PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

Abstract

BACKGROUND & AIMS\nOral therapies targeting the integrin α4β7 may offer unique advantages for treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models, and established safety, pharmacokinetic/pharmacodynamic relationships and efficacy in a phase 2a trial in ulcerative colitis (UC) patients.\n\n\nMETHODS\nIn-vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks.\n\n\nRESULTS\nPTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues (GALT). In healthy volunteers, PTG-100 demonstrated dose dependent increases in plasma exposure and blood target engagement. While this phase 2a study initially did not meet the primary endpoint, a blinded re-read of the endoscopy videos by a third-party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood.\n\n\nCONCLUSIONS\nPTG-100 demonstrated local GI tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well-tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and demonstrated a dose response reflecting similar activities in preclinical models and healthy subjects. These data suggest local gut activity of an oral α4β7-integrin antagonist, distinct from full target engagement in blood, are important for efficacy and treatment of UC.