Let’s get ready to rumble!


If the heavy weights of MS drugs go head to head in the boxing ring, it is anyone’s guess who will come out on top. The MS Base publication in 2019 states that starting on fingolimod, alemtuzumab or natalizumab is superior to glatiramer acetate or interferon beta.

This March, the Italians have sneakily put together their own contest between fingolimod and natalizumab. You may say this one is a stitch up (maybe) but unsurprisingly natalizumab is the clear winner here. This is in terms of relapse rates, EDSS (disability) progression, and new T2 and/or Gd+ lesions on MRI (see figure below). Of course, the long term strategy is weak, with NEDA rates even on natalizumab falling from 63% to 46% by 4 years meaning their still room for improvement.

Figure: Primary and secondary
outcomes (NEDA-3 and its


Neurol Sci. 2021 Mar 6. doi: 10.1007/s10072-021-05127-z. Online ahead of print.

Long-term comparative analysis of no evidence of disease activity (NEDA-3) status between multiple sclerosis patients treated with natalizumab and fingolimod for up to 4 years

Tommaso GuerraFrancesca CaputoBianca OrlandoDamiano PaolicelliMaria Trojano Pietro Iaffaldano 

Background: Comparative effectiveness of natalizumab and fingolimod over a follow-up longer than 2 years has been not addressed yet.

Objectives: To compare the effect on no evidence of disease activity (NEDA-3) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab or fingolimod for at least 4 years.

Methods: We included RRMS patients switched from first-line agents to natalizumab or fingolimod. Patients were propensity score (PS)-matched on a 1-to-1 basis. Percentages of patients reaching NEDA-3 status at 2 and 4 years of follow-up were compared using the chi-square test. The risk of not achieving NEDA-3 at 4 years was explored in matched samples by Cox regression models.

Results: We evaluated 174 PS-matched patients. Patients receiving natalizumab reached a NEDA-3 status at 2 and 4 years more frequently than those exposed to fingolimod (63% vs 44%, p=0.037; 45.7% vs 25.8%, p=0.015, respectively). Patients receiving natalizumab were at a significant lower risk of not achieving the NEDA-3 status at 4 years compared to those exposed to fingolimod (hazard ratio (95% confidence interval): 0.54 (0.36-0.80), p=0.002).

Conclusions: Although both medications were effective in patients non-responding to first-line agents, natalizumab seems to be superior to fingolimod in RRMS in obtaining NEDA-3 status at 4 years.

About the author

Neuro Doc Gnanapavan


    • I dont know but it has been done academic style, the trial is called STAR-MS and is on the NIHR website and it says 200 pwMS so 100 per arm. This seems low
      https://fundingawards.nihr.ac.uk/award/16/126/26 Once COVID is done they can begin they have only been waiting for 3 years and now they will struggle to recruit to alemtuzumab that is why ocrelizumab is an alternative

      • I believe the study is adequately powered (STAR-MS study), primary efficacy outcome is NEDA status like here 90% power to detect a difference from the control arm. Well at least that was the original study!

      • Why will they they struggle to recruit to an alemtuzumab arm? If run under a clinical trial, can’t they administer it out of indication (i.e as first line treatment)? Or, is it because of the safety concerns with this drug and people’s reluctance to receive it? We desperately need head to head studies of high efficacy treatments and if 100 per arm is adequate to power the study, then this seem more feasible than I previously understood. Comparing IRTs against beta interferon or dimethyl fumarate just doesn’t cut it anymore. Nobody believes those designs demonstrate equipoise.

        • Alemtuzumab is not longer first line treatment according to the label after the EMA investigated.Remember it used to evidence on activity i.e. one lesion. It is now
          highly active relapsing remitting multiple sclerosis (RRMS) for the following patient groups: (a) Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT) (This means it is second line) or (b) Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI. This may be compatible with HSCT indication. Are we going to get 100 of these.

          I agree with you about the trials but new agents continue go against the lower efficacy options

          • But if administered during a clinical trial, are you bound by the labelled indication? For example, if you write a protocol and get ethics and regulatory approval, you can administer the drug in accordance with the protocol, not the registered indication. Or, is the issue funding? Cheaper and easier to run it within the current indication so the drug cost is incurred by the NHS. I imagine trying to get a Sponsor company to fund such a study is like pissing into the wind.

            God knows how high efficacy vs low efficacy DMT studies obtain ethics approval. Actually, I’ve seen some atrocious studies obtain approval so maybe I shouldn’t be that surprised.

  • I’m ‘N E D Progression’ a/c to my MRI result of Oct 2020. I assume this means exactly the same? But I’m not an any DMDs. I suppose that is OK? These both have fairly serious side effects. It must depend as much on peoples’ attitude to risk as efficacy. The risk of more profound risks associated with one or the other is down to the patient I guess.
    What is the chi-square test?

    • NEDA-3 is based on no evidence of clinical relapses, no EDSS (disability) progression, and no MRI activity as a composite score. So it’s more than NED progression based on MRI.

      The Chi-square looks for difference between the certain variable that you’re looking at in two groups; in this case the NEDA status in natlizumab treated versus fingolimod. The finding was significant.

      NEDA-3 status at 2 and 4 years more frequently than those exposed to fingolimod (63% vs 44%, p=0.037; 45.7% vs 25.8%, p=0.015, respectively).

    • The chances that you’ll have no progression in the long run without a DMD are very low, even if you’re fine now. I think a lot of people that are worried about the risks with DMDs forget about or minimize the risks associated with MS and leaving it untreated.

      • I completely agree, as a Neurologist my current MS caseload is just under 370 and have been in MS since 2007. It is difficult to appreciate when you have just been diagnosed to see what I see.



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