Prediction of clinical responses in a simulated phase III trial of Crohn's patients administered the antisense phosphorothioate oligonucleotide ISIS 2302: comparison of proposed dosing regimens.

ISIS 2302, an antisense phosphorothioate oligonucleotide (ODN) targeting human intercellular adhesion molecule-1 (ICAM-1) mRNA, is currently being evaluated for treatment of patients with Crohn's disease. From data collected in phase II clinical studies with ISIS 2302, validated population pharmacokinetic and exposure-response models were developed and used to simulate the plasma exposure and clinical response results for a proposed phase III trial design involving 100 patients treated with active drug and 50 patients treated with placebo. Simulated results of 1000 replications of the trial were calculated for various proposed dosing regimens. Overall, the simulated results indicated that a fixed dose regimen (250-400 mg, depending on patient sex and total body weight) given three times weekly provides both desirable ISIS 2302 plasma exposure and a high rate of clinical response in this patient population. However, the simulated results also suggest that inclusion of a larger number of patients than projected may be necessary to provide a desirable probability of study success (i.e., >80%), regarding demonstration of statistically significant differences between the active treatment and placebo groups for the primary clinical response measure (CCR rate).