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

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Abstract

The immunomodulatory drug fingolimod (FTY720, GilenyaR) 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 S1P1 subtype by induction of receptor downregulation. Since S1P1 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.

Section snippets

Historic development of fingolimod

Fingolimod (FTY720, GilenyaR, 2-amino-2[2-(4-octylphenyl)ethyl]-1,3-propanediol) was originally synthesized by the Japanese chemist Tetsuro Fujita from Yoshitomi Pharmaceutical Industries Ltd. (present Mitsubishi Tanabe Pharma Corporation, Japan) (Adachi et al., 1995) using the natural compound myriocin (ISP-1) as a lead. Myriocin was previously isolated by the same group from the culture broth of Isaria sinclairii, the imperfect or asexual stage of the genus Cordyceps sinclarii

Mechanism of action of fingolimod

The main immunomodulatory mechanism of action of fingolimod is based on its effect on lymphocyte homing. It reversibly redistributes T and B cells from the circulation to secondary lymphoid organs like peripheral and mesenteric lymph nodes and Peyer's patches, thereby causing a state of peripheral lymphopenia (Chiba et al., 1998). Since fingolimod resembles in chemical structure the sphingolipid molecule sphingosine, it can serve as a substrate for sphingosine kinase (SphK) to become

The S1P1 receptor

As outlined above and because of its binding to and activation of the various S1P receptor subtypes, except for S1P2, “active” fingolimod is pharmacologically considered an unselective S1P receptor agonist (Brinkmann, 2007, Brinkmann et al., 2002, Mandala et al., 2002). Moreover, it causes sustained desensitization of the S1P1-mediated signaling pathway by inducing receptor internalization and degradation, which on the cellular level results in functional antagonism. This effect of fingolimod

Pharmacokinetic characteristics of fingolimod

The pharmacokinetic characteristics of fingolimod as shown in Table 1 were summarized from the report NDA 22–527 submitted to the FDA for drug approval. A major advantage of fingolimod as a therapeutic agent is the possibility of oral application. Absorption is food-independent and slow (maximal plasma concentration after 12–16 h), but extensive, and its bioavailability is high (93%). It reaches steady-state concentrations after 1–2 months during daily intake (Clinical Pharmacology and

Fingolimod as a therapeutic agent

From its main effect to deplete peripheral lymphocytes, it is obvious that fingolimod has potential for the treatment of diseases associated with inappropriate immune responses, such as in allograft rejection and autoimmunity. First preclinical studies in rats, mice and dogs revealed a delay in allograft rejection with fingolimod alone and an even synergistic effect when used together with CSA (Chiba et al., 1996, Suzuki et al., 1996). It was then tested in several phase 1 to phase 3 clinical

Adverse effects of fingolimod

Table 2 summarizes some of the adverse events reported from patients with RRMS treated with low doses of 0.5 mg fingolimod daily for 24 months (FREEDOMS II). Those seen more frequently with fingolimod than with placebo included lymphopenia, increased liver transaminases, herpes viral infections, hypertension, and initial bradycardia and first degree AV block both as first-dose effects. Of note, analysis of pooled safety data from various phase 2 and phase 3 studies revealed that the risk for

Perspectives

Fingolimod was the first S1PR modulator reported to have immunosuppressive activity and it is so far the only one that was approved for clinical use. However, fingolimod is a nonspecific S1PR agonist and therefore new functionally related compounds have been developed, which better discriminate between the various S1PR subtypes and hence are expected to have improved efficacy and tolerability. These include the S1P1 selective compounds KRP-203, ponesimod and cenerimod, the S1P1 + 5 selective

Acknowledgments

This work was supported by the Swiss National Science Foundation (3100A0-111806).

Conflict of interest

None.

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