Safety and Efficacy of Escalating Doses of Ingenol Mebutate for Field Treatment of Actinic Keratosis on the Full Face, Full Balding Scalp, or Chest

May 2017 | Volume 16 | Issue 5 | Original Article | 438 | Copyright © 2017

C. William Hanke MD MPH FACP,a Brian Berman MD PhD,b Neil Swanson MD,c David M. Pariser MD,d Jonathan S. Weiss MD,e Michael Bukhalo MD,f Torsten Skov MD PhD,g John Villumsen MSc,g and Daniel Siegel MDh

aThe Laser Skin and Skin Surgery Center of Indiana, Carmel, IN bCenter for Clinical and Cosmetic Research, Aventura, FL cOregon Health and Science University, Portland, OR dEastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA eGwinnett Dermatology, Snellville, GA fArlington Dermatology, Arlington Heights, IL gLEO Pharma A/S, Ballerup, Denmark hLong Island Skin Cancer & Dermatologic Surgery, Smithtown, NY

Abstract

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.

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INTRODUCTION

Indications, strengths, and dosages of ingenol mebutate (IngMeb) gel apply to its use on one contiguous skin area of approximately 25 cm2 for the topical treatment of actinic keratosis (AK).1,2 However, AK may involve larger areas, which can contain numerous well-defined, confluent, and/or subclinical lesions.3-6 Subclinical AKs are common, particularly on sun-damaged skin, and may exceed the number of visible lesions by 10-fold.3 Untreated subclinical lesions may become visible over time and account for apparent recurrences.3 Because subclinical AK cannot be detected by inspection, all visible lesions and perilesional areas should be treated.7Anderson et al studied IngMeb gel 0.05% applied to contiguous areas up to 100 cm2 on the forearm as field therapy for AK.8 The mean composite local skin response (LSR) scores increased with larger treatment areas (25 cm2 to 100 cm2).8,9 When treatment areas were pooled by size, there appeared to be a correlation between larger areas and the occurrence of some LSRs.8 The authors concluded that IngMeb 0.05% gel has a good safety profile when applied to an area up to 100 cm2 on the forearm, with acceptable tolerability and LSR profiles.8 A Phase 1/2 study was conducted to evaluate IngMeb for treatment of AK on contiguous areas up to 250 cm2. Part 1 (dose escalation) was designed to ascertain the maximum tolerated dose (MTD) when treating AK on the face. Previous studies reported that composite LSR scores on the face were generally higher than those on the scalp.10,11 The MTD was determined by observing dose-limiting events (DLEs) with IngMeb gel at 7 different concentrations. Based on data from a limited number of

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