Further details on selected drug discovery programmes for the treatment of cancer

Horizon Discovery next-generation synthetic lethality targets collaboration

Our exclusive target discovery partnership with Horizon Discovery Group plc (“Horizon”) will validate novel synthetic lethal oncology targets that have been identified by Horizon’s cutting-edge CRISPR-Cas9 technology. We are applying our proprietary 4D shape-based chemistry technology (Conformetrix) to discover drug candidates and generate potential new drugs for patients with limited effective treatments such as colorectal and lung cancer and out-license them to clinical development partners.

The therapeutic concept of harnessing synthetic lethality in cancer with tumour-specific mutations has been demonstrated with the recent approval of the poly(ADP-ribose) polymerase (PARP) inhibitors Lynparza® Zejula® and Rubraca®. These drugs are effective in indications that are poorly served by immunotherapy drugs, such as checkpoint inhibitors, and have become an established treatment in ovarian cancer. They work by targeting a specific DNA repair pathway that cancer cells, with mutations such as BRCA, become over-reliant on. Inhibiting this critical DNA repair pathway causes the tumour cells to self-destruct, resulting in the terminology ‘synthetic lethality’.

The gene-editing tool, CRISPR-Cas9, has enabled systematic ‘functional genomic’ screening to identify novel synthetic lethal genes in cancer cells with specific mutations. Horizon has utilised its target discovery platform to conduct high quality CRISPR gene knock-out studies across multiple cancer cell lines, screening around ~3000 genes suitable as the basis for small molecule drug targets. This cutting-edge approach has identified a shortlist of ~20 novel, high value synthetic lethal genes following a secondary screen to further validate them as targets.

The partnership has been established to complete the target validation package for these novel targets, leading to the initiation of drug discovery programmes by C4XD should it exercise its options on a target-by-target basis. C4XD is funding the work plan and Horizon will receive a share of all future revenues C4XD receives should any drug discovery programmes lead out-licensing for clinical development.

Immuno-oncology programmes

We have two key therapeutic programmes for the treatment of cancer at the evaluation stage. Both of these targets have been subject to industry licensing deals recently and there continues to be demand for further novel molecules for these targets, particularly for use in combination with other agents. These programmes are being prosecuted as part of the multi-target risk-sharing alliance with Evotec AG (“Evotec”)