A randomized, placebo controlled trial of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 in the treatment of severe rheumatoid arthritis.

OBJECTIVE: To determine the safety of an antisense oligodeoxynucleotide to intercellular adhesion molecule-1 (ICAM-1) (ISIS 2302), administered in an intensive 4 week regimen with dose escalation; and to provide preliminary evidence for efficacy in rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a 6 month, double blind, placebo controlled, dual center, dose escalation (0.5, 1, and 2 mg/kg) study. Subjects received a total of 13 intravenous ISIS 2302 infusions, given on alternate days for 2 weeks and then 3 times a week for another 2 weeks. Doses of corticosteroids (< or = 10 mg/day) and disease modifying antirheumatic drugs (stable > or = 3 months) remained constant throughout the study. The primary efficacy endpoint was the Day 26 Paulus index, with secondary evaluations at Months 2-6. RESULTS: A total of 43 patients were enrolled with 11, 10, 3, and 19 patients receiving placebo or 0.5, 1, or 2 mg/kg of ISIS 2302, respectively. There were no differences between groups after randomization and the mean baseline swollen joint count was 22.5. Pharmacokinetic studies revealed a T(1/2) of 63 min and first-order kinetics with slight dose dependency, suggesting a saturable clearance process, although no accumulation was noted with repeat dosing. The Paulus 20% responses at Day 26 were 20%, 0%, and 5% for patients treated with ISIS 2302 (0.5, 1, 2 mg/kg, respectively) and 36% with placebo. For Months 2-6, the average intent-to-treat Paulus 20% responses were 21.2% for ISIS 2302 and 12.6% for placebo. Only ISIS 2302 treated subjects (19%) achieved Paulus 50% responses. ISIS 2302 was well tolerated. An expected and transient mean activated partial thromboplastin time increase of roughly 7 s was observed at the highest dose (2 mg/kg), as were small and clinically insignificant increases in serum C3a levels. T/B cell immunophenotyping, recall antigen skin testing, and serum immunoglobulin levels revealed no significant immunosuppressive effects. CONCLUSION: This study shows that 13 ISIS 2302 infusions over 4 weeks are well tolerated in patients with active RA. Although significant efficacy was not evident at the primary endpoint (1 month), the study lacked sufficient power to draw any formal conclusions. We tested a 4-fold drug concentration range, which led to a lower area under the curve range than was therapeutic in a subsequent Crohn's disease trial. Any further evaluation of this well tolerated ICAM-1 antisense agent should therefore be conducted at higher dosing.

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