The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients.
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.


CONCLUSIONS
FK778 is pharmacologically active, well-tolerated, and safe. To fully benefit from this promising new drug, FK778 dosing will be optimized in subsequent studies.
Vanrenterghem
Yves
Y
Inwendige Geneeskunde-Nefrologie, Universitaire Ziekenhuizen Gasthuisberg, Leuven, Belgium. yves.vanrenterghem@uz.kuleuven.ac.be
van Hooff
Johannes P
JP
Klinger
Marian
M
Wlodarczyk
Zbigniew
Z
Squifflet
Jean-Paul
JP
Mourad
Georges
G
Neuhaus
Peter
P
Jurewicz
Adam
A
Rostaing
Lionel
L
Charpentier
Bernard
B
Paczek
Leszek
L
Kreis
Henri
H
Chang
Rene
R
Paul
Leendert C
LC
Grinyó
Josep M
JM
Short
Colin
C
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D007555:Isoxazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010349:Patient Compliance; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016896:Treatment Outcome
D000480:Alkynes; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D011239:Prednisolone; D016559:Tacrolimus