Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group

Over more than 15 years, the first-line treatment of RRMS predominantly consisted of four DMDs: Interferon (IFN) beta-1b (Betaferon^® 250 mg s.c. every other day), IFN beta-1a (Avonex^® 30 mg i.m. once a week), IFN beta-1a (Rebif^® 22 mg or 44 mg s.c. three times a week), and GA (Copaxone^® 20 mg s.c. once a day).

These agents have been approved by the European Medicines Agency (EMA) for the treatment of patients with RRMS after successful class I-randomized placebo-controlled trials [6‐15]. Further studies in patients who have had a single attack of demyelination (clinical isolated syndrome, CIS), and who were considered to be at high risk for clinically definite MS, led to the approval for Avonex^®, Betaferon^® , and Copaxone^® in this early stage of MS [16‐20]. Following one positive trial, Betaferon^® received approval from the EMA also for the treatment of patients with SPMS and superimposed relapses [21].

The benefit/risk profile of these DMDs was positively assessed on their efficacy to significantly reduce disease activity by reducing the number of relapses and the occurrence of new and enhancing lesions detected by magnetic resonance imaging (MRI) and delaying relapse-related progression of disability compared to placebo. Studies in CIS and data from natural history studies have led to a consensus to consider treatment at least as soon as the diagnosis of MS is established or after a CIS if there is a high risk to develop clinically definite MS.

The moderate efficacy of the DMDs is accompanied by a safety profile with mild to moderate frequent adverse events. For IFN beta products, these comprise of injection site reactions/pain and the post injection flu-like syndrome for 12–24 h which are often transient and subside after the first 6 weeks, and of rare local skin necrosis. With GA injection, site reactions include erythema, pain, and lipoatrophy and the rare post injection systemic reaction, which includes vasodilatation, chest tightness, and shortness of breath lasting 5–15 min, which may occur once during treatment in about 20 % of patients [22‐25].

Besides lack of therapeutic efficacy and the inconvenience of side effects, particularly in the first months of treatment, the fact that all first-line DMDs have to be applied by injection limits adherence to long-term treatment with these drugs.

Complete adherence to the dose regimen was found in 75 % of 2,648 patients with average treatment duration of 31 months in a multicenter observational study [26]. Patients and physicians received paper questionnaires regarding adherence to the prescribed treatment regimen. Adherence was defined as not missing a single injection within 4 weeks before the study. The most common reasons for nonadherence were forgetting to administer the injection and other injection-related reasons. Another recently published study assessed the impact of adherence to DMDs on clinical and economic outcomes in a cohort of 2,446 patients [27]. Adherence was assessed in this study using the medication possession ratio (MPR) derived from the administrative claims database. Patients with MPR ³ 80 % were regarded as adherent. A total of 59.6 % of the patients were adherent to their treatment. Adherence was associated with better clinical and economic outcomes including lower risks for MS-related hospitalization, MS relapses, and less MS-related medical costs. In an adherence study comparing data from retrospective self-reports, medication diaries and electronic monitoring of needle disposal, Bruce found that nearly one-fifth of the patients missed more than 20 % of the injections and concludes that studies using self-reports and diaries may underestimate poor adherence [28].

Fingolimod is the first orally bioavailable sphingosine 1-phosphate (S1P) receptor modulator. S1P is derived from sphingosine, phosphorylated by ubiquitously appearing sphingosine-kinases. S1P binds to five cell-surface high-affinity G-protein-coupled receptors, the S1P_1–5. Distribution and signalling function varies between the subtypes. S1P_1–3 are mainly distributed in the immune system, CNS and cardiovascular organs, S1P₄ in lymphoid tissue and S1P₅ in CNS white matter [42, 43].

S1P and its receptors regulate circulation of lymphocytes between blood and lymphoid organs depending on specific requirements of the immune system and accomplished by enzymes that regulate sphingolipid metabolism and partly by a concentration gradient between lymphoid organs and blood [43].

Specifically S1P₁ on lymphocytes regulates homing and egress of lymphocytes in and from lymphoid organs. The active phosphorylated form of fingolimod binds with high affinity to S1P₁ and to a less extent to S1P_3–5. For the treatment of MS, the most important consequence of the down-regulation (internalization) of S1P₁ is that T-lymphocytes, including potentially auto-aggressive T cells, remain retained in lymph nodes and their number in the circulation is considerably reduced (Fig. 1).

Experimental and clinical data indicate that fingolimod retains naïve T cells and central memory T cells (TCMs) including Th17 cells in lymphoid tissue. The proinflammatory Th17 cells may have a central role in CNS inflammation [44]. In a small prospective observational study, fingolimod reduced the number of Th17 (IL17 producing cells) by > 90 % [45]. The retention of lymphocytes does not lead to an enlargement of lymph nodes since normally only 2 % of the total number of these cells circulate in the blood.

Fingolimod crosses the blood–brain barrier and the oral formulation can result in biologically active concentration in the CNS. It is likely that the drug interacts directly with S1P receptors on neurons, oligodendrocytes, astrocytes, and their progenitor cells. In rodent experimental autoimmune encephalomyelitis models, fingolimod has demonstrated prophylactic and therapeutic efficacy, reversing central inflammation, favouring preservation of the integrity of the blood–brain barrier, and inducing structural and functional restoration of the CNS parenchyma [42, 46‐50]. Ongoing preclinical and clinical studies are looking at whether the direct interaction with S1P receptors in the CNS contributes to the clinical efficacy of the drug and can provide a clinically relevant reduction of neurodegenerative processes or initiate repair mechanisms in MS patients [50].

Clinical efficacy and safety of Fingolimod have been evaluated in an extensive development program which has been already reviewed elsewhere [50‐52]. In short, the phase II study program consisted of a six-months placebo-controlled core study of 281 patients with relapsing MS and a six-months extension switching placebo patients to active treatment which showed a significant reduction in the detection of new MS lesions on MRI and of clinical disease activity for both daily doses of 1.25 or 5.0 mg of fingolimod [53]. In the subsequent follow-up of these patients, all patients receiving fingolimod 5.0 mg were switched to 1.25 mg during months 15–24 with no indication that lowering the dose from 5.0 to 1.25 mg was associated with a reduction of efficacy [54]. This consistent therapeutic effect was also confirmed after 36 months [55].

The phase III program consisted of two large trials, the placebo-controlled FREEDOMS (FTY Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) and the TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis) studies.

In FREEDOMS, which included a total of 1,272 RRMS patients, all clinical and MRI efficacy endpoints significantly favoured both active-treated groups over placebo with no difference in efficacy between the two fingolimod doses after 24 months [56]. The annualized relapse rate (ARR) was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg fingolimod, and 0.4 with placebo (p < 0.001 for both fingolimod doses versus placebo). Fingolimod reduced the risk of disability progression, confirmed after 3 months, over the 24-months period (hazard ratios were 0.70 for the 0.5 mg dose and 0.68 for the 1.25 mg dose; p = 0.02 vs placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7 % for fingolimod 0.5 mg, 16.6 % for fingolimod 1.25 mg, and 24.1 % for placebo. The risk of disability progression confirmed after 6 months was also reduced with both doses of fingolimod over the study period. EDSS scores and MSFC z-scores remained stable or improved slightly in the active treatment groups and worsened in the placebo group. Both fingolimod doses were also superior to placebo with regard to MRI-related measures. Actively treated patients had significantly fewer Gd⁺ lesions than patients on placebo (mean 0.2 vs 1.1) and significantly fewer new or enlarged lesions on T2-weighted MRI scans at 24 months (mean 2.5 vs 9.8). Ninety percent of actively treated patients were free of Gd⁺ lesions compared to 65 % of placebo-treated patients. Beneficial effects of fingolimod were also noted on the volume changes in lesions on T2- and T1-weighted scans and brain volume reduction was significantly smaller with fingolimod [56].

TRANSFORMS compared the efficacy of fingolimod 0.5 or 1.25 mg daily with that of IFN beta-1a at weekly doses of 30 mg IM over a 12-months period in 1,292 patients with RRMS [57]. The ARR defined as the primary efficacy endpoint was significantly lower in both groups receiving fingolimod compared with the INF beta-1a group (0.20 in the 1.25 mg group, 0.16 in the 0.5 mg group—Fig. 2—and 0.33 in the INF beta-1a group; p < 0.001). Significantly more relapse-free patients were found in the two fingolimod groups compared to INF beta-1a-treated patients (79.8 % for 1.25 mg, and 82.6 % for 0.5 mg vs 69.3% for INF beta-1a; p < 0.001). Confirmed disability progression was infrequent in all study groups. There were no significant differences in the time to progression of disability or in the proportion of patients with confirmed progression among the study groups. MRI findings supported the primary clinical results. Patients in the two fingolimod groups had significantly fewer new or enlarged hyperintense lesions on T2-weighted images (1.5 for 1.25 mg, 1.7 for 0.5 mg, and 2.6 for INF beta-1a) at 12 months compared to the INF beta-1a group and fewer Gd⁺ lesions (0.23, 0.14 vs 0.51). The mean percent reduction in brain volume from baseline to 12 months was significantly lower in the two fingolimod groups than in the INF beta-1a group [57].

In the TRANSFORMS extension study switching from INF beta-1a to fingolimod led to enhanced efficacy while continuous treatment with fingolimod over 2 years provided a sustained treatment effect [58].

The most frequent reported adverse events in MS-studies with fingolimod 0.5 mg were influenza viral infections, nasopharyngitis, fatigue, back pain, diarrhea, bronchitis, and nausea. The most common laboratory abnormalities observed with fingolimod were lymphopenia and abnormal liver function tests. In the FREEDOMS study, treatment was discontinued due to adverse events in 7.5 % of patients on fingolimod 0.5 mg, in 14.2 % of patients on fingolimod 1.25 mg, and in 7.7 % of patients on placebo, the rate of any serious adverse event was 10.1, 11.9, and 13.4 %, respectively [56].

The overall rate of infections was similar in the fingolimod and placebo groups. Lower respiratory tract infections were more frequent in the fingolimod groups compared to the placebo group (9.6, 11.4 vs 6.0 %). After the first month of the trial, the blood lymphocyte counts were reduced by 73 % with fingolimod 0.5 mg and by 76 % with fingolimod 1.25 mg.

After the first dose of fingolimod, heart rate decreased with a maximum reduction of resting pulse rate of 8 bpm with fingolimod 0.5 mg and 10 bpm with fingolimod 1.25 mg. Bradycardia was reported in nine patients on fingolimod 0.5 mg and in 14 on fingolimod 1.25 mg. Seven of these cases were assessed as serious adverse events and resolved within 24 h without treatment. Two patients from the fingolimod 0.5 mg group, six patients from the fingolimod 1.25 mg group, and three patients of the placebo group developed first- or second-degree atrioventricular (AV) block. During extended treatment, no effects on heart rate were observed.

Macular edema was reported in 7 patients of the fingolimod 1.25 mg group. The majority of the cases were diagnosed within the first 3 months of the study and resolved within 6 months after discontinuation of fingolimod.

Malignant neoplasms were reported in four patients on fingolimod 0.5 mg, four receiving fingolimod 1.25 mg, and in ten patients of the placebo group. Eleven of these cases were skin cancers (basal-cell carcinoma, malignant melanoma, or Bowen’s disease), three cases in the fingolimod 1.25 mg group, four cases in the 0.5 mg group, and four with placebo. All were removed successfully.

The safety profile of the TRANSFORMS trial (Fig. 3) was very similar to the FREEDOMS study with the addition of two cases of macular edema and one case of second-degree AV Block in the 0.5 mg fingolimod group [57].

Based on the pharmacodynamic properties of fingolimod and its mode of action in MS, special safety areas have to be mentioned and closely monitored:

Initiation of treatment with fingolimod results in a transient decrease in heart rate and may induce AV conduction delays (AV block first or second degree). This also applies to recommencing treatment after an interruption of more than 14 days. After the first dose, the decline in heart rate starts within 1 h and is maximal at approximately 4–5 h. With continued administration, heart rate returns to baseline within 1 month. Conduction abnormalities were usually asymptomatic, did not require treatment, and resolved within 24 h (in the study, two patients were treated with atropine and one patient was treated with isoproterenol).

Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20–30 % of baseline levels because of the reversible sequestration of lymphocytes in lymphoid tissues. Fingolimod may therefore increase the risk of infections, some serious in nature. In MS studies, the overall rate of infections (72 %) and serious infections (2 %) with the 0.5 mg dose was similar to placebo. However, lower respiratory tract infections, primarily bronchitis and, to a lesser extent, pneumonia were more common in fingolimod-treated patients.

Two fatal cases of herpes infections occurred with the 1.25 mg dose: a case of herpes simplex encephalitis in a patient in whom initiation of acyclovir treatment was delayed by one week, and a case of primary disseminated varicella zoster infection in a patient not previously exposed to varicella receiving concomitant high-dose steroid therapy for an MS relapse. Even though fatal infection occurred only in the high-dose group, opportunistic infection could also happen with lower doses.

Macular edema with or without visual symptoms has been reported in 0.4 % of patients treated with fingolimod 0.5 mg and in 1.1 % of patients with the higher dose of 1.25 mg, predominantly in the first 3 to 4 months of treatment. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed at routine ophthalmological examination. The macular edema generally improved or resolved spontaneously after discontinuation of fingolimod treatment.

During clinical trials, fingolimod 0.5 mg was associated with a threefold or greater elevation in liver transaminases in 8 % of treated patients compared to 2 % of the placebo patients. The mechanism of this effect has not been identified. The elevation of liver enzymes was generally asymptomatic, observed after 3 to 4 months of treatment and turned to normal within approximately 2 months after discontinuation of fingolimod treatment.

Animal studies have shown reproductive toxicity including fetal loss and organ defects. S1P receptors are known to be involved in vascular formation during embryogenesis.

Clinical trial data suggest that no wash-out period is needed when switching from INF beta or GA to fingolimod if any immune effects of such therapies have resolved. In the clinical trials, patients were excluded if treated with natalizumab, other monoclonal antibodies or cytotoxic drugs in less than 6 months prior to fingolimod therapy [56, 57].

Fingolimod 0.5 mg daily is the first oral drug for the treatment of RRMS. At present, it is approved as a first-line treatment for relapsing forms of MS in the United States, in Russia, Switzerland, and in the United Arab Emirates.

In Europe, the CHMP defined the indication for fingolimod as a disease-modifying monotherapy in highly active RRMS:

From a clinical point of view, treatment failure is defined as continuing disease activity (in the form of relapses supported by new or active MRI lesions) and progression of disability. According to expert opinion this applies in a similar manner to prior treatment with GA as to that with INF beta. In clinical practice, unbearable side effects and low compliance also constitute a kind of treatment failure. Since no combinations of DMDs and immunosuppressant or cytotoxic drugs are approved in the case of a treatment failure and no robust clinical studies on the efficacy of such combinations are published, the concept of escalating immunotherapy of the Multiple Sclerosis Therapy Consensus Group is still appropriate for this situation [59]. The proposed algorithm for patient evaluation and decision-making is provided in Fig. 4. In a hierarchy of the existing approved and labelled treatments of RRMS, fingolimod is positioned equal to natalizumab in Europe (Fig. 5). The reason for the identically labelled indications of the two substances in Europe may on one hand come from their comparable efficacy in clinical and MRI endpoints of clinical studies. On the other hand, the potential risk of fingolimod treatment may have been assessed with caution while long-term experience, as with any new drug before introduction into clinical practice, is limited. Excluding the patients at risk by careful pretreatment examination and follow-up according to the above recommendations will contribute to the safety of fingolimod in clinical practice and serve to maximize patients’ benefits from the advantages of this new drug.

In conclusion, large phase III studies with fingolimod have shown favorable efficacy compared to placebo and to a standard treatment with INF beta-1a i.m. and an acceptable safety profile. The position of fingolimod in clinical practice will be influenced by issues of long-term adherence, quality of life, and long-term safety of patients. To ensure best use of this new treatment for patients with RRMS, treatment should be initiated by experienced MS-centers and monitored and documented according to the recommendations in the six special safety areas.