Crohn's disease alicaforsen
Crohn's disease is a particularly unpleasant and incurable condition. In the intestinal tract of sufferers, sections become thickened, inflamed and ulcerated, particularly in the terminal part of the ileum. In its chronic form, the intestine can become partially obstructed, leading to pain, diarrhoea and the maladsorption of food, and complications can occur, particularly fistulae that develop between adjacent loops of the intestine, or even between the intestine and other organs. In severe cases, surgery is the only option, but various drugs can be used to ameliorate less severe symptoms, notably steroids and 5-amino salicylic acid derivatives.
A very different agent that is under development by Isis Pharmaceuticals is alicaforsen, formerly referred to as ISIS 2302, an antisense phosphorothioate oligodeoxynucleotide. Alicaforsen is an antisense inhibitor of ICAM-1, a molecule that plays a key role in a variety of inflammatory and autoimmune conditions. It is involved in the recruitment and activation of immune cells associated with the inflammatory response in these diseases. CAMs, or cellular adhesion molecules, can be found on the surface of virtually every cell within the body, including the cells that line the inflamed gastrointestinal tract in Crohn's patients.
A total of 299 patients with active, steroid-dependent Crohn's disease were given placebo or 2mg/kg alicaforsen three times a week for two or four weeks.1 They were treated in months one and three, with steroid withdrawal attempted by week 10. Steroid withdrawal was successful in more patients given the active than those given placebo.
A higher dose was given in another trial to a total of 22 patients.2 Patients weighing over 50kg with active Crohn's disease were randomly assigned to two alicaforsen treatment groups, and given 300 or 350mg of alicaforsen, infused intravenously three times a week for four weeks.
Patients weighing between 36 and 50kg were given doses of 250mg. Background aminosalicylates, antibiotics, immunosuppressives and corticosteroids were permitted, but tumour necrosis factor alpha inhibitors were prohibited. Over half of the evaluable subjects experienced remission, and the median duration of remission was 14 weeks, indicating that alicaforsen at these fixed doses may well be an effective therapy for Crohn's disease.