Clinical Research, San Diego, CA, USA; 6JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV, USA; 7George Washington School of Medicine and Health Sciences, Washington, DC, USA; 8Avant Health LLC, Bethesda, MD, USA; 9Almirall SA, Barcelona, Spain. IMPACT OF ACTINIC KERATOSIS ON PATIENT-REPORTED AK SYMPTOMS, EMOTIONS AND FUNCTIONING MEASURED USING SKINDEX-16, AMONG PATIENTS WITH ACTINIC KERATOSIS ADMINISTERED TIRBANIBULIN IN REAL-WORLD COMMUNITY PRACTICES ACROSS THE U.S. (PROAK STUDY) Objectives: Objective of the analysis is to evaluate changes in patient- reported AK symptoms, emotions and functioning, among patients with AKs treated with tirbanibulin in community practices across the U.S. Methods: A single-arm, prospective cohort study (PROAK) was conducted among adult patients with AKs on the face or scalp who were newly initiated with tirbanibulin treatment in real-world community practices in the U.S, as part of usual care. Patients and clinicians completed surveys and clinical assessments at baseline, week-8 (timeframe for main endpoints) and week-24. Skindex-16, completed at baseline and week-8, is a 16-item survey with 3 domains: symptoms (items 1-4), emotions (items 5-11) and functioning (items 12-16), with each item scored on a seven-point adjectival response scale, with a potential score of 0 (never bothered) to 6 (always bothered). Changes from baseline in proportion of patients reporting a score of 0 or 1 (never or least bothered; i.e., least disease burden) was analyzed for all Skindex-16 items at week-8. Results: A total of 290 patients with AKs completed the study assessments at week-8 (female: 31.38%; Fitzpatrick skin type: I: 7.59%, II: 71.38%, III: 18.62%, IV: 1.38%, V: 1.03%). Patient self-reported skin- texture was – dry: 39.66%, smooth: 47.59%, rough: 19.66%, bumpy: 18.62%, scaly: 35.17%, blistering/peeling: 6.55%. Within symptoms domain of Skindex-16 related to itching, burning/stinging, hurting, and irritation, proportion of patients reporting “never or least bothered” increased significantly for each item at week-8 (p<0.0001). Within emotions domain of Skindex-16 related to persistence of condition, worries about skin, appearance, frustration, embarrassment, being annoyed, and feeling depressed, proportion of patients reporting “never or least bothered” increased significantly for each item at week-8 (p<0.0001). Within functioning domain of Skindex-16 related to interactions with others, desire to be with others, show affection, effect on daily activities, and effect on work or enjoyable activities, proportion of patients reporting “never or least bothered” increased significantly for each item at week-8 (p<0.0001). Conclusion: Patients with AKs who used once-daily tirbanibulin treatment for 5-days reported a significant reduction in the AK burden, as indicated by the improvement in AK symptoms and emotional/functional impact, at week-8. SYNOPSIS CONCLUSIONS • Patients with AKs who used once-daily tirbanibulin treatment for 5-days reported a significant reduction in AK burden, as indicated by the improvement in AK symptoms and emotional/functional impact, at week-8. • The demonstrated effectiveness and the safe and tolerable profile of once-daily tirbanibulin treatment highlights the benefits associated with this novel therapeutic option in routine community practice settings, for optimal management of AKs. METHODS • A single-arm, prospective cohort study (PROAK) was conducted among adult patients with AKs on the face or scalp who were newly initiated with once-daily tirbanibulin treatment (5-day course) in real-world community practices in the U.S, as part of usual care. • A total of 300 subjects were enrolled from 32 community practices across the U.S. • Patients and clinicians completed surveys and clinical assessments at baseline, week-8 (timeframe for main endpoints) and week-24, concerning safety and effectiveness of tirbanibulin. • Skindex-16, a validated PRO instrument, was completed by patients at baseline and Week-8. • This 16-item survey has 3 domains, namely, symptom domain (4 items), emotions domain (7 items) and functioning domain (5 items). • All items are scored on a seven-point adjectival response scale, with a potential score of 0 (never bothered) to 6 (always bothered). • Changes from baseline in proportion of patients reporting a score of 0 or 1 (never or least bothered; i.e., least disease burden) was analyzed for each of the Skindex-16 items at week-8. OBJECTIVE • Actinic Keratosis (AK) has been shown to negatively affect emotional functioning and skin-related quality of life of patients1. Impact of tirbanibulin treatment in alleviating AK disease burden in patients with AKs is not adequately understood. Objective of the analysis is to evaluate changes in patient-reported AK symptoms, emotions and functioning, among patients with AKs treated with tirbanibulin in community practices across the U.S. Reference: 1. Br J Dermatol. 2013;168(2):277-283. • PROAK study (NCT05260073) was initiated in 2022, with more than 75% of the study patients treated with tirbanibulin between April and August of 2022. • Out of 300 enrolled patients, a total of 290 patients with AKs completed the study assessments at Week-8, and hence included in the analyses. • All patients (100%) completed their 5-day once-daily treatment course. • Ten patients were not included in the week-8 analyses: 1 patient had missing data, and 9 patients were discontinued from the study due to patient voluntary withdrawal of consent or lost to follow-up. • No discontinuations were related to adverse drug reactions (ADRs), and there were no Serious ADRs reported at week-8. RESULTS In comparison to baseline: *p<0.001. Patient’s AK burden significantly reduced over the 8-week tirbanibulin treatment period, as indicated by the SKINDEX-16 responses. 53.29% 82.35% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 89 ) Reporting ‘never or least bothered’ SK1: Over the past week, how often have you been bothered by itching? CFB: 29.07%* 34.15% 75.00% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 84 ) Reporting ‘never or least bothered’ SK5: Over the past week, how often have you been bothered by persistence/recurrence of skin condition? CFB: 40.85%* 33.10% 76.66% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N = 28 7) Reporting ‘never or least bothered’ SK6: Over the past week, how often have you worried about your skin condition spreading, worsening, scarring (etc.)? CFB: 43.55%* 33.68% 75.79% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 85 ) Reporting ‘never or least bothered’ SK7: Over the past week, how often have you been bothered by the appearance of your skin condition? CFB: 42.10%* SKINDEX-16 Symptoms Domain 55.52% 87.54% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 81 ) Reporting ‘never or least bothered’ SK9: Over the past week, how often have you been embarrassed by your skin? CFB: 32.02%* 39.34% 79.41% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 72 ) Reporting ‘never or least bothered’ SK8: Over the past week, how often have you been frustrated by your skin? CFB: 40.07%* 43.11% 78.80% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 83 ) Reporting ‘never or least bothered’ SK10: Over the past week, how often have you been annoyed about your skin? CFB: 35.68%* 73.52% 90.24% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 87 ) Reporting ‘never or least bothered’ SK11: Over the past week, how often have you been feeling depressed about your skin condition? CFB: 16.75%* SKINDEX-16 Emotions Domain 77.92% 91.41% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 86 ) Reporting ‘never or least bothered’ SK13: Over the past week, how often has your desire to be with people been affected by your skin condition? CFB: 17.48%* 71.86% 90.91% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 86 ) Reporting ‘never or least bothered’ SK12: Over the past week, how often has your interactions with others been affected by your skin condition? CFB: 19.23%* 87.19% 98.22% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 81 ) Reporting ‘never or least bothered’ SK14: Over the past week, how often has skin condition made it hard to show affection? CFB: 11.03%%* 73.52% 91.64% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 87 ) Reporting ‘never or least bothered’ SK15: Over the past week, how often has your skin effected your daily activities CFB: 18.12%* 80.35% 91.93% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 85 ) Reporting ‘never or least bothered’ SK16: Over the past week, how often has skin condition made it hard to work or do what you enjoy? CFB: 11.75%* SKINDEX-16 Functioning Domain Table 1: Baseline Patient Characteristics N=290 Age, mean years [min, max] 66.30 [30.00, 90.00] Gender, % FemaleMale 31.38 68.62 Primary health insurance, % Private Insurance Medicaid Medicare Uninsured 41.72 3.10 53.79 1.38 History of skin cancer, % 61.72 Fitzpatrick skin type, % Type I Type II Type III Type IV Type V 7.59 71.38 18.62 1.38 1.03 Baseline patient self- reported skin-texture, % Dry Smooth Rough Bumpy Scaly Blistering Peeling 39.66 47.59 19.66 18.62 35.17 0.34 6.21 Baseline severity of skin photodamage in AK affected area, % Absent Mild Moderate Severe 1.03 21.38 56.55 20.34 Table 2: Site Characteristics N=32 Current workplace: Private, office-based practice, % 100 Total number of board-certified dermatologists in the clinic/practice, Mean 3.53 Number of patients with AKs managed by the clinic in a given month, Mean 136.34 Number of years practicing dermatology, Mean 15.66 77.51% 91.35% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 88 ) Reporting ‘never or least bothered’ SK2: Over the past week, how often have you been bothered by Burning or Stinging? CFB: 13.54%* 52.84% 84.04% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 82 ) Reporting ‘never or least bothered’ SK4: Over the past week, how often have you been bothered by your skin condition being irritated? CFB: 31.21%* 80.34% 94.29% 0.00% 100.00% Baseline Week - 8 P ro po rti on o f p at ie nt s (N =2 80 ) Reporting ‘never or least bothered’ SK3: Over the past week, how often have you been bothered by your skin condition hurting? CFB: 13.93%*