Abstract
Abstract Background To identify novel therapeutic targets for ulcerative colitis (UC), a disease-agnostic Knowledge Graph1, comprising multi-modal data sources was used as input to a machine learning gene/protein prioritisation model2. Following in-depth target assessment, phosphodiesterase 10 (PDE10) was selected as a promising novel target for further investigation. Methods Our aim was to develop a novel therapeutic target for UC that will have not just anti-inflammatory properties but improve barrier function. PDE10 hydrolyses both cAMP and cGMP. In UC patients, reduced cAMP levels promote inflammation, while guanylate cyclase-C and its endogenous activators are downregulated in the colon, with lower levels correlating to higher disease severity. Our transcriptional analysis revealed that PDE10 is upregulated in UC patients’ colonic mucosa, correlating with disease severity, suggesting that PDE10 inhibition could potentially restore normal cyclic nucleotide signalling. Following successful experimental target validation, we developed BEN8744 a potent, selective, peripherally restricted oral PDE10 inhibitor. Supporting its therapeutic potential, BEN8744 significantly reduced TNFα, IL-6, and IL-8 in ex vivo inflamed UC patient colonic mucosa biopsy samples, and improved barrier integrity in an in vitro intestinal epithelial cell model. In a Phase 1, randomised, double-blind, placebo-controlled trial with 74 healthy subjects, we assessed the safety, tolerability, pharmacokinetics (PK), and food effect of BEN8744 (NCT06118385). The trial was in 3 parts: Part A investigated single ascending oral doses of BEN8744; Part B was a 2-way crossover assessment of the effect of food on the PK of BEN8744; and Part C investigated multiple ascending oral doses of BEN8744 for 14 days. Results All treatment emergent adverse events (TEASs) were mild or moderate in severity with no clinically significant findings in physical examination, laboratory variables, ECGs, OAAS/S or VAS results, during the study. No class effects previously seen with centrally active PDE10 inhibitors were observed in the present trial. Neither were there any dose dependent nervous system related TEAEs. Conclusion BEN8744 is a potent, peripherally restricted, well tolerated Phase 2 ready PDE10 inhibitor targeting a novel mechanism of action for the treatment of UC. The Phase 1 study showed a favourable safety, tolerability, and PK profile for BEN8744, supporting its further development. We are now planning a study in patients with moderate to severely active ulcerative colitis.
Published Version
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