The Effects of FK778 in Combination With Tacrolimus and Steroids: A Phase II Multicenter Study in Renal Transplant Patients

Abstract

BACKGROUND: In animal and in vitro models, FK778 inhibits acute rejection, modifies vasculopathy, and shows anti-viral activity. We report first efficacy and safety data of FK778 in human kidney transplant recipients at two concentration-controlled ranges. METHODS: In a double-blind manner, 149 patients were randomized to a 12-week treatment with FK778 in combination with tacrolimus (Tac) and corticosteroids (S). Of the high-level group (H), 49 patients received 2 x 600 mg/day FK778 and continued on 150 mg/day, 54 patients of the low-level group (L) got 1 x 600 mg/day followed by 75 mg/day, and 46 patients received placebo (P). Subsequent FK778 doses were adjusted to trough levels of 100-200 microg/mL (H) and 10-100 microg/mL (L). The primary endpoint was the incidence of biopsy proven acute rejection (AR). RESULTS: In 93% of the patients in group L, targeted plasma trough levels were reached by Day 3; in half of the patients in group H, the targeted levels were reached by Day 9. Graft survival at week 16 was 89.7%, 88.8%, and 91.3%, and the incidences of AR were 26.5%, 25.9%, and 39.1% for groups H, L, and P. For the subgroup of patients in which target levels were reached by week 2, incidences were 7.7%, 27.1%, and 39.1%, respectively. Anemia, the most frequently reported adverse event especially in group H, was reversible. Mean total cholesterol and LDL-cholesterol levels were reduced during FK778 treatment compared with group P. CONCLUSION: FK778 is pharmacologically active, well-tolerated, and safe. To fully benefit from this promising new drug, FK778 dosing will be optimized in subsequent studies.