FTY720 versus MMF with Cyclosporine in de novo Renal Transplantation: A 1-Year, Randomized Controlled Trial in Europe and Australasia

Abstract

FTY720 is a novel immunomodulator investigated in de novo renal transplantation and other therapeutic areas including multiple sclerosis. This 1-year multicenter, randomized, phase III study in 668 de novo renal transplant patients compared FTY720 2.5 mg plus full-dose cyclosporine (FDC) or FTY720 5.0 mg plus reduceddose cyclosporine (RDC), with mycophenolate mofetil (MMF) plus FDC. The primary efficacy endpoint was the composite incidence of first treated biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation at month 12. Primary efficacy with FTY720 2.5 mg and MMF (32.4% and 30.2%; p = NS), plus mortality and BPAR incidence, were comparable. Patients receiving FTY720 5.0 mg plus RDC were discontinued from treatment due to increased risk of acute rejection (primary endpoint incidence 47.3%). FTY720 was associated with lower creatinine clearance (month 12: 53.1, 56.0 vs. 65.1 mL/min; p < 0.001) and more macular edema cases (2.2% and 1.3% vs. 0%), whereas cytomegalovirus infections were higher with MMF (6.2% and 10.6% vs. 18.1% p < 0.0001 and p = 0.0139, respectively). FTY720 2.5 mg provided comparable rejection prophylaxis over 12 months versus MMF; however, FTY720 5.0 mg did not support a 50% reduction in cyclosporine exposure. The cause of macular edema cases and lower creatinine clearance with FTY720 in de novo transplantation needs further investigation.

CCR7 Signaling Inhibits T Cell Proliferation

“…This drug induces a migratory block that prevents lymphocytes from exiting the lymph nodes. A notable immunosuppressive effect could be demonstrated in human solid organ transplantation (6,7).…”

Fingolimod: therapeutic mechanisms and ocular adverse effects

“…The clinical trials assessing the use of fingolimod as an antirejection agent in renal transplant patients was reported by Salvadori et al 27 and Tedesco-Silva et al 28 Both these clinical trials evaluated higher-dose fingolimod (5 and 2.5 mg) in association with cyclosporine, and both reported higher rates of macular oedema (Salvadori et al: 2.2% at 5 mg dose, 1.3% at 2.5 mg dose), (Tedesco-Silva et al: 3.4% at 5 mg dose and 1.7% at 2.5 mg). Tedesco-Silva and Salvadori did not exclude patients with diabetes in the sample population.…”

“…25,26 Incidence of FAME Macular oedema has been a well-documented side effect of fingolimod since it was originally evaluated as an anti-rejection agent for renal transplantation. 27,28 Fingolimodassociated macular oedema was therefore monitored for and reported in the initial clinical trials investigating the efficacy of fingolimod for RRMS. The FREEDOMS study was a phase III multicentre, 24-month, double blind randomised study comparing 0.5 mg (n = 425) and 1.25 mg (n = 429) fingolimod daily treatment with placebo (n = 418) in patients with RRMS.…”

Emerging Therapies for Multiple Sclerosis

“…Unexpectedly, both FTY720 treatment arms were associated with lower creatinine clearance and higher incidence of macular edema. 56,57 These results, unexplained but believed to be attributable to nonimmunological renal toxicity, indicated that FTY720 provided no benefit in comparison to standard care and resulted in temporary stopping of the development of FTY720 for renal transplantation.…”