Cellestia

The Pipeline

Science

Background & Clinical Relevance of the NOTCH Pathway

NOTCH-driven cancers

More than 250´000 patients are diagnosed annually with NOTCH-dependent cancers, with no targeted therapies currently available. The NOTCH pathway is one of the pivotal cell-to-cell communication mechanisms in developing organisms from fruit flies to humans. Abnormal activation of the NOTCH pathway due to genetic lesions, leads to the oncogenic transformation of normal cells and causes what are known as NOTCH-driven cancers.
In recent clinical investigations, NOTCH activation has been confirmed to be an important negative prognostic factor across multiple cancer indications such as salivary gland cancer, breast cancer and specific hematological malignancies like T-cell acute lymphoblastic leukemia. Due to the role of NOTCH in cancer initiation, promotion, progression and metastasis, patients “positive” for a NOTCH-driven cancer have a significantly reduced chance of survival. The ability to pharmacologically inhibit this signalling pathway is expected to substantially benefit patients suffering with NOTCH-driven cancers.

What we know

One of the critical complexities of the NOTCH pathway in humans is that there are 5 NOTCH ligands and 4 different receptors that act in specific pairs to fine tune NOTCH activation during development. An interaction between NOTCH ligands and receptors leads to gamma secretase complex mediated cleavage of the NOTCH intracellular domain (NICD) that translocate and activate NOTCH target gene expression in the nucleus of cells.
In human cancers, abnormal pathway activation due to ligand-receptor interaction can be inhibited by weakening or dampening the activity of the gamma secretase complex. However, the gamma secretase complex is also involved in proteolytic cleavage (the process of breaking the peptide bonds between amino acids in proteins) of more than 90 membrane-spanning proteins. Therefore targeting the gamma secretase complex (by inhibitors called GSIs) leads to several on- and off-target toxicities as well as non-specificity in blocking the NOTCH signaling. In other words, blocking all 90 membrane spanning proteins of NOTCH signalling when you only want to block the signals that are leading to the oncogenic transformation of normal cells.
An alternative to inhibiting the gamma secretase, is the use of anti-ligand or anti-receptor monoclonal antibodies (mAbs). However due to their specificity against a specific ligand or receptor, the spectrum of NOTCH-positive tumours that can be treated with these antibodies is very limited. In addition, owing to their long half-life, the use of blocking antibodies also lead to severe on-target toxicities.
In combination with preclinical genetic data, these clinical studies validate NOTCH as a clinically relevant therapeutic target. Despite their limitations and problems with toxicity, the first and second generation of NOTCH inhibitors represented by GSIs and mAbs have shown clinical efficacies in NOTCH-positive cancers.
Studies over the past two decades have shown that direct targeting of the NOTCH transcription complex in the nucleus might help overcome the limitations and toxicities associated with the use of GSIs and mAbs in clinics. However, due to the globular nature of protein-protein interactions in transcription complexes, pharmacological targeting of the NOTCH transcription complex remains challenging.

TESTIMONIALS

Cellestia Biotech’s scientific platform allows the drugging of previously undruggable oncogenic targets through precisely silencing of the transcription of oncogenic genes. This is an exciting new approach to helping cancer patients live longer and better lives.

David R. Epstein
Chairman of Cellestia’s Strategic Advisory Boards

Cellestia's approach

By building on in-house know-how generated over more than a decade, Cellestia Biotech has developed a drug discovery platform to directly target the NOTCH transcription complex using small molecule inhibitors. Cellestia’s lead clinical-stage drug candidate, CB-103, acts as a first-in-class protein-protein interaction inhibitor of the NOTCH transcription complex and thereby inhibits NOTCH signalling at the most downstream event in the cascade. Due to its unique mode of action, CB-103 acts as a pan-NOTCH inhibitor and circumvents the gastrointestinal tract toxicities associated with GSIs and mAbs.

Differentiation of Cellestia Technology

CB-103 controls NOTCH pathway activation by targeting the NOTCH transcription factor complex. In contrast, competitors block the pathway either at the receptor/ligand interface on the cell surface or by blocking the NICD activation with gamma-secretase inhibitors.

In an ongoing Phase I trial, CB-103 has not only demonstrated excellent safety, due to its unique mode of action, but has also achieved target engagement in cancer patients. Based on Cellestia’s expertise in targeting transcription complexes, we are striving to bring safer and lifesaving medicines to cancer patients.

Cellestia is developing
a novel therapy for currently
untreatable cancers.

Pipeline

Clinical Lead Candidate CB-103

CB-103 is a small molecule, first-in-class, oral pan-NOTCH inhibitor. It selectively blocks NOTCH pathway activation related gene transcription by binding to NOTCH-specific proteins 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 unique mode of action allows the blocking of NOTCH signaling independently of the genetic lesions which have activated the pathway. Cellestia is currently conducting a Phase l-lla study in solid tumors to determine the safety and efficacy of CB-103.

Pipeline projects

In addition to CB-103, Cellestia is pursuing development of novel drug candidates targeting NOTCH for life cycle management (CB-203/303 compound series) targeting oncogene transcription factors. Cellestia is also working on currently undisclosed targets for treatment of cancer targeting oncogene transcription factors.

Biomarkers

There is a diagnostic biomarker program to support patient selection running in parallel to the ongoing drug development.  Technologies covered through this program are next generation sequencing, immunohistochemistry (IHC) and gene expression profiling.  Cellestia is also developing proprietary diagnostic antibodies for IHC.

Clinical trials

Cellestia is currently recruiting patients in an ongoing Phase l-lla clinical trial to treat patients with solid tumours.  Please follow the link below for more information.

Cellestia Ph l-lla Trial

Drug Development programs

Research
Discovery


In Vivo PoC

Development
Preclinical


Phase 1


Phase 2

CB-103 Lead Program

CB-203/303 Series

New Oncology Indication A

New Oncology Indication B

Biomarkers Programs

NOTCH-Specific

Proprietary Biomarkers

Drug Development programs

Research
Discovery      In Vivo PoC

Development
Preclinical     Phase 1

CB-103 Lead Program

Research
Discovery      In Vivo PoC

CB-203/303 Series

Research
Discovery

New Oncology Indication A

Research
Discovery

New Oncology Indication B

Biomarkers Programs

Research
Discovery      In Vivo PoC

Development
Preclinical     Phase 1

NOTCH-Specific

Research
Discovery      In Vivo PoC

Proprietary Biomarkers

Intellectual property

Cellestia Biotech holds a worldwide exclusive license from EPFL on the intellectual property rights (IPR) for CB-103 and the related series of analogues, both for development and commercialization. The patent has been granted in key regions such as the EU, US, Japan and China.  In addition, Cellestia continues to file new patents on its discovery programs and biomarker development.

Patent granted

Patent filed for examination