Targeting the NOTCH signaling pathway in its most downstream part with a unique mode of action as an innovative approach to address unmet medical need in cancer treatment and elimination of cancer stem cells!
The NOTCH signaling pathway plays a central role in cell differentiation, growth and stem cell maintenance. It is tightly regulated at cellular and tissue microenvironment levels. When the NOTCH pathway is inappropriately activated by genetic lesions, it becomes a major driver for NOTCH-dependent cancers and can cause resistance to standard of care treatment. Over 250´000 patients are annually diagnosed with NOTCH dependent cancers, with no specific therapy available to date.
Lead development candidate CB-103 is a small molecule, first-in-class, oral pan-NOTCH inhibitor. CB-103 has a unique mode of action, which allows CB-103 to block NOTCH signaling at the level of the NOTCH transcription complex, independently of the genetic lesion which has activated the pathway. CB-103 has completed preclinical phase of the development and has been selected as a development candidate for targeted oncology therapy. First-in-human phase I/IIA clinical study in cancer patients is under preparation.
To allow a personalized medicine approach, development of CB-103 is complemented with a companion diagnostic to stratify oncology patients with tumors harboring an activated NOTCH pathway.
CB-103 pre-clinical “proof of concept” has been achieved, with efficacy demonstrated in vitro as well as in vivo in various animal models, e.g. breast cancer and T-cell acute lymphoblastic leukaemia (T-ALL) models. Most importantly, anti-leukemic efficacy was shown for CB-103 alone and in combination with various chemotherapy regimen, eliminating ex-vivo leukemic cells from patients-derived blood samples.
Small molecule CB-103 is administered orally and very well tolerated at pharmacologically efficacious doses in mouse, rat and dog. It has excellent drug-like properties, e.g. rapid uptake and distribution after oral dosing. It is metabolized and excreted readily, with a relatively short half-life, allowing repeat dosing. Based on the favourable safety profile seen in the GLP safety pharmacology and toxicology studies in dog and rat, preparations for the first-in-human phase I/IIA clinical study for CB-103 have been initiated.