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* = Presenting author

DOP022 Targeting immune cell metabolism: LYC-30937, a novel therapeutic approach for inflammatory bowel disease

L. Carter1, R. Morgan1, C. Lesch1, M. Spahr1, L. Franchi2, I. Monteleone3, G. Monteleone3, G. Glick2, H. J. Wilkins1, P. Higgins*2

1Lycera, Ann Arbor, Michigan, United States, 2University of Michigan, Ann Arbor, Michigan, United States, 3Tor Vergata, Rome, Italy

Background

Novel therapeutic modalities are needed to improve remission rates and decrease treatment-associated immune suppression and adverse events in inflammatory bowel diseases (IBD). Apoptosis-resistant, chronically activated lymphocytes participate in the pathogenesis of IBD. These cells have a unique metabolic phenotype that can be selectively targeted by small molecule drugs such as LYC-30937, a new oral agent in clinical development for IBD. LYC-30937 targets the F1F0-ATPase to induce redox-regulated apoptosis of chronically activated lymphocytes.

Methods

The potency and selectivity of LYC-30937 was characterised in mitochondrial and cell based assays then progressed into rodent models of inflammatory colitis. Ex vivo apoptosis and cytokine production studies were performed on lymphocytes from IBD patients. Phase 1 clinical trials were performed in healthy volunteers and ulcerative colitis patients.

Results

LYC-30937 acts on respiratory complex V, slows the rate of ATP production, increases intracellular superoxide, and induces apoptosis (EC50 < 75nM). In rodent TNBS-induced colitis models, oral administration of ATPase modulator compounds inhibits pro-inflammatory cytokine production, reduces weight loss, and decreases gross pathology and histopathology scores. The efficacy observed with LYC-30937 treatment is equivalent or superior to prednisolone or 5-ASA. LYC-30937 is designed to distribute drug to the gastrointestinal (GI) tract and reduce systemic exposures. In preclinical IBD models, LYC-30937 is efficacious at low systemic drug concentrations suggesting that local drug levels in lamina propria drive the effects on disease. Consistent with the pro-apoptotic mechanism of action, increased death of lamina propria lymphocytes was observed following ATPase modulator treatment of diseased animals. Although the F1F0-ATPase is expressed in all cells, normal lymphocytes and immune responses are not effected by ATPase modulator compounds as evidenced by normal cytokine production following in vitro stimulation of whole blood, unaltered lymphocyte counts following > 28 days of dosing, and normal development of in vivo T-dependent antibody responses. The selective induction of apoptosis in chronically activated lymphocytes is conserved in human PBMCs from IBD patients where activated CCR9+ gut-tropic T-cells are more sensitive to ATPase modulator-induced cell death than CCR9-T-cells.

Conclusion

LYC-30937 is an oral, gut-directed agent with a novel therapeutic mechanism of action for the selective depletion of pathogenic cells in the gastrointestinal tract. This molecule has completed Phase 1 clinical trials and is progressing into Phase 2 trial in ulcerative colitis.