In MS, there is a distinction between first- and second-line disease-modifying therapies (DMTs). Newly-diagnosed pwMS often start with a so called ‘first-line’ drug. These drugs balance low to medium efficacy with a favourable long-term safety profile. This is a potentially interesting DMT choice when it’s not entirely clear yet how ‘active’ an individual’s MS will be. Protagonists are Tecfidera, Copaxone, Aubagio and interferons. All these drugs tend to modulate B and T cells towards a less pro-inflammatory state. When pwMS are still active under a first-line DMT or have very active MS at disease onset, they are directed towards a second-line DMTs. These drugs strongly deplete B and/or T cells (i.e. cladribine, alemtuzumab, ocrelizumab) or block access for these cells to the central nervous system (ie. natalizumab).
However, some DMTs are the equivalent of “gender-neutral” when it comes to the first- or second-line box. Meet Fingolimod. This DMT sequesters B and T cells into the lymph nodes without killing them. Efficacy data are right in the middle between first- and second-line treatments: 48% relapse rate reduction against placebo whereas interferons bob around 30% and second-line drugs around 60%. Regulatory authorities feed fingo’s second line image by licensing the drug after failure of other first-line DMTs.
However, an observational cohort of pwMS suggests it’s time for a paradigm shift. Boziki et al. compared the efficacy of natalizumab and fingolimod. From a cohort of 138 unmatched pwMS, they included 31 pwMS with similar features at onset in each comparator group. All pwMS failed on first-line platform treatments or had highly active MS at diagnosis. At the end of the 4-year follow-up, pwMS on natalizumab were three times more likely to remain relapse- and MRI activity free than pwMS on fingolimod. Moreover, the number of pwMS discontinuing their treatment because of persistent MRI activity was eight times higher in fingolimod versus natalizumab.
These data leave no doubt about the fact that natalizumab outperforms fingolimod in active MS. Does this mean fingolimod is a bad choice for pwMS? No, not at all. It means that the drug does not differ sufficiently in terms of efficacy from other first-line DMTs to justify a second-line treatment label. On the flip side, it’s side effect profile does also not allow to tag it as a first-line drug. In fingolimod, medium efficacy comes at a safety price: teratogenicity, rebound disease activity when stopping, absent vaccine responses, risk of macular edema (first six months) and risk of benign skin cancers.
In summary, fingolimod and by extension other sphingosine-1 receptor modulators (e.g. ozanimod, siponimod) are a DMT species of their own: efficacy sheeps in wolf’s clothing.
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Front. Neurol., 23 August 2021 | https://doi.org/10.3389/fneur.2021.699844
Long-Term Efficacy Outcomes of Natalizumab vs. Fingolimod in Patients With Highly Active Relapsing-Remitting Multiple Sclerosis: Real-World Data From a Multiple Sclerosis Reference Center
Marina Boziki, Christos Bakirtzis, Virginia Giantzi, Styliani-Aggeliki Sintila, Stylianos Kallivoulos, Theodora Afrantou, Ioannis Nikolaidis, Panagiotis Ioannidis, Theodoros Karapanayiotides, Ioanna Koutroulou, Dimitrios Parissis and Nikolaos Grigoriadis*
Background: Natalizumab (NTZ) and fingolimod (FTY) are second-line disease modifying treatments (DMTs) approved for Relapsing – Remitting Multiple Sclerosis (RRMS). Few studies are available on a direct comparison between NTZ and FTY, based on post-marketing experience, with conflicting results and reporting relatively short follow-up period. Aim: We hereby report real-world experience of a MS Center with respect to NTZ vs. FTY comparison in terms of efficacy and safety, referencing long-term follow-up. Methods: We used retrospective data for all patients that received 2nd-line treatment NTZ (since May 2007) or FTY (since September 2011). Primary endpoints were, among others, annual EDSS score (mean change from baseline), time to disability worsening or improvement, Annualized Relapse Rate (ARR) after 12 and 24 months and upon total treatment duration, time to first relapse and time to radiological progression. Results: A total of 138 unmatched patients, 84 treated with NTZ and 54 treated with FTY were included. Following Propensity Score (PS) matching, 31 patients in each group were retained. Mean follow-up period for NTZ- and FTY-treated patients was 4.43 ± 0.29 and 3.59 ± 0.32 years (p = 0.057), respectively. In the matched analysis, time to disability improvement and time to disability worsening was comparable between groups. A higher proportion of patients remained free of relapse under NTZ, compared to FTY (Log Rank test p = 0.021, HR: 0.25, 95% CI: 0.08–0.8), as well as free of MRI activity (Log Rank test p = 0.006, HR: 0.26, 95% CI: 0.08–0.6). Treatment discontinuation due to MRI activity was significantly higher for FTY-treated patients compared to NTZ (Log Rank test p = 0.019, HR: 0.12, 95% CI: 0.05–0.76). Conclusion: Our results indicate toward NTZ superiority with respect to relapse and MRI activity outcomes. The fact that NTZ-treated patients may achieve long-standing clinical and radiological remission points toward the need for long follow-up data.