FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.
BACKGROUND
FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation.


METHODS
This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up.


RESULTS
The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation.


CONCLUSIONS
FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.
Tedesco-Silva
Helio
H
Hospital do Rim e Hipertensao, Borges Lagoa 960, Sao Paulo, SP 04038-002, Brazil. heliotedesco@hrim.com.br
Mourad
Georges
G
Kahan
Barry D
BD
Boira
Josep Grinyo
JG
Weimar
Willem
W
Mulgaonkar
Shamkant
S
Nashan
Björn
B
Madsen
Soren
S
Charpentier
Bernard
B
Pellet
Pascale
P
Vanrenterghem
Yves
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D002102:Cadaver; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008875:Middle Aged; D011409:Propylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012449:Safety; D013110:Sphingosine / Q000031:analogs & derivatives; D014019:Tissue Donors; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine