Emollient CP=clobetasol propionate; IngMeb=ingenol mebutate. Figure 1 was republished with permission of Journal of American Academy of Dermatology from Topical corticosteroid has no influence on inflammation or efficacy after ingenol mebutate treatment of grade I to III actinic keratoses (AK): A randomized clinical trial, Erlendsson AM, et al. J Am Acad Dermatol 2016 Apr;74(4):709-15. Evaluation of Different Approaches in Managing Local Skin Reactions With the Use of Ingenol Mebutate 0.015% and 0.05% During the Treatment of Actinic Keratosis Scott Freeman,1 Miriam Bettencourt,2 Meg Corliss,3 Nikeshia Dunkelly-Allen,3 Karen A. Veverka3 1Spencer Dermatology & Skin Surgery Center, St. Petersburg, FL; 2Department of Dermatology, University of Nevada, Las Vegas, NV; 3LEO Pharma Inc, Madison, NJ, USA Introduction • Actinic keratoses (AKs) are epidermal lesions on the skin caused by damage from chronic exposure to UV rays from the sun and/or indoor tanning1 • AKs have a risk of progressing to invasive squamous cell carcinoma (SCC) if untreated; the majority of clinically diagnosed SCCs originate from concomitant AKs1 • Ingenol mebutate (IMB) (0.015% or 0.05%) gel is a topical AK treatment used to treat AK on the trunk and extremities, but it can elicit local skin reactions (LSRs) at the application site2-4 – LSRs are associated with erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration – Managing LSRs during treatment of AK may be important for treatment adherence and setting patient expectations • Previous clinical data have demonstrated that the treatment burden of LSRs associated with IMB gel is minimal, manageable, and short lasting5 Objective • To perform a systematic review of approaches used for managing or decreasing LSRs during treatment of AK with IMB Materials and Methods • We systematically searched the electronic databases PubMed and Medline to identify all relevant records through August 2019 • Search terms included “ingenol mebutate,” “ambulatory care facilities,”“actinic keratosis,” “therapy,” and “LSR” – All relevant clinical studies in humans examining the clinical utility of IMB were included – Scientific review articles, as well as studies not published in English, were excluded – There were no limitations for date of publication • The literature search returned 49 results – Titles, abstracts, and full text articles of the search results were screened for relevance – 6 studies were identified for in-depth analysis Results • The 6 studies selected for the analysis represented a range of study designs (Table 1) – Retrospective chart reviews1,6,7 n=3 – Randomized controlled trial8 n=1 – Investigator-initiated single-blinded study9 n=1 – Observational longitudinal cohort study10 n=1 • The 6 studies examined a total of 1437 patients; 1424 patients were evaluated for LSRs associated with IMB • 3 of the studies only examined the resolution of LSRs over time in the absence of any intervention6,7,10 • The other studies evaluated different approaches in managing or minimizing LSRs during the treatment of AK – Use of various topical moisturizers1,2,10 – Implementing a low-dose regimen of IMB6 – Application of dimethicone9 – Application of clobetasol propionate8 In-Depth Analysis of Individual Studies Erlendsson AM et al, 2016 • In a blinded, randomized controlled trial, Erlendsson AM et al, treated patients with multiple AKs on the face and scalp with IMB daily for 3 days8 • For each patient, 1 of 2 areas was randomized to receive topical clobetasol propionate (0.05%) twice daily for 4 days to treat LSRs, while the other area was left untreated • LSR rates in patients treated with IMB were: – Erythema (100%) – Flaking (100%) – Crusting (91%) • Areas randomized to receive clobetasol propionate had no benefit over untreated areas in reducing LSRs and their associated pain and pruritis (Figure 1) – By 2 weeks after treatment initiation, LSRs had returned to baseline both in areas treated with IMB (0.67) and in areas treated with IMB + clobetasol propionate (0.38; P=.250) Jim On SC et al, 2017 • Jim On SC, et al, studied 20 patients with multiple facial AKs being treated with IMB gel, 0.015%9 • 1% dimethicone lotion was applied once daily to 1 of 2 areas on the face containing 3-8 AKs in an investigator-blinded manner • LSRs included the following and were graded on a scale from 0 (no reaction) to 4 (severe reaction) – Erythema – Flaking/Scaling – Swelling – Vesiculation/Pustulation – Erosion/Ulceration • Dimethicone lotion with IMB had no significant effect on LSR severity over treatment with IMB alone (Figure 2) Figure 2. Mean LSR scores in patients treated with IMB vs IMB + 1% dimethicone9 0 1 2 3 4 5 6 7 8 9 10 11 2 4 8 15 29 57 M ea n (± SE ) L SR T ot al S co re Day IMB Only IMB + Dimethicone SE=standard error. Figure 2 republished with permission of Journal of Drugs in Dermatology from Assessment of Efficacy and Irritation of Ingenol Mebutate Gel 0.015% Used With or Without Dimethicone Lotion for Treatment of Actinic Keratosis on the Face, Jim On SC, et al. J Drugs Dermatol. 2017; 16(5):432-436. Neri L et al, 2017 • Neri L et al, conducted an observational, multicenter, longitudinal cohort study in 1136 adult patients with multiple grade I/II AKs10 • LSRs were assessed at 2 follow-up visits: – T1: 8 days after initiation of AK treatment – T2: 25-30 days after initiation of AK treatment • Approximately 37% of patients received treatment for LSRs at T1 – 53% received topical antibiotics – 47% received emollient creams • Roughly 14% received treatment at T2 – 70% received emollient creams – 29% received antibiotics • There was a steep decrease in average LSR score (scale=0-4) from the first follow-up visit (2.6±1.5) to the second follow-up visit (0.9+1.0), which was seen in both LSR-treated and untreated groups Bettencourt MS, 2016 • Bettencourt MS conducted a study at a community dermatology practice in 78 male patients with recurring and relapsed scalp AK2 • All patients exhibited LSRs on the first day of treatment – Erythema (100%) – Flaking/Scaling (97%) – Crusting (66%) – Swelling (6%) – Vesiculation/Pustulation (32%) – Erosion/Ulceration (13%) • 44% of the patients treated their LSRs with a topical product (Figure 3) • LSRs were resolved in 10-14 days regardless of the use of a topical product – In 1 patient, LSRs were resolved at day 20 Bettencourt MS, 2014 • Bettencourt MS conducted a retrospective chart review of 135 patients who had a prolonged history of AKs treated with IMB7 • Regardless of body area or use of LSR treatment, most patients had developed LSRs by day 2 of treatment (Table 2) • Most patients used no additional treatment for their LSRs – Face: 83% used no treatment vs 17% used additional treatment – Scalp: 85% used no treatment vs 15% used additional treatment – Trunk/Extremities: 92% used no treatment vs 8% used additional treatment Bettencourt MS, 2014 (cont’d) Table 2. LSR Incidence and Resolution by Severity7 Erythema Flaking/Scaling Crusting Resolution of LSRs Without Treatment Mild Moderate Mild Moderate Mild Moderate Severe Mild, Moderate, & Severe Face (n=72) 72% 28% 75% 25% 19% 7% 1% 60/72 (83.3%) Scalp (n=72) 73% 33% 34% 66% 7% 5% 0% 35/41 (85.4%) Trunk/ Extremities (n=24) 75% 4% 0% 8% 13% 4% 0% 22/24 (91.7%) • LSRs improved by 1 week after peak inflammation, despite being untreated in most patients7 • LSRs may resolve over time without the need for additional treatment Joe HJ et al, 2017 • Joe HJ et al, retrospectively evaluated patients with AK treated with normal (recommended-amount) or low-dose (low-amount) IMB6 • Recommended-amount group (RAG) 18.8 mg/cm2 (n=20) • Low-amount group (LAG)a 10 mg/cm2 (n=27) • Although the low-dose IMB produced a significantly lower LSR score, the mean AK clearance rate in the RAG was significantly greater than that of the LAG – Maximum composite LSR score, mean ± SD: 15.45 ± 2.70 in the RAG vs 12.18 ± 3.29 in the LAG, P<.001 – Maximum pain score (VAS), mean ± SD: 7.95 ± 0.99 in the RAG vs 6.55 ± 1.42 in the LAG, P<.001 – AK clearance rate, mean ± SD: 88.16 ± 12.30 in the RAG vs 75.56 ± 9.44 in the LAG, P<.001 – AK clearance rate (%), range: 66.67-100 in the RAG vs 63.64-100 in the LAG, P<.001 Clearance rate = (the number of AKs decreased after treatment/the number of AKs before treatment) x 100 (%); P value, independent samples test. VAS=visual analog scale; SD=standard deviation. aDose used in the LAG is lower than the approved labelling for IMB. Conclusions • Topical application of IMB gel in patients with AK elicits LSRs at the application site • Based on available literature, LSRs in most patients treated with IMB resolve spontaneously over time without the need for additional treatment – Evidence is lacking to support a singular strategy for reducing or preventing IMB-induced LSRs – Studies evaluating the role of topical lotions, antibiotics, or moisturizers to treat LSRs found that these treatments provided no significant benefit in improving LSR severity over treatment with IMB alone • After treatment with IMB gel, 0.015% or 0.05%, LSRs only peak in intensity up to 1 week following treatment completion, and resolve spontaneously in 2-4 weeks without treatment3 – Therefore, LSRs are unlikely to influence patients’ adherence behavior to IMB – An understanding that LSRs typically resolve spontaneously over time may help manage patient expectations and improve patient satisfaction References 1. Berman B, Cohen DE, Amini S. What is the role of field-directed therapy in the treatment of actinic keratosis? Part 1: Overview and investigational topical agents. Cutis. 2012;89(5):241-250. 2. Bettencourt MS. Tolerability of ingenol mebutate gel, 0.05%, for treating patients with actinic keratosis on the scalp in a community dermatology practice. J Clin Aesthet Dermatol. 2016;9(3):20-24. 3. Picato (ingenol mebutate) gel 0.015%, 0.05% [package insert]. Madison, NJ: LEO Pharma Inc.; 2019. 4. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010-1019. 5. Hanke WC, Norlin JM, Mark Knudsen K, et al. Quality of life in treatment of AK: treatment burden of ingenol mebutate gel is small and short lasting. J Dermatolog Treat. 2016;27(5):450-455. 6. Joe HJ, Oh BH. Ingenol mebutate in low amounts for the treatment of actinic keratosis in Korean patients. Clin Cosmet Investig Dermatol. 2017;10:93-98. 7. Bettencourt MS. Use of ingenol mebutate gel for actinic keratosis in patients in a community dermatology practice. J Drugs Dermatol. 2014;13(3):269-273. 8. Erlendsson AM, Karmisholt KE, Haak CS, et al. Topical corticosteroid has no influence on inflammation or efficacy after ingenol mebutate treatment of grade I to III actinic keratoses (AK): a randomized clinical trial. J Am Acad Dermatol. 2016;74(4):709-715. 9. Jim On SC, Hashim PW, Nia JK, Lebwohl MG. Assessment of efficacy and irritation of ingenol mebutate gel 0.015% used with or without dimethicone lotion for treatment of actinic keratosis on the face. J Drugs Dermatol. 2017;16(5):432-436. 10. Neri L, Peris K, Longo C, et al; Actinic Keratosis — TReatment Adherence INitiative (AK-TRAIN) study group. Physician-patient communication and patient-reported outcomes in the actinic keratosis treatment adherence initiative (AK-TRAIN): a multicenter, prospective, real-life study of treatment satisfaction, quality of life and adherence to topical field-directed therapy for the treatment of actinic keratosis in Italy. J Eur Acad Dermatol Venereol. 2019;33(1):93-107. Disclosures Dr. Freeman is an advisor and has received honoraria from Foamix Pharmaceuticals Inc, Castle Biosciences, Galderma USA, LEO Pharma Inc and Novartis; he participates in speaker bureaus and has received honoraria from Foamix Pharmaceuticals Inc, LEO Pharma Inc and Novartis. Dr. Bettencourt is an advisor and has received honoraria from Bristol Myers Squibb; she participates in speaker bureaus and has received honoraria from AbbVie, Almirall, Celgene, LEO Pharma Inc, Ortho Dermatologics, Pfizer and Sun Pharmaceuticals. Drs. KA Veverka, N Dunkelly-Allen and M Corliss are employees of LEO Pharma Inc. Funding This study was funded by LEO Pharma. Acknowledgments Editorial support funded by LEO Pharma Inc was provided by p-value communications. Poster No. 16258 Reference Study Design Number of Patients in Study Number of Patients Evaluated for LSRs Treatment for LSRs Used Conclusions 1 Erlendsson AM et al. J Am Acad Dermatol. 2016;74(4):709-715. Randomized controlled trial 21 21 Clobetasol propionate, twice daily for 4 days, to one of 2 areas on the face or scalp Patients randomized to receive clobetasol propionate had no benefit over untreated patients in reducing LSRs and their associated pain and pruritus 2 Jim On SC. J Drugs Dermatol. 2017;16(5):432-436. Investigator-initiated single-blinded study 20 20 1% dimethicone lotion, applied once daily to one of 2 areas on the face containing 3-8 AKs Dimethicone lotion with IMB had no significant effect on LSR severity over treatment with IMB alone 3 Neri L et al. J Eur Acad Dermatol Venereol. 2019;33(1):93-107. Observational longitudinal cohort study 1136 420 during first 8 days; 149 during follow-up Follow-up 1 • Emollient creams: 47% • Topical antibiotics: 53% Follow-up 2 • Emollient creams: 70% • Antibiotics: 29% There was a steep decrease in average LSR score (0-4) from the first follow-up visit (2.7±1.4) to the second follow-up visit (0.8±0.8), which was seen in both LSR-treated and untreated groups 4 Bettencourt MS. J Clin Aesthet Dermatol. 2016;9(3):20-24. Retrospective chart review 78 65 34 of 78 treated their LSRs with: Moisturizers (n=16) Neosalus hydrating cream (n=9) Skin barrier emollient cream (n=3) Antipruritic hydrogel (n=3) Petrolatum-based cream (n=2) Dimethicone-based cream (n=2) Anti-itch hydrogel (n=1) LSRs were resolved by 10-14 days in 98% of patients evaluated regardless of their use of moisturizers or emollients • In 1 patient, LSRs resolved by day 20 5 Bettencourt MS. J Drugs Dermatol. 2014;13(3):269-273. Retrospective chart review 135 total Face (n=77) Scalp (n=45) Trunk (n=32) Face (n=72) Scalp (n=41) Trunk (n=24) No treatment: 26% Moisturizers & creams: 4% Oral prednisone & tacrolimus 0.1%: 1 patient LSRs were cleared 1 week after peak inflammation in most patients, independent of treatment with moisturizers, creams, or oral prednisone and tacrolimus 6 Joe HJ, Oh BH. Clin Cosmet Investig Dermatol. 2017;10:93-98. Retrospective chart review 47 47 None Below-recommended dosing of IMB (10 mg/cm2) significantly reduced LSR score and pain score but was associated with a significantly lower AK clearance rate vs recommended dose IMB (18.8 mg/cm2) Presented at the 2020 American Academy of Dermatology, Annual Meeting, Denver, Colorado, March 20-24, 2020. Table 1. Profile of Studies Evaluating Management of LSRs With the Use of IMB in Treating AK Dimethicone-based emollient cream [CeraVe – L’Oréal Group] 3% Antipruritic hydrogel [Exeltis USA] 4% Skin barrier emollient cream [Encore Dermatology, Inc.] 4% Neosalus hydrating topical cream [Quinnova Pharmaceuticals LLC] 12% Anti-itch hydrogel [Valeant Pharmaceuticals International] 1% Moisturizers 21% No Treatment 56% Petrolatum-based emollient cream [Galderma Laboratories] 3% Figure 3. Treatments used for LSRsFigure 1. Development of LSRs in a patient treated with IMB with or without clobetasol propionate – Swelling (91%) – Vesiculation (69%) – Erosion (29%)