PTG-100, an Oral α4β7 Antagonist Peptide
| Autor: | Raj Bhandari, Rish K. Pai, Larry C. Mattheakis, David Pugatch, David Liu, Scott D. Lee, Nishit B. Modi, Brian Bressler, Bittoo Kanwar, Stefan Schreiber, Brian G. Feagan, Silvio Danese, Geert R. D'Haens, Richard Shames, William J. Sandborn, Suneel K. Gupta |
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| Přispěvatelé: | Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Integrins Time Factors Colon Receptor expression T-Lymphocytes Administration Oral Pharmacology Inflammatory bowel disease Severity of Illness Index PROPEL Study Cell Line Mucoproteins Pharmacokinetics Double-Blind Method Gastrointestinal Agents α4β7 Integrin Clinical endpoint Cell Adhesion Medicine Animals Humans Ulcerative Colitis Crohn's disease Hepatology business.industry Inflammatory Bowel Disease Gastroenterology Antagonist PTG-100 Middle Aged medicine.disease Ulcerative colitis Mice Inbred C57BL Disease Models Animal Treatment Outcome Pharmacodynamics Colitis Ulcerative Female business Peptides Cell Adhesion Molecules |
| Zdroj: | Gastroenterology, 161(6), 1853-1864.e10. W.B. Saunders Ltd |
| ISSN: | 0016-5085 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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