Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension

Fingolimod (FTY720) 0.5 mg once daily is the first oral therapy approved for relapsing multiple sclerosis (MS) in many countries, including the USA [1], for relapsing-remitting MS (RRMS) with high disease activity in the European Union [2], and for the treatment of MS in Japan [3]. Fingolimod binds to sphingosine 1-phosphate receptors (S1PRs) on lymphocytes leading to retention of circulating lymphocytes in the lymph nodes. This reversible reduction in the number of peripheral blood lymphocytes is postulated to be mechanistically important in MS, decreasing the recirculation of autoreactive lymphocytes and preventing their infiltration into the central nervous system [4, 5].

Global phase 2 and 3 clinical studies have established a favorable efficacy and safety profile for fingolimod in predominantly Caucasian populations with MS [6‐9]. A 6-month, phase 2, registration study (ClinicalTrials.gov Identifier NCT00537082) in Japanese individuals demonstrated that fingolimod was associated with reduced inflammatory brain lesion activity and relapse rate compared with placebo [10].

This phase 2 extension study aims to assess the long-term efficacy, safety and tolerability of fingolimod in Japanese patients with relapsing MS. Here we report 12-month efficacy and safety data in individuals continuously receiving fingolimod and in those whose treatment was switched to fingolimod during months 7–12 from placebo during months 0–6 (termed the placebo-fingolimod group). The effects of delaying the initiation of fingolimod therapy can be assessed by comparing patients continuously treated with fingolimod from month 0 and patients switched to fingolimod 6 months later.

This extension study provides additional data with which to establish the efficacy and safety profile of fingolimod in Japanese patients with relapsing MS. Overall, the efficacy and safety findings were consistent with those in the core study [10]. Patients who received continuous fingolimod treatment for 12 months experienced sustained or improved efficacy outcomes during the extension phase and had reduced relapse rates and MRI lesion activity compared with those in the core study. Furthermore, efficacy endpoints were consistently superior at month 12 in the continuous fingolimod groups compared with the placebo-fingolimod groups.

The results of this trial are consistent with those of previously reported clinical studies of fingolimod in predominantly Caucasian populations [6‐8, 14]. The results are clinically important because there are genetic, metabolic and lifestyle differences between Caucasian and Japanese populations [15, 16], as well as differences in the presentation of MS that may affect response to therapy. It has been postulated that the higher prevalence of optic-spinal MS (OSMS) in Japan versus Western countries is due to a higher prevalence of NMO, which is also a demyelinating disease with some overlapping symptoms to MS and is characterized by LESCLs [10]. Historically, no distinction was made between MS and NMO. However, debate continues about whether OSMS is actually a distinct disease from both MS and NMO because many Japanese patients who present with OSMS are seronegative for anti-AQP4 (a marker for NMO) and remain free from LESCLs [17]. This study was designed to exclude NMO patients by using the presence of LESCLs on spinal MRI as exclusion criteria at screening. Patients were eligible for the study if the diagnosis of MS was confirmed by the study investigators and if they fulfilled MRI criteria. There was no exclusion criterion related to the presence of anti-AQP4 antibodies. The anti-AQP4 antibody test results were collected from medical records retrospectively for patients who consented to provide the data upon occurrence of a severe adverse event.

In both the continuous fingolimod and placebo-fingolimod groups, the safety profile was consistent with that seen in previous clinical studies [6, 8, 14, 18]. No new AEs, deaths, or fatal or serious infections were reported during the extension phase. The cardiac AEs reported in the placebo-fingolimod groups (transient asymptomatic bradycardia and second-degree AV block) were consistent with those observed in the core study and in global clinical studies [6‐8, 14], and have been shown to be an expected consequence of the interaction of fingolimod with S1PRs on atrial myocytes [5, 19]. Liver enzyme elevations were more common in the switch groups than in the continuous fingolimod groups, consistent with the early onset and transient nature of transaminase elevations with fingolimod [6, 8, 14]. Global fingolimod studies have identified macular edema [6‐8] as an AE of low frequency but of particular interest. In this relatively small study, specific safety monitoring did not identify any cases of macular edema up to month 12. Three cases of lymphoma, including the case of EBV-positive B-cell lymphoma described above, have been reported in the overall fingolimod clinical development program [20]. This is in line with epidemiological data reporting the background incidence of lymphoma (19.1 cases per 100,000 person-years [21]). However, because of the low incidence of malignancies and the limited duration of exposure, firm conclusions on an increased risk of malignancies with fingolimod treatment cannot be drawn yet.

Although it was reported that positivity for antibodies to AQP4 and evidence of LESCLs distinguish NMO from MS with 76% and 98% sensitivity, respectively [22], 4/68 (5.9%) patients in this extension study, which excluded individuals with LESCLs, were anti-AQP4 antibody-positive. It is therefore possible that not all cases of NMO were excluded. Exacerbation of NMO has been reported in Japanese patients treated with interferon beta for MS who were subsequently found to be positive for antibodies to AQP4 [23]. In addition, a case study of a patient who developed extensive brain lesions 14 days after initiation of fingolimod 0.5 mg in the phase 3 TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) has been published [24]. After this patient tested positive for anti-AQP4 antibodies, the initial diagnosis of MS was changed to NMO.

In the present study, three individuals positive for antibodies to AQP4 (patients 1, 2 and 4 from Table 4) developed relapses very rapidly after introduction of either dose of fingolimod (2, 5 and 9 days after, respectively). This is in accordance with the time-course of exacerbation in the previous case report of NMO during fingolimod therapy [24]. In the core study, the proportion of relapses that occurred in the 2 weeks after study entry out of the total number of relapses was relatively low (30%, 17% and 27% for the fingolimod 1.25 mg, 0.5 mg and placebo groups, respectively). Thus, although causality cannot be established from this retrospective analysis, it may be speculated that the relapses within the first 2 weeks following fingolimod initiation in patients positive for antibodies to AQP4 represented exacerbation of disease due to the temporal sequence of events here and in the previous case report of NMO [24]. A fourth anti-AQP4-positive patient (patient 3 from Table 4) presented with three relapses during 129 days of fingolimod therapy; however, this individual was considered to have high disease activity as indicated by additional relapses before and after fingolimod therapy. The frequent relapses during fingolimod therapy in patient 3 may also be partly attributable to exacerbation of relapse. In all anti-AQP4-positive patients, the nature of relapses developed after commencing fingolimod appeared to be similar to previous relapses (myelitis in patients 1, 2 and 3, and multifocal cerebral and cerebellar white matter lesions in patient 4). Accordingly, it is conceivable that fingolimod did not alter the nature of the disease; rather, it might have enhanced the original disease activity through an unknown mechanism. In the present study, corticosteroid pulse therapy appeared to alleviate the exacerbations that emerged after fingolimod initiation, leaving little or no residual effects (except in patient 4, who had moderate residual disability despite intravenous immunoglobulin administration in addition to steroid pulse therapy), although these observations on corticosteroid effects did not have a control for comparison. Together, the present findings suggest that caution is needed if introducing fingolimod in patients with idiopathic central nervous system demyelinating disease with atypical MS features without testing for anti-AQP4 antibodies first.

The limitations of this observational extension study include the need to switch treatment for all patients receiving fingolimod 1.25 mg to 0.5 mg and the small sample size, which prevented meaningful statistical interpretation – while larger cohorts would be desirable, the low incidence of MS in Japan presents a significant recruitment challenge.

Continuous fingolimod treatment for MS over 12 months is associated with consistent efficacy outcomes with no deterioration in the predictable and manageable safety profile.