Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease

doi:10.1053/gast.2001.24015

Gastroenterology

Volume 120, Issue 6, May 2001, Pages 1339-1346

https://doi.org/10.1053/gast.2001.24015 Get rights and content

Abstract

Background & Aims: ISIS-2302, an antisense oligonucleotide directed against intercellular adhesion molecule 1, was effective in steroid refractory Crohn's disease in a pilot trial. The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn's disease (CACD). Methods: A dose-interval, multicenter, placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD (Crohn's Disease Activity Index [CDAI], 200–400). The primary endpoint was steroid-free remission (CDAI <150) at week 14. Results: Only 2 of 60 (3.3%) ISIS-2302–treated and no placebo patients reached the primary endpoint. Steroid-free remission at week 26 (secondary endpoint) was reached in 8 of 60 (13.3%) active treatment and 1 of 15 (6.7%) placebo patients. A greater proportion of ISIS-2302–treated than placebo patients achieved a steroid dose <10 mg/day at weeks 14 and 26 (48.3% vs. 33.3% and 55.0% vs. 40.0%, respectively, and a glucocorticoid dose of 0 mg [prednisone equivalent] at week 26 [23.3% vs. 6.7%, respectively]). Treatment with ISIS-2302 was safe. The most common side effects were injection site reactions in the active treatment group (23% in ISIS-2302–treated patients vs. none in placebo patients). No statistically significant differences in the frequency of side effects were detected between dose groups. Conclusions: The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint. Positive trends were observed in some of the secondary endpoints.

GASTROENTEROLOGY 2001;120:1339-1346

Section snippets

Inclusion criteria

A double-blind, prospective, randomized, placebo-controlled, dose-interval, multicenter trial was conducted in patients with moderately active Crohn's disease of at least 2 years' duration (Crohn's Disease Activity Index [CDAI], 200–400) with long-term steroid use (10–40 mg prednisone per day for more than 6 months, stable for the last 2 weeks) with at least 1 unsuccessful attempt to taper dosage within the last 6 months. Systemic corticosteroids other than prednisone had to be converted to

Population

Eighty-three patients were screened, 78 randomized, and 75 treated with at least 1 dose of study drug. Overall, more women (63%) than men were enrolled. Baseline demographics and disease characteristics were not different between groups. All patients were white, mean CDAI was 262–294 points, and mean glucocorticoid dose at baseline (prednisone or equivalent) was 24–33 mg/day. Patients with open perianal fistula were included in all treatment groups with no differences in distribution, whereas

Discussion

ICAM-1, an adhesion molecule expressed on a host of different cells including endothelial cells, monocytes and macrophages, keratinocytes, and a subset of B and T cells is up-regulated in response to proinflammatory mediators.3, 4 Most anti-inflammatory drugs including glucocorticoids and infliximab directly or indirectly influence cell adhesion molecule expression.24, 25, 26

Monoclonal antibodies directed against ICAM-1 significantly decreased immunologic changes and clinical scores in animal

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^☆: Address requests for reprints to: Stefan Schreiber, M.D., First Department of Medicine, Christian-Albrechts-University, Schittenhelmstrasse 20/21, 24105 Kiel, Germany. e-mail: [email protected]; fax: (49) 431-597-1842.

^☆☆: Supported by grants from ISIS Pharmaceuticals, Inc., Carlsbad, CA, Boehringer Ingelheim KG, Biberach/Riss, Germany, and the Competence Network “Inflammatory Bowel Disease” of the Bundesministerium fuer Bildung und Forschung.

^★: Parts of the data have been presented at the 101st annual meeting of the American Gastroenterological Association, San Diego, CA, May 21–24, 2000.

^★★: Additional members of the German ICAM-1 study group were: Adler (Ulm), Böhm (Marburg), Bokemeyer (Minden), Buhr (Berlin), Caspary (Frankfurt), Emmerich (Rostock), Krakamp (Cologne), Kramm (Berlin), Malfertheiner (Magdeburg), Stange (Luebeck), Stoll (Muenster), Stremmel (Heidelberg), and Wellmann (Hannover).

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Alimentary TractAbsence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease☆,☆☆,★,★★

Abstract

Section snippets

Inclusion criteria

Population

Discussion

Gastroenterology

Semin Arthritis Rheum

Cell

Lancet

J Invest Dermatol

Mol Med Today

Gastroenterology

Gastroenterology

J Lab Clin Med

Immunol Today

Gastroenterology

The sensation and regulation of interactions with the extracellular enviroment: the cell biology of lymphocyte adhesion receptors

Annu Rev Cell Biol

Interactions between epithelial cells and T lymphocytes: role of adhesion molecules

J Leukoc Biol

Tubular expression of intercellular adhesion molecule-1 during renal allograft rejection

Transplantation

Immunohistochemical study of adhesion molecules in liver inflammation

Hepatology

Adhesion molecules in inflammatory bowel disease

Gut

Alimentary Tract
Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease☆,☆☆,★,★★