ISIS 2302, an antisense inhibitor of intercellular adhesion molecule 1

Abstract

ISIS 2302 is a 20 base phosphorothioate oligodeoxynucleotide (ODN) that inhibits intercellular adhesion molecule 1 (ICAM-1) expression through an antisense mechanism. Murine and rat analogues have been effective at doses of 0.06 - 10 mg/kg in a spectrum of models of human inflammatory diseases and allograft transplantation, and ISIS 2302 inhibits the upregulation of ICAM-1 expression in a variety of human cells in vitro. In animals, including primates, plasma distribution half-life ranges from 30 - 60 min, but tissue elimination half-lives range from 1 - 5 days, and the compound is metabolised as other nucleic acids. In a Phase I iv. study, the pharmacokinetic behaviour of ISIS 2302 was similar to that in other primates, and single and multiple every other day doses from 0.06 - 2 mg/kg infused over 2 h were well-tolerated. Phase IIa studies have been completed in Crohn’s disease, rheumatoid arthritis, and psoriasis, and a combined Phase I/II renal allograft acute rejection prophylaxis study has just completed enrolment. In these studies, ISIS 2302, 0.5 - 2 mg/kg, or placebo was administered iv. every 2 - 3 days over 14 - 26 days (7 - 13 infusions) to 17 - 52 patients, with follow up for 6 months. In the Crohn’s study, evidence of highly durable (5+ month) remission-inducing and steroid-sparing properties were demonstrated, without clinically important adverse events. A 300-patient, pivotal quality trial investigating the steroid-sparing and remission-inducing qualities of ISIS 2302 in patients with steroid-dependent Crohn’s disease is completely enrolled, with results expected in the first half of 2000. Modest efficacy and excellent tolerability were demonstrated in the psoriasis and rheumatoid arthritis trials. A Phase IIa trial of a topical formulation in patients with psoriasis is expected to commence in late 1999, as is a trial of an enema formulation in distal ulcerative colitis. Administration by nebulisation for asthma is undergoing preclinical evaluation. Execution of future plans in organ transplantation will await the results of the ongoing Phase I/II trial.

• antisense oligodeoxynucleotide
• Crohn’s disease
• intercellular adhesion molecule 1 (ICMA-1)
• psoriasis
• renal allografting
• rheumatoid arthritis