NOX-A12 is currently in mid-stage clinical development as a combination therapy in the brain cancer, glioblastoma, and is one of the few agents that we believe offers the potential to address the major unmet need in this and other solid tumors with high unmet need such as pancreatic cancer.
Our ongoing GLORIA Phase 1/2 clinical trial of NOX-A12 in combination with radiotherapy in newly diagnosed glioblastoma patients who will not benefit from standard chemotherapy has delivered top-line data from three dose-escalation cohorts showing consistent tumor reductions and objective tumor responses. GLORIA further evaluates safety and efficacy of NOX-A12 in other combinations where the interim results from the triple combination of NOX-A12 + radiotherapy + bevacizumab suggest even deeper and more durable responses. NOX-A12 in combination with radiotherapy has received orphan drug designation for glioblastoma in the United States and glioma in Europe.
OPERA & OPTIMUS
TME Pharma collaborates with MSD/Merck in the pancreatic cancer program. After TME Pharma delivered final top-line data with encouraging overall survival and safety profile from its OPERA Phase 1/2 combination trial with Merck’s Keytruda® in metastatic pancreatic and colorectal cancer (Source: Suarez-Carmona M, et al. J Immunother Cancer 2021), we have entered into our second clinical collaboration with Merck to further evaluate safety and efficacy of NOX-A12 in combination with anti-PD-1 and two different chemotherapy regimens as second-line therapy in patients with pancreatic cancer. The design of the Phase 2 OPTIMUS trial of NOX-A12 and pembrolizumab in second-line pancreatic cancer is in discussion with regulatory authorities in the US and Europe.
MECHANISM OF ACTION
NOX-A12 (olaptesed pegol) is an intravenously administered, PEGylated L-stereoisomer RNA aptamer that targets CXCL12 (C-X-C Chemokine Ligand 12), a key chemokine (signaling) protein. Chemokines can be thought of as road signs in the body that direct movement of cells that encounter them. Like road signs, chemokines are anchored in place (location information) and contain directions, such as “do not enter”, for cells that can “see” them with the appropriate receptors. In cancer, CXCL12 acts as a communication bridge between tumor cells and their environment, promoting tumor proliferation, new blood vessel formation and metastasis and reduces tumor apoptosis (cell death) (Source: Guo et al., 2015). NOX-A12 binds to the CXCL12 “road sign”, neutralizing both the ability to anchor and the ability to interact with receptors on passing cells. This destroys the location information by de-anchoring the chemokine as well as preventing signaling via CXCL12’s two receptors CXCR4 and CXCR7 present on various cell types in and around the tumor tissue.
NOX-A12 is designed to fight solid tumors by modulating the tumor microenvironment in two distinct ways:
- Break tumor protection enabling anti-cancer immune cells, such as killer T-cells, to enter the tumor with the aim of unleashing a coordinated anti-cancer immune response that can be further enhanced with immuno-oncology approaches, such as immune checkpoint inhibitors*
- Block tumor repair by preventing the attraction of ‘repair cells’ to the tumors obstructing tumor re-growth and revascularization following radiotherapy
*Fearon, D. T. (2014). "The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance." Cancer Immunol Res 2(3): 187-193.