Gilenya (Fingolimod): the first oral treatment: A changing treatment landscape for multiple sclerosis: challenges and opportunities

Fingolimod: the first oral treatment
Fingolimod (Gilenya) was the first oral treatment approved for RRMS and is also the first in class for drugs targeting sphingosine-1-phosphate receptors (S1PRs). This derivate of the fungus Isaria sinclairii and structural analogue of sphingosine acts as an antagonist on S1PRs. There are five known S1PRs, which are expressed on a number of different cell types. However, the main mechanism of action of fingolimod in MS is thought to be the sequestration of lymphocytes in lymph nodes due to blocking of S1PR1, which is present at variable levels on different types of immune cells (Fig. 2) [37]. Pharmacologically, fingolimod causes a pronounced lymphopenia in peripheral blood. The most prominent reduction in lymphocyte numbers is seen for naïve and central memory T cells (TCM), with a smaller reduction in peripheral effector memory T and B cells, and natural killer (NK) cells and monocytes are largely unaffected [38, 39]. Fingolimod reduces Th17-expressing TCMs, which are found mainly in the blood (90% of TCMs) and are believed to be important for MS pathogenesis, without affecting T cell activation [40]. Thus, similar to natalizumab, fingolimod mainly targets lymphocyte trafficking without affecting lymphocyte activation patterns. The half-life of fingolimod is approximately 1 week, and it takes at least 2 months for lymphocyte counts to recover upon stopping drug administration.

Fingolimod: efficacy and safety issues
Fingolimod was approved in the USA in 2010 (first line) and the EU in 2011 (second line) based on two pivotal Phase III studies: FREEDOMS to assess fingolimod 1.25 mg or 0.5 mg versus placebo over 2 years [41], and TRANSFORMS with the same doses of fingolimod versus weekly IFNβ over 1 year [42]. These two studies showed a reduction in ARR of 53–60% compared to placebo and of 38–52% compared to IFNβ, respectively. Secondary outcome measures in the FREEDOMS study were also significant, and close to 90% of treated patients were free of gadolinium-enhancing lesions compared to 65% in the placebo group. The deaths of two study subjects in the 1.25-mg arm of the TRANSFORMS study, one due to herpes encephalitis and the other to a primary varicella zoster virus (VZV) infection, caused concerns over the risk of opportunistic infections. It is therefore recommended that VZV immunity status should be determined before initiating therapy. Another safety concern is the fact that S1PRs are present in the heart and that pharmacological blockade perturbs electroconduction. In fact, bradycardia and heart block are known side effects, and fingolimod should therefore be used with care in patients with known heart conditions, especially as several cases of sudden death in MS patients treated with fingolimod have been reported [43]. A third safety concern is the risk of macular oedema, which has been detected in 0.5% (13 of 2564) of patients in the registration studies, although only in two patients receiving the approved 0.5-mg dose [44]. It is therefore recommended that patients undergo ophthalmological examination after initiating therapy. The risk of macular oedema is increased in patients with diabetes, and fingolimod should only be used after carefully considering alternative therapies for these patients. Fingolimod has been shown to mediate neuroprotective effects and to enhance remyelination in preclinical models of MS, which has fuelled hopes that the drug may also be effective in progressive forms of MS. This notion needs confirmation in clinical studies, and currently fingolimod is being tested in the ongoing INFORMS study, which is the largest PPMS trial to date [45]. In addition, several second-generation S1PR antagonists are in clinical trials for the treatment of MS. The two main advantages of these drugs are (i) a higher selectivity for the S1PR1 receptor subtype preferentially expressed on lymphocytes, thereby possibly reducing the risk of side effects and (ii) shorter half-lives, thus enabling faster washout if therapy needs to be interrupted.
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