Clinic speak: fingolimod and natalizumab are just as good as each other when used 2nd-line

Which is best; fingolimod or natalizumab? Does it matter? #MSBlog #MSResearch #ClinicSpeak

“All Pharma companies would like us  to think that their drug is best. It is not that simple. At present we have three highly-effective DMTs licensed in Europe; mitoxantrone, natalizumab and fingolimod. And soon we will have alemtuzumab. Which is better and does it matter? Until randomised head-2-head studies are done comparing these drugs with each other we won’t know which is the most effective. Using their relative effects on relapse and disability progression data to rank them is not appropriate as these drugs were tested in different populations and at different times. What we do know is that there has been a tendency for MSers entering contemporary trials have less active disease, i.e. fewer relapses, which makes it more difficult to show a treatment effect compared to placebo. For example, a 50% reduction in relapse rate compared to placebo in a more benign group of MSers could represent a 70% reduction in relapse rate in a more active group of MSers.  Therefore I personally don’t know which is the most effective drug and I don’t think it matters either. I simply slot DMTs into zones of efficacy in relation to their impact on relapses; i.e.

  1. low efficacy – laquinimod
  2. moderate efficacy – interferon-beta, glatiramer actetate, teriflunomide
  3. intermediate efficacy  – BG12
  4. high-efficacy – natalizumab, fingolimod, cladribine
  5. very high-efficacy – alemtuzumab, mitoxantrone, bone marrow transplantation 

These zones are based on an average effect on relapses and don’t necessarily tell you how the individual MSer will do on each drug. For example, you may go onto interferon-beta and be a good responder and be treated-2-target of NEDA (no evidence of disease activity). In comparison, you may choose fingolimod and don’t respond to it and continue to have relapses. What these zones of efficacy tell you is that you are more likely to respond to the individual drugs the higher you move up the treatment ladder; in other words it is game of probabilities. This is why we have truly entered an era of personalized medicine where we have to help you choose a drug that suits you and addresses your needs.”

“I am a firm believer in MSers choosing their own DMTs; each drug or class of drugs have their own risks and benefits and you need to weigh these up based on your disease profile and personal requirements. The following are a list of some of the questions you need to answer:

What type of MS do I have?
What prognostic group do I fall into?
Do I have active MS?
What is the risk of me not having any treatment?
Am I eligible for treatment with a DMT?
What DMTs are available to me?
What are the pros and cons of these treatments?

What is reassuring about this study below is that for MSers failing the so called 1st-line injectables is that they are as likely to respond to fingolimod or natalizumab. Am I surprised? No, both these DMTs are from the highly-effective group of DMTs and should on average have a similar impact on disease activity. Does it mean that fingolimod is as effective as natalizumab or is natalizumab as effective as fingolimod? No. To answer this question you have to do a randomised-controlled trial that is preferably double-blinded with a much larger number of MSers; 427 is simply too few MSers to answer a superiority or non-inferiority question. Hidden in the study below will be a lot of biases that cannot be excluded; for example MSers with more active disease could have been offered natalizumab more often than fingolimod based on the assumption that natalizumab may be more effective than fingolimod. All this study tells us that if you are failing 1st-line therapies and are offered fingolimod or natalizumab you are as likely to reach the target of relapse and disease-progression free with either drug.”

“The elephant in the room is the question of how much damage was accumulated by these 427 MSers whilst on 1st-line therapy before going onto a more effective treatment? Would this group of MSers be better off if they were treated with fingolimod or natalizumab initially? How many would not have developed bladder or sexual dysfunction, walking difficulties or cognitive impairment if they had been offered treatment from the outset with a highly effective DMT? I am extremely concerned about this issue and care passionately about it. If you have an unfavourable disease profile why take the chance of accumulating more irreversible damage when we have more effective treatments that will reduce the chances of this happening. Please note reduce, and not eliminate, the chance of this happening.”

“I hope there will come a time when all MSers are offered the option of starting on a high-efficacy DMTs from the outset. When this occurs I think we will make a big difference to the burden of disease at a population level.”

Epub: Braune et al. Second line use of Fingolimod is as effective as Natalizumab in a German out-patient RRMS-cohort. J Neurol. 2013 Sep 6.

Background: Although Fingolimod is registered as a second-line drug in RRMS in Europe there are no clinical studies available comparing Fingolimod (Fingo) and Natalizumab (Nz). 

Objectives: This observational cohort-study used health data routinely collected in outpatient neurology practices throughout Germany completing a treatment period of 12 months included 237 MSers starting on Nz and 190 patients on Fingo because of failure of the first-line treatment. 

Results: Mean relapse rate drastically decreased in both treatment groups within three months of therapy in a similar degree and remained on a low level. Both treatment groups saw a similar proportion of MSers with unchanged and improved EDSS (80.53 % in Fingo, 79.32 % in Nz). There was no statistically significant difference between the proportion of MSers being relapse free (75.79 % in Fingo, 71.73 % in Nz), progression free (87.39 % in Fingo, 82.70 % in Nz) or relapse and progression free (71.05 % in Fingo, 62.03 % in Nz) at 12 months in both strata. 

Conclusions: Clinical efficacy of Fingo and Nz in RRMS second-line-therapy was similar during the first 12 months of treatment.

CoI: Multiple

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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.


  • Prof G,

    Thanks for this post.

    The floodgates seem to have opened in terms of treatments (for RRMS).

    Are we likely to see more treatments in the next 2-3 years? I imagine some early stage trials might be showcased at ECTRIMS 2013.

    Given that inflammation has almost been addressed, over what sort of timeframe might neuroprotective agents and treatments which encourage repair be available.

    I had to see research teams around the world focus on head to head studies of DMTs for the next decade. If I was the King of MS research I'd declare that teams had 3 more years to work on DMTs and would then all have to focus on protection and repair.

    Best wishes

    • Neuroprotective trials are already underway. Laquinimod is the most interesting of the big pharma drugs. Despite it not being that effective at reducing relapses and MRI activity it has a robust effect on reducing the rate of brain atrophy and disease progression in MS. It seems to working downstream of inflammation and has the best data to support it as a neuroprotective compound. What needs to be done is laquinimod needs to go into progressive MS ASAP and to be added onto other drugs. I suspect that it has the potential to be the biggest selling MS drug of all time. That depends on how quickly, and intelligently, TEVA develop he drug and whether or not their competitors will partner with them to do combination studies.

      I am not king of MS research so can't comment on your last statement. However, there is a lot to be done on the anti-inflammatory front to make these drugs even more effective and safer.

    • Could they do laquinimod and glaterimer acetate together which could increase the effect on relapses?

      Why do you think BG-12 is not in the same league as the other new DMT?

    • BG12's average effective on relapse reduction is below 50% and its data on disease activity free is not as good as the drugs above it. However, BG12 appears to be safer than the drugs on the rung above, which explains why it has been so rapidly taken up in the US after its launch. Again it is not about which drug is more effective, but rather how you as an individual respond to the drugs. If you go onto to BG12 and become disease-activity free, bingo! It is horses for courses.

      The big worry in Europe remains whether or not Biogen-Idec will launch BG12. Without the necessary extended data, and hence patent, protection the Company is unlikely to launch BG12. A cheap generic BG12 will cannibalise the whole DMT market, including their Avonex and Tysabri franchises. It is all about Pharma shekels and lots of them.

    • A Head to Head sounds like a good idea…maybe (or really) we should put some generics in there too, and make it really interesting!!!!

      So the men will be sorted from the boys or the women from the girls the efficacy and risk can be stratefied and the value for money issue would be sorted and then maybe we will have some price differential.
      And the trial will be long enough and properly done, rather than some cut-priceunderpowered trial that really gives us the answer so we can see if it has any real benefit on disability.

      Now that would be an interesting trial, would pharma want to go this…if they are worried they won't come out on top…not so sure
      So who will pay for this….to do it properly it would cost pharma millions to do, Governments could do it cheaper.

      Would they do it and stifle innovation.

      They could and should do it within the UK because of the nature of the healthcare system. The government (we_ pay one way or another

  • Prof G, I have heard that neurologists prefer prescribing natalizumab over fingolimod as they make money from administering the infusions. Is this correct? If yes, this may explain the continuing popularity of natalizumab when there is an oral tablet that is as effective.

    • In UK this is not going to be an issue as it is not service for fee, at least not going to the neurologist.

      However if you are paying for your health care then there is an associated cost with each infusion and then there is a fee for the blood test. All added extras and profit for the neurologist so you may not be wrong

    • The "greedy neurologist" slogan applies in the UK as well. I was at a meeting last week when one of my colleagues from another centre told me how keen his NHS managers were for him to expand their infusion service as it was making so much money for their Trust or Hospital.

      What we don't realise that is simply Peter robbing Paul to pay the same bill. At the end of the day this is NHS expenditure that is paid by you and me as UK taxpayers.

      Maybe there is something to the arguments that we should be practicing cost-effective medicine. If this is the case and fingolimod was shown to be as effective as natalizumab then fingolimod would win hands down as it the more cost-effective of the two treatments.

      I wonder what our manager is going to say when we start our home infusion service? The latter will be cheaper and reduce the costs of providing natalizumab substantially; own hospital will not be able to charge for this service.

By Prof G



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