“CB-103 represents a UNIQUE example of small molecule drug that selectively inhibits transcription of specific genes by interacting selectively at the level of an oncogenic transcription factor, and thus the gene expression machine (contrary to the epigenetic approaches!)”
Dr. Doriano Fabbro, Scientific Advisory Board Member
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 is selectively blocking NOTCH pathway activation related gene transcription through binding to a NOTCH specific protein in the transcription factor complex. The blockade occurs by protein-protein interaction inhibition with a binding site critical for the assembly of the NOTCH transcription complex. This is a unique mode of action, which allows blocking NOTCH signaling independently of the genetic lesions which have activated the pathway. Cellestia has received regulatory approval to start clinical development with CB-103 in a first-in-human study Phase l – lla study investigating safety (Ph l) and preliminary single agent efficacy (Ph lla) of CB-103 in patients with advanced solid cancers and haematological malignancies.
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. triple negative 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 leukemic cells from patients-derived blood samples. In pre-clinical studies CB-103 is 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.
Cellestia is integrating the development of CB-103 with the development of a product specific multi-target biomarker program, to ensure selection of appropriate patients with NOTCH driven cancers for treatment only. This personalized medicine approach will ensure only the appropriate patients being treated. This biomarker program is already implemented at VHIO, Barcelona. This ongoing biomarker program will be complemented by development of Cellestia’s proprietary biomarkers program.
The elucidation of the novel mode of action of CB-103 has been achieved using multiple approaches, combining co-crystallization data, in silico docking, site directed mutagenesis, modulating sensitivity to CB-103 and biochemical and cell biological techniques. The outcome of this work has yielded an exact understanding of the mode of action of CB-103. Based on this know-how, novel protein-protein interaction inhibitors have been designed targeting additional indications.