BACKGROUND AND AIMS: Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. METHODS: In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03-10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α₄β₇⁺ lymphocytes was measured to demonstrate drug activity. RESULTS: No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α₄β₇⁺ lymphocytes in patients receiving PF-00547,659. CONCLUSIONS: The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.
RCT Entities:
BACKGROUND AND AIMS: Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. METHODS: In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03-10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α₄β₇⁺ lymphocytes was measured to demonstrate drug activity. RESULTS: No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α₄β₇⁺ lymphocytes in patients receiving PF-00547,659. CONCLUSIONS: The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.
Authors: C S Horjus Talabur Horje; C Smids; J W R Meijer; M J Groenen; M K Rijnders; E G van Lochem; P J Wahab Journal: Clin Exp Immunol Date: 2017-01-31 Impact factor: 4.330
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Authors: W J Pan; H Hsu; W A Rees; S P Lear; F Lee; I N Foltz; P Rathanaswami; K Manchulenko; B M Chan; M Zhang; X Z Xia; S K Patel; P J Prince; D R Doherty; C M Sheckler; K O Reynhardt; C D Krill; B J Harder; J A Wisler; J L Brandvig; J L Lynch; A A Anderson; L C Wienkers; D C Borie Journal: Br J Pharmacol Date: 2013-05 Impact factor: 8.739
Authors: Vipul Jairath; Guangyong Zou; Claire E Parker; John K Macdonald; Mahmoud H Mosli; Reena Khanna; Lisa M Shackelton; Margaret K Vandervoort; Turki AlAmeel; Mohammad Al Beshir; Majid AlMadi; Talal Al-Taweel; Nathan S S Atkinson; Sujata Biswas; Thomas P Chapman; Parambir S Dulai; Mark A Glaire; Daniel Hoekman; Andreas Koutsoumpas; Elizabeth Minas; Mark A Samaan; Simon Travis; Geert D'Haens; Barrett G Levesque; William J Sandborn; Brian G Feagan Journal: J Crohns Colitis Date: 2016-01-07 Impact factor: 9.071