Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study

Fingolimod (FNG), proven efficacious in three large phase III trials [1‐3] and in their extensions [4, 5], is a widely used oral medication licensed in the USA for the first-line treatment of relapsing-remitting form of multiple sclerosis (RRMS) and in the European Union (EU) for patients with highly active RRMS defined as either high disease activity despite treatment with at least one disease-modifying treatment (DMT) or rapidly evolving severe RRMS. A large number of post-marketing studies have confirmed the efficacy of FNG in a real-world setting, with data substantially overlapping those of pivotal trials [6‐13]. All this despite patients are included in observational studies being on average older, with longer disease duration and more severe neurological disability [14]. Moreover, in observational studies, only a minority of patients started FNG as first-line treatment, while the meta-analysis of pooled cohorts of the pivotal FREEDOMS and FREEDOMS II trials extensions showed better outcomes in treatment-naïve patients compared to those previously exposed to other DMTs [15].

So far, most studies have been conducted over short-term follow-up; just a few have reported composite outcomes [8, 10, 16, 17] and have analyzed FNG effectiveness stratified by previous treatment [4, 10, 16‐18].

In FinGolimod Real World EvideNce Italian mUlticenter observational Study in Multiple Sclerosis (GENIUS study), we conducted a large retrospective real-world data analysis of all the patients referring to five tertiary referral multiple sclerosis (MS) centres in Italy, which initiated FNG during the period 2013–2014 and with a 2-year follow-up, investigating short-term outcomes, namely, annualized relapse rate (ARR) and no evidence of disease activity (NEDA-3) [19], and sustained disability progression. Moreover, in the same patients, a retrospective analysis was carried out up to 2 years prior to the initiation of FNG treatment.

Performing a comprehensive reassessment after 1 and 2 years in a well-characterized group of patients, systematically followed, may provide a unique opportunity to better understand the benefits of FNG on the composed outcomes of disease activity.

This study is a secondary data, non-interventional observational cohort study. A retrospective medical chart review method was used to abstract data from hospital medical charts of RRMS patients who initiated FNG treatment within the period 2013–2014. Patients referred to five high-volume tertiary care MS centres, mainly (4 out of 5) academic, located in Italy (in the cities of Turin, Milan, Bari, Rome, Naples).

Data were abstracted from medical charts (paper or electronic) by trained data abstractors and filed in a centralized database for analysis. Data abstractors remained blind to the study hypothesis in order to minimize any kind of bias. A key abstractor leader was named, who trained, assisted, supervised, and audited the site-specific data abstractors. The inter-rater reliability was assessed (see Online Resource #1 for details).

Date of first FNG dispensation was designed as index date. A “pre-FNG period” was defined as the 2 years prior to the index date and the “FNG period” as the 2 years follow-up post index date. Each site abstracted data from about 100 patients’ medical charts, for a planned total number of about 500 patients. Patients inclusion criteria were (a) age ≥ 18 years at index date; (b) diagnosis of MS [20]; (c) starting FNG (> 1 dose) within the period 2013–2014; and (d) available follow-up data for both the pre-FNG and FNG periods. All patients participating in any other clinical trial were excluded. The following endpoints were assessed, both for the pre-FNG period and the FNG period: (a) ARR and (b) NEDA-3 status and its subcomponents (clinical relapses, magnetic resonance imaging (MRI) activity and disability worsening). Relapses were defined as appearance of new neurological deficit that lasted more than 24 h in the absence of fever or infection, which occurred at least 30 days after the onset of a preceding event [21]. Sustained disability progression was defined as a one-point increase sustained for at least 3 or 6 months from an Expanded Disability Status Scale (EDSS) lower or equal to 5.5 or an increase of 0.5 for patients with an EDSS of 6 or greater [22]. The MRI activity was considered in the presence of new T2 lesions (compared to last scan before index date) or Gd-enhancing lesions. Patients with rapidly evolving MS (REMS) were defined as those with two or more disabling relapses in 1 year and evidence of increasing lesions on two consecutive MRI scans.

In MS, there is a growing emphasis on obtaining data of “real” patients, beyond randomized clinical trials. Post-marketing studies are important for providing information on compliance with current treatment guidelines, identifying suboptimal therapies, defining treatment responder subgroups, optimizing treatment algorithm, and detecting rare serious adverse events. Although not providing a level of evidence as high as randomized controlled trials, real-world studies provide crucial information on effectiveness outcomes of a given therapy, by investigating a more diverse group of patients than those included in clinical trials. Real-world studies provide data that can be generalized across the population of patients with MS in clinical practice.

The GENIUS study used clinical and MRI data collected in clinical practice to assess FNG effectiveness in terms of ARR, NEDA-3 status, and disability progression in a large cohort of patients with RRMS in Italy. Real-world FNG effectiveness data were analyzed, stratifying patients into treatment-naïve ones and those previously treated with other DMTs.

Our results largely confirm the effectiveness data of FNG in reducing ARR in RRMS, by 65% and 70% reduction in risk of relapses, in the 1-year and 2-year of treatment, respectively. Notably, in naive subjects, the ARR reduction is more marked than in patients starting FNG after other DMTs. In NTZ+, while observing a slight increase in ARR in the first year, a substantial stabilization is achieved by the second year of treatment.

The effectiveness results obtained in our study are in line with the efficacy data shown in the 0.5-mg/day FNG arm of the 12-month TRANSFORMS and the 24-month FREEDOMS trial [1‐3], despite our sample was composed of a lower percentage of naïve patients, who generally show a greater response to FNG, and of a larger rate of NTZ+ patients, who instead are more at risk of disease reactivation [4, 13, 23, 24]. Regarding the NEDA-3 status, our study showed that 67.9% and 54.6% of RRMS patients was NEDA-3 after the first year and the second year of treatment. Our results are similar to those obtained in other cohorts of patients. Prosperini et al. showed that in patients switching from other treatments, FNG delivered a higher proportion of NEDA-3 patients than dimethyl fumarate, after 18 months of follow-up, while the two treatments had similar results in naive patients [16]. Similarly, in another Italian cohort, almost half of patients maintained NEDA-3 status after 2 years of FNG treatment, with rates comparable to ours both in NTZ+ patients and in patients previously treated with other DMTs [8].

To our knowledge, this is one of the largest real-world series of patients with RRMS treated with FNG with composite outcomes assessment and for which composite effectiveness outcomes assessment data are available for the 2 years before and after FNG treatment initiation. Similarly to other real-world studies [6, 7, 11, 12, 24], patients under FNG treatment maintained a low ARR and thus a high proportion of relapse-free patients, as compared to the pre-FNG period, with a high rate of treatment persistence. Regarding the subgroup analysis, our data showed that FNG brings a benefit on MS patients regardless of the previous DMT used, although to a lesser extent in the NTZ+. Although NTZ+ patients showed an increased ARR in the first year of treatment with FNG, two thirds of them were relapse-free after 2 years, more than half of them maintain NEDA-3 status in the first year and 42% in the second year of treatment. These results are in line with the previous observations [6, 11, 13, 18, 24‐26]. Furthermore, we confirmed that previous NTZ treatment, just as younger age, and ≥ 1 relapse in the pre-treatment year are significantly associated with an increased risk of relapsing under FNG treatment, as previously demonstrated [8]. The risk of having sustained disability progression is also influenced by the relapses in the pre-treatment period (≥ 1 relapse) and the previous NTZ treatment but not by the younger age. We did not collect data about the duration of the washout period between NTZ cessation and the start of FNG. This prevents us drawing any definite conclusions, as timing of treatment initiation may be critical for achieving an optimal effect [27, 28].

The GENIUS study has several strengths. First, it is the largest real-word FNG study conducted in Italy so far, and it provided evidences for effectiveness outcomes referred to a short-term observation period. Second, homogeneous data collection and centralized data analysis ensured results reliability. Third is the use of NEDA-3 as a composite outcome for effectiveness evaluation, in addition to the ARR. Finally, the subgroup analysis based on previous treatments is a valuable data to a better definition of therapeutic algorithms.

The limits of the study are intrinsic to the retrospective nature of the analysis. Our study has collected data from five different tertiary referral MS centres in Italy of which 4 were academic. Although outcomes were assessed in a large cohort, we cannot exclude a selection bias and a certain lack of homogeneity in the clinical assessments; however, as recently demonstrated by an American real-world study [17], no significant differences exist between academic and non-academic centres in proportion of patients who achieved NEDA-3 at 24 months after FNG. Moreover, in our study, the reading of MRI scans was not centralized, and detailed data on tolerability and safety (in terms of occurred adverse events) have not been collected; in any case, the discontinuation rates for safety and tolerability issues are in line with clinical and observational studies. Finally, in the absence of a comparison group, our findings should be interpreted with caution since longitudinal data may be influenced by the regression to the mean phenomenon [29].

FNG provided consistent effectiveness benefits in the Italian real-world setting. This was observed also after treatment with other DMTs across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of FNG may depend on age and type of previous treatment. These findings suggest that most benefit will be gained by patients who start FNG early in the disease course, but the findings also suggest that FNG treatment will benefit patients later in the disease course when they have already accrued disability.