Research

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)

Peplin's research identified the active components responsible for the selective cytotoxic effects of E. peplus. 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-tumor effects both in vitro and in vivo.

PEP005 (ingenol mebutate) 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 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
• a wound healing effect, restoring normal skin architecture. This positive cosmetic effect has been observed clinically

Ongoing research

At low concentrations of PEP005 (ingenol mebutate) might be used for systemic treatment, PEP005 (ingenol mebutate) demonstrated growth inhibition against a wide range of cancers. In particular, most leukaemia's 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 leukaemia cells, appears to be mediated by the translocation of protein kinase C delta.