BenevolentAI SPAC Presentation Deck

Phosphodiesterase 10 (PDE10) — a novel target for UC Transcriptomics data support the rationale for PDE10 as a novel target for UC PDE10 regulates signal transduction by hydrolysing cGMP PDE10 is significantly upregulated in UC-derived colon and colonic mucosa samples, whilst guanylyl cyclase, which makes cGMP, is down-regulated ● Reduced levels of guanylyl cyclase correlate with increased TNF-a in UC colonic mucosa* CGMP is downregulated in UC and its expression inversely correlates to disease severity PDE10 is well-studied in CNS disorders but not in inflammation with zero linkage to UC PDE10 was experimentally validated as a novel target using ex vivo biopsies from pharmacotherapy resistant UC patients Inflammatory cytokine release from UC samples significantly reduced with PDE10 inhibition nitric oxide synthase arginine soluble guanylyl cyclase NOS NO readily diffuses across plasma membranes activates GC GTP *Brenna et al, 2015 PDE10 degrades cGMP CGMP activates protein kinases and other proteins breaks down phosphodiesterase e.g. PDE10 GUCYZC ". LogFC PDE 10A LogFC Differential RNA expression of PDE10A and GUCY2C: normal vs UC colonic mucosa IL-6(pg/ml) 20000- 15000- 10000- 5000- 0 DMSO Prednisolone Tofacitinib BEN-3218 IL-8(pg/ml) 30000- 20000- 10000- 0 DMSO al Prednisolone Tofacitinib BEN-3218 Selective PDE10 inhibition showed comparable reduction of IL-6 and IL-8 to the positive controls in ex vivo UC biopsies Benevolent 26

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