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.