Ingenol Mebutate (DB05013): A Comprehensive Monograph on a Novel Topical Agent from Discovery to Market Withdrawal

Executive Summary

Ingenol mebutate (DrugBank ID: DB05013) is a small molecule cytotoxic agent that emerged from the investigation of a traditional botanical remedy into a regulated pharmaceutical product for the treatment of actinic keratosis (AK). Derived from the sap of Euphorbia peplus, the drug garnered significant interest due to its unique dual mechanism of action and an exceptionally short treatment course of only two to three days, a stark contrast to the weeks or months required for existing topical therapies. Its mechanism involves the rapid induction of primary necrosis in dysplastic keratinocytes, followed by a robust, neutrophil-mediated inflammatory response intended to clear residual abnormal cells. This activity is driven by its function as a potent modulator of Protein Kinase C (PKC) isoforms, key regulators of cellular signaling. Pivotal Phase III clinical trials demonstrated statistically significant efficacy in clearing AK lesions on the face, scalp, trunk, and extremities, leading to its approval by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2012 under the brand name Picato.