A SUPPLEMENT TO This supplement is supported by LEO Pharma Inc. Treatment of Actinic Keratosis With Picato® (ingenol mebutate) Gel Stephen K. Tyring, MD, PhD Clinical Professor Departments of Dermatology, Microbiology and Immunology, and Internal Medicine University of Texas Health Science Center Houston, Texas INTRODUCTION Actinic keratoses (AK) are precancerous keratinocytic lesions caused by overexposure to ultraviolet radiation.1 Actinic keratoses are confined to the epidermis, and have variable presentation. Actinic keratoses may present as rough, dry, or scaly patches of skin, horny growths, and may be pigmented or skin-toned. Lesions vary in size and may have clearly defined and/or diffuse margins. Itching, burning, and tenderness may be present around the lesion.2 Multiple lesion types may be present in a single patient, and nonvisible lesions—known as subclinical lesions— are common, especially in sun-damaged skin.3 Subclinical lesions, like visible lesions, have focal areas of abnormal keratinocyte proliferation and differentiation. All AK lesions have the potential to evolve into squamous cell carcinoma (SCC) and warrant treatment.1,3-5 In the United States, AK is the second most common reason for visits to dermatologists.2 It is most prevalent among light-skinned peoples, with Caucasian men having the greatest risk, along with immunocompromised individuals, and those with mutations to the p53 tumor suppressor gene. Cumulative sun exposure, however, is the primary cause of AK.2,6 The age-adjusted prevalence in the United States is estimated at 6.5%, but it is much higher among specific age groups. For example, among those aged 60 to 69 years, 83% of men and 64% of women have at least 1 lesion.2 In total, 58 million individuals are estimated to have at least 1 lesion during a calendar year, and 26 million (≈45%) of these individuals are aged ≥65 years.2 In 2004, AK was associated with annual direct costs of approximately $1.2 billion, the vast majority of which ($1 billion or 92%) was accounted for by in-office treatments and prescription drugs ($60 million or 5%).2 Indirect costs from lost productivity were estimated at $295 million.2 Although AK does not pose immediate health risks, these lesions, over time, are associated with progression to SCC, but it is impossible to accurately predict which AK lesions are mostly like to convert to cancer.1-3,7 Therefore, treatment of all AK lesions is recommended, and a variety of topical and nontopical treatment options are available, making patient-tailored treatment strategies possible.6 This supplement will focus on topical treatment options, specifically Picato® (ingenol mebutate) gel, the most recent US Food and Drug Administration (FDA)-approved treatment. TREATMENT OPTIONS FOR ACTINIC KERATOSIS When selecting treatment for AK, a variety of factors require consideration, such as the size, location, and duration of lesions; patient’s age and medical history; DISCLOSURES: Dr. Tyring discloses that he has conducted clinical research and given presentations sponsored by LEO Pharma Inc., the manufacturer of Picato®. costs of treatment; physician’s familiarity and comfort with specific treatments; and the patient’s personal preference. Lesion-directed treatment options, such as cryosurgery (the most widely used treatment option in the United States), produce high cure rates for individual lesions.3,6 However, when treating patients with multiple lesions over large swaths of skin or when subclinical lesions are suspected, field-directed therapy with topical agents may be more appropriate.3 Nevertheless, although the number of subclinical lesions may be 10 times higher than visible lesions in a single patient, a 2004-2005 survey of 293 dermatologists found that 74% of patients receive only lesion-directed therapy (usually cryosurgery), 16% field-directed therapy alone, and only 10% received both (sometimes known as sequential therapy).3 Multiple topical treatments are available for AK. These include various formulations of 5-fluorouracil (5-FU), imiquimod cream 5%, 3.75%, and 2.5%, and diclofenac sodium gel 3%. These topical treatments are generally associated with complete clearance rates of about 50% and partial response rates of about 70%.3 However, these agents are limited by prolonged application periods and the potential for severe local skin reactions, especially with 5-FU, which may limit adherence and, therefore, outcome (Table 1).8-13 For example, cure rates with 5-FU may reach TABLE 1 Application Frequency and Duration of Treatment With Topical Actinic Keratosis Therapies Treatment Application Frequency Duration of Treatment 5-FU 0.5%8 Once daily Up to 4 weeks 5-FU 5%9 Twice daily 2-4 weeks Imiquimod 2.5%, 3.75%10 Once daily 6 weeks (2 weeks on, 2 weeks off, 2 weeks on) Imiquimod 5%11 Twice weekly 16 weeks Diclofenac sodium 3%12 Twice daily 60-90 days Ingenol mebutate gel 0.015% (Picato®)13 Once daily 3 days Ingenol mebutate gel 0.05% (Picato®)13 Once daily 2 days 93% when used completely and correctly, but unfortunately, many patients discontinue treatment early because of adverse events, leading to failure rates of up to 60%.3,6 Picato® (ingenol mebutate) gel, an inducer of cell death indicated for the topical treatment of AK, is the newest topical treatment for AK, approved by the FDA in 2012.13 The application periods of ingenol mebutate’s formulations are substantially shorter than other available treatments: for the face and scalp, the 0.015% formulation is applied once daily for 3 consecutive days; for the trunk and extremities, the 0.05% formulation is applied once daily for 2 consecutive days.13 The shorter treatment periods with Picato® may improve patient adherence and outcome.3 proximately 1 gram of Picato® gel 0.05% was applied to an area 100 cm2 of the dorsal forearm once daily for 2 consecutive days. Blood levels of Picato® and its 2 metabolites were below the lower limit of quantification in all patients.13 The safety and efficacy of Picato® were evaluated in 4 randomized, vehiclecontrolled studies in 2008 and 2009. All patients enrolled were at least 18 years of age and had 4 to 8 visible AK lesions within a 25-cm2 contiguous field on the face or scalp or trunk or extremities.7 Two stud- FIGURE 1 Picato® Gel: Cell Death Within Hours TREATMENT WITH PICATO® GEL Picato® is derived from the Euphorbia peplus plant and has long been used in the treatment of cutaneous lesions, including skin cancers.7 Ingenol mebutate’s mechanism of action in the resolution of AK lesions is unknown, but it is believed to induce direct cell death via mitochondrial swelling of precancerous cells and also a secondary immune response via activation of protein kinase C delta (Figure 1 and Figure 2).3,7,13 Systemic absorption of Picato® is nondetectable and was assessed in 2 studies with a total of 16 patients. In both studies, ap2 TREATMENT OF ACTINIC KERATOSIS WITH PICATO® (INGENOL MEBUTATE) GEL ies (N = 547) randomized patients with face or scalp lesions to Picato® 0.015% (n = 277) or vehicle (n = 270). The 2 other trials (N = 458) randomized patients with lesions on the trunk or extremities to Picato® 0.05% (n = 226) or vehicle (n = 232). In all studies, safety endpoints included local skin reactions (LSR), pigmentation, and scarring evaluated at days 3 (trunk or extremity lesions) or 4 (face and scalp lesions), and days 8, 15, 29, and 57. The primary efficacy endpoint for all studies was the complete clearance rate in FIGURE 2 Picato® Gel: Immune Response Within Days the treatment area at day 57. The secondary efficacy endpoint was partial clearance, defined as a 75% or more reduction in the number of visible lesions, at day 57. In the face and scalp studies combined, the partial clearance rates with Picato® and vehicle were 63.9% and 7.4%, respectively (P < .001). The complete clearance rates were 42.2% versus 3.7%, respectively (P < .001). Overall, in the Picato® arm, there was a median 83% reduction from baseline in the number of AK lesions versus no reduction in those treated with vehicle.7 In the trunk and extremity combined studies, partial clearance rates with Picato® and vehicle were 49.1% vs 6.9%, respectively (P < .001). Complete clearance was achieved by 34.1% of ingenol mebutate-treated patients versus 4.7% in vehicle-treated patients (P < .001). The mean number of AK lesions was reduced by 75% with Picato® vs 0% with vehicle.7 Safety was evaluated quantitatively using a 4-point LSR grading scale. Patients were scored for 6 responses: erythema, flaking or scaling, crusting, swelling, vesiculation or pustulation, and erosion or ulceration. Scores were summed for a composite LSR at each follow-up visit. In the face and scalp studies, the mean maximum composite LSR in ingenol mebutate-treated patients was 9.1 versus 1.8 among vehicle-treated patients. The composite score peaked at day 4 for most patients and then rapidly declined, returning to baseline at 2 weeks. Application site reactions were the most common adverse event, occurring in 19% and 2.6% of ingenol mebutate- and vehicle-treated patients, respectively. Other adverse events are shown in Table 2. Only 1 patient (0.4%) in each arm discontinued treated because of an adverse event.7 In the trunk and extremity studies, the mean maximum composite LSR were 6.8 and 1.6 for Picato® and vehicle, respec- TABLE 2 Adverse Events Occurring in >2% of the Study Population Face & Scalp Studies Picato® 0.015% (n=274) Vehicle (n=271) Trunk & Extremities Studies Picato® 0.05% (n=225) Vehicle (n=232) Number of patients (percent) Any adverse event 102 (37.2) 60 (22.1) 8 (3.6) 12 (5.2) 52 (19) 7 (2.6) 27 (12) 6 (2.6) 22 (8) 3 (1.1) 19 (8.4) 0 38 (13.9) 1 (0.4) 5 (2.2) 0 Application site irritation 5 (1.8) 0 8 (3.6) 1 (0.4) Application site infection 7 (2.6) 0 0 1 (0.4) 2.6 0 0 0 6 (2.2) 3 (1.1) 1 (0.4) 0 Any application site event Application site pruritus Application site pain Periorbital edema Headache TREATMENT OF ACTINIC KERATOSIS WITH PICATO® (INGENOL MEBUTATE) GEL 3 tively. Composite LSR were highest at days 3 or 8 for most patients (55.1% and 32.4%, respectively), with some patients peaking at day 15 (8.4%), returning to baseline values at 4 weeks. Application site reactions were the most common adverse events (12% with Picato® vs 2.6% with vehicle), and no serious adverse events leading to treatment discontinuation were reported (Table 2).7 SEQUENTIAL TREATMENT WITH CRYOSURGERY AND PICATO® GEL A phase III, multicenter, randomized, double-blind study examined the efficacy and safety of Picato® after cryosurgery as part of sequential treatment for AK.14 All patients (N=329) received cryosurgery with liquid nitrogen and were randomized to receive treatment with Picato® 0.015% gel (n=167) or vehicle (n=162) 3 weeks thereafter. The study results demonstrated that complete clearance rates were greater with Picato® compared with vehicle at 11 weeks after cryosurgery (60.5% vs 49.4%, respectively) and at 12 months (30.5% vs 18.5%, respec- tively).15 Picato® also demonstrated a greater reduction in the number of AK lesions compared with baseline at 11 weeks (82.7% vs 75.6%, respectively) and at 12 months (68.2 vs 54.1, respectively).15 Treatment with Picato® after cryosurgery was well tolerated. TALKING WITH PATIENTS ABOUT PICATO® GEL Prevention is the best treatment of AK and skin cancer. Patients should be advised to avoid sun exposure, and to wear sunscreens and protective hats and clothing. When prescribing Picato®, it is important that patients understand the need for treatment and, more specifically, the need for field-directed therapy. Physicians should explain to patients that AK are precursors to SCC, but that it is not possible to predict which specific lesions—those that are visible and not-yet-visible—will convert to malignancy. To prevent cancer, the safest course is to treat all AK lesions, both visible and subclinical. To ensure that patients complete treatment, thereby creating the greatest po- REFERENCES 1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratosis: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523-2530. 2. Lewin Group. The burden of skin diseases: 2005. http://www.lewin.com/~/ media/Lewin/Site_Sections/Publications/april2005skindisease.pdf. Accessed May 12, 2014. 3. 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. 4. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers RP. Frequency of preexisting actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol. 1998;37(9):677-681. 5. Czarnecki D, Meehan CJ, Bruce F, Culjak G. The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg. 2002;6(3):207-209. 6. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol. 2000;42(1 pt 2):S25-S28. A supplement to CONCLUSIONS Actinic keratoses are common skin lesions caused by overexposure to sunlight with the potential to convert to malignancy. As it is impossible to predict which lesions will convert to cancer, treatment of all AK lesions is recommended. Topical treatments offer the best strategy for treating large areas of clinically visible and subclinical lesions. Of the available topical treatments, Picato®, available in 2 formulations, and proven to safely and effectively clear AK, has the shortest application period, which may help improve patient adhere and overall outcomes. 7. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010-1019. 8. Carac [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2012. 9. Fluorouracil Cream 5% [package insert]. Randolph, NJ: Spear Pharmaceuticals; 2006. 10. Zyclara [package insert]. Scottsdale, AZ: Medicis Pharmaceutical; 2012. 11. Aldara [package insert]. Bristol, TN: Gateway Pharmaceuticals, LLC; 2010. 12. Solaraze [package insert]. Melville, NY: PharmaDerm; 2012. 13. Picato [package insert]. Parsippany, NJ: LEO Pharma Inc.; 2012. 14. Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results. J Drugs Dermatol. 2014;13(2):154-160. 15. Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results. J Drugs Dermatol. 2014;13(6):741-747. Editorial assistance was provided to the authors by Skin & Allergy News and LEO Pharma Inc. Copyright © 2014 Frontline Medical Communications Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Frontline 4 tential for a good outcome, prepare them for possible adverse events, the duration of adverse events, and emphasize that adverse events are transient and quick to resolve. Photographs showing patients before, during, and after treatment can help reinforce the transience of adverse events and outcome potential. Patients should also be advised to keep Picato® refrigerated, ensure it dries completely after application, and to avoid showers immediately after application. TREATMENT OF ACTINIC KERATOSIS WITH PICATO® (INGENOL MEBUTATE) GEL Medical Communications Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. The opinions expressed in this supplement do not necessarily reflect the views of the Publisher.