Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Abstract

Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod-phosphate (fingolimod-P), is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod-P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P 1 S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti-inflammatory and possibly neuroprotective/ reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10Â the approved 0.5mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.

Fingolimod treatment in multiple sclerosis leads to increased macular volume

“…12 The S1P system, however, is also involved in many other biological processes, including maintenance of endothelial barrier function in a wide variety of tissues 13 as well as vascular permeability.…”

Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis

“…Recent studies with an EAE model using CNS-specific conditional S1P1 knock-out mice found that S1P1 was involved in the pathogenesis of EAE by regulating cells residing in the CNS, such as astrocytes [32,33], suggesting the possibility that S1P1 receptor agonists inhibit onset of EAE through not only immunological effects but neurological modulation. These studies demonstrated that functional From the day of grouping (day 0 of treatment) to day 55 of treatment, 0·5% methylcellulose (MC) or ONO-4641 (0·01, 0·03 or 0·1 mg/kg) was administered orally to each group once daily for 8 weeks.…”

Targeting molecules involved in immune cell trafficking to the central nervous system for therapy in multiple sclerosis

“…56,59 In lymph nodes, fingolimod acts as a potent agonist, leading to the internalization of S1P1 receptors with subsequent inhibition of C-C chemokine receptor type 7-positive lymphocytes egressed from lymph nodes. 61,62 Naive T cells and central memory T cells express the chemokine receptor C-C chemokine receptor type 7, which induces homing to the lymph nodes. As a consequence, fingolimod treatment blocks the migration of T cells to the CNS and suppresses MS. 59,63 Adverse effects accompanied by fingolimod treatment include increased susceptibility to viral infection as a result of lymphopenia.…”