The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

Abstract

The immunomodulatory drug fingolimod (FTY720, Gilenya) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P subtype by induction of receptor downregulation. Since S1P is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

“…(19) In addition, in our hands, relatively low concentrations of fingolimod were needed to achieve effective inhibition of the SKs, (14,55) which is opportune considering the toxicity potential of fingolimod. (15) In conclusion, we suggest that the S1P metabolic pathway can constitute a novel therapeutic target in the treatment of SpA. Moreover, fingolimod is the only US Food and Drug Administration (FDA)-approved drug to date targeting S1P signaling; notwithstanding, it also possesses numerous other molecular targets.…”

“…To our knowledge, this is the first study establishing that the drug can also inhibit SK2 activity, which is convenient because both SK1 and SK2 were implicated in chondrocyte and osteoblast mineralization in our previous study . In addition, in our hands, relatively low concentrations of fingolimod were needed to achieve effective inhibition of the SKs, which is opportune considering the toxicity potential of fingolimod …”

“…(13) Moreover, fingolimod can also inhibit SK1 activity (14) so that it is acknowledged as a general inhibitor of S1P metabolic pathway. (15) Fingolimod has been used since 2010 as an oral medication for the treatment of multiple sclerosis (Gilenya ® ; Novartis, Huningue, France), meaning that a good perspective on its potential in clinical therapeutics has been acquired. (16) Importantly, S1P is involved in the regulation of bone homeostasis (for review, see (17) ).…”

The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: A meta‐analysis

“…Fingolimod is the first sphingosine 1-phosphate (S1P) receptor modulator with high activity. 11,12 Although fingolimod is recommended as a second-line treatment in some countries including Canada and Europe, 13,14 it was approved as a first-line oral therapy in the USA for patients with RMS. 15 The efficacy of fingolimod has been Ting Yang and Xin Tian have contributed equally to this work.…”

Frequency and clinical characteristics of Multiple Sclerosis rebounds after withdrawal of Fingolimod

“…The underlying mechanism is elusive but may include a prompt repopulation of immune cells, which is also supported by preclinical studies. 3,4 Magnitude and phenotype of the rebound phenomenon are still under investigation. We therefore aimed to evaluate the frequency and clinical characteristics of rebounds in an independent cohort of patients with MS.…”