Efficacy and Safety of Ingenol Mebutate 0.015% Gel After Cryosurgery of Actinic Keratosis: 12-Month Results

June 2014 | Volume 13 | Issue 6 | Original Article | 741 | Copyright © June 2014

Brian Berman MD PhD,a Gary Goldenberg MD,b C. William Hanke MD,c Stephen K. Tyring MD PhD,d
Wm Philip Werschler MD,e Kim Mark Knudsen PhD,f Thomas Larsson Dr Med Sci,g and Neil Swanson MDh

aDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
bDepartment of Dermatology, Mount Sinai School of Medicine, New York, NY, USA
cDermatologic Surgery, Laser and Skin Surgery Center of Indiana, Carmel, IN, USA
dDepartments of Microbiology and Immunology, Dermatology and Internal Medicine, University of Texas Health Science Center, Houston, TX, USA
eDepartment of Medicine/Dermatology, University of Washington School of Medicine, Seattle, WA, USA
fBiostatistics and Data Management, LEO Pharma A/S, Ballerup, Denmark
gCentre of Excellence Scientific Affairs, LEO Pharma A/S, Ballerup, Denmark
hDepartment of Dermatology, Oregon Health and Science University, Portland, OR, USA

INTRODUCTION: Recurrence rates of actinic keratosis (AK) lesions after cryosurgery are high, and this treatment does not address field cancerization. We investigated the efficacy and safety of field treatment of AKs with ingenol mebutate gel following cryosurgery.
METHODS: In this phase 3, randomized, double-blind, vehicle-controlled study (NCT01541553), patients ≥18 years with four to eight clinically typical, visible, discrete AKs within a contiguous 25-cm2 treatment area on the face or scalp underwent cryosurgery followed 3 weeks later by once-daily ingenol mebutate 0.015% or vehicle gel for 3 consecutive days. Endpoints included complete clearance at week 11 and safety and efficacy over 12 months.
RESULTS: In 329 randomized patients, complete clearance rates were greater with ingenol mebutate than vehicle (week 11: 60.5% vs 49.4%; P=.04; month 12: 30.5% vs 18.5%; P=.01). Fewer patients experienced the emergence of new lesions with ingenol mebutate than with vehicle (38.9% vs 51.9%; P=.02). At month 12, mean percentage reduction of AKs was higher with ingenol mebutate than with vehicle (68.2% vs 54.1%; P=.002). The probability of remaining free of lesions was sustained longer with ingenol mebutate compared with vehicle gel: 78% vs 68% at 6 months; 64% vs 57% at 9 months; 55% vs 40% at month 12, respectively. Ingenol mebutate 0.015% gel was well tolerated and no unexpected adverse events occurred; all adverse events resolved within 2 weeks of starting treatment.
CONCLUSIONS: Field treatment with ingenol mebutate 0.015% gel following cryosurgery significantly enhanced clearance of baseline lesions, and was well tolerated. Furthermore, ingenol mebutate 0.015% gel following cryosurgery reduced development of new lesions in the treated field.

J Drugs Dermatol. 2014;13(6):741-747.


Actinic keratosis (AK) is one of the most common dermatologic diagnoses that affects individuals ≥40 years (11–50% of the population in the United States and Australia,1 and 11–25% in Europe2,3). AK rates are increasing,4-6 with factors such as thinning of the ozone layer leading to greater UV radiation,7 work-related exposure to the sun over long periods, and increased tanning8 playing their part. Consequently, prevalence rates are higher in countries with high sun exposure and a largely fair-skinned population (typically Fitzpatrick skin type I, II, and III). Histologically, AK is characterized by atypical keratinocytes in the deeper layers of the epidermis, with defective maturation of the superficial epidermis.9 The risk of progression to squamous cell carcinoma (SCC) for AK lesions is estimated to be between 0.025 and 16% per year;10,11 60%–72% of SCCs originate from AK lesions.12
Treatment options include ablation of individual lesions or field therapy to treat AK lesions that are numerous or subclinical in a sun-damaged field.13-15 The major limitation of all lesion- directed therapies is that they fail to address field cancerization. In addition to the visible clinical lesions, there is strong evidence of early neoplastic changes in keratinocytes in surrounding skin that has been subjected to equivalent carcinogenic stimulus.9 Hence, recurrence rates with cryosurgery are high.16Increased awareness of the relationship between AK and SCC has resulted in a new therapeutic approach combining lesion-directed treatments such as cryosurgery with field therapies, particularly topical agents, that treat the entire actinically damaged field.17
Ingenol mebutate gel is a recently introduced topical agent for field-directed treatment of AK,18 approved in the United States,