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The effectiveness of fingolimod in a Portuguese real-world population
Multiple Sclerosis and Related Disorders, Volume 6, March 2016, Pages 41-48
Fingolimod is an oral treatment for Relapsing-Remitting Multiple Sclerosis (RRMS) with established efficacy in clinical trials. Post-marketing studies are important to assess its effectiveness in real-world populations.
To report the effectiveness and safety of fingolimod in a real-world population.
A retrospective study of patients with RRMS treated with fingolimod for at least six months. The demographic characteristics, Annualized Relapse Rate (ARR), Expanded Disability Status Score (EDSS), previous treatments and Adverse Events (AE) were analysed.
104 patients were included, with a mean treatment duration of 21.06 months. First-line disease modifying therapy failure patients (n=56) had an ARR decrease of 68.53% (1.43 vs. 0.45, p<0.001), 66.07% of them were relapse-free, EDSS significantly decreased (2.5 vs. 2.0, p<0.001) and 91.07% showed no disability progression. In patients previously treated with natalizumab as a second-line drug mainly switched due to safety concerns (n=41), although the differences were not statistically significant, both the ARR and EDSS increased in 41.46% and 19.51% of patients, respectively. In treatment-naive patients (n=7) the ARR decreased 94.90% (1.57 vs. 0.08, p=0.027) and there was no disability progression. 56.7% of all patients experienced AE not considered serious in any of the cases.
In this population, fingolimod was an effective treatment after first-line treatment failure, decreasing both the ARR and EDSS, and may be an effective option after natalizumab.
- Fingolimod was an effective treatment after first-line treatment failure.
- Fingolimod was an effective option after natalizumab in more than 58% of patients.
- Fingolimod was well tolerated, without serious adverse events.
Keywords: Multiple Sclerosis, Fingolimod, Relapsing/remitting, Second line treatment, Treatment Response, Outcome measurement.
Phosphorylated fingolimod acts as a functional antagonist of the sphingosine 1-phosphate (S1P) type 1 receptor, which is important for cell migration from the lymph nodes into the systemic circulation (Brinkmann, 2009). The relative dependence of the lymphocytes on the S1P gradient for egression from the lymph node has an impact on the profile of lymphocytes in the circulation (Yopp et al., 2004), resulting in a 25–40% reduction in circulating lymphocytes in patients using fingolimod. Naive and central memory T cells, including the Th17 subset, but not effector memory T cells, remain in the lymph node (Mehling et al, 2008, Kappos et al, 2006, O’Connor et al, 2009, and Mehling et al, 2010).
Fingolimod is licensed to treat Relapsing-Remitting Multiple Sclerosis (RRMS) at a dose of 0.5 mg once daily, based on the efficacy and safety demonstrated in two pivotal phase 3 studies, FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) and TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis). Another pivotal trial was FREEDOMS II, which started shortly after the previous studies and was carried out predominantly in the USA, incorporating FDA requirements. After these trials, only a few studies regarding fingolimod use in a real-world population have been published (Al-Hashel et al, 2014 and Hersh et al, 2015). In this article we report our experience with fingolimod.
2. Materials and methods
This was a retrospective study including all patients diagnosed with RRMS according to the McDonald Criteria of 2005, and who were followed in the Neurology Department of a Portuguese University Hospital, and treated with fingolimod for at least six months since the drug approval by European Medical Agency (EMA) in 2011. All the patients met EMA criteria for a second line treatment and were over 18 years old. Patients with Progressive Multiple Sclerosis, incomplete medical records, or fingolimod treatment of under 6 months were excluded.
A relapse was defined as the occurrence, recurrence, or worsening of symptoms of neurologic dysfunction lasting more than 24 hours and usually ending with a partial or complete remission (Lublin and Reingold, 1996).
Progression of disability was defined as a one-point increase in the EDSS score (or a half-point increase for patients with a baseline score above 5.0) that was confirmed at 3 months for up to 24 months (Calabresi et al., 2014). Confirmed EDSS improvement was defined as a decrease of at least 1.0 point in the EDSS score sustained for six months (Phillips et al., 2011). A rebound of disease activity was defined as a higher individual relapse rate after cessation of natalizumab than before taking it (Sorensen et al., 2014).
Adverse events were reported when there were serious infections, neoplasms, cardiac events including atrioventricular conduction abnormalities, macular oedema, or abnormal laboratory results such as a lymphocyte count under 0.5×109/L, or liver transaminases increased to more than five times the upper normal limit.
Data from magnetic resonance imaging (MRI) of the brain was not included, as imagiological evaluation was not performed in our radiological department in all cases.
Patients were evaluated at months 1, 3, 6 and 12 in the first year and thereafter at six-month intervals. Data regarding relapses, the Expanded Disability Status Scale (EDSS) score and adverse events were recorded in our Multiple Sclerosis (MS) consultation database using the program IMED®.
The following data were obtained for all patients: the gender, age at MS diagnosis, age at fingolimod start, disease duration, previous Disease Modifying Therapy (DMT), previous Annual Relapse Rate (ARR), which was defined as the number of confirmed relapses during a 12-month period, ARR with fingolimod, EDSS previous to fingolimod treatment and EDSS at the last observation on fingolimod. In selected cases, the EDSS previous to natalizumab treatment and washout period between natalizumab and fingolimod were also assessed.
Demographic characteristics were presented as means and standard deviations for continuous variables, and as frequencies and percentages for categorical variables. The patient ARR, a continuous variable, was described as the mean and standard deviation and the EDSS, a categorical variable, as the median and interquartile range. Safety outcomes were reported descriptively. In our sample all the variables had a non-normal distribution, except for age at MS diagnosis and age at fingolimod start; we therefore opted to use nonparametric tests. The Wilcoxon Signed Ranks Test was used to compare related continuous and related ordinal samples and the Mann-Whitney Test was used to compare different groups of patients. The statistical significance was considered when p<0.05, and 95% Confidence Intervals (CI) were used in the graphs. Data were analysed using IBM SPSS Statistics® version 20.0.
3.1. Demographic characteristics of the patients
104 patients were included, 61.5% of whom were female, and the mean age at diagnosis was 29.1 years. Fingolimod was started 10.3 years after RRMS diagnosis at a mean age of 39 years. The mean treatment duration was 21.4 months. The demographic characteristics of the total population are presented in Table 1.
|Female, n (%)||64 (61.54%)|
|Age at MS diagnosis, years (min–max, SD)||29.10 (15–55,±8.97)|
|Age at fingolimod start, years (min–max, SD)||39.0 (19–65,±9.35)|
|Disease duration at fingolimod start, years (min–max, SD)||10.29 (0–31,±7.27)|
|Treatment duration, months (min–max, SD)||21.37 (6–48,±10.57)|
Abbreviations: DMT – disease modifying treatment; MS – Multiple Sclerosis; min – minimum; max – maximum; SD – standard deviation
3.2. Our cohort
However, this population was heterogeneous in terms of previous treatment (Fig. 3) and reasons for fingolimod prescription. Therefore, three groups of patients were defined according to the previous treatment: first-line DMT failure (n=56) where patients previously treated with a first-line DMT (glatiramer acetate and interferons) or with immunosuppressive drugs were included; patients previously treated with natalizumab as a second-line drug (n=41); and treatment-naive patients (n=7) in which fingolimod was used as the first treatment.
Overall, 10.6% of patients discontinued treatment.
3.3. First-line DMT failure patients
This group includes patients switched to fingolimod due to drug failure, defined either clinically by the occurrence of relapses and disability progression, or radiologically by an increase in T2 lesion load or new gadolinium-enhancing lesions in brain MRI evaluated by an experienced neuroradiologist.
The distribution of patients is shown in Fig. 3. Fifty-two patients were previously treated with a first-line DMT (glatiramer acetate and interferons) and four patients were treated with immunosuppressive drugs.
Regarding the patients previously under immunosuppression, who had refused injectable therapies, three were treated with azathioprine (for 12, 50 and 78 months) and one was on mycophenolate mofetil (for 11 months).
With fingolimod treatment, there was a 68.53% decrease in the ARR (1.43 vs. 0.45, p<0.001) (Fig. 4). The ARR decreased in 66.07% of the patients, stabilized in 21.43% and increased in 12.50%.
On first-line DMT, in the year prior to fingolimod initiation, only 17.86% of patients had been relapse-free (but had shown disability progression and/or lesion load increase in brain MRI). However, this number increased to 66.07% relapse-free during the entire fingolimod treatment time, although this increase was not statistically significant (p=0.084). With treatment continuation, there was a progressive increase in the proportion of relapse-free patients (75.0% in the first year, 76.32% in the second and 82.35% in the third), and a progressive reduction in the ARR (Fig. 5).
Regarding disability, 91.07% of patients had no disability progression and there was a confirmed EDSS improvement in 25.0% of patients, with significant improvement in the median EDSS under fingolimod treatment (median EDSS 2.5 vs. 2.0, p=0.015) (Fig. 6).
The response to fingolimod was studied across different subgroups of patients defined according to several demographic and clinical variables, using the ARR and EDSS as outcome measures (Table 2).
|Annualized relapse rate, mean (SD)||EDSS, median (IQ)|
|1.62 (±1.33)||0.52 (±1.11)||<0.001||2.75||2.0||0.061|
|1.14 (±0.83)||0.33 (±0.55)||<0.001||2.25 (2.50)||2.0 (2.13)||0.111|
|Age at diagnosis|
|1.50 (±1.27)||0.51 (±0.58)||0.012||3.0 (2.13)||2.25 (2.13)||0.063|
|1.36 (±0.93)||0.39 (±0.90)||<0.001||2.5 (2.5)||2.0 (2.0)||0.035|
|1.71 (±2.14)||0.67 (±1.49)||0.276||3.5||3.5||0.785|
|Age at fingolimod start|
|1.39 (±0.88)||0.42 (±0.71)||<0.001||2.25 (2.0)||1.75 (2.0)||0.127|
|1.46 (±1.43)||0.45 (±1.11)||0.001||3.0 (2.0)||2.0 (2.75)||0.051|
|1.57 (±1.22)||0.42 (±1.07)||0.003||1.5 (2.0)||1.5 (2.0)||0.480|
|1.19 (±0.98)||0.51 (±0.82)||0.006||3.0 (1.88)||2.75 (2.0)||0.277|
|1.50 (±1.27)||0.42 (±0.95)||0.001||3.0 (2.0)||2.25 (2.63)||0.055|
|1.45 (±0.99)||0.30 (±0.62)||<0.001||1.5 (0.5)||1.5 (0.25)||0.378|
|1.52 (±1.36)||0.64 (±1.21)||0.002||4.0 (1.0)||3.5 (1.75)||0.019|
|0.0 (±0)||0.16 (±0.23)||0.317||6.0*||6.0*|
|1.41 (±1.37)||0.38 (±1.09)||0.007||2.5 (2.0)||2.0 (2.25)||0.455|
|1.80 (±1.14)||0.32 (±0.57)||0.007||1.5 (1.63)||1.5 (1.63)||0.317|
|1.50 (±1.31)||0.98 (±1.42)||0.068||4.0 (2.5)||3.25 (1.88)||0.250|
|1.29 (±1.10)||0.42 (±0.72)||0.010||2.0 (1.25)||2.0 (1.0)||0.250|
|1.00 (±0)||0.10 (±0.20)||0.059||4.25 (3.38)||3.5 (2.5)||0.102|
Abbreviations: DMT – disease-modifying treatment; SD – standard deviation; IQ – interquartile range.
Fingolimod consistently reduced the ARR irrespective of gender, disease duration and age at fingolimod start. Regarding the age at MS diagnosis, the subgroup of patients diagnosed at over 40 years of age did not present a significant reduction in the ARR. Considering the previous DMT treatment, fingolimod was associated with a reduction in the ARR in all groups, even though it did not reach statistical significance in the IFNb-1a sc and immunosuppression subgroups. In the latter group, there was a major reduction in the ARR and the lack of significance may be due to the small sample size.
With regard to effect of fingolimod on disability, there was no significant variation in the EDSS across any subgroup except for the group of patients diagnosed between the ages of 21 to 40 years old and the group with previous EDSS between 3.0 and 5.5, who presented a significant reduction compared to baseline.
Three patients suspended fingolimod treatment, two of them because of treatment failure and the other due to an adverse event.
3.4. Patients previously treated with natalizumab as a second-line drug
This population (n=41) was composed of patients with a very aggressive disease. Among these patients, only 9.80% were relapse-free but presented confirmed disability progression or severe increase in brain MRI T2 lesion load at the time of natalizumab initiation. 53.7% had an ongoing relapse. The EDSS was less than 3.0 in only 31.70%. With natalizumab treatment there was a 76.97% decrease in the ARR (1.78 vs. 0.41, p<0.001) and a 23.94% decrease in the EDSS (3.55 vs. 2.70, p<0.001).
Only 7.31% (n=3) of the patients switched to fingolimod due to natalizumab failure and 4.88% (n=2) due to adverse events, with the remaining patients (87.80%, n=36) switching because they were seropositive for the JC virus and therefore presented an increased risk of Progressive Multifocal Leukoencephalopathy (PML). The mean washout period between the last natalizumab infusion and fingolimod was 2.15 months with progressive reduction over the years to avoid disease rebound.
Evaluating the entire group, the ARR on fingolimod treatment was not significantly different from the ARR on natalizumab (0.41 vs. 0.64, p=0.128, Fig. 9). However, although these results were not statistically significant, with fingolimod there was a decrease in the proportion of relapse-free patients (73.17% vs. 56.10%, p=0.099), and the ARR increased in 41.46% of patients (Fig. 10), mainly during the first year (Fig. 11). 14.63% of patients experienced relapses during the first 6 months of fingolimod treatment and these patients had a higher baseline median EDSS (4.0 vs. 2.0, p=0.019), without other significant differences.
Considering disability, there was no disability progression in 80.49% of patients, 19.51% experienced confirmed disability progression and 12.20% experienced confirmed EDSS improvement (Fig. 12), but without a statistically significant difference between groups (median EDSS 2.5 vs. 2.0, p=0.350, Fig. 13).
There was a rebound of disease activity in 14.63% of the patients (n=6). One of these patients and five others without a rebound stopped fingolimod due to treatment failure with a very high ARR and increase in the EDSS.
Regarding the three patients who stopped natalizumab due to treatment failure, two continued having relapses with fingolimod and one experienced an increase in disability.
3.5. Treatment-naive patients
In our population, seven patients were treated with fingolimod as the first DMT since they presented rapidly evolving severe RRMS and were seropositive for the JC virus. Four of these patients had had two disabling relapses in the previous year, gadolinium enhancing lesions and a high T2 lesion load in brain MRI. Three patients had had one very severe relapse in the previous year, with a high lesion load in brain MRI, including several gadolinium enhancing lesions, and therefore a decision was made to proceed with fingolimod.
There was a significant 94.9% decrease in the ARR (1.57 vs. 0.08, p=0.027), 71.43% of the patients (n=5) became relapse free and there was no disability progression in any patient.
Two patients eventually discontinued fingolimod, one before becoming pregnant and the other because of treatment failure, switching to natalizumab.
There were adverse events in 56.7% of the patients (n=59, Table 3); however, only one patient stopped fingolimod due to serious adverse events. In patients presenting lymphopenia below 0.2×109/L on routine analysis, fingolimod was suspended until a normal count of lymphocites was achieved, and only then was it re-introduced. There were no cases of recurrent lymphopenia below 0.2×109/L.
|Adverse Event||n (%)|
|Lymphopenia >0.2–0.4×109/L||41 (39.4%)|
|Lymphopenia ≤0.2×109/L||8 (7.7%)|
|Elevated liver enzymes||5 (4.8%)|
|Bradycardia in the first administration||1 (1%)|
|Herpes-zoster infection||2 (1.9%)|
|Basal cell carcinoma||1 (1%)|
In our study, fingolimod was shown to be an effective treatment after first-line treatment failure. However, the fingolimod results in our population are quite different from the results achieved in the pivotal trials.
Both FREEDOMS and FREEDOMS II were 24-month placebo-controlled studies, comparing the efficacy of once-daily fingolimod with placebo, and TRANSFORMS was a 12-month head-to-head trial with an active comparator, comparing the efficacy of once-daily fingolimod with interferon beta-1a im. The ARR in the 0.5 mg group decreased from 1.5 at baseline to 0.18 in FREEDOMS, from 1.4 to 0.21 in FREEDOMS II, and from 1.5 to 0.16 in TRANSFORMS (Kappos et al, 2010, Calabresi et al, 2014, and Cohen et al, 2010).
In our patients who started fingolimod after first-line DMT failure, the previous ARR was similar to that previously reported in pivotal studies; however, the ARR with fingolimod was higher in our population (1.43–0.45). This result may be related to the differences inherent in the population, as our patients started fingolimod after first-line treatment failure, indicating an aggressive disease, which was not the case in all pivotal trial patients, where fingolimod was mostly used in treatment-naïve patients. In the subgroup of patients without previous treatment we found results similar to the previous studies (1.57 to 0.08), although, due to the small size of our treatment-naive sample, these results should be interpreted carefully.
A few studies regarding fingolimod use in a real-world population have been published. In Hersh et al. (2014), 317 patients were included and after a one-year follow-up, 87.3% remained relapse free (Hersh et al., 2015), compared to 75.0% in our population. In Al-Hashel et al. (2014), a total of 175 patients were included with a mean disease treatment of 22 months, and there was a significant improvement in the proportion of relapse-free patients (86.3% vs. 32.6% pre-treatment) (Al-Hashel et al., 2014). In our population, 66.07% of the patients became relapse-free, compared to only 17.86% of patients pre-treatment. These differences may be related to a more aggressive disease in our patients, since the pre-treatment relapse-free proportion was lower.
A progressive reduction in the ARR was noted with treatment continuation, which may be related to the need to achieve a steady-state for fingolimod maximum efficacy. However, this interpretation should be made cautiously since it could be due to a selection bias, with non-responder patients discontinuing treatment.
Regarding disability, in FREEDOMS, FREEDOMS II and TRANSFORMS there were no significant changes in the EDSS from baseline (median 2.0) (Kappos et al, 2010, Calabresi et al, 2014, and Cohen et al, 2010). In the Al-Hashel et al. (2014) study, there was a significant improvement in the mean EDSS (at the last visit 2.26 vs. 2.6 pre-treatment) (Al-Hashel et al., 2014). In our population we also found a significant decrease in the EDSS (2.88 vs. 2.61) and no disability progression in 91.07% of the patients.
After first-line DMT failure, both fingolimod and natalizumab are viable options. Natalizumab is a highly effective treatment approved as second-line treatment for RRMS by the EMA and FDA. However, there are some safety concerns regarding its use, mainly the risk of developing PML in JCV seropositive patients. Therefore, patients on natalizumab usually have a very aggressive disease and many reports have been published regarding rebound activity after natalizumab interruption, in particular with fingolimod treatment (Rinaldi et al, 2012, Sempere et al, 2013, Cohen et al, 2014, and Kappos et al, 2015). Currently, there is Class II evidence that shorter natalizumab washout periods before starting fingolimod are associated with less MRI disease activity (Kappos et al., 2015) and washout periods shorter than 3 months have been recommended (Cohen et al., 2014),
In our population, most natalizumab treated patients were considered clinically stable. In light of this statement, for fingolimod to be considered an effective treatment, it had to be shown not to be associated with an increase in the ARR and EDSS. In this study, we found a non-significant increase in the ARR and a decrease in relapse-free patients. In addition, we found that the ARR increase was more evident during the first year of fingolimod treatment, for which there could be several explanations. This finding may suggest that the efficacy of fingolimod is not completely achieved in the first months of treatment, probably due to the need for the drug to reach a steady state. This may also explain why longer natalizumab washout periods are associated with a higher relapse rate. Our mean washout period was 2.15 months which is in agreement with the most recent recommendations. In a study by Cohen et al. (2014) (Cohen et al., 2014), a cohort of 333 patients were switched from natalizumab to fingolimod, mainly due to safety concerns regarding PML, since 71% of these patients were seropositive for the JC virus. In this study, 20% of patients relapsed in the first six months of fingolimod treatment, which is similar to our results (14.63%).
However, the progressive decrease in the ARR observed in our population may also be related to a bias in the selection of patients after the first year, since patients with a highly active disease discontinued fingolimod.
Regarding disability progression, there were no significant changes after switching from natalizumab to fingolimod. In fact, despite the non-significant increase in the ARR, there was no significant progression of disability and the majority of the patients experienced a decrease or stabilization in the EDSS with fingolimod treatment.
A rebound of disease activity, defined as a higher individual relapse rate after cessation of natalizumab than before treatment with natalizumab (Sorensen et al., 2014), occurred in 14.6% of our patients compared to 22% in the study by Sorensen et al. (2014) (Sorensen et al., 2014), in which the same criteria to define rebound were used. However, considering that this population had a very aggressive disease with a high ARR before starting natalizumab, many patients failed to be classified as having a rebound of disease activity with fingolimod, although they had an increase in the ARR. In fact, only one of the six patients who discontinued fingolimod due to treatment failure was considered as having a rebound of disease activity.
After patients start on fingolimod, it is our clinical practice to perform a brain MRI after 6 months of treatment, and then annually or earlier if clinically indicated, to detect sub-clinical MS activity.
In the pivotal studies, safety concerns were raised, particularly lymphopenia and elevated liver-enzyme levels, herpes zoster infection, mild hypertension, first-dose bradycardia and first-degree atrioventricular block (Kappos et al, 2010, Calabresi et al, 2014, and Cohen et al, 2010). In FREEDOMS II, 15% of patients in the 0.5 mg fingolimod group experienced serious adverse events over 24 months, which included basal-cell carcinoma (3%), macular oedema (1%), infections (3%) and neoplasms (4%) (Calabresi et al., 2014). In the Al-Hashel et al. study (2014), 24.6% of the patients experienced adverse events, mainly headaches and lymphopenia (Al-Hashel et al., 2014). In our population, fingolimod was shown to have a good safety profile. Although many adverse events were reported, mainly laboratory abnormalities, serious adverse events leading to treatment discontinuation were rare. We experienced a discontinuation rate of 10.6%, lower than the discontinuation rate reported in FREEDOMS (19.8%), FREEDOMS II (32%) and TRANSFORMS (13%), and by Al-Hashel et al. (11.4%) and Hersh et al. (24.8%) (Kappos et al, 2010, Calabresi et al, 2014, Cohen et al, 2010, and Al-Hashel et al, 2014).
The limitations of our study are mostly related to the retrospective nature of the data collection. Moreover, it represents a single-centred, observational and nonrandomized study. Nevertheless, our results represent the first Portuguese post-marketing data and one of the few published works on the use of fingolimod in a real-life setting.
Fingolimod was an effective and safe treatment in our real-world population of RRMS patients after a first-line treatment. Similarly, after the switch from natalizumab, fingolimod was revealed to be an effective treatment for the majority of our patients, without significant rebound activity.
Conflict of Interests
Dr. Inês Correia, Dr. Inês Brás Marques, Dr. Mário Sousa and Dr. Rogério Ferreira have nothing to disclose.
Dr. Sónia Batista has received grant support from Biogen and compensation for serving in speaker’s bureaus for Biogen, Novartis and Merck.
Dr. Carla Nunes, Dr. Maria do Carmo Macário and Dr. Lívia Sousa have received compensation for serving on scientific advisory boards or in speaker’s bureaus for Biogen, Novartis, Teva, Bayer, Genzyme and Merck.
No financial support has been provided for the conduct of this study.
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a Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto-Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal
b Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto-Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal
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