PEP-010 is PEP-Therapy's first CP&IP-based product and a first-in-class targeted approach to cancer therapy. The binding of caspase-9 to PP2A prevents caspase-9 to play its role in apoptosis (programmed cell death). PEP-010 dissociates this complex, thus liberating caspase-9 which can be activated to enter into its normal apoptotic role, restoring normal apoptosis in cancer cells.
PEP-010 in a single linear 30-aa peptide comprises:
A CPP to deliver the active peptide into the cellular cytosol;
An interfering active peptide, blocking caspase-9/PP2A interaction.
PEP-010 has demonstrated preclinical proof of concept (Arrouss et al., 2013):
In vitro: PEP-010 triggers apoptosis in cancer cells with no effect on healthy cells. It induces cell death in human tumour cell lines and B cells from chronic lymphocytic leukemia patients without affecting T, NK, monocytes (healthy cells). This demonstrates preferential activity on cancer cells which are “primed for death” due to their increased sensitivity to apoptosis;
In patient-derived xenograft (PDX) models: PEP-010 inhibits tumour growth in human breast and ovary primary tumours.Targeting apoptosis through activation of caspase-9 will also allow the use of PEP-010 in combination with existing chemotherapy regimens (different mechanism of action – successfully tested in vitro).
GLP toxicity studies by intravenous route in rat and monkey species are completed. PEP-010 is in the final stages of preparation prior to Phase I/II clinical studies in 2020.
In a personalized medicine approach, PEP-Therapy has also pre-validated predictive companion biomarkers for the identification of patients likely to respond well to PEP-010 treatment.
The first and most advanced biomarker takes the form of a 7-gene signature detected by RT-qPCR. This has been correlated to PDX models with a good response to treatment and is present in 70% of a cohort of 226 breast cancer patients (de Cremoux, 2011).
Pharmacodynamic (PD) biomarkers have also been identified and are currently under development.
PEP-010, first therapeutic product
PEP-020, our second CP&IP product, is an exploratory molecule in early pre-clinical PoC for the treatment of Uveal Melanoma, a rare disease without any therapeutic solution. It targets the Hippo signalling pathway, a key target for the treatment of cancers. The CPP transports a therapeutic peptide into the nucleus where it triggers apoptosis of tumour cells.
Our CP&IP technology can be applied to other new peptide projects for in-licensing.
PEP-010 companion biomarkers