Ingenol Mebutate: Expanded Utility

February 2020 | Volume 19 | Issue 2 | Original Article | 156 | Copyright © February 2020


Published online January 24, 2020

Yasmin Khalfe , Theodore Rosen

Department of Dermatology, Baylor College of Medicine, Houston, TX

Abstract
Ingenol mebutate (IM) is a novel drug that was developed for the treatment of actinic keratosis (AK). The drug works by a dual mechanism of action -- a rapid induction of cell death by necrosis along with a delayed neutrophil-mediated cellular cytotoxicity response.¹ Currently, IM is available as a 0.015% or 0.05% topical gel and has only been FDA-approved for the treatment of actinic keratosis. However, IM has also been extensively used off-label, and found to be efficacious in the treatment of multiple other skin disorders. In this review, we discuss the current literature that provides evidence for the successful use of ingenol mebutate as treatment for dermatologic disorders beyond actinic keratosis.

J Drugs Dermatol. 2020;19(2)156-161 doi:10.36849/JDD.2020.4731

INTRODUCTION

Ingenol mebutate (IM), brand name Picato®, is derived from the sap of Euphorbia peplus, a plant used for centuries as a natural remedy for skin conditions. IM works by a dual mechanism of action. First it induces rapid cell death by necrosis, followed by neutrophil-mediated, antibody-dependent cellular cytotoxicity.1 This mechanism allows the drug to not only kill cells rapidly, but also prevent recurrence. IM was initially developed to treat actinic keratosis (AK), a common skin cancer precursor. In randomized control studies, investigators demonstrated effective clinical and histologic clearance of AK with IM treatment.2 The Food and Drug Administration approved IM for treatment of AK in January 2012, and currently it is available commercially as a 0.015% or 0.05% topical gel.3

There are multiple advantages to IM therapy compared to other treatments, as the latter can require high compliance, longer treatment courses, and access to provider-administered therapies. Ingenol mebutate, by contrast, is a viable treatment option as a topical therapy that can be patient, or caretaker administered. Another major advantage is that IM requires fewer applications and has a shorter treatment duration than other topical drugs which can result in improved adherence.2 With these advantages and its effective mechanism of action, IM has the potential to be a valuable therapeutic drug for disorders other than AK. In the past few years, investigators have recognized this potential and have reported IM use as an off-label treatment for multiple illnesses. Numerous case reports and studies have been recently published demonstrating the novel use of the drug. This review summarizes the current literature and synthesizes evidence for the use of ingenol mebutate as treatment for dermatologic disorders beyond actinic keratosis.

Bowen’s Disease
Bowen’s Disease (BD), also known as squamous cell carcinoma in situ, is an intra-epidermal malignancy with the potential to progress to invasive squamous cell carcinoma at a risk of 3-5%.4 The lesions are usually asymptomatic and present as well-defined, scaly patches or plaques. Treatment options include surgery, photodynamic therapy, cryotherapy, topical fluorouracil and imiquimod. There is, however, limited data to guide the definitive choice of therapy. Because actinic keratosis is a pre-malignant precursor of SCC, IM’s effectiveness against AK suggests efficacy against BD. In fact, in a Phase I/II clinical study, Ramsay et al studied the effectiveness of E. peplus sap (in which IM is an active compound) on nonmelanoma skin cancers (NMSC).5 The investigators found that 94% of patients with an intraepithelial carcinoma treated with E. peplus sap had a complete clinical response at 1-month post-treatment which decreased to 75% at 15 months follow up. For SCC’s, the results showed a complete clinical response rate of 75% after 1 month and 50% after 15 months.5 Since then, multiple cases of BD treated with commercial IM have been reported.

In one of the first cases reported, Braun et al treated a 74-year-old man with two lesions on his trunk consistent with BD.6 The patient was given 0.05% IM, and two months post-treatment the lesions had completely cleared clinically and histopathologically. Similarly, Salleras et al reported 3 separate cases in which IM was used to treat Bowen’s Disease: An 80-year-old woman with a large BD lesion in the pre-tibial area failed treatment with photodynamic therapy and imiquimod 5% cream, so IM 0.05% was applied twice, 24 hours apart.7 The patient had local reactions that cleared gradually, and histopathologic clearance was noted at 9 weeks. The second case was of a 73-year-old woman