P0815 Oral alpha 4 beta 7 (α4β7) integrin antagonist EA1080 (NSHO-101) demonstrates target engagement and α4β7 integrin receptor occupancy following once-daily administration in healthy volunteers

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Abstract Background EA1080 (NSHO-101) is a selective, oral small molecule α4β7 integrin antagonist being advanced for the treatment of inflammatory bowel disease (IBD). EA1080 (NSHO-101) was safe and well tolerated and resulted in near complete inhibition of MAdCAM-1 binding to α4β7 integrin (receptor occupancy) on peripheral blood CD4+ T cells following twice-daily dosing with Formulation X in a healthy volunteer phase 1 study (DDW 2024: Su1789; NCT04223960). No effect on peripheral blood lymphocyte count was observed, confirming no specific engagement of α4β1 integrin. Here pharmacokinetics (PK) and pharmacodynamics (PD) results from a once-daily formulation are presented. Methods The PK and PD results from multiple ascending dose (MAD) cohorts with a formulation utilizing once-daily dosing were assessed in a healthy volunteer phase 1 study. Peripheral blood lymphocyte counts were assessed across the dosing period. Results Once-daily administration of EA1080 (NSHO-101) resulted in sustained, near-complete inhibition of MAdCAM-1 binding to α4β7 integrin on peripheral blood CD4+ T cells (≥95% receptor occupancy) across the dosing interval (24 hours). This correlated with plasma concentrations of active metabolite of EA1080 (EA1080-M) and approximated the level of receptor occupancy seen with twice-daily dosing with Formulation X. Plasma concentrations of EA1080-M reached steady-state levels within 3-4 days, and this correlated with maximal inhibition of MAdCAM-1 binding (receptor occupancy). No consistent trend in peripheral blood lymphocyte counts was observed across the dosing period. Conclusion These results demonstrate that once-daily oral administration of EA1080 (NSHO-101) results in near complete inhibition MAdCAM-1 binding to α4β7 integrin (≥95% receptor occupancy) across the dosing interval. No effect on peripheral blood lymphocyte counts was observed, confirming no specific engagement of α4β1. These results support continued development of a once-daily dosing formulation for future clinical studies.