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A phase 1 open‐label trial shows that smad7 antisense oligonucleotide ( GED 0301) does not increase the risk of small bowel strictures in Crohn's disease
Author(s) -
Zorzi F.,
Calabrese E.,
Monteleone I.,
Fantini M.,
Onali S.,
Biancone L.,
Pallone F.,
Monteleone G.
Publication year - 2012
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.12051
Subject(s) - medicine , crohn's disease , oligonucleotide , crohn disease , gastroenterology , disease , pharmacology , immunology , biology , biochemistry , gene
Summary Background In Crohn's disease ( CD ), knockdown of Smad7, an inhibitor of Transforming Growth Factor ( TGF )‐β1 activity, with a specific antisense oligonucleotide ( GED 0301) seems to be safe and tolerable and associates with TGF ‐β1‐mediated suppression of inflammatory pathways. Aim Since TGF ‐β1 has pro‐fibrogenic effects in many organs, we evaluated whether GED 0301 treatment associates with the formation of small bowel strictures. Methods Fifteen patients with active, inflammatory CD , receiving oral GED 0301 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 (b FGF ) 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 MMP s ( TIMP 1) were analysed at day 0 and day 180 by ELISA . Crohn's disease activity index ( CDAI ) changes were also monitored. Results 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. GED 0301 treatment induced no significant change in the circulating levels of bFGF , YKL ‐40, MMP s and TIMP 1. Seven of 12 patients who reached clinical remission following GED 0301 treatment maintained a CDAI < 150 at day 180. Conclusion 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.