BenevolentAl Therapeutics Pipeline and Triage

PDE10 inhibition: potential to normalise dysregulated mechanisms in IBD Th1 IFNY Dendritic Cell TNF-KB- IL-12 IL-6 Macrophage IL-18 M1 M2 IL-1ẞ IL-23 TNF PGE2 TNFOX IL-2 ILC3 ↑IL-17A IL-22 Th17 ↑ IL-17A IL-17F IL-21 IL-22 IL-23 • Reduced inflammatory cytokine release from intestinal epithelia via ↓ NFkb (1) • Reduced tissue-resident macrophage activation Reduced intestinal inflammation Source: (1) doi:10.1371/journal.pone.0079180: (2) doi:10.1371/journal.pone.0016139; (3) doi:10.3109/00365521.2015.1038849 Na Nutrients PDE10 inhibition ↑ CGMP ↑ CAMP fluid claudins PAMR ZO-1 occludin MLCK MLCK Nutrients TNF • Improved TJ assembly via PKG/PKA-mediated pMLC (2) • Improved fluid/mucus homeostasis. via PKG phosphorylation of intestinal CFTR (3) Improved barrier integrity Benevolent 41 Al

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