Journal of Clinical and Aesthetic Dermatology

DEC 2017

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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19 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY December 2017 • Volume 10 • Number 12 O R I G I N A L R E S E A R C H A Actinic keratosis (AK) is a common skin condition visibly characterized by thickened, cornified, scaly lesions and histologically characterized by atypical epithelial proliferation. 1 AK lesions usually develop on areas of the body that are frequently exposed to the sun (e.g., the face, ears, scalp, neck, forearms, and the back of the hands). 2 AK typically arises in people with fair skin (i.e., in those with Fitzpatrick Types I or II skin). 3 Reported prevalence rates for AK in Europe and the United States are approximately 11 to 25 percent of the population, while estimates in Australia have been reported to be up to 60 percent. 4 Evidence suggests that AK lesions are on a continuum with in situ and invasive squamous cell carcinoma (SCC) 5 and, if left untreated, can develop into SCC, resulting in increased morbidity. 6 Sun-damaged areas of skin can contain fields of cancerization, which are characterized by multiple subclinical and clinically visible AK lesions, along with the presence of multifocal pre-neoplastic changes and genetic mutations. 7 Subclinical AK lesions can progress into clinically visible lesions and/or SCC and new subclinical AK lesions can develop, warranting therapies that treat the entire cancerized field. 6 Invasive SCC can develop from lesions that are limited to the epidermal basal layer (AK 1) or in a stepwise progression along the classical pathway. 8 This is corroborated by histological data reporting that the severity of dysplasia or expression of tumor protein p53 is not predicted by lesion thickness, 9 suggesting that all AKs are equally invasive and should be treated whether subclinical or clinical. Previous trials with ingenol mebutate gel (Picato®; LEO Pharma, Ballerup, Denmark) have demonstrated that treatment over a small area of 25cm 2 provides a high rate of complete clearance as compared with vehicle gel. 10 In addition, ingenol mebutate has a favorable safety profile demonstrated by local skin responses (LSR) that return to baseline levels by Week 4 and mild-to-moderate adverse events (AEs) that resolve without sequelae. However, there are patients who require treatment over an area of field cancerization greater than 25cm 2 . Ingenol disoxate (LEO 43204) gel is a novel ingenol derivative in development for the field treatment of AK; this compound builds on the established chemical, efficacy, A B S T R A C T OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of ingenol disoxate gel using a once- daily, three-day field treatment regimen in patients with actinic keratosis. DESIGN: This was a Phase II, multicenter, open-label trial (clinicaltrials.gov: NCT02305888). SETTING: The study was conducted in 20 trial sites in the United States. PARTICIPANTS: Participants included patients with 5 to 20 clinically typical actinic keratosis lesions on the full face/chest (250cm 2 ), scalp (25–250cm 2 ), or the trunk/extremities (250cm 2 ). MEASUREMENTS: We measured incidence of dose-limiting events based on local skin responses. Percentage reduction in actinic keratosis lesion count from baseline, complete clearance, and partial clearance (≥75%) of actinic keratosis lesions were assessed at Week 8. RESULTS: Nine of 63 (14.3%) patients in the face/chest group reported dose-limiting events; zero of 63 patients in the scalp group reported dose-limiting events; and 11 of 62 (17.7%) patients in the trunk/extremities group reported dose-limiting events. Mean composite local skin response scores peaked at Day 4, then rapidly declined, reaching or approaching baseline levels by Week 4. Less than five percent of patients reported severe adverse events; the most common treatment-related adverse events were application site pain and pruritus. The reduction in actinic keratosis lesion count was 78.9, 76.3, and 69.1 percent for the face/chest, scalp, and trunk/ extremities groups, respectively. Complete clearance was achieved in 36.5, 39.7, and 22.6 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Partial clearance was achieved in 71.4, 65.1, and 50.0 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. CONCLUSION: Ingenol disoxate demonstrated adverse events and local skin reaction profiles similar to results seen in trials evaluating shorter two-day regimens and was effective in patients with actinic keratosis. These data support the use of ingenol disoxate gel for actinic keratosis field treatment. KEYWORDS: Actinic keratosis, ingenol disoxate, safety, efficacy, field treatment Three-day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: A Phase II Trial by DANIEL M. SIEGEL, MD; STEPHEN T YRING, MD, PhD; WALTER K. NAHM, MD, PhD; MARIE LOUISE ØSTERDAL, MSC; ASTRID H. PETERSEN, PhD; and BRIAN BERMAN, MD, PhD Dr. Siegel is with Long Island Skin Cancer and Dermatologic Surgery in New York, New York. Dr. Tyring is with the Center for Clinical Studies in Houston, Texas. Dr. Nahm is with University Clinical Trials, Inc. and the University of California School of Medicine, San Diego in San Diego, California. Dr. Petersen and Ms. Østerdal are with LEO Pharma AS in Ballerup, Denmark. Dr. Berman is with the Center for Clinical and Cosmetic Research in Aventura, Florida. J Clin Aesthet Dermatol. 2017;10(12):19–26 FUNDING: This study was funded by LEO Pharma. DISCLOSURES: Dr. Siegel acknowledges being compensated for lectures and advisory board participation by LEO Pharma within the past two years. Dr. Nahm is an investigator for LEO Pharma. Dr. Petersen and Ms. Østerdal are LEO Pharma em- ployees. Dr. Bermanis a consultant, speaker, and investigator for LEO Pharma. Dr. Tyring has no conflicts of interest relevant to the content of this article. CORRESPONDENCE: Daniel M. Siegel, MD; Email: cyberderm@dermsurg.org

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