New Drug Approvals 2012 - Pt. II - Ingenol mebutate (PICATO®)

On Jan 23rd 2012 the FDA approved Ingenol mebutate gel for the topical treatment of actinic keratosis (AK). Ingenol mebutate (trade name: PICATO®, formally known as PEP-005) is a natural product derived from the euphorbia plant.

Actinic, or solar keratosis (Wikipedia; NIH; OMIM) is a pre-cancerous pigmented lesion on the skin, most commonly occurring in skin that has been frequently exposed to the sun. If left untreated, about 20% of cases transform into Squamous Cell Carcinoma.

Ingenol mebutate induces cell death in Actinic Keratosis. The precise targets responsible for the mechanism of action is not known, however, Ingenol derivatives (see e.g. CHEMBL346507) have been shown to have anticancer activities. Many of these derivatives have activity on several Protein Kinase C isoforms. Mechanistically Ingenol mebutate causes rapid lesion necrosis and also specific neutrophil-mediated, antibody-dependent cellular cytotoxicity

Ingenol mebutate (IUPAC: 2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro 5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta [a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) - or (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11 oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6 yl (2Z) 2 methylbut-2-enoate). Ingenol mebutate is the mebutate ester of ingenol, and is a natural product isolated from the plant Euphorbia peplos. Ingenol is a diterpene, and is part of a diverse super-family of bioactive natural products - including phorbol esters, Reseniferatoxin and Gnidimacrin. Specifically, Ingenol mebutate is a member of the Ingenane family of natural products, and contains a Bicyclo[4.4.1]undecane ring system with in – out stereochemistry. Ingenol esters found in Euphorbiaceae, and were traditionally used in the treatment of tumors, migraines, parasites, gingivitis, and also as purgatives.

Its molecular formula is C25H34O6; molecular weight is 430.5 Da. It is a clear gel provided in two concentrations: 0.015% and 0.05%. These contain 150 mcg and 500 mcg of ingenol mebutate, respectively. It is applied to the lesion and the immediately surrounding skin. Pharmacokinetic studies have shown that absorption into the bloodstream (systemic exposure) is undetectable.

Picato® is produced and marketed by Leo Pharma.

The full prescribing information can be found here.

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