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

Gastroenterology. 2021 Dec;161(6):1853-1864.e10. doi: 10.1053/j.gastro.2021.08.045. Epub 2021 Aug 30.

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, Number NCT02895100; EudraCT, Number 2016-003452-75).

Keywords: Inflammatory Bowel Disease; PROPEL Study; PTG-100; Ulcerative Colitis; α4β7 Integrin.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Cell Adhesion / drug effects*
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Colitis, Ulcerative / diagnosis
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / metabolism
  • Colon / drug effects*
  • Colon / immunology
  • Colon / metabolism
  • Disease Models, Animal
  • Double-Blind Method
  • Female
  • Gastrointestinal Agents* / administration & dosage
  • Gastrointestinal Agents* / adverse effects
  • Gastrointestinal Agents* / pharmacokinetics
  • Humans
  • Integrins / antagonists & inhibitors*
  • Integrins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mucoproteins / metabolism
  • Peptides* / administration & dosage
  • Peptides* / adverse effects
  • Peptides* / pharmacokinetics
  • Severity of Illness Index
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Time Factors
  • Treatment Outcome

Substances

  • Cell Adhesion Molecules
  • Gastrointestinal Agents
  • Integrins
  • MADCAM1 protein, human
  • Madcam1 protein, mouse
  • Mucoproteins
  • PTG-100 peptide
  • Peptides
  • integrin alpha4beta7

Associated data

  • ClinicalTrials.gov/NCT02895100
  • EudraCT/2016-003452-75