FTY720/Cyclosporine Regimens in De Novo Renal Transplantation: A 1-Year Dose-Finding Study

Abstract

FTY720 is a novel immunomodulator being investigated for rejection prophylaxis in renal transplantation when combined with full-dose cyclosporine (CsA; FDC). This 1-year phase II study compared FTY720 plus FDC (Neoral ® ) with FTY720 plus reduced-dose CsA (RDC) and mycophenolate mofetil (MMF) plus FDC in de novo renal transplant patients. Patients were randomized 2:2:2:1 to FTY720 5 mg plus RDC (n = 72); FTY720 2.5 mg plus RDC (n = 74); FTY720 2.5 mg plus FDC (n = 76); or MMF plus FDC (n = 39) for 12 months. CsA exposure in the RDC group was reduced on average by 50% as assessed by C 2 monitoring. The primary efficacy endpoint was the composite incidence of biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation. The incidences for this composite endpoint were 24% and 22%, respectively, for FTY720 5 mg plus RDC and FTY720 2.5 mg plus FDC versus 39% for MMF plus FDC. Patients receiving FTY720 2.5 mg plus RDC were discontinued from treatment due to risk of under-immunosuppression. FTY720 2.5 mg plus FDC and FTY720 5 mg plus RDC were safe and effective in de novo renal transplant patients over 12 months.

“Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets

“…It was expected that FTY720 would decrease the required doses of conventional immunosuppressive agents such as cyclosporine, particularly for renal transplantation, which is a known nephrotoxin. Unfortunately, recent results of multiple large clinical trails were all quite disappointing, failing to demonstrate a large advantage of FTY720 over standard care (Tedesco-Silva et al, 2005Mulgaonkar et al, 2006;Salvadori et al, 2006).…”

“…Two phase 2 clinical trials evaluating the efficacy of FTY720 for immunosuppression in renal transplant recipients have been published (Tedesco-Silva et al, 2005;Mulgaonkar et al, 2006). The first study was a multicenter, open-label, dose-finding study comparing FTY720 with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids (Tedesco-Silva et al, 2005).…”

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

“…The novel immunomodulator, FTY720, was developed to address this need (2), and is being investigated in the de novo renal transplant population (3)(4)(5)(6) as well as other therapeutic areas, such as multiple sclerosis (MS) (7). FTY720 is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1P-R) modulators (8)(9)(10).…”

“…The efficacy of FTY720 in preventing acute rejection in de novo renal transplant recipients has been evaluated in two phase II studies (5,6) demonstrating that FTY720 2.5 mg plus full-dose cyclosporine (FDC) microemulsion (Neoral ® , Novartis Pharma AG, Basel, Switzerland) (5) and FTY720 5.0 mg plus reduced-dose cyclosporine (RDC) (6) …”

Therapy of autoimmune diseases by novel immunosuppressant FTY720

“…However, despite promising phase II results, patients receiving 5mg FTY plus RDC exhibited higher incidence of humoral acute rejection (AR). This suggested that 5mg FTY did not support a 50% reduction in CsA exposure for the prevention of AR and thus, patients in this study arm were prematurely discontinued from study medication 25,26) . FTY was highly effective in Phase II clinical trials with relapsing multiple sclerosis (MS) 27,28) .…”