olaptesed pegol (NOX-A12)

P1/2, N=117, Active, not recruiting, TME Pharma AG | N=27 --> 117 | Trial completion date: Dec 2024 --> Dec 2028 | Trial primary completion date: Dec 2024 --> Dec 2028

P2, N=60, Not yet recruiting, TME Pharma AG | Trial completion date: Oct 2027 --> Oct 2028 | Trial primary completion date: Oct 2026 --> Oct 2027

In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.

8 In this study we aimed to address the role of CXCL12 and its inhibition by NOX-A12 (with and without immune checkpoint inhibitors, ICI) in modulating the immune landscape in mice bearing GBM...Conclusions Inhibition of CXCL12 resulted in a time-dependent array of changes in peripheral blood and tumor-bearing brains but no clear survival benefit. Whether immune-related brain edema, or insufficient activation of immune cells in TME contributed to this result will be clarified by comparing response between intracranial and flank tumor, to better understand the mechanism of immune cell trafficking and polarization mediated by CXCL12 in GBM.

Conclusions m IF of matched pre-/post-therapy tissue samples from the ongoing GLORIA trial supports the proposed modes of action of RT and NOX-A12 counteracting vasculogenesis and modulating the iTME reflected through its spatial rearrangement. This opens up the question of a targetable, compartment-specific role of CXCL12 to be further assessed.

P1/2, N=27, Active, not recruiting, TME Pharma AG | Recruiting --> Active, not recruiting

We show superior clinical efficacy of RT and NOX-A12 in patients with high frequency of CXCL12 expressing endothelial and glioma cells, suggesting the use of the EG12 score as a novel predictive biomarker for CXCL12-directed therapies in GBM. Clinical trial information: NCT04121455.

Interim data from the ongoing GLORIA trial demonstrates safety of RT plus OLA and suggests promising clinical efficacy of a new class of drugs targeting CXCL12 in GBM.

Plerixafor, BKT140, LY2510924, PF-06747143, ulocuplumab, and NOX-A12 are among the most well-known CXCR4 and CXCL12 modulators that their therapeutic efficacies have been evaluated in different pre-clinical and clinical studies of hematologic malignancies. To have an overview of the importance of CXCL12/CXCR4 and CXCL12/CXCR7 axes in the pathogenesis of leukemia and to gather information about the latest advances as well as challenges in targeting these axes in clinical settings, the present review has begun with a discussion about how aberrant expression of CXCL12/CXCR4 and CXCL12/CXCR7 pathways might regulate leukemogenesis and ended by outlining the key news of preclinical and clinical investigations in leukemia treatment.

Patients received continuous (24/7) i.v. infusions of 200mg/week (n=3), 400mg/week (n=3) or 600mg/week (n=3) of the CXCL12 inhibitor olaptesed pegol (OLA) for 26 weeks during and after normo- or hypofractionated RT (60Gy/40.05Gy)...CONCLUSIONS Advanced MRI and multiplexed immunofluorescence suggest efficacy of combined radiotherapy and CXCL12 inhibition in unmethylated GBM. Funded by NOXXON Pharma AG; ClinicalTrials.gov number, NCT04121455.

P1/2, N=21, Recruiting, NOXXON Pharma AG | Active, not recruiting --> Recruiting | Trial completion date: Sep 2022 --> Dec 2024 | Trial primary completion date: Sep 2022 --> Dec 2024

We demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.

However, blockade of CXCL12-CXCR4 signaling axis by inhibitors like Nox-A12, FDA approved CXCR4 inhibitor drug AMD3100 have shown limited clinical success in cancer treatment...In our pursuit to understand the impact of chemokine signaling in carcinogenesis, we reveal that instead of CXCR4-CXCL12 signaling, presence of CXCR4 intracellular protein augments paclitaxel resistance and pro-tumorigenic functions...Finally, performing TCGA data mining and using human breast cancer patient samples, we demonstrate that expression of CXCR4 and DR5 are inversely regulated. Together, our data suggest that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.

It is therefore of great interest to investigate CXCR4/CXCR7/CXCL12 modulators in clinical development, with several CXCR4 and CXCL12 modulators such as plerixafor, ulocuplumab, balixafortide, and olaptesed pegol having already reached this stage...Contrary to CXCR4 and CXCL12 modulators, CXCR7 modulators have, thus far, not been extensively studied. Therefore, more (pre)clinical investigations are needed.

Funding: NOXXON Pharma AG. Clinical trial identification: NCT03168139; EudraCT 2016-003657-15.

A trend towards agglomeration of T cells within tumors was observed in about half of the patients where NOX-A12 had induced a Th1-type cytokine response. This agglomeration was accompanied by reduced distances between T cells and cancer cells, suggesting increased infiltration of effector immune cells into tumor tissue. Treatment with NOX-A12 plus pembrolizumab in the combination therapy part of the study resulted in stable disease in 25% of patients, and prolonged time on treatment vs.