New DMT species: An efficacy sheep in wolf’s clothing

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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. 

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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.

Twitter: @SmetsIde

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.

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19 comments

  • Surely now an IRT or high efficacy, should be given as standard, straight after diagnosis? The study’s are out there

    Are there any more IRTs in the pipeline?

    • I guess the most realistic new IRT will actually be ocrelizumab. There is more and more emerging evidence that we are overdosing, and that pwMS can stop after a certain number of cycles. Cfr. the ADIOS-IM study.

      • Overdosing? Really? I thought Prof G’s claim was that we are underdosing and that more exposure has a greater effect on brain atrophy regardless of peripheral cell counts.

        • Overdosing when it comes to the number of infusions, not the actual dose in mg. Probably it will be a better balance between efficacy and safety if ocrevus would be halted after for example 4 infusion cycles.

          • I am not so sure about this… I remember that follow up data indicate that the ARR is stable at about 0.1 indicating that inflammatory activity is not totally and indefinitely suppressed. At five years some relapses occurred and no signal in normalization of BVL was seen. Probably we need more than few cycles 🙁

          • A partial explanation of a remaining ARR of 0.1 is that no treatment will ever eradicate pseudorelapses. More importantly, stopping treatment with ocr does not necessarily mean no treatment. A potential strategy would be to de-escalate to a first line or platform therapy.

          • “Overdosing when it comes to the number of infusions, not the actual dose in mg.”

            Ahh…confusion here…are you sure about this..?…cause they are giving 1200 and 1800 mg doses of Ocrevus in the trial

            “Brief Summary:
            This is a randomized, double blind, controlled, parallel group, multicenter study to evaluate efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab per intravenous (IV) infusion every 24 weeks in participants with RMS, in comparison to the approved 600 mg dose of ocrelizumab.”

            “Drug: Ocrelizumab
            The actual higher dose of ocrelizumab will be assigned to participants based on their body weight at baseline: 1200 mg (participants’s body weight /=75 kg). The first dose of ocrelizumab will be administered as two 600 mg or 900 mg intravenous (IV) infusions given 14 days apart. For the subsequent doses, ocrelizumab will be administered as a single 1200 mg or 1800 mg IV infusion every 24 weeks.”

            https://clinicaltrials.gov/ct2/show/NCT04544436

  • I have been on Tysabri since the start in the trial but was on placebo, i had quite few relapse. In the firs few years changed 2005 to real Natalizumub and been neda till this year 2 very small lesion on brain and maybe because gone 4- to 6 infusin.

      • Very apt post for me. I have been recommended fingolimod following relapse and although there were parts of it I liked, I could not bring myself to go for it due mainly to the rebound risk, and this is from someone who’s had alemtuzumab.
        I am going with consultant’s second option, tecfidera, as on researching both drugs found that tecfidera came in only slightly behind fingolimod in the relapse stats. I was very surprised to see that you had ranked it with interferon etc. I haven’t started it yet, have I missed something? Fingolimod is still available if I change my mind or tecfidera doesn’t suit.

          • Two. I can’t have another dose due to ongoing problems with ITP, due to the original alemtuzumab.

        • Why not HSCT if you failed alemtuzumab? I think both tecfidera and fingolimod are very unlikely to work.

          • Reasons why you think neither would work? It’s been 9 years since last dose of alemtuzumab,

          • “Reasons why you think neither would work? It’s been 9 years since last dose of alemtuzumab,”

            Because neither get you down to normal brain atrophy…which is .2 and only hsct gets people to normal. In general ms atrophy is horrible “Natural history studies have shown brain atrophy rates in patients with MS in the range 0.7%–1% per year,”

  • When I was diagnosed the first-line drugs were the only drugs (except natalizumab) so starting me on interferons made sense, but I am really having trouble with the logic of doing the same thing today. “We have drugs that are much better at preventing brain damage, but we’re going to start you on one of the drugs that’s no worse at preventing brain damage and then see how much more brain damage you get before we let you have one of the better drugs.”

    I wouldn’t start on fingolimod today, either, but at the time it was clear interferon wasn’t working for me and fingolimod had just come out. Given the rebound issues and the fact fingolimod has been working well for me (I have not had a relapse or new activity on my MRIs since I started taking it about 10 years ago), I’m reluctant to change, however.

    • ““We have drugs that are much better at preventing brain damage…”

      Sorry…we don’t.
      None of the DMT drugs get you down to normal brain loss rate which is
      .2 Prof G said 50% of alemtuzumab get to normal if treated in the first 2 years of diagnosis.
      This is why hsct is the best bet..to save your brain..and your life.

      Problem is neurologists like getting paid…and don’t want to refer all their patients to hematology.

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