ClinicSpeak: natalizumab is more effective than fingolimod

Stating the obvious: natalizumab is more effective than fingolimod. #ClinicSpeak #MSResearch #MSBlog

“A head-2-head study comparing fingolimod vs. natalizumab is unlikely to happen; it would be too expensive and fingolimod is almost off-patent. Apart from comparing the phase 3 trial data, which indicates that natalizumab is more effective than fingolimod, the next best thing is looking at real-life data and matching subjects to see which group does best. The statistical technique for matching groups of non-randomised MSers at baseline is called propensity matching. The MSBase team have done this and compared fingolimod to natalizumab; surprise, surprise natalizumab-treated MSers do better on average than fingolimod treated MSers. The problem with natalizumab it is only really appropriate to be using it in JCV-negative subjects; the risk of PML is simply too high to justify using it long-term in subjects who are JCV-positive, unless we can derisk the drug in the future (see my previous post on this topic). We also know from brain atrophy data that natalizumab is better and reducing the rate of brain atrophy in MSers after year 1 (~0.24%) compared to fingolimod (~0.4%). Fingolimod, however, is the best of  the orals at reducing brain atrophy rates or end-organ damage.”

“Please remember that this data represents the average response and there will be a significant proportion (~20%) of fingolimod-treated MSers who are rendered NEDA-4 (no disease activity and a brain atrophy rate of <0.4% per annum). Therefore I see nothing wrong with a strategy of using fingolimod and if you are not responding to switch to a more effective DMT. I suspect that as soon as fingolimod comes off-patent and we have generic fingolimod available it will be the drug of choice 1st-line, with the more effective high-cost drugs being used second line.”

“Does this mean that we should be using natalizumab 1st-line? Yes, this would be a valuable option in those MSers who are JCV-seronegative (~45% in the UK). Unfortunately, this is not an option in the UK where natalizumab has a very restricted indication. Interestingly, I have been told that in New Zealand the healthcare system is about to recommend only two DMTs; fingolimod and natalizumab. If MSers and neurologists want to use any other drug they are going to have to make a case for them. I wonder how the NZ payers came to this conclusion?”

Epub: Kalincik et al. Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol. 2014 Dec . doi: 10.1002/ana.24339.

Objective: In MSers with disease activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these two agents. 

Methods: Using MSBase, a large international, observational multiple sclerosis registry, we identified RRMSers experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomisation with propensity score-based matching was used to select sub-populations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. 

Findings: Out of the 792 included MSers, 578 MSers were matched (natalizumab n=407, fingolimod n=171). Mean on-study follow-up was 12 months. The annualised relapse rates decreased from 1·5 to 0·2 on natalizumab and from 1·3 to 0·4 on fingolimod, with 50% relative post-switch difference in relapse hazard (p=0·002). A 2·8-times higher rate of sustained disability regression was observed after switch to natalizumab in comparison to fingolimod (p<0·001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under disability-time curve) differed between natalizumab and fingolimod (0·12 vs. 0·04 per year, respectively, p<0·001). 

Interpretation: This study suggests that in active multiple sclerosis during treatment with injectable disease modifying therapies, switch to natalizumab is more effective than switch to fingolimod in reducing relapse rate and short-term disability burden.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • "Interestingly, I have been told that in New Zealand the healthcare system is about to recommend only two DMTs; fingolimod and natalizumab. If MSers and neurologists want to use any other drug they are going to have to make a case for them."

    I'm glad I don't live in New Zealand

    • I suspect the New Zealanders' have decided that the data on high efficacy drugs is so good, why waste valuable tax-payers money on drugs that don't work.

    • Thank you for your response. Are there people working on finding a way to eliminate the JC Virus from the body ?
      Is JC Virus only a threat when it gets into the Spinal Fluid or can it travel to the brain through bloods ?

    • it looks like jc lurks in the bone marrow but tysabri brings it into the blood and from there it can hitch a lift into the brain and once it gets into brain cells then it becomes a time bomb

    • Is it more prone to invade the brain through the spinal fluid or does it get into the brain via blood ?
      They test for JC Antibodies through Lumbar puncture. Why is that the case ?

    • Seems to be from the blood as JC can penetrate the blood:brain barrier but could also be that there is a dormant population of JC lurking in the brain waiting to reactivate when immunosurveilance is reduced by Tysabri.
      The reason they look for JC antibodies by lumbar puncture is that the presence of antibodies in cerebrospinal fluid indicates that an active infection is occurring in the brain rather than in the periphery (antibodies do not normally get into the brain and the presence in CSF indicates they are being produced in the brain itself).

    • Thank you for your responses it makes much more sense to me now.
      One last Question about PML in relation to Tecfidera, What is the low level of Lymphocytes that can lead to PML as in the case recently ?

    • I have been on Tysabri for 7 years I am JC positive with a 2.6 stratify-2 index I get MRI every 3 months and am being told i have 1 in 70 chance of developing PML. With that being said Gilenya is the drug they want me to make the decision on switching to,wouldnt a lumbar puncture be prudent to detecting PML?

  • I see the logic in screening patients for JC Ab before using natalizumab but why would a Dr. prescribe a less effective drug than the more highly effective alemtuzumab, fingolimod and maybe tecfidera? It would seem more cost effective in the long run to hit the disease early with the most effective therapies rather than wait for disability to accumulate. Interferons, copaxone, teriflunomide – maybe they have served their purpose of bridging the gap to better drugs.

By Prof G



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