Preclinical Characterization of PTG-100, an Oral α4β7 Integrin Peptide Antagonist for Ulcerative Colitis

PTG-100 is a selective oral peptide antagonist of α4β7 integrin with minimal systemic exposure, and is effective in blocking T cell homing and preventing mucosal damage in murine models of IBD.  PTG-100 and the clinically validated anti-α4β7 antibody vedolizumab have comparable potency and selectivity in a variety of assays including cell adhesion and binding to human CD4⁺ memory T cells.  PK studies in normal or dextran sodium sulfate (DSS) treated mice and rats show that oral dosing results in marked drug exposure in the small intestine, Peyer’s Patches, colon, and mesenteric lymph nodes (MLN), but no significant measurable levels in the blood and urine.  To measure the effect of oral dosing on trafficking of endogenous memory T cells, DSS mice were orally dosed daily with PTG-100 for 9 days, and harvested tissues were analyzed by FACS.   FACS analysis showed a dose dependent reduction of CD4⁺ CD44^high CD45RB^low β7⁺ T cells in the MLN and Peyer’s Patches, and a concomitant increase in the spleen and blood. There was also a dose-dependent reduction in body weight loss and mucosal injury as assessed by endoscopy. These results support clinical advancement of PTG-100.