Larry C. Mattheakis

Tu1869 Establishing the Human Equivalent Dose for Ptg-100, an Oral Peptide Antagonist of Integrin α4β7

PTG-100, a selective novel oral peptide antagonist of α4β7 integrin, is being developed for the treatment of patients with moderate to severe ulcerative colitis. PTG-100 alters trafficking of gut homing T cells in preclinical animal models, and its potency and selectivity are similar to that of the approved anti-α4β7 antibody vedolizumab. Pharmacokinetic studies in rodent or cynomolgus (cyno) monkeys show that PTG-100 exposure in the blood is <0.1% of dose, but >10% of dose in the small intestine and colon and up to 40% in feces, which indicate PTG-100 is orally stable and largely gut restricted. To help establish the potential efficacious dose range in humans, we developed a receptor occupancy assay to measure occupancy of CD4+ memory α4β7+ T cells in mouse blood and gastrointestinal (GI) tissues and in cyno blood. Daily dosing of PTG-100 and other similar antagonists in DSS (dextran sodium sulfate) treated mice showed a significant reduction in disease activity index (DAI), mucosal histopathology, and number of β7+ positive cells in the distal colon lesions. At these efficacious oral doses, α4β7 receptor occupancy in the blood, mesenteric lymph nodes, and Peyer’s Patches ranged from 46-81% at 4 h post dose. Single and multiple oral gavage administration of PTG-100 in healthy cynos showed that despite low systemic exposure, occupancy of blood α4β7 by PTG-100 is dose proportional, time-dependent, and influenced by the type of vehicle and fasted state of the animal. Allometric scaling from the mouse to human based on whole body surface area suggests that a similar level of blood receptor occupancy is associated with the cyno equivalent dose. The data suggests that 100% receptor occupancy over 24 h in the blood or GI in the mouse DSS model is not required for efficacy by an oral gut-restricted α4β7 antagonist. Together, these studies point to blood receptor occupancy and possibly receptor expression as useful clinical surrogates for the local effects of PTG-100 in the intestine. CONCLUSIONS