FTY720 and central memory

Abstract

The oral sphingosine 1 phosphate modulator, FTY-720 (Fingolimod, Gilenia®), demonstrated efficacy in 2 relapsing-remitting multiple sclerosis (MS) phase III clinical trials, FREEDOMS1 and TRANSFORMS,2 and may become one of the first oral therapies approved for MS. FTY720 binds 4 (S1P1, 3, 4, and 5) of the 5 S1P cell surface receptors, a family of G protein-coupled receptors that permit lymphocytes to exit lymph nodes. Upon binding, FTY720 causes internalization and degradation of S1P1, acting as a functional antagonist.3 As a result, FTY720 traps lymphocytes in lymph nodes, providing the initial rationale for testing it in inflammatory organ-specific autoimmune diseases, including MS. In FREEDOMS, 2 doses, 0.5 mg or 1.25 mg daily, reduced relapsed rate by more than 50% in comparison to placebo over 24 months, and in TRANSFORMS, both doses demonstrated superiority over IM interferon β-1a at 12 months. Consistent with its presumed mechanism of action, and results from a previous phase II MS trial,4 FTY720 treatment in these phase III trials was associated with reduction in circulating lymphocytes. A previous study by Mehling et al.5 demonstrated that FTY720 selectively reduced circulating T cells that either had not yet reacted to an antigen (naive T cells [TN]) or resting T cells that had previously been educated to respond to a specific antigen …