Research Program
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Peplin's core technology is a group of naturally occurring and naturally sourced compounds, generally substituted diterpenes with anti-cancer properties, from the sap of E. peplus.
PEP005 (ingenol mebutate)
The active components responsible for the selective cytotoxic effects of E. peplus sap have been identified from research conducted by Peplin. Pharmacological activity has been linked to macrocyclic diterpenes of three families, namely ingenane, pepluane and jatrophane. Research has focused on the ingenane family, which comprises ingenol-3-angelate (PEP005 (ingenol mebutate)), 20-O-acetyl-ingenol-3-angelate (PEP008) and 20-deoxy-ingenol-3-angelate (PEP006). PEP005 (ingenol membutate) has been identified as the major active principle, based on its potent anti-tumour effects both in vitro and in vivo.
Peplin is developing PEP005 (ingenol mebutate) for a number of forms of cancer. PEP005 (ingenol mebutate) is Peplin's lead compound and chemically is described as an angeloyl substituted ingenane. PEP005 (ingenol mebutate) is a well characterized, single molecular entity isolated and purified from a rapidly growing and common non-indigenous plant. It is not a botanical for regulatory purposes.
PEP005 (ingenol mebutate) mode of action
PEP005 (ingenol mebutate) is a lipophyllic diterpene ester, and the first of a new class of investigational agent with a novel mechanism of action.
PEP005 (ingenol mebutate) is a chemotherapeutic agent that when present in high localized concentrations has a dual mechanism of action. Its primary mode of action is direct primary necrosis; it induces rapid membrane disruption, mitochondrial swelling and cell death by primary necrosis within hours.
Its secondary mode of action is a localized activation of protein kinase C leading to activation of cytokines that contribute to:
- an induction of a localized innate immune response recruiting and activating neutrophils at the site of application; and
- a wound healing effect, restoring normal skin architecture. This positive cosmetic effect has been observed clinically.
At low concentrations of PEP005 (ingenol mebutate), such as might be used for systemic treatment, PEP005 (ingenol mebutate) demonstrated growth inhibition against a wide range of cancers. In particular, most leukemias and certain cell lines tested by the NCI, including many of the significant solid tumor types in humans, are highly sensitive to the molecule. These doses of PEP005 (ingenol mebutate) induce apoptosis, growth arrest, and/or cellular differentiation. PEP005 (ingenol mebutate) is a modulator of certain members of the protein kinase C family of proteins. The apoptotic cell death, at least in leukemia cells, appears to be mediated by the translocation of protein kinase C delta.
Ongoing research
Peplin has an active ongoing research program into aspects of the mechanism of action of PEP005 (ingenol mebutate). The direct cytoxicity of the drug is well established and Peplin has unpublished data establishing the importance of neutrophil activation in the complete clearance of tumors. Peplin are also actively pursuing the biological and molecular activities of PEP005 (ingenol mebutate) that lead to its observed wound healing properties.
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