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  • Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease

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Inflammatory bowel disease
Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS 2302), in active steroid dependent Crohn's disease
  1. B R Yacyshyn1,
  2. W Y Chey2,
  3. J Goff3,
  4. B Salzberg4,
  5. R Baerg5,
  6. A L Buchman6,
  7. J Tami7,
  8. R Yu7,
  9. E Gibiansky8,
  10. W R Shanahan7
  1. 1University of Alberta, Edmonton, Alberta, Canada
  2. 2University of Rochester, Rochester, New York, USA
  3. 3Western States Clinical Research, Arvada, Colorado, USA
  4. 4Atlanta Gastroenterology Association, Atlanta, Georgia, USA
  5. 5Tacoma Digestive Center, Tacoma, Washington, USA
  6. 6University of Texas, Houston, Texas, USA
  7. 7Isis Pharmaceuticals, Carlsbad, California, USA
  8. 8GloboMax LLC, Hanover, Maryland, USA
  1. Correspondence to:
    Dr B R Yacyshyn, Division of Gastroenterology, University of Alberta, Suite 2E3.11 Walter Mackenzie Centre, 8440-112 St, Edmonton, AB T6G 2R7, Canada;
    bruce.yacyshyn{at}ualberta.ca
    www.gut.ca

Abstract

Background and aims: To evaluate the safety and efficacy of the intercellular adhesion molecule 1 (ICAM-1) antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) in Crohn's disease.

Methods: Active (Crohn's disease activity index (CDAI) 200–350), steroid dependent (prednisone 10–40 mg) Crohn's patients were randomised into three treatment groups: placebo versus ISIS 2302 (2 mg/kg intravenously three times a week) for two or four weeks. Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14.

Results: A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027).

Conclusions: Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy for steroid dependent Crohn's disease.

  • intercellular adhesion molecule 1
  • Crohn's disease
  • alicaforsen
  • ISIS 2302
  • aPTT, activated partial thromboplastin time
  • AUC, area under the curve
  • CDAI, Crohn's disease activity index
  • Cmax, maximum concentration
  • IBDQ, inflammatory bowel disease questionnaire
  • ICAM, intercellular adhesion molecule
  • PK, population pharmacokinetics
  • sICAM, soluble ICAM-1
  • TNF, tumour necrosis factor

https://doi.org/10.1136/gut.51.1.30

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    Footnotes

    • ISIS 2302-CS9 Investigators: F Anderson, G Koval, C Barish, M Safdi, D Taniguchi, L Sutherland, P Rutgeerts, W Depew, R Pruitt, S Hanauer, B Winston, B Dolin, W Koltun, R McCabe, J Scholmerich, S Van Deventer, G Wild, J Breiter, R Burakoff, J Deren, J Linne, M Regueiro, H Schwartz, B Shivakumar, D Binion, C Cattano, J Colombel, S Galandiuk, J Katz, V Rustgi, C Springgate, G Varilek, D Dalke, L Herzog, M Lamet, D Pambianco, J Singleton, E Torres, H Van Dullemen, R Baldassano, F Cortese, D James, P Moses, A Raedler, D Riff, D Stanton, S Wilkofsky

    • Conflict of interest: B Yacyshyn is a medical advisor for ISIS pharmaceuticals. W R Shanahan, R Yu, and J Tami, are current or past employees of ISIS pharmaceuticals, Carlsbad, California, USA.