A PHASE I STUDY: THE SIDE-EFFECT PROFILE OF AN INTERCELLULAR ADHESION MOLECULE-1 ANTISENSE PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE, ISIS 2302.

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244 Purpose: A phase I study in quiescent cyclosporine-prednisone(CsA-Pred) -treated renal transplant patients was performed to assess the safety and efficacy of ISIS 2302. Method: 16 stable cadaveric renal transplant patients (mean 3.2 years post-transplant) on a CsA-Pred dual-drug regimen received eight i.v. infusions of the intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in an ascending dose (0.05, 0.5, 1, or 2 mg/kg), double-blinded, placebo-controlled trial, with drug infusions over 6, 4, and 2 hours. Patients were randomized to active drug: placebo 3:1 ratio. Results: The outcomes were compared with a phase I trial in 44 normal volunteers. The primary side effects of ISIS 2302 were a significant and dose-related increase in PTT and a trend toward a decrease in platelet count. The effect was less pronounced with the slower infusion rate (6 hours vs. 2 hours) and did not increase with multiple dosing. In contrast to experience in normal volunteers, there were no significant changes in C3a, or indeed in C4a and C5a. No consistent changes from baseline or alteration in mean values were observed for serum creatinine, serum transaminases, bilirubin, hematocrit, or white blood cell count. Two profiles of CsA pharmacokinetics were unchanged from pretransplant profiles. There were no adverse clinical events associated with drug administration; specifically, there was no tendency toward a bleeding diathesis. However, one treated patient reported epistaxis, and one control patient experienced menorrhagia at a time remote from the infusion. Thereafter, we initiated a phase I/II trial(currently underway and still blinded). Using similar ascending doses, ISIS 2302 was administered for seven doses on a q.o.d. schedule to de novo renal transplant recipients. We have completed the first two dose levels randomized in a 3:1 active drug: placebo ratio and are almost finished with the last dose level (6:2 active drug: placebo). The safety is apparent; the efficacy will be reported following unblinding. Conclusions: The phase I trial showed that ISIS 2302 is a safe and efficacious drug in stable renal transplant patients, with fewer side effects than in normal volunteers. The dose-related increase in PTT was not clinically significant and can be abrogated by slower infusion rates. These data provide a foundation for wider clinical trials.TableMean Post-Pre PTT Difference