@article{b5e3ca16a8ce4e288d68d9577af24fc9,
title = "PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis",
abstract = "Background & Aims: Oral therapies targeting the integrin α4β7 may offer unique advantages for the 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 patients with ulcerative colitis (UC). Methods: In 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. Results: PTG-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. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread 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. Conclusions: PTG-100 showed local gastrointestinal 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 showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov,",
keywords = "Inflammatory Bowel Disease, PROPEL Study, PTG-100, Ulcerative Colitis, α4β7 Integrin",
author = "Sandborn, {William J.} and Mattheakis, {Larry C.} and Modi, {Nishit B.} and David Pugatch and Brian Bressler and Scott Lee and Raj Bhandari and Bittoo Kanwar and Richard Shames and Geert D'Haens and Stefan Schreiber and Silvio Danese and Brian Feagan and Pai, {Rish K.} and Liu, {David Y.} and Suneel Gupta",
note = "Funding Information: Desiree Hollemon, MSN, MPH, provided writing assistance for the manuscript that was paid for by Protagonist Therapeutics. William J. Sandborn, MD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Supervision: Lead; Writing – original draft: Lead; Writing – review & editing: Lead); Larry C. Mattheakis, PhD (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Project administration: Supporting; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting); Nishit B. Modi, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing – original draft: Supporting; Writing – review & editing: Equal); David Pugatch, MD (Data curation: Supporting; Formal analysis: Supporting; Project administration: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting); Brian Bressler, MD, MS, FRCPC (Investigation: Equal; Writing – review & editing: Supporting); Scott Lee, MD (Investigation: Equal; Writing – review & editing: Supporting); Raj Bhandari, MD (Investigation: Equal; Writing – review & editing: Supporting); Bittoo Kanwar, MD (Conceptualization: Supporting; Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Project administration: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting); Richard Shames, MD (Conceptualization: Supporting; Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting); Geert D'Haens, MD, PhD (Conceptualization: Equal; Investigation: Equal; Writing – review & editing: Supporting); Stefan Schreiber, MD, PhD (Conceptualization: Equal; Investigation: Equal; Writing – review & editing: Supporting); Silvio Danese, MD, PhD (Investigation: Supporting; Writing – review & editing: Supporting); Brian Feagan, MD (Conceptualization: Equal; Investigation: Equal; Writing – review & editing: Supporting); Rish K. Pai, MD, PhD (Formal analysis: Supporting; Methodology: Supporting; Writing – review & editing: Supporting); David Y. Liu, PhD (Data curation: Supporting; Formal analysis: Supporting; Project administration: Supporting; Resources: Supporting; Supervision: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting); Suneel Gupta, PhD (Data curation: Supporting; Formal analysis: Supporting; Project administration: Supporting; Resources: Supporting; Supervision: Supporting; Writing – original draft: Equal; Writing – review & editing: Supporting). Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = dec,
doi = "10.1053/j.gastro.2021.08.045",
language = "English (US)",
volume = "161",
pages = "1853--1864.e10",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",
}