A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn's disease
Article first published online: 12 SEP 2012
© 2012 Blackwell Publishing Ltd
Alimentary Pharmacology & Therapeutics
Volume 36, Issue 9, pages 850–857, November 2012
How to Cite
Zorzi, F., Calabrese, E., Monteleone, I., Fantini, M., Onali, S., Biancone, L., Pallone, F. and Monteleone, G. (2012), A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn's disease. Alimentary Pharmacology & Therapeutics, 36: 850–857. doi: 10.1111/apt.12051
- Issue published online: 3 OCT 2012
- Article first published online: 12 SEP 2012
- Manuscript Accepted: 29 AUG 2012
- Manuscript Revised: 22 AUG 2012
- Manuscript Revised: 31 JUL 2012
- Manuscript Received: 10 JUL 2012
- Giuliani SpA
- Broad Medical Research Foundation. Grant Number: 0301R
In Crohn's disease (CD), knockdown of Smad7, an inhibitor of Transforming Growth Factor (TGF)-β1 activity, with a specific antisense oligonucleotide (GED0301) seems to be safe and tolerable and associates with TGF-β1-mediated suppression of inflammatory pathways.
Since TGF-β1 has pro-fibrogenic effects in many organs, we evaluated whether GED0301 treatment associates with the formation of small bowel strictures.
Fifteen patients with active, inflammatory CD, receiving oral GED0301 once daily for 7 days, were monitored for the formation of small bowel strictures by Small Intestine Contrast Ultrasonography (SICUS). Serum basic fibroblast growth factor (bFGF) and human chitinase 3-like 1 (also known as YKL-40), two markers of CD-related intestinal strictures, and matrix metalloproteinases (MMP) and tissue inhibitor 1 of MMPs (TIMP1) were analysed at day 0 and day 180 by ELISA. Crohn's disease activity index (CDAI) changes were also monitored.
Fourteen patients completed the 6-month study; the remaining underwent intestinal resection for a severe relapse not responsive to medical treatment. No patient developed small bowel stricture and none experienced obstructive symptoms during the study period. GED0301 treatment induced no significant change in the circulating levels of bFGF, YKL-40, MMPs and TIMP1. Seven of 12 patients who reached clinical remission following GED0301 treatment maintained a CDAI < 150 at day 180.
Short-term treatment of patients with Crohn's disease using GED0301 is not associated with the development of small bowel stricture, thus reinforcing the concept that this drug is safe at least at early time points.