Inflammatory Diseases
Further details on selected drug discovery programmes for the treatment of Inflammatory Diseases

Oral NRF-2 activator programme

C4XD has designed and discovered novel potent activators of the NRF-2 pathway, which is important in mediating lung diseases such as chronic obstructive pulmonary disease (“COPD”), pulmonary arterial hypertension (“PAH”), and other inflammatory diseases. In addition, recent scientific attention for this target has also extended to Sickle Cell Disease (“SCD”) where pre-clinical data suggests that the anti-oxidant and anti-inflammatory activity provided by NRF-2 activators may ameliorate haemolysis-related complications such as severe pain episodes, organ damage, heart attacks and stroke.

COPD represents an area of substantial unmet medical need and a $41 billion market and, therefore, activators of NRF-2 are the subject of considerable interest by the pharmaceutical industry. GSK has filed several further patents on its molecules against this target in the last 12 months and is likely to be close to clinical development. C4XD has made critical progress in the programme recently, with multiple C4XD compounds now shown to significantly increase NRF-2 activation in the lungs and other target tissues following low dose oral administration in pre-clinical studies. These novel compounds are currently being optimised for solubility and pharmacokinetic properties ahead of pre-clinical candidate short-list selection.

Oral IL-17 Inhibitor programme

Interleukin-17 (“IL-17”) is a high value clinically validated target for inflammation and autoimmune diseases such as psoriasis (estimated to be worth $9 billion per annum). As previously reported, our programme has identified small molecules that can selectively block IL-17 activity whilst keeping the molecular size of the molecule in the traditional “drug-like” range. To date, the identification of orally available small molecules has proved extremely challenging but they are highly sought after by the pharmaceutical industry. Recently we have identified multiple potent compounds suitable for oral delivery and have shown that these can inhibit the release of IL-17 induced cytokines in the blood in vivo when administered orally prior to IL-17 administration. Commercially this is a critical requirement as current marketed drugs that target IL-17 are based on injectable monoclonal antibodies so an oral treatment would increase the number of patients who can access drugs targeting this mechanism. This is highly desired by potential partners. Currently, a novel lead oral compound is being extensively profiled ahead of being selected to be examined in a disease efficacy model driven by endogenous IL-17.

Oral α4β7 integrin inhibitor programme

During 2018, C4XD initiated an evaluation stage drug discovery programme to harness the synergy between its proprietary Conformetrix technology and protein crystallography to expedite the identification of novel, selective α4β7 integrin inhibitors for the treatment of Inflammatory Bowel Disease (“IBD”). IBD is a collection of idiopathic diseases caused by a dysregulated immune response to host intestinal microflora. The most common sub-types are ulcerative colitis and Crohn’s disease. Moderate/severe patients that do not respond to immunosuppressants are progressed on to biological therapies which have revolutionised the treatment of moderate/severe disease.

Unfortunately, a significant proportion of patients do not respond to biological therapies and the first effective oral treatment for decades in this disease area is highly sought after. C4X Discovery were recently awarded and InnovateUK Feasibility Award to part-fund the early stages of this project.

New Targets from the Treatment of Rheumatoid arthritis

Analysis of a rheumatoid arthritis dataset using C4XD’s proprietary target discovery technology Taxonomy3® identified 66 novel genes that have not previously been associated with this major disease. Of these, nine were prioritised based on corroborative biology in the scientific literature and druggability. These potential targets are from protein families whose function suggests that any resulting drug molecules will have a very different biological impact on disease from that of existing rheumatoid arthritis therapies, enabling considerable therapeutic and commercial differentiation. One of these highly novel drug targets is currently being evaluated as a potential new pipeline programme.