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 Sickle Cell Disease (“SCD”), chronic obstructive pulmonary disease (“COPD”), pulmonary arterial hypertension (“PAH”), and other inflammatory diseases. Multiple C4XD compounds have shown >12 hour NRF-2 activation in the lungs and other target tissues following low dose oral administration in pre-clinical studies. These novel compounds are being optimised for solubility and pharmacokinetic properties for pre-clinical candidate short-list selection.

Pre-clinical data suggests that the anti-oxidant and anti-inflammatory activity provided by NRF-2 activators may ameliorate haemolysis-related complications in SCD such as severe pain episodes, organ damage, heart attacks and stroke and the $41 million COPD market represents an area of substantial unmet medical need.

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). Our programme identified small molecules that can selectively block IL-17 activity whilst keeping the molecular size of the molecule in the traditional “drug-like” range. We have completed optimisation of our lead novel oral compounds which have shown that they can inhibit the release of IL-17 induced cytokines in the blood in vivo when administered orally prior to IL-17 administration. 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 and offer the pharmaceutical industry an alternative treatment regime.

Oral α4β7 integrin inhibitor programme

C4XD received an InnovateUK Feasibility Award to fund the early stages of an Oral α4β7 integrin inhibitor programme and we have 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 but a significant proportion of patients do not respond to biological therapies and the first effective oral treatment in this disease area is highly sought after.

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.