Alicaforsen for the treatment of inflammatory bowel disease

ABSTRACT

Introduction: Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue. Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-regulates ICAM-1 mRNA.

Areas covered: We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen for the treatment of ulcerative colitis (UC), pouchitis and Crohn’s disease (CD).

Expert opinion: After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn’s disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European Medicines Agency.

KEYWORDS:

• Inflammatory bowel disease
• ulcerative colitis
• anti-integrin
• alicaforsen
• safety
• adverse events

Article highlights

• Alicaforsen is a 20 base intracellular adhesion molecule-1 (ICAM-1) anti-sense oligonucleotide developed by ISIS pharmaceuticals Inc. (Carlsbad, CA, USA) and assigned the name ISIS 2302. It is a highly selective ICAM-1 inhibitor, leading to downregulation of ICAM-1 mRNA.

• In CD, it was not found to be any more effective than placebo in phase 2 and 3 trials, via parenteral administration.

• For UC, administered as a topical enema, it was significantly more effective than placebo in the treatment of distal colitis. There was no difference in comparison to mesalamine enemas, although alicaforsen appears to have a more durable treatment effect.

• An open label trial in patients with pouchitis showed encouraging results, now awaiting confirmation in a multi-national phase III trial which is currently recruiting

• No major safety signals have emerged to date

• Currently alicaforsen is accessible as an unlicensed medicine in selected EU countries through a named patient program in accordance with international regulation.

• It has potential to establish a new therapeutic class for treatment of pouchitis and has been granted fast-track and orphan designation for this indication by the FDA accordingly.

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Declaration of interest

V. Jairuth has received scientific advisory board fees from Abbvie, Sandoz, Ferring and Janssen; speaker’s fees from Takeda and Ferring. B. Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie, and J&J/Janssen. R. Khanna has received honoraria from AbbVie, Janssen, and Takeda PharmaThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.