C4X Discovery Holdings plc

("C4XD", "C4X Discovery" or the "Company")

MALT-1 Inhibitor Programme Update

Profiling of C4XD lead series shows no UGT1A1 liability at clinically meaningful doses

C4XD series potentially differentiated for safety profile

1 June 2023 - C4X Discovery Holdings plc (AIM: C4XD), a pioneering Drug Discovery company, provides an update on its MALT-1 inhibitor programme for cancer.  C4XD has successfully completed a preclincial study demonstrating its MALT-1 lead compounds are free of UGT1A1¹ liability shown by competitor chemistries.  The C4XD MALT-1 inhibitor programme is continuing to identify a shortlist of pre-clinical candidates for further development and a partnering programme has been initiated.

MALT-1 is one of the key regulators of B-cell receptor (BCR) and T-cell receptor (TCR) signalling.  Mutations that lead to activation of MALT-1 are associated with aggressive forms of non-Hodgkin B-cell lymphoma, and inhibition of MALT-1 has potential therapeutic applicability as a mono therapy for MALT-1-driven cancers and in combination with BTK inhibitors across multiple haematological indications, as well as broader potential in solid tumours and inflammation.

Bilirubin is a toxic pigment produced naturally in the body as a result of the breakdown of red blood cells and is normally cleared in the bile by the enzyme UGT1A1.  Excessive bilirubin (hyperbilirubinemia) has been observed clinically in patients treated with a range of tyrosine kinase inhibitors, including BTK inhibitors, and has been associated with inhibition of UGT1A1 by these drugs.  BTK/MALT-1 combination therapies represent a desirable therapeutic dosing regimen and little or no activity against UGT1A1 by a MALT-1 inhibitor is essential to reduce UGT1A1 inhibition burden.

Dr Nick Ray, CSO of C4XD, said: "Yet again, our Conformetrix technology has delivered molecules that have the potential to be best-in-class.  Building on promising anti-cancer activity in a preclinical xenograft study, we have now favourably observed little or no inhibition of UGT1A1 at clinically meaningful concentrations, whereas representative examples from other clinical and pre-clinical programmes showed significant UGT1A1 activities.  We believe this is due to the degree of chemical differentiation in the C4XD series compared to competitors and we are confident of identifying a pre-clinical candidate shortlist with a desirable safety profile in the near future."

1.   UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)

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About C4X Discovery

C4X Discovery ("C4XD") is a pioneering Drug Discovery company, combining scientific expertise with cutting-edge Drug Discovery technologies to efficiently deliver world‑leading medicines.  We have a highly valuable and differentiated approach to Drug Discovery through our enhanced candidate molecule design and patient stratification capabilities, generating small molecule drug candidates across multiple disease areas focused on immuno-inflammation.  Our commercially attractive portfolio ranges from early-stage target opportunities to late-stage Drug Discovery programmes and we have three commercially partnered programmes with one candidate in clinical development.

For more information visit us at www.c4xdiscovery.com or follow us on twitter @C4XDiscovery.