Tuesday, 21 February 2017

Guest Post MSBaseGold: Comparisons of DMT

Today we are delighted to have another Guest post from Tomas Kalincik from University of Melbourne, Australia, please see his Biography on his previous post.

Kalincik et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017 Feb 10. pii: S1474-4422(17)30007-8.

BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.


METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.


FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006).


INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.


FUNDING: National Health and Medical Research Council, and the University of Melbourne.



Tomas Kalincik

"This large collaborative study brought together investigators from MSBase and clinicians from six academic MS centres in Cambridge, Cardiff, Swansea, Bristol, Dublin and Dresden. We have used propensity score matching, pairwise censoring and weighting in order to create a composite cohort of sufficient size to enable conclusive comparisons of alemtuzumab (a monoclonal antibody depleting circulating B and T lymphocytes, which was approved in multiple countries for use in relapsing-remitting MS in 2015) and three other commonly used therapies - interferon beta, fingolimod and natalizumab.

The comparison of alemtuzumab with interferon beta allowed us to replicate the results of the pivotal phase 3 trials of alemtuzumab (CARE-MS 1 and CARE-MS 2), anchoring our study in the existing evidence. It showed that the effect of alemtuzumab on suppressing relapses was superior to that of interferon beta. In patients with previously highly active disease, alemtuzumab was also more likely to prevent worsening of disability and even lead to some disability reversal. We have used this replication of the previous studies as a validation of our methodology before applying it to a new scenario - the comparison with fingolimod and natalizumab.

Alemtuzumab was superior to fingolimod in decreasing relapse incidence. However, its effect on disability (whether disability accrual or its resolution) was similar to that of fingolimod. On the other hand, alemtuzumab and natalizumab had very similar effects on suppressing MS relapses and worsening of disability. However, natalizumab was more often associated with improvement in disability early after patients commenced therapy. This difference in treatment effect was mostly seen during the first year of treatment.

Our study focused on comparing clinical efficacy of alemtuzumab and the three therapies. It did not compare the effect of the therapies on brain MRI, neither did it answer the question of its relative treatment safety."


CoITK reports grants from National Health and Medical Research Council (Australia), and Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; grants, personal fees, and non-financial support from Biogen; personal fees from Roche, Teva, and BioCSL; and personal fees and non-financial support from Sanofi Genzyme, Merck, Novartis; and personal fees from WebMD Global.

MouseDoctor says:

As we are looking at MS drugs in the Real World today, we would like to thank Tomas for discussing his recent work. If you can spare a minute and can understand Australian:-). 

You can have a view of  Dr.Kalincik in the News (Click here)


Drug companies generally only do head to head studies when they know their product will win. Therefore it is great that registries exist, to allow comparisons of effects to be undertaken. This study confirms what we suspect in terms of drug hierarchies. 

12 comments:

  1. Australian news item sounds very sunny and positive - for those with RR.

    For those with PP - ......................

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  2. What is the indication for alemtuzumab in Australia and is it used in the way it is used here (Norway) - it is not first or second treatment choice. If alemtuzumab is given to patients who failed on every other drug - then it is not a fair comparison. And then there is the time effect - can one really compare something that has been on the market for over 10 years with something that has been used for a few years. I am sure the cohorts were matched as best as one could match them, but still...

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  3. Ok, so it is basically: unless you tried and failed natalizumab, do not jump into alemtuzumab (I think most MSers are taking drugs to prevent disability rather than to prevent spots on MRI or attacks).

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  4. "Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab" ... so interesting and not mentioned at all in the commentary. Personally, I saw an improvement on fingolimod but only ever got worse in four years on natalizumab.

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  5. Its alemtuzumab used as 3 lane on Australia? If its that way many of them failed natalizumab... I can also critizice a low n on alemtuzumab, the low number indicates me that they are saving alemtuzumab for those going badly... Then its no surprise that its not doing as good on improvement as natalizumab... All that said, its a great paper as its shows real world data.

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    Replies
    1. The alemtuzumab treated patients are not from Australia, but from non-MSBase centres in the UK, Ireland and Germany treated between Nov 1, 2015, and June 30, 2016.

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    2. I need to read the paper. The follow-up is too short to judge disease improvement post-alemtuzumab. Most occur in years 2 and 3 post-alemtuzumab. We are even seeing improvements occurring in years 4 and 5.

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  6. Any mention on the effects of conversation to SPMS from RRMS? This is the one thing that is lacking in all these studies. Is it because most of these drugs have a max 10/15 year life span and then progressive disease in going to happen regardless? If this is the case then should this be a consideration when choosing treatment in my opinion.

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    1. Shhh......nobody talks about progression when it comes to dmts. It is all about ARR and quelling inflammation by targeting b&t cells. You have broached a taboo subject.

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    2. in about six hours you will be proved wrong.

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    3. MouseDoctor - care to elaborate?

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    4. we posted on HSCT and progressive MS

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